I

Rosacea, A Comprehensive View

First edition

Ana Kaminsky
Full Professor of Dermatology, School of Medicine, University of Buenos Aires, Argentina.
Master of Argentine Medicine (SAD), of Argentine Dermatology (Argentine Medical Press) and Ibero-Latin American Dermatology (CILAD).

Jaime Piquero Martín

Emeritus Professor of Dermatology at the Dr. Jacinto Convit Institute of Biomedicine, Central University of Venezuela (UCV).
Master of Venezuelan Dermatology (SVDMQE) and Ibero-Latin American (CILAD).
Editor of the online magazine http://piel-l.org/blog/

María Isabel Herane

Assistant Professor of Dermatology, University of Chile (1994-2008).
Former president and emeritus member of the Chilean Society Dermatology.
Co-editor of the Chilean Journal of Dermatology and Venereology.

Juan Carlos Diez de Medina

Head of teaching and research at the Fundación Piel, Bolivia.
Former President of the Latin American Society for Photodermatology and Photomedicine.
Guest professor at the CNSS medical residence, La Paz, Bolivia.

Mercedes Flórez-White
Associate Professor, Director of Medical Education, Department of Dermatology, Herbert Wertheim College of Medicine,
Florida International University, Miami, (USA).

Editor: Mercedes Flórez-White

Editorial Assistant: Valerie Sanders
Project Manager and Design: Juan Sosa
Translation Team: Florencia Barbieri (Coordinator),
Juana Nicolaou,
María Cecilia Ibarguren
Illustration: Juan Sosa
 Rosacea, a comprehensive view / Ana Kaminsky... [et al.] ; editor literario Mercedes
Florez-White.- 1a ed .- Ciudad Autónoma de Buenos Aires : Ana Rosental de
Kaminsky ; Miami : Valerie Sanders, 2020.
Libro digital, PDF

Archivo Digital: descarga y online

Traducción de: Florencia Barbieri ; Juana Nicolaou ; María Cecilia Ibarguren.
ISBN 978-987-86-4512-4

1. Dermatología. I. Kaminsky, Ana. II. Florez-White, Mercedes, ed. Lit. III. Barbieri, Florencia, trad. IV. Nicolaou,
Juana, trad. V. Ibarguren, María Cecilia, trad.
CDD 616.5

© 2020 Grupo Ibero-Latinoamericano de Estudio del acné y la rosácea – GILEAR

(Iberian Latin American Group of Acne and Rosacea Studies - ILAGARS).

1st Edition (English) All right reserved

1st edition (Spanish) © 2018

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, record-
ing or any information storage and retrieval system, without permission in writing from the publisher…………

ISBN 978-987-86-4512-4

NOTICE
Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our
knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product
information provided by the manufacturers of medications to verify the recommended dose, method and duration of administration and contraindica-
tions. It is the responsibility of the practitioner, relying on experience and knowledge of the patients, to determine their best treatment and dosage of
the medications to be administered. Neither the Publisher nor the authors assume any liability for any injury and/or damage to persons or property
arising from this publication.
GILEAR (Iberian Latin American Group of Acne and Rosacea Studies - ILAGARS)

III
The Iberian-Latin American Group for the Study of
Rosacea (GILER) is very grateful to Bioderma Laboratoire
Dermatologique for their unrestricted grant and support for
the production of this book.

IV
Table of Content
The Red Face Nosological Clas- Treatment
Section 1 Section 4 Section 7
Title page sification, Clinical
and Histological
1. The Red Face Saga Features 24. General Measures to Manage
2. Flushing: A Dermatological Approach 10. Nosological Classification and Rosacea
to Diagnosis and Management Severity Grading 25. Topical Treatment
3. Differential Diagnosis of Red Faces 11. Classical Forms Antiparasitic Drugs
Copyright Erythematotelangiectatic Rosacea Azelaic Acid
Papulopustular Rosacea Sodium Sulfacetamide and Sulphur
The Sensitive Skin Hyperplastic/Phymatous Rosacea Alpha-Agonists
Section 2
Ocular Rosacea Calcineurin Inhibitors:Tacrolimus
12. Special Forms and Pimecrolimus.
Contributors 4. Definition and Characteristics of Childhood Rosacea 26. Systemic Treatment
Sentitive Skin Extrafacial Rosacea Antibiotics
5. Pathophysiology 13. Granulomatous Rosacea Oral Isotretinoin
6. Management 14. Most common histopathological Zinc Salts
findings in rosacea Oral Ivermectin
Foreword Beta-Adrenergic Blockers
Definition, Etiology Differential 27. Complementary Treatments
Section 3 Section 5
and Pathogenesis Diagnosis Dermocosmetic Management – Skin care
of Rosacea Light Therapy
7. General Considerations 15. Differential Diagnoses Other Complementary Treatments
Preface to the 8. Epidemiology 16. Demodicidosis Surgical Treatment of Phymas
English Editión 9. Pathogenesis 17. Perioral or Periorificial Dermatitis 28. Treatment Guidelines
Skin Barrier and Rosacea 18. Seborrheic Dermatitis
Rosacea Genetics 19. Adult Acne and Rosacea: A Diag- Specials
Section 8
Vascular Hiperreactivity nostic Challenge Considerations
Preface to the Neurovascular Changes: Neuropeptides 20. Morbihan Disease
Spanish Edition Stress in the endoplasmic reticulum 29. Rosacea Comorbidities
Immune System Complementary 30.Neurogenic Rosacea
Section 6
Chronic Inflammation and Fibrosis Diagnostic 31. Rosacea and Pregnancy
Microbiome, Antimicrobial Peptides, D. Techniques 32. Rosacea and Skin Color
folliculorum, St. epidermidis, H. pylori 21. Dermoscopy 33. Rosacea and Diet
Acnowledgment Summary 22. Confocal Microscopy 34. Quality of Life
23. Color Doppler Ultrasound
V

Gilberto J Adame Miranda
Former president of the Mexican Academy of Dermatology and
the Mexican Foundation for Dermatology.
Associate professor of the specializing course on diagnosis and
treatment in dermatology, Children’s Hospital of Mexico and UNAM.
Former President RADLA México
Carlos Roberto Antonio
Professor of Dermatology and Chief of Dermatological Surgery at
the Base Hospital of the State School of Medicine, Sao Jose de
Rio Preto (FAMERP). Sao Paulo, Brazil.
Author of an online dermatology book, Ipele (www.ipele.com.br).
João Roberto Antonio
Master of Dermatology, CILAD.
Emeritus Professor and Chief of Dermatology, State School of
Medicine, Sao Jose de Rio Preto, Sao Paulo, Brazil.
Former President of the Brazilian Society of Dermatological
Surgery and of the Brazilian Society of Dermatology.
Isabel Arias Gómez
Professor of Dermatology, National Autonomous University of Mexico
(UNAM) and the General Hospital of Mexico City, Mexico
Lívia Arroyo Trídico
Assistant professor of Dermatology, San José de Rio Preto
Hospital, Sao Paulo, Brazil.
Aline Armas- Vazquez
Dermatologist, General Hospital of México “Dr. Eduardo
Liceaga”, México City
Ediléia Bagatin
Associate Professor, Chair, Department of Dermatology,
Paulist School of Medicine, Federal University of Sao Paulo.
(UNIFESP), Brazil
contributors
María del Carmen Boente
Director, Integral Dermatology Center, S. M. de Tucumán.
Former Head of Service of the Hospital of the Child Jesus.
Tucumán, Argentina.
Horacio Cabo
Professor of Dermatology. School of Medicine, University of
Buenos Aires, Argentina.
Consultant of Dermatology, Aguirre Lanari Medical Research
Institute, University of Buenos Aires.
Former president of the Argentine Society of Dermatology
President of CILAD (Latin American College
of Dermatology)
José Gabriel Casas
Full Profesor Consultant. Department of Pathology
School of Medicine, University of Buenos Aires, Argentina
Master of Argentine Dermatology (SAD).
Javier Fernando Casiraghi
Associate Professor of Ophthalmology, University of Buenos
Aires, Argentina.
Head of the Glaucoma Service, Ophthalmology Division,
Hospital de Clínicas. Buenos Aires, Argentina.
Editor-in-Chief, Clinical and Experimental Ophthalmology
(OCE), of the Argentine Council of Ophthalmology
(CAO).
Daniela Castrejón Pérez
Private practice Dermatologist. Mexico City
Sonia Chávez A.
Associate professor of the specializing course on
dermatological and oncological surgery, Dr. José Eleuterio
González University Hospital, Autonomous University of
Nuevo León, Mexico.
VI
Mildreth Cid
Collaborator at the Research and Extension Center of the Health
Sciences, Division of Tec Salud, Monterrey, Monterrey Campus,
Mexico.
Emilia N. Cohen Sabban
Associate professor in Dermatology, University of Buenos Aires,
Argentina.
Head of the Dermatology Service, Aguirre Lanari Medical
Research Institute, University of Buenos Aires,Argentina.
Manuel del Solar
Head of the Dermatology Service, Cayetano Heredia Hospital,
Lima, Peru.
Professor and coordinator of the Dermatological Clinic Course,
Universidad Peruana Cayetano Heredia, Lima, Peru.
Former Secretary General of the Iberian-Latin American College
of Dermatology (CILAD).
Patricia Della Giovanna
Associate Professor of Dermatology, School of Medicine,
University of Buenos Aires, Argentina.
Head of the Dermatology Service, Posadas National Hospital, Argentina.
Brigitte Dréno
Head of the Department of Dermatology
Director of Cell and Gene Therapy Unit – CIRCNA- Hotel
Dieu Nantes University Hospital
Vice Dean of Research in Faculty of Medicine, Nantes University,
France
María José Fiandrino
Head of the Dermatology Service at the Child Jesus Hospital,
Tucumán, Argentina.
Dermatologist at the Integral Center of Dermatology, Tucumán,
Argentina.
 Leonel Fierro Arias
Professor, National Autonomous University of Mexico and
Anáhuac University.
Specialist of the Dermatology Service at the
General Hospital of Mexico, Dr Eduardo Liceaga, Mexico
City.
Medical Director, DERMADEF, Mexico City.
Linda García H.
Associate Dermatologist, Department of Dermatology
of the National Institute of Medical Sciences and
Nutrition,Salvador Zubiran
(INCMNSZ).
Professor, School of Medicine of UNAM, Mexico.
President of the Mexican Academy of
Dermatology
Sandra García G.
Dermatologist, University Hospital “José E. González” (UANL)
Monterrey, Nuevo Leon, Mexico.
Jorge Garza
Associate professor University Hospital “José E.
González “ from the Autonomous University of
Nuevo León (UANL) and University of Monterrey
(UDEM), Monterrey, Mexico.
Elda Giansante
Professor and Coordinator of the Connective Tissue Diseases
Clinic, University Hospital of Caracas, Central University of
Venezuela (UCV).
Former President of the Venezuelan Society of Medical, Surgical
and Aesthetic Dermatology.
Minerva Gomez F.
Professor and Head of postgraduate program,
Dermatology Service, Hospital Universitario UANL,
Monterrey, Mexico.
Elena González-Guerra
Associate Professor of Medical-Surgical Dermatology and
Venereology. Department of Medicine, Faculty of Medicine,
Complutense University, Madrid.
Associate doctor of Dermatology at the Hospital Clinico San
Carlos, Madrid, Spain.
Aurora Guerra-Tapia
Full professor of medical-surgical dermatology and venereology.
Department of Medicine, Faculty of Medicine, Complutense
University, Madrid, Spain.
Head of the Dermatology Section of the 12 de Octubre
University Hospital, Madrid, Spain.
Hans Gubelin A.
Fourth year student, Faculty of Medicine, University of Chile.
Walter Gubelin Harcha
Full Professor of Dermatology, Faculty of Medicine, Universidad
de Los Andes. Chile.
María Cecilia Isernia
Consulting dermatologist, Dr. Jacinto Convit Institute of
Biomedicine, Central University of Venezuela, Caracas, Venezuela.
Dermatologist at the Medical Laser Unit (UNIMEL), Caracas.
Edgar La Rotta Higueras
Master in Advanced Cutaneous Pathology, University of Barcelona
Private practice Dermatologist, Epidermos, Barcelona, Spain
Pedro Lobos
Dermatologist, Department of Dermatology, Las Condes Clinic, Chile
Jose Luis López Estebaranz
Head of the Dermatology Service. Alcorcón Foundation
University Hospital.
Associate Professor, Rey Juan Carlos University, Spain.
DermoMedic Clinic. Madrid. Spain
VII
M. Cecilia Marini
Corneal Transplant Team Leader. El Cruce Hospital. Buenos
Aires province. Argentina.
Coordinator of the Cornea and Surface Section,
Hospital El Cruce. Province of Buenos Aires,
Argentina.
Associate professor University of Salvador, Argentina
Lidia Maroñas-Jiménez
Assistant professor of Dermatology, Department of
Medicine, Faculty of Medicine, Complutense University,
Madrid, Spain.
Associate Physician of Dermatology at the Hospital Universitario
12 de Octubre, Madrid, Spain.
Perla Meneses Rodríguez
Dermatologist, University Hospital, Caracas, Venezuela
Lorena Merino G.
Fourth year student, Faculty of Medicine, Universidad del
Desarrollo, Chile.
Carlos Montenegro Infante
Postgraduate professor of Dermatology, Private University “San
Martin de Porres”. Peru.
Jorge Moreno González
Graduate Professor of Dermatology, Northeast National Medical
Center, Mexico.
Dermatologist Director of Dermavanz Salud.
Patricia Patiño
Consultant and collaborator of postgraduate teaching, Dr. Jacinto
Convit Institute of Biomedicine, Central University of Venezuela.
Caracas.
Adjunct ad hoc. in Stomatology, Dermatology Service of the Hospital
Vargas and the teaching medical center La Trinidad,
Caracas.
 Ricardo Pérez Alfonzo
Postgraduate Professor of Dermatology and Syphilology. Institute
of Biomedicine Dr. Jacinto Convit, Central University of
Venezuela, Caracas, Venezuela.
Past-President Iberian-Latin American College of Dermatology
(CILAD).
Jaime Piquero Casals
Dermatologist and specialist in Mycology. Master in Medical
Sciences, University of São Paulo, PhD in Dermatology,
Autonomous University of Barcelona
Dermatologist, Dermik Clinic, Barcelona, Spain.
. Hotel Dieu, Nantes. University Hospital, France
Vanesa Piquero-Casals
Professor of Cosmetic Medicine, School of Pharmacy, Central
University of Venezuela.
Dermatologist, Dermik Clinic, Barcelona, Spain.
Nélida Raimondo†
Full Professor of Dermatology, Maimonides University.
Buenos Aires, Argentina.
Associate Professor of Dermatology, University of
Buenos Aires, Argentina.
Head of the Dermatology Service, Central Aeronautical Hospital,
Argentina.
Mónica Rivera Jay-Lung
Assistant professor at El Bosque University (Bogotá,
Colombia).
Vice President of the Colombian Society of Laser
Dermatology.
Mary Ann Robledo Prada
Private practice Dermatologist, Medellin, Colombia.
Mélanie Saint Jean
Doctor, Dermatologist in the department of
Dermatology
Denise Steiner
Full Professor and Head of Dermatology Service at the
Mogi das Cruzes University. Brazil.
Deputy Secretary General, Iberian Latin-American
College of Dermatology
Jerry Tan MD FRCPC
Windsor Clinical Research Inc., Windsor, ON,
Canada
Schulich School of Medicine and Dentistry, Western
University, Windsor Campus, ON, Canada
Adriana Tytiun
Adjunct professor, University of Buenos Aires, Argentina.
Physician of the Cornea Section of the Hospital de Clínicas, Buenos Aires.
President of the Argentine Society of Cornea, Refractive and
Cataract (SACRYC).
Francisco Urbina
Former assistant professor of Dermatology, Faculty of Western
Medicine, University of Chile. Santiago, Chile.
Ximena Wortsman
Radiology Specialist. Subspecialist in dermatological ultrasound.
Institute for Research and Diagnostic Imaging in skin and soft
tissues (IDIEP), Santiago, Chile.
Associate professor of the departments of Dermatology,
Universidad de Chile and Pontificia Catholic University of Chile.
Emilia Zegpi Trueba
Associate Professor Department of Dermatology, University of
Chile. Santiago, Chile.
Christos C. Zouboulis
Prof. Dr. med. Prof. honoraire. Departments of Dermatology,
Venereology, Allergology and Immunology, Dessau Medical Center,
Brandenburg Medical School Theodore Fontane, Dessau, Germany

VIII

Rosacea is a frequent, complex, polymorphous and
chronic inflammatory skin disorder characterized by
remissions and exacerbations. It develops mainly in
the face, with a broad variety of clinical manifesta-
tions, like erythema (fixed or transient) and inflam-
matory papules and pustules. Some patients develop
phymatous changes or ocular signs and symptoms.
The key factor that distinguishes rosacea from acne
is the absence of blackheads in patients with rosacea;
however, in some cases, both entities may be present.
The pathophysiologic processes which trigger the
development of rosacea are many and diverse. Often
rosacea starts as a vascular inflammatory disease in
patients with a genetically sensitive skin, especially
sensitivity to ultraviolet radiation. When diagnosing
and treating rosacea, clinicians should always be
mindful of the great impact that this disease has on
the patient’s quality of life.
As skin care specialists, we have learned that ro-
sacea, rather than a single entity, represents a com-
plex syndrome with diverse origins and polymorphic
manifestations. Therefore, the basic therapeutic ob-
jectives must be clear: to improve symptomatology
and physical appearance; to maintain remission and
avoid exacerbations; to delay or prevent the devel-
opment of advanced stages; and to achieve an im-
proved quality of life.
Foreword
The tireless and fruitful work of the Iberian-Latin
American Group for the Study of Rosacea (GIL-
ER), as part of the Chapter on Acne, Rosacea and
Related Disorders, and under the authority of the
Iberian-Latin American College of Dermatology
(CILAD), led by doctors Ana Kaminsky, Mercedes
Florez White, María Isabel Herane, Jaime Pique-
ro Martín and Juan Carlos Diez de Medina, is em-
bodied in the publication of the “2016-Iberian-Latin
American Consensus Report on the Clinical and
Therapeutic Classification of Rosacea”. Med Cut
Iber Lat Am 2016; 44 (1) 6-10 and now, in this extraor-
dinary work: Rosacea, A Comprehensive View. As
a result of a great organizational effort undertaken
with passion and tenacity, the authors have man-
aged to bring together a large number of opinion
leaders with great expertise in the field, both from
Iberian-Latin America and the rest of the world, to
create this outstanding work.
The book has been divided into eight parts where
all aspects of rosacea are masterfully detailed: red
face, sensitive skin, definitions, pathophysiology,
classification, clinical manifestations and pathology,
as well as differential diagnoses. In the last sections,
there is a thorough analysis of current treatments
and consideration of specific topics which will stim-
ulate the reader to deepen their knowledge of this
IX
disease. The rigorous selection of the professors in-
volved and the material collected, both written and
photographic, will make this book a classic reading
and consultation resource among all those inter-
ested in rosacea. The flexible format of this splen-
did browsable e-book makes it easy to read on any
electronic device and represents an important con-
tribution to Iberian-Latin American dermatology,
with text available both in Spanish, Portuguese an
English. It is sure to become a tool of great help in
unravelling this mysterious yet treatable disease.
The Board of Directors of the Iberian-Latin Amer-
ican College of Dermatology is deeply honored to
have sponsored and participated in this successful
and useful project, and we acknowledge and thank
the editors and authors involved in this work.
Ricardo Pérez Alfonzo
CILAD-President
Manuel del Solar
CILAD-Secretary General
 Preface to the English Edition
After the success obtained with the Spanish edition of the eBook “Rosacea, una visión integral” launched in 2018, and at
the request of several international colleagues, we set ourselves the task of carrying out the English edition of the book.
This new version took two years of work, starting with the translation from Spanish to English, implemented by an excellent
group of medical translators and the unconditional support of an excellent medical writer, who acted as editorial assistant.

The result of this effort is reflected in this eBook entitled Rosacea, A Comprehensive View that we are pleased to deliver
to our English-speaking colleagues and those who prefer publications in this language. We know that medical knowledge
is continuously changing, and it may be that, as of the time of the publication of this book, some concepts could have been
already updated.

Ana Kaminsky, Jaime Piquero Martín, María Isabel Herane,

Juan Carlos Diez de Medina, Mercedes Flórez-White
 Preface to the Spanish Edition
The idea of addressing the complexity of rosacea the Clinical and Therapeutic Classification of Rosa- tinguished from the four classic subtypes of rosacea:
originated in May 2015, at the Annual Meeting of cea“ published in CILAD’s official journal [Medicina erythematotelangiectatic, papulopustular, hypertro-
Latin American Dermatologists (RADLA), held in Cutánea Ibero-Latinoamericana 2016; 44(1):6-10]. phic/phymatous and ocular.
Lima, Peru, when members of the Iberian-Latin
American Group for the Study of Acne (GILEA- The impact of both the classification and the An updated review of both the pathogenesis and
CILAD) decided to study every aspect of this entity. therapeutic guide motivated us to undertake an the therapeutic approaches to rosacea was also cre-
To do so, it was necessary to create another spe- even more ambitious project: a text covering all ro- ated, and three interesting chapters on diagnostic
cific research group. This is how the Iberian-Latin sacea aspects in which CILAD experts and presti- techniques were introduced: dermatoscopy, ultra-
American Group for the Study of Rosacea (GILER) gious colleagues from other geographical regions sonography and confocal microscopy. Naturally, as
was created, which together with GILEA is part of and related specialties would participate. With this medicine is neither an exact nor even a static sci-
the chapter Acne, Rosacea and Related States of aim in mind, we invited Jerry Tan from Canada, Bri- ence, the concepts outlined here, especially those
CILAD. The founders and coordinators of GILER gitte Dréno and Mélanie Saint Jean from France, concerning pathogenesis and therapeutics, are not
are Ana Kaminsky (Argentina), Mercedes Flórez- Christos Zouboulis from Germany, imaging special- intended to be absolute truths.
White (Colombia-U.S.A.), Jaime Piquero Martín ist Ximena Wortsman from Chile, and ophthalmol-
(Venezuela), María Isabel Herane (Chile) and Juan ogists Javier Fernando Casiraghi, Adriana Tytiun In order to continue on the established path, the
Carlos Diez de Medina (Bolivia). and Cecilia Marini from Argentina. The result is this group has already prepared a new working plan to
book, in electronic format, with a “comprehensive keep the knowledge on this disease updated, as it
The initial task was to gather opinions among ex- overview” that will hopefully contribute to a greater affects so many individuals who are condemned to
perts from different countries, searching common understanding of this complex skin disease. a life of lower quality.
points of agreement that would enable the harmoni-
zation of criteria on the different variables observed GILER has developed a new classification that, in We would like to thank CILAD for the confidence
in rosacea. To this end, many of them were invited our opinion, may provide a more rational overview granted, which allows us to continue with such an
to join GILER. At the founding meeting of the group of the different types of rosacea. The major feature exciting activity, not only connecting us in the sci-
in May 2015, two goals were established: classifica- of this classification is incorporation of childhood entific field, but also creating important bonds of
tion and therapeutics. Since then, the group has rosacea and extrafacial rosacea as special forms, affection.
met on several occasions and has held regular on- which are not included in any other classification
line conferences, especially among coordinators. of the literature worldwide. The group considered Ana Kaminsky, Jaime Piquero Martín, María
The results of the discussions were released in the that these forms of rosacea are “special” because Isabel Herane, Juan Carlos Diez de Medina,
“2016-Iberian-Latin American Consensus Report on they have characteristics that allow them to be dis- Mercedes Flórez- White

XI
Section 1
„„ Chapter 1. The Red Face Saga

„„ Chapter 2. Flushing: A
The Red Face Dermatological Approach to
Diagnosis and Management

„„ Chapter 3. Differential
Diagnosis of Red Faces
“Joseph saw his brother Benjamin af-
ter an absence of twenty-two years, he
grew nervous and restless (vaymaher)
and, trying to hide his emotional reac-
tion, he blushed (nichm’roo rachmov),
his emotions warmed his skin; he felt
like crying (y’vakesh livkoss), so he
left to an antechamber and sobbed.”
As early as this quote from Genesis
(Bible, Old Testament), blushing was
portrayed as an expression of em-
barrassment or shame. Throughout
the history of civilization, the sudden
reddening of the face, or flushing, is
present in every cultural aspect of hu-
man beings. Mark Twain used to say
that “humans are the only animals that
blush,” a not-so-true statement, since
it has been observed that dogs also
do so.1
“Red face” describes areas of red-
ness exclusively or predominantly lo-
cated on the face, covering all or part
of it. Erythema may manifest alone or
may be associated with other lesions,
such as papules, pustules, plaques,
and edema. Its development can be
acute or progressive, fluctuating or
chronic. Historically, the red face has
been most closely associated with
rosacea. Although this is not the only
skin disease accompanied by facial er-
ythema, it is the most frequently ob-
served. Facial erythema is a significant
part of daily medical-dermatological
practice and deserves much more at-
tention than it has received so far.2
Chapter 1
The Red Face
Saga
Jaime Piquero-Martín
After centuries of ignorance about
the pathogenesis of the red face,
progress is now being made in un-
derstanding the condition, especial-
ly as regards the role played by skin
barrier homeostasis and stress-asso-
ciated signaling in the endoplasmic
reticulum. These important advanc-
es in understanding the pathogen-
esis of rosacea should facilitate the
search for optimal therapeutic man-
agement.3-5
The history concerning the knowl-
edge of the red face is associated
with that of rosacea. Although this is
not the only skin disease accompa-
nied by facial erythema, it is the most
frequently observed.
Hippocrates of Cos (469-370 BC)
(Fig. 1-1) was the first to coin the term
“erythema” (εδυθημα) as a synonym
for “redness” of the skin.6 Several
2
Fig. 1-1. Hippocrates of Cos (469-370
BCE). Source: https://es.wikipedia.org/
wiki/Hipocrates.6
centuries later, Galen of Pergamum
(129-216 AD) described red face for
the first time. However, after the ex-
traordinary contributions made by the
latter to the advance of medicine, ro-
sacea/red face fell into relative obscu-
rity. As Christianity rose in the Roman
Empire, health care became empiric,
based on imploring saints and martyrs
for their help. As examples, sufferers
of chorea prayed to Saint Vitus, those
with baldness turned to Saint Ag-
nes, desperate cases were yielded to
Saint Jude Thaddeus, and those with
eczema prayed to Saint Lawrence.
Similarly, Saint Cosmas and Saint Da-
mian become the new patron saints of
medicine, replacing Aesculapius, the
Greco-Roman god of medicine. There
were invocations to the saints for ev-
erything - Saint Maderic was even in-
voked for those who were fed up with
marriage. The art of healing became
a task restricted to monks and clergy-
men, physicians were relegated to the
background and the sarcastic phrase
“two out of three doctors are atheists”
arose. True medicine was sustained
in the Islamic world, where Galen’s
works were studied, systematized and
disseminated, keeping them from be-
ing lost in time.7
One thousand years after Galen,
Guy de Chauliac (1300-1368) suggest-
ed that the red face “improved with a
diet of cooling, bleeding of the frontal
vein, and leeches applied to the nos-
trils as a purge” and Ambroise Paré
(1510-1590) used the term “gutta rosa-
cea” (Paré A. Complete works. Book
XXI, Des venins, page 790). Hierony-
mus Mercurialis (1530-1606), the first
physician to follow Galen’s teachings
again, referred to the red face in his
well-known treatise on dermatology
De morbis cutaneis (1572), considered
by many specialists as the first book
on Dermatology.8
In his remarkable treatise Diseases
Incident to the Skin (1718), the English
physician Daniel Turner devoted a
chapter (Fig. 1-2) to what he called “dis-
eases incident to the skin of the face.”
There he wrote: “I give instructions to
my patients on how to lessen the red
and burning complexion, to level those
monstrous pustules or spots, with oth-
er alterations that disfigure the face
so much and move beauty away from
beauties.” He was one of the first phy-
sicians to speculate on the pathogen-
esis of the red face, theorizing that it
was caused by “Blood thickened by
hepatic disorders, especially caused
by alcohol, although it is sometimes
seen in those more moderate and ab-
stemious individuals.”9
The first modern descriptions
of red face were written in France
between the 17th century and the
early 18th century by Jean Astruc
(1684-1766), Louis XV’s physician. He
distinguished three forms of rosa-
Fig. 1-2. Turner D. Treatise of Diseases Incident to the Skin (1714). Cover of the
book with a portrait of the author. Yale University.
cea: the first characterized only by
skin redness; the second called “var-
icose” - due to dilation of the facial
veins; and the third characterized by
scaling. In this way, the signs of rosa-
cea had been established and, based
on them, a more detailed observation
of the red face began. Also in the
18th century, dermatology pioneers,
Joseph Plenk (1735-1807) in Vienna
and Robert Willan (1757-1812) with his
3
pupil Thomas Bateman (1778-1821) in
London, described red face in detail.
Plenk wrote that “gutta rosacea” de-
veloped as red spots grouped on the
face and nose, and described nine
variants directly related to rosacea.1
Willan, through Bateman, character-
ized rosacea extensively under the
name “acne rosacea,” and differentiat-
ed rosacea from “acne simplex,” “acne
punctata” and “acne indurata.” Prom-
inent French dermatologists made
the final descriptions of rosacea in the
19th century. Jean Louis Alibert (1768-
1837), father of dermatology and chief
medical officer at the Saint Louis Hos-
pital in Paris, named it “rosacea varus,”
writing: “We chose this name due to
the consistently pink color lent to the
facial skin, and that it does not pose
any serious danger or dramatic suf-
fering, though it is indeed observed in
people with no hygiene habits, being
negligent or lazy” (Fig. 1-3).10-13
Years later, by the end of the 19th
century, Hallopeau and Leredde is-
sued a comprehensive description
in Pratique dermatologique, where
the red face is shown as a disease
“caused by functional disturbances,”
and pointed out that this acne variant
appeared together with vascular dis-
orders, which resulted in the develop-
ment of acne pimples (Fig. 1-4).14,15
In Vienna, one thousand kilome-
ters away, professor Ferdinand von
Hebra (1816-1880), as well as his pupil
and son-in-law Moritz Kaposi (1837-
1902) described rosacea as a separate
condition from acne, developing from
an initial diffuse redness, with telangi-
ectasias (couperose) followed by pap-
ules and nodules.16,17
Across the ocean, in Pennsylvania,
U.S.A., the pioneer of American Der-
matology Louis A. Duhring (1845-1913)
 wrote in his 1876 atlas that “acne and
rosacea may develop simultaneous-
ly.”17 Meanwhile, Charles Darwin, the
most prestigious scientist of the time,
stated in 1872 that the red face is “the
most peculiar and most human of all
expressions.”18
By the 20th century, the French
dermatologist Ferdinand-Jean Dari-
er, contradicting his French prede-
cessors, said that “Acneic folliculitis
related to redness patches has been
mistakenly confused with the papu-
lopustules present in acne vulgaris”
while Paul Gerson Unna (a derma-
tologist from Hamburg, 1850-1929)
pointed out the acne could be distin-
guished from rosacea by “differences
in the absence of blackheads, prefer-
ential placement, focal nature of le-
sions and patients’ age. ”19-22
In Nouvelle Pratique Derma-
tologique (Fig. 1-4), a book published
in 1936, rosacea is definitely differen-
tiated from acne.23 Although it took
several centuries and a long historical
journey to come to this conclusion, it
has not stopped there; instead, dis-
cussions are still being held in the
21st century. However, in 1975, Gerd
Plewig and Albert M Kligman, in their
book Acne. Morphogenesis and Treat-
ment, warned against confusing both
Fig. 1-3. The Tree of Dermatoses, by Alibert. Frontispiece of Clinique de l’Ho- diseases and wrote that “The disease
pital Saint Louis ou Traitement complet des Maladies de la Peau (1833). Source: was originally called acne rosacea,
https://en.wikipedia.org/wiki/Jean-Louis-Marc_Alibert. an inept term which is still used. Ig-
4
norance of the basic characteristics
of acne vulgaris is presumably the
reason why many disorders include
the term “acne” when in fact most of
these are not even second-degree
relatives.”24
During the last forty years, an ava-
lanche of papers on the understand-
ing, classification and treatment of
red faces have been written. A brief
review of bibliographic references
showed that in the first nine months
of 2017, twenty-six scientific papers
were published in accredited derma-
tological journals. The cosmeceutical
product industry has also in recent
years focused on the development
of product lines devoted to cam-
ouflaging and mitigating annoying
blushing.
In 1992, the National Rosacea Soci-
ety (NRS) (https://www.rosacea.org/),
was founded in the United States, with
the mission of improving the quality
of life of the people living with this
condition through awareness, educa-
tion and medical research support. At
the time of its creation, only 200,000
Americans were believed to have this
disorder; currently, it is estimated that
more than 16,000,000 American citi-
zens live with this problem..
The NRS, together with the Iberi-
an-Latinamerican Group for the Study
of Rosacea (GILER) have reached a
 In 2013, two co-
ordinators of this
book published the
text Rosácea y Afec-
ciones Relacionadas,
(Rosacea and Related
Conditions), with the
contribution of ex-
perts from Argentina,
Brazil, Bolivia, Chile,
Colombia, Spain, Mex-
ico, Peru, Uruguay and
Venezuela, as well as
invited experts from
Egypt and Germany.2
THE RED FACE IN
SOCIETY
A red face or flush on
the cheeks or nose
is taken as a sign
of shyness, embar-
rassment, too much
alcohol, or poor hy-
giene. People may
even think it is a con-
sequence of being
irresponsible and not
having used the ap-
Fig. 1-4. Title page of volume VII of Nouvelle pratique propriate sunscreen.
dermatologique, 1936.23. Frequently, people
with facial erythe-
consensus to establish a definition re- ma have to answer questions about
flecting the disease and an adequate their condition, particularly women,
classification system, as well as updat- and the persistence of this disorder
ed algorithms for the treatment of ro- may lead to serious disruptions in
sacea. The conclusions are presented personal relationships. The children
in this work. affected are harassed or bullied, and
5
their classmates mock at them using
nicknames such as “Joe Red-Face” or
“Mary Pink-Face.”25,26 Although it has
been said that flushing only appears
in human beings (Mark Twain), it has
been proved that it also affects pets,
like cats and dogs.
Exogenous physical stimuli, such as
mechanical irritation, heat, cold and
light, can worsen redness, couper-
ose or rosacea. Therefore, the people
who have rosacea-associated signs
and symptoms tend to avoid outdoor
activities and describe this situation
as a real detriment to their quality of
life, implying a heavy burden for their
social life.1,26
From the Middle Ages until now,
writings have discredited people with
facial redness, although not men and
women equally. Among men, a red
face may be a sign of good living,
showing a sanguine and manly tem-
perament, although it is also associ-
ated with alcohol consumption (Fig.
1-5). In the Middle Ages, it was said
that rosacea was typical of those men
called “buzicagua” (wine cask).1 In 19th
century Europe, the term couperose,
that the French dermatologist Alibert
used in his papers, did not have the
meaning we give it today, as a syn-
onym of rosacea. In those times, ro-
sacea was “varus gutta-rosea”, and,
specifically, the redness caused by
rosacea was called “gutta-rosea.” This
term was then used generally to indi-
cate people who showed no respect
for others, had shameful sexual hab-
its and led an unhealthy lifestyle. As
the term became popular, and more
pejorative, its pronunciation changed,
becoming similar to couperose.12 Per-
haps the associations made between
couperose and sin arose because of
its red color, which could be associ-
ated with crime, dirt, impurity and
menstrual blood, as well as with rev-
olutions. However, this color also sym-
bolizes martyrs, and cardinals use it in
their tunics to represent Christ’s sac-
rifice and the power of the Church’s
princes.
Today, there is an increasing array
of dermocosmetic products to help
conceal these stigmatizing lesions. In
this sense, there is a very well-estab-
lished industry focused on concealing
the annoying flushing.25
The Red Face in Literature
Among authors, Mark Twain is not
the only one to make allusions to
flushing. Edmund Spenser, the re-
nowned English poet who wrote his
famous work “The Faerie Queene”
for Queen Elizabeth I included the
following:27
“Her pure and eloquent blood
Spoke in her cheeks, and so
distinctly wrought That one might
almost say her body thought...”

Fig. 1-5. Diego Velázquez. The Triumph of Bacchus (The Drunks). Museo del
Prado. Source: https://es.wikipedia.org/wiki/El_triunfo_de_Baco_(Velazquez).
Likewise, without mentioning all
the allusions made to flushing and
red faces in literature over time,
we have found a good example
in Venus and Adonis, by Shake-
speare:1
“He burns with bashful shame: she
with her tears
Doth quench the maiden burning
of his cheeks;
Then with her windy sighs and
golden hairs
To fan and blow them dry again
Another radiant secretary pointed by José Díaz Benito, 1864, and Clíni-
at me with her finger. How wonderful! ca Iconográfica de las Enfermedades
You still have the elegance to blush. de la Piel o Dermatosis, by José Ola-
Her impertinence provoked another vide 1871).30 Magnificent watercolors,
blush on top of the first.”28 engraved on copper plates of great
beauty, and then presented as delicate
The Red Face in Visual Arts and ambitious lithographs full of de-
Great works of art have shown the aesthet- tails and with a high level of scientific
ic expression of emo-
tions through red faces.
Examples include Por-
trait of an Old Man
and his Grandson,
by Doménico Ghirlan-
daio (1480) (Fig. 1-6),
one of the oldest rep-
resentations of rosa-
cea, where the artist
shows an afflicted old
man gently leaning
towards his grand-
son, and Rembrandt
van Rijn’s self-portraits
(Fig. 1-7)29 including
she seeks: the Self-Portrait with
He saith she is immodest, blames Beret and Turned-Up
her ‘miss; Collar (1659). Also, fine
What follows more she murders representations of red
with a kiss”. faces were made by
18th and 19th century
In Latin American literature, Ga- medical artists and
briel García Márquez wrote the fol- embodied in beau-
lowing in his novel Memories of My tiful atlases of der-
Melancholy Whores (2004): matological schools
from France, Italy,
“A burning flash flamed across my Austria and Spain (At- Fig. 1-6. Ritratto di vecchio con nipote (Portrait of an Old
face. Damn it, I thought, blushing is so las de Enfermedades Man and his Grandson). Domenico Ghirlandaio, 1490. In:
disloyal. Venéreas y Sifilíticas, https://es.wikipedia.org/wiki/Un_anciano_con_su_nieto
6
accuracy and artistic talent marked an
era in which, again, medicine and art
shook hands (Figs. 1-8 to 1-10).30-33 Wax
moulage quickly began to appear in
dermatology, a technique that had pre-
viously been used by anatomists. The
first cutaneous moulages probably
date back to the end of the 18th centu-
ry and the beginning of the 19th centu-
ry and may have been made by Franz
Heinrich Marten (1778-1805) from Jena,
Germany. Facial moulages were mold-
ed in wax and then painted in exquisite
form and humanized by the addition of
hair and crystal eyes.34,35 The first great
dermatologic moulages were created
by Joseph Towne (1806-1879) in Lon-
don. It is believed that this illustrator
and moulage artist created more than
550 pieces. At the Vienna School of
Dermatology, Professor Ferdinand von
Hebra, who had an extraordinary wa-
tercolour collection, invited the doctor
and illustrator Anton Elfinger (1821-
1864) to create moulages. In healthy
competition with the artist Jules Bar-
etta (1833-1923), from the Saint Louis
Hospital in Paris, they managed to
make their works, together with others,
become the best educational resource
of the time. The museum belonging to
the Saint Louis Hospital managed to
collect more than 3,500 dermatologi-
cal molds, creating the world’ s largest
collection. The majority of these moul-
ages are still preserved in the Museum
of the Saint Louis Hospital. In this col-
lection, there are more than 20 pieces
on rosacea. At the Olavide Museum in
Madrid, Professor Luis Conde Salazar,
along with other dermatologist friends
and artists from Madrid, have made a
major effort to recover Professor Ola-
vide’s moulages (Figs. 1-11 to 1-13).36,37
In the 1870s, casts published in
some books on skin diseases became
popular, although they were no lon-
ger taken directly from patients, but
from moulages. In this way, samples
lost their artistic sophistication and
became flat and trivial images.1 In ad-
dition, the first medical photographs
began to appear. Daguerreotypes
showing skin diseases were first re-
corded in 1845, though they were not
very revealing due to their under-rep-
resentation of rosacea. In 1883, photo-
graphs were attached to a cardboard
and colored by hand; these images
were not excellent and lost accura-
cy when printed in successive prints.
Though inaccurate, they launched
the era of illustrative photography.38
By 1900, the first book of high-qual-
ity black-and-white photographs was
published, written by Dirk van Har-
en Noman (1854-1896), a Dutch doc-
tor. However, these illustrations still
lacked the color that could provide
rosacea details (Fig. 1-14). As a result,
photographs did not immediately re-
place illustrator artists, who contin-
Fig. 1-7. Rembrandt van Rijn. Self-Portrait with Beret and Turned-Up Collar, ued working throughout the first half
1659. Oil on canvas. National Gallery of Art, Washington. https://es.m.wikipedia. of the 20th century. It was not until
org/wiki/Archivo: Rembrandt_van_Rijn_-_Self-Portrait_-_Google_Art_Project.jpg. the 1950s that color photographs re-
7

Fig. 1-8. Varus Gutta Rosea. Macmillan, 1833.26
placed illustrations in dermatology.
Since then, every respected derma-
tology department has had photogra-
phers devoted to the specialty.38-40
The Red Face Among Celebrities
Many well-known people have suf-
fered from the stigma of the red
face, from comedians and movie stars
(such as WC Fields)1 to businessmen
Fig. 1-9. Acne Rosacea. From von Hebra’s Book.26
and bankers like John Pierpont Mor-
gan (1837-1913). The latter was one of
the most important and influential fi-
nancial tycoons of his time. A tall and
sturdy person with dreadful manners,
a red face and an enormous phyma-
tous nose (despite that he was a tee-
totaler who abstained from alcohol),
he suffered for his intimidating face
and was “disliked by the women he
8
wooed.” Therefore, in despair about
his red face and after consulting the
best doctors of the time, he offered
US $100,000 to whoever would cure
him. This challenge was taken up by
Louis Duhring, Dermatology Profes-
sor at the University of Pennsylvania.
Both of them, doctor and patient,
passed away frustrated the same year,
in 1913.41
There have been presidents, prime
ministers, film stars and sportsmen fa-
mous for their red faces and allusions
to alcohol or sins of the flesh. Perhaps,
the most famous was Winston Leon-
ard Spencer Churchill (1874-1965),
politician, statesman, writer, artist,
historian and Nobel Prize Laureate
in Literature, a man with a red face
who was considered one of the 20th
century’s greatest leaders. Known for
his sharp tongue, heavy smoking and
good drinking: Sir Winston Churchill’s
caustic linguistic witticisms, reddish
face topped with a long cigar, lon-
gevity and good-natured overweight
were epic. Many anecdotes about
him have been told, such as the time
when, while giving a speech in parlia-
ment, he saw a liberal congressman
moving to the bench of the Labor Par-
ty and stopped his speech to squeal:
“It’s the first time I see a rat actually
swimming out to join a sinking ship.”
Then, on his way out, an angry wom-
an, Lady Nancy Astor, approached
him and told Churchill in public: “If I
were your wife, I would put poison in
your coffee” and he replied: “And if I
were your husband, I would drink it.”42
FINAL CONSIDERATIONS
The high incidence of the red face
among the inhabitants of northern
Europe is widely known, and suggests
the existence of a genetic factor.
Therefore, it has been hypothesized
that an increase in the stress response
Fig. 1-10. Lithographed watercolors. Atlas Clínico de Dermatología. Olavide Fig. 1-12. Moulages from the Olavide Museum collection. Madrid, Spain. Con-
Museum collection. Madrid, Spain. Contribution of Luis Conde Salazar.30 tribution of Luis Conde Salazar.30

Fig. 1-11. Moulages from the Olavide Museum collection. Madrid, Spain. Con- Fig. 1-13. Moulages from the Olavide Museum collection. Madrid, Spain. Con-
tribution of Luis Conde Salazar.30 tribution of Luis Conde Salazar.30
9

Fig. 1-14. Black-and-white photo of a pa-
tient with rosacea. From van Haren Noman’s
book39
of the endoplasmic reticulum may be
involved in rosacea pathogenesis. This
would link the disease to a survival fac-
tor common among the Celtic people.
So the traditional phrase that rosacea
is “the curse of the Celts” could be
wrong; instead, it should be thought
of as a “blessing of the Celts,” since
the condition could represent an im-
provement of antimicrobial defenses,
especially during periods of deficient
ultraviolet radiation. This
view would disregard the
atavistic perception linking
rosacea to alcohol abuse
and other sins, which gen-
erate not only stigma from
society, but also a strong
wish among patients to
improve their appearance
and remove the feeling of
discouragement and fear of
flushing (erythrophobia).43
References
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2. Herane MI, Pique-
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afecciones relacionadas. 1a ed.
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Baillière, 1900.
16. Hebra F. Traité des maladies de la
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17. Kaposi M. Pathologie et traitement
des maladies de la peau. París. Mas-
son, 1891.
18. Darwin C. Expression of the emo-
tions, 1872. Quoted in: The Macmil-
lan book of proverbs, maxims, and
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19. Gibert CM. Traité pratique des mal-
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phique du front. In: Besnier E,
Fournier A, Teneson, Hallopeau,
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Rueff et Cie, 1897.
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Flushing is an unpleasant condition of
warmth possibly associated with tran-
sient redness of the skin. This can be
a feature of multiple dermatological
conditions with a differential diagnosis
that ranges from common and banal
to rare and life-threatening. In view of
the common presentation of flushing
with physiological changes and poten-
tial associations with various diseases,
this review provides insight into cur-
rent understanding and management.
We provide an update on the current
understanding of pathogenesis and a
pragmatic clinical approach to evalua-
tion and management of flushing.
DEFINITION
Flushing is an episodic sensation of
warmth or burning which may be as-
sociated with increased skin redness
particularly of the central face and
malar regions.1,2 It can also extend to
involve the neck, upper anterior chest,
ears and scalp. The predilection for
these sites likely reflects enhanced
cutaneous blood flow, superficial lo-
cation of vasculature and reactivity of
these vessels to autonomic control.
The sensation perceived by the pa-
tient may be a more sensitive indica-
tor of flushing as it may be the initial
physiological response to underlying
biological pathways prior to vasodi-
lation. While some authors include
a more continuous or constant phe-
nomenology,2 it is more typically de-
fined as transient and episodic.3,1
Chapter 2
Flushing: A
dermatological
approach to
diagnosis and
management
Jerry Tan, Mary Ann Robledo Prada(*)
EPIDEMIOLOGY
The overall prevalence of flushing is
unknown and depends on the under-
lying diagnosis. However, as emotional
blushing is common and hot flashes
(a form of flushing) are reported in al-
most 75% of postmenopausal women,4
we infer that flushing is very common.
PSYCHOSOCIAL IMPACT
Socially, facial redness has a negative
connotation as it may be perceived
(*) Conflict declarations. Jerry Tan has been an advisor, consultant, speaker, and/or investigator for
Allergan, Bayer, Cipher, Galderma, Pierre Fabre, Roche, and Valeant. Mary Ann Robledo Prada
declares no conflicts of interest. Funding None.
12
by others as embarrassment, shame,
anger or excessive alcohol inges-
tion. Indeed, subjects with severe
rosacea are anxious about the social
consequences of blushing and flush-
ing–leading them to avoid situations
where they may undergo scrutiny.5
People in general tend to perceive
those with facial redness to have
negative personality traits and poor
health. Therefore, those with facial
redness from rosacea or other caus-
es of flushing encounter bias due to
the negative impressions of those
around them.6 Those with rosacea fre-
quently report feelings of stigmatiza-
tion, defined as a discrediting feature
eliciting disapproval from others. An
online survey conducted in the Unit-
ed Kingdom, France, Germany and
United States of people with rosacea
demonstrated that 1/3 reported feel-
ings of stigmatization. This group had
higher depression rates (36.7% vs.
21.1%) and was more likely to avoid so-
cial situations (54.2% vs. 2.0%).7
EVALUATION MEASURES
Flushing severity requires assessment
of frequency, duration, site and extent
of involvement and intensity. A num-
ber of flushing scales have been de-
veloped in response to the undesired
side effect of flushing associated with
niacin, a pharmacological interven-
tion for hyperlipidemia. The flushing
assessment tool (FAST), has demon-
strated reliability, responsivity and
construct validity. Furthermore, a min-
imally important difference has been
determined for resultant scores. This
tool is based on an electronic patient
diary comprised of a 22-item self-ad-
ministered questionnaire.8 Another
severity instrument developed for
niacin induced flushing is an 11 item
self-administered patient electronic
diary termed the Flushing Symptom
Questionnaire*(FSQ). This instrument
has also been shown to have construct
and clinimetric validity. Of particular
interest for clinical practice, a single
question – “Overall, during the past
24 hours, how would you rate your
flushing symptoms (including redness,
warmth, tingling or itching of your
skin)?” - was found to be adequate
and appropriate for flushing severity,
obviating the need for the entire 11
items when used in this setting.9 These
instruments provide a template upon
which to develop a severity question-
naire for flushing in general and in de-
termining interventional efficacy.
PATOGENIA
PATHOGENESIS
The pathophysiological mechanisms
in rosacea that result in the symptom
of redness or “flushing” have not yet
been fully elucidated. Several hypoth-
eses and different mechanisms have
been proposed, but there is not a
definitive answer. Possibly more than
one factor or, perhaps, a group of fa-
tors could trigger this symptom exhib-
ited by certain patients with rosacea.
Brinnel et al. found that the tempera-
ture of the forehead in patients with
rosacea was higher when compared
with subjects from the control group.
These researchers demonstrated that
the flow of venous blood from the skin
to the brain seems to be suppressed
in patients with rosacea in states of hy-
perthermia, and that this suppression
inhibited selective cooling of the brain
under hyperthermic conditions.10
Some authors have proposed neu-
rological mechanisms within the sym-
pathetic autonomic nervous system
as causative for episodes of redness
in rosacea. The sympathetic nervous
system controls many involuntary
functions in animals and in humans;
thus, it is theorized that stress (partic-
ularly when experienced along with
changes in body and environmental
temperature or in addition to ultravi-
olet light) could trigger redness epi-
sodes. However, other factors such
as alcohol consumption, some spices
and certain types of food also seem
to be involved (2,3).11,12 Metzler-Wilson
et al. conducted a comparative study
of 20 patients with rosacea and 20
controls, and showed hyperactivity
of sympathetic function in those with
rosacea. Sympathetic function and
temperature were assessed while
subjects performed mathematical
tests and physical exercises; at the
same time, the activity of the supra-
orbital nerve and blood pressure
were observed. Rosacea subjects had
more sweating and supra orbital mi-
cro neurography vs controls but had
comparable blood pressure and tem-
perature values.13
Rosacea has been described as a
chronic inflammatory dermatological
disease, although more recently it
has been defined as an inflammatory
systemic syndrome because it is asso-
ciated with other comorbidities, with
13
genetic, immunological, and neuroim-
munological mechanisms.14
Kendall associates a patient with a
disorder in the decrease of intestinal
transit and the interaction of intes-
tinal bacteria with the activation of
the “quinine-kallikrein” system, which
would act on the hypersensitivity of
afferent facial neurons through bra-
dykinin.15 However, further studies
would be necessary to confirm this
observation.
Additionally, an increase of 21.1%
to 53.5% in antinuclear antibody ti-
ters above 1: 160 has been reported
in two series of rosacea patients.16,17
The authors of the second study fol-
lowed patients who had titers equal
to or greater than 1: 640, and none
of them developed lupus over the
2-year follow-up period.17 Possibly
these titers could be associated with
the photodamage that is present in
many patients with rosacea; the ti-
ters also could potentially influence
the presence of telangiectasias, va-
sodilation and redness of the skin,
but the presence of high titers of
antinuclear antibodies (ANA) would
not explain the flushing episodes.
In this type of patients, follow-up
should be carried out for a longer
period of time and other histologi-
cal and immunological studies must
be performed to rule out the diag-
nosis of lupus.
In an investigation of 45 patients
with rosacea and 100 healthy controls,
Yazci described the presence of a ge-
netic polymorphism in the glutathione
S-transferase gene, a genetic mod-
ification associated with high levels
in the production of reactive oxygen
species (ROS).18 This allowed Baz et al.
to propose a hypothesis based on the
presence of a coinfection with Heli-
cobacter pylori, a microorganism that
would decrease antioxidant activity
but maintain high oxidative levels of
ROS, as well as vasodilation, which in
turn would result in increased blood
flow seen in patients with rosacea.19
The association of rosacea in peo-
ple with infestation by Demodex fol-
liculorum and Demodex brevis mites
(greater than that observed in con-
trols), has been shown in a meta-anal-
ysis carried out by Zhao et al.20
In 2015, Robledo and Orduz pub-
lished a hypothesis about the patho-
physiology of flushing in rosacea
based on the association of Demo-
dex infestation and coinfection of H.
pylori in patients with rosacea.21 This
was based on several premises as in-
dicated in Fig. 2-1. For this purpose,
it should be remembered that there
is a flushing syndrome in Asians who
suffer from a congenital deficiency of
the enzyme acetaldehyde dehydro-
genase 2 (ALDH2)22 and whose symp-
toms are similar to those of patients
with rosacea. Rosacea is associated
with Demodex infestation, which - in
turn - have Bacillus oleronius in the
intestine.23 O’Reilly and colleagues
found that 80% of patients with ro-
sacea had antibodies against a 62
KD protein of that bacillus, whose
sequencing was identical to that of a
thermal shock protein (HSP) called the
human Groper Chaperona.24 The Gro
Chaperone protein acts in humans
by helping to assemble the enzyme
ALDH2 which is directed to the mito-
chondria to metabolize acetaldehyde.
Hypothetically, antibodies against the
GroEl chaperone protein from B. ole-
ronius could cross-react against the
human protein GroEl chaperone, to
block the normal assembly of ALDH2
in the mitochondria.. Acetaldehyde
is a potent vasodilator, and it can be
produced by H. pylori by metabolizing
ethanol and carbohydrates from the
diet.25 If the enzyme ALDH2 cannot
be assembled due to the blockage
of antibodies against human GroEl
chaperone, the acetaldehyde would
spend more time in the circulation be-
fore being metabolized in the liver by
the PYP2E1 protein (P450) resulting
in “flushing” following the same mech-
anism in Asians with the congenital
defect of the same enzyme.22,26 It has
been demonstrated in an experimen-
tal model (embryonated eggs) that
the repeated supply of acetaldehyde
can induce angiogenesis through the
production of endothelial growth hor-
Demodex mites are increased in patients with rosacea
Bacillus oleronius is an endosymbiotic bacterium of the Demodex
B. oleronius has a 62 KDa GroEl Chaperonin thermal shock protein
Antibodies against the GroEl Chaperone protein of B. oleronius
(80% of patients with rosacea)
GroEl Chaperonine antibodies block the normal folding of ALDH2
ALDH2 is not able to assemble in the mitochondria
NAD+ NAH+ H
H. pylori = Ethanol ® ADH ÝAcetaldehyde ALDH2 ß Acetato
NADPH NADP H+
Ý Acetaldehyde in blood ®
Liver CYP2E1 (p450)
Acute increase of Acetaldehyde = erythema and vasodailation = Flushing
Increase of Acetaldehyde chronically = (VEGF) ÝAngiogenesis = Telangiectasia
Fig. 2-1. Mechanisms of the etiopathogenesis of “flushing” in rosacea demod-
icidosis
14
mone (VEGF).27 The above hypothesis
could be tested by means of ELISA or
protein immunoblotting to determine
cross-reaction of antibodies against
GroEl chaperone and human chaper-
one proteins.
As mentioned at the beginning,
the true mechanisms on the occur-
rence of redness or “flushing” in
rosacea are not yet fully clarified. If
some of the hypotheses mentioned
in this review could be solved, it
would be possible to finally elucidate
a better understanding of the patho-
physiological mechanisms of redness
in rosacea.
CLINICAL EVALUATION
Clinical evaluation of flushing should
focus on characteristics of the epi-
sodes including associated features
and possible triggering factors, in-
gested substances and medications
(including vitamins and “health food”
supplements), concomitant prior dis-
eases and family history. Associat-
ed clinical features to be specifically
queried include change in skin color,
sweating, urticarial or angioedema, re-
spiratory symptoms such as wheezing
and shortness of breath, tachycardia,
vascular compromise such as hypo- or
hypertension including anaphylaxis
or anaphylactoid reactions, abdominal
pain or diarrhea, and somatic features
including embarrassment, anxiety, and
impending sense of doom.
 In some conditions, specific ma-
neuvers may be helpful in diagnosis.
In mastocytosis, stroking of suspect-
ed lesions may lead to a wheal and
flare reaction (Darier’s sign). In ret-
rosternal goiter or mediastinal mass,
bilateral elevation of arms results
in facial plethora indicating jugular
vein compression (Pemberton’s sign).
Maintaining a flare diary to document
trigger factors, frequency and dura-
tion of episodes, and associated clin-
ical features should be considered.
Photographs for imaging of such ep-
isodes can also be of value in specific
flushing features including intensity,
coloration of cutaneous changes and
location of involvement.
Physical exam should focus on as-
pects relevant to the acuteness of
the presentation. Particular attention
should focus on dermatological, thy-
roid, respiratory and abdominal exam-
inations.
ETIOLOGIES
Potential underlying causes range
from benign and common disorders to
rare conditions with potential for sig-
nificant morbidity. The most common
are emotional or idiopathic and climac-
teric. Other potential causes of flush-
ing include rosacea, ingestants (drugs
and ingested toxins), and internal dis-
eases (thyrotoxicosis, carcinoid, masto-
cytosis, pheochromocytoma, medullary
carcinoma of thyroid, renal or pancre-
atic carcinoma). Potential triggering
ingestants include alcohol, scombroid
fish toxin and monosodium glutamate
or sulfites in food products. Drugs
implicated in flushing include vasodi-
lators (e.g. nitrates, calcium channel
inhibitors, angiotensin converting en-
zyme inhibitors), phosphodiesterase
inhibitors (medications to treat erectile
dysfunction), nicotinic acid, disulfiram,
opiates, cyclosporine, chlorpropamide,
and prostaglandins. The clinical imper-
ative is in separation of benign from
potentially life-threatening conditions
associated with flushing by appropri-
ate evaluation and subsequent therapy
Benign cutaneous flushing
This describes flushing associated
with warmth triggered by emotion,
exercise, temperature changes, and
certain foods and beverages. Women
are more frequently affected. Emo-
tional or alcohol induced flushing are
straightforward diagnoses when the
symptoms develop within the con-
text of emotional situations or alcohol
ingestion.2 Certain foods and bev-
erages may contain factors that can
trigger flushing such as tyramine, his-
tamine, higher chain alcohols, mono-
sodium glutamate, aldehyde, nitrites,
and sulfites. Spicy foods containing
capsaicin, may also provoke flushing.1
Benign cutaneous flushing is oth-
erwise a diagnosis of exclusion and
patients should be periodically reas-
sessed to evaluate for development
15
of other symptoms suggestive of sys-
temic etiologies.
Perimenopausal hot flashes
Hot flashes and hot flushes are used
synonymously in the gynecological
literature and are characterized by
sudden onset of heat, sweating, and
flushing of face and chest. This can
often be accompanied by palpitations
and anxiety. They are considered the
cardinal symptom of menopause and
are the most bothersome symptom of
this condition for most women.28 They
occur in up to 85% of postmenopaus-
al women (50%–85%).29 The cause of
hot flashes is not well understood but
is likely due to declining estrogen lev-
els and change in neurotransmitters
occurring during menopausal transi-
tion, leading to narrowing of the ther-
moneutral zone. This narrowing leads
to internal sensation of heat and cold
at otherwise inappropriate periods.30
Rosacea
Flushing, previously considered a car-
dinal diagnostic feature of rosacea31 is
no longer considered independently
diagnostic.32 This is supported by evi-
dence from an observational study of
135 rosacea subjects from Germany
where the diagnosis was established
by a dermatologist from clinical fea-
tures. In that cohort, facial flushing
was reported by 66% with highest
frequency in those with background
facial erythema, and less in those
with papules or pustules (56%) and
phymas (48%). Median frequency of
flushing was 3 times per week with
a median duration of almost 20 min-
utes. Most frequently affected re-
gions were cheeks (100%), followed
by nose (38%), neck (31%), and other
facial sites. Involvement of the neck
and chest was reported by one quar-
ter. Intensity of redness during flush-
ing was self-reported as mild in 6%,
moderate in 40% and intense in 53%.
Common associations with flushing
were sensation of heat (97%), ten-
sion (36%), and burning (25%) and
sweating was reported by 30%. The
most frequently reported triggers for
flushing were emotions (76%), alcohol
(67%), heat (60%), spicy food (54%),
cold temperatures and/or cold wind
(52%) and sun (52%).33 Current under-
standing of the pathophysiology and
management of rosacea is detailed
elsewhere in this publication.
Mast cell disorders
Mast cell disorders, comprising
mastocytosis and mast cell activa-
tion syndromes (MCAS), result from
proliferation and accumulation of ge-
netically abnormal mast cells or the
inappropriate release of mast cell
mediators, respectively, and creating
symptoms in multiple organ systems.
Mastocytosis
In mastocytosis, there is a clonal ex-
pansion of mast cells with activating
KIT mutations. In humans, the mast/
stem cell growth factor receptor (SC-
GFR) is encoded by the KIT gene.34
This condition is characterized by
proliferation of abnormal mast cells
in various organs including skin, lym-
phoreticular tissue and bone mar-
row. This can lead to a diversity of
symptoms including flushing, itching,
abdominal pain with diarrhea and
severe anaphylaxis. There are 7 sub-
types: cutaneous mastocytosis, indo-
lent systemic mastocytosis, systemic
mastocytosis with an associated (clon-
al) hematologic non-mast-cell disease
(SM-AHNMD), aggressive system-
ic mastocytosis, mast cell leukemia,
mast cell sarcoma and extracutane-
ous mastocytoma.35
Mast cell activation syndrome
(MCAS)
This is a recently proposed condition
presenting as a complex of mast cell
mediator-induced symptoms, failure
to meet the WHO criteria for diag-
nosis of systemic mastocytosis, and
exclusion of relevant differential diag-
noses (such as allergy and neuroendo-
crine tumor).36 Proposed diagnostic
criteria for MCAS include episodic
symptoms consistent with mast cell
mediator release affecting two or
more organ systems (examples in-
clude urticaria, angioedema, flushing,
nausea, vomiting, diarrhea, abdominal
cramping, hypotensive syncope or
near syncope, tachycardia, wheez-
ing, conjunctival injection, pruritus,
and nasal stuffiness). In a prospective
study of 18 patients - most common
symptoms were episodic abdominal
pain in 94%, dermatographism in 89%
and flushing in 89% with 72% having
all 3. Additionally, they also reported
headache, diarrhea, and difficulties
with memory and concentration.37 A
larger study of 413 patients demon-
strated that the majority were white
females with young median age at
symptom onset (9 years) and delayed
diagnosis (age 49 years) with median
time from symptoms to diagnosis be-
ing 30 years.38 Supportive laboratory
evidence includes increased serum
markers (tryptase, histamine metab-
olites, heparin, prostaglandin D2, his-
tamine and chromogranin A) above
baseline value during symptomatic
episodes on more than two occasions,
or baseline serum tryptase levels that
are persistently elevated.39
Neuroendocrine tumors
Neuroendocrine causes of flushing in-
clude carcinoid syndrome, pheochro-
mocytoma, medullary thyroid cancer,
and pancreatic neuroendocrine tu-
mors.
Carcinoid tumors
These are gut endocrine tumors ac-
counting for up to 1/3 of all tumors of
the small bowel. Peak incidence is in
the 6-7th decades although children
may also be affected.40 They are de-
16
rived from primitive stem cells and
are typically found in the gut wall
but can also involve other visceral or-
gans. A practical classification based
on embryonic derivation of the gut
includes the following: foregut in-
cludes tumors arising in lungs, stom-
ach, liver, biliary tract, pancreas, and
first portion of the duodenum; midgut
includes the mid and distal duode-
num, small intestine, appendix, right
colon, and proximal transverse co-
lon; while hindgut includes the distal
transverse colon, the left colon, and
the rectum.40 Carcinoid syndrome is
the association of flushing, secretory
diarrhea, sweating, abdominal pain,
and bronchospasm with carcinoid tu-
mors, the most common of endocrine
gut tumors. However, this syndrome
is only observed in less than 10% of
those with carcinoid tumors. Inci-
dence of these tumors is estimated
at 1.5 per 100,000 cases. While it can
affect all ages, peak incidence is in the
sixties and seventies. These tumors
derive from primitive stem cells of the
gut but may occasionally also involve
the pancreas, ovary and lung. They
may be episodically symptomatic and
may be undiagnosed for years until
presenting clinically with carcinoid
syndrome features. Flushing with car-
cinoid may be provoked by alcohol
and tyramine-rich food such as blue
cheese, chocolate, sausage, and red
wine. The features of flushing vary
with location of the carcinoid tumor.
With foregut carcinoids, flushing is in-
tense, of longer duration, affects face,
upper trunk and possibly the upper
limbs; may impart a purple discolor-
ation and have long term sequelae
such as telangiectases, acrocyanosis
and skin thickening leading to a leo-
nine facial appearance. In contrast,
midgut carcinoid flushing is faint pink
and involves face and upper trunk and
short in duration (a few minutes) with-
out residual permanent discoloration.
Flushing in carcinoid syndrome has
been ascribed to multiple potential
mediators including prostaglandins,
kinins, serotonin (5-HT), dopamine,
histamine, 5-hydroxyindoleacetic
acid, kallikrein, substance P, neuroten-
sin, motilin, SRIF, VIP, neuropeptide K,
and gastrin-releasing peptide.
Pheochromocytoma
Flushing may accompany the neuroen-
docrine tumors, pheochromocytoma
and paraganglioma (PPGL). These rare
tumors derive from neuroendocrine
chromaffin cells which produce cate-
cholamines in the adrenal glands and
autonomic neural ganglia, respective-
ly. The estimated prevalence is 1:6500
and 1:2500, respectively, and they may
account for 0.05% to 0.1% of those with
sustained hypertension. However, half
of the patients with these tumors have
paroxysmal hypertension or normoten-
sion.41 Pheochromocytomas typically
produce catecholamines (epinephrine,
norepinephrine, and dopamine) and
can lead to secondary diabetes mel-
litus or hypertension. Hypertension,
sustained or paroxysmal, is the most
frequent finding. A typical episode
features headaches, diaphoresis, pal-
pitations, and possible flushing.31 Vaso-
active catecholamines are thought to
induce thermal vasodilation leading to
flushing. Other potential flushing me-
diators include calcitonin gene-related
peptide, vasoactive intestinal polypep-
tide (VIP), and adrenomedullin, a po-
tent vasodilatory peptide with potent
cutaneous vasodilatory effects.42,31 Cat-
echolamines are metabolized within
chromaffin cells to metanephrines and
diagnosis is established by plasma me-
tanephrines or 24-h urinary metaneph-
rines.43 Fractionated metanephrines
are more sensitive and specific com-
pared to their parent catecholamines
(norepinephrine/normetanephrine and
epinephrine/metanephrine, respective-
ly).41 Subsequent management includes
imaging for localization and surgery.
Medullary thyroid cancer
Medullary thyroid cancer (MTC) is a
parafollicular C cell, neural crest-de-
rived, malignant tumor. A spectrum of
biologically active substances may be
secreted that can cause flushing and
sweating including adrenocortico-
tropic hormone (ACTH), corticotro-
pin-releasing hormone, calcitonin,
histamine, ketacalcin, levodopa, pros-
taglandins and substance P. Caused
by mutations in the RET proto-onco-
gene, MTC may be sporadic or au-
tosomal dominantly inherited as part
of multiple endocrine neoplasia (ME-
N2A and MEN2B) or familial MTC. In
symptomatic patients, diarrhea is the
most prominent feature while flush-
ing of the face and upper extremities
is seen less frequently.44 Diagnosis is
based on needle aspirate from a thy-
roid nodule with supportive evidence
from elevated serum calcitonin and
Carcinoembryonic antigen (CEA) lev-
els. Thyroidectomy and nodal dissec-
tion is the treatment of choice.
Pancreatic neuroendocrine tumors
Flushing can accompany pancreatic
neuroendocrine tumors (PNETs) and
present with itchy red-brown macules
and patches with annular and arci-
form patterns in a widespread distri-
bution. Chronic flushing with PNETs
may result in cutaneous thickening
with telangiectasia and bluish discol-
oration of the central face. PNETs are
neuroendocrine neoplasms derived
from pancreatic pluripotent cells.45,46
While prevalence ranges from 1- 10%
on autopsy, the majority are asymp-
tomatic.47 Symptoms in affected pa-
tients derive from effects of ACTH
(adrenocorticotropic hormone), cal-
citonin, growth hormone releasing
factor (GnRF), insulin, gastrin, gastric
inhibitory polypeptide, glucagon, me-
lanocyte stimulating hormone, neu-
rotensin, parathyroid hormone related
peptide, pancreatic polypeptide, pros-
17
taglandin, somatostatin and vasoactive
intestinal peptide (VIP). Subtypes with
flushing as a prominent feature include
neurotensinomas (manifest with hy-
potension, hypokalemia, weight loss,
flushing, and hyperglycemia), calci-
toninomas (watery diarrhea and facial
flushing), malignant gastrinomas which
are usually typically located at the head
of the pancreas; insulinomas (flushing
during hypoglycemic episodes), and
glucagonomas (hyperglycemia and a
characteristic necrolytic migratory ery-
thema).31 Diagnosis will require demon-
stration of elevated relevant hormones
and peptides and localization will re-
quire specialized imaging.
Miscellaneous
Scombroid poisoning is due to con-
version of free histidine to histamine
during storage of fish of the Scomb-
ridae and Scomberesocidae families -
including tuna, bonito and mackerel.48
These chemicals may have a metallic
flavor and cooking may not adequately
inactivate the toxins. Symptoms usu-
ally develop rapidly - within minutes
after ingestion of affected fish and can
include oral burning/tingling, skin rash,
hypotension, headache and flushing.
These usually resolve within 24 hours.49
Geographical patterning of facial
flushing and erythema has been re-
ported in 2 Japanese boys aged 8
years. They presented with episodic
geographical facial erythema occa-
sionally associated with headache but
without underlying systemic disease.
Episodes were triggered by exercise
and were limited in duration to 30
minutes.50
Frey’s syndrome (auriculotemporal
syndrome) presents with unilateral
flushing due to parasympathetic auric-
ulotemporal nerve fibre injury (such as
with parotidectomy, birth or other trau-
ma, infection, and parotid tumours).
Subsequent aberrant neural regenera-
tion results in stimulation of the facial
sweat glands and cutaneous blood
vessels instead of the parotid gland.
The consequence is unilateral facial
erythema and sweating provoked by
gustatory stimuli.51 Typically, treat-
ment for unilateral Frey’s syndrome is
not required as spontaneous remis-
sion occurs within 2–5 years among
non-postoperative cases. However,
in recalcitrant or severe cases - man-
agement may include anticholinergics,
topical antiperspirants, botulinum tox-
in injection, or surgery. Bilateral Frey’s
syndrome is rare and typically due to
congenital malformation.52
MANAGEMENT
Management of flushing requires de-
termination of the underlying etiology
as subsequent therapy can then be
more specifically directed at cause if
one exists. For recurrent episodes of
flushing associated with systemic fea-
tures, appropriate lab testing to eval-
uate for underlying systemic disease
should be conducted. These tests will
be guided by the attendant clinical
features. In this regard, a clinical di-
agnostic approach is important and is
outlined below:
1. Is there an obvious clinical etiology?
A. Emotional blushing or flushing
B. Perimenopausal hot flashes
C. Rosacea
2. Is there a history of ingestants
or medications that can trigger
flushing?
A. If so, exclude these agents if possible
B. If not, are there associated symp-
toms?
i. Cutaneous
1. Urticarial - Consider mast
cell activation syndromes,
and mastocytosis
2. Pallor - Consider pheochromo-
cytomaurticaria, angioedema,
flushing, nausea, vomiting, di-
arrhea, abdominal cramping,
hypotensive syncope or near
syncope, tachycardia, wheez-
ing, conjunctival injection, pru-
ritus, and nasal stuffiness)
3. Persistent centrofacial ery-
thema - Rosacea
4. Phyma - Rosacea
5. Purple discoloration with flush-
ing and telangiectases, acro-
cyanosis, skin thickening with
leonine facies - Foregut carci-
noids
6. Central facial cutaneous
thickening, telangiectasia
and bluish discoloration -
Pancreatic neuroendocrine
tumors
7. Annular erythema
a. Necrolytic migratory ery-
thema - Pancreatic neuroen-
docrine tumors specifically
glucagonomas
b. In pediatric age group -
Geographical flushing of
children
8. Other
a. Oral burning/tingling
dysesthesia-Scombroid
poisoning
b. Itching - Mastocytosis; Mast
cell activation syndrome
c. Conjunctival injection -
Mastocytosis; Mast cell ac-
tivation syndrome
18
d. Nasal congestion - Masto-
cytosis; Mast cell activa-
tion syndrome
e. Sense of heat - Perimeno-
pausal hot flashes
ii. Respiratory
1. Wheezing - Carcinoid syn-
drome; Mastocytosis; Mast
cell activation syndrome
iii. Cardiovascular
1. Hypotension - Pancreat-
ic neuroendocrine tumors
specifically neurotensinomas
manifest with hypotension,
hypokalemia, weight loss,
flushing, and hyperglycemia;
Mastocytosis; Mast cell acti-
vation syndrome
2. Hypertension - Pheochromo-
cytomas
3. Palpitations - Pheochromo-
cytomas; Mastocytosis; Mast
cell activation syndrome;
Perimenopausal hot flashes
iv. Endocrinologic
1. Hypoglycemia - Pancreatic
neuroendocrine tumors spe-
cifically insulinomas (flushing
during hypoglycemic episodes),
2. Hyperglycemia - Pancreatic
neuroendocrine tumors specif-
ically glucagonomas (hyper-
glycemia and a characteristic
necrolytic migratory erythe-
ma); and neurotensinomas
manifest with hypotension,
hypokalemia, weight loss,
flushing, and hyperglycemia;
pheochromocytomas.
v. Neuropsychiatric
1. Unilateral facial flushing -
Frey’s syndrome
2. Headaches - Pheochromocy-
tomas
3. Anxiety - Perimenopausal hot
flashes; Benign cutaneous
flushing
4. Emotional trigger - Benign
cutaneous flushing
vi. Gastrointestinal
1. Diarrhea - Pancreatic neuro-
endocrine tumors specifically
calcitoninomas; Medullary
thyroid cancer; Carcinoid syn-
drome; Mastocytosis; Mast
cell activation syndrome
2. Abdominal pain - Carcinoid
syndrome; Mastocytosis; Mast
cell activation syndrome
 vii.Other
1. Sweating - Perimenopausal
hot flashes; Medullary thy-
roid cancer; Pheochromocy-
tomas; Carcinoid syndrome
2. Anaphylaxis, Angioedema -
Mastocytosis; Mast cell acti-
vation syndrome
3. Nausea/vomiting - Mast cell
activation syndrome
Laboratory investigations
Further laboratory testing may be
particularly appropriate in patients
presenting with associated system-
ic features. Testing depends on the
potential differential diagnosis as
derived from the clinical assessment
outlined above. For example, 24 hour
urinary collections are of value in var-
ious internal conditions associated
with flushing: carcinoid syndrome - 5
hydroxyindoleacetic acid; pheochro-
mocytoma – catecholamines and frac-
tionated metanephrines; mastocytosis
– methylhistamine and prostaglandin
D2. In the latter condition, serum trypt-
ase is also useful. For medullary carci-
noma of the thyroid, consider serum
calcitonin levels.
TREATMENT
Whether flushing should be treated
will depend on how much the condi-
tion adversely impacts the patient. In
view of the multiple pathogenic fac-
tors involved in flushing, there is no
singular effective therapy for all types
of flushing. However, some general
principles may be worth considering.
1. Abrogation of flushing from mul-
tiple causes may be attempted by
simple measures such as sucking on
ice chips to cool facial arterial inflow
or application of cool water spritzes
to the face and neck to facilitate fa-
cial skin cooling by convection.
2. Behavioral feedback or beta-block-
ers may be useful if flushing is
associated with a significant emo-
tional component or if it leads to
increased anxiety.
3. Intracutaneous injection of botu-
linum toxin has been reported to
be effective in treatment of facial
flushing. This effect is likely due to
inhibition of neurovascular signal-
ing pathways mediated by acetyl-
choline.53-55
4. For flushing associated with sweat-
ing indicating autonomic neural acti-
vation, such as with perimenopausal
hot flashes - these may respond to
clonidine, selective serotonin and
norepinephrine reuptake inhibitors
as well as hormone replacement
therapy.56,57 If associated with itch
or urticaria, oral antihistamines may
be useful.
19
5. For flushing associated with rosa-
cea, two open label studies demon-
strated that the oral beta blocker
propranolol was effective at 20-40
mg daily.58,59 Carvedilol, a nonse-
lective a-adrenergic antagonist
with a1-antagonist selectivity, was
shown effective in a case of refrac-
tory rosacea-associated flushing.60
6. For nicotinic acid-induced flushing,
mediated by prostaglandin activa-
tion, ingestion aspirin may be help-
ful to reduce flushing.61
7. In neuroendocrine tumors, man-
agement is focused on tumor
removal where possible. Use of
medical therapy, however, may be
required in nonresectable lesions.
Depending on the specific bioac-
tive agents involved in flushing with
these tumors, treatments may in-
clude somatostatin analogues such
as octreotide and lanreotide which
can abrogate flushing in addition to
other associated symptoms.62
8. Urgent management is man-
dated for those with flushing pre-
senting with anaphylaxis, loss of
consciousness or cardiorespiratory
distress. Where appropriate, emer-
gency maneuvers are mandated
including vital signs monitoring, par-
enteral epinephrine, and appropri-
ate cardiorespiratory maintenance
including protection of airways.
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Redness on the cheeks could be
considered an ambivalent condition,
because it is often seen as a feature
identified with good health,1 particu-
larly in pale phototypes and usually
among women living in areas with
low oxygen tension, or as a normal
hyperemic response to different
causes, such as simple sun exposure,
consumption of spicy foods or al-
cohol, high temperature or fever. It
also appears as a result of increased
intra-abdominal pressure in a forced
Valsalva’s maneuver.2 This “physiolog-
ical” redness has no other symptoms,
is not limited to a particular area, and
does not have a defined pattern. This
redness is rather homogeneous and
center-facial, with extension to the
periphery of the cheeks up to, and
including, the back of the pinnas. Its
color is a low intensity shade of pink;
however, the people visiting the doc-
tor because of facial redness, with or
without the feeling of heat or sting-
ing do so because they have noticed
something that is not normal, and
have identified a problem: a dermato-
sis that is surely an important problem
that deserves action.3
PATHOGENESIS
The mechanisms that trigger facial
redness are heterogeneous and de-
pendent on the underlying cause.
Different mediators have been sug-
gested.3 Physiological facial redness
is mainly mediated by the sympa-
Chapter 3
Differential
Diagnosis of Red
Faces
Jorge Moreno González, Daniela Castrejón Pérez
thetic autonomic nervous system via
epinephrine. In contrast, the patho-
genic pathway for rosacea includes
stimulation of sensory nerve recep-
tors, through a variety of neuropep-
tides and inflammatory cytokines
(pituitary adenylate cyclase-activat-
ing polypeptide, vasoactive intestinal
peptide, tyramine, histamine, sulfites,
nitrates, metabolic alcohol products,
5-hydroxytryptamine, substance P,
prostaglandins, epinephrines and
cathelicidins), as well as inflammato-
ry mediators such as oxygen reactive
species and proteases.4,5 Chronic use
of adrenal steroids causes the over-
production of nitric oxide (NO) in the
23
vascular endothelium; when released,
NO acts as a relaxing factor, produc-
ing vascular dilation. This vascular
dilation is inhibited by adrenal ste-
roids, which cause vasoconstriction
and, consequently, the accumulation
of different metabolites to counter
this effect, including nitric oxide. As
exposure to adrenal steroid contin-
ues, tachyphylaxis appears, i.e. the
vasoconstrictive effect of the drug is
lost and the blood vessel dilates and
exceeds its original diameter due to
the accumulation of NO. This in turn
exacerbates erythema, heat and itch-
ing when the adrenal steroid is with-
drawn, driving the patient to use it
again in an attempt to relieve symp-
toms. Consequently, an addiction to
steroids can develop over a period
of two to four months of use and may
persist for up to 30 months after dis-
continuing the adrenal steroid.6
RED FACE SYNDROME
The red face is treated as a syndrome
in few textbooks because for most
researchers facial erythema is just a
sign that occurs with different disease
states with diverse etiology. These
disorders can be divided into three
groups, according to their frequency:
the most common, those less com-
mon, and the rare or uncommon (Ta-
bles 3-1 and 3-2), with red face being
either a primary symptom, isolated, or
part of a symptom complex.
Thus differential diagnosis of red
face can be challenging7 and correct
diagnosis requires perseverance, pa-
tience and a detailed clinical history.8
Diagnosis is primarily based on to-
pography and morphology, as well as
the mode of onset and associated sys-
temic symptoms. Proper diagnosis is
critical, because it enable the clinician
to establish appropriate treatment
and hygienic measures.”
The most common diseases that in-
volve facial redness are atopic eczema,
seborrheic dermatitis, rosacea, con-
tact dermatitis, lupus erythematosus
and phototoxicity or photosensitivity
Table 3-1. Differential Diagnose (Most Frequent Entites)

Transient Persistent
Entities Erythema Erythema Clinical Data Keys to Diagnosis

Rosacea + + Occurrence > 1: transient or persistent erythema, papules or pustules, Clinical diagnosis, :absence of blackheads and infundibular cysts,
telangiectases different from acne.
Other: stinging or itching, peripheral erythema, xerosis, edema, phymatous Keep biopsy in case of suspicion of other diagnoses
changes, ocular manifestations..

Seborrheic + Onset in puberty or adolescence. Clinical Diagnosis:

Dermatitis It can affect the scalp, eyebrows, the retroauricular region and the trunk. It improves in summer and worsens in winter, whereas rosacea improves
may coexist with rosacea (Dessinioti, 2017).. in winter and worsens in summer.
In addition, seborrheic dermatitis presents with yellowish scales and
different topography (Dessinioti, 2017).

Contact Dermatitis + On occasions, the triggering agent is not obvious. Patch and photo patch tests (Dessinioti, 2017).
In cases of irritant contact dermatitis, look for a history of use of soaps
with alkaline pH or products containing retinol, lactic acid or glycolic acid
(Dessinioti, 2017)..

Chronic use of + Erythema, telangiectases and papules. History of steroid use for dermatosis such as seborrheic dermatitis,
topical steroid (red May appear during use or when discontinued, even for several months. cosmetic irritation, melasma, acne, dry skin (Dessinioti, 2017)..
face syndrome).

Phototoxicity + It appears some hours after sun exposure. Medical history Most frequent causes of photoxic reactions are: amiodarone,
On the face, it affects upper eyelids, submental region and folds. It affects quinidine, furosemide, thiazide diuretics, naproxen, piroxicam, chlorpromazine,
other photo-exposed areas. ciprofloxacin, sulfonamides, sulphonylureas, coal tar, doxycycline, psoralenes..
There is erythema with itching and, in severe cases, blisters with stinging
sensation.

24
Table 3-2. Differential Diagnose (Less common entities)

Transient Persistent
Entities Erythema Erythema Clinical Data Keys to Diagnosis

Demodicidosis + Erythema, fine follicular scaling on face, eyelids, auricular region and neck. Direct cyanoacrylate test: 5 > Demodex/cm2 (Dessinioti, 2017).
Sandpaper appearance (Dessinioti, 2017).

Psoriasis + It most frequently affects the forehead and peri-auricular region, but may also It is considered a severity marker.
affect the centralfacial region, pinnas and eyelids. Look for comorbidities: fasting serum glucose, 2 times blood pressure
It affects the scalp in almost all patients (Park, 2014) (Woo, 2008).. reading, lipid profile, transaminases, body mass index and abdominal
perimeter (Park, 2014) (Woo, 2008) (Boehncke, 2015).

Lupus + Oral mucous erythema, with scaling and even facial edema, is triggered by sun Pathological study of skin, with direct immunofluorescence. Initially
erythematosus exposure and heals without leaving scars. request: BHC, PCR, VSG, liver enzymes, creatinine and serum urea,
Oral or nasal mucosal ulcers.. general urine examination.
Immunological studies: ANA, anti-dsDNA, anti-Sm, anti-phospholipids,
complement (C3, C4, CH50).
American College of Rheumatology Criteria (Kuhn, 2014)

Menopause + Facial erythema appears in conjunction with a heat sensation Follicle-stimulating hormone (Dessinioti, 2017)..

Facial erysipelas + Erythematous plaque, shiny, well-defined, with perifollicular edema (orange peel Clinical diagnosis, sudden onset, fever and local temperature rise
appearance). (O’connor, 2009)..
In the face, it usually affects the malar region, and can produce a butterfly-wing
pattern (O’Connor, 2009)..

Ringworm + Erythematosquamous plate with a raised edge and a clear centre. Direct mycological examination with potassium hydroxide. Culture
of the face Atypical shape: diffuse condition (Welsh, 2014). (Welsh, 2014).

25
reactions. Less common causes among
adults include exanthematous viral in-
fections, erysipelas or facial cellulitis,
sarcoidosis (lupus pernio), dermatomy-
ositis and ulerytema ophryogenes.
Excessive use of topical steroids,
a frequent cause of facial erythema,
leads to telangiectases and acne-like
papular eruptions. These lesions pre-
dominantly appear in the perioral
area, so the condition is called peri-
oral dermatitis. These diseases are
clinically differentiated, and some can
be confirmed by laboratory tests (see
Tables 3-1 and 3-2).
The “red face syndrome” is both a
diagnostic and therapeutic chal-
lenge for the dermatologist, as this
syndrome is generally obscured or
veiled by the presence of chronic sun
damage, topical steroid use and an
atopic diathesis. It is suspected most-
ly among female patients when the
origin of the medical condition is not
very clear and, in general, they have
already undergone different treat-
ments with a temporary response
and frequent recurrences despite an
initially positive response. In addition
to facial redness, this group of pa-
tients have dry skin that is rough to
the touch and hyper-reactive to facial
cleansers, cosmetics, corticosteroids
and, in some cases, even to water.
Burning sensation may be reported,
and may be associated with periods
of exacerbation due to sun exposure,
infrared radiation from heaters or the
feeling of public embarrassment; the
burning sensation may extend to the
pinnas and neck.9
Rapaport used the term “red face syn-
drome” in the 1980s for cases related
to chronic use of and addiction to top-
ical steroids.10-12 It has been described
that this addiction starts with the use
of these drugs to manage problems
like dry skin, mild acne, ulerytema
ophryogenes, melasma, nonspecific
eyelid itching or seborrheic dermati-
tis.13 Erythema temporarily improves
but has a relapsing course, prompt-
ing sufferers to try application of a
new steroid. The affected area usual-
ly does not involve the nasal dorsum
and upper lip (a phenomenon known
as the headlight sign).14 After discon-
tinuing the steroid, the exacerbation
can lead to eyelid edema and bullous
cheeks, both associated with intense
erythema. Histological findings are
nonspecific: epidermal spongiosis and
atrophy, dilated vessels (telangiecta-
ses) in the mid and superficial dermis,
with mild interstitial and perivascular
lymphocytic infiltrates.15
In 1999, Griffiths16 used the term
“red face syndrome” after excluding
common facial erythema etiologies,
such as contact dermatitis, seborrheic
eczema and photodermatitis. Accord-
ing to the stage of the illness among
26
these patients, he divided them into
three groups: one characterized by
symptoms of intense erythema and
absence of burning or heat symp-
toms, which he called erytromelanosis
faciei,17 also known as Broq’s keratosis
pilaris rubra or ulerythema ophryo-
genes. If this intense vasomotor ery-
thema appears with marked sensitivity
and stinging sensation, he suggested
this characterized a second group,
which he labeled erythrodysesthesia.
The third group included symptoms
mixed with signs of androgenization,
such as melasma, acne, rosacea, seb-
orrheic eczema and hirsutism or the
suggested acronym MARSH.18 In this
case, acne-like papules typically ap-
pear in areas of androgenization.
Atopic Dermatitis
Atopic dermatitis (AD) is character-
ized by dry skin with alterations of
the skin barrier, hypersensitivity to
environmental factors such as exog-
enous proteins and irritant substanc-
es as well as an excessive immune
response.19 Although it is described
mostly in children, there are many
cases in adults. Individuals with AD
very frequently display facial derma-
tosis with redness and high-potency
topical steroids are often used as
treatment. These steroids can cause
addiction and worsen the disease
when used for a long period of time
(which happens in more than 80% of
cases). In atopic individuals, symp-
toms often begin on the eyelids (Fig.
3-1) and subsequently extend to the
whole face, with areas of lichenifica-
tion mainly in adults. Facial erythema
can also have an exudative appear-
ance, which may become fissures in
severe cases. AD patients typical-
ly have a history of rhinitis, asthma
and urticaria as well as keratinization
disorders, including keratosis pilaris
and ichthyosis vulgaris. Restoration
of the skin barrier is a cornerstone
of treatment for AD. A subgroup of
patients with recalcitrant facial er-
ythema develop photosensitivity to
ultraviolet radiation (most commonly
UVA) within two to three years after
the initial diagnosis of AD.20,21 Other
causes of AD exacerbation are irri-
tants, often in cosmetic products, or
colonization by either Staphylococ-
cus or Malassezia.22
Rosacea
Rosacea is a chronic facial dermatosis
characterized by increased skin sen-
sitivity and inflammatory response, in
addition to facial vasomotor dereg-
ulation. It is most frequently found
among women and individuals from
northwestern Europe. The most sig-
nificant clinical features are paroxys-
mal transient erythema, sometimes
associated with local heat, and per-
sistent erythema in the central-facial
area, with involvement of the fore-
head, glabella, nasal dorsum, cheeks
and chin, as well as papulopustular
Fig. 3-1. Palpebral dermatitis in atopic patient. Fig. 3-3. Demodicosis with mild facial erythema and skin rough to the touch.
On dermatoscopy, multiple whitish follicular projections, correspoding to De-
modex sp., can be observed.
A B
lesions and telangiectases. In a more
advanced stage, there is hyperplasia
of the connective tissue and seba-
ceous glands (phyma). Rosacea may
also occur in an ophthalmic form (Fig.
3-2) with compromise of the eyelids
and conjunctiva. Erythema can persist
even when treatment resolves papu-
lopustular lesions, and is worsened by
the intake of certain foods, changes
in weather conditions and the use of
steroids.
Demodicidosis
In patients with rosacea, Demodex (D.
folliculorum and D. brevis) has a high
Fig. 3-2. A. Erythematotelangiectatic rosacea and B. Papulopustular rosacea prevalence of up to 55%. In individuals
with palpebral disorder.. with high Fitzpatrick phototypes and
27
immunosuppression, this saprophytic
parasite can cause a pathology called
demodicisosis due to overpopulation
in the pilosebaceous unit. It appears
as a rosacea-like dermatosis, with ery-
thema, minute perifollicular scale and
sandpaper skin, rough to the touch.
Whitish follicular projections, blunt-
tipped, corresponding to Demodex
can be observed on dermoscopy (Fig.
3-3). Inflammatory response may oc-
casionally cause granulomas, which
may be pruritic.
In some cases, the inflammatory
response is quite mild, with little er-
ythema. There are even rare cases
presenting as an anergic form with
Demodex in each follicle, providing
an appearance of multiple spicules.
Superficial cyanoacrylate biopsy can
be used to make the diagnosis if more
than five Demodex per square centi-
meter are found.23
Seborrheic Dermatitis
Seborrheic dermatitis is a chronic dis-
ease. Its main etiological factors are
increased oil secretion and the pres-
ence of Malassezia spp. It is more
frequently found in men and is dis-
tinguished by its topography, as it af-
fects oily areas of the face, such as the
forehead, eyebrows, nose, pinnas, na-
solabial folds and labiomental groove.
It can affect the beard (Fig. 3-4), as
well as the scalp and, occasionally,
areas with hair from the chest or pu-
Fig. 3-4. Facial seborrheic dermatitis, with yellowish scales in the beard.
bis. Lesions are erythematosquamous
plaques; erythema is mild and the
scale is thin, yellowish and oily. It can
sometimes be extremely severe, so
much so that it resembles psoriasis or,
conversely, psoriasis can cause facial
erythema with little scaling, particu-
larly at the onset of an erythroderma
case.19
Contact Dermatitis
Up to 10% patients with contact der-
matitis have it located on the face.
Most of them are women (5:1 for wom-
en vs men ratio). This may result from
a type IV or delayed hypersensitivity
reaction; patients are sensitized to
an allergen by contact and develop
erythema, fissures, and an eczem-
atous appearance 48-72 hours af-
28
ter initial exposure or immediately
if there is previous sensitization. In
contact dermatitis or photocontact,
exposure to allergens may be due
to direct contact or to contaminated
objects: pillow surfaces, masks, tele-
phones, via the air with aerosols or
suspended particles, by exposure of
an already contaminated partner, by
ectopic transfer and even by systemic
administration. Another type of con-
tact dermatitis is primary irritation of
the contact agent and it happens im-
mediately. The affected areas of the
face are the spots where the contact
agent was distributed or applied. The
most common irritating agents are
cosmetic ingredients or metals used
in jewelry-making; other causes of
contact dermatitis are products from
the workplace or home, or substances
related to recreational activities (hob-
bies). The uncontrolled use of steroids
may lead to the persistence of erythe-
ma and result in a “status cosmeticus”
with facial erythema, as described by
Fisher.
Phototoxicity
Dermatosis due to photosensitivity
or phototoxicity due to drugs ap-
pears in photo-exposed areas, both
on the face and limbs, as well as on
the V-shaped neck. Erythema asso-
ciated with phototoxicity tends to
be bright and is sometimes coupled
with edema, vesiculation and later
scaling. When it affects the face, the
rash appears most prominently on
the forehead, nasal dorsum, upper
lip and upper cheek areas. An im-
portant factor differentiating pho-
totoxicity from other causes of the
red face is the noticeable difference
between the skin exposed to the
sun and that covered by clothes.24 If
the person was wearing a shirt with
a U-shaped or very acute V-shaped
neck then erythema will take those
forms on the chest, while in the up-
per limbs it will stretch to where the
sleeve ended. On cold days, sun ex-
posure may affect only the face, par-
ticularly at higher altitudes. The list
of substances that may cause these
phototoxicity includes sunscreens
with benzophenone, antihypertensive
drugs (Fig. 3-5), thiazide diuretics,
NSAIDs, antiarrhythmics and sulpha
drugs. Both UVB and UVA sun radia-
tion can be responsible for phototox-
icity or photoallergy induction.
Autoimmune Diseases
Autoimmune diseases, such as erythe-
matosus systemic lupus and dermato-
myositis, may involve facial erythema.
The redness of the face in erythema-
tosus systemic lupus appears on the
malar region, with a butterfly-wing
pattern, plus mild atrophy and tel-
angiectases in chronic cases. There
is sometimes mild edema and hy-
perchromia in light skin phototypes.
In dermatomyositis, the erythema
is more purplish and located on the
 eyelids (heliotrope erythema), malar
regions and neckline. The chronic
condition shows poikiloderma, with
areas of reticulated hyperchromia, at-
rophy and telangiectases. On derma-
toscopy, erythematosus lupus shows
distinctive follicular corneal plugs.
Specific clinical criteria and immuno-
logical tests, as well as skin biopsy in
the case of lupus and muscle biopsy
in the case of dermatomyositis, will
confirm diagnosis. Tumid lupus ery-
thematosus is a form of cutaneous lu-
pus with remarkable photosensitivity.
It is characterized by erythematous
plaques, rounded or annular, edem-
atous in photo-exposed areas of the
face and limbs, without systemic man-
ifestations and a benign but recurring
course.25
Ulerythema Ophryogenes
Ulerythema ophryogenes [keratosis
pillaris rubra atroficans faciei (Brocq),
ulerythema ofryogenes (Taenzer-Un-
na), folliculitis rubra (Wilson)] is known
for the appearance of inflammatory
keratotic papules in the face. These
lesions can be followed by scarring,
atrophy and alopecia. The prevalence
is unknown; however, it is known to
mainly affect children and young
adults, and it is uncommon. Erythe-
ma with mild hyperkeratosis of the
Fig. 3-5. Facial erythema, with edema due to induced phototoxicity by antihy- hair follicles is observed, resulting in
pertensive agent. rough papules on the cheeks and lat-
eral areas of the eyebrows. Occasion-
ally, it extends to the scalp adjacent to
29
the ears and forehead. Compromise
of the extensor surface of the limbs
is rare. Symptoms regress with age,
although the sides of the eyebrows
may be lost. While there are many
occasional cases, an autosomal domi-
nant inheritance has also been report-
ed. There is no specific treatment, but
patients should avoid sun exposure
without UV protection.26
Acute Infections (Erysipelas,
Erythema Infectiosum)
Some acute infectious diseases can
also cause facial redness,27,28 such
as erysipelas and erythema infectio-
sum. Erysipelas is a superficial infec-
tion of the dermis by beta-hemolytic
streptococcus, which is spread through
the lymphatic pathways. Other agents
such as Staphylococcus aureus, Strep-
tococcus pneumoniae, Haemophilus
and Yersinia have been sometimes
cultivated. It is more common among
adult women, elderly or immunosup-
pressed and after trauma or a disrupt-
ed skin barrier (Fig. 3-6). Erythema
appears rapidly, usually bilaterally,
with edema and a shiny, warm ap-
pearance to the touch, with a slightly
raised, well-defined edge. As it de-
velops, lymphedema or vesicles and
serous blisters may appear; fever is
also typically present. Blood cultures,
aspiration culture and biopsy are not
entirely reliable for diagnosis. Elevat-
ed anti-streptolysin O (ASO) 10 to 15
days after onset of symptoms favors

Fig. 3-6. Patient with CREST syndrome, under im-
munosuppressive therapy, who developed facial
erysipelas.
diagnosis; but by that time the prob-
lem is usually resolved.
Erythema infectiosum caused by
parvovirus B19 appears like a slap-
mark on the cheeks (Fig. 3-7). It can
also affect the trunk and limbs, man-
ifesting with a distinctive net-like pat-
terned rash. It is more common among
children and in most cases it has an
indolent course. Among
adults, the disease is more
florid, with ankle and knee
arthropathy and hepato-
splenomegaly. Diagnosis
is based on the charac-
teristic rash and may be
confirmed by elevated
specific IgM antibodies.
This disease is general-
ly self-limiting; however,
it may involve aplastic
anemia in patients with
underlying hemolytic dis-
ease; hydrops fetalis and
congenital anemia may
occur during pregnancy;
and a papular syndrome,
painful and purpuric, may
occur in adults in areas
covered by gloves and Fig. 3-7. Infectious exanthema due to parvovirus B19. Reddened cheeks, as
socks. if slapped, and erythema in net-like patterned arms. Note the patient’s good
general condition.
Other Causes
Even though almost any ythema as well as papular and nodular factors that play a significant role in
granulomatous disease eruption can be very similar to papu- pathophysiology. Here we will only
can cause a red face, the lopustular and granulomatous rosacea, deal with the management of facial
most common agents even in pathology. The presence of erythema without covering other as-
are infectious (tuberculosis, leishman- extracutaneous granulomatous lesions pects of the therapeutics of each eti-
iasis, fungi and parasites), and inflam- and the patergia phenomenon help ology.
matory diseases, such as sarcoidosis. to differentiate them. A pathological
Clinically they appear with a discrete study is essential in diagnosis determi- It is particularly important for the
morphology, multiple papules, or nation, as well as special cultures, intra- atopic individual to adopt hygiene
plaques and nodules, sometimes ab- dermal reactions and imaging studies. measures.29 Skin barrier problems
scessed and ulcerated with annular or are treated and prevented with emol-
lymphocutaneous patterns. Sarcoid- TREATMENT lients and skin barrier restorers and
osis is a great imitator particularly of The treatment of the red face is by avoiding the use of aerosols or
the lupus pernio pattern (Fig. 3-8). Er- planned considering the different other contact irritants suspended in
30
 dermatitis. Nitrates or sul-
phates, such as foods with
preservatives and red wine,
among many others, should
be avoided in the diet.
The most important as-
pect of the treatment is to
discontinue the use of cor-
ticosteroids and treat the
resulting exacerbation with
other measures. Calcineurin
inhibitors, such as tacrolim-
us, have performed well;5,30,31
however, there are reports of
exacerbation or rosacea-like
dermatosis, with the appear-
ance of demodicidosis.32,33
The use of vasoconstric-
tors to reduce erythema,
such as topical 0.5% brimo-
nidine, is currently approved
for rosacea, but is also appli-
cable in other cases of va-
sodilation-associated facial
erythema. Vasoconstriction
Fig. 3-8. Lupus pernio (cutaneous sarcoidosis) with the phenomenon of patergia on the induction during the first
left cheek due to biopsy. 30 minutes tends to work
effectively, after which the
the air (powders) or those present tion and reduce the penetration of facial erythema disappears for 9-12
in cosmetics or hair dyes. In cases of infrared rays, which can cause great- hours.34 Some patients, usually those
phototoxicity or photosensitivity it is er vasodilation. It is advisable to re- with atopic diathesis or seborrheic
very important to take into account move all types of jewelry or metal skin, experience exacerbation after
the wavelength causing the dermato- items from the hands before apply- several days of use. Treatments based
sis.24 Mineral or inorganic sunscreens ing the sunscreen, as minerals in the on intense pulsed light or pulsed-dye
are most useful, since they block the sunscreen can release metal particles laser are also quite effective when
entire spectrum of ultraviolet radia- from the jewelry and trigger a contact performed with brimonidine. Brimo-
31
nidine improves absorption of pulsed
light energy into telangiectases by
eliminating underlying erythema. In-
tense pulsed light also performed
well, particularly in refractory cases of
facial erythema in atopic dermatitis36
and in different types of rosacea.37
Filters with wavelengths from 540 to
950 nm were used in three sessions,
with a high degree of patient satis-
faction. Vasodilators such as niacin, in
oral doses of 125-250 mg, cause a tran-
sient erythema at 30 minutes which
makes the vessels more susceptible
to pulsed light treatment.
Second generation antihistamines
can reduce vascular response and
skin reactivation in atopic or dermo-
graphic patients. Tetracyclines, such
as minocycline or doxycycline, act on
erythema by inhibiting nitric oxide
synthetase35 and, consequently, va-
sodilation. They also work well in the
treatment of the red face syndrome
and even other chronic steroid-in-
duced erythema, such as the red
scrotum syndrome. In addition, their
anti-inflammatory properties inhibit
the formation of telangiectases. Al-
though in the past doxycycline doses
of 50-100 mg/day were used, to avoid
bacterial resistance 200 mg/day are
recommended, divided into two dos-
es every 12 hours for 3 months. In ro-
sacea, subantimicrobial doses of 40
mg/day are administered in extend-
ed-release tablets.
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Section 2
„„ Chapter 4. Definition and
Characteristics of Sensitive Skin
The Sensitive Skin „„ Chapter 5. Pathophysiology

„„ Chapter 6. Management
The clinical manifestations charac-
terizing or defining sensitive skin
were described several decades
ago. However, the understanding of
sensitive skin continues to evolve.
Thiers was probably one of the first
to refer to this very special feature of
the skin.1 In 1987, Maibach described
the cosmetic intolerance syndrome
(CIS), a syndrome that probably cov-
ers most of the clinical presentation
of the sensitive skin syndrome.2 In
2006, Berardesca et al. refer to the
sensitive skin syndrome (SSS) as a
state of hyperreactivity to environ-
mental stimuli, which presents with a
clinical picture as a result of a disease
or combination of underlying diseas-
es.3 Sensitive skin can be defined in
subjective and objective terms.4 Typ-
ically, sensitive skin is a subjective
sensation, with no apparent clinical
signs; as such, it is difficult to iden-
tify, quantify and manage both for
the physician and the patient.5 Klig-
man defines it as a biological reality,
as valid as any other dermatological
condition (Table 4-1).6 Misery et al.
clinically define sensitive skin as the
occurrence of abnormal stinging,
burning, and tingling sensations (and
sometimes as pain or pruritus or itch-
ing) in response to multiple factors
that may be physical (UV, heat, cold,
wind), chemical (cosmetics, soaps,
water, pollutants) and sometimes
psychological (stress) or hormon-
al (menstrual cycle).7 Sensitive skin
The International Forum for the Study
of Itch (IFSI), devoted to the study of
Chapter 4 itching, agreed to organize a study
group called Special Interest Group
Definition and
on Sensitive Skin, since itching may be
one of the symptoms reported by the
sensitive-skin patient. This group is
Characteristics of
made up of dermatologists, psychol-
ogists and biologists, none of whom
have any ties with cosmetic compa-
Sensitive Skin
nies. Recently, the group utilized the
Delphi Method,8 an opinion technique
that results in an expert consensus, to
refine the definition of sensitive skin.
The group agreed that sensitive skin
is “a syndrome marked by the appear-
ance of unpleasant sensations (sting-
Ana Kaminsky ing, burning, pain, itching and tingling)
in response to stimuli that should not
Table 4-1. Definitions* normally cause any such sensations.”8
Subjective Irritation: Irritant response with no visible clinical signs Sensitive skin affects the entire in-
tegument, but exposed areas are the
Neuro-sensitive irritation: neurologically mediated response such as itching, stinging, burning, and most susceptible. The face is the most
tightness frequently involved area; further, the
nasolabial fold is the most sensitive,
Chemosensitive irritation: sensitive responses produced by chemicals to physical mechanisms and since it has a permeable stratum cor-
environmental factors neum, high density of sweat glands
and hair follicles, and profuse inner-
Psychophysical irritation: involves a psychological component vation (Fig. 4-1).9 Data are unclear re-
garding the involvement of legs and
* Kligman AM, Sadiq I, Zhen Y, et al. Experimental studies on the nature of sensitive skin. Skin Res Technol. 2006;12:217-22. trunk.
is also known as “reactive skin” or confused with the skin sensitized by Another definition that includes all
“over-reactive skin”, “intolerant skin” an allergic disorder.7 Most current aspects of sensitive skin is that of
and “irritable skin”. For some authors, publications use sensitive skin (SS), Scales-Taberner et al: “... can be de-
the term “reactive skin” is preferred which is the name to be used in this fined as a condition characterized by
to “sensitive skin” because it may be chapter. high subjective sensitivity, can occur
35
with or without clinical signs, alone or
in association with other skin diseas-
es, and with an impact on the quality
of life [health-related quality of life
(HRQOL)]. ”10
However, the definition that most
closely matches a situation that can
only be evaluated by symptoms is that
of Misery et al. (2017) “a syndrome de-
Fig. 4-1. Face sites where the sensitive skin syndrome is more frequently ap-
pears.
fined by unpleasant sensations (sting-
ing, burning, pain, itching and tingling
sensation) in response to stimuli that
normally should not produce them.”9
From the wealth of available litera-
ture, it can be assumed that there is
not a clear explanation for sensitive
skin, because its symptoms, intensity
and trigger factors are variable, and
36
there are no objective signs to con-
firm them.11 Several studies highlight
that individuals with sensitive skin,
face psychological and social issues
because the condition alters their
quality of life which in turn worsens
their problem.12
EPIDEMIOLOGY
Several epidemiological studies of
sensitive skin have been carried out
in populations from 1 to 89 years of
age. Their methodologies in terms of
data collection - gender, age, head of
household occupation, type of geo-
graphical area and region - have been
very similar.
The first was held in the United
Kingdom in 2001 and the following
ones in Belgium, France, Germany,
Greece, Italy, Spain, Portugal, Switzer-
land, the United States, Brazil, Japan
and Russia.13
Global prevalence is estimated
at approximately 40% with a strong
upward trend, as suggested by the
comparative result of four studies
conducted in the USA in 2013.14,15 In
a study involving more than 400
patients belonging to similar popu-
lations in terms of average age (40
years) and sex, the results showed
that most of the individuals were born
in Europe and had the following pho-
totypes: I, 1.4 %; II, 24.5%; III, 61%; IV,
12.1%; V, 1.1%. Of these, 85% had sen-
sitive skin on the face, and 70% in
other areas: hands (58%), scalp (36%),
feet (34%), neck (27%), torso (23%) or
back (21%). Triggers were cold (66%),
heat (28%), stress (61%), sun exposure
(51%), wind (42%), shower water (29%)
or swimming pool (40%); soaps (42%),
cosmetics (28%) and pollution (18%).
Clothing friction was observed in 28%
of cases. In most cases, sensitive skin
was seen primarily as redness, along
with several subjective symptoms.
This study clearly shows that the face
is not the only site where sensitive
skin may occur.16
Another study involving 2,966 sub-
jects between ages 1 and 89 years
(mean 39 years) showed that the ma-
jority of subjects with sensitive skin
were women (85.7%). This study re-
ported dry skin in 34.9% of subjects,
oily skin in 14.1%, and combination skin
in the remaining 51% of subjects. Sen-
sitive skin was associated with eczema
in 19.5% of subjects, 19.5%, seborrheic
dermatitis in 12.7% of subjects, acne in
9.1% of subjects, and rosacea in 3% of
subjects.17
CLINICAL MANIFESTATIONS
It is very difficult to establish which
factors influence the pathophysiolo-
gy of sensitive skin. There is a percep-
tion that the skin reacts excessively to
different stimuli, such as topical sub-
stances, cosmetics and daily toilet-
ries, as well as environmental factors.
 A B
Fig. 4-2. Skin clinical differences between A, sensitivity (clinically normal skin); B, irritation; and C, allergy.
Subjective perceptions of sensitive
skin appear immediately after the ap-
plication of a substance or after some
minutes, hours or days. The signs,
which are objective, are observed
on clinical examination and include a
large number of skin reactions. Sen-
sitive skin is prone to irritation and
allergies, which can be considered
triggers and are the response of this
type of skin to exogenous stimuli.
There are differences and similari-
ties between sensitive skin, irritation
and allergies (Fig. 4-2; Table 4-2).18
Sensitive skin triggers can be physi-
cal (ultraviolet radiation, heat, cold,
wind), chemical (cosmetics, soaps,
water, pollutants) or occasionally,
psychological (stress) and hormonal
(menstrual cycle). The variety of trig-
ger factors suggests that there may
be abnormal activation of sensitive
receptors of the transient protein
receptor family, since these proteins
are the only ones known to be acti-
vated by both physical and chemi-
cal factors.19 However, the causes of
sensitive skin remain unknown and
may be multivariate, due to psycho-
logical changes, genetic susceptibili-
ty, environmental factors (e.g. drugs,
cosmetics, cleansers, pollution) or
psychological or behavioral factors
(e.g. stress, triggering agents).9
As regards etiology, there are in-
trinsic, extrinsic and endogenous fac-
tors (Table 4-3).20
A study showed that the degree
of sensitivity was higher in summer
than in cold seasons, higher among
women; in addition, women also had
greater deterioration in their quality
of life, especially from the psychologi-
cal viewpoint.21
Sensitive skin syndrome (SSS) is a
self-diagnosed disorder that is very
difficult to quantify.
37
C and temporarily visible dermatoses
According to Pons Guiraud, sensi-
tive skin may be classified as:
UU Very sensitive (intrinsic skin): dry
or oily.
UU “Environmentally” sensitive: pho-
totype 1, dry and thin.
UU “Cosmetically” sensitive. Easily
recognizable.5
Stalder et al. have suggested there
are three categories of sensitive skin,
which are stimulated by general, en-
vironmental and cosmetic factors, re-
spectively (Table 4-4).22 As with many
syndromes, the clinical approach
must consider a wide range of relat-
ed problems which can be helpful in
highlighting the diagnosis. According
to Le Tov et al., visible and invisible
mechanisms must be taken into ac-
count (Table 4-5).23 Visible dermato-
ses are relatively easy to diagnose,
should be examined using specific
tests adapted to each of them. With
so-called invisible dermatoses, it is
assumed that objective irritation is
caused by a subclinical inflammatory
process due to a hidden dermatosis.
The mechanism of subjective irrita-
tion is unknown, and this diagnosis
probably encompasses more than
one condition. For Maibach, the most
frustrating situation is subjective ir-
ritation, which is a common cause of
cosmetic intolerance syndrome. Since
sensitive skin is frequently very diffi-
cult to evaluate because it lacks ob-
jective signs, a way of establishing the
intensity of the discomfort has been
explored.
One of the most interesting stud-
ies on this topic is that of Misery et
al. which included 2,966 patients
with sensitive skin (from 1 to 89 years
old, 39 on average) from 11 coun-
tries. They tested two versions (14-
item and 10-item) of a comparative
scale for sensitivity (Table 4-6).17 In
a first appointment each patient was
examined, and therapeutic measures
were prescribed. The two scales
were administered at the second ap-
pointment and data were analyzed.
The results showed that individual
therapeutic measures can improve
the quality of life of patients with
sensitive skin. In addition, the 10-
item version was faster and easier to
Table 4-2. Differences and similarities between sensitive skin, irritation and allergies* Table 4-3. Etiology of Sensitive Skin*

Properties Skin Sensitivity Skin Irritation/Reaction Allergy Intrinsic Factors Extrinsic Factors Endogenous Factors

Causes 1. Skin barrier damage 1. Sensitive skin 1. Poor barrier function/ Associated Cosmetics and cleaning Essentials
2. Neurobiological 2.Stimuli: chemical, physical (acid sensitive body structure Seborrheic diathesis products Female Youth
dysfunction substances, organic solvents, 2.Allergens (fat-soluble Atypical psoriasis Environmental Susceptibility to blushing or flushing
surfactants) substances of low Rosacea Life style: Skin pigmentation
molecular weight) Perioral dermatitis Diets Thin stratum corneum
Erythrocuperosis Body hygiene practices Decrease in epidermal hydration
Cells Keratinocytes, fibroblasts, Mast cells, basophil granulocytes, Langerhans cells, Atopic dermatitis Work activities Disruption of the stratum corneum
neurons non-specific T-cells phagocytes, specific Increased epidermal innervation
T-cells Increased sweat gland function
Increase in neutral lipids and
Substances Cells and other components 1. Histamine 1. Histamine decrease in sphingolipids
related to the stratum 2.Quininogenases (catalyzes the 2.Quininogenases High transepidermal water loss
corneum structure formation of plasmoquine, bradykinin) (catalyzes the formation of (TEWL)
plasmoquine, bradykinin)
Farage MA, Katsarou A, Maibach HI. Sensory, clinical and physiological factors in sensitive skin: a
Manifestations 1. Epidermis structural damage 1. Erythema, edema, scaling 1. Similar to stimuli review. Contact Dermatitis 2006; 55:1-14.
2.Dryness, shrinkage, erythema 2.Keratinocytes (amyloidosis 2.Systemic disease
vesiculation) Table 4-4. Types of Sensitive Skin*

Characteristics 1. Poor tolerance to irritants 1. Direct response after contact 1. Incubation period Type 1. General Type 2. Environmental Type 3. Cosmetic
(threshold reduction) 2.Local response (triggered by re-exposure)
2.Greater susceptibility to 3.It may be caused by some substances 2.Complex response Extremely reactive to: Highly reactive to: Moderately reactive to:
allergic reactions (critical density) throughout the body Topical treatments Heat Cold Topical treatments
3.Affection in symmetrical Environmental factors Temperature changes Certain components
sites Stress Cigarrettes (tobacco) Observation of the
Dry, mixed or oily skin Alcohol allergy type for detection
extreme intolerance Dry skin of minimal sensitizer or
Similarities 1. Sensitive skin is prone to irritations and allergies, and can be regarded as a reason for its occurrence. Frequent blush transferred by hands
2. Skin irritations and allergies are sensitive skin responses to exogenous stimuli. Minimum redness with
subjective sensations

* Fan L, He C, Jiang L, et al.Brief analysis of causes of sensitive skin and advances in evaluation of anti-allergic activity of cosmetic products. Int * Stalder JF, Tennstedt D, Deleuran M, et al. Fragility of epidermis and its consequence in dermatolo-
J Cosmet Sci. 2016 Apr;38(2):120-7 gy. J Eur Acad Dermatol Venereol. 2014 Jun; 28(Suppl 4):1-18.

38
Table 4-5. Sensitive Skin Syndrome Table 4-6. Scores in the sensitivity scale (severity)* scale. Patients are asked to mark
Underlying Mechanisms* (p < 0.0001) n = (1-89 y/o, 39 average) on the line the point indicating the
intensity of their symptom and it is
Visible Dermatosis Appointment 1 (n = Appointment 2 (n = measured with a millimeter ruler. The
Eczema 2,966) average % 2,549) average % intensity is expressed in centimeters
Atopic dermatitis or millimeters (Fig. 4-3). Any of these
Rosacea SSS-14 43,67 10,32 scales could be used in the SSS and
Seborrheic Dermatitis SSS-10 36,49 8,99 at least one tool would be available
Temporary Visible Dermatosis Irritation 5,09 1,63 to assess the outcomes of the treat-
Contact Dermatitis. Stinging 2,91 0,78 ment prescribed and subsequently
Photocontact Dermatitis Burning 3,73 0,87 carried out by the patient.
Non-Immunologic Contact Urticaria Heat sensation 3,51 0,86
Immunologic Contact Urticaria Tightness 4,18 0,95 Undoubtedly, although this prob-
Invisible Dermatosis Itching 4,06 0,91 lem has no visual expression nor
Objective irritation (hidden skin condition) Pain 1,57 0,24 significant symptomatological alter-
Subjective irritation (unknown cause) General malaise 3,29 0,69 ations, it affects the quality of life of
Body dysmorphic disorder Blush 3,31 0,81 those suffering it. Thus, it is important
Erythema 5,06 1,51 for clinicians to try to understand, di-
* Lev-Tov H, Maibach HI. The sensitive skin síndrome. Scaling** 3,40 0,73 agnose and manage sensitive skin.
Indian J Dermatol 2012; 57(6):419-23. Perspiration** 2,09 0,35
Exudation** 0,68 0,13
complete with the same consisten- Scabs** 1,14 0,23
cy as that of 14, as the 4 additional References
items (desquamation, sweating, ex- * Misery L, Jean-Decoster C, Mery S, et al. A new ten-item questionnaire for assessing 1. Thiers H. Peau sensible. In: Les Cos-
udation and scabs) are very rarely sensitive skin: the Sensitive Scale-10. Acta Derm Venereol. 2014 Nov;94(6):635-9. métiques (2ème édition). Edited by
observed. ** Not in the 10-item scale.. Thiers H. Paris, Masson; 1986.

There are several scales for the
assessment of pain intensity on nu-
merical scales (0-10 or 0-100) which
may be helpful in the case of sensi-
tive skin; like pain, sensitive skin is
a subjective perception. In the cat-
egory scale, 0 is nothing, 4 is little,
6 is quite a bit, and 10 is a lot. The
intensity visual analogue scale (VAS)
is a horizontal line of 10 cm; on the far
left is the absence of pain and on the
Fig. 4-3. Sensitivity analogue visual scale
far right, the greatest pain imagin-
able (unbearable). Similarly, for sensi-
tive skin the maximum expressions of
39
2. Maibach HI. The cosmetic intoler-
ance syndrome. Ear Nose Throat J
1987; 66:29-33.
3. Berardesca E, Fluhr JW, Maibach HI.
What is sensitive skin? In: Berardes-
ca E, Fluhr JW, Maibach HI, editors.
Dermatology: Clinical and Basic
a symptom may be found at the right Science Series, Sensitive Skin Syn-
of the VAS, while absence or lesser drome. New York: Taylor and Francis
intensity is located at the left of the Group; 2006. p. 1-5.
4. Draelos ZD. Sensitive skin: Percep-
tions, evaluation, and treatment.
Contact Dermatitis 1997; 8:67-78.
5. Pons-Guiraud A. Sensitive skin: a
complex and multifactorial syn-
drome. J Cosmet Dermatol 2004;
3:145-8.
6. Kligman AM, Sadiq I, Zhen Y, et al.
Experimental studies on the nature
of sensitive skin. Skin Res Technol
2006; 12:217-22
7. Misery L, Jean-Decoster C, Mery S,
et al. A new ten-item questionnaire
for assessing sensitive skin: the Sen-
sitive Scale-10. Acta Dermatol Vene-
reol 2014; 94(6):635-9.
8. Dalkey NC. The Delphi method: an
experimental study of group opin-
ion. Santa Monica: Brown; 1969.
9. Misery L, Ständer S, Szepietowski
JC. Definition of sensitive skin: An
expert position paper from the Spe-
cial Interest Group on Sensitive Skin
of the International Forum for the
Study of Itch. Acta Dermatol Vene-
reol 2017; 97(1):4-6.
10. Escalas-Taberner J, González-Guer-
ra E, Guerra-Tapia A. Sensitive skin:
A complex syndrome. Actas Dermo-
sifiliogr 2011; 102(8):563-571.
11. Richters R, Falcone D, Uzunbajaka-
va N, et al. What is sensitive skin?
A systematic literature review of
objective measurements. Skin Phar-
macol Physiol 2015; 28:75-83.
12. Farage MA, Maibach HI. Sensitive
skin: closing in on a physiological
cause. Contact Dermatitis 2010;
62:137-149.
13. Misery L, Myon E, Martin N, et al.
Peaux sensibles en France: aproche
épidémiologique. Ann Dermatol Ve-
nereol 2005; 132:425-429.
40
14. Misery L, Loser K, Ständer S. Sensi-
tive skin. J Eur Acad Dermatol Ve-
nereol 2016; 30:2-84.
15. Farage MA, Miller KW, Wippel AM,
et al. Sensitive skin in the United
States: Survey of regional differ-
ences. Family Med Medical Sci Res
2013; 2:3.
16. Saint-Martory C, Roguedas-Con-
tios AM, Sibaud V, et al. Sensitive
skin is not limited to the face. Br J
Dermatol 2008; 158:130-133.
17. Misery L, Jean-Decoster C, Mery S,
et al. A new ten-item questionnaire
for assessing sensitive skin: the Sen-
sitive Scale-10. Acta Dermatol Vene-
reol 2014; 94(6):635-9.
18. Fan L, He C, Jiang L, et al. Brief anal-
ysis of causes of sensitive skin and
advances in evaluation of anti-aller-
gic activity of cosmetic products.
Int J Cosmet Sci 2016; 38(2):120-7.
19. Tóth B, Oláh A, Szöllősi AG, et al.
TRP channels in the skin. Br J Phar-
macol 2014; 171:2568-2581.
20. Farage MA, Katsarou A, Maibach
HI. Sensory, clinical and physiologi-
cal factors in sensitive skin: A review.
Contact Dermatitis 2006; 55:1-14.
21. Misery L, Myon E, Martin N, et al.
Sensitive skin: psychological effects
and seasonal changes. J Eur Acad
Dermatol Venereol 2007; 21:620-8.
22. Stalder JF, Tennstedt D, Deleuran
M, et al. Fragility of epidermis and
its consequence in dermatology. J
Eur Acad Dermatol Venereol 2014;
28(Suppl)4:1-18.
23. Lev-Tov H, Maibach HI. The sensi-
tive skin síndrome. Indian J Derma-
tol 2012; 57(6):419-23.
Sensitive skin syndrome refers to a
clinical condition described by Thiers
in the 1980s, although this disease
was originally reported in 1947.1-4 Its
basic feature is the sensation of skin
discomfort, clinically expressed as
itching, burning, stinging and tingling
sensations, after exposure to various
factors such as water, temperature
changes (either cold or heat), wind,
cosmetics, cleansers, and ultraviolet
radiation.
Different theories have been pro-
posed to explain the pathophysiology
of sensitive skin, but it remains poorly
understood. Among the factors that
could have greater relevance in its
development, the following can be
mentioned:
1. Abnormalities in the skin barrier.
2. Innate immune response with acti-
vation of the inflammatory cascade.
3. Neurogenic disorders.
Skin Barrier Function. While skin
barrier function is thought to have a
role, the exact nature of the role re-
mains mysterious. Confocal RAMAN
microspectrophotometry studies in
patients with sensitive skin show no
differences in skin thickness, natural
moisturizing factor content or tran-
sepidermal water loss compared to
controls with non-sensitive skin.2,6
Chapter 5
Pathophysiology
Nélida Raimondo†
Innate Immune Response. Recently,
Yamasaki and Gallo proposed that the
innate immune system could trigger an
abnormal inflammatory reaction, which
would favor the onset of sensitive
skin symptoms, as in rosacea. These
authors have focused on the role of
cathelicidins as inflammatory cascade
inducers and cytokine activators.7
Neurogenic Disorders. Abnormal
sensations of vasodilation, as well as
atypical reactions to rapid changes in
temperature, are highly suggestive of
the existence of a sensitive nervous
system compromise at the skin level,
especially of the transient receptor
potential (TRP) channels. These chan-
nels are expressed in nerve endings
and, once activated, they promote
the release of neuropeptides induc-
ing neurogenic skin inflammation.8
The latest research studies aim at
evaluating the role of sensitive hyper-
41
activity in the development of sensi-
tive skin. Stress situations generate
neurogenic inflammation and induce
the production of neuropeptides, such
as substance P and vasoactive intesti-
nal peptide (VIP), which cause vasodi-
lation and mast cell degranulation.9
As in rosacea, the transient poten-
tial receptors of the vanilloid family
(TRPV-1), when activated by thermal
stimuli (heat) and pH changes, pro-
duce pain and pruritus associated
with a burning sensation. These ther-
mosensitive ion channels are overreg-
ulated by inflammatory mediators.10
Therefore, although the pathophys-
iology of sensitive skin is not fully
elucidated, it is thought it involves a
reduction in the level of skin tolerance
due to a dysfunction of the cutaneous
sensory nerves. However, it was not
yet possible to determine if there are
changes in the density of nerve fibers
or an abnormal perception of pain.1
Skin sensations are mediated by dif-
ferent types of fibers. Pain and itching
are mediated by unmyelinated C fibers,
while thermal sensation is mediated
by unmyelinated A fibers, and tactile
sensation is mediated by myelinated
A fibers. C fibers have sensitive neu-
roreceptors, such as endothelin (ET),
and pain and thermal receptors, such
as TRPs, which are not only expressed
in nerve endings but also in keratino-
cytes. Endothelins, produced by endo-
theliocytes in dermal vessels and mast
cells, induce neurogenic inflammation,
which is expressed as a sensation of
pain and burning itching. Endothelin
binds to its receptors (ETA and ETB)
and induces the production of tumor
necrosis factor (TNF-a) and interleu-
kin-6 (IL-6) in mast cells, as well as an
increase in the production of vascular
endothelial growth factor (VEGF) and
growth-stimulating factor, which acti-
vates the inflammatory pathway. ET-1
activates nociceptors responding to
pressure which are capable of induc-
ing allodynia.
Sensitive skin can worsen with tem-
perature changes. The Ca++ channels,
belonging to the transient receptor
potential family, include more than 30
cation channels. The vanilloid groups
(TRPV), which are heat-sensitive, and
the melastatine groups (TRPM-8), which
are cold-sensitive, are expressed at the
skin level and activated by different
temperature levels. Thermoreceptors
act as non-selective cation channels, al-
lowing Ca++ entry to the cells and depo-
larization of nerve fibers.
ET-1 closely interacts with TRPV-1
in thermal hyperalgesia, by lowering
the thermal threshold for TRPV-1 ac-
tivation. This interaction may contrib-
ute to the expression of symptoms
observed in individuals with sensitive
skin. After being stimulated by capsa-
icin, TRPV-1 produces pain or burning
itching; but it can also be stimulated
by bradykinins, prostaglandins and
nerve growth factor (NGF), which
lowers the activation threshold and,
thus, induces itching and pain. Tran-
sient receptor potential melastatin
(TRPM-8) and ankirine (TRPA-1) are
cold-sensitive receptors that are acti-
vated by menthol and allicin (present
in garlic), which are useful as thera-
peutic tools in the suppression of itch-
ing mediated by cold.11 Cold allodynia
may be favoured by hyperreactivity of
TRPM-8.
NGF is a neurotrophin with regula-
tory functions in nociception.12 At the
skin level, after a harmful nociceptive
stimulus, NGF is overexpressed, act-
ing on receptors and sensitizing them
through thermal, mechanical and
chemical stimuli, leading to itching
and pain. Persistently high levels of
NGF may contribute to the develop-
ment of sensitive skin via sensitization
of thermoreceptors.12
In short, sensitive skin could be
the result of the interaction between
chemical mediators (substance P,
VIP, histamine, neurotransmitters),
endothelins and transient recep-
tor potential channels. For now,
the pathophysiology is best under-
stood as a heterogeneous condition
whose expression depends on vari-
ous factors.
References
1. Buhé V, Vié K, Guéré Ch, et al.
Pathophysiological study of sensi-
tive skin. Acta Dermatol Venereol
2016; 96:314-318.
2. Richters R, Falcone D, Uzunba-
jakava N, et al. What is sensitive
42
skin? A systematic literature re-
view of objective measurements.
Skin Pharmacol Physiol 2015;
28:75-83.
3. Misery L, Ständer S, Szepietowski
JC, et al. Definition of sensitive skin:
An expert position paper from the
Special Interest Group on Sensitive
Skin of the International Forum for
the Study of Itch. Acta Dermo Vene-
reol 2017; 97:4-6.
4. Rodrigues Barata AR, Conde-Sala-
zar Gomez L. Existe la piel sensible?
Dermatol Venez 2012; 50(1):10-14.
5. Schmid-Wendtner MH, Korting HC.
The pH of the skin surface and its
impact on the barrier function. Skin
Pharmacol Physiol 2006; 19:296-
302.
6. Richters RJ, Falcone D, Uzunbaja-
kava NE, et al. Sensitive skin: As-
sessment of the skin barrier using
confocal raman microspectrosco-
py. Skin Pharmacol Phisiol 2017;
30:1-12.
7. Yamasaki R, Gallo J. The molecular
pathology of rosacea. K Dermatol
Sci 2009; 55:77-81.
8. Berardesca E, Farage M, Maibach
H. Sensitive skin: an overview. Int J
Cosmet Sci 2013; 35:2-8.
9. Ständer S, Schneider SW, Weishaupt
C, et al. Putative neuronal mecha-
nisms of sensitive skin. Exper Der-
matol 2009; 18:417-423.
10. Kueper Th, Krohn M, Haustedt
LO, et al. Inhibition of TRPV1 for
the treatment of sensitive skin.
Exper Dermatol 2010; 19:980-
986.
11. Tóth BI, Oláh A, Szöllősi AG, et al.
TRP channels in the skin. Br J Phar-
macol 2014; 171:2568-2581.
12. Grewe M, Vogelsang K, Ruzicka T,
et al. Neurotrophin-4 production
by human epidermal keratinocytes:
Increased expression in atopic der-
matitis. J Invest Dermatol 2000;
114:1108-1112.
Sensitive skin is a common clinical
condition, consisting of some un-
pleasant skin sensations, such as
itching, stinging/burning, prickling
or tightness. Usually, there is no ev-
idence of large epidermal changes,
and its main manifestation is ery-
thema.1-6
Like many skin entities, its etiol-
ogy is multifactorial. It has a signifi-
cant impact on the patient’s quality
of life, and its treatment poses a
great challenge, both for the derma-
tologist and for the pharmaceutical
industry.1,7-10
TREATMENT
Sensitive skin, as stated by Pons, is
“...a complex phenomenon, difficult
to identify, quantify and manage,
both by the physician and by the pa-
tient…” There are no standardized
treatments and so, in many cases, its
management depends on the expe-
rience of the physician.11
The specialist must consider two
very important aspects: general
measures, which include identify-
ing and avoiding triggering factors
as well as the rational selection of
products; and specific measures,
aimed at patient recovery, such as
skin cleansing, restoration of the
skin barrier function, and control
and treatment of vascular reactivity
and inflammatory response.
Chapter 6
Management
Manuel del Solar
General Management Measures
Identifying and Avoiding Trigger
Factors
Sensitive skin usually results in one
of the following skin changes: altered
barrier function, intensified neuro-
sensitivity and increased immune
response, so certain stimuli or skin
contact with certain substances may
cause a reaction.9 Therefore, the ther-
apeutic process will begin with the
identification of the factors that trig-
ger the condition (Table 6-1), in order
to reduce its effect and avoid expo-
sure to the nosological agent, aspects
that are dealt with in another section
of this book, and to which we refer
the reader.2,5,12,13
Rational Selection of Products
Since ancient times, human beings
have used various products for skin
care, hygiene and ornamentation,
but also for curing some of their dis-
eases. In the first case, they resorted
43
The development of the pharma-
ceutical and cosmetics industry led
to the emergence of cosmeceuticals.
This term was coined by Kligman in
1984 to refer to intermediate sub-
stances between cosmetics and med-
icines. The first cosmeceuticals were
developed for facial rejuvenation,
but now there are additional derma-
tological targets.17 Although cosme-
ceuticals include substances capable
of causing changes in the skin, they
do not often have the therapeutic
to the use of cosmetics, which are potential of medicines. Therefore,
products capable of modifying the the administrative requirements for
skin’s appearance in order to beauti- their development, manufacture and
fy it.14,15 In the other cases, they used marketing are lower than for medi-
medications, which are substances cines. However, this does not make
designed to mitigate, treat, cure or them any less efficient.17,18 The compo-
prevent certain diseases. These are nents of cosmeceuticals may include
formulations consisting of one or vitamins; oils from seeds, flowers or
more drugs capable of inducing bi- their dried buds; fruit acids, wax-
ological changes in the structure or es and fats; and others ingredients
function of the organism; therefore, with moisturizing, anti-oxidant, an-
they must be indicated or prescribed ti-inflammatory or anti-aging effects
by a physician.16 are well-suited for the use in prod-
ucts.18,19 For sensitive
Table 6-1. Sensitive Skin: Triggers* skin care, the product
selection must take
Physical triggers Ultraviolet radiation, heat, cold, wind into account some im-
portant aspects: few
Chemical triggers Cosmetics, soaps, water, pollution ingredients, absence
of sensitizing agents,
Psychological triggers Stress minimum number of ir-
ritating ingredients, and
Hormone-relatedtriggers Menstrual cycle absence of skin sensi-
tive stimulants and
* Modified from Misery.5
vasodilators.1,11,18,20
Specific Measures
Skin Cleansing
Detergents are surface-active sub-
stances that have the chemical prop-
erty of dissolving dirt or impurities
from an object without corroding
it. Among the products most fre-
quently used for washing and daily
hygiene, soap has occupied a privi-
leged place and will probably contin-
ue to do so due to the development
of the personal care industry.21 Skin
cleansing products date back to the
29th century BC in ancient Babylon,
but the first to use soap for that pur-
pose were the Phoenicians. Egyptians
and other ancient cultures also used
soap for medicinal purposes. In the
2nd century AD, Galen observed that
cleansing had a curative effect on
skin diseases and encouraged its use.
During the Middle Ages, the Catho-
lic Church banned the use of soap, in
the belief that exposing the skin was
a sin.22-25 Later, with the development
of science, and the full knowledge of
infections and their relationship with
bacteria, the soap industry expanded
as well as medicinal use of soap. In
the 19th century, Ferdinand Von He-
bra and Paul Gerson Unna used soap
as treatment of various skin disorders,
such as scabies, tinea, psoriasis, and
acne, among others, obtaining good
results in many cases.24
Soap utilizes a chemical reaction
between a fatty acid and an alkaline
base, a process known as saponifica-
tion. Due to its alkaline pH and abili-
ty to remove the lipid mantle by the
action of the surfactant –which does
not discriminate between sebum and
intercellular lipids– soap is not an op-
tion for sensitive skin cleaning. Soap
negatively affects barrier function by
alkalinizing and drying skin, so its use
should be avoided in those with sensi-
tive skin.26,27
In Germany, during the First World
War, due to the scarcity of natural fats
and oils –essential components for the
manufacturing of soap–a soap-free
synthetic detergent known as syn-
det (synthetic detergent) was creat-
ed. This invention, attributed to Fritz
Gunther in 1916, had a surfactant that
turned out to be very abrasive, so the
product was only used for industrial
purposes.24 During the Second World
War, Gunther’s creation was revisited
due to the need for solid cleansing
bars for hygiene which could with-
stand various conditions of use espe-
cially “hard” water for sailors at sea.
Thus, a syndet for cosmetic use was
developed. This became available
commercially in Europe and the USA
by the end of 1940 and the beginning
of 1950.27
The use of mild cleansers became
so popular that they displaced soap
from the consumer preference in
many countries, because syndets are
44
gentler on the skin than soap. This is
due to the type and concentration of
the surfactant used as well as the pH.
With syndets, skin pH is preserved
and the lipid barrier is minimally al-
tered, which are very important con-
siderations in the management of
sensitive skin.28,29
It has been reported that use of
gentle cleansers with emulsifiers and
moisturizers leads to clinical improve-
ment in patients with sensitive skin.
Newer cleansers have more sophisti-
cated formulation schemes, with tech-
nology that incorporates emulsified
lipids into the skin during washing,
providing gentle cleansing and a sig-
nificant improvement of dry skin.28-30
Micellar water cleansers are a new
galenic form of cleansing solutions
They are made of fatty acid esters
with an amphiphilic property, i.e. mol-
ecules having both hydrophobic and
hydrophilic groups in their chemical
structure. They are gentle cleansers
and make-up removers that drag se-
bum, detritus, and cosmetics without
upsetting the skin; in addition, micel-
lar water cleansers do not require
subsequent rinsing with water and, in
many cases, have hydrating and an-
ti-inflammatory properties.31
Some authors suggest the use of
mineral or thermal waters to replace
soap for the management of sensi-
tive skins. This is due to its biological
cutaneous activity, mainly actions on
immune pathways and anti-inflamma-
tory effects, which help correct part
of the problem. In some reports, an-
tibacterial and antifungal actions are
attributed to these waters.32-35
Restoring Skin Barrier Function
The stratum corneum (or horny lay-
er) is made up of corneocytes, kera-
tinized cells protected by an internal
sheath, composed of various proteins,
such as filaggrin, loricrin and involu-
crin, among others, and intercellular
lipid domains, consisting mainly of
ceramides, sterols, and fatty acids.
These forms an outer sheath that
protects the skin from environmental
damage and prevents transepidermal
water loss (TEWL).36-38
Likewise, sebaceous secretion –
constituted by triglycerides, free fat-
ty acids, cholesterol, waxy esters and
squalene– as well as eccrine, funda-
mentally aqueous, hypotonic secretion
(electrolytes, amino acids, urea and
other solids in lower concentration)
and acidic pH (4.5-5.5), covers, mois-
turizes and lubricates the epidermis,
constituting the lipidic acid mantle that
helps the skin maintain its elasticity
and its barrier function intact.28,36
Similarly, the natural moisturizing
factor (NMF), a term coined by Jacobi
et al. in 1959, plays a very important role
in maintaining the hydration of the epi-
dermis. NMF is a complex of water-sol-
uble molecules present in the stratum
corneum that retain water and absorb
atmospheric humidity, thus acting as
a very efficient moisturizer.39-41 NMF
consists of amino acids and their deriv-
atives (pyrrolidine carboxylic acid and
urocanic acid), as well as lactic acid,
urea, sugars and mineral salts from the
eccrine and holocrine glandular se-
cretions (Table 6-2). Together with the
lipidi mantle, it preserves the integrity
of the stratum corneum by controlling
the flow of water into it.39,42
Pyrrolidine carboxylic acid, a me-
tabolite of filaggrin, is the most im-
portant component of the NMF,
due to its high hygroscopic capacity,
which regulates epidermal water flow
(the amount and bioavailability of in-
tra-epidermal water) and transepider-
mal water loss (TEWL). Urocanic acid,
also derived from filaggrin, has a trans
isomer that, apart from its photopro-
tective action (currently questioned)
regulates the skin’s pH level and main-
tains acidity.43-46
Epidermal water flow can be af-
fected by structural damage to the
skin barrier, alteration of intercellular
lipids, and environmental changes;
e.g., temperature change (cold) and
decrease of environmental humidity
(less than 70% relative humidity). This
leads to changes in the skin, making
Table 6-2. Natural hydrating factor* The main objective of a
moisturizing product (Ta-
Chemical Composition % ble 6-3) is to maintain and
increase the water level in
Amino acids 40,0 the stratum corneum, which
under optimal conditions
Ions (Na+, K+, Ca2+, Mg2+, PO43–, Cl–) 18,5 is 10% to 20%. This proce-
dure can be accomplished
Pyrrolidine carboxylic acid 12,0 in two ways: by retaining
water within the skin, which
Lactates 12,0 is a passive procedure, or
by capturing external mois-
Sugars, organic acids, peptides, and others 8,5 ture, which is an active
process.43,51,52 The former is
Urea 7,0 achieved by applying for-
mulations whose ingredi-
Ammonia, uric acid, glucosamine, and creatinine 1,5 ents have an occlusive or
semi-occlusive action and
Citrates 0,5 prevent water loss. The lat-
ter is related to external
* Adapted from Fowler.47 moisture, and it consists of
imitating the activity carried
it dry, rough and tight and it can also out by the NMF. For this purpose,
cause erythema and itching, as early topical water-based preparations
signs of inflammation.6,46-48 containing hygroscopic ingredients
are used.51,52
Sensitive skin is usually dry, which
increases the permeability of the stra- Table 6-3. Skin Hydration*
tum corneum and increases TEWL.
Such a weakened barrier facilitates Passive Active
exposure to irritating stimuli that can
penetrate more easily, worsening the Occlusion lipids Moisturizers
problem of sensitive skin. For this rea-
son, treatment should promote the Amphoteric lipids Hydro-captors
restoration of the normal condition of
the skin, including re-hydrating and re- Occlusive Colloids Emollients
storing the lipid mantle (for example,
by using moisturizers).1,6,49, 50 * Adapted from Fábregas.52
45
The group of passive moisturizers
consists mainly of substances of a
greasy nature, with moisturizing, lu-
bricating and protective properties.
These include occlusive lipids (pet-
rolatum, waxes, oils, silicones and
triglycerides), amphoteric lipids (cer-
amides, sterols, lanolin, phospholipids
and hydro-alcohols), as well as colloid
substances (natural and synthetic hy-
dro-colloids), which are derived from
cellulose and proteins, and protein
hydrolysates with occlusive power.52
Petrolatum is a hydrocarbon grease,
derived from petroleum, which ap-
peared in 1872 when Chesebrough
reported its use for the treatment
of chapped hands. Its success is not
only due to its occlusive property, but
also to its ability to spread between
the layers of the stratum corneum,
creating a suitable environment for
repairing the skin barrier and avoid-
ing TEWL. It is very effective and in-
expensive.53-58
Ceramides, comprise a significant
proportion of the lipid composition of
the stratum corneum (40-50%). They
are essential for the preservation of
the “intercellular cement”, since they
inhibit the action of elastase and col-
lagenases, enzymes that degrade
elastin and collagen, respectively.
Alterations in ceramides create an
imbalance in the skin barrier, which
enables the penetration of irritating
agents, allergens, and microorgan-
isms. This, in turn, stimulates inflam-
mation and increases TEWL.38,52,53,59,60
Formulas with mixtures of cera-
mide analogues, cholesterol and free
fatty acids, in a lipid composition simi-
lar and proportional to that of the skin
(3:1:1), have been shown to have an im-
proved moisturizing capacity. When
these mixtures reach the nucleated
cell layers, the “physiological lipids”
of the formula target the emerging
lamellar bodies and, finally, are se-
creted in the interstice of the stratum
corneum.49,61-64
Thanks to nanotechnology, it is
possible to improve the transdermal
transport of many ingredients. For
example, infusing ceramides into sol-
id lipid nanoparticles of delivery en-
hancers (liposomes, transfersomes,
etosomes and niosomes) provides a
better result in skin recovery. In the
future, perhaps the application of
nanotechnology will extend to several
systemic medications 65-69
Active moisturizers can be humec-
tants, hydro-captors and emollients.
The first two are ingredients with hy-
groscopic capacity, that function to
recover the water content of the skin.
Emollients are mainly lipids in the liq-
uid phase; they function to restore
the balance between the quality and
quantity of intercellular lipids and the
hydrolipid layer, so that, in addition to produce important moisturizing ef- degree of environmental humidity,
having moisturizing action, they are fects on the skin.78-80 hydro-captors do not require this fac-
lubricants and softeners.52 tor. An extensive list of substances
It has been reported that dermal belongs to this group: urea, alpha-hy-
Moisturizers can be organic, inor- application of an extract of leaves droxy acids, panthenol, pyrrolidine
ganic, or organometallic. The first are and shoots of ajuga (Ajuga turkestani- carboxylic acid (PCA) and its derived
the most widely used in cosmetic for- ca), a perennial plant (Fig. 6-1) rich in salts (PCA-sodium, arginine-PCA,
mulation. These include glycols (glyc- phytoecdysteroids, seed oil of Arabic stearyl-PCA, lauryl-PCA), as well as
erol, propylene glycol, polyethylene coffee (Coffea arabica), an African macromolecules (hyaluronic acid, col-
glycol, sorbitol) and polyoxyethylene shrub (Fig. 6-2), and bark of Agnico lagen and elastin).43,51,52
sugars (acetamide, monoethanol- (Fig. 6-3) or cebil (Piptadenia colubri-
amine). Glycerol or glycerin is a power- na) branches, induces the expression Urea is a basic component of the
ful humectant, with great hygroscopic of AQP-3. This, in turn, improves the NMF. It has been used in hand creams
capacity, which stabilizes and lique- differentiation of keratinocytes and since 1940. Apart from being an effec-
fies the corneocyte cell membrane facilitates skin hydration.80-85 tive hydro-captor, it has a mild anti-
(cornified envelope) and hydrates pruritic effect. It is thought that urea
the enzymes necessary for the deg- Unlike humectants, whose abili- facilitates the transcutaneous pene-
radation of its desmosomes.43,52,53,70-72 ty to capture water depends on the tration of some active principles, such
Glycerin is also capable of producing
a long-term moisturizing effect by
modulating the water flow through
the generation of water channels,
called aquaporins. Aquaporins (AQP)
were discovered by Peter Agre, who
won the Nobel Prize in Chemistry for
this achievement in 2003. They are
transmembrane proteins which act
as gates, regulating the permeabil-
ity of the membrane to water.73-77 To
date, thirteen AQPs located in the
cell membranes of all cells have been
identified. The most abundant in the
skin is AQP-3, located primarily in the
basal layer keratinocytes. Expression
of ACP-3 increases under certain
skin conditions (dryness), increasing
TEWL. When combined with occlu-
sive agents, glycerin has the ability to Fig. 6-1. Ajuga.
46
 as corticoids and retinoids, though
this action is still somewhat contro-
versial. Also, clinicians should consid-
er that topical urea can be associated
with unpleasant sensations (stinging,
itching and heat).86-90
Macromolecules form films on skin,
and their moisturizing action is due to
a large number of hydrophilic groups.
High molecular weight prevents them
from penetrating the stratum corne-
um. Hyaluronic acid is a glycosamino-
glycan that can be applied to the skin
in the form of its sodium or potassium
salt (hyaluronate). Hyaluronate forms
a semipermeable hygroscopic film
Fig. 6-2. Coffee. which facilitates the passing of ions
and nutrients. It hydrates and also re-
generates and strengthens cell cohe-
sion.43,91,92
Allantoin is a product of the deg-
radation of uric acid in humans and
animals. It is also present, as such, in
many plants. Due to its versatility, al-
lantoin is used in the manufacture of
cosmetic and personal care products.
It has hydrating action, behaving like a
hygroscopic “polyurea.” Allantoin also
has re-epithelizing, analgesic and an-
ti-inflammatory properties, making it
a useful and safe ingredient for use in
patients with sensitive skin.93-96
Several plants have a high content
of allantoin, including the root and
Fig. 6-3. Angico. leaves of comfrey (Symphytum offic-
47
inale), also known as wound-healing
herb or cut-healing herb (Fig. 6-4), as
well as horse-chestnut tree (Aescu-
lus hippocastanum). For this reason,
these plants have been incorporated
in several cosmetic, pharmaceutical
formulations; however, most products
utilize synthetic allantoin.97-101
The third group of active moistur-
izers are emollients, a term coming
from the Latin word emolliens (-entis)
which means “to make soft.” Emol-
lients primarily consist of non-occlu-
sive oily substances (vegetable oils)
rich in essential fatty acids (EFA). Al-
pha-linolenic acid (ALA) and linoleic
acid (LA) are part of phospholipids
and ceramides; therefore, the lack of
these acids will lead to alterations in
keratinization.102-105 The hydrophobic
component of EFAs softens the stra-
tum corneum, while favoring water
retention. Disadvantages of EFAs are
that they are easily oxidizable and
need the presence of antioxidants to
maintain action without degrading.
EFAs come from animals (blue fish,
especially salmon), and plants (chia,
linseed, sacha inchi, rosehip, borage,
evening primrose, soy, and sunflow-
er).64,104,106,107
The oils of Chia seeds (Salvia his-
panica) along with linseed or flax
seeds (Linum usitatissimum) and sa-
cha-inchi or Inca peanut (Plukenetia
volubilis) contain the highest con-

A B
C association with other ingredients,
Fig. 6-4. Comfrey, “wound-healing herb” or “cut-healing herb”. A. Bell-shaped flower. B. Rhizomes. C. Roots.
centration of shorter-chain omega-3
EFA (alpha-linolenic acid) (58%, 55%
and 48%, respectively). This property
has made their consumption in diets,
as well as use in the manufacture of
moisturizing products, increasingly
frequent (Figs. 6-5 to 6-7).
Silicones are high molecular
weight polymers made of silicone
and oxygen, which are not easi-
ly biodegradable due to their high
thermal and chemical stability. They
have multiple applications; for ex-
ample, silicones have been used in
the manufacturing of cosmetics and
personal care products ranging from
lipsticks, deodorants, repellents, shav-
ing creams through to shampoos.108
Since 1945, they have been used in
48
various areas of medicine, including
antacids (simethicone), as lubricants
for artificial joints, coatings for sur-
gical equipment and materials, and
implants. Silicones have also been
used in skin moisturizing formula-
tions, because they have emollient
properties, they are non-irritating,
and make skin feel silky and velvety
to the touch.109-111
One of the most commonly used
silicones is dimethicone (dimethyl-
polysiloxane) which, in natural con-
ditions, forms a film permeable to
water vapor on the skin surface due
to its flexible chemical structure.
Chemical processes (alkylation) are
used to create copolymers with low-
er permeability and with occlusive
properties similar to petrolatum from
dimethicone.112-114
When used in combination or in
moisturizers contribute to re-estab-
lishing skin hydration. Therefore, they
help to preserve the mechanical con-
ditions (elasticity and turgor) and to
recover the aesthetic qualities of the
skin (appearance, removal of flakes
and roughness, color and luminosity)
which are necessary properties for its
normal functioning.48,51,52
In individuals with sensitive skin,
the suggestion of a particular mois-
turizer requires a rigorous assess-
ment of the skin condition. The
composition of the compound must
be tailored for each case and stan-
dardized prescriptions should be
avoided. Use of an inappropriate
compound (one that is excessively
occlusive, causes irritation, or has
too much hygroscopicity or emol-
lience) may increase discomfort and
lead to poor compliance or even dis-
continuation of therapy.
Fig. 6-5. Chia seeds.
Fig. 6-7. Sacha inchi fruits.
49
Fig. 6-6. Lin seeds.
Monitoring and Treating
Inflammatory Response/Modulating
Vascular Reactivity
In most inflammatory skin diseases,
topical treatment usually includes cor-
ticosteroids or immunomodulators;
however, in the management of sensi-
tive skin, it is suggested to avoid use
of these drug classes. The reason is
that they can have cutaneous atrophic
effects, alter the lipid mantle, or cause
itching and burning (calcineurin inhibi-
tors) and may worsen the condition.1,5
The pharmaceutical industry has
developed products for sensitive
skin. These products include diverse
ingredients aimed at controlling the
vascular reactivity and treating the
inflammatory response. Many ingredi-
ents are from natural sources, based
on plant extracts and their derivatives
which, combined with moisturizers
and free of irritants, generate a favor-
able response in sensitive skin, thus
enabling its recovery.
Flavonoids. These are polyphenols,
substances of vegetable origin that
play various roles in plants; for exam-
ple, they are a key component of the
pigment causing the bright yellow,
orange, red and blue colors of their
flowers and fruits. As part of the hu-
man diet, they are micronutrients,
have an antioxidant effect and cap-
ture free radicals; they protect the
skin from ultraviolet radiation (UVR)
and help prevent chronic sun damage
as well as improve photoaging.115-118
Flavones, flavonols, flavans and
anthocyanidins make up the group
of flavonoids, each with particular
chemical characteristics and a wide
pharmacological activity. Due to their
protective, antioxidant and anti-in-
flammatory effects, many are used
in the prevention and treatment of
various diseases, such as diabetes,
cancer, heart disease and thrombop-
athies, peptic ulcer disease, as well as
in the treatment of sensitive skin.119
Genistein is an isoflavone found
in soy (Glycine max), a species in the
legume family whose grains (Fig. 6-8)
also contain phytoestrogens. It has
antioxidant and anti-inflammatory
acvitity, and genistein inhibits the pro-
duction and expression of pro-inflam-
matory mediators, as well as matrix
metalloproteinases (MMP). Thanks
to its action on vascular endothelial
growth factor (VEGF), it helps reduce
erythema, has a photoprotective ef-
fect and stimulates collagen produc-
tion.120-128
Kaempferol is a flavonol, a bioac-
tive component obtained from the
extract of leaves of the ginkgo tree
(Ginkgo bilobá), “longevity tree” (Fig.
6-9). Ginko originated in China and
is used in Asian traditional medicine.
It has been reported that oral use of
ginko biloba improves blood circu-
lation, has an antiplatelet aggrega-
tion effect and an anti-aging action.
Topical application reduces erythe-
ma and has an anti-inflammatory ef-
fect.6,129-131
Quercetin is a plant flavonoid (fla-
vonol) with strong antioxidant and an-
tiinflammatory properties interesting
for skin protection. However, its poor
water solubility limits its penetration
and so its efficiency on skin, which is
the reason why quercetin must be
used in lipid nanocapsules between
20 nm to 50 nm in size. Quercetin is
found mostly in onions, grapes, ber-
ries, cherries, broccoli, and citrus
fruits.132
Hamamelis virginiana also known
as witch hazel (Fig.6-10), contains tan-
nin, the most important healing con-
stituent in this herb, which gives the
shrub its astringent efficacy. It is ob-
tained from the bark and leaves of the
witch hazel bush. Research has shown
that the shrub’s antioxidant activities
may also trigger anti-inflammatory
effects. A comparative study of the
hamamelis virginiana concentrate
and hydrocortisone creams showed
equal effectiveness in reducing acute
eczema. As a natural astringent, witch
hazel can help to control the red face
by decreasing redness and oil secre-
tion.133,134 A comparative study of top-
ical witch hazel extract showed the
efficacy in sensitive skin. The extract
produced an increase in collagen in
cell culture, similar to that produced
by TGF-b1. UVR-induced erythema
and TEWL were reduced and the skin
barrier function improved without irri-
tation or comedogenesis.20 Fig. 6-8. Soy plants and beans.
50

Fig. 6-9. Ginkgo leaves.
Fig. 6-10. Witch hazel leaves.
51
The caper-bush (Capparis spinosa)
is a Mediterranean shrub, whose edi-
ble buds (capers) are highly treasured
in gastronomy (Figs. 6-11 and 6-12). It
has a huge number of applications
in traditional medicine, and pharma-
cobiological studies have reported
benefits in diabetes and atherosclero-
sis, as well as antioxidant properties,
anti-inflammatory and immunomodu-
latory effects, and antimicrobial and
antiviral activity.135-139 Almost the entire
plant (root, leaves, fruits, flowers and
seeds) provides some medicinal ben-
efit because it contains large amounts
of bioactive constituents, flavonols
(quercetin and kaempferol) –whose
effects have already been discussed–
glycosides (routine), which have the
property of inhibiting the VEGF, as
well as hydroxycinnamic acids (ferulic,
caffeic, coumaric and cinnamic acids)
that have an antioxidant action.140-144
Epigallocatechin gallate is a flava-
nol contained in green tea (Camellia
sinensis) (Figs. 6-13 to 6-15). Multiple
investigations have shown that it has
important antioxidant and anti-inflam-
matory effects. Anti-carcinogenic and
antimicrobial actions are also attributed
to it, as well as neuroprotective and pho-
toprotective properties, which means
that it has a great therapeutic potential
against various human diseases.6,145-155
Epidemiological evidence and lab-
oratory studies –both in vitro and in
vivo– suggest that routine consump-
tion of these polyphenols, or topical
treatment, in combination with skin
care creams and lotions, may provide
effective protection against the harm-
ful effects of UVR. They are also useful
for controlling inflammatory reactions
and restoring the skin barrier.116,128,156-161
Phenylpropanoids. Like flavonoids,
phenylpropanoids are phenolic com-
pounds synthesized by plants that
perform several functions: they are
part of the cell wall structure, defend
against various pests, act as repel-
lents, and are flower pigments and
fragrances. They also play a specific
ecological role by attracting insects
for pollination.162-164
In his book De Materia Medica,
Dioscorides (77 A.D.) points out the
medicinal properties of the rodia
riza or golden root (Rhodiola rosea),
an herbaceous plant that grows in
the cracks of the mountains in the
northern hemisphere’s cold regions
(Fig. 6-16). The root is used to re-
duce fatigue and improve physical
performance. Its active ingredients
are stimulating substances, called
phyto-adaptogens, which provide
energy, protect against stress and
improve concentration.165,166 The main
compounds of rhodiola –rosavin and
salidroside– have therapeutic effect.
An antioxidant action and anti-inflam-
matory effect was reported, since
Fig. 6-11. Caper-bush in blossom. Fig. 6-13. Green tea.

Fig. 6-12. Caper. Fig. 6-14. Green tea leaves.

52
Fig. 6-15. Ground green tea.
they significantly reduce peptide lev-
els related to the calcitonin gene and
substance P. These compounds also
increase the release of proopiomela-
nocortin peptides. Topical application
reduces inflammation and improves
the patient’s subjective response to
annoying or irritating sensations.167-170
The therapeutic potential of Rhodi-
ola rosea as a neuromodulator, and
that of l-carnosine as an antioxidant
led to research into the effects of the
compound Rhodiola rosea-carnosine
for alterations of sensitive skin. The
results showed a reparative/protec-
tive effect on the skin barrier and
improvement of the sensitive state,
which would be explained by a signif-
icant increase in the release of opioid
peptides, an inhibition of neuropep-
Fig. 6-16. Rhodiola.
tide production and modulation of
cytokine production in keratinocytes
exposed to UVR.171
Terpenoids. Glycyrrhetinic acid is
a pentacyclic triterpenoid deriva-
tive obtained from liquorice or lico-
rice (Glycyrrhiza glabra) root extract
(Figs. 6-17 to 6-19), a fabaceous plant
from Mediterranean Europe and Asia
Minor. It has antioxidant and anti-in-
flammatory properties and reduces
the production of pro-inflammatory
cytokines (IL-1a and IL-8). In addition,
antibacterial (Staphylococcus aureus),
antiviral (herpesvirus) and anti-cancer
effects have been reported.172-177 It has
corticosteroid-mimetic properties, so
it is also called enoxolone. Glycyrrhe-
tinic acid prevents the cortisol-corti- Fig. 6-17. Liquorice.
53

Fig. 6-18. Liquorice root.
Fig. 6-19. Liquorice candy.
54
sone conversion and slows down the
elimination of steroids by inhibiting
certain enzymes such as D5-reduc-
tase, other than 5a-reductase. This
enzyme slows down the elimination of
steroids and extends plasma average
life. Its use in topical preparations, in
association with moisturizing agents,
improves the recovery response in in-
flammatory conditions. Glycyrrhetinic
acid is also used for the treatment of
melasma and post-inflammatory pig-
mentation disorders.178-182
Polysaccharides. Algae are aquatic
plants that carry out photosynthesis
and are essential for marine life. Their
size is variable, from unicellular forms
(microalgae) to multicellular struc-
tures (macroalgae). They can be found
free-floating in surface layers (plank-
tonic algae) or attached to rocks (ben-
thic algae). Algae have served as food
in many cultures due to their high
nutritional value (salts and proteins);
they also have agricultural, pharma-
co-cosmetic and industrial use.183,184
They can be brownish, red, green and
blue. The cell wall of algae is made up
of polysaccharides, known as phyco-
colloids, which provide them with the
flexibility to adapt to sea currents and
wave friction. These hydrocolloids
(alginate, agar and carrageenan) are
gelling, viscous, stabilizing and emul-
sifying substances; in addition, they
are very resistant to biodegradation
and have great rheological capacity
and high hygroscopicity. For these
reasons, algae are valuable ingredi-
ents for the formulation of moisturiz-
ing products.185-188
The other components of algae, mac-
ronutrients and micronutrients, bioanti-
oxidants, phytohormones and biotoxins,
confer different characteristics to each
group (phaeophyceae, rodophyceae,
chlorophyceae and cyanophyceae).
Several of them, including fucoxan-
thines, fucosterol, chloroglucinol and
bromophenol, phycobilins, have great
therapeutic potential due to as antiox-
idant, antidiabetic, anti-inflammatory,
antifungal, or anti-bacterial proper-
ties.188-191
The extract of golden seaweed (Fig.
6-20) or kombu (Laminaria ochroleu-
ca) is rich in vitamins A and E, and has
anti-inflammatory action by inhibiting
interleukin-1 (IL-1), IL-6 and prostaglan-
din E2. When extracts of rockweed
(Fig. 6-21), Norwegian kelp (Ascophyl-
lum nodosum), or harpoon seaweed
(Asparagopsis armata) (Fig.6-22) are
used in combination, they can reduce
the expression of VEGF and prosta-
glandin E2 (PgE2); therefore, they are
ingredients with important biological
actions for formulations for sensitive
skin treatment.192,193
Other Active Substances
Clinical trials by Kalliomaki et al.
reported between 2001 and 2007

Fig. 6-22. Asparagopsis armata or
Fig. 6-20. Golden weed. harpoon seaweed.
suggested that oral probiotic supple-
ments might be useful in the treat-
ment of atopic dermatitis and dry skin.
Since then, interest has increased in
the use of these semi-active forms of
bacteria to develop topical prepara-
tions for the treatment of these con-
ditions, as well as for the management
of sensitive skin.194-198
Several researchers demonstrat-
ed that the extract of certain bac-
terial strains of the Lactobacillus
genus have anti-adherence and an-
timicrobial properties after its ap-
plication on the skin and mucous
membranes. Another study proved
the efficacy of Bifidobacterium long-
Fig. 6-21. Rockweed. um lysate in decreasing the irritated
55
skin sensitivity and increasing the
resistance of the skin barrier, while
maintaining the concentrations of
NMF.92,199-202
Trans-4-tert-butylcyclohexanol is a
promising ingredient for the control
and management of sensitive skin, be-
ing a specific inhibitor of vanilloid re-
ceptors. Kueper et al. demonstrated
that the application of a 0.4% prepa-
ration blocks neuronal sensitivity to
capsaicin by inhibiting the activation
of transient receptor potential vanil-
loid1 (TRPV1), which improves erythe-
ma and skin sensitivity.5,6,203-210
Recently, other researchers eval-
uated the efficacy and tolerabili-
ty of the association between this
compound and licochalcone A in
the treatment of sensitive skin and
rosacea (subtypes I and II). The re-
sults were very good, either in as-
sociation with other therapies or
not. This means that the therapeutic
arsenal for the management of sen-
sitive skin is on the rise, for the ben-
efit of patients and the satisfaction
of the specialist.211-214
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Section 3
„„ Chapter 7. General Considerations

„„ Chapter 8. Epidemiology
Definition, Etiology and
„„ Chapter 9. Pathogenesis
Pathogenesis of Rosacea
Rosacea is a chronic inflammatory
disease affecting the face, difficult to
characterize and with unclear bound-
aries.1 The frequency with which it
occurs in the general population is un-
known, but it probably affects 10% of
middle-aged people. It is uncommon
in darker-skinned individuals and oc-
curs predominantly in those of Celtic
origin, with pale, sun-sensitive skin.2
Its etiology is controversial. Be-
cause rosacea affects patients with
sun-sensitive skin and is located in
photo-exposed areas, ultraviolet light
is thought to play a part in its patho-
genesis. In addition, alterations in
vascular reactivity have been found
as an underlying cause, while certain
uncommon bacteria and the overpop-
ulation of parasites, such as Demodex
folliculorum, have been proposed as
causative agents. Blood flow, local
temperature, volume and consistency
of various components of the sebum
and the meibomian glands, as well as
alterations in the pH and skin barrier
function of the affected areas, help
to partially establish the etiology and
pathogenesis of this disease.1-3
To fully understand rosacea, it is
necessary to know the normal struc-
ture and function of the skin.
Reactive vascular phenomena,
such as flushing and blushing, are
normal in facial skin as a response
Chapter 7
General
Considerations
María I. Herane H.
to various stimuli, such as food, heat,
seasoning and alcohol, or in some
emotional situations. Frequent and
prolonged flushing is a common mani-
festation in patients with psychosocial
distress or in cases of systemic diseas-
es, such as the carcinoid syndrome.
In patients with rosacea, recurrent
flushing may appear in delimited areas
and be accompanied by other clinical
signs as part of the disease, such as
erythema, telangiectases, papules,
pustules, glandular hyperplasia, phy-
mas and ocular compromise. The
accompanying signs and symptoms
determine the classification by clini-
cal type and severity. The Iberian-Lat-
in American Group for the Study of
Rosacea (GILER), chapter of the Ibe-
rian-Latin American Association of
Dermatology (CILAD,) classifies the
classical forms of rosacea, according
65
to severity degree and type, as ery-
thematotelangiectatic rosacea (ETR)
(subtype 1), papulopustular rosacea
(PPR) (subtype 2), phymatous rosacea
(PR) with or without plaques (phymas)
(subtype 3) and ocular rosacea (OR)
(subtype 4). In addition, GILER con-
siders childhood rosacea (CHR) and
extrafacial rosacea as special forms,
and granulomatous rosacea (GR) as a
variant.4
The general principles of skin care,
the use of cosmetics, education, as
well as topical and systemic therapies
are all important in limiting outbreaks
of this chronic disease.5,6
SKIN STRUCTURE3
The skin is the outermost layer of our
organism. It interacts with the envi-
ronment, protecting us from poten-
tially harmful physical and biological
agents. Skin acts as a barrier to pre-
vent the loss of body fluids, electro-
lytes, and other substances. It weighs
4 to 5 kg and has a total surface area
of 1.5 m2. It plays important immune
and sensory roles, such as the de-
tection of temperature and pain, the
sense of touch and pressure. Skin
also participates in temperature reg-
ulation and the production of energy,
melanin pigment and vitamin D, as
well as in the excretion of water and
salts. Facial skin is especially import-
ant, because blood flow alterations
determined by shame, fear or other
psychosocial reactions occur in the
midface area.
Epidermis. The epidermis is the out-
ermost layer of the skin. The cells of
the stratum corneum, or horny layer,
are desquamated and become part
of the surface film, which consists of
a hydrolipidic emulsion formed by the
secretions from the skin glands (seba-
ceous, apocrine and eccrine), bacte-
ria, yeasts and, sometimes, Demodex
folliculorum. Although the functions
of this film are not fully known, it is
thought to contribute to skin integrity
and provide protective lubrication to
the skin by complementing the barri-
er function of the stratum corneum.
The composition of this surface film
may vary according to the skin type,
and its integrity is affected by envi-
ronmental factors, such as exposure
to ultraviolet light, humidity, air con-
ditioning, and various components
of environmental pollution. Cosmet-
ics and other topical substances also
alter the hydrolipidic film, increasing
skin sensitivity. In patients with ro-
sacea, there is an increased sensi-
tivity to minor stimuli such as wind,
temperature changes, and cosmetic
products.
The hydrolipidic film rests on the
stratum corneum, which is the outer-
most layer of the skin and is made up
of a compact layer of keratinized cells
(corneocytes) stacked one upon the
other, cemented together by intercel-
lular bridges (corneodesmosomes),
which gives it the appearance of a
brick wall. It is a flexible, waterproof
and almost non-penetrable barrier
that preserves the functionality of
skin. The thickness of the stratum cor-
neum depends on the body location:
in sites exposed to friction, such as the
palms of the hands and the soles of
the feet, it is thicker. It also thickens in
response to repeated ultraviolet light
exposure. The stratum corneum acts
as a first defense against infectious
agents, and maintains homeostasis by
preventing loss of water, body fluids
and electrolytes.
The stratum granulosum, or gran-
ular layer, which lies under the stra-
tum corneum, is made up of cuboidal
cells that show signs of degeneration
and shed their nucleus. These cells
are responsible for the production of
amorphous protein particles, called
pro-filaggrins, which are synthesized
in the granular cytoplasm and trans-
formed into filaggrin. By binding to
intercellular cement, filaggrin con-
tributes to the stratum corneum co-
hesion.
The squamous layer, which lies di-
rectly beneath the granular layer, is
composed of partially flattened cells,
with keratin and soluble proteins such
as involucrin, an integral component
that determines the quality of the
stratum corneum.
The basal, germinative or prolifer-
ative layer is the one from which the
other layers of the epidermis arise,
over a period of approximately 30
days (turnover time). This time varies
with age, season, and other condi-
tions, such as pregnancy and skin dis-
eases. The turnover time in patients
with rosacea is normal.
Other important cells in the epi-
dermis include melanocytes (account-
ing for one in every ten basal cells),
responsible for the production of
the melanin pigment in specialized
organelles called melanosomes. The
color of the skin (white, brown, or
black) is determined by the degree
of melanization. Each melanocyte
transfers melanosomes to several
squamous layer cells up to stratum
66
corneum, maximizing the UV screen-
ing effect. Most patients with rosacea
have very poorly melanized skin and
often, a skin biopsy shows phenome-
na of sun damage (solar elastosis) in
the upper dermis, reflecting suscepti-
bility to sun damage.
Ultraviolet light stimulates the pro-
duction of vitamin D in keratinocytes;
increased vitamin D, in turn, induces
greater expression of cathelicidin LL-
37, the central factor of inflammation
described in the pathophysiology of
rosacea.
Langerhans cells are immuno-
logically competent dendritic cells
which are found in a suprabasal lay-
er. Their role is to order the process
of immune response against foreign
bodies. In skin exposed to ultraviolet
light, there is a reduced number of
these cells.3,7,8
Dermis. Thickness of the dermis also
varies according to the body area
(thinner on the face; thicker on the
back). It is separated from the epi-
dermis by the basement membrane,
and there are fibrils and filaments
that anchor one layer to the other.
The basement membrane provides
mechanical support to the basal cells
and constitutes a kind of semi-per-
meable filter, allowing the passage
of nutrients from the dermis to the
epidermis.
The dermis provides structural
support to the skin through the col-
lagen matrix (produced by the net-
work of fibroblasts) which supports
the mesh of blood vessels, nerves
and lymphatic vessels. The degen-
eration of collagen by exposure to
ultraviolet light (solar elastosis) is a
frequent finding in the biopsies of
patients with rosacea. With age, col-
lagen fibers develop cross-linkages,
and collagenase enzymes (which are
activated by ultraviolet light) metab-
olize the fibrous structure. Elastic fi-
bers make up only 2% of the dermis
fibers, but they give firmness to the
skin, while the ground substance fills
intercellular spaces and provides tur-
gor and capacity to prevent the skin
from deforming.
Sebaceous, apocrine and eccrine
glands, and hair follicles (terminal, vel-
lus or sebaceous, depending on the
type of hair) are located in the der-
mis. The sebaceous glands are large,
richly vascularized and androgen-sen-
sitive. They secrete sebum (a mixture
composed of cholesterol, cholesterol
esters, squalene, wax esters and fatty
acids) and are located in the T zone of
the face (central forehead, nose, and
central chin). These glands are larger
and more active in men. While they
are key in the development of acne le-
sions, their relevance in the develop-
ment of inflammatory rosacea lesions
is under discussion.
 The temperature of the skin can
affect the viscosity of sebum, alter-
ing its ability to spread into the skin.
Some studies of increased facial skin
temperature in rosacea show variable
results but, in general, it is thought
that temperature of affected skin is
1-1.5 °C higher than in the rest of the
face. This can affect the viscosity of
sebum, altering its lubricating quali-
ties and possibly increasing skin sen-
sitivity.
In addition to sebum, there is a
mixture of keratinized cell flakes, cell
detritus, and various microorganisms
such as Pityrosporum ovale, Propioni-
bacterium acnes, Staphylococcus epi-
dermidis, and Demodex folliculorum
on the skin surface. These bacteria
stimulate TLR-2 (toll-like receptors-2)
in the keratinocytes, increase prote-
ase activity and cathelicidin-induced
inflammation. Bacillus oleronius, iso-
lated from D. folliculorum, produces
lipoproteins that additionally stimu-
late TLR-2s,3,7,9 Demodex folliculorum
is found in greater numbers on the
facial skin of patients with rosacea
and this may have a pathogenic sig-
nificance.3
Eyelids. Meibomian glands are
modified sebaceous glands found
in the tarsal plate of the upper and
lower eyelids. They produce the lip-
id component of lacrimal fluid, nor-
mally made up of sterols, waxes,
triglycerides and free fatty acids.
The tear film has lubricating action
and antibacterial properties. In cases
of rosacea with ocular involvement,
there is an alteration in the quantity
and quality of tears, which makes the
tear breakup time abnormally short,
resulting in ocular dryness and for-
eign body sensation. The progressive
worsening of the condition even leads
to keratitis and corneal ulcers. In chil-
dren under the age of 12 with a family
history of rosacea, a higher incidence
of styes and chalazion was reported;
therefore, their existence should raise
suspicion of rosacea development.10
Thermoregulation of the Skin. The
sudoriferous (sweat) glands make it
possible to reduce body temperature
by evaporation. The vascular plex-
uses are networks of blood vessels
that intercommunicate and act with
thermoreceptors of nerve endings
to regulate temperature by vaso-
dilation. In the facial skin, there are
abundant blood vessels. In patients
with rosacea, the reactivity of these
vessels is thought to be abnormal, so
vasodilation occurs for long periods
in response to stimuli such as cold,
heat, stress, alcohol, hot foods or sea-
sonings. This can result in flushing and
blushing episodes.11
Lymphatic vessels. Lymphatic ves-
sels are located in the upper dermis
and drain into the superficial plex-
67
uses. They also interconnect with
deeper plexuses located between
the dermis and the subcutaneous
fat, and from there to the central
lymphatic system. The malfunction
of this facial lymph-draining network
would explain the swelling that oc-
curs in cases of edematous rosacea
or Morbihan disease, and justifies
why facial massages in a rotating
fashion are useful in the manage-
ment of this type of rosacea.3
Neuromediators. Sensory nerve end-
ings and some cells (keratinocytes,
activated endothelial cells, and fibro-
blasts) release neuromediators that
trigger sensations of stinging, pain,
or burning, and also express toll-like
receptors (TLRs), thus creating a link
between the innate immune system
and the nervous system. Neurogenic
inflammation leads to the release of
pro-inflammatory cytokines, resulting
in vasodilation, edema and inflamma-
tion, with manifestations of erythema,
stinging, burning sensation and even
fibrosis by activation of the mast cells.
In neuronal and non-neuronal tissues,
including keratinocytes or endothe-
lial cells, the so-called transient re-
ceptor potential (TRP) channels are
expressed. The most important of
these are TRP vanilloid (TRPV1), re-
lated to capsaicin receptors activated
by spicy seasonings, alcohol and heat,
and TRP ankyrin (TRPA1), related to
pain and activated by cold, formalin
and other substances. The activation
of TRPV1 and TRPA1 releases sub-
stance P (crucial to produce edema)
and peptide related to the calcitonin
gene (important in the dilating effect
of arterioles). There is a genetic pre-
disposition related to the mutation
of a receptor involved in neurovas-
cular regulation (over-expression or
over-stimulation of TRP) involving the
release of neuropeptides (leading to
flushing and edema).7
Subcutaneous Cellular Tissue. This
is the deepest layer of the skin and
serves as a shelter that allows conser-
vation of energy and heat. The subcu-
taneous cellular tissue layer contains
large blood vessels, lymphatic ves-
sels, nerves, and sweat, eccrine and
apocrine glands.
SKIN FUNCTIONS
The functions of the skin are the fol-
lowing: 1) protection (via the stratum
corneum, surface film, Langerhans
cells, nerves, and subcutaneous fat);
2) temperature regulation, through
the network of dermal vessels, ec-
crine secretions, and subcutaneous
fat; 3) sensation, through free nerve
endings; 4) transepidermal absorp-
tion into dermal lymphatic vessels; 5)
possible excretion of toxins by action
of sebaceous, apocrine, and eccrine
glands; 6) synthesis of keratin and
vitamin D; 7) attraction, through the
pleasant effect caused by the skin col-
or and turgor; and 8) communication,
through emotional changes manifest-
ed mainly in the facial skin, and elec-
trical changes (blushing).
SKIN TYPES
According to the Fitzpatrick classifi-
cation, skin types range from 1 to 6,
based on the level of skin reaction to
sun exposure.12
Type 1 is white skin, which always
burns and never tans. Freckles are
present in sun-exposed areas. It is as-
sociated with blond or reddish hair,
and blue or grey eyes.
Type 2 is composed of pale-skinned
individuals. They burn at first, and
eventually tan discreetly. They devel-
op freckles and other characteristics
of type 1 skin.
Type 3 includes individuals with
pale, yellowish skin. They tan easily
and rarely get sunburned. Their hair
is brown or black and their eyes are
brown.
Type 4 is made up of individuals
whose skin is brown, never burns, but
always tans and darkens. Hair and
eyes are like type 3.
Type 5 is composed of individu-
als of Asian origin. They rarely burn,
their eyes are brown, and their hair
is dark.
Type 6 includes people with black
skin, brown eyes and dark hair, that
hardly ever burn.
The color of hair and eyes is a good
parameter to determine the ability to
get sunburned. This occurs mainly in
types 1 and 2, composed of people
with light-colored eyes (blue, green
or grey) or blond and light brown to
reddish hair.
It is important to remember that
patients with rosacea mostly belong
to skin types 1 and 2. Belonging to
these skin groups, the prevalence of
the disease in the midface area, with
extrafacial locations such as the cleav-
age or alopecic areas of the scalp in
males, are data that suggest the im-
portance of sunlight in the pathogen-
esis.
Sensitive Skin
Sensitive skin is a condition that is
not fully understood. It is character-
ized by being a subjective state of
skin hyperreactivity to environmen-
tal, occupational, cosmetic and even
psychological factors. This condition
has a great impact on the quality of
life of patients. The prevalence, which
is high, has been estimated at up to
50%, and increases in adulthood.13
Intrinsic factors that promote sen-
sitive skin include sex (greater occur-
rence in women), phototype (more
68
severity in types 1 and 2), age (greater
susceptibility in young patients), and
hormonal status.
The face is the most common area
of sensitive skin, especially in women
who have a thinner skin barrier due to
more nerve endings in the face and
also to the use of cosmetics. Some
diseases, such as atopic dermatitis,
subclinical contact dermatitis, and ro-
sacea, may lower the skin irritability
threshold.
There is controversy regarding
the ethnic factor, since the inherent
characteristics of the skin and its col-
or can affect skin sensitivity. In black
and Asian skins, there is a higher rate
of transepidermal basal water loss
than in Caucasian skins. However,
there is also reduced percutaneous
absorption which correlates to skin
darkness and leads to less suscepti-
bility to irritants and allergens than
in Caucasians.
Irrespective of these findings, from
an epidemiological point of view, fair-
ly similar numbers of self-perception
of sensitive skin are seen in the dif-
ferent ethnic groups. This phenom-
enon can be explained in relation to
the way of expressing skin discomfort
and the triggering of skin sensitivity,
according to socio-cultural habits in-
herent to each group. For example,
African Americans have a lower skin
reactivity to environmental factors
and alcohol; Asians are more sensitive
to food, seasonings, wind, and alco-
hol; Caucasians have a higher preva-
lence of skin reactivity to alcohol than
Hispanics and are more susceptible to
environmental factors than other eth-
nic groups.14
In the skin structure, these are ad-
ditional intrinsic factors that contrib-
ute to the phenomenon of sensitive
skin: decrease and alteration of the
stratum corneum, decrease in elec-
trical capacitance, a high basal tran-
sepidermal water loss(TEWL) level,
increase in epidermal nerve endings,
number of sweat glands, neutral lipids
and decrease in the amount of sphin-
golipids.15 In cases of sensitive skin,
as previously mentioned, there is a
defective skin barrier, an increase in
the TEWL, an imbalance in hydration,(
i.e. in the diffusion of moisture to the
stratum corneum), and an imbalance
of liquids secreted by the sudorifer-
ous glands. Among the characteris-
tics that predispose to sensitive skin
are the rate of evaporation of mois-
ture from the skin surface and the
difficulty in retaining moisture by the
stratum corneum, the lipid film and
the lipid content.
Patients with sensitive skin rarely
develop allergic contact dermatitis
from the use of topical antibiotics,
cosmetics, preservatives, or agents
included in cosmetics. A deteriora-
tion in the course of the appropriate
treatment of a patient with rosacea
may indicate a contact dermatitis, and
a skin patch test is required. Patients
with sensitive skin, including rosacea
carriers, react intensely to stimuli such
as solar radiation, wind and tempera-
ture. These reactions do not occur if
the skin is normal.3,15
References
1. Cribier B. Rosacée: Nouveautés por
une meilleure prise en charge. Ann
Dermatol Venereol (2017), http://dx.
doi.org/10.1016/j.annder.2017.06.010.
2. Two AM, Wu W, Gallo RL, et al. Ro-
sacea. Part I. introduction, categori-
zation, histology, pathogenesis, and
risk factors. J Am Acad Dermatol
2015; 72(5):749-58.
3. Powell FC. Structure, function, and
sensitivity of skin. In: Powell FC,
Rosacea. Diagnosis and Treatment.
Chapter 1. Informa Healthcare. USA,
Inc. New York; 2009. Pp.:1-14.
4. Kaminsky A, Flórez-White M, Pique-
ro Martin J, et al. (Grupo GILER).
Informe de Consenso IberoLati-
noamericano 2016 sobre la clasifi-
cación clínica y terapéutica de la
rosácea. Med Cutan Iber Lat Am
2016;44(1):6-10. (2016 Iberian-Latin
American Consensus Report on the
Clinical and Therapeutic Classifica-
tion of Rosacea)
5. Two AM, Wu W, Gallo RL, et al. Ro-
sacea. Part II. Topical and systemic
therapies in the treatment of rosa-
cea. J Am Acad Dermatol 2015;72(5):
761-770.
6. Del Rosso JQ, Thiboutot D, Gallo R,
et al. Consensus recommendations
from the American Acne & Rosacea
Society on the management of rosa-
69
cea, part 3: A status report on system-
ic therapies. Cutis 2014;93 (1):18-28.
7. Steinhoff M, Achauber J, Leyden JJ.
New insights into rosacea pathophys-
iology: A review of recent findings. J
Am Acad Dermatol 2013;69: S15-26.
8. Antal AS,Dombrowski Y,Koglin S, et
al. Impact of vitamin D3 on cutane-
ous inmunity and antimicrobial pep-
tide expression. Dermatol endocri-
nol 2011;3:18-22.
9. Braff MH, Zalou M, Fierer J, et al.
Keratinocyte production of catheli-
cidin provides direct activity against
bacterial skin pathogens. Infect Im-
mun 2005;73:6771-81.
10. Arriaga C, Domingues M, Castela
G,et al. Pediatric ocular rosacea, a
misdiagnosed disease with high mor-
bidity: Proposed diagnostic criteria.
World J Dermatol 2016;5 (2):105-114.
11. Powell FC. Flushing and Blushing.
In: Powell FC, Rosacea. Diagnosis
and Treatment. Chapter 2. Informa
Healthcare. USA, Inc. New York;
2009. Pp.:15-31.
12. Fitzpatrick TB. The validity and
practicality of sun-reactive skin
types 1 through 6. Arch Dermatol
1998;124:869-71.
13. Berardesca E, Farage M, Maibach
H. Sensitive skin: an overview. Int J
Cosm Sci 2012;1-7.
14. Jourdain R, De Lacharriere O, Bas-
tien P, et al. Ethnic variations in
self-perceived sensitive skin: epide-
miological survey. Contact Dermati-
tis 2002;46:162-169.
15. Rodrigues-Barata AR, Conde-Sala-
zar Gómez L. Piel sensible. Piel
(Barc)2013;28(9):520-530.
Rosacea is a chronic inflammatory
skin disease that affects more than 15
million adults in the United States. It is
associated with a great psychosocial,
physical and economic compromise.1
Rosacea is also associated with high
utilization of health services –plus an
indirect cost related to low or no la-
bor productivity– and this has a great
impact on quality of life. A recent re-
view of 17 studies on the psychosocial
impact of rosacea found that rosacea
patients have a higher incidence of
shame, social anxiety, depression and
a lower quality of life (QoL) compared
with the general population. Fortu-
nately, proper treatment of symptoms
improves QoL.2
According to the National Rosacea
Society (NRS), rosacea is 2 to 3 times
more prevalent in women, most of
whom are between 30 and 50 years
old.1
WORLDWIDE EPIDEMIOLOGY
Rosacea is a chronic skin entity that
has been studied around the world.
Its prevalence has been investigated
through population-based studies,
but the available data are disparate
and depend to a large extent on the
locale of the study, the population
studied, the phototypes involved, and
the methodology used.
The first study, conducted in 1948
in Denmark (Faroe Islands), estimat-
Chapter 8
Epidemiology
Emilia Zegpi Trueba
ed rosacea prevalence at 0.09 %.3
A Swedish study that evaluated 809
office employees estimated it at 10
%4, while studies conducted in Ger-
many and Estonia reported figures
of 2.2 % and 22 %, respectively.5,6 Lat-
er, Augustin et al. assessed 91,000
German workers and found a prev-
alence of 2.3%; but, unlike in other
available studies, the authors did not
find a higher prevalence of rosacea
in women (2.4% in men and 2.1% in
women).7
Between 1995 and 2009, a large
observational study was performed
using the general practice research
database of the United Kingdom’s
health service. The objective was to
establish the incidence of rosacea
and describe the demographic char-
acteristics and the prevalence of oc-
ular symptoms associated with the
disease. In addition, factors such as
70
smoking and alcohol consumption
were compared for those with rosacea
against control groups. The results
showed an incidence of 1.65/1000
persons per year, with higher rates
in females, and a peak incidence be-
tween 40 and 59 years of age. Eighty
per cent of the cases occurred in pa-
tients over 30 years of age and 61.5 %
were women.8 Ocular symptoms were
reported in 20.8 % of the cases, the
most frequent being the history of
chalazion, followed by conjunctivitis,
dry eye and epiphora. There was a re-
duced relative risk for rosacea among
smokers compared to non-smokers
(odds ratio 0.64; with a confidence in-
terval of 95 % between 0.62 and 0.67).
Alcohol consumption was associated
with a marginally increased risk.8
In the United States, studies con-
ducted by Romanowicz et al. in
9,151,174 people found a rosacea prev-
alence of 1.34 %, while Bamford et al.
found a prevalence of 2.1 %.9,10 In Tuni-
sia, Khaled et al. found a prevalence
of 0.2 %,11 in 244 patients, and Kyriakis
et al. reported a prevalence of 1.2% af-
ter studying 50,237 Greek individuals
examined by dermatologists.12
A recent study conducted in Ger-
many and Russia by Tan et al. to as-
sess the prevalence of rosacea in
the general population recruited
adult individuals from 9 or 10 cities
in each country to ensure adequate
geographical representation. A to-
tal of 3052 and 3013 patients were
screened, respectively in Germany
and Russia. Rosacea prevalence was
12.3 % (confidence interval of 95 %
between 10.2 and 14.4) in Germany
and 5.0 % (confidence interval of 95
% between 2.8 and 7.2) in Russia. The
profile of the individuals with rosa-
cea included 75 % of women with a
mean age of 40 years, who primarily
had skin phototypes II or III and sen-
sitive skin characteristics. One third
of each group reported a moderate
to severe impact on their quality of
life caused by rosacea. Most patients
had not been previously diagnosed.13
There are few studies on the prev-
alence of rosacea in Latin America. A
study of dermatological pathologies
related to climate phenomena in Peru
described 2 % of a total of 3,294 pa-
tients with rosacea in a general hospi-
tal setting. In this study, rosacea was
primarily associated with spring, sun
exposure, and humidity.14 In Colom-
bia, a study of 10,204 patients who
attended dermatological consultation
showed an overall rosacea prevalence
of 2.85 %; among these patients, 43.3
% had erythematotelangiectatic rosa-
cea (ETR), 48.7 % had papulopustular
rosacea (PPR), 4.8 % had phymatous
rosacea and 1 % had ocular rosacea
(OR) as predominant subtypes. Rosa-
cea patients were mostly women with
a mean age of 49 years.15
FAMILY AND GENETIC
FACTORS
Information on the inheritance of ro-
sacea is scarce and unclear. Family
history and some cases in twins sug-
gest there may be a genetic influence.
Two single-nucleotide polymorphisms
(SNPs) have been identified in DNA
of patients with rosacea, and 3 HLA
alleles, all MHC class II proteins (HLA-
DRB1, HLA-DQB1 and HLA-DQA1),
have been significantly associated
with rosacea.16 Studies of identical
twins have established the impor-
tance of genetic factors (46 %) versus
environmental factors, such as UV
radiation exposure, alcohol, smoking,
history of skin cancer, cardiac comor-
bidities, and age.17 Family history of
affected parents or relatives is often
present, with various studies report-
ing percentages of 15-20 %; family
history of rosacea constitutes a risk
factor for the disease, especially in
cases of childhood rosacea.10,15,18,19
Although the frequency is higher
in patients with light colored skin, it
is more difficult to recognize in col-
ored skin and, therefore, most likely
is underdiagnosed in darker-skinned
individuals. The exact epidemiology
of rosacea in dark skin is not known
because there are no extensive stud-
ies and because facial redness can be
masked by darker pigmentation. It is
possible also that those with dark skin
have a lower risk of rosacea due to
the protective mechanisms of melanin
against UV radiation; UV radiation is
known to trigger the disease in light-
skinned populations. A North Ameri-
can study that gathered information
from a large database between 1993
and 2010 estimated rosacea preva-
lence at 2 % in black patients, 2.3 % in
Asians, and 3.9 % in Latinos.20
RISK FACTORS
Rosacea is more common in women
(3:1), but when it develops in men, it
is usually associated with more com-
plications. The phymatous subtype
is more prevalent in males. The ex-
act pathophysiology of rosacea is
unknown and many risk factors have
been proposed, such as exposure to
UV light, immune dysregulation, and
infectious agents. UV radiation has
been recognized as a potential risk
factor. It is known that UV light plays
71
a key role in the pathogenesis which
may be due to a loss of connective
tissue, mediated by metalloprotein-
ases, and through stimulation of the
cathelicidin pathway, especially in fair-
skinned individuals. The UV risk factor
is mainly associated with the erythe-
matotelangiectatic subtype, as well as
hot baths and exercise.21 An Irish study
of 1,000 individuals –500 of them with
a history of low UV exposure and 500
with high UV exposure– showed a
prevalence of papulopustular rosacea
of 2.6 % and 2.8 %, respectively (P =
NS for difference between groups).
Therefore, exposure to ultraviolet
light may not be the only factor affect-
ing the prevalence of this subtype of
rosacea.22
Another factor to consider is the
influence that smoking may have
on patients with rosacea, which has
been assessed in very few published
studies. One study describes rosa-
cea as a non-smoker’s disease and
another as an ex-smoker’s disease.18
In a recent prospective study, 200
adult patients with rosacea (66%
smokers) were compared to 200
controls (21% smokers) and the risk
of developing rosacea was shown
to be higher in active smokers. The
ratio of erythematotelangiectatic
subtype (43.5 %) was significantly
higher among active smokers (p <
0.001), probably due to the vaso-
constricting effect of nicotine on
the skin microcirculation, which re-
duces oxygen pressure and stimu-
lates angiogenesis. Moreover, the
proportion of patients with a posi-
tive family history was significantly
higher in this subgroup.19
Another potential rosacea risk fac-
tor that has been studied is alcohol
consumption, which is also under dis-
cussion because some studies do not
consider it a risk factor.18
To determine the association be-
tween alcohol consumption and risk
of rosacea in women, a cohort study
was conducted and results showed
that increased alcohol intake was as-
sociated with a significantly higher
risk of rosacea. A more detailed exam-
ination of the types of alcoholic bev-
erage consumed revealed that white
wine (P trend < 0.0001) and liquor
intake (P trend = 0.0006) were highly
associated with an increased risk of
developing the disease.23
Many years of exposure to high
temperatures that generate facial heat
constitutes an additional risk factor. An
interesting Turkish study, which includ-
ed 200 women exposed for several
years to 400 °C in bread baking ovens,
showed that flushing, erythema and
telangiectases occurred due to the
vasodilation –and more angiogenesis–
were caused by exposure to such high
temperatures.24
 Several comorbidities have also
been associated with rosacea.
Among these, migraine stands out
with reports from more than 30
years ago; Tan and Cunliffe reported
data from 137 patients with rosacea,
60 of which (44 %) had migraine.25
This association was supported by
a recent Danish study, which ana-
lyzed a national health database
and established a significantly high-
er prevalence of migraine in women
with rosacea, and especially among
those 50 years or older (7.3 % in the
reference population vs. 12.1 % in pa-
tients with rosacea). Similar results
were published by Berg and Liden,
who describe a co-occurrence of
migraine and rosacea but only in
postmenopausal women (27 % vs. 13
% of women with and without rosa-
cea, respectively). Undoubtedly, this
is due to vascular abnormalities and
triggering factors such as stress and
alcohol, which are implicated in both
conditions.26-28
Neurological disorders have
also been associated with rosacea,
including multiple sclerosis, Par-
kinson’s disease and Alzheimer’s
disease; the connection between
diseases may be partly explained by
a genetic predisposition, but also
by the role of the intestinal micro-
flora and gastrointestinal barrier as
a nexus through various neuroim-
mune pathways.29,30
It is worth mentioning the associ-
ation between rosacea and inflam-
matory bowel disease, especially
ulcerative colitis. Both are chronic in-
flammatory epithelial diseases whose
pathophysiologic backgrounds cor-
respond to alterations of the innate
immune system. A study in the United
Kingdom, based on a large database,
showed increased risk of developing
both diseases, especially short-term
ulcerative colitis and during inflamma-
tory crises of the intestinal tract.31
It is well known the rosacea has
an impact on self-esteem because
it affects the face. Rosacea has also
been associated with a poor quality
of life, and greater risk of depression
and anxiety compared with healthy
individuals. A Danish study, based
on a large database of the national
health system and a follow-up of up
to 15 years, confirmed this association,
which was also correlated with the se-
verity of the facial condition.32
Other systemic comorbidities as-
sociated with moderate to severe
rosacea include hyperlipidemia, hy-
pertension, type 1 diabetes, rheu-
matoid arthritis, and cardiovascular
disease.33
In conclusion, epidemiological
studies on rosacea estimate wide vari-
ations as regards its prevalence, which
result from differences in the studies’
72
design, environmental factors, and
phototype of the studied population
(Table 8-1). Studies on the prevalence
of rosacea in the pediatric population
and in very dark phototypes are al-
most non-existent.
Table 8-1. Risk factors18,19,22-24
Definitive
Skin phototypes I-II
Heat and exercises
Family history
Smoking
Possible
Gender
Caffeine/Alcohol intake
Presence of H. pylori
Educational level
Occupational
It is necessary to refine the diagnos-
tic criteria in the different subtypes of
rosacea, particularly in subtypes such
as ocular rosacea, in order to have
more precise data and continue to
make progress in the study and treat-
ment of this condition.
References
1. Okhovat JP, Armstrong AW. Up-
dates in rosacea: Epidemiology, risk
factors, and management strategies.
Curr Derm Rep 2014; 3:23-8.
2. Moustafa F, Lewallen RS, Feldman
SR. The psychological impact of ro-
sacea and the influence of current
management options. J Am Acad
Dermatol 2014; 71(5):973-80.
3. Lomholt G. Prevalence of skin dis-
eases in a population; a census
study from the Faroe Islands. Dan
Med Bull 1964; 11:1-7.
4. Berg M, Liden S. An epidemiological
study of rosacea. Acta Derm Vene-
reol 1989; 69:419-23
5. Schaefer I, Rustenbach SJ, Zim-
mer L, et al. Prevalence of skin
diseases in a cohort of 48,665 em-
ployees in Germany. Dermatology
2008,217:169-72.
6. Abram K, Helgi S, Marge O. Prev-
alence of rosacea in an Estonian
working population using a stan-
dard classification. Acta Derm Vene-
reol 2010; 90:269-73.
7. Augustin M, Herberger K, Hintzen
S, et al. Prevalence of skin lesions
and need for treatment in a cohort
of 90,880 workers. Br J Dermatol
2011;165 (4):865-73.
8. Spoendlin J, Voegel J, Jick S, et al.
A study on the epidemiology of ro-
sacea in the UK. Br J Dermatol 2012;
167:598-605.
9. Romanowicz M, Stephenson JJ,
Del Rosso JQ, et al. Healthcare uti-
lization and costs of patients with
rosacea in an insured population. J
Drugs Dermatol 2008;7 (1):41-9.
10. Bamford JT, Gessert CE, Reni-
er CM, et al. Childhood stye and
adult rosacea. J Am Acad Dermatol
2006;55 (6):951-5.
11. Khaled A, Hammami H, Zeglaoui F,
et al. Rosacea: 244 Tunisian cases.
Tunis Med 2010; 88(8):597-601.
12. Kyriakis KP, Palamaras G, Terzoudi
S, et al. Epidemiologic aspects of
rosacea. J Am Acad Dermatol 2005;
53(5):918-9.
13. Tan J, Schöfer H, Araviskaia E, et al.
Prevalence of rosacea in the gen-
eral population of Germany and
Russia-The RISE study. JEADV 2016;
30:428-34.
14. Gutierrez EL, Galarza C, Ramos W, et
al. Influence of climatic factors on the
medical attentions of dermatologic
diseases in a hospital of Lima, Peru.
An Bras Dermatol 2010; 85:461-8.
15. Rueda LJ, Motta A, Pabón JG, Bar-
ona MI, et al. Epidemiology of ro-
sacea in Colombia. Int J Dermatol
2017. doi:10.1111/ijd13491.
16. Chang Al, Raber I, Xu J, et al. Assess-
ment of the genetic basis of rosacea
by genome wide association study. J
Invest Dermatol 2015; 135:1548-55.
17. Aldrich N, Gerstenblith M, Fu Ping-
fu, et al. Genetic vs environmental
factors that correlate with rosacea:
a cohort-based survey of twins.
JAMA Dermatol 2015, e1-e7. doi:
10.1001/jamadermatol. 2015.2230.
18. Abram K, Silm H, Maaroos H-I, et al.
Risk factors associated with rosa-
cea. J Eur Acad Dermatol Venereol
2010; 24:565-71.
19. Kucukunal A, Altunay I, Arici J, et al.
Is the effect of smoking on rosacea
still somewhat of a mystery? Cutan
Ocul Toxicol 2016; 35(2):110-4.
20. Al-Dabagh A, Davis S, Mc Michael A,
et al. Rosacea in skin of colour: not
a rare diagnosis. Dermatol Online J
2014; 20(10): pii:13030/qt1mv9r0ss.
73
21. Steinhoff M, Schauber J, Leyden J.
New insights into rosacea patho-
physiology: A review of recent
findings. J Am Acad Dermatol.
2013;69: S15-S26
22. McAleer M, Fitzpatrck P, Powell F.
Papulopustular rosacea: Prevalence
and relationship to photodamage. J
Am Acad Dermatol 2010; 63:33-9
23. Suyun Li, Eunyoung Cho, Aaron M,
et al. Alcohol intake and risk of rosa-
cea in US women. J Am Acad Der-
matol 2017; 76(6):1061-67.
24. Ozkol H, Calka O, Akdeniz N, et al.
Rosacea and exposure to tandoor
heat: Is there an association? Int J
Dermatol 2015; 54:1429-43.
25. Tan SG, Cunliffe WJ. Rosacea and
migraine. Br Med J 1976; 1:21.
26. Egeberg A, Ashina M, Gaist D, et
al. Prevalence and risk of migraine
in patients with rosacea: a popula-
tion-based cohort study. J Am Acad
Dermatol 2017; 76(3):454-8.
27. Barkum JM. Migraine triggers and
oxidative stress: a narrative review
and synthesis. Headache. 2016;
56:12-35.
28. Berg M, Liden S. Postmenopausal
female rosacea patients are more
disposed to react with migraine.
Dermatology 1996; 193:73-4.
29. Egeberg A, Hansen PR, Gislason
GH, et al. Clustering of autoimmune
diseases in patients with rosacea. J
Am acad Dermatol.2016; 74(4):667-72.
30. Klingelhoefer L, Reichmann H. Patho-
genesis of Parkinson disease: the gut-
brain axis and environmental factors.
Nat Rev Neurol 2015; 11(11):625-36.
31. Spoendlin J, Karatas G, Furlano R, et
al. Rosacea in patients with ulcerative
colitis and Crohn disease: A popula-
tion-based case-control study. In-
flamm Bowel Dis 2016; 22:680-7.
32. Egeberg A, Hansen PR, Gislason
GH, et al. Patients with rosacea
have increased risk of depression
and anxiety disorders: A Danish Na-
tionwide cohort study. Dermatolo-
gy 2016, DOI:10.1159/000444082.
33. Rainer BM, Fischer AH, Luz Felipe
da Silva D, et al. Rosacea is associat-
ed with chronic systemic diseases in
a skin severity-dependent manner:
results of a case-control study. J Am
Acad Dermatol 2015; 73(4):604-8.

Although the pathogenesis of rosa-
cea is not well known, recent advanc-
es point to the importance of the
interaction between the skin and en-
vironmental factors: physical, chemi-
cal and microbiological ones. Altered
barrier function and activation of the
innate immune defense system are
the most important contributors to
the persistence of the inflammatory
response in rosacea-affected skin.1
SEBUM PRODUCTION
Rosacea may develop both in patients
with dry skin and in those whose skin
has a high seborrheic index.2 Lip-
ids produced by sebaceous glands
are known to be responsible for the
three-dimensional structure of surface
lipids; this structure contributes to the
integrity of the skin barrier. Skin lipids
have potent antimicrobial activity, and
also bring antioxidant molecules to the
Chapter 9
Pathogenesis
Skin Barrier and Rosacea
Mercedes Flórez-White
surface and express pro-inflammato-
ry and anti-inflammatory properties,
which maintains a slightly acidic pH.3
Study of lipids of the sebaceous glands
in the sebum of patients with papulo-
pustular rosacea (PPR) showed an im-
balance in the concentration of fatty
acids. Myristic acid was present at a
higher concentration in rosacea vs. the
control group, while the concentration
of saturated long-chain fatty acids (be-
henic, tricosanoic and lignoceric), as
well as monounsaturated cis-11-eicosa-
noic acid, were lower in rosacea com-
pared with the control group. These
data support the evidence that the
production of sebum, fatty acids in
74
particular, may influence the barrier in-
tegrity of patients with PPR.2,4
PERMEABILITY OF THE
STRATUM CORNEUM AND
DAMAGE TO BARRIER FUNCTION
Deterioration of the stratum corneum
(SC) permeability, which affects the skin
of the midface area in patients with ro-
sacea, is an important factor in patients
with erythematotelangiectatic rosa-
cea (ETR) and PPR. This deterioration
seems to contribute to the appearance
of sensitive skin, with (visible or not)
signs of “low-grade” facial dermatitis
(fine scales and erythema), known as
dermatitis caused by rosacea.5
The increase in transepidermal water
loss (TEWL) as well as the decrease
in hydration and the deterioration of
the SC permeability barrier explain,
at least partially, the signs and symp-
toms referred to by patients with PPR
at the beginning of the therapy, de-
spite not being in active treatment.
Deterioration of the SC permeability
predisposes the skin to intolerance to
common products such as cleansers,
retinoids, lactic acid, and moisturiz-
ers; in rosacea, this intolerance/sensi-
tivity may contribute to a burning and
stinging sensation. It is also important
to recognize that the SC permeability
barrier and the antimicrobial barrier,
including the cathelicidin and serine
protease (SP) systems, are structur-
ally and functionally interrelated and
co-regulated. The expression and
secretion of antimicrobial peptides
(AMPs) increases in response to the
altered permeability barrier, including
the cathelicidin-derived peptide LL-
37, required for the maintenance of
epidermal barrier homeostasis.5,6
SKIN BARRIER AND IMMUNE
SYSTEM
The role of the skin as a physical barri-
er is important for the innate immune
system. In several chronic inflammato-
ry skin diseases, such as rosacea, atop-
ic dermatitis and psoriasis, alterations
in the epidermal barrier are believed
to be the main pathogenic factor. In
the skin of patients with rosacea, dam-
age to the epidermal barrier is evi-
denced by increased TEWL.7 A study
by Ni Raghallaigh and Powell showed
a reduction in epidermal hydration
levels in the skin of patients with PPR
whose epidermis in the midface was
also more alkaline than that of healthy
control groups. Since protease activity
increases at alkaline pH, the abnormal
epidermal barrier function in rosacea
patients may be associated with an
increased activation of epidermal pro-
teases, especially kallikrein 5 (KLK-5).8,9
There is also evidence that the pattern
of innate immune response is altered
by increased expression of TLR-2
(toll-like receptor 2), resulting in an
increased expression of KLK-5 in ke-
ratinocytes. Thus, the barrier damage
observed in patients with rosacea is
possibly exacerbated by the increased
expression of kallikrein, which would
remain at normal or even reduced
concentrations in other inflammatory
dermatoses.7
Skin Barrier Alteration and
Colonization by Demodex folliculorum
Colonization by Demodex, an aggra-
vating factor of inflammation in ro-
sacea, appears to be more common
in patients with abnormalities in the
skin barrier.10 A study by Zhao et al.
on facial skin diseases with a higher
prevalence of Demodex (perioral der-
matitis, seborrheic dermatitis, steroid
dermatitis, and rosacea dermatitis)
showed higher levels of infestation in
abnormal (drier or more seborrheic)
skins than inthose with normal levels
of hydration and sebum secretion;
this difference was particularly pro-
nounced in patients over 30 years
of age.11 Chitins (proteins from De-
modex) activate the inflammatory re-
sponse in keratinocytes, in addition
to inflammation induced by increased
protease activity and cathelicidins.2
In conclusion, the function of
the skin barrier is compromised in
patients with rosacea, which is ev-
idenced by increased TEWL and
reduced hydration. Damage to the
barrier leads to a change in the func-
tions of the innate immune system,
which increases AMPs such as the
cathelicidin-derived peptide LL-37 re-
quired to maintain epidermal barrier
homeostasis. In some cases, alteration
of barrier function allows a greater
75
infestation by Demodex folliculorum,
which leads to increased inflamma-
tion due to activation of TLR-2s and,
consequently, to the alteration of the
innate immunity. Skin barrier repair is
vital in the treatment of rosacea, espe-
cially in the papulopustular subtype.
Therefore, it is important to keep
this in mind when thinking about the
treatment. The use of barrier-repair
cleansers and moisturizers –products
that are free of potentially irritating
substances– can play a very important
role in the proper management of the
disease, helping to reduce inflamma-
tion and, consequently, symptoms.
References
1. Zhou M, Xie H, Cheng L, et al. Clinical
characteristics and epidermal barrier
function of papulopustular rosacea: A
comparison study with acne vulgaris.
Pak J Med Sci 2016;32(6):1344-1348.
2. Addor FAS. Skin barrier in rosacea.
An Bras Dermatol 2016;91(1):59-63.
3. Zouboulis CC. Acne and seba-
ceous gland function. Clin Dermatol
2004;22:360-6.
4. Ní Raghallaigh S, Bender K, Lacey
N, et al. The fatty acid profile of
the skin surface lipid layer in pap-
ulopustular rosacea. Br J Dermatol
2012;166:279-87.
5. Del Rosso JQ. Advances in under-
standing and managing rosacea:
Part 1 connecting the dots between
pathophysiological mechanisms and
common clinical features of rosacea
with emphasis on vascular changes
and facial erythema. J Clin Aesthet
Dermatol 2012;5(3):16-25.
6. Elias PM. The skin barrier as an in-
nate immune element. Semin Immu-
nopathol 2007;29:3-14.
7. Dirschka T, Tronnier H, Folster-Holst R.
Epithelial barrier function and atopic
diathesis in rosacea and perioral derma-
titis. Br JDermatol 2004; (150): 1136-1141.
8. Woo YR, Lim JH, Cho DH, et al. Ro-
sacea: Molecular mechanisms and
management of a chronic cutaneous
inflammatory condition. Int J Mol Sci
2016;17(9):1-23.
9. Ni Raghallaigh S, Powell FC. Epidermal
hydration levels in patients with rosa-
cea improve after minocycline therapy.
Br J Dermatol 2014; ( 171): 259-266.
10. Forton F. Papulopustular rosacea, skin
immunity and Demodex: Pityriasis fol-
liculorum as a missing link. J Eur Acad
Dermatol Venereol 2012; ( 26): 19-28.
11. Zhao YE, Peng Y, Wang XL, et al.
Facial dermatosis associated with
Demodex: a case-control study. J
Zhejiang Univ Sci B 2011;12:1008-15.
Although the causes of rosacea are het-
erogeneous and not entirely known, it
has been suggested that genetics and
the environment may play an import-
ant role.1 Some factors strongly associ-
ated with risk of rosacea are: having a
first-degree relative with rosacea, ad-
vanced age, clear and photosensitive
phototypes, as well as sun exposure
and smoking. This suggests a complex
process with a multifactorial basis that
includes genetic and environmental in-
fluences.2,3 To date, little research has
been conducted on the influence of
genetics on rosacea.
THE EVIDENCE
Some studies that shown overex-
pression of some genes in patients
with rosacea, the presence of some
polymorphism or, simply, the fami-
ly condition found in identical twins.
Studies carried out in previous years4
found an association between the
vitamin D receptor (VDR) gene and
patients with rosacea fulminans. Al-
lelic polymorphisms of this receptor
were studied and a predominance of
the VDR receptor allele 1 was found
in these patients. In addition, it was
established that the VDR and reti-
noic acid receptor (RXR) pathways
may correlate,5 which suggests an
involvement of the VDR/RXR path-
way. Another study reported GSTM1
and GSTT1 polymorphisms in patients
with rosacea. These genes are asso-
ciated with glutathione S-transfer-
Rosacea Genetics
Sandra Cecilia García-García
ases, which play an important role in
cell defense against reactive oxygen
species (whose levels are elevated
in rosacea).6 A more recent study7
assessed the contribution of genetic
and environmental factors in a cohort
of identical twins (monozygotic twins,
which share 100 % of their genetic
material) and fraternal twins (dizy-
gotic twins, which share 50 % of their
genetic material). This study evaluat-
ed 275 twin pairs (233 identical twins
and 42 fraternal twins) and found a
significantly higher rate of rosacea in
identical twins. Furthermore, the cor-
relation of the total National Rosacea
Society (NRS) score was higher in
identical twins than in fraternal twins,
where a genetic contribution of about
46 % was calculated. Other variables
were also significantly correlated with
a higher NRS score: body mass index,
smoking, alcohol consumption, car-
diovascular comorbidities, and skin
cancer prevalence. With these data,
the authors concluded that 50 % of
the contribution to the NRS score
could be accounted for by genetics
and the other 50 % by the environ-
ment. This study is the only one that
formally defines the genetic and envi-
ronmental contribution of rosacea in
twin patients.
76
A 2015 study of the human genome
which included 22,952 individuals
(mostly of European origin) reported a
prevalence of rosacea of 11 %.8 In this
study, 2,618 individuals had rosacea
and 20,334 did not, a full genome anal-
ysis was carried out and statistically
significant single nucleotide polymor-
phisms (SNPs) were detected in the ro-
sacea group compared to the control
group. Rosacea was associated with
rs763035 SNP; this SNP is intergenic
and located 12,774 bp (base pairs) up-
stream of HLA-DRA (major histocom-
patibility complex class II antigen, DR
alpha chain) and 19,945 bp downstream
of BTNL2 (butyrophilin-like 2, major
histocompatibility complex class I).
Skin biopsies of papulopustular rosa-
cea lesions were stained and positive
for HLA-DRA and BTNL2, proving
the pathogenic importance of these
two molecules. The region located in
HLA-DRA has been associated with
multiple sclerosis, an inflammatory
entity like rosacea.9 BTNL2 belongs to
the immunoglobulin gene superfami-
ly, associated with other autoimmune
diseases such as inflammatory bowel
disease and sarcoidosis.10 The latter is
a granulomatous condition involving
skin; although they are distinct pathol-
ogies, there is a subtype of rosacea
that can also display granulomas.11 In
the same study of the genome8, the
relationship between the SNP and
its closest genes was analyzed, with
significant associations. One of them
was HLA-DRB1*03:01, which has been
associated with diabetes and diabet-
ic retinopathy, a vascular proliferative
disorder of the eye. Rosacea also ex-
hibits abnormal proliferation of blood
vessels, including the ocular conjunc-
tiva. Another association was with
HLA-DQB1*02:01, related with celiac
disease. Although it would be difficult
to establish a causal relationship, this
disease is known to involve the small
intestine, and rosacea has been associ-
ated with bacterial overgrowth condi-
tions located in the small intestine too.
These data strongly suggest a role for
antigen presentation by class II HLA
in the etiology of rosacea, as well as a
potential connection between rosacea
and other human diseases, such as dia-
betes and celiac disease.
Another bibliographic contribution
of genetics in rosacea is a study con-
ducted in 2015,12 in which 26 cases of
ETR were compared with 20 cases of
telangiectatic photoaging and with
11 control patients. Gene expression
was analyzed in all three groups, and
15 overexpressed genes were found
in patients with rosacea compared to
controls; 10 of them were significant
compared to patients with telangiec-
tatic photoaging. Some of these im-
portant overexpressed genes were
those associated with neuropeptides,
such as calcitonin gene-related pep-
tides (CGRP) CALC A AND CALC B,
in addition to the tachykinin precursor
TAC 1 gene, which encodes substance
P, neurokinin A, neuropeptide K, and
neuropeptide gamma.Other overex-
pressed genes were associated with
mast cell chemotaxis and inflammatory
mediators, including the CXCL12 and
CXCR4 genes, and IL-12B and TNF-a
genes. Other t genes associated with
matrix remodelling were also implicat-
ed, including collagen I and III (COL1,
COL3) angiogenic inducer rich in
cysteine (CYR61), Decorin (DCN) an
important dermal proteoglycan and,
MMP1, MMP3, and MMP9.
Finally, another overexpressed gene
associated with innate immunity was
identified, the DEFA1 gene, which
encodes defensin alpha-1. Although
the complex interaction between the
cellular and molecular pathways of
rosacea is not fully known, with this
information, the authors proved an
important role of mast cells and neu-
ropeptides in the erythematotelan-
giectatic variety of this disease. It is
worth mentioning that other groups
had previously demonstrated mast cell
participation and increased number in
rosacea.13,14 Further, overexpressed cy-
tokines in patients with rosacea, such
as CXCL12 and its CXCR4 receptor,
play an important role in mast cell mi-
gration.15 CGRP and substance P neu-
ropeptide levels were also found to be
significantly elevated.12
In conclusion, rosacea is a chron-
ic, multifactorial inflammatory entity,
common in the general population;
however, few studies have investigat-
ed the genetic factors underlying ro-
sacea. Although little is known about
the subject, the findings reported in
the literature contribute to discover-
ing more and more genes, molecular
pathways and cytokines involved in
rosacea, which corroborate the high
complexity that surrounds this dis-
ease. Genetics in rosacea is an area
that should be further explored to
gain deeper insight into the complex
associations, and thus contribute to a
better understanding of this disease,
as well as a better diagnostic and
therapeutic approaches.
References
1. Chosidow O, Cribier B. Epidemiology
of rosacea: updated data. Ann Derma-
tol Venereol 2011;138 Suppl 3:S179-183.
2. Abram K, Silm H, Maaroos HI, et al.
Risk factors associated with rosa-
cea. J Eur Acad Dermatol Venereol
2010;24(5):565-571.
3. Steinhoff M, Schauber J, Leyden JJ.
New insights into rosacea pathophysi-
77
ology: a review of recent findings. J Am
Acad Dermatol 2013;69(6 Suppl 1):S15-26.
4. Jansen T, Krug S, Kind P, et al. BsmI
polymorphism of the vitamin D re-
ceptor gene in patients with the
fulminant course of rosacea conglo-
bata (rosacea fulminans). J Dermatol
2004;31(3):244-246.
5. Carlberg C. Mechanisms of nu-
clear signalling by vitamin D3. In-
terplay with retinoid and thyroid
hormone signalling. Eur J Biochem
1995;231(3):517-527.
6. Yazici AC, Tamer L, Ikizoglu G, et al.
GSTM1 and GSTT1 null genotypes
as possible heritable factors of rosa-
cea. Photodermatol Photoimmunol
Photomed 2006;22(4):208-210.
7. Aldrich N, Gerstenblith M, Fu P, et
al. Genetic vs environmental factors
that correlate with rosacea: A co-
hort-based survey of twins. JAMA
Dermatol 2015;151 (11):1213-9.
8. Chang AL, Raber I, Xu J, et al. As-
sessment of the genetic basis of
rosacea by genome-wide asso-
ciation study. J Invest Dermatol
2015;135(6):1548-1555.
9. Hafler DA, Compston A, Sawcer S, et
al. Risk alleles for multiple sclerosis
identified by a genomewide study. N
Engl J Med 2007;357(9):851-862.
10. Valentonyte R, Hampe J, Huse K, et al.
Sarcoidosis is associated with a trun-
cating splice site mutation in BTNL2.
Nat Genet 2005;37(4):357-364.
11. Rallis E, Korfitis C. Isotretinoin for
the treatment of granulomatous
rosacea: case report and review of
the literature. J Cutan Med Surg
2012;16(6):438-441.
12. Helfrich YR, Maier LE, Cui Y, et al.
Clinical, histologic, and molecular
analysis of differences between ery-
thematotelangiectatic rosacea and
telangiectatic photoaging. JAMA
Dermatol 2015;151(8):825-836.
13. Aroni K, Tsagroni E, Kavantzas N,
et al. A study of the pathogenesis
of rosacea: How angiogenesis and
mast cells may participate in a com-
plex multifactorial process. Arch
Dermatol Res 2008;300(3):125-131.
14. Schwab VD, Sulk M, Seeliger S, et al.
Neurovascular and neuroimmune
aspects in the pathophysiology of
rosacea. J Investig Dermatol Symp
Proc 2011;15(1):53-62.
15. Juremalm M, Hjertson M, Olsson
N, et al. The chemokine receptor
CXCR4 is expressed within the
mast cell lineage and its ligand stro-
mal cell-derived factor-1alpha acts
as a mast cell chemotaxin. Eur J Im-
munol 2000;30(12):3614-3622.
Facial erythema is the primary feature
of all subtypes of rosacea, especially
erythematotelangiectatic and papu-
lopustular ones, and may also occur
in phymatous rosacea (PR) and ocular
rosacea (OR). It is usually diffuse, local-
ized to the central region of the face,
and persists despite the resolution of
inflammatory lesions.1 Vascular chang-
es observed in rosacea (Table 9-1) occur
in susceptible individuals and are trig-
gered after exposure to environmental
factors and certain lifestyles (exposure
to UV radiation, temperature changes,
exercising and consumption of spicy
food or alcohol, among others).2
From the clinical point of view,
three types of vascular changes can
be identified:
1. Transient erythema: occasional red-
ness that lasts minutes to hours.
2. Persistent erythema: redness that
lasts days to weeks.
3. Perilesional erythema: redness that
appears around papules or pus-
tules,3 and disappears with inflam-
matory lesion clearance.1
It is not known whether the patho-
physiological processes of transient
or persistent types of erythema are
different. However, triggering factors
that induce erythema in patients are
variable.
Vascular Hyperreactivity
Linda García Hidalgo
A fourth vascular reaction is blush-
ing, which appears as a lighter, pink
erythema, not predominantly located
in the T zone of the face (central fa-
cial region) but more usually homoge-
neously distributed in the central area
of the face and peripheral cheeks, and
behind the ears (not present in flush-
ing). Blushing is mediated by the sym-
pathetic nervous system, as a response
to emotions or stress, is transient and
is not associated with inflammation,
unlike erythema associated with rosa-
cea. It can be a confounding factor in
rosacea.3-5 Flushing shares many clini-
cal and histological features, as well as
the development of capsaicin-induced
neurogenic inflammation, comprising
sustained vasodilation, edema of super-
ficial dermis and leukocyte infiltration.
Flushing is triggered by stimulation of
the sensory nerves, through release of
neuropeptides which generate acute
neurogenic inflammation. Patients with
ETR have a marked mast cell infiltrate
and significant local increase of inflam-
matory neuromediators and cytokines,
which indicates that flushing is an acute
inflammatory process induced by sen-
sory nerves.6 Recent studies with colour
laser Doppler detected blood flow after
iontophoresis of acetylcholine, which
indicates that an axon reflex mechanism
78
is responsible for enhanced flushing in
patients with the most severe rosacea
symptoms.7
In addition to erythema, extensive
telangiectases throughout the super-
ficial and middle dermis are a main
histological feature of ETR. There
may also be telangiectasia in the oth-
er types of rosacea. Signs of blood
vessel angiogenesis only occur in the
phymatous (PR) subtype (Table 9-1).
VASCULAR MEDIATORS
Erythema is the result of an acute in-
flammatory process, induced by the
stimulation of the sensory nerves,
leading to a local increase in mast cell
infiltrate, inflammatory neuromedia-
tors and cytokines.5 Critical vascular
mediators that induce persistent ery-
thema include potent vasoregulatory
neuropeptides such as pituitary ade-
nylate cyclase-activating polypeptide
(PACAP), vasoactive intestinal peptide
(VIP) or calcitonin gene-related peptide
(CGRP), which induce prolonged vaso-
dilation.3,8 Other potent vasodilators
are nitric oxide, substance P, reactive
oxygen species (ROS) and proteases.3,8
All 3 skin-subtypes of rosacea demon-
strate similar histopathological changes
Table 9-1. Vascular changes in
rosacea
Changes in the blood flow
Increased blood flow in facial skin.
Decreased venous flow from the periphery to
the brain induced by heat.
Stimulation of vasodilation and angiogenesis
Cathelicidin LL-37- Promote angiogenesis
and neovascularization through the
activation of the NLRP3 complex, which
is responsible for activation of inflammatory
processes
VEGF increase that stimulates angiogenesis
Increase in endothelial nitric oxide and
proteases that induces vasodilation
Progressive chronic vasodilation and
angiogenesis
Larger and dilated blood vessels with
subsequent formation of telangiectases..
with enlarged, dilated arterioles, capil-
laries and venules in the upper dermis,
postcapillary edema and transmigra-
tion of leukocytes (predominantly T
cells and monocytes). 2,8
MMPs are increased more than
300 times in all three non-ocular sub-
types of rosacea, especially MMP-12,
-1 and -9, which contribute to tissue
destruction and the subsequent de-
velopment of telangiectases6.
In patients with rosacea, mRNA
levels of markers for angiogenesis or
lymphatic vessel regulation, such as
vascular endothelial growth factor A
(VEGF A), CD31, podoplanin or lym-
phatic (D2-40) are also increased.1
These mRNA levels for angiogenesis
do not correlate with immunohisto-
chemistry data that indicate marked
vasodilation in ETR and PPR, although
angiogenesis is present in phymatous
rosacea; this raises a question regard-
ing an eventual progression from
ETR/PPR to phyma through chronic
inflammatory processes that result in
fibrotic changes.8 Despite all structur-
al changes, vascular responsiveness in
patients with rosacea remains intact,
with increased and sustained vasodi-
lation in response to the above-men-
tioned trigger factors.1
TRANSIENT RECEPTOR
POTENTIAL CHANNELS
Another main player in vascular
changes of rosacea are ionic chan-
nels, such as the members of the
transient receptor potential (TRP)
family, including TRPV (vanilloid re-
ceptor) and TRPA (ankyrin recep-
tor). They are located in nociceptive
nerve endings and are activated by
several trigger factors for rosacea,
especially spicy food, heat, exercis-
ing and alcohol consumption, and
produce prolonged vasodilation and
neurogenic inflammation.9 Patients
with rosacea have a higher density
of TRPV-1-positive nerve fibres, in-
creased levels of TRPV-1 expression,
and longer-than-normal activation of
TRP channels on nociceptors, leading
to longer-lasting erythema.3
The cutaneous vasculature can be-
come structurally altered due to con-
tinuous vasodilation and inflammatory
responses; these are caused by medi-
ators such as LL-37 peptide, vascular
endothelial growth factor (VEGF)
and some MMPs.1 The mechanism
by which LL-37 enhances the release
of inflammatory mediators and pro-
motes angiogenesis is through NLRP3
gen, inflammasome activation. IL-1b
modifies angiogenesis by decreas-
ing LL-37 and works synergistically
to enhance the angiogenic function
of endothelial cells. The vicious circle
of vascular and inflammatory changes
causes a persistent dilation of blood
and lymphatic vessels, neo-angiogene-
sis, telangiectasia formation and der-
mal matrix degradation, typical of this
disease3 (see Table 9-1).
NEUROGENIC REGULATION OF
ERYTHEMA
In humans, facial skin perfusion mech-
anisms are modulated by neuronal
(sympathetic, parasympathetic and
nociceptive) and non-neuronal (local
inflammation) pathways. The sympa-
thetic innervation has a thermoregu-
latory function, with vasoconstriction
being mediated by the release of nor-
adrenaline and neuropeptide Y, aided
by local vasoconstriction upon cooling
by a2c-receptors and b2-adrenocep-
79
tors. Further, facial skin has a network
of arteriole-venule anastomoses that
are controlled by both sympathetic
and nociceptive innervation. If dilated,
these arteriole–venule (A-V) shunts in-
crease skin temperature and shortcut
superficial blood flow.
Therefore, facial erythema can be
reduced by the cutaneous application
of selective alpha-adrenergic ago-
nists, such as brimonidine (selective
a2-adrenergic agonist), oxymetazo-
line (selective a1-adrenergic agonist)
or by the use of beta-adrenergic
antagonists such as beta-blockers
(carvedilol).3
References
4. Del Rosso JQ. Advances in under-
standing and managing rosacea:
part I: connecting the dots between
pathophysiological mechanisms and
common clinical features of rosacea
with emphasis on vascular changes
and facial erythema. J Clin Aesthet
Dermatol 2012;5:16-25.
5. Cribier B. Rosacea under the mi-
croscope: characteristic histological
findings. J Eur Acad Dermatol Vene-
reol 2013; 27: 1336-1343.
6. Steinhoff M, Schmelz M, Schauber J.
Facial erythema of rosacea. Aetiolo-
gy, different pathophysiologies and
treatment options. Acta Derm Vene-
reol 2016; 96 (5): 579-86.
7. Wilkin J, Dahl M, Demar M, et al.
Standard Classification of rosacea:
Report of the National Rosacea So-
ciety Committee on the classifica-
tion and staging of rosacea. J Am
Acad Dermatol 2004;46:584-7
8. Steinhoff M, Buddenkotte J, Aubert
J, et al. Clinical, cellular, and molec-
ular aspects in the pathophysiolo-
gy of rosacea. J Investig Dermatol
Symp Proc 2011; 15 (1): 2-11.
9. Schwab VD, Sulk M, Seeliger S, et
al. Neurovascular and neuroimmune
aspects in the pathophysiology of
rosacea. J Investig Dermatol Symp
Proc 2011;15:53-62.
10. Drummond PD, Su D. Endo-
thelial and axon reflex vasodila-
tation to acetylcholine in rosacea
affected skin. Arch Dermatol Res
2012;304:33-7.
11. Steinhoff M, Schauber J, Leyden JJ.
New insights into rosacea patho-
physiology: A review of recent find-
ings. J Am Acad Dermatol 2013; 69:
S15-26.
12. Aubdool AA, Brain SD. Neurovas-
cular aspects of skin neurogenic
inflammation. J Investig Dermatol
Symp Proc 2011; 15: 33-39.
In rosacea, the relationship of neu-
ro-immune and neurovascular fac-
tors has been visualized or obtained
by clinical observation. However, it is
increasingly clear that the complex
pathophysiology of this entity en-
compasses a wide variety of cells and
molecules in the skin. Several factors
are suggested to influence the onset
of rosacea, which occurs in individuals
whose inappropriate innate immune
responses to environmental stimu-
li lead to inflammation and vascular
abnormalities.1 This suggests that cu-
taneous neurovascular dysfunction
has a key role in the pathophysiology,
triggered by environmental factors.2
To better understand these theories,
we need to differentiate the import-
ant roles played by the vascular and
lymphatic systems.
ANGIOGENESIS VERSUS
VASODILATION
Increased vascular response and per-
sistent facial erythema in rosacea are
of particular interest, due to growing
evidence that, possibly, blood and
lymphatic vessels together play an im-
portant role in both acute and chron-
ic forms.3 In inflamed skin, vessels
have some important changes: they
remodel or change their phenotype,
increase their permeability, enlarge
their networks with an increased
blood flow and facilitate the influx
of inflammatory cells at the sites of
chronic inflammation. Activated vas-
Neurovascular Changes: Neuropeptides
Jorge Garza Gómez
cular endothelial cells express a vari-
ety of receptors, adhesion molecules
and cytokines, which allow leukocytes
to bind and migrate into the skin to
major inflammation sites.
In rosacea, activation of pre-cap-
illary arterioles causes vasodilation,
which is clinically manifested as ery-
thema. Simultaneously, activation of
post-capillary venules causes protein
leakage, which results in edema and
the recruitment of leukocytes through
the regulation of selectins and cell ad-
hesion molecules. Blood vessels, stim-
ulated by growth factors or external
agents, increase in number, leading to
angiogenesis. The role of angiogen-
esis in rosacea is a matter of debate;
some researchers argue that it plays
a significant role in the pathophysiol-
ogy,4 while others emphasize that the
increase in vascular tissue, in biopsy
samples, is mainly a consequence of
vasodilation.2
An increase in VEGF-A –which pro-
motes an increase in angiogenesis or
lymphangiogenesis– has been report-
ed;3,4 however, other researchers have
found an increase in the volume and
size of blood and lymphatic vessels,
while angiogenesis was only limited
80
to phymatous rosacea. In contrast,
lymphatic vessels thickening was ob-
served in all 3 subtypes of rosacea,
whilst lymphangiogenesis was not
seen.2,5
These vascular theories are
strengthened because the inhibition
of blood vessel activation has been
shown to have anti-inflammatory ef-
fects.3 Besides, vasoconstriction –by
activating b2-adrenergic receptors
(e.g., brimonidine, oxymetazoline) from
smooth muscle cells in arteries and
arterioles– results in a significant im-
provement in the facial erythema of
rosacea.6
MAST CELLS
Schwab et al.2 reported the significant
presence of mast cells, non-myelin-
ated sensory nerves, blood vessels
and myofibroblasts in early stages of
rosacea. There is a close anatomical
relationship between sensory nerves,
blood vessels, and immune cells, as
well as neuroimmune and neurovas-
cular communication signals, resulting
in vasodilation rather than angiogene-
sis, dilated lymphatic vessels, and an
increase in the number of mast cells
and fibroblasts. In sensory nerve
endings, an increase in receptors of
mediators released by mast cells has
been found, suggesting a substantial
neurovascular and neuroimmune in-
teraction in the pathophysiology of
the disease.
LYMPHATIC VESSELS AND
NEUROPEPTIDES
The lymphatic system, in its important
role as a contributor to chronic inflam-
mation,7 is likely to be involved in the
early process of rosacea, but not in
later subtypes, although signs of ede-
ma are observed in advanced stages
of the disease.8 It has been suggest-
ed that this edema is related to an
increase in the number of lymphatic
vessels;4 however, recent studies do
not show such an increase compared
to normal skin. Some neuropeptides
have been described as affecting the
function of lymphatic vessels; for ex-
ample, substance P, which has a de-
pendence on the calcitonin gene and
inhibits the vasomotion of lymphatic
vessels.9 However, it is not yet known
which neuropeptides may affect the
lymphatic function in the pathophys-
iology of rosacea.
NEUROGENIC INFLAMMATION
A recent popular theory about the
pathophysiology of rosacea sug-
gests that the involvement of neu-
rogenic inflammatory mechanisms
may reflect the early and late clinical
features of the disease, including
flushing, erythema, and induction of
leukocyte infiltration, especially of
mast cells.5,10,11 Indicators of a tenden-
cy toward increased nerve density
have been found, particularly in ETR
and, later on, a decrease in phyma,
which may explain the sensations of
“prickling, burning, or pain” predomi-
nant in ETR and PPR.8,12
SEROTONIN AND ROSACEA
The neuropeptides historically im-
plicated in rosacea were calcitonin
gene-related peptide and substance
P (tachykinin, precursor 1).13 However,
no increase in these neuropeptides
or their receptors was observed in
recent studies; on the contrary, mo-
lecular studies showed a decrease
in their levels, suggesting that the
relevance of these neuropeptides is
marginal. A new molecular pathway
has been investigated. Gene analy-
sis showed an increase in serotonin
receptors, HTR3A. Serotonin (5-hy-
droxytryptamine) is an important
inflammatory and neurosensory me-
diator, released from platelets and
mast cells, which contributes to no-
ciception and vascular regulation.14
The HTR3A receptor is expressed
by primary afferent nerve fibres to
convey their excitation and sensiti-
zation. Serotonin and its receptors
have already been investigated for
other inflammatory skin diseases.15
It has been reported that HTR3A
antagonist ondansetron led to good
remissions of symptoms of flushing.16
Thus, inhibition of the HTR3A recep-
tor may be a promising future thera-
peutic approach.
Other peptides
Cathelicidin
As mentioned before, the antimi-
crobial peptide cathelicidin is up-
regulated in all subtypes of rosacea.
It is processed by the KLK-5 gene
(kallikrein-5) and its proinflammatory
activity promotes angiogenesis and
chemotaxis.17,18 It has been suggested
that cathelicidin is an important factor
eliciting an exacerbated response of
the innate immune system.19
Pituitary adenylate cyclase-
activating polypeptide (PACAP),
vasoactive intestinal polypeptide
(VIP) and proadrenomedullin (ADR2)
It has been demonstrated that these
polypeptides are enhanced in ro-
sacea.2 PACAP, linked to the patho-
physiology of psoriasis and atopic
dermatitis, can mediate vasodilation
and plasma extravasation, and influ-
ence neurogenic inflammation via
activation of VPAC receptors.20 Both
PACAP and VIP are capable of stim-
ulating mast cell degranulation.21,22
Under inflammatory conditions, PA-
CAP can be released by endothelial
cells, suggesting a possible effect
of these neurotransmitters on the
pathophysiology of rosacea. When
activated by neuropeptides, mast
cells may be important amplifiers of
81
neural impulses, causing increased
release of histamine or tryptase to
the vasculature and other cells of the
immune system.5
The effect of neurovascular and
neuroimmune networks on the de-
velopment of rosacea is clear. Both at
the histological and molecular levels,
neurogenic inflammation has been
shown to be an important component
of pathophysiology, resulting in vaso-
dilation, but not in angiogenesis, and
contributes to the fibrotic processes
observed in this chronic inflammatory
disease.
While some new driving pathways
appear promising, they have yet to
be clarified and validated in detailed
studies. More needs to be learned
about the different factors and inter-
action pathways involved, which will
provide new therapeutic options.
References
1. Steinhoff M, Buddenkotte J, Aubert
J, et al. Clinical, cellular, and molec-
ular aspects in the pathophysiology
of rosacea. J Invest Dermatol Symp
Proc 2011; 15(1):2-11.
2. Schwab VD, Sulk M, Seeliger S, et al.
Neurovascular and Neuroimmune
Aspects in the Pathophysiology of
Rosacea. J Invest Dermatol Symp
Proc Soc Investig Dermatol Inc Eur
Soc Dermatol Res 2011; 15(1):53-62.
3. Huggenberger R, Detmar M. The
cutaneous vascular system in chron-
ic skin inflammation. J Investig Der-
matol Symp Proc 2011;15(1):2432.
4. Gomaa AHA, Yaar M, Eyada MMK,
et al. Lymphangiogenesis and angio-
genesis in non-phymatous rosacea.
J Cutan Pathol 2007; 34(10):748-53.
5. Steinhoff M, Ständer S, Seeliger S,
et al. Modern aspects of cutaneous
neurogenic inflammation. Arch Der-
matol 2003; 139(11):1479-88.
6. Fowler J, Jarratt M, Moore A, et
al. Once-daily topical brimonidine
tartrate gel 0·5% is a novel treat-
ment for moderate to severe facial
erythema of rosacea: results of two
multicentre, randomized and vehi-
cle-controlled studies. Br J Derma-
tol 2012 ;166(3):633-41.
7. Huggenberger R, Ullmann S, Proulx
ST, et al. Stimulation of lymphangio-
genesis via VEGFR-3 inhibits chron-
ic skin inflammation. J Exp Med 2010
Sep 27;207(10):2255-69.
8. Crawford GH, Pelle MT, James
WD. Rosacea: I. Etiology, patho-
genesis, and subtype classifica-
tion. J Am Acad Dermatol 2004;
51(3):327-341.
 9. Hosaka K, Rayner SE, von der Weid
P-Y, et al. Calcitonin gene-related
peptide activates different signalling
pathways in mesenteric lymphatics
of guinea pigs. Am J Physiol Heart
Circ Physiol 2006; 290(2):H813-822.
10. Roosterman D, Goerge T, Schneider
SW, et al. Neuronal control of skin
function: The skin as a neuroim-
munoendocrine organ. Physiol Rev
2006; 86(4):1309-79.
11. Reich A, Wójcik-Maciejewicz A, Slo-
minski AT. Stress and the skin. G Ital
Dermatol E Venereol Organo Uff
Soc Ital Dermatol E Sifilogr 2010;
145(2):213-9.
12. Sobottka A, Lehmann P. Rosacea
2009: New advances in pathophysi-
ology, clinical staging and therapeu-
The endoplasmic reticulum (ER) is a
cellular apparatus in which intracel-
lular and extracellular signals are de-
tected, integrated and transmitted.
This makes it possible to initiate de-
fense or repair responses.1 Newly syn-
thesized polypeptides must be folded
before being transported to their tar-
get organelles. Proteins that do not
properly fold within a certain time are
partially degraded by the ER, via the
ubiquitin-proteasome system.2 In or-
der to support proper protein folding
and prevent aggregation in the ER lu-
tic strategies. Hautarzt Z Dermatol
Venerol Verwandte Geb 2009;
60(12):999-1009.
13. Lonne-Rahm S, Nordlind K, Edström
DW, et al. Laser treatment of rosa-
cea: A pathoetiological study. Arch
Dermatol 2004; 140(11):1345-9
14. Oliveira MCG, Pelegrini-da-Silva
A, Parada CA, et al. CH 5-HT acts
on nociceptive primary afferents
through an indirect mechanism to
induce hyperalgesia in the sub-
cutaneous tissue. Neuroscience
2007;145(2):708-14.
15. Nordlind K, Thorslund K, Lonne-
Rahm S, et al. Expression of sero-
tonergic receptors in psoriatic skin.
Arch Dermatol Res 2006; 298(3):99-
106.
Stress in the endoplasmic reticulum
Sonia Chávez Álvarez
men, it is necessary to maintain an en-
vironment with a high concentration
of proteins and enzymes responsible
of folding proteins and assisting them
in maturation by glycosylation and di-
sulfide bond formation.2
Patients with rosacea have in-
creased stress signalling in the ER.1
Keratinocytes mainly have an in-
82
16. Wollina U. The response of ery-
thematous rosacea to ondansetron.
Br J Dermatol 1999; 140(3):561-2.
17. Yamasaki K, Di Nardo A, Bardan A,
et al. Increased serine protease ac-
tivity and cathelicidin promotes skin
inflammation in rosacea. Nat Med
2007; 13(8):975-80.
18. Yamasaki K, Kanada K, Macleod DT,
et al. TLR2 expression is increased
in rosacea and stimulates enhanced
serine protease production by ke-
ratinocytes. J Invest Dermatol 2011;
131(3):688-97.
19. Morizane S, Yamasaki K, Kabigting
FD, et al. Kallikrein expression and
cathelicidin processing are inde-
pendently controlled in keratino-
cytes by calcium, vitamin D(3), and
creased expression of TLR-2, which
modulates antimicrobial signalling
involving kallikrein 5 (KLK5). This, in
turn, modulates the antimicrobial ac-
tivity of LL-37.3,4 In skin with rosacea,
these factors are increased.4 TLR-
2 and TLR-4 activate the ER stress
sensor, Inositol requiring enzyme 1a
(IRE1a) kinase and its successor, X-box
binding protein 1 (XBP1), which pro-
retinoic acid. J Invest Dermatol
2010; 130(5):1297-306.
20. Seeliger S, Buddenkotte J,
Schmidt-Choudhury A, et al. Pitu-
itary adenylate cyclase activating
polypeptide: an important vascular
regulator in human skin in vivo. Am
J Pathol 2010; 177(5):2563-75.
21. Peters EMJ, Ericson ME, Hosoi J,
et al. Neuropeptide control mecha-
nisms in cutaneous biology: physio-
logical and clinical significance. J In-
vest Dermatol 2006; 126(9):1937-47.
22. Lenti L, Zimmermann A, Kis D, Oláh
O, Tóth GK, Hegyi O, et al. PACAP
and VIP differentially preserve neu-
rovascular reactivity after global
cerebral ischemia in new-born pigs.
Brain Res 2009;1283:50-7.
duces proinflammatory cytokines in
macrophages.5,6
WHAT IS ENDOPLASMIC
RETICULUM STRESS?
ER stress describes the accumulation
of misfolded proteins inside the ER.5
There are several factors that inter-
fere with the ER quality control, lead-
ing to the accumulation of misfolded
proteins. This impacts cells, which pre-
pare the misfolded protein response
(MPR).2 To avoid this situation, there is
the unfolded protein response (UPR),
a cell repair mechanism that modi-
fies the way cells are transcribed and
translated under stress conditions
(e.g., ultraviolet radiation or thermal
shock).4 This response improves the
ER’s ability to fold proteins and synthe-
size lipids. This system protects cells so
that they can adapt; however, severe
and prolonged stress can generate
cytotoxicity and induce apoptosis. ER
stress-induced apoptosis is involved
in several diseases, such as diabetes,
atherosclerosis, neurodegenerative dis-
eases, and renal disease.2
In the ER membrane lumen, there
are three protein sensors. They de-
tect irregularities (misfolded proteins)
and initiate the unfolded protein re-
sponse (UPR).
1. IRE1a.
2. Protein kinase RNA (PKR)-like ER
kinase (PERK).
3. Activating transcription factor
6 (ATF6).2
These three pathways collaborate
to maintain protein folding and de-
crease the burden of misfolded pro-
teins.2
In unstressed cells, the ER chaper-
one BiP (which is an ATPase involved
in ER quality control) binds to the lu-
menal domains of the ER stress sen-
sors –IRE1a, PERK and ATF6– and
keeps them inactive.2 However, un-
der ER stress conditions, BiP binds
to misfolded proteins and activates
them.2 The stress response localizing
protein of ER (IRE1a) is a transmem-
brane molecule of ER. By binding
with signalling proteins, TNF recep-
tor-associated factor 2 (TRAF2) and
sphingosine 1-phosphate (S1P), IRE-1a
is activated with endoribonuclease,
stimulates nuclear factor–kappa-light-
chain-enhancer of activated B cells.
(NF-kB) and binds to CCAAT-en-
hancer-binding protein alpha (C/
EBP-a). This stimulates the produc-
tion of AMP/cathelicidins. The result-
ing excess of AMP formation, due to
ER stress, further increases inflam-
mation rather than serving as a de-
fense against pathogens.7 IRE1a also
cleaves its mRNA portion to XBP1 to
generate pro-inflammatory cytokines
in macrophages.2
The homodimerization of PERK
phosphorylates the translation initia-
tion factor (eIF2a), which delays the
start of the mRNA translation, while
the selected mRNAs are translated in
the presence of the phosphorylated
F2a. Therefore, ER stress leads to a
higher expression of the transcription
factor (ATF4)5. This promotes the ex-
pression of TLR-2 in epithelial cells
during periods of ER stress. In skin
with rosacea, this expression of TLR-2
increases cathelicidin and KLK5 medi-
83
ated by C/EBP-a, which increases LL-
37 levels.1 Overexpression of TLR-2 is
the first line of defense of the innate
immune system in epidermal kerati-
nocytes. It is now known that exacer-
bating factors of rosacea (e.g., stress)
modulate the signalling of TLRs.1
Response to undeployed pro-
teins promotes the activation of NF-
kB, which induces the expression of
pro-inflammatory cytokines (including
cathelicidins) and the generation of
reactive oxygen species (ROS), which
are necessary for protein folding.1,5
ROS modulate inflammation and par-
ticipate in the pathogenesis of rosa-
cea.5
Lipid participation
Sphingosine-1-phosphate (S1P) –a
lipid mediator of inflammation in
the ER– modulates cell proliferation
and differentiation through G pro-
tein-coupled receptor mechanisms.
S1P is produced from sphingosine
kinase 2 (SK2). In rosacea, under ER
stress, this occurs independently of
G-protein receptors.1,7 The activating
transcription factor (ATF4) induces
the activation of SK2, which partici-
pates in the formation of cis-4-meth-
ylsphingosine phosphate. It activates
p38 mitogen-activated protein kinase
(p38 MAPK). p38 MAPK phosphory-
lates and thus activates the transcrip-
tion factor C/EBP-a.1 S1P signalling
regulates epithelial innate immune
responses and is essential for the ex-
pression of stress-induced cathelici-
dins, through the activation of NF-kB
and EBP-a by a vitamin D-indepen-
dent pathway.1,7
To stimulate defense mechanisms
in epithelial cells, ER stress-induced
metabolites –ceramide-1-phosphate
(C1P) and sphingosine-1-phosphate
(S1P)– act as alteration sensors and
increase the level of 2 cathelicidins/
antimicrobial peptides (hBD2 and
hBD3)8 (Fig. 9-1).
STRESS TRIGGERING FACTORS
IN ROSACEA
All factors that exacerbate rosacea
are also thought to cause ER stress.
In rosacea, this activates the inflam-
matory, angiogenic, neurosensitive,
lipogenic, fibrogenic and antimicro-
bial signalling pathways.5 Ultraviolet
radiation, heat, cold, stress, gluco-
corticoids, spicy food or microorgan-
isms modulate, generate or induce
ROS, MMPs, TLR signalling or neu-
ropeptides. These factors also play a
role in mediating the immune system
and releasing cytokines and chemo-
kines.1
Ultraviolet Radiation (UVR)
UVR induces stress on the epidermal
ER which then increases C/EBP pro-
tein. This protein is a transcription
factor produced by the PERK path-
way.5 UVA radiation (0.2-10 J/cm2)
activates several pathways due to
excessive oxidative stress; for exam-
ple, the ATF6 pathway, which caus-
es its retention in the ER lumen; the
IRE1a pathway, and the induction of
the cleavage of XBP1 mRNA (X-box
binding protein).8 NF-kB is another
pathway activated by UV radiation,
by inhibiting the synthesis of IkBa
and activating the PERK-eIF2a path-
way. The stress generated in the ER
due to ultraviolet radiation induces
cathelicidin/AMP production.5
Oxygen Free Radicals (ROS)
Oxygen free radicals affect ER pro-
tein folding, which generates stress.
This alters the folding of extracellular
matrix proteins, such as collagen and
elastin, which prolongs their retention
within the ER. Reduced expression of
these proteins accelerates dermal ag-
ing. The PERK pathway and the oxi-
dative stress response pathway are
connected, making the PERK path-
way more vulnerable to UVA radiation
stimulation.9
Extrinsic Factors
Rosacea skin is very sensitive to tem-
perature changes, especially heat. The
stress induced by high temperatures
alters the immune response by gen-
erating thermal shock proteins. These
proteins increase the expression of
70 kilodalton heat shock proteins
(HSP70), TLR-2 and TLR-4, and acti-
vate p38 kinase and NF-kB. This gen-
erates a reaction pattern similar to that
of the unfolded protein response.5
Food
Resveratrol –an aromatic hydrocarbon
which is present in red wine– increas-
es cathelicidin/AMP mRNA and the
expression of keratinocyte proteins
in cultures. The intake of resveratrol
could modify cathelicidin expression
in keratinocytes in vivo, and this ER
stress response is manifested as an
exacerbating factor of rosacea.5
Neural Control
Psychic stress exacerbates rosacea.
By means of neuropeptides (sub-
stance P) released from autonomic
or sensory nerve fibres, dermal and
epidermal cells, the cutaneous ner-
vous system modulates cell growth,
Fig. 9-1. Pathogenesis of stress in the endoplasmic reticulum.1,4-6 IRE1, PERK differentiation, immunity and inflam-
and ATF6 are the ER membrane proteins. IRE1a stimulates XBP1 (X-box bind- mation.5 Substance P induces the
ing protein 1) to induce the production of pro-inflammatory cytokines in macro- release of free oxygen radicals by
phages. ER stress activates S1P which, in turn, activates p38 MAPK. The latter neutrophils.9 Primary sensory neurons
phosphorylates and activates C/EBP-a, which increases cathelicidins/antimi- increase and TLRs are expressed in
crobial peptides (LL-37) expression and induces inflammation, angiogenesis, peripheral nerves, which increases
and sebaceous gland dysfunction. S1P also stimulates the transient receptor neuronal TLR signalling to the ER
potential vanilloid family of ion channels type 1 (TRPV1) and induces skin hy- stress response.4 This upregulation
persensitivity, as well as the sphingosine-1-phosphatase receptor (S1PR) with of TLR2 participates with innate im-
which it induces vasodilation. ATF4 activates TLR-2 and NF-kB. Subsequently , munity and TLR2-mediated neuro-
it follows the same pathway as S1P to stimulate LL-37, in addition to stimulating regulatory networks and lowers the
vascular endothelial growth factor (VEGF) and generating angiogenesis (mod- pain threshold.1,5
ified from Melnik BC).1
Sebocytes
Sebocytes express TLR-2 that medi-
ates protection against infections.5
Cathelicidins/AMPs are subsequently
84
produced after exposure to vitamin
D3, and then processed to LL-37.10 In
keratinocytes and sebocytes, ATF4
and glucocorticoids increase TLR-2
expression, contributing to the devel-
opment of steroid-induced rosacea.5,11
C/EBP-a is a dominant transcription
factor for the activation of sebocytes,
lipogenesis and sebocyte-derived
cathelicidin production; so, increased
ER stress also increases cathelicidin
expression.1
Angiogenesis
In rosacea, ER stress and upregulat-
ed LL-37 promote angiogenesis. In
addition, VEGF A expression is asso-
ciated with ER stress via ATF4. The
latter binds to a VEGF promoter and
this induces angiogenesis and lymph-
angiogenesis.1,5 In addition, the sphin-
gosine-1-phosphate receptor (S1PR)
induces vasodilation.1
Skin Hypersensitivity
In patients with rosacea, there are
alterations in the facial epidermal
barrier, which make them prone to
irritation.12 The components of termi-
nal differentiation and repair of the
epidermal barrier are signalled by
ER stress via the release of calcium
stored in the stratum granulosum.
These alterations are associated with
a decrease in calcium, which activates
the ER-stress-induced response by
transcription factor XBP1.13 In addition,
the affected skin has a lower thresh-
old for heat-induced pain.15 Peripheral
neurons express TLR, which modulate
neuronal plasticity even under inflam-
matory conditions.14 During periods of
ER stress, increased ATF4 and TLR-2
in sensory peripheral nerves explains
this hypersensitivity. In human mono-
cytes, ATF4, which is recruited by
TLR-4 signalling, regulates inflamma-
tory TLR4-triggered cytokines.5 Mast
cells also participate, increasing TLR-
2 expression by increasing substance
P levels.5
PHYMATOUS ROSACEA AND
ER STRESS
ER stress is also involved in the patho-
genesis of phymatous rosacea. The in-
crease of ATF4 induced by ER stress
increases the signalling of amino-ac-
id activated pathways, which induce
fibrosis and type I collagen synthe-
sis.5,15 In addition, sebaceous hyper-
plasia is precipitated by activation
of sterol regulatory element binding
proteins (SREBP1c and 2) and cellular
lipid accumulation associated with ER
stress.5,16
In brief, knowledge of rosacea
pathogenesis increases in complexi-
ty as the various intrinsic and extrin-
sic factors involved are studied. ER
stress helps to explain the partici-
pation of lipids, ultraviolet radiation,
peripheral nerve cell alterations, and
other mediators in the development
of rosacea.
85
References
1. Melnik BC. Rosacea: The Bless-
ing of the Celts: An approach to
pathogenesis through translational
research. Acta Dermatol Venereol
2016; 96: 147-156,
2. Gardner BM, Pincus D, Gotthardt K,
et al. Endoplasmic reticulum stress
sensing in the unfolded protein re-
sponse. Cold Spring Harb Perspect
Biol 2013; 5(3):a013169.
3. Holmes AD., Steinhoff M. Integra-
tive concepts of rosacea patho-
physiology, clinical presentation
and new therapeutics Exp Der-
matol 2017; 26:659-667, doi:10.1111/
exd.13143.
4. Park K, Lee S, Lee YM. Sphingo-
lipids and antimicrobial peptides:
Function and roles in atopic derma-
titis. Biomolecules & Therapeutics
2013; 21, 251-257, doi:10.4062/bio-
molther.2013.058 .
5. Melnik BC. Endoplasmic reticulum
stress: Key promoter of rosacea
pathogenesis. Exp Dermatol 2014;
23(12):868-73.
6. Martinon F, Chen X, Lee AH, et
al. TLR activation of the tran-
scription factor XBP1 regulates
innate immune responses in mac-
rophages. Nat Immunol 2010;
11(5):411-8.
7. Park K, Ikushiro H, Seo HS. ER stress
stimulates production of the key
antimicrobial peptide, cathelicidin,
by forming a previously unidenti-
fied intracellular S1P signalling com-
plex. Proc Natl Acad Sci USA 2016;
113(10):E1334-42.
8. Kim YI, Park K, Kim JY, et al. An
endoplasmic reticulum stress-ini-
tiated sphingolipid metabolite,
ceramide-1-phosphate, regulates
epithelial innate immunity by stim-
ulating beta-defensin production.
Mol Cell Biol 2014; 34(24):4368-
78.
9. Komori R, Taniguchi M, Ichika-
wa Y, et al. Ultraviolet A induc-
es endoplasmic reticulum stress
response in human dermal fibro-
blasts. Cell Struct Funct 2012;
37(1):49-53.
10. Schneider MR, Paus R. Sebocytes,
multifaceted epithelial cells: Lipid
production and holocrine secre-
tion. Int J Biochem Cell Biol 2010;
42(2):181-5.
11. Shibata M, Katsuyama M, On-
odera T, et al. Glucocorticoids
enhance Toll-like receptor 2 ex-
pression in human keratinocytes
stimulated with Propionibacteri-
um acnes or proinflammatory cy-
tokines. J Invest Dermatol; 2009
129(2):375-82.
 12. Darlenski R, Kazandjieva J, Tsankov
N, et al. Acute irritant threshold cor-
relates with barrier function, skin
hydration and contact hypersensi-
tivity in atopic dermatitis and rosa-
cea. Exp Dermatol 2013; 22(11):752-3.
13. Celli A, Mackenzie DS, Crumrine
DS, et al. Endoplasmic reticulum
Rosacea is a chronic inflammatory
condition whose pathogenesis re-
quires further research.1 It is known
that rosacea has a multifactorial etiol-
ogy, including a genetic component,
abnormalities in blood and lymphatic
vessels, fibroblasts and cells, as well as
processes of the innate and adaptive
immune system are involved.1-5 Other
factors include: neuronal dysregula-
tion, vasomotor instability and release
of proinflammatory neuropeptides.4
INNATE IMMUNE SYSTEM
The function of the skin’s innate im-
mune system is to protect it against
environmental aggressions and patho-
gens.6 It plays an important role be-
cause keratinocytes have sensors and
communicate with each other when they
recognize signs of danger or pathogens.
This interaction can trigger pro-inflam-
matory cascades and a coordinated im-
mune response.7
Keratinocytes, mast cells, sebocytes,
and eccrine glands secrete AMPs as
Ca2+ depletion activates XBP1 and
controls terminal differentiation in
keratinocytes and epidermis. Br J
Dermatol 2011; 164(1):16-25.
14. Sulk M, Seeliger S, Aubert J, et
al. Distribution and expression of
non-neuronal transient receptor
potential (TRPV) ion channels in
Immune System
Minerva Gómez F.
defense factors; AMPs can destroy
gram-positive bacteria, gram-negative
bacteria, viruses and fungi. Their ex-
pression and function are regulated at
the transcriptional and post-transcrip-
tional levels. Most AMPs are synthe-
sized as pro-peptides and activated by
binding with precursor molecules. In
the skin, the most studied AMPs are the
defensins and cathelicidins.7 Cathelici-
dins are 2.5 times increased in rosacea,
and are also involved in the pathogen-
esis of psoriasis, atopic dermatitis, sys-
temic lupus erythematosus, rheumatoid
arthritis, and atherosclerosis.6,7
The increase in expression of
cathelicidins, AMPs, and kallikrein 5 is
explained by altered signalling path-
ways.8 As already mentioned, pro-pep-
tides are required to be activated by
various factors. In the skin, cathelicidin
86
rosacea. J Invest Dermatol 2012;
132(4):1253-62.
15. Walter P, Ron D. The unfolded pro-
tein response: From stress pathway
to homeostatic regulation. Science
2011; 334(6059):1081-6.
is processed by the KLK family, par-
ticularly by kallikrein 5, also known as
the stratum corneum tryptic enzyme.7
KLK5 and KLK7 are primarily respon-
sible for processing cathelicidins in the
skin. KLK5 is increased in rosacea and
it processes aberrant forms of cathe-
licidin that promote the development
of the disease.4 Increased KLK5 can
be induced by injury, physical stimuli
and microbial agents, indicating that
kallikreins, proteases and protease-ac-
tivated receptors are an additional sys-
tem within the innate immune system,
which detects harmful agents that trig-
ger rosacea.7 KLK5 binds the pro-form
of human cathelicidin AMP (hCAP-18)
to LL-37, which then becomes active.6,8
Expression and processing of the
cathelicidin precursor protein depends
on the tissue microenvironment, which
is specific to the disease state.6
16. Colgan SM, Hashimi AA, Austin RC.
Endoplasmic reticulum stress and
lipid dysregulation. Expert Rev Mol
Med 2011; 13:e4.
The peptide formed –LL-37– pro-
motes inflammatory cascades and
vascular responses that lead to inflam-
matory cell chemoattraction, vasodi-
lation with perivascular edema, and
increased vascular endothelial growth
factor.1 LL-37 exerts a broad antimicro-
bial activity which is somewhat less
than the cathelicidins found in normal
skin.7,9 This peptide is processed into
smaller fragments that can promote
endothelial cell proliferation to initi-
ate angiogenesis, activate and control
immune responses, such as leukocyte
chemotaxis, local immune system cells
and expression of extracellular matrix
components.7,8 Its expression in kerati-
nocytes may be induced by vitamin D,
which is activated by ultraviolet light,8
and this may explain why rosacea ap-
pears mainly in the face, which is the
most photo-exposed site.7
The innate immune system de-
pends on a family of pattern rec-
ognition receptors (the TLRs) to
detect the environment. These
molecules respond to external stim-
uli (molecular structures of microor-
ganisms such as chitin or cell wall,
chemicals, and trauma) and internal
stimuli (UV-induced tissue damage
or apoptosis) and initiate immune
responses.4,7 Many of the exacer-
bating factors of rosacea also stim-
ulate the TLR system. In the skin
of patients with rosacea, TLR-2 is
overexpressed, induced by envi-
ronmental stimuli, and the result is
an increased production of KLK5
–by keratinocytes– and of aberrant
forms of cathelicidins, promoters of
the disease.4 NF-kB, some chemo-
kines, and cytokines also increase.3
Propionibacterium acnes is a mi-
croorganism of characteristic facial
predominance which can activate
TLR-2 receptors.4
There is a link between Demodex
folliculorum infestation, rosacea devel-
opment and TLR-2 increase. The chi-
tin released from these mites activate
TLRs in the keratinocytes as well as
heat-shock proteins and lipoproteins
associated with Bacillus oleronius, a
symbiont of Demodex.7,8 This, in turn,
increases the expression and activity
level of KLK-5 and LL-37, and their frag-
ments.8 In addition, TLR-2 indirectly in-
creases the production of cathelicidins
by stimulating vitamin D activation.4
Matrix metalloproteinases (MMPs)
participate in tissue remodelling
during wound healing processes and
also activate KLK proteases that in-
duce overproduction of pro-inflamma-
tory and proangiogenic cathelicidin
fragments.4 MMP-2 and MMP-9 ac-
tivate KLK 5 and LL-37.8 In the skin
of patients with rosacea, the mech-
anisms responsible for the increased
production of cathelicidins and pro-
teases are still unclear. Both seem to
be regulated by activation cascades
which depend on cytokines, reti-
noids, and vitamin D.7
Cellular Innate Immune System
In rosacea, there is an important in-
flammatory infiltrate of perivascu-
lar predominance, composed of Th1
cells and macrophages even in the
absence of inflammatory lesions, sug-
gesting the activation of the innate
immune system.1
Upon degranulation, mast cells par-
ticipate in cathelicidin-induced inflam-
mation by releasing LL-37, stimulating
the production of MMP-9 and proin-
flammatory cytokines.4,8 They may also
release mediators that increase inflam-
mation and promote angiogenesis.
Mast cells are activated by cutaneous
neuropeptides, such as PACAP, which
is associated with rosacea flare-ups
and flushing. This is because neuropep-
tides can trigger mast cell proteases
and the expression of pro-inflammato-
ry cytokines. Their activity represents
the link between innate immunity, neu-
87
ronal activity, stress and the pathogen-
esis of rosacea.4
Neutrophils are present in inflam-
matory and pustular lesions, since
chemoattraction is induced by the
increase in IL-8 and LL-37.1 There is
also an increase in ROS, COX-2 tran-
scriptase, and CD163 and CD45RO
leukocyte markers.6,10 LL-37 stimu-
lates ROS generation by activating
nicotinamide adenine dinucleotide
phosphate (NADPH) and intracellular
calcium mobilization.11 ROS, such as
superoxide, hydrogen peroxide, and
hydroxyl radicals, initiate oxidative
tissue damage and subsequent in-
flammation.6 The importance of ROS
explains the effectiveness of metro-
nidazole in the treatment of rosacea,
which inactivates and decreases their
production.12 Autoinflammation also
participates in the pathogenesis of
rosacea, as demonstrated by the in-
creased expression of IL-1a and nu-
cleotide binding domain (NOD)-like
receptor protein 3 (NALP3), compo-
nents of the inflammasome and coun-
terpart of TLR-2.3
All these alterations at the level of
the immune system –diffuse inflamma-
tory infiltrate in the dermis, chemoat-
traction of neutrophils, vasodilation
with perivascular inflammation and new
vascularization– cause dermal manifes-
tations including erythema, edema, tel-
angiectasias and inflammatory lesions.1
Adaptive Immune System
The origin of rosacea, especially pap-
ulopustular rosacea (PPR), is thought
to be an alteration in the immune sys-
tem.9 The adaptive immune system is
activated from the first stage –ETR–
and is exacerbated by the appearance
of PPR.1 The cells that play the most
important role are Th1 CD4 lympho-
cytes, mast cells, and macrophages.13
CD4 T-cells are more abundant than
CD8 cytotoxic T-cells in a ratio of 2:8,
mainly in PPR; however, this alteration
has also been identified in ETR and
PR.3,5 A predominance of Th1 and Th17
cells, as well as macrophages and mast
cells, has been demonstrated in all
three subtypes of rosacea.5 This con-
tributes to the increase in inflamma-
tory cytokines such as IL-17, TNFa and
interferon gamma.14 Table 9-2 shows a
detail of the cell predominance in the
different subtypes of rosacea.1,5,14
Table 9-2. Predominant cells in the
different types of rosacea
Rosacea Predominant
Subtype Cells
Erythematotel T-cells (Th1/Th17)
angiectatic
Papulopustular Neutrophils
Phymatous Plasma cells
Neutrophils
Table 9-3. Therapeutic targets and drugs
Therapeutic target
LL-37
TLR-2
Matrix metalloproteinases
Kallikrein 5, cathelicidin, PPAR
Oxygen free radicals (neutrophils)
Mast cells
NF-kB transcription factor (TLR-2, IL-1B, IL-8, Ivermectin
TNF and COX2)
DEMODEX, ROSACEA AND
IMMUNE SYSTEM
Patients with rosacea are prone to
Demodex infestation, possibly due to
the alteration of the immune system,
as evidenced by the lower number of
CD4+ and CD8+ lymphocytes.3 Demo-
dex numbers are six times higher than
in the normal population, especially in
patients with ETR.10 The parasite in
the follicles predisposes to the devel-
opment of a perifollicular lymphocyt-
ic infiltrate. In granulomatous rosacea
there is a Demodex infiltration into
the dermis, where the mites are
phagocytized by giant cells. However,
Demodex are also present in PPR and
ETR.9 The inflammatory infiltrate of T
helper cells (Th-17), lymphocytes and
Drug
Semi-synthetic glycosaminoglycan esters
Isotretinoin
Tetracyclines
Azelaic acid
Metronidazole
Sodium cromoglycate
macrophages, which is seen around
the vessels and glands associated
with the presence of Demodex, is the
first stage of a type IV hypersensitivity
reaction.9 These mites express the Tn
antigen, which is a carbohydrate that
covers and hides them from the im-
mune system. At the local level, it also
modulates the secretion of cytokines
and inflammatory cells (IL-8, TNF-a
and TLR). These changes, generated
by the mite, affect the TH2 response,
thus facilitating infestation.15
Apart from being an inflammation
trigger, Bacillus oleronius, an endo-
symbiotic bacterium from Demodex,
interacts with highly immunogenic
serum proteins. At the local level, Ba-
88
Fig. 9-2. Scheme of the pathophysiology of the immune system and rosacea
[Adapted from reference 3].
cillus activates neutrophils in the pi-
losebaceous unit and contributes to
the immune response and inflamma-
tion associated with rosacea (Fig. 9-2).16
In some patients, papules and pustules
begin to appear upon restoration of
immunity with the treatment.9
Advances in the knowledge of the
pathophysiology of rosacea have led
to advances in its treatment,3,4,6,17 as
can be seen in Table 9-3.
To conclude, acknowledging the
importance of immune alterations
in rosacea reinforces the notion that
this disease has a large component of
individual susceptibility according to
the immune response. Although more
studies on the inflammatory pathways
in rosacea are still needed, knowledge
of the immune system alterations can
help dermatologists to properly ad-
dress and improve their therapy.
References
1. Del Rosso JQ, Gallo RL, Kircik L, et al.
Why is rosacea considered to be an
inflammatory disorder? The primary
role, clinical relevance, and therapeu-
 tic correlations of abnormal innate im-
mune response in rosacea-prone skin.
J Drugs Dermatol 2012; 11(6):694-700.
2. Schwab VD, Sulk M, Seeliger S, et
al. Neurovascular and neuroimmune
aspects in the pathophysiology of
rosacea. J Investig Dermatol Symp
Proc 2011;15(1):53-62.
3. Holmes AD, Steinhoff M. Integrative
concepts of rosacea pathophysiol-
ogy, clinical presentation and new
therapeutics. Exp Dermatol 2017;
26(8):659-667.
4. Dorschner RA, Williams MR, Gal-
lo RL. Rosacea, the face of innate
immunity. Br J Dermatol 2014;
171(6):1282-1284.
5. Buhl T, Sulk M, Nowak P, et al. Mo-
lecular and morphological charac-
terization of inflammatory infiltrate
in rosacea reveals activation of Th1/
Rosacea trigger factors have a variable
activation pattern depending on the
stimuli, and activation of selective re-
ceptors by individual trigger factors de-
termine a phenotypic outcome. Some
dysregulated receptors cause abnor-
mal sensitivity in rosacea skin. The acti-
vation of neurogenic inflammation and
innate immunity pathways results in
the production of different mediators,
which can facilitate the predominant
Th17 pathways. J Invest Dermatol
2015;135(9):2198-2208.
6. Salzer S, Ruzicka T, Schauber J.
Face-to-face with anti-inflammatory
therapy for rosacea. Exp Dermatol
2014; 23(6):379-381.
7. Steinhoff M, Schauber J, Leyden
JJ. New insights into rosacea patho-
physiology: a review of recent find-
ings. J Am Acad Dermatol 2013;69(6
Suppl 1):S15-26.
8. TwoAM, WuW, GalloRL, et al. Ro-
sacea: part I. Introduction, categori-
zation, histology, pathogenesis, and
risk factors. J Am Acad Dermatol
2015;72(5):749-758.
9. Forton FM. Papulopustular ro-
sacea, skin immunity and Demodex:
pityriasis folliculorum as a missing
link. J Eur Acad Dermatol Venereol
2012;26(1):19-28.
Chronic Inflammation and Fibrosis
Juan Carlos Diez de Medina
clinical manifestation, whether erythe-
ma, inflammatory lesions or phymas.
Those triggers that stimulate multiple
types of receptors, with shared inflam-
mation axes, cause mixed clinical forms.
The chronic nature of rosacea can be
89
10. Casas C, Paul C, Lahfa M, et al.
Quantification of Demodex follic-
ulorum by PCR in rosacea and its
relationship to skin innate immune
activation. Exp Dermatol 2012;
21(12):906-910.
11. Zhang J, Xu X, Rao NV, et al. Nov-
el sulfated polysaccharides disrupt
cathelicidins, inhibit RAGE and re-
duce cutaneous inflammation in a
mouse model of rosacea. PloS One
2011;6(2):e16658.
12. Narayanan S, Hunerbein A, Getie M,
et al. Scavenging properties of met-
ronidazole on free oxygen radicals in
a skin lipid model system. J Pharm
Pharmacol 2007; 59(8):1125-1130.
13. Steinhoff M, Buddenkotte J, Aubert
J, et al. Clinical, cellular, and molec-
ular aspects in the pathophysiolo-
gy of rosacea. J Investig Dermatol
Symp Proc 2011;15(1):2-11.
explained by a poorly defined genetic
predisposition, repeated exposure to
triggers, and a positive feedback due
to the presence of leukocytes, lympho-
cytes, inflammatory mediators, or vaso-
active components.
14. Reinholz M, Ruzicka T, Steinhoff M,
et al. Pathogenesis and clinical pre-
sentation of rosacea as a key for a
symptom-oriented therapy. J Dtsch
Dermatol Ges 2016; 14 Suppl 6:4-15.
15. Moran EM, Foley R, Powell FC. De-
modex and rosacea revisited. Clin
Dermatol 2017; 35(2):195-200.
16. O’Reilly N, Menezes N, Kavanagh
K. Positive correlation between
serum immunoreactivity to De-
modex-associated Bacillus pro-
teins and erythematotelangiec-
tatic rosacea. Br J Dermatol 2012;
167(5):1032-1036.
17. Elewski BE, Draelos Z, Dreno B, et
al. Rosacea - global diversity and
optimized outcome: proposed in-
ternational consensus from the Ro-
sacea International Expert Group.
J Eur Acad Dermatol Venereol
2011;25(2):188-200.
RELATIONSHIP BETWEEN
CHRONIC INFLAMMATION AND
FIBROSIS
Phymatous rosacea is more common in
males, and most frequently develops
from the papulopustular form. It is asso-
ciated with two basic events: hyperpla-
sia of sebaceous glands and a chronic
inflammatory process that results in
fibrosis. The fibrotic changes may be
preceded by PPR with its characteris-
tic inflammation; however, a subgroup
of patients develop phymas without
clinical signs of erythema, papules, or
pustules. Recent studies, based on the
analysis of transcriptomes combined
with immunohistochemistry, show that
even without inflammatory clinical
signs, a lymphomonocytic infiltrate is
evident under the microscope.2,3 The
greater the Demodex infestation, the
greater the inflammatory infiltrate is,
since there are more inflammatory le-
sions. This parasitic load is greater in
cases of PPR.
The genes and molecules that
regulate the interaction between the
inflammatory system and the extra-
cellular matrix, which eventually de-
termines fibrosis in rosacea, are not
fully known.3 Candidates include re-
active oxygen species (ROS), metallo-
proteinases (MMP), serine proteases,
growth factors (GF), and cytokines/
chemokines. Based on research in
animal models, it seems that certain
receptors for cytokines, chemokines,
growth factors and proteases may
be involved in the conversion from
an inflammatory change to a fibrotic
stage. The best candidates for this
link between chronic inflammation and
fibrosis would be
growth factors
of fibroblasts, cy-
tokines and pro-
teases.
Processes Involved
In patients with rosacea, the proin-
flammatory peptide LL-37 activates
caspase 1 and the NLRP3 inflam-
masome. This, in turn, activates IL-1b
and enhances the induction of spe-
cific inflammatory effectors TLR-2,
which are regulated by keratinocytes.
CAMPs, which in rosacea are abnor-
mally increased, promote a dysfunc-
tion of the sebaceous gland that
determines its hyperplasia and also
an alteration in the composition of the
sebum; at the
same time, they
promote great-
er inflammation,
stimulate angio-
genesis and, along with osteopontin,
will determine the formation of gran-
ulomas and, finally, fibrosis.3-6
Sphingosine-1-phosphate is an im-
portant skin regulator of fibrosis and
responsible for a cascade of patholog-
ical fibrogenesis events. Apart from
injuring tissues by inflammation, these
events promote the release of fibro-cy-
tokines and fibroblast growth factor,
such as FGF, which stimulate the pro-
duction of extracellular matrix.4,6 Tis-
sue destruction and fibrosis are also
induced by metalloproteinases (MMP)
and serine proteases, especially MMP-
9 and MMP-2. This activation may re-
sult from an increase in the number

Fig. 9-4. Rupture of the glandular wall,

Fig. 9-3. Hyperplasia of the sebaceous gland and periglandu-
lar lymphocytic infiltrate [Courtesy of Dr. Martín Sangüeza].
partial disappearance of the gland, in-
tense inflammatory infiltrate and for-
mation of granulomas [Courtesy of Dr.
Martín Sangüeza].
90
Fig. 9-5. Only glandular lumen, massive inflammatory in-
filtrate and the onset of fibrosis remain [Courtesy of Dr.
Martín Sangüeza].
of mast cells, as well as the activation
of keratinocytes and macrophages.
The number and activity of fibroblasts
could be regulated by this pathway;
but, in addition, in patients with phy-
matous rosacea, there is an increased
expression of the transforming growth
factors TGF-b1 and b2 that contribute
to the activation of fibroblasts, with the
consequent fibrosis and formation of
rhinophyma. In parallel, keratinocytes,
T-cells and macrophages release cy-
tokines, chemokines, GF, MMPs, and
proteases, and regulate the expression
of integrins, occludins and claudins,
which amplify inflammatory phenome-
na and subsequently induce increased
fibrosis.2,8,9
Phymatous rosacea has a character-
istic gene expression pattern; for this
reason, although it shares inflammato-
Often, skin bacteria is associated
mentally with “skin infection”. But,
in recent years, research has shown
that the bacteria and microorgan-
isms living in our bodies and on our
skin also have many beneficial effects
that may have an important role in
the treatment of skin diseases, such
as atopic dermatitis, psoriasis, acne,
rosacea, seborrheic dermatitis, chron-
ic wounds, and even some skin can-
cers. The development of informatics,
nanotechnology, molecular biology,
immunology, and genomic technolo-
ry phenomena with different types of
rosacea, only patients with a specific
transcriptome will have PR. Mast cells
are closely related to chronicity and,
therefore, chronic persistence of mast
cells results in a chronic inflammatory
process and the subsequent deposi-
tion of connective tissue, leading to
fibrosis.8,9 Of course, these processes
are perfectly orchestrated: changes
such as sebaceous gland hyperplasia
–with the consequent alteration of the
lipid composition that determines the
release of multiple pro-inflammatory
substances– the subsequent rupture
of the glandular wall and the formation
of a periglandular granuloma, to finally
result in fibrosis, are sensitive events
that are not yet fully known. Figures
9-3 to 9-5 show the histopathological
events of chronic inflammation pro-
cesses and fibrosis.
Microbiome, Antimicrobial Peptides,
Demodex folliculorum, Staphylococcus
epidermidis, Helicobacter pylori
Walter Gubelin H., Lorena Merino G., Hans Gubelin A.
gies has led to a better understand-
ing of the relationship between
different microorganisms (bacteria,
viruses, fungi, parasites) and the or-
gans of our body and, in particular,
91
References
1. Holmes AD, Steinhoff M. Integrative
concepts of rosacea pathophysiol-
ogy, clinical presentation and new
therapeutics. Exp Dermatol 2016; 1-9.
2. Steinhoff M, Schauber J, Leyden J.
New insights into rosacea pathophys-
iology: A review of recent findings. J
Am Acad Dermatol 2013; 69:S15-26.
3. Steinhoff M, Buddenkotte J, Aubert
J, et al. Clinical, Cellular, and Molec-
ular Aspects in the Pathophysiolo-
gy of Rosacea. J Investig Dermatol
Symp Proc 2011; 15(1): 2-11.
4. Melnik B. Rosacea: The blessing of
the Celts – An approach to patho-
genesis through translational re-
search. Acta Derm Venereol 2016;
96:147-156.
their interrelation with the intestine
and the skin.1,2
Bacteria are the easiest micro-
organisms to isolate in the labora-
5. Kato A, Okura T, Hamada C, et al.
Cell stress induces upregulation of
osteopontin via the ERK pathway in
type II alveolar epithelial cells. PLoS
One 2014; 9:e100106.
6. Gerber PA, Buhren BA, Steinhoff
M, et al. Rosacea: the cytokine and
chemokine network. J Investig Der-
matol Symp Proc 2011; 15:40-7.
7. Schwalm S, Pfeilschifter J, Huwiler A.
Sphingosine-1-phosphate: a Janus-faced
mediator of fibrotic diseases. Biochim
Biophys Acta 2013; 1831:239-250.
8. Woo YR, Lim JH, Cho DH, et al. Ro-
sacea: Molecular mechanisms and
management of a chronic cutane-
ous inflammatory condition. Host
defense mechanism. Int J Mol Sci
2016 Sep 15; 17(9):1-23.
tory; however, despite significant
improvements in bacterial culture
and isolation techniques, less than 1
% of the bacterial population living
with humans are cultivated. Selec-
tive culture is even more difficult to
do with viruses, parasites and fungi.3
Traditional culture techniques have
begun to reveal the microbiota, also
known as microflora, which is the set
or community of microorganisms
that are normally located in different
epithelia, sites or habitats of the hu-
man body.
 Cultivation of each individual mi-
croorganism has its limitations. It is a
difficult and time-consuming process,
but thanks to advances in DNA am-
plification and sequencing technolo-
gy, the genome of the 16S ribosomal
RNA of a variety of microorganisms
have been analyzed. This is equivalent
to finding a true genomic fingerprint,
seal, or “signature” for each of them.
Now it is possible to identify microor-
ganisms individually and collectively,
to study thousands of microorganisms
simultaneously, accurately, and at an
increasingly low cost. In part, this was
achieved thanks to the Human Micro-
biome project, launched in 2008 by
the U.S. National Institutes of Health
(NIH) to support the identification
and characterization of the microbio-
ta and study its role in health and dis-
ease.4-6 As time goes on, the genomic
material of all microorganisms will be
studied, in a given epithelium, and
the genome of the microbiota will be
called metagenome.
The study of the genetic materi-
al of microorganisms gave rise to the
term “microbiome” which refers to the
population or community of different
microorganisms from a reasonably
well-defined habitat. The microbiome
has a function, activity and relatively
distinctive and defined physicochemi-
cal properties. Understanding the mi-
crobiome includes the identification
of microorganisms, their genes, their
environment, the way they relate to
each other, and the way they relate to
epithelial cells.
It is only recently that we have be-
gun to understand the complex com-
munities of microorganisms that live
on human epithelial surfaces. These
communities have the ability to com-
municate with each other; as a unit,
they also affect the immunity, physi-
ology and pathophysiology of each
epithelium, and form an ecosystem
associated with health and disease.
The skin microbiome is of great
importance in dermatology. It is esti-
mated that the skin has about one tril-
lion bacteria, with each centimeter of
skin hosting approximately a million
organisms with hundreds of differ-
ent species in a 10:1 relationship with
epithelial cells. This is why some au-
thors call the microbiome the second
genome. Not only does it cover the
surface of the skin, but it also resides
deep within appendages and glands.
The growth of different bacterial
populations depends on whether the
area is moist, dry, oily, thin, thick, and
whether it is exposed to light or not.
The microbiota protects against in-
fection,7 and its imbalances –whether
primary or secondary– lead to cellular,
immune and microbiological dysfunc-
tions.8 Among the most important
functions of the microbiota are: a) it
92
keeps epithelial microbial receptors
busy, which hinders colonization by
exogenous bacteria, especially patho-
gens; b) it competes with foreign mi-
croorganisms for the nutrients in the
environment; c) it releases mediators
that create an inhospitable environ-
ment for foreign microorganisms; d)
it participates in the bioconversion
of epithelial nutrients and complex
molecules; e) it releases antimicrobial
peptides (AMP) produced by bacte-
ria, called bacteriocins which, at nano-
molar concentrations, will protect
commensal species; f) it promotes the
release of healthy epithelial AMPs,
which favour wound healing, immu-
nomodulation, and death of foreign
microorganisms; g) it releases pro-
teases that hinder the formation of
bacterial biofilm by pathogenic bac-
teria; h) it modulates the action of
bacteriophages; i) it participates in an
epigenetic interaction with the epi-
dermis, interacting with the epider-
mal exchange; j) the metabolism of its
bacteria can modify the bioavailability
of certain drugs; k) it educates and
assists the immune system and influ-
ences it through a synergic mutual
interaction, to regulate it and vice ver-
sa. In brief, all these functions limit the
survival of pathogens, decrease skin
inflammatory conditions and increase
the skin’s innate immune defenses.
From an ecological point of view,
in addition to being influenced by the
relationships between organisms, the
skin microbiome is affected by the
use of soaps, shampoos, creams, an-
tibiotics, diets, genetic factors, inter-
action with family and animals, stress,
age and lifestyle. Sustained ecological
pressure on the microbiota can lead
to dysbiosis capable of favouring the
onset of chronic diseases.9 Ultimately,
there is a close symbiosis between
the host and its microbiome; any al-
teration in one of them can result in
negative effects on both, and lead to
a possible disease in the host.10
Many studies on the microbiome
have focused on assessing how it
changes in different skin diseases. A
healthy skin has a balanced commu-
nity of bacteria that live together in
harmony. This has a positive influence
on skin immunity, modulating the pop-
ulation of resident T-cells and collab-
orating in regulation of tolerance or
inflammation when necessary. But
in dysbiosis - an imbalance in bacte-
rial populations - the skin is brought
to a pro-inflammatory condition ca-
pable of dysregulating the immune
system, allowing disease. Knowing
how healthy bacteria can educate the
immune system and how adaptive im-
munity is able to modulate bacteria,
new lines of research can be devel-
oped to “transplant good bacteria”
into dermatological treatments. For
this to happen, it is essential that the
environment where these bacteria
are transplanted has adequate phys-
ical-chemical parameters of the skin
barrier and is supported by prebiotics
that enable the growth and mainte-
nance of the transplant.
Most studies of microbiota have
been conducted in the intestines.
Thanks to this, successful therapeu-
tic applications have been obtained
when transplanting fecal microbiota
in intestinal infections. Intestinal mi-
crobiota has been linked to renal and
cardiovascular disease. A healthy in-
testinal microbiota has been associat-
ed with a lower frequency of chronic
inflammatory conditions and a better
immune response to tumours. It has
been observed that, in some cases,
the intestinal microbiota also influ-
ences skin health. Many of the micro-
biome concepts in the gut have been
extrapolated to the skin, as they have
common characteristics, and this has
helped to a more rapid development
of the concept of skin microbiome.
As long as biotechnology centers
working in bacterial genetic engi-
neering manage to modify the bac-
terial genome or create synthetic
bacteria, with a 100 % artificial ge-
nome, it will be possible to manipulate
the microbiome directly or indirectly
by the production of prebiotics from
new artificial bacteria introduced in
the skin microbiota. At present, many
pharmaceutical companies are eval-
uating therapeutic applications with
the microbiome in various patholo-
gies, although the most well-stud-
ied applications involve the intestine
or the skin. In the skin, microbiomes
may potentially work on pathologies
such as dermatitis, atopic dermatitis,
acne, rosacea, seborrheic dermati-
tis, tumours, inflammatory diseases,
chronic wounds and cosmeceutical
treatments. As examples, there is in-
vestigation of treatment for acne with
non-pathogenic Propionibacterium
acnes that would replace pathogenic
strains, or strains that convert glandu-
lar ammonium into nitrite and nitric
oxide; this would help to eliminate
pathogens and promote healthy skin
in patients with rosacea and acne.
ANTI-MICROBIAL PEPTIDES
(AMPs)
These peptides are key effector mol-
ecules for the proper functioning of
innate immunity, the control of infec-
tions, and the maintenance of normal
microbiota. They are mainly released
by keratinocytes and mast cells. More
than 1800 AMPs have been described
in the animal and plant kingdom, and
more than 20 have been found in the
skin. They are small molecules, from 15
to 45 amino acids, mostly with positive
charges and amphipathic structure,11
which allows them to interact with
the negative charges of phospholip-
ids and hydrophobic fatty acid chains
of microbial membranes. This leads
93
to permeation of the membrane and
incorporation of peptides, resulting
in the formation of true pores, and, in
turn, release of intracellular compo-
nents and microbial death.12
AMPs also have an immunoregula-
tory function and are involved in the
pathogenesis of skin diseases such
as psoriasis, rosacea and atopic der-
matitis. They modify the inflammatory
response of the host through several
mechanisms; the most important are
angiogenesis induction, regulation
of cell proliferation (scarring), and
the ability to function as chemotactic
agents on neutrophils, lymphocytes,
macrophages and some epithelial
cells. These cells release inflammato-
ry and anti-inflammatory mediators.13
AMPs also are important as immuno-
regulators because of their ability to
inhibit or stimulate TLRs signals.14
Among the most important AMPs
of the skin are cathelicidins and b-de-
fensins, which have a wide range of
antimicrobial action against gram-neg-
ative and gram-positive bacteria, vi-
ruses, fungi and parasites. In the skin,
keratinocytes produce AMPs as a de-
fensive barrier. Mast cells, especially
perivascular ones, have the ability to
release cathelicidins and AMPs, which
is why they play an important role af-
ter the occurrence of skin damage or
inflammation.15 In addition to being
produced by molecular patterns asso-
ciated with pathogens, they will also
be produced by molecular patterns
associated with trauma or skin dam-
age.16,17 AMP synthesis, metabolism,
and half-life are subject to strict con-
trols. Cathelicidins are synthesized as
pro-peptides on which serines will act
and may cleave them into molecules
of various sizes. This confers different
antimicrobial activities with inactivity
on human cells. AMPs play an import-
ant role in defining the microbiota of
a given epithelium and in maintaining
an appropriate balance with it.
Another type of AMP –bacterio-
cin- is produced by some bacteria of
the normal resident microbiota, which
constitute a true epidermal shield.
Bacteriocins are produced mainly by
gram-positive bacteria, such as Staph-
ylococcus (especially S. epidermidis),
Streptococcus, Lactococcus, Strepto-
myces and Micrococcus, and inhibit
the growth of foreign bacteria or bac-
teria alien to the epithelium without
affecting other residents of the mi-
crobiota. Some AMPs attract neutro-
phils, which amplifies the ability to kill
microorganisms.18
ROSACEA AND MICROBIOME
Rosacea is a chronic disease whose
cause is not exactly known. Being of
multifactorial and complex etiology, in
this entity, the facial skin has a basal
state of variable inflammation, asso-
ciated with vasomotor instability and
barrier dysfunction. The microbiome,
and in particular some microorgan-
isms of the microbiota, are involved
to a different degree in rosacea
pathophysiology, although it is not
yet possible to accurately assess the
importance of microbial agents in re-
lation to the rest of the pathophysio-
logic factors. Generally, the presence
of microorganisms in the skin does not
lead to an inflammatory response; but
in patients with rosacea and a genet-
ic predisposition, microorganisms will
activate TLRs, which would result in
cutaneous intolerance to the environ-
ment and to these microorganisms.
Studies on the microbiome seek,
among other things, to know the pop-
ulation differences of microorganisms
in healthy and diseased skin. In the
case of rosacea, there are differenc-
es in the microbiota, mainly in relation
to commensal species such as Demo-
dex folliculorum, Demodex brevis and
Staphylococcus epidermidis, and in
bacteria that are not part of the skin
microbiota, such as Helicobacter py-
lori.19,20 It is not clear enough whether
this variation in the microbiota has a
rosacea-triggering role or whether
the change is due to “environmental”
conditions that are secondary to the
pathophysiological changes of rosa-
cea.21 D. folliculorum usually lives in
the sebaceous glands of healthy skin,
and patients with rosacea generally
have a higher amount of this parasite
than healthy control patients. 35-50 %
of patients have an increased count of
the parasite, which is defined as more
than 5 mites per square centimetre.22
Patients with ETR and PPR have, on
average, a 6-times greater density of
D. folliculorum, which has been associ-
ated with an overall increase in inflam-
matory mediators.23 It was suggested
that a decrease in the load of this
parasite should improve the condi-
tion, but in patients treated with met-
ronidazole at 0.75 % and permethrin
5 % in cream –the latter being more
effective–it was found that there was
no substantial improvement in the De-
modex population and rosacea. Thus,
it is thought that Demodex alone is
not responsible for rosacea, although
it has an adjuvant role in its overall
pathophysiology, due to the release
of chitin by D. folliculorum which ac-
tivates TLR-2.24,25 This increases levels
of kallikrein 5 (see Immune System in
this chapter) which, in turn, raises the
levels of mediators and peptides that
trigger the pathophysiology of rosa-
cea. It is estimated that there may be
a genetic predisposition in patients
infested by this parasite, which could
be related to –the presence of Cw2 al-
lele in demodicidosis, or the absence
of the HLA-A2 allele in papulopustu-
lar lesions.26 In addition, degenerative
solar elastosis could facilitate an inva-
sion of mites into the dermis, which
would favour the development of
granulomatous reactions.27
94
Bacillus oleronius, a gram-negative
bacterium, can live in Demodex fol-
liculorum intestines. When Demodex
disintegrates after death, B. oleronius
is released into the environment and,
since it produces highly immunogenic
proteins, its contact with the serum of
some susceptible patients with PPR
will produce inflammation.28 Neutro-
phils of healthy individuals exposed
to B. oleronius increase production of
MMP 9, IL-8 and TNF.29,30
Another important bacterium is
Staphylococcus epidermidis. It is the
most important component of the
commensal microbiota in normal skin,
and plays a critical role against skin
infections caused by pathogenic bac-
teria, primarily by keeping bacterial
receptors occupied and by producing
AMPs (especially against S. aureus).31
S. epidermidis are frequently isolat-
ed from rosacea pustules, but these
strains are different from those iso-
lated from healthy skin. Most S. epi-
dermidis are beta-hemolytic, which
suggests that they secrete virulence
factors and antigens that will be rec-
ognized by TLR-2s. This leads to an
increase in AMPs, which stimulates
immunity and triggers rosacea.32
The relationship of some intestinal
microbiota bacteria with the patho-
physiology of rosacea may be import-
ant, and Helicobacter pylori is the
most strongly implicated gut bacteria.
Strains of H. pylori, which are positive
for the Cytotoxin-associated Gene A
(CagA) virulence factor, have been
isolated in about 70 % of patients with
rosacea with a similar antibody titer
response. The pathophysiological in-
teraction between this microorganism
and the disease is not known; nor is it
sufficiently clear whether treatment
of H. pylori leads to improvement of
rosacea. In short, the role played by
this bacterium in rosacea is currently
controversial and some authors un-
derestimate its importance.33
SEBORRHEIC DERMATITIS AND
MICROBIOME
The pathophysiology of seborrheic
dermatitis has been typically relat-
ed to Malassezia, which is part of the
microbiota but may also causes dis-
ease when its growth is uncontrolled.
Malassezia mainly affects facial areas,
scalp and thorax. The most frequently
found species are M. restricta and M.
globosa. Improvement in seborrheic
dermatitis is observed when antifun-
gals are applied but no changes are
observed with the use of antibacteri-
als. In seborrheic dermatitis associated
with Malassezia, there is more cutane-
ous sebum, since the fungus has a li-
pase that smooths sebum and releases
metabolites of irritating free fatty ac-
ids. This results in epithelial hyperpro-
liferation and flakes, in addition to the
production of arachidonic acid, which
also leads to inflammation.34
 Recent studies of microbiota sug-
gest that other bacteria may also be
important in seborrrheic dermatitis.
Staphylococcus, Streptococcus and
Acinetobacter provide nutrients and
favour a suitable prebiotic environment
for Malassezia to grow. It is argued
that Bacteroides, Propionibacterium
and Chryseobacterium affect the se-
verity of symptoms, with an imbalance
of fungi and bacteria being the primary
cause of seborrheic dermatitis.35,36
A pharmaceutical company devel-
oped a product with a bacterial ex-
tract of a filamentous microorganism,
called Vitreoscilla filiformis, which was
formulated in thermal water with an-
ti-inflammatory properties. Treatment
with this product resulted in an im-
provement of erythema, scaling and
pruritus at day 8 along with a main-
tenance effect. The authors attribute
this improvement, in part, to the fact
that V. filiformis contains factors ca-
pable of restoring cutaneous homeo-
stasis through its immunomodulating
activity by normalizing the microbio-
ta. This product may also be useful in
other inflammatory skin diseases.37
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cea. A randomized double-blind
placebo-controlled study. Derma-
tology 2002; 205(3):265-270.
25. Ferrer L, Favera I, Silbermayr K.
Immunology and pathogenesis of
canine demodecosis. Vet Dermatol
2014; 25(5):427-e65.
26. Mumcuoglu KY, Akilov OE. The role
of HLA A2and Cw2 in the patho-
genesis of human demodicidosis.
Dermatology 2005; 210(2):109-114.
Multiple pathways are altered or
susceptible to inflammation in the
pathophysiology of rosacea, and are
triggered by the action of several
factors, such as cold, heat, sun, tem-
perature changes, spicy food, alcohol,
injuries, etc. (Fig. 9-6).1 The higher in-
cidence of the disease in individuals
of Celtic and northern European or-
igin suggests a genetic component.2
In ETR, there is a higher expression
of proinflammatory and vasoregula-
tory genes, as well as of those acting
on innate and adaptive immunity.3 In
27. AroniK, TsagroniE ,Lazaris AC, et
al. Rosacea: A clinicopathologi-
cal approach. Dermatology 2004;
209(3):177-182.
28. Chang YS, Huang YC. Role of De-
modex mite infestation in rosa-
cea: A systematic review and me-
ta-analysis. J Am Acad Dermatol
2017:S0190-9622(17)30429-2.
29. Jarmuda S, McMahon F, Zaba R,
et al. Correlation between serum
reactivity to Demodex-associated
Bacillus oleronius proteins, and al-
tered sebum levels and Demodex
populations in erythematotelangi-
ectatic rosacea patients. J Med Mi-
crobiol 2014; 63:258-62.
30. O’Reilly N, Bergin D, Reeves EP, et al.
Demodex-associated bacterial pro-
Summary
María Isabel Herane, Minerva Gómez
ETR, the lymphocytic infiltrate cor-
responds primarily to T cells (80%),
and to a much lesser degree to B lym-
phocytes (10-20%). There is greater
participation of mast cells in the pap-
ulopustular and phymatous varieties
of rosacea.4 In patients with rosacea,
the existence of two single nucleotide
polymorphisms (SNPs) has also been
96
teins induce neutrophil activation. Br
J Dermatol 2012; 166(4):753-760.
31. Gallo RL, Nakatsuji T. Microbial
symbiosis with the innate immune
defense system of the skin. J In-
vest Dermatol 2011; 131(10):1974-
1980.
32. Wanke I, Steffen H, Christ C, et al.
Skin commensals amplify the innate
immune response to pathogens
by activation of distinct signalling
pathways. J Invest Dermatol 2011;
131(2):382-390.
33. Dahlqvist G, Piessevaux H. Irrita-
ble bowel syndrome: the role of
the intestinal microbiota, patho-
genesis and therapeutic targets.
Acta Gastroenterol Belg 2011;
74(3):375-80.
demonstrated: GSTM1 and GSTT1
polymorphisms. They are associated
with glutathione-S-transferases and
have an important role in cellular de-
fense against increased levels of reac-
tive oxygen species.5-7 The association
with multiple sclerosis, diabetes, and
diabetic retinopathy, among other
entities, can be explained by the shar-
34. Schommer N, Gallo R. Structure
and function of the human skin mi-
crobiome. Trends Microbiol 2013;
21:660-8.
35. Park T, Kim HJ, Myeong NR, Lee
HG, et al. Collapse of human scalp
microbiome network in dandruff
and seborrheic dermatitis. 2017.
36. Tanaka A, Cho O, Saito C, et al.
Comprehensive pyrosequencing
analysis of the bacterial microbiota
of the skin of patients with sebor-
rheic dermatitis. Microbiol Immunol
2016; 60(8):521-6.
37. Cathelineau AC, Bastien P, Esdaile
J, et al. Vitreoscilla filiformis bio-
mass improves seborrheic dermati-
tis. J Eur Acad Dermatol Venereol
2008;22(8):1014-5.
ing of certain HLA antigens. The inci-
dence of rosacea is higher in identical
twins than in heterozygotes.2,8 It has
been suggested that the vitamin D
and retinoic acid receptor (VDR and
RXR) pathways participate in the pro-
cess triggered by UVL.9
BARRIER FUNCTION
The compromise of the skin barri-
er function is demonstrated by less
hydration and increased transepi-
dermal water loss.10,11 Damage to the
barrier leads to a change in the in-
nate immune system functions: anti-
microbial peptides (AMPs) increase,
such as the cathelicidin-derived pep-
tide (LL-37), which is required for
the maintenance of epidermal barri-
er homeostasis. On the other hand,
the alteration of the barrier function
enables a greater infestation by De-
modex folliculorum, which leads to
greater inflammation –by activation
of TLR2s– and, consequently, to the
alteration of innate immunity. The
Fig. 9-6. Triggering factors, cellular process involved and clinical response.
alteration of the normal signalling
pathways translates to an increase in
cytokines and AMPs due to trigger-
ing of the innate immune system.
DYSREGULATION OF THE
INNATE IMMUNE SYSTEM
In the skin of patients with rosacea, and
without knowing the triggering cause,
there is an increase in the expression
of cathelicidin (which is a cationic anti-
bacterial protein of 18:hCAP18), AMP,
97
and kallikrein-5 (KLK5), the serine pro-
tease responsible for the cleavage of
cathelicidin LL37 to an active peptide
(Fig. 9-7). These molecules differ from
those existing in normal skin: frag-
ments of LL-37 are smaller and capa-
ble of regulating processes such as
angiogenesis, expression of extracellu-
lar matrix components and leukocytic
chemotaxis.2,12 Vitamin D, activated in
keratinocytes by UV light, is a strong
inducer of cathelicidin expression.8
Rosacea skin also has increased
levels of TLR2, which participate in
the recognition of pathogen mole-
cules, and are activated by Demodex
chitin, by Bacillus oleronius lipopro-
teins –gram-negative bacteria present
in Demodex intestines–and possibly
Helicobacter pylori and Staphylococ-
cus epidermidis also. This activation
of TLR2 in keratinocytes leads to an
increased expression and activity of
KLK5 and LL-37 levels.2,12-14
An increase in the expression of
matrix metalloproteinases (MMP)
is observed, especially MMP2 and
MMP9. The latter activates the pre-
proenzyme of KLK5, which increases
the production of KLK5 and LL-37.12,13
Mast cells, also key players in the
pathogenesis of rosacea, secrete LL-
37, MMP9 and trigger the release of
cytokines.
Pure and crude Bacillus oleronius
proteins activate neutrophils through
the inositol triphosphate (IP3) path-
way, suggesting the central role of
PMNs in defending against patho-
gens involved in rosacea.15
A predominance of Th1 and Th17
cells, as well as macrophages and
mast cells, has been demonstrated in
all three subtypes of rosacea.16 This
contributes to the increase of inflam-
matory cytokines, such as Il-17, TNF-a
and interferon g.17
 ER STRESS
Both TLR2 and TLR4 activate IRE1a
kinase and its successor, XBP1; and
both IRE1a and XBP1 are inducers
of pro-inflammatory cytokine pro-
duction in macrophages. These mol-
ecules act as sensors of ER stress,
defined as the accumulation inside
ER of misfolded proteins under cer-
Fig. 9-7. Processes of innate immunity.
tain conditions, such as UV radiation
or thermal shock. Unfolded protein
response (UPR) is a cell repair mech-
anism that modifies the way cells are
transcribed and translated under
these conditions.18
Three protein sensors are known
–located in the ER membrane lumen–
98
that detect misfolded proteins and
initiate UPR.
1. Inositol-requiring enzyme 1
(IRE1a).
2. Protein kinase similar to dou-
ble-stranded RNA-dependent ER-ki-
nase (PERK).
3. Activating transcription factor 6
(ATF6).
All factors that exacerbate rosacea
are also thought to cause ER stress.
ER stress, in turn, activates inflam-
matory, angiogenic, neurosensitive,
lipogenic, fibrogenic and antimicro-
bial signalling pathways. Ultraviolet
radiation, heat, cold, stress, glucocor-
ticoids, spicy food or microorganisms
modulate, generate or induce ROS,
MMPs, TLR-2 signalling or neuropep-
tides. All of these factors may play a
part in the mediation of the immune
system and the release of cytokines
and chemokines.19
MICROORGANISMS/
MICROBIOME
The exact mechanism by which mi-
croorganisms participate in the patho-
genesis of rosacea is unclear. Usually,
they do not produce an inflammatory
response; but in genetically predis-
posed patients, these agents activate
TLRs, leading to inflammation. In the
case of rosacea, there are differences
in the microbiota, mainly in relation to
commensals such as Demodex follic-
ulorum, Demodex brevis and Staphy-
lococcus epidermidis, and to bacteria
that are not part of the skin micro-
biota, such as Helicobacter pylori. It
is not sufficiently clear whether this
variation in the microbiota has a role
in triggering rosacea or whether “en-
vironmental” conditions –secondary
to the pathophysiological changes of
this disease– lead to changes in it.
Patients with ETR or PPR have, on
average, an increase of 5.7 to 6 times
the density of D. folliculorum, which
has been associated with an overall
increase in inflammatory mediators.
This parasite, by itself, would not be
responsible for the disease, but acts
as a co-agent. It has been argued that
the chitin released by D. folliculorum
can activate TLR-2, which would lead
to increased levels of KLK5 and trig-
ger the immune cascade. It is thought
that there may be a genetic predispo-
sition in patients infested by this par-
asite. This would entail the existence
of the Cw2 allele, which is related
to demodicidosis, or the absence of
the HLA-A2 allele, which is related to
deep papulopustular lesions. In ad-
dition, degenerative solar elastosis
could facilitate an invasion of mites
into the dermis, which would favour
the development of granulomatous
reactions. Bacillus oleronius, which
lives in Demodex folliculorum intes-
tines, is also considered a TLR2 acti-
vator.20
Staphylococcus epidermidis is the
most important component of com-
mensal microbiota in normal skin. This
bacterium is often isolated from rosa-
cea pustules, but its strains differ from
those isolated from healthy skin. They
are producers of other proteins, most-
ly beta-hemolytic ones. This suggests
that they secrete virulence factors
and antigens that will be recognized
by TLR-2s; this leads to an increase
in AMPs and immunity stimulation,
which triggers the disease.21 The role
of Helicobacter pylori and other intes-
tinal bacteria is controversial and the
findings, variable.
NEUROVASCULAR CHANGES
AND PEPTIDES (FIG. 9-8)
Cutaneous neurovascular dysfunc-
tion plays a key role in pathophys-
iology, activated by environmental
triggers. To better understand these
theories, it is necessary to differenti-
ate the important roles of the vascu-
lar and lymphatic systems in rosacea.
Erythema in rosacea is the result of
the acute inflammatory process in-
duced by stimulation of the sensory
nerves. This leads to a local increase
of mast cell, inflammatory neurome-
diator and cytokine infiltrate. Critical
vascular mediators that induce per-
sistent erythema include powerful
vasoregulatory neuropeptides, such
as the pituitary adenylate cyclase
activating polypeptide (PACAP), the
vasoactive intestinal peptide (VIP),
and the calcitonin gene-related pep-
tide (CGRP), which produce pro-
longed vasodilation. Other powerful
vasodilators in rosacea include nitric
oxide, substance P, reactive oxygen
species, and proteases.4 Erythema
may be transient (minutes to hours),
99
persistent (days to weeks) or perile-
sional (around papules or pustules,
disappears with clearance of the in-
flammatory lesions); and flushing and
blushing are added.
The three subtypes of rosacea
show histopathological changes: larg-
er size and dilation of arterioles and
capillaries, and dilated venules in the
upper dermis, with post-capillary ede-
ma, and transmigration of leukocytes
(predominantly T-cells and mono-
cytes). MMPs are increased more
than 300 times in the 3 subtypes of
rosacea, especially MMP 12, 1 and 9
which contribute to tissue destruc-
tion and subsequent development of
telangiectases.
Markers for angiogenesis at mRNA
or lymphatic vessel regulation level,
such as vascular endothelial growth
factor A (VEGF-A), CD31, podo-
planin, or lymphatics (D2-40) are also
increased in patients with rosacea.1
These levels of angiogenesis do not
correlate with immunohistochemical
information indicating marked vaso-
dilation in ETR or PPR. Angiogenesis
occurs in PR, which raises a question
about an eventual progression from
ETR/PPR to PR by a chronic inflam-
matory process that triggers fibrotic
changes.
Despite all structural changes, vas-
cular responsiveness in patients with
rosacea remains intact, with increased
and sustained vasodilation in response
to triggers. Activation of pre-capillary
arterioles produces vasodilation, clin-
ically manifested as erythema; while
activation of post-capillary venules
produces protein leakage and caus-
es edema and leukocyte recruitment,
through the regulation of selectins
and cell adhesion molecules.
Rosacea triggers activate the
sensory nerves. Two subfamilies of
cationic channel receptors emerge
as possible participants in patho-
genesis, based on their functions
and their ability to mediate sensory
and inflammatory signals. These are
TRPV (vanilloid) and TRPA (ankyrin),
located in nociceptive nerve endings
and activated by various triggering
factors. The first group are TRPVs,
compatible with 6 different channels,
of which at least 4 are active in rosa-
cea.2-4,13 Patients have a higher den-
sity of TRPV-1-positive nerve fibers,
increased TRPV-1 expression levels,
and longer-than-normal activation
of TRP channels in nociceptors. This
leads to longer-lasting erythema.
TRPV-2 participates in innate immu-
nity, inflammation, nociception, heat
sensation, and vascular regulation.
TRPV-3 and TRPV-4 are activated by
temperature changes. The former is
involved in thermal sensation, while
TRPV-4 acts as an osmoreceptor, pro-
motes vasodilation and causes mechan-
Fig. 9-8. Neuroimmune and neurovascular changes, and therapeutic strategies.
100
ical and inflammatory hyperalgesia.
The second group of receptors are
the TRPAs (subfamily of the TRPVs).
They are located in primary sensory
neurons and are 50 % co-expressed
with TRPV receptors, suggesting an
interaction between them. TRPA-1s
have thermal sensitivity, are activated
with spicy foods and trigger flushing
crises. They also act as ROS sensors
and cause vasodilation. It has been
described that TRPA-1 are localized
along with protease-activated recep-
tor 2 (PAR2). Rosacea skin has high
activity of serine proteases; therefore,
they can activate PAR2 and contrib-
ute to an increase of the inflammatory
process and to a greater sensitization
of TRPA-1. Consequently, there will be
an exacerbation of the inflammatory
response mediated by TRPA-1.13,22
PHYMAS AND PROCESSES
INVOLVED
PR is associated with two basic events:
hyperplasia of the sebaceous glands
and a chronic inflammatory process
that will result in a fibrotic process.
The latter may be preceded by PPR;
however, a subgroup of patients de-
velop PR without other clinical signs
(Fig. 9-9).
Recent studies have shown that
even without inflammatory clinical
signs, visible under the microscope,
there is evidence of a lymphomono-
cytic infiltrate. The more inflammatory
lesions there are, and the greater the
Demodex infestation, the greater the
inflammatory infiltrate will be.
The processes involved in PR are
defined as follows:
UU The proinflammatory peptide LL-
37 activates caspase 1, the NLRP3
inflammasome, and therefore, IL-1.
Cathelicidin antimicrobial pep-
tides (CAMPs), which in rosacea
are abnormally increased, promote
a dysfunction of the sebaceous
gland which determines its hyper-
plasia, as well as an alteration in the
composition of the sebum. At the
same time, they promote greater
inflammation, stimulate angiogen-
esis and, along with osteopontin,
will determine the formation of
granulomas and, finally, fibrosis.
UU Sphingosine 1 phosphate is an im-
portant skin regulator of fibrosis
and responsible for a cascade of
pathological fibrogenesis events.
Apart from injuring tissues by in-
flammation, they promote the
release of fibrocytokines and fibro-
blast growth factor, which stimu-
late the production of extracellular
matrix. Tissue destruction and fi-
brosis are also induced by MMPs
and serine proteases, especially
MMP-9 and MMP-2. This activa-
tion may result from an increase in
the number of mast cells, as well
101
as the activation of keratinocytes
and macrophages. The number
and activity of fibroblasts could be
regulated by this pathway; but, in
addition, in patients with PR, there
is an increased expression of the
transforming growth factors b1 and
b2 (TGF-b1 and b2) that contribute
to the activation of fibroblasts,
with the consequent fibrosis and
formation of rhinophyma.
UU In parallel, keratinocytes, T-cells
and macrophages release cyto-
kines, chemokines, GF, MMP, and
proteases, and regulate the ex-
pression of integrins, occludins
and claudins, which amplify inflam-
matory phenomena and subse-
quently induce increased fibrosis.
UU PR has a characteristic gene ex-
pression pattern. For this reason,
although it shares inflammatory
phenomena with different types
of rosacea, only patients with a
specific transcriptome will have
PR. Mast cells are closely related
to the chronicity of the disease
and, therefore, their chronic per-
sistence results in a chronic inflam-
matory process and fibrosis.18,23
ULTRAVIOLET RADIATION (UVR)
UVR is a known flushing trigger,
but its role in rosacea is still contro-
versial. However, it is known that it can
worsen the symptoms, affecting mainly
fair-skinned individuals, and that biop-
sies show solar elastosis. UVR causes
an overexpression of MMPs, collagen
denaturation and increase of reactive
oxygen species. This activates the
TLR-2s and triggers the inflammatory
cascade via KLK. In keratinocytes, UVB
radiation increases the production and
secretion of fibroblast growth factor
2 (FGF-2) and vascular endothelial
growth factor 2 (VEGF-2), which con-
tributes to hypervascularity in these
patients. Cathelicidin expression in
these cells is heavily induced by vita-
min D, which is activated by UVR; this
is another mechanism by which UVR
exposure increases damage in patients
with rosacea. Figures 9-7 to 9-9 show
tables summarizing the pathogenesis
of rosacea.
References
1. Abram K, Silm H, Maaroos HI, et al.
Risk factors associated with rosa-
cea. J Eur Acad Dermatol Venereol
2010; 24(5):565-571.
2. Steinhoff M, Schauber J, Leyden JJ.
New insights into rosacea patho-
physiology: a review of recent find-
ings. J Am Acad Dermatol 2013;
69(6 Suppl 1):S15-26.
3. Del Rosso JQ. Advances in under-
standing and managing rosacea:
(part 1) connecting the dots be-
tween pathophysiological mecha-
nisms and common clinical features
Fig. 9-9. General summary and process leading to phymatous rosacea [JC Diez de Medina].

102
 of rosacea with emphasis on vascu-
lar changes and facial erythema. J
Clin Aesthet Dermatol 2012;5:16-25.
4. Steinhoff M, Schmelz M, Schauber
J. Facial erythema of rosacea. Aeti-
ology, different pathophysiologies
and treatment options. Acta Derm
Venereol 2016; 96 (5):579-86.
5. Chang AL., Raber I., XU J. et al. Assess-
ment of the genetic basis of rosacea
by genome-wide association study. J
Invest Dermatol 2015; 135:1548-55.
6. Ahn CS., Huang WW et al. Rosacea
pathogenesis. Dermatol Clin 2017.
7. Yazici AC, Tamer L, Ikizoglu G, et al.
GSTM1 and GSTT1 null genotypes
as possible heritable factors of ro-
sacea. Photodermatol Photoimmu-
nol Photomed 2006; 22(4):208-210.
8. Aldrich N., Gerstenblith M, Fu P, et
al. Genetic vs environmental factors
that correlate with rosacea. JAMA
Dermatol 2015; 151: 1213.
9. Carlberg C. Mechanisms of nuclear
signalling by vitamin D3. Interplay with
retinoid and thyroid hormone signal-
ling. Eur J Biochem 1995; 231(3):517-527.
10. Zhou M, Xie H, Cheng L, et al. Clin-
ical characteristics and epidermal
barrier function of papulopustular
rosacea: A comparison study with
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32(6):1344-1348.
11. Addor FAS. Skin barrier in rosacea.
An Bras Dermatol 2016; 91(1):59-63.
12. Dorschner RA, Williams MR, Gallo RL.
Rosacea, the face of innate immunity.
Br J Dermatol 2014; 171(6):1282-1284.
13. Two AM, Wu W, Gallo RL, et al. Ro-
sacea: part I. Introduction, categori-
zation, histology, pathogenesis, and
risk factors. J Am Acad Dermatol
2015; 72(5):749-758.
14. Forton FM. Papulopustular rosacea,
skin immunity and Demodex: Pityri-
asis folliculorum as a missing link. J
Eur Acad Dermatol Venereol 2012;
26(1):19-28.
15. Mc Mahon F, Banville N, Kavanagh
K, et al. Activation of neutrophils
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via IP 3 pathway following expo-
sure to Demodex- associated bac-
terial proteins. Inflammation 2015
(DOI:10.1007/s10753-015-0264-4).
16. Buhl T, Sulk M, Nowak P, et al. Mo-
lecular and Morphological Charac-
terization of Inflammatory Infiltrate
in Rosacea Reveals Activation of
Th1/Th17 Pathways. J Invest Derma-
tol 2015; 135(9):2198-2208.
17. Reinholz M, Ruzicka T, Steinhoff M,
et al. Pathogenesis and clinical pre-
sentation of rosacea as a key for a
symptom-oriented therapy. J Dtsch
Dermatol Ges 2016; 14 Suppl 6:4-15.
18. Melnik BC. Rosacea: The blessing
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genesis through translational re-
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19. Melnik BC. Endoplasmic reticulum
stress: Key promoter of rosacea
pathogenesis. Exp Dermatol 2014;
23(12):868-73.
20. Lacey N, Delaney S, Kavanagh K,
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gens stimulate inflammatory cells
in rosacea.Br J Dermatol 2007;
157(3):474-481.
21. Holmes AD. Potential role of micro-
organisms in the pathogenesis of
rosacea. J Am Acad Dermatol 2013;
69(6):1025-32.
22. Steinhoff M, Schmelz M, Schaub-
er J. Facial erythema of rosacea.
Aetiology, different pathophys-
iologies and treatment options.
Acta Derm Venereol 2016; 96 (5):
579-86.
23. Steinhoff M, Schauber J, Leyden JJ.
New insights into rosacea patho-
physiology: A review of recent find-
ing. J Am Acad Dermatol 2013; 69:
S15-26.
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Section 4 „„ Chapter 10. Nosological
Classification and Severity Grading
„„ Chapter 11. Classical Forms
„„ Chapter 12. Special Forms
Nosological „„ Chapter 13. Granulomatous
„„Rosacea
Capítulo 7. Generalidades
Classification, Clinical „„ Capítulo 8. Epidemiología
Chapter 14. Most common

and Histological Features histopathological findings

„„ Capítulo 9. Patogenia
in rosacea
Rosacea is a chronic inflammatory skin
condition that mainly affects the cen-
tral face, and whose cause is unknown.
It occurs in a broad age group, from
children to senior adults, affects both
sexes, and usually develops between
the third and fourth decades of life.
This condition is more frequent among
fair-skinned people (Fitzpatrick photo-
types I and II), although it can also be
observed –to a lesser extent– among
individuals of other ethnicities or with
other skin color.1 The prevalence of
rosacea, published in multiple epide-
miological studies corresponding to
different geographical areas, is be-
tween 1 % and 20 %, although these
figures do not necessarily reflect what
happens in the general population or
in each of the clinical forms.2
It is characterized by a broad spec-
trum of clinical manifestations, includ-
ing primary signs, such as transient or
persistent center-facial redness, tel-
angiectases, papules, and inflamma-
tory pustules. Other characteristics
are dryness, scaling, edema, plaques
(confluent areas of inflammation be-
tween papules and pustules), glandu-
lar or fibrous hyperplasia (phymas),
and sometimes ophthalmic disorders
corresponding to secondary signs.
The latter may appear along with
primary signs or independently. Oc-
casionally, lesions may be observed
in extra-facial areas such as the cleav-
age or scalp (Tables 10-1 to 10-3).
Chapter 10
Nosological
Classification and
Severity Grading
Ana Kaminsky, Mercedes Flórez-White, Jaime Piquero
Martín, María I. Herane, Juan C. Diez de Medina
Rosacea is a disease of high psycho-
social impact, in which the sensation of
burning, stinging and other unpleasant
subjective manifestations contribute
to the patient’s discomfort.3
The pathogenic mechanisms are
not sufficiently elucidated, which hin-
ders the possibilities of establishing
an effective treatment.
Table 10-1. Primary Signs
Transient facial redness.
Persistent facial redness
Telangiectases.
Inflammatory papules.
Inflammatory pustules.
105
Table 10-2. Secondary Signs
Dryness.
Scaling.
Edema.
Inflammatory plaques (between papules and
pustules).
Fibrous or glandular hyperplasia (phymas).
Extrafacial lesions.
Ocular disorders.
This brief introduction of some
outstanding facts about rosacea mo-
tivated dermatologists from different
countries –experts in rosacea, who
are part of the Iberian-Latin Ameri-
can Group for the Study of Rosacea
(GILER)– to propose a nosological
classification based on consensus.
The goal was to provide a basis for
conducting epidemiological, clinical,
pathogenic and therapeutic studies.
Such studies must necessarily con-
sider different variables including
climate, population, ethnicity, the
color of the skin and the area of the
territory where the study will be per-
formed.4
This work was carried out in ac-
cordance with the guidelines of the
Delphi Method, which “is classified as
one of the general forecasting meth-
ods that seeks to arrive at consensus
of a group of experts based on the
analysis and reflection regarding a
defined problem.”5
During the meetings held by
GILER, either in person or aided by
technological means, three import-
ant working points emerged:
1. Is it possible to define a condition
using generic terms, such as sub-
types?
Table 10-3. Secondary Signs,
Symptoms
Burning
Stinging
Dryness
Itching
Intolerance to topical products
Tightness
2. Are all the so-called “subtypes” in-
dependent forms of rosacea?
3. Is there a degree of severity?
Classifications published by authors
from different academic, healthcare or
research institutions were reviewed,
and it was decided to adopt the most
in vogue classification, published in
2002 by the rosacea expert group of
the U.S. National Rosacea Society, as
the basis of the GILER study. In this
classification, the three stages are re-
placed by subtypes and a fourth sub-
type, ocular rosacea, is added.6
The four subtypes are determined
by the predominant morphologi-
cal aspects and the accompanying
symptomatology. The 2002 classifi-
cation does not define pre-rosacea
and, among the special forms, it only
considers granulomatous rosacea,
which is referred to as a variant, and
excludes persistent edema (Morbihan
disease), steroid rosacea, rosacea ful-
minans and rosacea conglobata (Ta-
bles 10-4 and 10-5).6 Ocular rosacea
was included as a subtype because it
may appear simultaneously with cuta-
neous signs of rosacea or, in 20 % of
cases, precede those signs.9 It is esti-
mated that ocular compromise occurs
in 6 to 50 % of patients with cutane-
ous rosacea, and if the studies come
from ophthalmologic sources, such
percentage may be 6 to 72 %.10,11
The Iberian-Latin American group
of experts agrees on this categori-
zation of clinical forms; however, the
group considers that it is much clear-
er and evident if the word subtype is
replaced by the morphological fea-
tures of the lesions and refers to them
as classical forms.
UU Erythematotelangiectatic rosacea
(subtype 1).
UU Papulopustular rosacea (sub-
type 2).
UU Phymatous or hyperplastic rosa-
cea (subtype 3).
UU Ocular rosacea (subtype 4).
Although these varieties are per-
fectly defined, it must be borne in
mind that a patient can have multiple
subtypes simultaneously.
GILER experts agree with a re-
cent study where it was found that
only a small proportion of individuals
with erythematotelangiectatic rosa-
cea eventually develops papulopustu-
lar rosacea and, similarly, phymatous
rosacea.4
As regards the granulomatous
form, the GILER classifies it as a vari-
ant of rosacea because of its clinical
aspect and the histopathological find-
ings. Granulomatous rosacea may
106
Table 10-4. Classification by Stages*
Stages Symptoms
Pre-rosacea Intermittent transient erythema, blushing
Easily irritated skin
Stage I Persistent erythema
Erythematotelangiectatic Telangiectases of varying severity
rosacea Stinging, burning, and itching
Stage II Inflamed erythematous papules and pustules
Papulopustular rosacea Center-facial erythema and telangiectases of varying severity
Stage III Big nodules and inflammatory plaques.
Glandular hyperplastic rosacea Tissue and sebaceous gland hyperplasia (phymas)
Ocular rosacea is not defined as a separate stage. Ocular manifestations may appear regardless of the
stage of rosacea. Eyes are affected by chronic inflammatory processes, ulcerations and infiltrated nodules
Granulomatous rosacea Reddish-brown papules or nodules
Diffuse redness of the skin
Persistent edema (Morbihan disease), steroid rosacea/rosacea fulminans/rosacea conglobata
* German Dermatological Society guidelines7
mimic various facial granulomatous studies were found in the literature
conditions, including lupus miliaris to indicate the prevalence of these
disseminatus faciei, micropapular sar- groups in relation to general rosacea.
coidosis, or cutaneous tuberculosis12 The studies refer to particular situa-
(Fig. 10-1). tions of each group and are analyzed
in the corresponding chapters (see
As a result of the opinion exchang- Chapter 12).13,14 The GILER believes
es among GILER experts, childhood that these situations occur perhaps
rosacea and extra-facial rosacea were more frequently than imagined, and
taken into consideration for the dis- that they are probably not adequately
cussion. No relevant epidemiological diagnosed. For this reason, it is con-
Table 10-5. Classification by Subtypes* NOSOLOGICAL CLASSIFICATION

Subtypes Symptoms

Pre-rosacea: not defined

Subtype 1 Flushing
Erythematotelangiectatic Central erythema
Telangiectases, stinging, burning, roughness, scaling may be present

Subtype 2 Persistent central facial erythema

Papulopustular Papules, pustules Fig. 10-1. The GILER classification (2016).4
Telangiectases may be present
component, transient erythema with liculorum. It affects the face and may
Subtype 3 Thickening, thickened skin recurrent or permanent erythema, also occur on the scalp, submandib-
Phymatous Enlarged pores as well as preferential distribution ular region, neck, chest and upper
Tissue hyperplasia of lesions on the convex areas of back; it has been observed on the
Nodules the face. In this age group, ocular upper limbs and, in isolated forms,
manifestations (relapsing chalazion, on hands. The morphology is very
Subtype 4 Burning, stinging, dryness. ocular hyperaemia and keratitis) are similar, although sometimes granulo-
Ocular Foreign body sensation. Possible telangiectases of the conjunctiva frequent, as well as family history. matous lesions are seen.16
It differs from acne vulgaris due to
Rosácea granulomatosa Reddish-brown papules or nodules the absence of comedones and the DEGREE OF SEVERITY
Diffuse redness of the skin presence of vascular compromise. Knowing the degree of severity of
Although childhood rosacea may be a disease is important for treatment
Morbihan disease, steroid rosacea are not considered as variants of rosacea confused with perioral dermatitis, and prognosis.
the latter is characterized by punc-
* Classification of the National Rosacea Society Expert Committee (2002)6 tate papules, scarce small pustules In a condition such as rosacea,
and, sometimes, perioral microvesi- which is expressed through different
cles, respecting the labial vermilion; morphological aspects and in which
unlike rosacea, no telangiectases are two or more forms may coexist in a
sidered that they should be classified agnosed, as it can be confused with observed (see Chapter 12).15 single patient, a pattern of severity is
separately as special forms. This will other diseases, mainly acne vulgaris difficult to establish.
allow to keep them in mind and deep- and perioral dermatitis. In children, Extrafacial rosacea is uncommon.
en their study (see Figure 10-1). rosacea is characterized by at least It is believed that solar elastosis, re- We have mentioned that patients
two of the following signs: papules sulting from chronic sun exposure, with rosacea present with primary
Rosacea is very unusual during and pustules without blackheads may be a predisposing factor with and secondary signs, and also symp-
childhood, or perhaps it is under-di- and predominance of the vascular some involvement of Demodex fol- toms that are included in this last
107
group. Given these characteristics, mild persistent erythema. And in the
it is very difficult to determine which severe degree, erythema is intense
will be the most important to assess. and persistent.
The classification of Wilkin et al., Regarding telangiectasia, if they
2004,17 was taken as a reference. In are absent, the degree is mild; if they
such classification, the severity of the are scarce, isolated, and more evi-
four classical clinical forms (subtypes) dent with magnification, the degree is
is graded –in relation to the presence moderate; and if they are observable
of papules, pustules and plaques– as with the naked eye and in large num-
mild, moderate and severe, a criterion bers, the degree is severe.
with which the GILER agrees. Howev-
er, this group introduced two parame- We believe that this proposal may
ters that are considered significant, as be a useful guide; however, this con-
they are part of the primary and typi- dition has such a wide variety of clin-
cal features of rosacea: erythema and ical aspects that it is very difficult to
telangiectasia (Fig. 10-2).4 establish a degree of severity by sim-
ply following fixed guidelines. There-
Concerning erythema, only epi- fore, the degree of severity in any of
sodic erythema (flushing) is observed its ranges (mild, moderate, or severe)
in the mild forms; in the moderate will arise from the evaluation made by
degree, flushing is accompanied by a each physician of his or her patient.
DEGREE OF SEVERITY
Fig. 10-2. Adapted from J. Am Acad Dermatol 2004; 50:907-912.4
108
This recommendation concerning
the degree of severity is for the sole
purpose of clinical evaluation. It is not
an evaluation concerning the patient
in particular, since the psychosocial
compromise of rosacea shows that
a patient with clinically mild rosacea
may feel a very significant impairment.
References
1. Vemuri RC, Gundamaraju R,
Sekaran SD, et al. Major patho-
physiological correlations of
rosacea: a complete clinical ap-
praisal. Int J Med Sci 2015 May
5;12(5):387-396
2. Tan J, Berg M. Rosacea: current
state of epidemiology. J Am Acad
Dermatol 2013; 69 (6 Suppl 1):
S27-S35.
3. Two AM, Wu W, Gallo
RL, et al. Rosacea. Part
I. Introduction, cate-
gorization, histology,
pathogenesis, and risk
factors. J Am Acad
Dermatol 2015; 72 (5):
749-758.
4. Kaminsky A, Flórez
White M, Pique-
ro-Martín J, et al. In-
forme de Consenso
Ibero-Latinoameri-
cano 2016 sobre la clasificación
clínica y terapéutica de la Med
Cutan Iber Lat Am 2016; 44 (1):
6-10 (2016 Ibero-Latinamerican
Consensus Report on the Clin-
ical and Therapeutic Classifica-
tion of Rosacea)
5. Varela-Ruiz M, Díaz-Bravo L, García-
Durán R. Descripción y usos del
método Delphi en investigaciones
del área de la salud. Inv Ed Med
2012;1(2):90-95.
6. Wilkin J, Dahl M, Detmar M, et al.
Standard classification of rosacea: re-
port of the National Rosacea Society
Expert Committee on the Classifica-
tion and Staging of Rosacea. J Am
Acad Dermatol 2002; 46 (4): 584-587.
7. Plewig G, Kligman AM. Acne and
Rosacea, 2nd ed. SpringerVerlag,
Berlin, Heidelberg, 1993: 433-443.
8. Rosazea LP. Klinik, Pathogenese,
Therapie. Hautarzt 2005; 56: 871-885.
9. BlountBW, Pelletier AL. Rosacea:
a common, yet commonly over-
looked, condition. Am Fam Physi-
cian 2002;66(3):435-40. Summary
for patients in: Am Fam Physician
2002;66(3):442.
10. Vieira AC, Höfling-Lima AL, Mannis
MJ. Ocular rosacea–A review. Arq
Bras Oftalmol 2012 Oct;75(5):363-9.
11. Potz-Biedermann C, Mehra T,
Deuter C, et al. Ophthalmic ro-
sacea: case report in a child and
treatment recommendations. Pe-
diatr Dermatol 2015; 32 (4): 522-
525.
12. Lee GL, Zirwas MJ. Granuloma-
tous rosacea and periorificial
dermatitis: controversies and re-
view of management and treat-
ment. Dermatol Clin 2015; 33 (3):
447-455.
13. Kroshinsky D, Glick SA. Pediatric
rosacea. Dermatol Ther 2006; 19:
196-201.
16. Bostanci O, Borelli C, Schaller
14. Al Balbeesi AO, Halawani MR.
Unusual features of rosacea in
saudi females with dark skin.
Ochsner J. 2014 Fall;14(3):321-7.
109
15. Chamaillard M, Mortemousque
B, Boralevi F, et al. Cutaneous
and ocular signs of childhood ro-
sacea. Arch Dermatol 2008; 144
(2): 167-171.
M. Treatment of extrafacial ro-
sacea with low-dose isotretinoin.
Acta Derm Venereol 2010; 90:
409-410.
17. Wilkin J, Dahl M, Detmar M, et al.
Standard grading system for rosa-
cea: report of the National Rosacea
Society Expert Committee on the
classification and staging of rosa-
cea. J Am Acad Dermatol 2004; 50
(6): 907-912.

Rosacea manifests through sever-
al primary clinical signs, including:
temporary erythema, persistent
erythema, papules, pustules, fibro-
sis and glandular hyperplasia. Ro-
sacea symptoms vary according to
the susceptibility of each patient;
some feel a burning sensation and
stinging or pain may coincide with
flushing. Rosacea also has ocular
manifestations, which shall be de-
scribed at the final section of this
chapter (ocular rosacea).
The Iberian-Latin American Group
for the Study of Rosacea (GILER),
includes as classic forms: erythema-
totelangiectatic rosacea (ETR), the
papulopustular (PPR), hyperplastic/
glandular phymatous (PR) and ocular
rosacea (OR).1 These forms of presen-
Chapter 11
Classical Forms
erythematotelangiectatic rosacea
Ana Kaminsky, María I. Herane
tation correspond to subtypes 1, 2, 3, signs between ETR and PPR. Conse-
and 4 from the classification of the quently, the form of rosacea presenta-
rosacea International Expert Group tion could be more precisely defined
(ROSIE).2 as, “phenotype,” as has been recently
proposed by several opinion leaders.
Several clinical forms may coexist Erythema constitutes its most com-
in the same patient. Rosacea is not a mon primary sign of rosacea, particu-
static condition and trigger factors larly in the ETR
may affect the clinical appearance.
The clinical features may have a wax- form. However, erythema is also
ing and waning course, especially in present in PPR, PR and ocular (OR)
patients belonging to the two first forms.
classic forms.
ETR often starts with a diffuse and
In contrast with the phymatous transitory vascular erythema in the
form, there are no pathognomonic middle of the face. This type of er-
110
ythema can last minutes or hours or
may become a much more persistent
feature of rosacea, lasting days or
weeks (Figs 11-1 to 11-3). Erythema
spreads from the back of the nasal
dorsum, through the central part of
the face, also called centrofacial and
involve the convexes of the face in-
cluding, the mid and central areas
of the cheeks, ending up just close
to the atrial tragus, nose, forehead
and chin and it may also extend to
the perioral and periocular areas.4.
Normally, the borders of the erythe-
ma in rosacea are located below the
inferior mandibular ramus and above
the upper area of the malar bones.
The central area of the forehead
and the chin may also be affected.
Its unilateral location is considered
exceptional. (Figs 11- 4 and 5). The
 Fig. 11-3. Erythematotelangiectasic rosacea.

this roughness susceptibility to irritation that ro-

is due to a flaw sacea patients typically complain
Fig. 11-1. Erythematotelangiectasic rosacea. Fig. 11-2. Erythematotelangiectasic rosacea. in the oil con- about.
tent, or to the
concept of ETR, as a rosacea clinical bluish, almost cyanotic tone. The hydration level of the stratum cor- It is worth noting that the diffuse
form or subtype, consists in a pattern look of the facial erythema may neum or the superficial protectant facial erythema often persists -es-
of persistent facial erythema with fluctuate and be influenced by the film of the skin, also called acid pecially in the central part of the
or without multiple telangiectasias factors mentioned in Table 11-1.5 On mantle, which could explain the face- even after the inflammatory
in the face and, in some patients, a close inspection, the skin may re-
tendency to frequent flushing. The veal multiple dilated blood vessels Table 11-1. ETR triggering Factors5
combination of these skin lesions of small and medium caliber that
constitutes ETR. flow through the skin surface on Alcohol (especially red wine and beer) Abrasive or exfoliant preparations
the central and lateral areas of the Hot beverages (contrary to caffeine, heat is critical) Facial massage or vigorous rubbing
The tone of erythema may span cheeks, and along the nose. Fur- Hot food (in large quantities or with hot spices) Tonics or moisturizers with glycolic acid
a spectrum from pale pink/red on thermore, a small degree of facial Solar exposure (all year round) Medicines that aggravate flushing (see chapter 2)
the periphery of the cheeks to an edema can be observed, as well as Wind exposure (especially cold) Hot and wet environments (saunas, hot immersion baths)
intense red on the central cheek. a light roughness or flaking on the Perfumed facial products containing sorbic acid or Strenuous exercise (mainly in hot weather)
As the patient ages, the color tends surface of the skin, sometimes called its compounds
to intensify and is modified into a “rosacea-like dermatitis”. Probably, Astringents and cleansers with acetone or alcohol Psychological stress and emotional disturbances
111

Fig. 11-4. Unilateral ETR.
lesions (papules and pustules) have
resolved. Individuals with rosacea
and with lighter skin phototypes (I
and II, especially those of type I)
who generally have sensitive skin,
are more prone to vascular disor-
ders, such as blood vessel dilation,
with increase in the vascular perme-
ability and edema.
ETR may be triggered by multi-
ple factor. As discussed in Chapter
9, several hypothesis and different
mechanisms have been described in
rosacea, but none has been proven
as responsible. The diagnosis is pri-
Fig. 11-5. Unilateral ETR.
marily clinical. Currently there is not
a single laboratory test that allows its
diagnosis.
With respect to the symptomatol-
ogy, there is no specific symptom for
RET. The patient usually refers to a
sensation of heat, burning, stinging
or dryness, but it is important to
note that there is no specific symp-
tom.
The patient expresses experi-
encing rosacea symptoms when ex-
posed to trigger factors –which are
generally associated with the initi-
112
ation of a more intense erythema.
Some patients may have episodic
and transient blushing. This consists
of an involuntary, sudden and tem-
porary event, triggered by emotions
(anger, shame, etc.).3
While pathophysiological mecha-
nisms of ETR and transient blushing
have not been sufficiently elucidat-
ed; the first sign is usually erythema,
which increases and may become
severe as the disease progresses. As
rosacea advances, dilated vessels may
appear, contributing to a parallel ery-
thema due to a different pathophys-
iologic mechanism (vasodilation vs
neuronal/inflammatory) (Figs.11-6 and
11-7).6 For Gomaa et al., the increase in
vascular instability over time, could be
due to stimulation by reactive oxygen
species (ROS) and matrix metallopro-
teinases (MMPs) which damage and
degrade both vascular tissue and the
support of the extracellular matrix.
Holmes and Steinhoff have proposed
that vasodilation results from the lib-
eration of vasoactive neuropeptides
and nitric oxide, as a response to the
activation of transient potential re-
ceptors (TPR).7
This is covered in depth in Chapter 9.
Some of the most important key
points are related to an increase in
the activation and response of the
immune system as well as to vascu-
lar deregulation.8,9 However, in the
so called “pre-rosacea” or “early
rosacea”, which manifests itself by
transitory erythema or flushing, with
no other signs or symptoms, such
aspects are not sufficiently studied.10
In all rosacea subtypes, research-
ers have found an up regulation, in
the genes involved in neurogenic
vasoregulation and inflammation.11
The most promising preliminary ev-
idence related to the pathogenesis
of erythematic induction, vasodi-
lation and telangiectasias, is linked
to antimicrobial peptides and pro-
teases, as well as to the mediators
that intervene in vasodilation, neu-
ropeptides, calcium channel recep-
tors and neurogenic factors.10 (See
chapter 9).
When evaluating centrofacial
distribution of telangiectasias, the
following should be ruled out: peri-
nasal telangiectasias, which are
almost always present in adult in-
dividuals, corticosteroid-associated
telangiectasias (Figs.11-8 to 11-10),
and those due to dermatoheliosis
or chronic actinic damage from sun
exposure.
Cribier has described in great
detail the histological characteris-
tics of the 4 classical forms of ro-
sacea in an aptly named treatise
“Rosacea Under the Microscope”.12
Histological alterations are char-

Fig. 11-6. ETR. Persistent erythema with telangiectases.
acteristically absent in ETR. Only a
mild or moderate edema of the up-
per dermis is observed. However,
microscopic evaluation may show a
growth in size of dilated capillaries
and venules within the dermis; these
vessels assume a bizarre disposition
with multiple angles and few promi-
nent endothelial cells. In most cases,
Demodex folliculorum can be found
Fig. 11-7. ETR. Persistent erythema with telangiectases.
within the follicular infundibulum studies that identify CD 31, but not
in rosacea patients, even in the ab- the lymphatic marker D2-40.12
sence of papules and pustules.
Occasionally, there may be some The inflammatory infiltrate in ETR
spongiosis with lymphocyte exo- is found across the thickness of the
cytosis on the epidermis. Howev- whole dermis (upper, middle and
er, this spongiotic dermatitis is not lower) with perivascular and inter-
specific to rosacea. The lymphatic stitial characteristics. In macular le-
vessels remain relatively normal, as sions with no evident clinical edema,
evidenced by immunohistochemical the infiltrate is located in the upper
113
dermis and is composed primarily
(70-80%) of CD3+ with a smaller pro-
portion (10-20%) of CD20+ lympho-
cytes. There are very few histiocytes.
Plasma cells or mast cells can be
observed in all forms of rosacea and
constitute an important reference
for the diagnosis.4
To establish a differential diag-
nosis of flushing/blushing, the main
features are emotional erythema,
flushing and embarrassment or blush-
ing (Fig. 11-11) (see chapter 2). This type
of pink erythema has a more homo-
geneous distribution. Apart from the
face, it extends to the neck, to the ar-
eas behind the ears and to the thorax.
It is not uniform and sometimes, in its
final location it has the appearance of
blotches.
This blushing is mediated by the
sympathetic nervous system, and in
susceptible individuals, it becomes
a way of response to emotional or
stressing situations that may af-
flict healthy individuals or rosacea
patients, but the pathophysiologi-
cal mechanisms are different from
those of rosacea.13 Another very
important differential diagnosis in-
cludes photoaging (Figs.11-12 and 11-
13). In 2015, Helfrich et al., pointed
out that photoaging is characterized
by a more reduced and transitory
erythema, of lateral distribution and
with telangiectases. There is also a
Fig. 11-8. Erythema and telangiectases by topical cor- Fig. 11-9. Erythema, flaking and papular lesions Fig. 11-10. Erythema and papulose lesions sec-
ticosteroids. secondary to the use of topical corticosteroids. ondary to the use of topical corticosteroids..

downregulation of the neurogenic
activation of mast cells, together
with a restructuring of the matrix
metalloproteinases. This shows that
telangiectatic photoaging is a dif-
ferent clinical entity from ETR. A
distinction can be drawn relying on
clinical and histological information
and through gene expression find-
ings. ETR is more common in mid-
dle-aged women, while the typical
patients with photoaging character-
istics are generally older men.14 In
2015, Wilkin suggested that actinic
damage can also help to differen-
tiate photoaging from other forms
of erythema.15,16 This reinforces the
hypothesis that dilated vessels in
114
ETR do not show the same damage
in perivascular collagen as is seen
with photoaging, despite the obser-
vations of Helfrich et al. This does
not rule out the fact that, in patients
suffering intense flushing episodes,
the actinic damage makes an im-
portant contribution to the patho-
genesis of ETR. This could also be
coherent with the progression of
ETR into papulopustular rosacea,
through photo-damaging accumu-
lation. Other longitudinal studies
should explore a second group of
patients, who have important traits
of photo-damaging parallel to in-
tense flushing.15
Fig. 11-11. Emotional erythema (blushing).
References
1. Kaminsky A, Flórez-White M,
Piquero Martín J, et al. GILER.
Informe de Consenso Ibero-Lati-
noamericano 2016 sobre la cla-
sificación clínica y terapéutica
de la rosácea. Med Cutan Iber
(2016-Ibero Latin-american Report
on the Clinical and Therapeutic
Classification of rosacea). Med
Cutan Iber Lat Am 2016;44(1): 6-10.
2. Elewski BE, Draelos Z., Dreno B,
et al. Rosacea-global diversity and
optimized outcome: Proposed in-
ternational consensus from the Ro-
Fig. 11-12. Photoaging.
sacea International Expert Group.
Eur Acad Dermatol Venereol
2011;25(2):188-200.
3. Tan J, Almeida LM, Bewley A, et
al. Updating the diagnosis, classifi-
cation and assessment of rosacea:
recommendations from the glob-
al ROSacea COnsensus (ROS-
CO) panel. Br J Dermatol 2017
Feb;176(2):431-438.
4. Cribier B. Pathophysiology of rosa-
cea: Redness, telangiectases, and
rosacea. Ann Dermatol Venereol
2011 NOV;138 Suppl 3:Sl84-91.
115
Fig. 11-13. Photoaging..
5. Powell FC. Erythematotelangiectat-
ic rosacea. En: Powell FC. Rosacea.
Diagnosis and Management. lnfor-
ma Heathcare USA.Inc New York,
2008,pp:43-60.
6. Gomaa AH, Yaar M, Eyada MM, et
al. Lymphangiogenesis and angiogé-
nesis in non-phymatous rosácea. J
Cutan Pathol 2007:34:748753.
7. Holmes AD, Steinhoff M. Integrative
concepts of rosacea pathophysiol-
ogy, clinical presentation and new
therapeutics. Exp Dermatol 2017
Aug;26(8):659-667.
8. Del Rosso JQ. Management of fa-
cial erythema of rosacea: What is
the role of topical-adrenergic re-
ceptoragonist therapy? J Am Acad
Dermatol 2013; 69: S44-56.
9. Cribier B. Rosacea under the mi-
croscope: characteristic histological
findings. J Eur Acad Dermatol Vene-
reol 2013; 27:1336-1343-
10. Steinhoff M, Schmelz M, Schauber
J. Facial erythema of rosacea aeti-
ology, different pathophysiologíes
and treatment options. Acta Derm
Venereol 2016 Jun 15;96(S):579-86.
 11. Schwab VD, Sulk M, Seeliger S,
et al. Neurovascular and neuro-
immune aspects ¡n the patho-
physiology of rosacea. J Inves-
tig Dermatol Symp Proc 2011;
53-62.
12. Cribier B. Rosacea under the mi-
croscope: characteristic histologi-
PPR is characterized by a centrofacial
erythema with transient, inflammato-
ry, erythematopapular, pustular and
papulopustular lesions.1
Telangiectases can also be ob-
served, parallel to vasodilation. No
blackheads appear, unless the patient
is simultaneously suffering from acne
vulgaris. This form of rosacea corre-
sponds to Subtype 2, in accordance
with the classification of the Rosacea
International Expert Group.2 The in-
flammatory lesions are dome-shaped
and variable in size (approximately
3 mm, but sometimes bigger). They
appear isolated or as an outbreak
and they can persist up to several
weeks. (Figs.11–14 and 11–15). A small
seropustule appears on the upper
zone of some papules, which justifies
the name of papulopustular rosacea
(PPR) given to this clinical form.
In general, the first lesions are lo-
cated on the cheeks and as the symp-
toms evolve, they may extend to the
cal findings. J Eur Acad Dermatol
Venereol 2013; 27:1336-1343-
13. Drummond PD, Minosora K, Little G, et
al. Topical ibuprofen inhibits blushing
during embarrassment and facial flush-
ing during aerobic exercise in people
with a fear of blushing. Eur Neuropsy-
chopharmacol 2013; 23:1747-1753.
Papulopustular rosacea
Ana Kaminsky
forehead, chin, and nose (Figs. 11–16 to
11-22). Very rarely, the lesions may be
extended to other zones, either ad-
joining or far from the facial area. Due
to its location, away from the face,
the GILER considers that this last
condition is so special that it justifies
the name of “extra facial rosacea.” To-
gether with childhood rosacea, they
both differ in characteristics from the
classic forms, whether by the age of
appearance, by the location of the le-
sions or by other clinical aspects.1
Lesions evolve and in 5 to 20 days,
they produce an erythematous zone,
that gradually disappears until it re-
cedes, leaving no scars. However, on
rare occasions, when there are deeper
inflammatory lesions, very superficial
and discrete dents may remain. In dark-
er phototypes (IV to VI), contrary to
116
14. Helfrich YR, Maier LE, Cui Y, et al.
Clinical, histologic, and molecular
analysis of differences between ery-
thematotelangiectatic rosacea and
telangiectatic photoaging. JAMA
Dermatology 2015:15l(8):825-3.
15. Wilkin JK. Erythematotelangiectat-
ic rosacea and telangiectatic pho-
what happens with acne, postinflamma-
tory hyperpigmentation doesn’t occur
just a residual, mild, hyperpigmented
macula. Furthermore, while some of the
signs and symptoms disappear, others
arise, with the aggregate of mild tel-
angiectases. When the patients have
been exposed to the sun for decades,
and they have photodamage, the skin
may have a yellowish color, with signs
of elastosis, big, prominent, follicular or-
ifices and even solar blackheads. In very
severe cases of rosacea, there might be
a slight scab-like scaling, which must not
be confused with seborrheic dermatitis
(Figs.11-23 and 11-24).
Localized edema commonly ap-
pears in the affected areas or neigh-
boring zones, and may persist for
weeks and even months (Figs.11-25
and 11-26). In exceptional cases, the
toaging: Same, separate, and/or
sequential? JAMA Dermatol 2015
Aug;15l(8):821-3.
16. Wilkin JK. Rosacea: Pathophysiol-
ogy and treatment. Arch Dermatol
1994:130(3):359-362.
typical lesions of ETR or of PPR may
be observed (Fig. 11-27) on one side
of the face, mainly on the cheek, also
including edema and ocular complica-
tions (Fig.11-28). This characteristic of
unilateralism was described for the
first time in 1989, in an epidemiological
study of 809 patients, published by
Berg and Lidén. Among the 809 sub-
jects, 81 individuals had rosacea (14%);
11 with unilateral lesions. Notably,
the majority (10) had unilateral ETR
and 1 had unilateral PPR.3 Unilateral
rosacea has also been described in
patients with facial nerve palsy, a find-
ing that some consider a particular
situation in an immunocompromised
location and was called neurogen-
ic rosacea location, this finding was
considered special and it was named
“neurogenic rosacea”.4,5 (see Chapter
22) In 1989, Shelley et al., described a
case of “unilateral demodectic rosa-
cea”, in a 36 year old man, who pre-
sented with erythematous plaques on
the right cheek, along with localized
flushing and a few telangiectases and
Fig. 11-14. Mild PPR. Fig. 11-15. Mild PPR. Fig. 11-16. Mild PPR. Fig. 11-17. Moderate PPR.

Fig. 11-18. Moderate PPR. Fig. 11-19. Severe PPR. Fig. 11-20. Severe PPR. Fig. 11-21. Severe PPR.
117
Fig. 11-22. Severe PPR. Fig. 11-23. Severe PPR and rhinophyma. Fig. 11-24. Severe PPR. Extrafacial Fig. 11-25. Severe PPR. Scabby le-
(neck). sions.
pustular lesions. After evolving for 4
years, it appeared to be unilateral lo-
calized rosacea. The histopathologi-
cal study showed great quantities of
Demodex folliculorum. This patient
was cured from his lesions with the
specific treatment for demodicidosis.6
In order not to confuse the diagnosis,
it is important to consider the clinical
aspects of both entities.

The symptomatology of PPR is vari-

able -slight itching and not very well-de-
fined discomforts- depending on the
emotional condition of each individual.
The high psycho-social impact that this
or any other facial disease causes, must Fig. 11-28. Severe unilateral PPR with
be taken into consideration. Fig. 11-26. Severe PPR. Intense edema. Fig. 11-27. Unilateral PPR. ocular complications.
118
 The histopathological study shows rosacea. Morbihan disease is charac- References sacea). Med Cutan Iber Lat Am
an inflammatory infiltrate on the upper terized by a solid and persistent facial 1. Kaminsky A, Flórez-White M, 2016;44(1): 6-10.
dermis, extending to deeper zones, edema; there is also pronounced com- Piquero Martín J, et al. GILER.
with numerous plasma cells, neutrophils promise of lymphatic vessels accom- Informe de Consenso Ibero-Lati- 2. Elewski BE, Draelos Z, Dréno B, et
and some eosinophils. It also shows an panied by erythema and sometimes noamericano 2016 sobre la cla- al. Rosacea - global diversity and
increase of mast cells in the lesions. by scarce papules.10,11 We also consider sificación clínica y terapéutica optimized outcome: proposed in-
However, these are neither related to that Morbihan disease is not a variant de la rosácea. Med Cutan Iber. ternational consensus from the Ro-
the severity, nor to the duration of the of rosacea, but instead a condition of (2016-Ibero Latin-american Con- sacea International Expert Group.
disease.7,8 A pending dilemma would be singular, clinical and evolutionary char- sensus Report on the Clinical and J Eur Acad Dermatol Venereol
whether the origin of the pustules is fol- acteristics.1,2 (see Chapter 20). Therapeutic Classification of ro- 2011;25(2):188-200.
licular or extrafollicular. Lesions normal-
ly involve the follicle and the infiltrate
is, in general, perifollicular, with neutro-
phils and the almost certain presence
of Demodex folliculorum, although
some small, extrafollicular abscesses
can be observed. As it is the case with
acne, at times, the rupture of the fol-
licle with a dense infiltrate may occur.
There appear no elements of retention,
like dermic follicular cysts.9 Frequently,
some spongiosis, exocytosis and acute
folliculitis, can be observed on the ad-
joining areas.

Elastosis is a typical histological find-

ing with no clinical evidence. There are
patients who could present with transi-
tory, localized or diffuse facial edema,
accompanied by erythema and telan-
giectases, which is usually reversed by
the correct treatment. Gram-negative
folliculitis, associated to rosacea, is
rarely seen (Figs.11-29 and 11-30).

Some authors consider that, due to

its special characteristics, Morbihan Fig. 11-30. PPR. Gram-negative folliculitis, erythema
disease constitutes a special form of Fig. 11-29. PPR. Gram-negative folliculitis. and edema.
119
 3. Berg M, Lidén S. An epidemiological
study of rosacea. Acta Derm Vene-
reol 989;69(5):419-23.
4. Piccolo V, Ruocco V, Russo T, et
al. Unilateral rosacea in patients with
facial nerve palsy: a mere example
of immunocompromised district. J
Dermatol 2013;40(10):850.
5. Cabete J, Serrão V, Lestre S. Unilat-
eral rosacea in a patient with Bell’s
palsy. J Dermatol 2013;40(5):403-4.
Phymatous rosacea (PR), has been
defined as a persistent, non-painful
edema, compromising the tissue of
the nose, chin, ears, forehead and
eyelids. It is characterized by edema,
frequently associated with erythema
and sometimes with other manifes-
tations of rosacea (papules, pustules
and telangiectases), as well as with
occasional eye swelling.1 Within the
nosological classification of the Ibe-
rian-Latin American Group for the
Study of Rosacea (GILER), this clin-
ical form is called hyperplastic/phy-
matous rosacea, due to sebaceous
hyperplasia and the thickening of the
skin, caused by a localized Lymphede-
ma and by fibrosis.2 It corresponds to
the sub-type III of the Rosie. Rosacea
International Expert Group) (2011).3
Clinically, phymatous rosacea is
characterized by increased skin thick-
6. Shelley WB, Shelley ED, Burmeister
V. Unilateral demodectic rosacea. J
Am Acad Dermatol 1989; 20:915-74.
7. Cribier B. Pathophysiology of ro-
sacea: redness, telangiectases, and
rosacea. Ann Dermatol Venereol
2011;138 Suppl 3:S184-91.
8. Aroni K, Tsagroni E, Kavantzas N,
et al. A study of the pathogenesis of
rosacea: how angiogenesis and mast
cells may participate in a complex
Hyperplastic/phymatous rosacea
Ana Kaminsky, María I. Herane
ness, hypertrophic formations with
nodular appearance, and by distortion
of the soft tissue with normal skin col-
or. It should be distinguished from the
edema which, in some circumstances,
may accompany severe clinical forms
of rosacea. Vascular irregularities and
swelling do not account for the de-
velopment of phymas and the belief
that alcohol contributes to its occur-
rence, especially on the nose, is not
backed up by evidence. (Figs. 11-31 and
32). Crawford et al. described a rosa-
cea phenotype, similar to the phyma,
which was named “glandular rosa-
cea.”4 It is more common in men with
thick skin and abundant sebaceous
glands. There may also be edematous
120
multifactorial process. Arch Derma-
tol Res 2008;300(3):125-31.
9. Cribier B. Rosacea under the mi-
croscope: characteristic histological
findings. J Eur Acad Dermatol Vene-
reol 2013; 27:1336-1343.
10. Balakirski G, Baron JM, Megahed M.
Morbihan disease as a special form
of rosacea: review of pathogenesis
and new therapeutic options. Hau-
tarzt 2013;64(12):884-6.
papules and very large pustules, as
well as nodulocystic lesions.
These lesions are often clustered
at the central zone of the face and in
the inner part of the cheeks, but they
can be observed in any area with er-
ythema. The phymatous classification
depends on the involved area: nose,
chin, ears, forehead, cheeks and eye-
lids (table 11-2).
RHINOPHYMA
(From the Greek rhinos = nose and
phyma = thickening)
Described by Hebra, in 1845, it con-
stitutes the most frequent localization
11. Wilkin J, Dahl M, Detmar M, et
al. Standard classification of ro-
sacea: Report of the National Ro-
sacea Society Expert Committee
on the Classification and Staging
of Rosacea. J Am Acad Dermatol
2002;46(4):584-7
Table 11-2. Phymas
Rhinophyma Nose
Gnatophyma Chin
Otophyma Ears
Metophyma Forehead
Zygophyma Cheekbones and chreeks
Blepharophyma Eyelids
of phyma and the simplest to recog-
nize. It is very rare in Africans and in
Japaneses.5 Rhinophyma is consid-
ered the most advanced or final stage
in rosacea, although it may present
itself de novo, or as an expression of
chronic actinic damage. (Figs. 11-31 to
11-43). In general, it appears in subjects
with a previous history of rosacea, or
in those affected by inflammatory ro-
sacea of different degrees of severity.
It may start very slowly, and may oc-
cur almost simultaneously or a short
time after the beginning of rosacea,
and may be accompanied by erythe-
ma, papules and pustules.6

While ETR affects mostly women

(70% of the cases); more than 95%
of the cases of rhinophyma appear
in men, in a range of 20:1. In other lo- Fig. 11-33. Rhinophyma.
calizations, the frequency between
women and men is the same.6,7 The
reason for the predominance in the
masculine sex is unknown, but it could
be linked to the fact that men have
more oily skin and more evidence of
sebaceous hyperplasia.

Rhinophyma usually starts on the Fig. 11-31. Rhinophyma. Fig. 11-32. Rhinophyma.
distal portion of the nose. The most
significant and distinctive fact is Fig. 11-36. Rhinophyma. Dilated ves-
the skin thickening into an irregular sels and telangiectases.
surface, sometimes with nodes and
hypertrophy by distortion of soft tis-
sues, with normal colored skin. The
pores look enlarged and dilated and
vasodilation and telangiectases may
be present on the nostrils. (see Figs.
11-36 and 11-37). In early stages, there
might be papulopustular lesions (see
Figs. 11-41 and 11-42). Ocular rosacea
may also be present with rhynophy-
ma (see Fig. 11-43). When the rhi-
nophyma becomes more evident
it produces such deformities that Fig. 11-37. Rhinophyma. Dilated ves-
sometimes it gives the nose a gro- Fig. 11-34. Rhinophyma. Fig. 11-35. Rhinophyma. sels and telangiectases.
121

Fig. 11-38. Rhinophyma.
Fig. 11-42. Rhinophyma. Papulopustu-
lar lesions.
Fig. 11-39. Rhinophyma. Unusual clinical pic-
ture (courtesy Dr. Eugenio Albín, Argentina).
Fig. 11-43. Rhinophyma and ocular rosacea. Telangiectases in the bulbar and
palpebral conjunctiva.
122
Fig. 11-40. Rhinophyma. Unusual clinical pic-
ture (courtesy Dra. Yolanda Ortiz, México).
Fig. 11-41. Rhinophyma. Papulopustu-
lar lesions.
tesque appearance. (see Figs. 11-35
and 11-38).
Phymatous changes must be differ-
entiated from the edema that, under
certain circumstances, may accompa-
ny other severe clinical forms.8
According to Powell, rhinophy-
ma may presents itself in different
forms: glandular, angiomatous, ac-
tinic, acneiform, fibrous and ob-
structive. Glandular, being the most
common form, is generally located
on the skin of the nostrils and on the
distal portion of the nasal dorsum.
The follicular orifices seem enlarged
and they become more prominent,
even before skin thickening has
started. Sebum in the follicular or-
ifices is darker and more accentu-
ated, due to oxidation mechanisms.
Later, a discrete edema may appear,
with an “orange skin look” on the
area at the tip of the nose. Progres-
sively, deep dents also appear on the
surrounding pore tissue at the distal
third of the nose, which often cause
asymmetry, making the abnormality
of the nose seem more evident. In
even later stages there is a nodular
growth of the nose that may spread
up to the nasolabial fold, distorting
it completely.
Patients with severe rhinophyma
very often perceive an unpleasant
smell, probably caused by an in-
crease of the sebaceous secretion in
the tissue overgrowth. Sometimes,
deep fissures develop within the de-
formed areas of the nose and these
might be contaminated with bacteria
or fungi. When paired with glandular
rhinophyma, seborrheic dermatitis
can also contribute to the growth
of yeast populations, which add er-
ythema and flaking to the cosmetic
impact.
The angiomatous form, is gener-
ally considered as an isolated find-
ing, particularly in patients with ETR
or PPR. It is more common in Fitz-
patrick’s skin types 1 or 2, which are
more sensitive to the sun. The first
finding is the enlargement over time
of the tiny vessels on the nostrils
that become considerably marked,
contributing to the reddening of the
face.
Sometimes, angiomatous rosacea
evolves into a distinctive purplish color.
In this form, there is a lesser nasal ede-
ma than in glandular rosacea and as a
rule, there is no distortion in the shape
of the nose. It is commonly called “top-
per´s nose” or “brandy nose.”
The actinic form is characterized
by sebaceous hyperplasia, a yellow-
ish color and irregular surface on the
nasal skin. It is more frequent in old-
er people and it is coupled by actinic
comedones and leathery skin (potato
nose). Very rarely, the affected area
grows in size.
The acneiform is more common
in older, masculine patients who have
been suffering from acne vulgaris, for
a long time. They present with oily
skin, comedones, cysts and scars in
the surrounding skin.
The fibrous form appears with dif-
fuse hyperplasia of the connective
tissue, giving a firm texture to the en-
larged nose.
The obstructive form is not a real
rhinophyma. It develops in individu-
als who wear glasses, causing deep
depressions and possible lymphatic
obstruction. The histological study of
these lesions, reveal mucin.
From the histological point of
view, other authors identify only four
123
types of rhinophyma: 1) glandular,
with an increase in the sebaceous
secretion; 2) fibrous, with predomi-
nance of connective tissue; 3) fibro-
angiomatous, with edema and venous
telangiectases and 4) actinic, with
nodular masses of elastic tissue.9,10
These different types of rhinophyma
might be related to their different
clinical characteristics, since some
patients have papulopustular lesions
and consequently a severe inflam-
mation in the dermis. In others, their
yellowish skin gives clear evidence
of actinic elastosis, with no signs of
inflammation.
The differential diagnosis of rhino-
phyma includes: lupus pernio, sarcoid-
osis, basal cell carcinoma, squamous
cell carcinoma, lymphoma, angiosar-
coma, acrocyanosis and discoid lupus
erythematous, among others.
Histopathology of rhinophyma
The histology shows abnormally
thickened epidermis and dermis,
with enlarged sebaceous glands, di-
lation of the follicular infundibulum,
filled with keratin, eosinophilic res-
idues and fibrosis. Very often, it is
possible to find microorganisms, es-
pecially Demodex folliculorum. Dila-
tion of the follicular infundibulum is
linked to the formation of epidermal
cysts that can rupture inducing in-
flammation. Inflammation is always
present (though to a lesser extent
than in PPR) but the inflammatory
changes are usually mild unless there
is a secondary infection or simulta-
neously some other inflammatory
elements, typical of PPR. The infil-
trate consists mostly of lymphocytes
and neutrophils, surrounding an en-
larged infundibulum. There may also
be small granulomas, but only in ad-
vanced stages of inflammation, with
follicular rupture.9,11
Telangiectatic vessels are more
obvious in angiomatous rhinophy-
mas.
In some patients, the histopathol-
ogy shows a marked fibrosis on the
reticular and superficial dermis, while
in others (mainly those with the ob-
structive form), the dermis shows the
presence of mucin. The most char-
acteristic findings can be observed
in the mid and deep dermis. In these
zones, there are multiple aggregates
of hyperplasic sebaceous glands,
asymmetrically distributed but with
normal morphology similar to what
is seen in sebaceous adenomas or in
isolated areas of sebaceous hyperpla-
sia. Also, there is an overgrowth of the
connective tissue and fibrous tracts
across the dermis, some of which
correspond to fissures seen clinically
among nodular overgrowths. In cases
of rhinophyma secondary to actinic
damage, a marked solar elastosis can
be observed.1
 Immunohistochemical studies proved
an increase in the local production of
the transforming growth factor b (TGF
b) and its receptors.12 Of the various
types of TGF, only subtype b1 induces
fibrosis, which is the one that induc-
es fibrosis and it is augmented in pa-
tients with rhinophyma.13 The causes
for the abnormality in the expression
of this factor are unknown. It would
be logical to consider that persistent
vascular abnormalities along with
rosacea inflammation, could lead to
fibrosis and skin thickening in suscep-
tible individuals.6,11
that of the normal skin or perhaps a
little bit more reddish. When it is ac-
companied by severe PPR, there may
be edema on the surrounding area,
but very often it goes unnoticed. It is
also uncommon to observe other clin-
ical lesions. Carlson et al., described a
case with intense lymphedema, asso-
ciated with Demodex folliculorum that
affected only one ear and its histology
showed rosacea with intense lymph-
edema.16 In phymas that compromise Fig. 11-44. Gnatophyma with papulo-
the outer ear canal, a reduction in pustular lesions.
hearing and even deafness are also Fig. 11-46. Otophyma.
mentioned .17

Gnatophyma (from the Greek gna-
thos = jaw and phyma = thickening) is
very rare and appears like a thicken-
ing in the skin of the jaw, flesh color
or a bit more reddish. It covers the
central part of the jaw and fades
when reaching the lateral zones,
though sometimes it can look irreg-
ular. Gnatophyma may be accompa-
nied by telangiectases and papular
or papulopustular lesions (Fig. 11-44).
Rare cases of gnatophyma with no
other rosacea lesions have been de-
scribed.14,15
Otophyma (from the Greek otos = ear
and phyma = thickening) describes
thickening of the lower part of the he-
lix and of the ear lobules. In general, it
is bilaterally located. (Figs. 11-45 to 11-
47). On the lobules, the surface looks
more uniform and its color resembles
Metophyma (from the Greek metopon
= forehead and phyma = thickening)
has clinical manifestations identical
to the other phymas and it covers the
central area of the forehead. At times,
it results in a padded look. Facial ede-
ma often appears when rosacea and
edema extend to the cheeks, reaching
up to the center and periocular zone
of the face. It may also co-exist with
other clinical lesions of facial rosacea18
(Figs. 11-48 and 11-49).
Zygophyma (from the Greek zygo-
ma = cheekbone; phyma = thickening)
can be observed in cheekbones and
cheeks with edematous, thickened
skin and, frequently, along with pap-
ules and pustules.19 (Fig. 11-50).
Blefarophyma (from the Greek
blepharon = eyelid; phyma = thicken-
124
Fig. 11-45. Otophyma.
ing) describes phymatous lesions on
the eyelids usually accompanied by
intense bilateral edema.20 (Fig. 11-51).
In general, blefarophymas appear in
combination with severe PPR or ocu-
lar rosacea and they tend to persist, Fig. 11-47. Otophyma.
even after the improvement of the in-
flammatory clinical symptoms. be thorough.8 The association of dif-
ferent phyma locations in the same
Some cases of Melkersson-Rosen- patients has been reported in very
thal syndrome are also described few cases, for example; otophyma
as associated to palpebral edema, and rhinophyma; otophyma and
thus, the differential diagnosis must zygophyma; otophyma and gnato-
Fig. 11-48. Metophyma, blepharophyma and rhinophyma. Fig. 11-49. Metophyima and blepharophyma.

phyma.19,21,22 We have observed con-

comitant metophyma, blefarophyma
and rhinophyma; metophyma and
blefarophyma, as well as zygophyma
and rhinophyma (see Figs. 11-48 to 11-
50). The differential diagnoses of the
phymas depend on their location. In
cases of rhinophyma, considerations
include: lupus pernio, sarcoidosis,
basal cell and squamous–cell carci-
nomas, lymphoma, angiosarcoma,
acrocyanosis and discoid lupus ery-
thematosus. In other forms of phy-
mas, usually very rare, one must
consider if the manifestations are
unique or if they are associated with
other signs of rosacea, which simpli-
fies the diagnosis. Fig. 11-50. Zygophyma and rhinophyma. Fig. 11-51. Blepharophyma.
125
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19. Blairvacq JS, Yachouh J, Calteux
N, et al. Otophyma, zygophyma
and giant rhinophyma: a rare as-
sociation. Ann Chir Plast Esthet
2008;53(5):441-7.
20. Lai TF, Leibovitch I, James C, et
al. Rosacea Lymphedema of the
eyelid. Acta Ophthalmol Scand
2004;82(6):765-7.
21. Wollina U, Lotti T, Tchernev G.
Otophyma, rhinophyma and
telangiectatic rosacea - A rare
combination in a female patient.
Open Access Maced J Med Sci
2017;5(4):531-532.
22. Ezra N, Greco JF, Haley JC, et
al. Gnatophyma and otophyma. J
Cutan Med Surg 2009;13(5):266-
72.
Rosacea may occur in the eyes in 58 to
72% of cases, one third of which pres-
ents corneal compromise, with risk
of important visual sequelae.1 Since
90% of the cases have only subtle
and non-specific signs (with or with-
out skin changes), ocular rosacea is
usually under-diagnosed. It is very im-
portant to note that ocular signs may
precede skin compromise in approxi-
mately 20% of cases.2 Very frequently,
patients do not spontaneously report
their ocular symptoms to the derma-
tologist, or their skin symptoms to
the ophthalmologist. Dermatologists
and ophthalmologists need to work in
partnership, in order to be able to re-
fer the patients, before they present
severe ocular and skin symptoms.
EPIDEMIOLOGY
According to the last epidemiolog-
ical study performed in the UK, the
incidence of ocular rosacea cases di-
agnosed by the general practitioner
were 1.65/1000 individuals per year.3
In the USA, it is estimated that rosa-
cea affects more than 16 million peo-
ple. Reports from Sweden indicate a
prevalence of 10% of the population.4
Both genders and all age groups,
including children, are equally af-
fected.1 The greatest prevalence of
rosacea is found between the ages of
30 and 60.3 There are no differences
among ethnic groups, but it must be
taken into account, that the dark skin
pigment hampers the diagnosis.5 The
Ocular Rosacea
Javier F. Casiraghi, Adriana Tytiun, M. Cecilia Marini
diagnosis is usually more frequent in
middle aged women, with fair skin,
blue eyes and blond hair, than in pho-
totypes V and VI. Phymatous signs
(rhinophyma) are more common in
men usually originating in middle
or old age. The incidence of ocular
rosacea (OR) ranges from 6 to 72%1
depending on the sources (in oph-
thalmologic papers, the detected per-
centage is higher).
ETIOLOGY AND
PHYSIOPATHOLOGY
As cutaneous rosacea, OR is also
considered a chronic inflammatory
process of unknown origin. Several
studies have found a higher concen-
tration of IL-1 alpha and beta, gelati-
nases B metalloproteinases (MMP9)
and collagenases (MMP8) in the tears
of patients suffering from ocular ro-
sacea. Both the ocular and skin forms
of rosacea respond to derivatives of
tetracyclines (doxycycline), via the
decline of MMP8 and MMP9, sup-
porting the role of inflammation in
these clinical manifestations.6,7 Oth-
er authors have found high levels of
the tumor necrosis factor (TNF-a),
and over expression of intercellular
adhesion molecules 1 (ICAM-1) and of
inflammatory markers HLA-DR in the
127
conjunctival epithelial cells of patients
with ocular rosacea.8,9
There is a very important associa-
tion between rosacea and Demodex,
a common parasite found in the folli-
cles of hair and eyelashes, sebaceous
and Meibomian glands. Rosacea pa-
tients tend to have higher levels of
colonization, which suggest an im-
portant role in the re-exacerbation
of certain sub-types, mostly in PPR.
In these patients, the chronic palpe-
bral inflammation generated by this
parasite, is greater. There exists a
commensalism theory, in Demodex
by Bacillus oleronius.10
CLASSIFICATION
According to the Rosacea American
Society, the OR diagnosis is based in
the observation of one or more of the
following signs and symptoms:
Red or aqueous eyes (interpalpe-
bral conjunctival hyperemia); sensa-
tion of foreign body; burning, stinging,
dryness of the eyes; photophobia; and
telangiectases in the conjunctiva, the
sclera and in the palpebral or periocu-
lar border. Blepharitis, recurrent con-
junctivitis, repeated styes/chalazions,
episcleritis, iritis, or loss of visual acu-
ity by corneal compromise (keratitis/
ulcers) may also be present.11,12
In 2004, the same committee pub-
lished a grading system, based on
ocular rosacea severity. The primary
signs were graded from 0 to 3 –ab-
sent, mild, moderate and severe, re-
spectively– and the secondary signs
as absent or present.12,13
The following classification was
suggested:
Grade 1 or mild: signs and symptoms
affecting only the palpebral border
and the Meibomian glands.
Grade 2 or moderate: signs and
symptoms affecting the superficial
conjunctiva, the tarsal conjunctiva
and the tear film.
Grade 3 or severe: signs and symp-
toms that do not respond to eyelid or
ocular surface treatments; episcleri-
tis, scleritis and corneal compromise
affecting the visual acuity.
CLINICAL MANIFESTATIONS
The symptomatology of ocular rosacea
typically progresses over time, with a
waxing and waning course. Patients of-
ten consult a physician for sensations
of foreign body in the eyes, tearing,
red eyes, burning, stinging or pho-
tophobia. In more severe cases and
depending on corneal compromise,
consultations may also involve testing
of visual acuity. Ocular compromise
is usually bilateral, and nonspecific in
signs. The severity of ocular and skin
symptoms are not always correlated.1,14
The presence of telangiectases (Fig.
11-52) is the cardinal sign of OR. Indeed,
there is no OR without telangiectases
in the eye. Moreover, the grade of ocu-
lar involvement might be related tothe
severity of telangiectases.
The physical examination should
proceed “from the outside in”. First
of all, the facial characteristics must
be observed (Fig. 11-53) searching for
erythema, papules or pustules. Ante-
rior blepharitis (Fig. 11-54), along with
dysfunction of the Meibomian glands
(Fig. 11-55) (posterior blepharitis), are
the most frequent ocular features in
patients with rosacea.1,14 In an ophthal-
mologic examination, telangiectases
can be seen on the palpebral border
even in asymptomatic patients. In
symptomatic patients, these findings
are more evident. Meibomian glands
are often surrounded by palpebral
telangiectases. These glands look di-

Fig. 11-53. Midface lesions respecting the periocular area (courtesy Dra. Ana
Kaminsky).

lated, obstructed or displaced (Fig. process, visible on the palpebral bor-

11-56) depending on degree of in-
volvement. The meibum suffers qual-
itative and quantitative changes in its
countenance (Fig. 11-57); for instance,
there may be an excess production of
Fig. 11-52. Telangiectases on the free margin of the lower eyelid. foam as the result of a saponification
128
der. (Fig. 11-58). All these changes may
generate atrophy and occlusion of the
glands. The line of Marks (Fig. 11-59) is
displaced in some patients, moving to
the front of the glandular orifices. Re-
current episodes of chalazion/styes
are quite frequent (Fig. 11-60). The
dysfunction of the Meibomian glands,
responsible for the instability of the
tear film, is the most frequent cause
of evaporative dry eye.
The majority of rosacea patients
have a decline in the tear breakup
time (BUT) (Fig. 11-61). Dry eyes with
a decline of the Schirmer test have
been reported in 56-62.5% of cases
(Fig. 11-62), with an associated drop in
the aqueous production.15,16
It is of the utmost importance to
keep in mind that there is no relation
between the grade of meibomitis and
the signs and symptoms of ocular ro-
sacea. Chronic conjunctivitis with pro-
nounced interpalpebral hyperemia
(Fig. 11-63), generally associated with
tarsal papillary reaction, often occurs.

Fig. 11-56. Obstructive Meibomian gland dysfunction. Qualitative changes in

the structure of the Meibomian glands, with glandular obstruction.

A B

Fig. 11-54. Anterior blepharitis: A. Deposits in collarette; B. Eyelash

sheathing.

A B

Fig. 11-55. A. Dysfunction in telangiectases associated with Meibomian glands

on the upper palpebral margin. B. Qualitative changes in meibomian sebum, Fig. 11-57. Meibomian gland dysfunction. Thick meibum. Qualitative changes
with loss in transparency and consistency gain. in meibomian secretion with consistency augmentation and transparency loss.
129
Fig. 11-58. Foamy tears. In Meibomian gland dysfunction, foam on the palpe- Fig. 11-59. Displacement of the Line of Marx. Qualitative and quantitative
bral margin can be observed as a result of the fat saponification effect. changes in Meibomian glands.

Fig. 11-61. Tear break-up time

test with fluorescein staining
(BUT). It assesses the stabil-
ity of the tear film, second
to its lipid component. After
the instillation of fluorescein
solution 2%, the time in which
the first tear film rupture
signs appear is measured in
seconds. Relative standard
values >7 seconds.

Fig. 11-60. A. Chalazion on the outer third of the lower lid, observed from the
skin, and B. another on the inner third, observed from the tarsal conjunctive.
130
Fig. 11-62. Schirmer Test. It assesses the
aqueous component of the tear film.
Reactive graph tapes are placed on the
external canthus and the amount of hu-
midity on the tape is measured after 5
minutes. Without anesthesia, the stan-
dard value should be >10 mm.
Tarsal scars are frequently found in
the lower and upper eyelids, (Fig. 11-
64)1,14 which constitute a mandatory
differential diagnosis with ocular cic-
atricial pemphigoid (OCP) or tracho-
ma, depending upon de geographical
area. In some cases, the scarring reac-
tion is such that it may result in a post-
surgical symblepharon.
Fig. 11-63. Chronic conjunctivitis associated to Meibomium gland dysfunction. Fig. 11-64. Scarring on the superior
Conjunctival hyperemia associated with Meibomian gland dysfunction and tel- tarsus, evidenced through palpebral
angiectases. eversion.
Corneal compromise is observed Some recurrent epithelial defects
in approximately 33% of cases.1 The -like pseudo-dendritic ulcers, pseu- or ghost vessels, an association with
typical initial clinical picture shows a do-keratoconus and infectious kerati- a skin pathology must be considered.
punctate keratitis on the lower third tis- have also been described. Visual Cases of iritis, scleritis (Fig. 11-70)
of the cornea (Fig. 11-65).23 In more acuity may be compromised by cor- and episcleritis (Fig. 11-71), as well as
advanced stages, a peripheral neo- neal unevenness or scarring due to of spontaneous scleral perforations,
vascularization can be observed on any of the above-mentioned clinical have also been reported.
the compromised sector, associated scenarios. Stromal ghost vessels can
with sub-epithelial aseptic infiltrates also be observed in patients with DIAGNOSIS
(Fig. 11-66). When left untreated, the symptoms that have resolved. (Fig. 11- The diagnosis is mainly clinical. Ocu-
central stroma may develop ulcers 69). It is worth noting that, once faced lar rosacea signs are nonspecific and
(Fig. 11-67) and even ocular perfora- with the finding of inexplicable corne- shared with various non-rosacea en-
tion. (Fig. 11-68). al pictures like leucoma, new vessels tities. For this reason, suspicion and
131
 A B

Fig. 11-65. Inferior punctate keratitis. Punctiform defect of

the corneal epithelium, with inferior predominance. C D

Fig. 11-66. A. Complete neovascularization. B. Neovascularization and leucoma on visual axe. C.

Neovascularization in hour 7. D. Neovascularization and corneal leucoma.

Fig. 11-67. Central corneal ulcer.

132
A B C

Fig. 11-68. Corneal perforation A. Corneal melting. B. Spontaneous corneal perforation. C. Corneal melting with risk of perforation.

Fig. 11-69. Ghost vessels. Erythrocytes Fig. 11-70. Neovascularization associated with scleritis. Fig. 11-71. Episcleritis. Inflammation of episcleral ves-
and bloodless vessels can be observed. sels.
133
research are in order. A diagnostic
test for rosacea (skin or ocular) is not
yet available. Neither are histologi-
cal or serological markers. There is
an ongoing research on biomarkers,
related to the tear and saliva glucan
profile. In the patient`s tears, the
presence of abundant oligosaccha-
rides (O-linked), has been scientifical-
ly proven to be linked with rosacea.16
Pediatric Diagnosis
Clinical signs in children are very sim-
ilar to those in adults. However, a lack
of skin involvement is more common
in children. For this reason, ocular
manifestations play a fundamental
role in detecting childhood rosacea.17
Skin involvement has been report-
ed to occur in approximately 56%
of childhood rosacea cases prior to
development of any ocular signs or
symptoms. When there is a positive
family history of rosacea and reversed
refractive defects, the appearance of
recurrent styes/chalazions in children,
would constitute an indirect sign of
ocular rosacea.
Differential diagnosis
UU Pure seborrheic and staphylococ-
cal blepharoconjunctivitis
UU Sebaceous glands carcinoma
(must raise suspicion in older pa-
tients with chronic palpebral le-
sions) (Fig. 11-72)
UU Cicatricial ocular pemphigoid (Fig.
11-73)
UU Acne vulgaris
UU Acneiform dermatitis
UU Lupus erythematosus
UU Carcinoid syndrome and mitral
valve failure causing erythema and
telangiectases
TREATMENT
The treatment of ocular rosacea aims
at mitigating the inflammatory pro-
cess and the possible development
of irreversible fibrosis, with its con-
sequent ocular morbidity. Ocular ro-
sacea -like all the pathologies of the
ocular surface- have a great impact
on the patient´s quality of life, some-
times even hampering daily activities.
The interdisciplinary management is
essential, since without proper treat-
ment of the skin condition, good re-
sults are not usually obtained in the
eye disorder. The treatment includes
general care and hygiene, topical
treatments and the use of oral tetra-
cyclines derivatives, an essential pillar
in the cases requiring them
General care
As with skin rosacea, it is important
to identify and avoid individual trig-
gering factors (spicy meals, alcoholic
beverages, sun exposure or sources
of heat like, ovens and stoves). Pa-
tients should also be educated about
the importance of photoprotection
and daily use of sunscreen (SPF-30)
should be recommended. This point
should be particularly stressed if the
patient is receiving treatment with
oral tetracyclines (to avoid the devel-
opment of photosensitivity).

A B C

Fig. 11-72. Sebaceous glands carcinoma. A. Sebaceous carcinoma on the upper eyelid of the left eye. B. External lateral view. C. View from the tarsal conjunctive
with eyelid eversion. (Courtesy Dra. Alejandra Billagra).
134
 Basic palpebral care includes use
of warm compresses (wet or dry), ex-
pression of the Meibomian glands,
mechanical cleaning of the eyelashes
(with neutral shampoo) and use of lu-
bricating eye drops and gel.1,14 Some
authors suggest the use of boiled wa-
ter without any soap, since soap could
exacerbate symptoms. The patients
must be responsible for their palpebral
care and hygiene. Clinicians should
emphasize the need to have regular
ophthalmologic evaluations and the
patient should understand that their
disease is manageable but not curable.
Palpebral hygiene is important in order
to reduce the inflammatory processes.
Compresses and mechanical cleaning
allow the removal of scabs, debris or
seborrheic secretions from the palpe-
bral border. Reducing meibum from
the Meibomian glands by heating in-
creases the lipid layer and the stability
of the tear film, reducing its evapora-
tion.18 Lubricants are useful because
changes in the ocular surface and dry-
ness, generate tissue stress, which in
turn, triggers the release of pro-inflam-
matory substances like IL-1 and MMP9.
The use of lubricants could prevent
this type of reaction, thus increasing
the clearance of these mediators.
Local treatment
For patients with moderate symp-
toms or persistent symptoms despite
good hygiene practices, the following
options are available:
Fig. 11-73. Scarring ocular pemphigoid. Conjunctival bridges: adherences be-
tween bulbar and tarsal conjunctives.
Use of antibiotics at night to com-
plement mechanical hygiene on the
palpebral border, with the purpose of:
1. Reducing bacterial colonization.
2. Adding another emollient to morn-
ing hygiene.
3. Indirectly forcing morning hy-
giene.
The antibiotic of choice may be azi-
thromycin 1% ophthalmic solution or
135
erythromycin 1%, although ciproflox-
acin, polymyxin B or fusidic acid may
also be used. Corticosteroids could
also be added. Metronidazole gel has
been used as treatment of blephari-
tis associated to rosacea, though its
efficacy is related more to its anti-in-
flammatory effect than to its antibiot-
ic action.19
The possible selection of resistant
bacterial strains and potential toxici-
ty of treatments must be considered.
For this reason, short treatment cy-
cles are fundamental for this group
of patients, who often simultaneously
have dry eyes. In dry eyes with corneal
or palpebral changes due to rosacea,
topical cyclosporine 0.05% -which in-
creases the aqueous production and
has an anti-inflammatory effect- is
more efficient than only lubricants.23,30
The minimum dose is prescribed twice
a day and ideally, four times a day at
least for four months. An increase
in the cyclosporinemia has not been
found with chronic treatment of ocu-
lar rosacea. In rosacea patients, top-
ical cyclosporine –compared to only
lubricants– extends the tear break-up
time (BUT); increases the Schirmer
test and improves the corneal stain-
ing.20,21
For managing initial inflammation,
short cycles of mild corticosteroid
topics may be used, in a dose of one
eye drop, four times a day (lotepre-
dnol 0.2%, 0.5% or fluorometholone
0.1%). The dose is gradually lowered
within a period no longer than four
weeks. Sometimes, it is convenient to
start cyclosporine and corticosteroids
together, and then transition to cyclo-
sporine alone.
In severe cases of iritis, scleritis or
corneal compromise, it is often neces-
sary to use anti-inflammatory agents
like topical corticosteroids and im-
munomodulators (cyclosporine, tac-
rolimus, at the same time.20,21 Topical
bevacizumab has been a good option
in selected cases of corneal neovas-
cularization.22,23
Systemic treatment
Systemic treatment is mandatory in
patients with moderate to severe
rosacea. It is based in the anti-in-
flammatory effect of certain drugs,
especially through the inhibition of
metalloproteinases.6,24 Tetracyclines
and its derivatives25-28 constitute the
cornerstone of the treatment, due to
their ability to:
4. Lower expression of metallopro-
teinases (MMP8 and MMP9) at cor-
neal epithelium level
5. Inhibit lipase production by Staph-
ylococcus
6. Decrease bacterial flora
7. Alter meibomian sebum secretion
8. Modulate levels of chemotaxis and
cytokine production
The most commonly used tetracy-
clines are: tetracycline, doxycycline
and minocycline, usually prescribed in
empirical doses. These antibiotics are
contraindicated in children, pregnant
women, in kidney and liver failure,
as well as in patients with allergy to
tetracyclines. To improve absorption,
tetracyclines should not be taken with
dairy products. Sun exposure should
be limited during tetracycline therapy
due to the potential for photosensi-
tivity (the appearance of sun spots on
the skin).25-28
Tetracycline: the prescribed dose is
of 500 mg every 12hs, for 2 to 3 weeks,
followed by a progressive decrease,
according to the clinical response.
Doxycycline: a dose of 100 mg
once or twice daily is suggested for
6 to 12 weeks. Doxycycline may be
chosen due to a lower potential for
adverse events compared with tetra-
cycline. Very often symptoms recur
when the medication is discontin-
ued. For this reason, many clinicians
prescribe maintenance therapy with
a low dose (50 mg/daily). Long-term
treatment may result in gastrointes-
tinal intolerance, due to dysbacteri-
osis. The main adverse effects are:
gastrointestinal intolerance, itching,
hives and other skin lesions.29,30 In
patients with OR who need an eye
surgery for any reason, it is conve-
nient to administer the antibiotic,
starting 5 days previous to the oper-
ation, up to the end of the immediate
post-operative period. Pre-surgical
stress may exacerbate the symp-
toms, due to increased inflammation
or an associated infection. In these
cases, a dose of 100 mg/daily is rec-
ommended. There is also a 40 mg
doxycycline formulation containing
136
30 mg of immediate release and 10
mg of slow release doxycycline. This
is the first tetracycline approved by
the FDA for the treatment and main-
tenance of skin rosacea. A significant
improvement in ocular rosacea has
been reported with once daily intake
of this 40 mg formulation, with no re-
currence after discontinuation of the
treatment with fewer adverse effects
compared with doxycycline 100 mg.
Ingestion on an empty stomach and
with plenty of liquid is recommend-
ed. The tolerability profile associat-
ed with treatment longer than nine
months is unknown.30
Minocycline: the dose is 50 mg/
daily for two weeks, followed by 100
mg/daily, for three months.26 this drug
produced a decline in the levels of
pro-inflammatory cytokines in the
tear film, which brought about an im-
provement of signs and symptoms in
patients with moderate dysfunction
of the Meibomian glands.
Minocycline seems to have more
effect both on palpebral flora35 and
on lipase inhibition than other tet-
racyclines. It is better tolerated than
doxycycline; however, some authors
prefer the last. The following ad-
verse effects of minocycline may
occur: gastrointestinal intolerance,
autoimmune syndrome, scleral pig-
mentation and alteration of dental
colouring.22,26,31
Azithromycin: Bakan, et al propos-
es 500 mg/daily, for three consecu-
tive week days, during four weeks;
a 5-week course of azithromycin 1 g/
daily once per week may also be used.
This macrolide antibiotic improves oc-
ular symptoms and is a good option
for patients who are intolerant to tet-
racyclines and in children.32,33
Erythromycin: can be used in preg-
nancy and in pediatric cases, when
the tetracyclines are contraindicated.
Dietary supplements
The current recommendation for
dietary supplementation in ocular
rosacea is to use a 4:1 ratio of ome-
ga-3 to omega-6 in the manner of the
Mediterranean diet. The long term
use of omega-3 fatty acids improves
the quality in the secretion of the
Meibomian glands via an anti-inflam-
matory effect. In contrast, omega-6
has a pro-inflammatory effect. The
natural sources of omega 3 are cold
water fish, flaxseed oil and ground
chia seeds. Flaxseed oil (100 mg/dai-
ly) exceeds olive oil in improving the
ocular surface disease index (OSDI:
Ocular Surface Disease Index), in
patients with blepharitis and Meibo-
mian glands dysfunction. Most of the
omega 3 formulas contain eicosapen-
taenoic acid (EPA) and docosahexae-
noic acid (DHA) in 1.000 mg capsules.
However, the ideal formula has not
yet been developed.34,35
Surgical treatments
Surgery is commonly used in the
management of complications asso-
ciated with ocular rosacea. Punctal
plugs (punctum plug) may be use-
ful in the management of moderate
dry eye, as long as eye swelling has
been managed. If necessary, a three-
month complete pharmacological
treatment should be conducted pri-
or to introduction of punctal plugs.
Plugs must not be placed when oc-
ular swelling is present because the
turnover of inflammation mediators
is reduced and the condition is ag-
gravated.
In patients with Meibomian gland
dysfunction with palpebral thickening
and obstruction and displacement
of the line of Marx, thermodynamic
therapy, with puncture of the glands
associated with exfoliation of the
palpebral border may be a good
option.36 It has been suggested that
pulsed laser light could become
a therapeutic option for the skin
and dry eye management of treat-
ment-resistant patients.37 Persistent
chalazion is treated surgically, with
(mandatory) studies of pathologi-
cal anatomy, to rule out sebaceous
glands carcinoma, especially in older
patients. Corneal perforation is not
a frequent complication but if it ap-
pears, it would require a spectrum
of techniques that go from using
simple tissue adhesives, conjuncti-
val coatings (Fig. 11-74) and amniotic
membranes (Fig. 11-75) to even trans-
plants. The visual sequels left by cor-
nea scarring, could be managed by
use of lamellar or penetrating corne-
al transplant. (Fig. 11-76). It is of fun-
damental importance to associate
any of these options to an efficacious
systemic treatment, otherwise any
procedure is doomed to fail.

Fig. 11-74. Partial conjunctival coating from upper quad- Fig. 11-75. Complete corneal coating with amniotic Fig. 11-76. Penetrating cornea transplant, with
rants. membrane. acute post-perforating continuous suture.

137
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sification and Staging of Rosacea. J
Am Acad Dermatol 2004;50(6):907-
12. Comment in: J Am Acad Derma-
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13. Alvarenga LS, Mannis MJ. Ocular
rosacea. Ocul Surf 2005;3(1):41-58.
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14. Lazaridou E, Fotiadou C, Ziakas
NG, et al. Clinical and laboratory
study of ocular rosacea in northern
Greece. JEur Acad Dermatol Vene-
reol 2011;25(12):1428-31.
15. Gudmundsen KJ O’Donnell BF,
Powell FC. Schirmer testing for
dry eyes in patients with rosa-
cea. J Am Acad Dermatol 1992;26
(2Pt1):211-4.
16. An HJ, Ninonuevo M, Aquilan J, et
al. Glycomics analyses of tear fluid
for the diagnostic detection of oc-
ular rosacea. J Proteome Res 2005;
4(6):1981-7.
17. Çetinkaya A, Okova YA. Pediatric
ocular acne rosacea: long term treat-
ment with systemic antibiotics. Am J
Ophthalmol 2006;142(5):816-21.
18. Goto E, Endo K, Suzuki A, et al.
Improvement of tear stability
following warm compression in
patients with meibomian gland
dysfunction. Adv Exp Med Biol
2002;506:1149-52.
19. Barnhorst DA Jr, Foster JA, Chern
KC, et al. The efficacy of topical
metronidazole in the treatment
of ocular rosacea. Ophthalmology
1996;103:1880-3.
20. Schechter BA, Katz RS, Friedman
LS. Efficacy of topical cyclosporine
for the treatment of ocular rosacea.
Adv Ther 2009;26:651-9.
21. Sall K, Stevenson OD, Mundorf TK,
et al. Two multicenter, randomized
studies of the efficacy and safety
of cyclosporine ophthalmic emul-
sion in moderate to severe dry eye
disease. CsA Phase 3 Study Group.
Ophthalmology 2000;107:631-639.
22. Van Zuuren EJ, Kramer SF, Carter BR,
et al. Effective and evidence-based
management strategies for rosacea:
summary of a Cochrane systematic
review. Br J Dermatol 2011;165:760-81.
23. Kılıç Müftüoglu I, Aydın Akova Y. Clin-
ical findings, follow-up and treatment
results in patients with ocular rosa-
cea. Turk J Ophthalmol 2016;46:1-6.
24. Iovieno A, Lambiase A, Micera A, et
al. In vivo characterization of doxycy-
cline effects on tear metalloprotein-
ases in patients with chronic blephari-
tis. Eur J Ophthalmol 2009;19:708-16.
25. Stone DU, Chodosh J. Oral tetra-
cyclines for ocular rosacea: an ev-
idence-based review of the litera-
ture. Cornea 2004;23:106-9.
26. Ta CN, Shine WE, McCulley JP, et
al. Effects of minocycline on the
ocular flora of patients with acne
rosacea or seborrheic blepharitis.
Cornea 2003;22:545-8.
27. Shine WE, McCulley JP, Pandya
AG. Minocycline effect on mei-
bomian gland lipids in meibo-
mianitis patients. Exp Eye Res
2003;76:417-20.
28. Wladis EJ, Bradley EA, Bilyk JR, et
al. Oral antibiotics for Meibomian
gland-related ocular surface dis-
ease: A Report by the American
Academy of Ophthalmology. Oph-
thalmology 2016;123(3):492-6.
29. Yoo SE, Lee DC, Chang MH. The
effect of low-dose doxycycline ther-
apy in chronic meibomian gland
dysfunction. Korean J Ophthalmol
2005;19:258-63.
30. Sobolewska B, Doycheva D, Deuter
C, et al. Treatment of ocular rosacea
with once-daily low-dose doxycy-
cline. Cornea 2014;33:257-60.
31. Bradfield YS, Robertson DM, Salo-
mao DR, et al. Ocular Rosacea: Mi-
nocycline-induced ocular pigmenta-
tion. Arch Ophthalmol 2003;121:144-5.
32. Haque RM, Torkildsen GL, Brubaker
K, et al. Multicenter open-label study
evaluating the efficacy of azithromy-
139
cin ophthalmic solution 1% on the
signs and symptoms of subjects with
blepharitis. Cornea 2010;29:871-877.
33. Opitz DL, Tyler KF. Efficacy of azith-
romycin 1% ophthalmic solution for
treatment of ocular surface disease
from posterior blepharitis. Clin Exp
Optom 2011;94:200-206.
34. Rand AL, Asbell PA. Nutritional sup-
plements for dry eye syndrome. Curr
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35. Bhargava R, Chandra M, Bansal U,
et al. A randomized controlled trial
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patients with dry eye symptoms.
Curr Eye Res 2016;41(10):1274-1280.
Epub 2016 Apr 6.
36. Wladis EJ. Intraductal meibomian
gland probing in the management
of ocular rosacea. Ophthal Plast
Reconstr Surg 2012;28(6):416-8. doi:
10.1097/IOP.0b013e3182627ebc.
37. Vora GK, Gupta PK. Intense
pulsed light therapy for the
treatment of evaporative dry eye
disease. Curr Opin Ophthalmol
2015;26(4):3

Rosacea is a condition especially af-
fecting middle-aged and fair-skinned
adults. Its prevalence among children
is low, although it is likely that not all
cases are reported due to the lack of
diagnostic criteria in this age group.1,2
In pediatric patients with rosacea, the
likelihood of having a positive family
history of rosacea is four times high-
er than the general pediatric popu-
lation.3,4 Besides skin phototype and
family disposition, triggers such as
exposure to the sun and heat sources
and, especially in children, the use of
topical facial or inhalational fluoride
corticosteroids must be taken into ac-
count.3
Chamaillard et al1 described three
types of clinical manifestations of
rosacea in children: papulopustular,
Chapter 12
Special Forms
Childhood Rosacea
María del C. Boente, María J. Fiandrino
telangiectatic and granulomatous
rosacea. The most frequent is the
papulopustular form, which is char-
acterized by the presence of papules
and pustules with fine scaling, typi-
cally over a background of erythema
and telangiectases, predominantly
located on the cheeks and chin, with
no involvement of the nasolabial fold
(Figs. 12-1 to 12-8). In the telangiectatic
form, lesions predominate in the con-
vex areas of the face. When flushing is
present, it may be triggered by sever-
al factors including exposure to heat.
Episodes of erythema are recurrent Fig. 12-1. Rosacea. Erythema on nose and cheeks with small er-
and last longer than non-pathological ythematosus papules.
140
Fig. 12-2. Rosacea. Mild erythema on cheeks. Nose and cheek papulopustular Fig. 12-4. Papulopustular rosacea. Center-facial papulopustular lesions and
lesions (by courtesy of Dr. Alicia Rosito). scaling. Conjuctival injection (courtesy, Dr. Margarita Larralde).

Fig. 12-3. Rosacea. Eythema on cheeks. Recent papular lesions (courtesy, Dr. Fig. 12-5. Erythema on cheeks and nose. Papulopustular lesions on the nose.
Carola Durán). History of inhalational steroids (courtesy, Dr. Alicia Rosito).
141
Fig. 12-6. Rosacea. Severe inflammatory papulopustular lesions on the ery-
thematous tissue of cheeks and nose (courtesy, Dr. Carola Durán).

Fig. 12-8. Papulopustular rosacea. Predominant lesions on cheeks (courtesy, Dr.

Fig. 12-7. Papulopustular rosacea, detail (courtesy, Dr. Alicia Rosito). Carola Durán).
142
flushing, which disappears in a few
minutes (Fig. 12-9). The less frequent
granulomatous form is characterized
by the appearance of firm, brownish
pinkish papules located in the perioral
and periocular zones. Frequently, this
form is associated with the use of top-
ical corticosteroids.
Ocular involvement may precede
skin lesions in children, as in adults.
Childhood ocular rosacea may ap-
pear as chalazion, Meibomian glands
inflammation, conjunctival injection,
blepharoconjunctivitis, keratitis, epis-
cleritis and, rarely, corneal ulcers (Fig.
12-10). Chalazion and ocular erythema
by conjunctival injection are the most
frequent forms of presentation (Fig.
12-11). In patients with a diagnosis or
Fig. 12-9. Erythematotelangiectatic rosacea. Dermatoscopy: telangiectases
(courtesy, Dr. Carola Durán).
suspected diagnosis of infantile rosa-
cea, consultation with the ophthalmol-
ogist is recommended.1 Patients with
repeated sties in childhood are more
likely to develop rosacea in adulthood
(see Fig. 12-11). In ocular rosacea, the
dysfunction of the Meibomian glands
leads to thickened secretions, gland
occlusion and thickening of the free
margins of the eye. The ocular symp-
toms in rosacea partly are due to a
failure in corneal protection by the
lipid layer of tears. As in facial rosa-
cea, there is also an alteration in in- Fig. 12-10. Papulopustular rosacea. Ocular compromise: conjuctival injection
flammatory mediators which may be (courtesy, Dr. Ana Kaminsky).
the cause of the change in tears.1,4-6
Given the increased frequency of ro-
sacea in patients with styes, it is nec-
essary to determine the existence of
relatives with rosacea among children
Fig. 12-11. Rosacea. Repeated sties from the very first month of life. Papulopus-
tular lesions on baseline erythematous, on the cheeks and perioral area, from
the 9th month of age.
143
who may have either erythematous
or papulopustular facial eruptions, or
both (Fig. 12-12).3,4
Differential diagnosis is deter-
mined through a range of dermato-
logical conditions that can clinically
and histologically emulate childhood
rosacea. The absence of comedones,
or the presence of flushing and telan-
giectases differentiate rosacea from
acne in childhood. Demodicidosis can
be confused with infantile rosacea
in its papulopustular form. Typically,
papules and pustules appear on the
cheeks, perioral area, and nasal dor-
sum, but neither erythema nor flush-
ing is observed with demodicidosis.
In childhood, demodicidosis is not
common among non-immunocompro-
mised patients. The scraping of the
pustules allows viewing Demodex.7
Frequent use of oily cosmetic
skin care or hair products can also
trigger facial papulopustular erup-
tions, the so-called ointment or
cosmetic acne. The characteristic
history, the location of the lesions,
and the absence of comedones and
the underlying erythema, and flush-
ing are useful in reaching a correct
diagnosis.7 Periorificial dermatitis
caused by topical or inhaled use of
corticosteroid may be considered a
rosacea-like eruption or within the
spectrum of infantile rosacea. The
history of corticosteroid use should
be collected among all patients with
papulopustular eruption, especial-
ly if it is located in the perinasal or
perioral region (see Fig. 12-5).8-10
Telangiectatic rosacea should be
differentiated from other childhood
causes of telangiectases, such as pho-
tosensitive diseases (cutaneous and
systemic lupus erythematosus and
poikilodermas). As regards the latter,
the absence of atrophy aids in mak-
ing the diagnosis. It should be noted
that frequent use of facial fluoride
corticosteroids can result in the de-
velopment of telangiectases and even
atrophy (Fig. 12-13).
Perioral granulomatous dermati-
tis deserves special consideration in
the differential diagnosis of granulo-
matous rosacea. It is characterized
by the appearance of smooth sur-
face papules, 1 to 3 mm in diameter,
red or yellow-brown in color, located
around the mouth, nose and eyes,

A B C D E

Fig. 12-12. Family history of rosacea. A. From the age of two, center-facial papular erythematous lesions on erythematous tissue. Ocular erythema. B. After a
five-year treatment. C. After a seven-year treatment. D. Mother: inflammatory lesions on cheeks. Baseline erythema and telangiectases on cheeks. E. Mother: as
a result of treatment, improvement of inflammatory lesions, telangiectases and erythema.
144
as well as ear helixes, which can re-
sult in ice-pick, punctiform scars. No
pustules develop with perioral gran-
ulomatous dermatitis. The pathology,
although not pathognomonic, shows
dermal granulomas, usually located
around the top of the hair follicles.
The eruption or rash, a peculiar reac-
tion to topical or systemic triggering
agents, disappears unaided in two or
three years. Some authors consider
it a variety of granulomatous rosa-
cea, ad referendum of future studies
that may confirm or deny it, since, al-
though both entities follow different
developmental courses, they have
similar triggers and therapeutic re-
sponse.10-13
Fig. 12-13. Lupus erythematosus. Post-treatment erythema and telangiectases,
which may resemble rosacea. Infiltrated lesions on forehead. The slate-co-
loured marks belong to a tattoo made with Indian ink (folk medicine).
Pediatric sarcoidosis is also in-
cluded in the differential diagnosis
of the granulomatous form. Pediatric
sarcoidosis is usually associated with
systemic compromise. The topog-
raphy of lesions, the characteristics
of papules and the absence of tel-
angiectases and baseline erythema
contribute to the differential diag-
nosis.14 Blau syndrome, an autosomal
dominant autoinflammatory disease,
occurs in childhood with cutaneous
granulomas, symmetrical polyarthri-
tis and ocular manifestations (uve-
itis, iritis, vitritis and angle-closure
glaucoma). Cutaneous involvement
is characterized by generalized,
non-pruritic erythematous papules
145
associated with chronic ulcers in the
lower limbs. Histologically, it is char-
acterized by non-caseating granu-
lomas. There may also be systemic
granulomatous compromise: pulmo-
nary, renal, CNS and arterial. This is
caused by missense mutations (loss
of sense) in the CARD15 gene.15
The Haber syndrome is an auto-
somal dominant inherited genoder-
matosis. It is characterized by an
infantile rosacea-like eruption ex-
acerbated by sun exposure. In addi-
tion, on the trunk, patients present
with keratotic pigmented wart le-
sions, facial acne-like scars and itch
in winter.17 Fig. 12-14. Idiopathic facial aseptic
granuloma (courtesy, Dr. Margarita
Concerning differential diagno- Larralde).
sis, another entity deserving special
attention is the idiopathic aseptic
facial granuloma. It appears in the
early childhood years and it is charac-
terized by the presence of an inflam-
matory nodule, similar to an abscess.
There generally appears only one,
though in some children there are
multiple lesions, localized on the mid
third of the face, which are sponta-
neously solved in several months
(figs. 12-14 y 12-15). From the histologi-
cal point of view, it constitutes a der-
mal inflammatory granuloma, with an
infiltrate of lymphocytes, histiosytes,
neutrophils and giant cells. At pres-
ent, it is considered within the spec- Fig. 12-15. Idiopathic facial aseptic
tre of childhood rosacea.17 granuloma (courtesy, Dr. Mariel Giovo).
 TREATMENT
Patients should avoid known triggers:
hot and spicy foods and drinks, as well
as exposure to heat and sun. Photo-
protection measures should be recom-
mended along with the treatment. In
adolescence, consumption of alcoholic
beverages should also be avoided.10
Repairing the skin barrier is very
important. So, skin cleansing with soft,
non-aggressive substances and emol-
lient and decongestive creams is rec-
ommended.
The pediatrician should be aware
of the need to avoid the use of
inhaled and topical corticoids in
these patients.
Systemic treatment should be con-
sidered in cases of papulopustular
and granulomatous rosacea.
Tetracyclines and derivatives,
which are frequently used in the
treatment of rosacea among adults,
are contraindicated in children un-
der eight years of age, so in this age
group they should be replaced by
erythromycin, although the response
is lower, and relapses, faster.2
In older age groups, if systemic
treatment is necessary, tetracyclines
are the preferred choice. Treatment
should be continued until the in-
flammation component is resolved.
The lowest possible dose should be
used to obtain the desired result:
doxycycline (40 mg/day) and tetra-
cycline, minocycline and limecycline
may be used as well. Oral metroni-
dazole (not less than 20 mg/kg/day)
is a therapeutic alternative. Treat-
ment should be continued for one
month or until clinical remission of
inflammation is observed. Low dos-
es of oral isotretinoin may be used
in obstinate cases. Oral ivermectin
may also be used in recalcitrant cas-
es when no response to other ther-
apies is achieved, and if Demodex
folliculorum is suspected.18,19
Topical Treatments
For milder cases, metronidazole
0.75% gel or 1% cream or azelaic acid
15-20% gel, cream or foam should be
applied twice a day.
Ocular involvement is treated with
gentle eye margin hygiene and intra-
ocular treatment with erythromycin
or metronidazole ophthalmic gel.1,2,4
In cases with inflammatory lesions,
topical ivermectin, 1% cream, applied
once a day, has anti-inflammatory, im-
munomodulatory and antiparasitic ef-
fects.18,19
Persistent telangiectases can be
treated with pulsed dye lasers or with
intense pulsed light in the range of
500 to 600 nm (IPL DYE).20
146
In childhood, the association of
persistent facial inflammatory derma-
tosis with ocular compromise should
lead to the clinical suspicion of ro-
sacea. In this case, the dermatolog-
ical treatment is combined with the
ophthalmological treatment to avoid
future ocular consequences.1,2 Al-
though rosacea is rare in childhood,
it should be considered in children
with chronic papulopustular facial
eruptions affecting the cheeks. Ery-
thema and telangiectases are part of
the clinical condition. Ocular involve-
ment is characterized by blepharitis,
keratoconjunctivitis, and episcleritis,
which when present aid in making
the diagnosis.
References
1. Taub AF. Treatment of rosacea with
intense pulsed light. J Drug Derma-
tol 2003; 1:254-259.
2. Chamaillard M, Montemousque
B, Boralevi F, et al. Cutaneous and
ocular signs of childhood rosacea.
Arch Dermatol 2008; 144:167-17.
3. Lacz NL, Schwartz RA. Rosacea
in the pediatric population. Cutis
2004; 74:99-103.
4. Chang AL, Raber I, Xu J, et al. As-
sessment of the Genetic Basis of
Rosacea by Genome-Wide Associa-
tion Study. J Invest Dermatol 2015;
135:1548-1555.
5. Nazir SA, Murphy S, Siatkowski RM,
et al. Ocular rosacea in childhood.
Am J Ophthalmol 2004; 137:138-144.
6. Dahl MV, Ross AJ, Schlievert PM.
Temperature regulates bacterial
protein production: possible role
in rosacea. J Am Acad Dermatol
2004; 50:266-272.
7. Bamford JT, Gessert CE, Renier
CM, et al. Childhood stye and adult
rosacea. J Am Acad Dermatol 2006;
55:951-955.
8. García Morrás P, Pérez Santos S,
Lomgo Imedio I, et al. Rosacea-like
demodicidosis in an immunocom-
promised child. Ped Dermatol 2003;
20:28-30.
9. Jansen T, Melnik BC, Schadendorf
D. Steroid-induced periorificial der-
matitis in children–clinical features
and response to azelaic acid. Ped
Dermatol 2010; 27:137-142.
10. Nguyen V, Eichenfield LE. Peri-
orificial dermatitis in children and
adolescents. J Am Acad Dermatol
2006; 55:781-785.
11. Khokhar O, Khachemoune A. A
case of granulomatous rosácea:
sorting granulomatous rosacea and
other granulomatous diseases that
affect the face. Dermatology online
J 2004; 10(1):6.
 12. Urbasch AJ, Fieden I, Williiams
M, et al. Extrafacial and general-
ized granulomatous periorificial
dermatitis. Arch Dermatol 2002;
138:1354-1358.
13. Goel NS, Burkhart CN, Mo-
rell DS. Pediatric Periorificial
Dermatitis: Clinical Course and
Treatment Outcomes in 222 Pa-
tients. Pediatric Dermatology 2015;
32(3)333-336.
Extrafacial or disseminated rosacea
is a very rare clinical form and there
are very few known published studies.
The Iberian-Latin American Group for
the Study of Rosacea (GILER) is the
only expert association that considers
that it should be included in the clas-
sification as a special form, as along
with infantile rosacea, due to its clini-
cal characteristics particularly related
to its location.1
In 1969, Marks and Jones were the
first experts to publish, under the title
“Disseminated rosacea,” research on
14 patients with rosacea and extrafa-
cial lesions (13 of their own and one of
Fountain and Sarkany’s) who, during
the course of their disease, devel-
oped typical papular and papulopus-
tular lesions in unusual areas. They
explained that they found nothing in
books or publications about extrafa-
cial locations, and mentioned that, in
14. Rodriguez-Caruncho C, Bielsa I, Fer-
nandez-Figueras MT, et al. Childhood
granulomatous periorificial dermatitis
with a good response to oral metroni-
dazole. Ped Dermatol 2013; 30:e98-e99.
15. Decams V, Bouscarat F. Cutaneous
manifestations of sarcoidosis. Ann
Dermatol Venereol 2016; 143:39-50.
16. Nguyen TV, Cowen EW, Leslie KS.
Autoinflammation: From monogenic
Extrafacial Rosacea
Ana Kaminsky
1967 and 1968, two patients with typ-
ical rosacea lesions on the face and
neck, as well as papules on arms and
wrists, were reported to the Derma-
tology Section of the Royal Society of
Medicine.2 In these cases, extrafacial
lesions occurred on the upper limbs,
back of the hand, and fingers, wrists,
legs, thighs, and buttocks. Histo-
pathological studies of lesions found
in atypical location were performed,
showing that the diagnosis was con-
sistent with rosacea, although some
differences were identified. The most
frequent findings were of two types:
one, perivascular edema, and edema
with irregular lymphohistiocytic infil-
trate, predominantly in the upper and
middle dermis; and two, a range focal
147
syndromes to common skin diseases.
J Am Acad Dermatol 2013; 68:834-853.
17. McCormack CJ, Cowen P. Haber’s
syndrome. Australas J Dermatol
1997; 38:82-84.
18. Noguera-Morel L, Gerlero P, Torrelo A,
et al. Ivermectina therapy for papulo-
pustular rosacea and periorificial der-
matitis in children: A series of 15 cases.
J Am Acad Dermatol 2017; 76:567-570.
granulomas, from focal collections
of histiocytes and epithelioid cells
composed of 3 or 4 cells to large and
diffuse granulomas occupying wide
areas of the dermis.2 In 1969, two cas-
es of rosacea were reported, one with
rhinophyma and both with presternal
lesions.3 Years later, there were 4 pa-
tients described with erythema, mul-
tiple telangiectases, and papular and
papulopustular lesions located in the
parietal, frontal and occipital regions
of the scalp.4,5
In 1979, Wilkin described a surpris-
ing case of a man with strong flushing
in the epigastric and facial region ob-
served after drinking wine. This patient
had a severe ETR, and presented iden-
19. Brown M, Hernández-Martín A,
Clement A, et al. Severe Demo-
dex folliculorum–associated oc-
ulocutaneous rosacea in a girl
successfully treated with iver-
mectin. JAMA Dermatol 2014;
150:61-63.
20. Prey S, Ezzedine K, Mazereeuw-Hau-
tier J, et al. IFAG and childhood
rosácea: a posible link? Ped Der-
matol; 2013 30(4)429-432.
tical lesions in the epigastric region,
with no other typical rosacea lesions
indicative of ETR. Wilkins referred to
Darwin, commented that blushing or
flushing could occur in the epigas-
tric region of the abdomen in his 1872
book “The Expression of the Emo-
tions in Man and Animals.”. Conse-
quently, Wilkins believed that flushing
in the epigastric region was probably
ETR in an unusual area.6
Pereira et al. reported the case
of a man with inflammatory papules,
pustules and nodules over a very er-
ythematous area with telangiectases,
which spread from the midfacial area
to the neck, upper chest and upper
limb.7 In other cases, mostly men, ex-
trafacial locations were observed on
the scalp, neck, retroauricular area,
shoulders, upper chest and arms.8,9
Another patient had the primary man-
ifestation of rosacea in the alopecic
area of the scalp with lesions in the
region of the vertex and extension to
the forehead and, to a lesser extent,
to the cheeks and nose, with small er-
ythematous and pustular papules, and
crusty lesions especially on the scalp.
This patient also had blepharitis and
conjunctivitis, both manifestations of
ocular rosacea.10
Necrotic papules on the neck,
forearms and hands were described
in a man with facial rosacea, who also
showed intense bilateral conjunctival
hyperemia and corneal opacity con-
sistent with ocular rosacea diagnosis.11
In a study conducted in Saudi Arabia
in 50 women with rosacea, among
which 20 (40%) were phototype IV;
9 (18%), phototype V, and 21 (42%),
phototype 6, extrafacial lesions were
found in the chest, dorsum, and ears
in 7 patients (14%).12 Our experience
is based on 18 cases observed in hos-
pital and private practice from 1990
to 2016. The ages ranged from 41 to
65 years, 12 were men and 6 were
women, with phototypes II and III. All
patients had been diagnosed with
rosacea before developing extrafa-
cial manifestations. In most cases,
these started abruptly in conjunction
with an exacerbation of the disease.
Flushing was visible on the face and
sometimes extended to the neck and
scalp. The most frequent locations of
papular and papulopustular lesions
were the neck (Figs. 12-16 and 12-17)
and extending over the thorax (Figs. The relationship between flushing,
12-18 a 12-23), thorax (Fig. 12-24), the rosacea exacerbation and extrafacial
retroauricular region, the back of the lesions cannot be established be-
hand (Fig. 12-25) and the scalp (Fig. cause it has not been reported in the
12-26). Three patients had conjuncti- literature. In our cases, just one man
val injection and one, corneal opacity. had severe facial rosacea and prest-
Biopsies were performed on three of ernal lesions, which worsened simul-
them in facial and extrafacial lesions, taneously; further, the man had the
with the same rosacea histopatholog- same symptoms in both areas.
ical characteristics. It should also be
noted that they improved simultane- ETIOPATHOGENESIS
ously with systemic antibiotic treat- The etiopathogenesis of extrafacial
ment, mainly doxycycline. Likewise, in rosacea is difficult to establish. Several Fig. 12-17. Rosacea on face, extended
more recent years, three patients had factors have been suggested, such as along the neck.
significant improvement with subanti-
microbial doses (40 mg).13
EXTRAFACIAL ROSACEA
CLINICAL COURSE
From the limited existing literature
and our experience, it can be stated
that extrafacial forms of rosacea are
more frequent in men, in phototypes
II and III (although some cases have
been observed in patients with higher
phototypes), and a those with a histo-
ry of rosacea.12 Ages of onset is gener-
ally within the fifth and sixth decades
of life. Extrafacial lesions are usually
located in areas of flushing or chronic
sun exposure. Expansion into the out-
er sides of the face, neck, ears, scalp,
and chest has been most frequently
observed. Acne-like lesions on the
chest, armpits, arms, and legs (thighs
and knees) are exceptional and usual-
ly occur in the granulomatous form of Fig. 12-16. Rosacea on face, extended Fig. 12-18. Rosacea on face, extended
rosacea.14-16 along the neck. along the neck and thorax.
148
Fig. 12-19. Rosacea on face, extended Fig. 12-20. Rosacea on face, extend- Fig. 12-21. Rosacea on face, extended Fig. 12-22. Rosacea on face and le-
along the neck and thorax. ed along the neck and thorax. along the neck and thorax. sions on thorax.

A B C

Fig. 12-23. Rosacea on face and le- Fig. 12-24. A and B. Rosacea on face. C. Same patient, single plaque on thorax.
sions on thorax.
149
Fig. 12-25. Rosacea on face and hand..
vascular reactivity disorders, genetic
predisposition, meteorological con-
ditions and immune response against
microorganisms, especially Demodex
folliculorum.17 In the first histological
descriptions of extrafacial lesions,
Marks and Jones showed that are sim-
ilar to facial lesions in terms of cellu-
lar inflammation, though with a more
prominent vascular component.2
If there is a rupture of the hair fol-
licle, peripheral granulomatous infil-
trates are described, and this is found
in about 10% of rosacea biopsies.
Caseation necrosis has been identi-
fied in about 10% of patients.18 Tran-
Fig. 12-26. Rosacea on face, extended along the scalp.
sepidermal elimination of necrobiotic
granulomas was observed in a case of
extrafacial papulonecrotic lesions.11
Two publications refer to rosacea
fulminans with extrafacial lesions.13,19
However, we prefer the original name
of facial pyoderma to that of rosacea
fulminans, suggested by Plewig in
1992, since they are different from the
clinical and evolutionary viewpoints.20
There are a large number of controver-
sies concerning this disease, described
in 1940 by O’Leary and Kierland, which
was also considered a variant of acne
conglobata and its etiology has still not
been well established.21
150
The treatment of extrafacial rosacea
does not differ from that of the classical
forms of rosacea and should take into
account the clinical course and extent
of the disease, as well as the special
characteristics of each patient.
References
1. Kaminsky A, Flórez-White M, Pique-
ro Martín J, et al. GILER. Informe de
Consenso Ibero-Latinoamericano
2016 sobre la clasificación clínica
y terapéutica de la rosácea. Med
Cutan Iber Lat Am 2016; 44(1): 6-10.
(2016 Ibero-Latinamerican Consen-
sus Report on the Clinical and Ther-
apeutic Classification of rosacea.)
2. Marks R, Jones EW. Disseminated ro-
sacea. Br J Dermatol 1969; 81(1):16-28.
3. Röckl H, Schröpl F, Scherer M. Ro-
sacea with extrafacial localization.
Hautarzt 1969; 20(8):348-51.
4. Gajewska M. Rosacea ofcommon
male baldness. Br JDermatol 1975;
93(1):63-6.
5. Dupont C. How common is extrafa-
cial rosacea?J Am Acad Dermatol
1986; 14(5 Pt 1):839.
6. Wilkin JK. Epigastric rosacea. Arch
Dermatol 1980; 116(5):584.
7. Pereira TM, Vieira AP, Basto AS.
Rosacea with extensive extrafacial
lesions. Int J Dermatol 2008; 47: 52-
55.
8. Bostanci O, Borelli C, Schaller M.
Treatment of extrafacial rosacea
with low-dose isotretinoin. Acta
Derm Venereol 2010; 90: 409-410.
9. Miguel-Gómez L, Fonda-Pascual
P, Vano-Galván S, et al. Extrafacial
rosacea with predominant scalp in-
volvement. Indian J Dermatol Vene-
reol Leprol 2015; 81: 511-513.
10. Fortuna MC, Garelli V, Pranteda G,
et al. A case of scalp rosacea treat-
ed with low dose doxycycline and
probiotic therapy and literature re-
view on therapeutic options. Der-
matol Ther 2016; 29(4):249-5.
11. Demitsu T, Tsukahara R, Umemoto
N, et al. Disseminated extrafacial ro-
sacea with papulonecrotic lesions. J
Dermatol Case Rep 2016; 10(4):68-
72.
12. Al Balbeesi AO, Halawani MR.Un-
usual features of rosacea in Saudi
females with dark skin. Ochsner J
2014; 14(3):321-7.
13. Smith LA, Meehan SA, Cohen DE.
Rosacea fulminans with extrafacial
lesions in an elderly man: success-
ful treatment with subantimicrobi-
al-dose doxycycline. J Drugs Der-
matol 2014; 13(6):763-5.
151
14. Ayres S Jr. Extrafacial rosacea is
rare but does exist. J Am Acad Der-
matol 1987;16: 391-392.
15. Helm KF, Menz J, Gibson LE, et al. A
clinical and histopathologic study of
granulomatous rosacea. J Am Acad
Dermatol 1991;25: 1038-1043.
16. Plewig G, Kligman AM. Acne and
Rosácea. 3rd ed. Berlin, Germany.
Springer-Verlag, 2000, 456-503.
17. Crawford GH, Pelle MT, James WD.
Rosacea. I. Etiology, pathogenesis,
and subtype classification. J Am
Acad Dermatol 2004; 51 (3):327-341.
18. Kim WB, Mistry N. Lupus miliaris
disseminatus faciei with isolated
axillary involvement. J Cutan Med
Surg 2016; 20:153-154.
19. Haugstvedt A, Bjerke JR. Acta
Derm Venereol 1998; 78(1):70-1. Ro-
sacea fulminans with extrafacial le-
sions.
20. Plewig G, Jansen T, Kligman AM.
Pyoderma faciale. A review and
report of 20 additional cases: Is
it rosacea? Arch Dermatol 1992;
128(12):1611-7.
21. Coutinho JC, Westphal, DC, Loba-
to LC, et al. Rosacea fulminans: un-
usual clinical presentation of rosá-
cea. An Bras Dermatol 2016; 91(5
Supl 1):S151-3.
Granulomatous rosacea (GR) is con-
sidered the only true variant1 of rosa-
cea recognized and included as such
in the classification of the Iberian-Lat-
in American Group for the Study of
Rosacea (GILER/CILAD), which lists
the classical forms according to the
degree and type of compromise: ery-
thematotelangiectatic rosacea (ETR);
papulopustular rosacea (PPR) phy-
matous rosacea (PR), presence or ab-
sence of plaques, phymas and ocular
rosacea (OR). In addition, the group
considers infantile rosacea (IR) and
extrafacial rosacea as special forms of
the disease.2
GR has well defined clinical and
histopathological features, with the
presence of granulomas justifying re-
garding it a variant. However, on oc-
casion, the similarity of GR with other
facial granulomatous lesions, such
as lupus miliaris disseminatus faciei
(LMDF), micropapular sarcoidosis or
cutaneous tuberculosis, can pose a
real clinical, diagnostic and therapeu-
tic challenge.3
CLINICAL MANIFESTATIONS
GR is more frequent among mid-
dle-aged women. It typically manifests
with yellow, red, brown or skin-colored
firm monomorphic papules or nod-
ules, located around the eyes, nose
and mouth on relatively normal skin. A
symmetrical distribution is usually ob-
served across the upper area of the
Chapter 13
Granulomatous
Rosacea
Ricardo Pérez Alfonzo, Elda Giansante,
Patricia Patiño Guinand
face and particularly around the eyes
and nose (periorificial lesions). These
lesions are found on the sides of the
face and neck below the jaws. Rare-
ly, extrafacial sites may be observed.
In a study of 53 patients with GR, 15%
had extrafacial lesions located on
ears, neck, armpits, shoulders, groin,
thighs, and knees.4 Other signs of ro-
sacea, such as flushing, erythema, or
telangiectases may be found though
they are not necessary to reach diag-
nosis (Figs. 13-1 to 13-6).3-6
GR tends to be a chronic condition,
which is difficult to treat and has an
unpredictable course when standard
rosacea therapies are applied. Based
on case reports, the clinical course is
variable from 6 months to 4 years.7
152
distinct form of rosacea that includes
granulomas in its histopathology.3,8,9
The term facial granulomatous
dermatitis is an aid in consolidating
this controversy present in GR, in
nomenclature and its multiple trig-
gers. The formation of granulomas
is a response to persistent antigens
and, therefore, antigens are sought as
triggers. Among them, the Demodex
folliculorum mite stands out, present
in granulomas in a high percentage of
HISTORY AND AN APPROACH TO
ETIOPATHOGENESIS
Papular lesions on the face, with a his-
topathology involving granulomas has
generated historical confusion and
is still difficult to explain. In 1917, Le-
wandowsky described a patient with
an apparent papular rosacea includ-
ing granulomas that resembled tuber-
culoid granuloma. Laymon reported
similar cases and called them “micro-
papular tuberculid.” However, in 1949
Snapp reported 20 patients with ro-
sacea-type tuberculids where all, but
one patient showed a low degree of
sensitivity to tuberculin. Thus, Snapp
concluded that tuberculoid rosacea Fig. 13-1. Granulomatous rosacea:
does not exist as a nosological enti- yellow reddish firm monomorphic
ty and ruled out association with M. papules and nodules, periocular and
tuberculosis and recognized GR as a cheek location.
Fig. 13-2. 40-year-old female patient with a diagnosis of granulomatous rosa- Fig. 13-3. Granulomatous rosacea in a Fig. 13-4. Granulomatous rosacea:
cea. Clinically, she has multiple yellowish and reddish papules on the frontal darker skinned male patient with mul- erythemathous papules and nodules
region and cheeks. tiple generalized, confluent, hyper- covering all the face.
chromic papules on the face.

Fig. 13-5. Granulo-

matous rosacea in
a 30-year-old wom-
an. Yellowish and Fig. 13-6. Granulo-
erythematous pap- matous rosacea. Er-
ules in the periocu- ythematous papules
lar region. in the frontal region.
153
GR cases; however, its presence is not
enough to completely explain GR, as
there are other important factors, in-
cluding location and density of mites
and host susceptibility.3
Ultraviolet radiation (UVR) and the
subsequent photodamage are also in-
volved in the etiopathogenesis of GR.
Recent studies have suggested that
UVR exposure increases metallopro-
teinases (MMP-2 and MMP-9), which
contribute to tissue remodeling by
recruiting inflammatory cells that lead
to the formation of elastolytic granu-
lomas in the dermis.10,11
It is worth noting the possible as-
sociation between gastrointestinal
disturbances caused by Helicobacter
pylori and GR. A study shows im-
provement of GR after eradicating H.
pylori with antibiotic and antiparasitic
therapy. However, there are no large
trials supporting this association.7
GR is likely to have a multi-facto-
rial origin, not always consistent with
rosacea etiopathogenic factors.7,12-14
Triggers may include systemic and
topical corticosteroids, UVR, heat,
spicy foods, alcohol, and infectious
microorganisms such as mites and
gastrointestinal bacteria, which act
as antigens. The formation of granu-
lomas would be the response to the
persistent presence of these anti-
gens.3
PATHOLOGY Fig. 13-7. Epithelioid
As noted above, Snapp et al. de- granuloma from upper
scribed granulomatous formations dermis to the depth of
in patients with GR in the 1940s.8 the cut, surrounded
In 1970 Mullanax et al. made a by a crown of lympho-
comprehensive clinical and histo- cytes (4X), and epithe-
pathological description of GR, lioid cell granuloma
describing noncaseating granulo- with a giant central
mas with lymphocytes, giant cells Langhans-type cell
and epithelioid cells (Figs. 13-7 and (40X).
13-9).9 Patterns of granulomas in pal-
isades, elastolytic granulomas, and
granulomas surrounding Demodex
folliculorum are also described.
Granulomatous infiltrate may oc-
cur following 4 patterns: nodular,
perifollicular, diffuse and combined
(Figs. 13-7 to 13-9).8,15,16
The nodular pattern consists of a
superficial and deep infiltrate of lym-
phocytes and histiocytes, with plas-
ma cells present in 50% of cases. The
perifollicular pattern shows a pre-
dominance of lymphocytes with neu-
trophils, giant cells and occasional
plasma cells in a perifollicular distri-
bution. The diffuse pattern involves
the reticular dermis and is mostly
composed of lymphocytes and his-
tiocytes with some multinucleated
cells and abscesses with neutrophils.
The combined pattern is very heter-
ogenous and shows peripheral and
nodular lymphocytic infiltrate mixed
with neutrophils and occasional mul-
tinucleated and plasma giant cells Fig. 13-8. Epithelioid granuloma from upper dermis to the depth of the cut,
(Fig. 13-10).8 surrounded by a crown of lymphocytes (10X).
154
Fig. 13-9. Epithelioid granuloma, surrounded by a crown of lymphocytes (40X).
Granulomas are usually tubercu-
loid, and differ from sarcoidosis na-
ked granulomas; they can have up
to 11% central caseous necrosis, in-
flammatory infiltrates and histiocyte
reactions,, which hinder differential
diagnosis with lupus vulgaris (Fig. 13-
11).4,17,18 In other subtypes, such as PPR
the, granulomatous infiltration can be
found in more than 10% of histolog-
ic specimens.4,18 Even in other condi-
tions, e.g. periorificial dermatitis, the
presence of tuberculoid granulomas
are reported.12
As a result of the overlapping of
granulomatous findings in conditions
other than GR, arriving at a clear di-
agnosis is sometimes subtle and diffi-
cult to delimit.
DIFFERENTIAL DIAGNOSES
The term dermatitis or facial gran-
ulomatous disease is very useful be-
cause it groups multiple conditions
with variable etiopathogenesis, but
with similar clinical and histopatho-
logical features. This may gener-
ate confusion as GR being has also
155
Fig. 13-10. Perifollicular infiltration with granulomatous tendency (10X) and in-
trafollicular cell structure, possible mite cut (40X).
been called rosacea-like tuberculid, the different differential diagnoses
granulomatous perioral dermatitis, of the various facial granulomatous
sarcoidal granulomatous dermati- dermatitis.3
tis, facial Afro-Caribbean childhood
eruption (FACE), lupus miliaris dis- Periorificial dermatitis, consid-
seminatus faciei (LMDF) or acne ered a variety of rosacea by some
agminata.19-21 In recent times Skow- authors, is characterized by a papulo-
ron et al. proposed the term FIG- pustular eruption located on the face
URE (Facial Idiopathic Granulomas which usually respects the vermillion
with Regressive Evolution) to group border. The patient has a history of fre-
conditions like LMDF and differen- quent use of fluoride-corticosteroids
tiate them from GR and cutaneous and sometimes even non-fluoride cor-
tuberculosis.22 Table 13-1 summarizes ticosteroids in the perioral area. Oth-
 Table 13-1. Differential Diagnosis of Facial Granulomatous Dermatitis*

Disorder Epidemiology Clinical manifestations Histopathology

Granulomatous Phototypes I-III Periorificial and extrafacial Epithelioid granuloma in

Rosacea 30-40 years papules general noncaseating with
Mainly middle- mixed inflammatory infiltrate
aged women

Periorificial Children or young Periorificial erythema with Perifollicular and perivascular

dermatitis women papules and pustules granulomatous infiltration

LMDF Adolescents Symetrical papules in the Perifollicular caseating granu-

or adults center of the face lomas with lymphohistiocytic
infiltrate and neutrophils

Sarcoidosis All ages Non inflammatory papules Naked noncaseating

and nodules on the face granulomas
Systemic symptoms

FACE Children Periorificial papules Perifollicular granulomatous

Fig. 13-11. Tuberculoid granuloma with central caseous necrosis (4X).
er causative agents involved are the
use of facial sunscreens in children,
23 physical factors (LUV, cold, heat),
microorganisms (fusobacteria, Can-
dida species, Demodex folliculorum),
fluoride toothpastes, inhalers with
steroids, and in adults (predominantly
women) the main cause are cosmet-
ics, use of oral contraceptives, chew-
ing gum, amalgams and stress.3 The
clinical and histological features are
similar to those of GR, but in typical
cases the histology includes granulo-
mas, with perifollicular inflammation,
focal rupture of the follicular wall,
and additional granulomas formed
in response to the expelled content.
This dermatitis has a rapid therapeu-
tic response, and in many cases, it re-
solves just by avoiding precipitating
factors; generally, it has a shorter clin-
ical course than the GR. Occasional-
ly, among children, papules, pustules
and periorificial erythematous lesions
may be found associated with a gran-
ulomatous histopathology, which is a
variety known as childhood granulo-
matous periorificial dermatitis.3,20-24
156
phototypes V-VI
Cutaneous All ages
tuberculosis
*Modified by Lee GL et al. Dermatol Clin 2015; 33.3
Lupus miliaris disseminatus faciei
(LMDF) or acne agminata is a rare
chronic, benign skin condition charac-
terized by symmetrically distributed
papules on the face, predominant-
ly found in the central area. Its main
histological findings are granulomas
with central caseous necrosis. This
disorder can be self-limited within 1 to
infiltration
Erythematous and scabious Caseating granuloma
papules Symmetrical
Systemic symptoms
2 years, although it causes permanent
scars.25-29
Sarcoidosis may manifest as gran-
ulomatous papules on the face in the
periorificial area that are skin-colored
or that may evolve into brownish
plaques. By means of the vitropres-
sure technique, the lesions show a
shade known as “apple jelly”, which
is translucent and yellowish. The pa-
tient may have extracutaneous symp-
toms, such as fatigue, weight loss and
dyspnea. Histological analysis shows
well differentiated epithelioid cells,
with few giant cells and lymphocytes
(called naked tubercles). Schaumann
and asteroid bodies can be seen in the
giant cells. These also may be present
in other granulomatous conditions, in-
cluding leprosy, tuberculosis, reactions
to foreign bodies and necrobiotic xan-
thogranuloma; occasionally fibrinoid
necrosis can be observed. Intracuta-
neous antigen testing is negative, indi-
cating a skin anergy. Elevated levels of
serum angiotensin-converting enzyme
(ACE) with hypergammaglobulinemia
and hypercalcemia may also be ob-
served. The hilar lymphadenopathies
are found in 90% of patients with sys-
temic sarcoidosis. Likewise, pulmonary
infiltrates and bone cystic lesions may
be found in the finger phalanxes of the
hands.30-32
Facial Afro-Caribbean Child-
hood Eruption (FACE) is similar to
periorificial dermatitis, but it is more
frequent among dark-skinned individ-
uals. Some researchers believe FACE
is also a GR variant.25,33
Rosace-like tuberculid
Tuberculids were described by Dari-
er in 1896. Three varieties of true
tuberculids are classically recog-
nized, namely micropapular (lichen
escrofulosorum), nodular (erythema
induratum of Bazin) and papular (pap-
ulonecrotic tuberculids). However,
many authors believe that the term
tuberculids should include many oth-
er disorders that were classified as
variants of tuberculids (Lewandows-
ky rosaceaform tuberculid, LMDF, or
acne agminata) and which are now
included in the broad group of facial
granulomatous dermatitis.26,29
We should always rule out tuber-
culosis (TB) when faced with a patient
with facial granulomatous dermatitis.
Request a tuberculin test (PPD), in-
terferon-gamma release assay (IGRA),
and screen for simultaneous (or previ-
ous) TB infection. On histopathologi-
cal examination, true tuberculids show
tuberculoid granulomas; PCR for M.
tuberculosis is erratic or false positive.
It is important to note that tuberculids
in general respond well to treatment
with tuberculostatic agents.34-38
There are other infectious and in-
flammatory diseases that may present
with clinical characteristics similar to
GR (which is why the histopathological
study is essential in differential diagno-
sis), e.g. Hansen’s disease, mycobacte-
riosis or infections by non-tuberculous
mycobacteria, leishmaniasis, syphilis,
granulomatous reactions to foreign
bodies, cutaneous lymphomas, leu-
kemoid reactions, among others.3,8,39
157
DIAGNOSTIC AND THERAPEUTIC
APPROACH
In patients with facial granulomatous
diseases, the various differential diag-
noses already pointed out should be
considered (Table 13-1). Diagnosis of
these conditions can be challenging.
The medical evaluation should include
a complete clinical history, physical
examination, and a skin biopsy. If tu-
berculosis or sarcoidosis is suspect-
ed, a chest X-ray and laboratory tests
including hematological and blood
chemistry should be performed, with
special attention to calcium and phos-
phorus levels, as well as the autoim-
mune panel, PPD, and IGRA.
Currently, there is no standard
treatment for GR, and therapeutic
effectiveness data are limited to iso-
lated case reports. Due to their an-
ti-inflammatory effect and probable
inhibitory action in the formation of
granulomas, tetracyclines are the pre-
ferred therapeutic choice as in other
forms of rosacea. Good results have
been reported with the use of tetra-
cycline (250 to 500 mg 3 times dai-
ly), doxycycline (50 to 100 mg twice
a day) or minocycline (50 to 100 mg
twice a day).3,9 However, in cases of
pregnancy or allergy to tetracycline
derivatives, eventual use of oral eryth-
romycin may be considered.
For refractory GR cases, benefits
have been reported with the use of
isotretinoin (a dose of 0.5 to 0.7 mg/
kg for 6 months).40 Oral dapsone has
been shown to be effective in some
cases of rosacea, including in the gran-
ulomatous variety.41 The use of pulsed
dye laser at 4-week intervals was ben-
eficial in some cases of ETR associated
with GR.1 Similarly, intense pulsed light
showed efficacy in refractory cases.42
The usefulness of photodynamic ther-
apy (ALA-PDT) in refractory cases was
also reported.43 Combined treatment
with oral metronidazole and oral iver-
mectin was shown to be the most ef-
fective treatment for the eradication of
D. folliculorum involved in the granulo-
matous reaction to mites.8,9,13
Topical therapeutic agents include
azelaic acid, benzoyl peroxide, and
topical metronidazole. In some spe-
cific cases, if a rapid anti-inflammatory
effect is necessary, the use of topical
or even oral corticosteroids for a short
time could be useful, always bearing
in mind that prolonged use will per-
petuate rosacea and granuloma for-
mation. Other topical agents whose
efficacy was demonstrated in case
studies are pimecrolimus, tacrolimus,
dapsone gel, and topical ivermec-
tin.44-47 The use of topical pimecroli-
mus associated with oral thalidomide
for 6 months was successful in a case
with therapeutic difficulties. It started
with thalidomide at a daily dose of 150
mg/day for 4 weeks, and then in de-
creasing doses every thirty days.48
 In summary, rosacea is not a single
nosological entity, rather it should be
considered a reaction pattern or a
syndrome in which multiple factors,
such as UVRs and various microor-
ganisms, interact in a genetically sus-
ceptible host, causing diverse clinical
manifestations in a spectrum-like
manner: from erythema, telangiec-
tases, papules, and pustules to the
formation of granulomas. GR is a
variant of rosacea which may or may
not be preceded or accompanied
by other signs of rosacea and when
the formation of granulomas is clin-
ically suspected, histopathological
study is mandatory. The term facial
granulomatous dermatitis includes
patients with granulomatous-appear-
ing lesions on the face with different
etiopathogenesis. This term helps to
address in a better way the historical
confusion existing among these dif-
ferent facial granulomatoses. The di-
agnosis, management and treatment
of GR represents a major challenge
for the clinician.
References
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12. Aroni K, Tsagroni E, Lazaris AC,
et al. Rosacea: a clinicopathologi-
cal approach. Dermatology 2004;
9:177-82.
13. Amichai B, Grunwald MH, Avi-
noach I, et al. Granulomatous ro-
sacea associated with Demodex
folliculorum. Int J Dermatol. 1992;
31:718-9.
14. Erbagei Z, Ozgoztasi O. The signifi-
cance of Demodex folliculorum den-
sity in rosacea. Int J Dermatol 1998;
37:421-5.
15. Ramelet AA, Perroulaz G. Rosa-
cea: étude histopatologique de 75
cas. Ann Dermatol Venerol 1988;
115:801-6.
16. Marks R, Harcourt-Webster JN. His-
topathology of rosacea. Arch Der-
matol 1969; 100:683-91.
17. Ferrara G, Cannone M, Scalvenzi
M, et al. Facial granulomatous dis-
eases: a study of four cases tested
for the presence of Mycobacteri-
um tuberculosis DNA using nest-
ed polymerase chain reaction. Am
J Dermatopathol 2001; 23:8-15.
18. Helm KF, Menz J, Gibson LE, et al. A
clinical and histopathologic study of
granulomatous rosacea. J Am Acad
Dermatol 1991; 25:1038-43.
19. Troiano G, Dioguardi M, Gianna-
tempo G, et al. Orofacial granulo-
matosis: clinical signs of different
pathologies. Med Princ Pract 2015;
24:117-22.
20. Miest R, Bruce A, Rogers R. Orofa-
cial granulomatosis. Clin Dermatol.
2016; 34:505-13
21. Marchell R, Thiers B, Judson M.
Sarcoidosis. In: Wolff K, Goldsmith
L, Katz S, et al (eds). Fitzpatrick.
Dermatología en Medicina gen-
eral. 7.a ed. Panamericana, 2010;
1484-92.
22. Skowron F, Causeret AS, Pabion C,
et al. F.I.G.U.R.E.: facial idiopathic
granulomas with regressive evolu-
tion is “lupus miliaris disseminatuse
faciei” still an acceptable diagnosis
in the third millennium? Dermatolo-
gy 2000; 201:287-9.
23. Urbina F, Herane MI. Dermatitis peri-
oral en la infancia. Arch Argent Der-
matol 2002; 52:191-94.
24. Moncourier M, Pralong P, Pinel N,et
al. Granulomatous periocular erup-
tion. Ann Dermatol Venereol. 2017;
144:430-3.
25. Lucas CR, Korman NJ, Gilliam AC.
Granulomatous periorificial dermati-
tis: a variant of granulomatous rosa-
cea in children? J Cutan Med Surg.
2009; 13:115-8.
26. Khokhar O, Khachemoune A. A case
of granulomatous rosacea: sorting
granulomatous rosacea from other
granulomatous diseases that affect
the face. Dermatol Online J 2004;
10:6.
27. Butsch F. Facial manifestations of
granulomatous diseases. Hautarzt
2017; 68:542-7.
28. Van der Scheur MR, Van der Waal RI,
Starink TM. Lupus miliaris dissemina-
tus faciei: a distinctive rosacea like
syndrome and not a granulomatous
form of rosacea. Dermatology 2003;
206:120-3.
29. Mullan E, Green P, Pasternak S. Lu-
pus miliaris disseminatus faciei with
extrafacial involvement in a 17-year-
old white girl. J Cutan Med Surg
2011; 15:340-3.
30. Sardana K, Chugh S, Ranjan R, et al.
Lupus miliaris disseminatus faciei: A
resistant case with response to cyc-
losporine. Dermatol Ther 2017; 30(4).
31. Pérez Alfonzo R, Giansante E. Sín-
dromes Simuladores de Rosácea:
Fronteras diagnósticas. In: Herane
M, Piquero J. Rosácea y afecciones
relacionadas. 1.a ed. Editorial Creser
Publicidad 2013 C.A., 2007; 241-46.
32. Osborne G, Mallon E, Mayou SC.
Juvenile sarcoidosis after BCG vac-
cination. J Am Acad Dermatol 2003;
48:S99-102.
33. William HC, Ashworth J, Pembroke
AC, et al. FACE facial afro-caribbean
childhood eruption. Clin Exp Derma-
tol 1990; 15:163-6.
34. Wilson-Jones E, Winkelmann RW.
Papulonecrotic tuberculide: a ne-
glected disease in western countries.
J Am Acad Dermatol 1986; 14:815-6.
35. Bae SH, Yun SJ, Lee JB, et al. Pap-
ulonecrotic Tuberculid: A Rare Skin
159
Manifestation in a Child with Mes-
enteric Tuberculous Lymphade-
nopathy. Acta Derm Venereol. 2017;
97:137-8.
36. Hallensleben MD, de Vries HJ, Let-
tinga KD, et al. Tuberculids: cuta-
neous indicator diseases of Myco-
bacterium tuberculosis infection in
young patients. J Eur Acad Dermatol
Venereol 2016; 30:1590-3.
37. Tirumalae R, Yeliur IK, Antony M, et
al. Papulonecrotic tuberculid clinico-
pathologic and molecular features
of 12 Indian patients. Dermatol Pract
Concept 2014; 4:17-22.
38. Moon SH, Shin MK, Lee MH. Case
of simultaneous occurrence of pap-
ulonecrotic tuberculid and erythema
induratum. J Dermatol 2013; 40:138-9.
39. Yates VM, Rook GAW. Mycobacte-
rial infections. Rook´s textbook of
dermatology. 7.th ed. London: Black-
well Science Ltd 2004; 28:20-2.
40. Rallis E, Korfitis Ch. Isotretinoin for
the treatment of granulomatous ro-
sacea: Case report and review of the
literature. J Cutan Med Surg 2012;
16(6):438-41.
41. Ehmann LM, Meller S, Homey B.
Succesful treatment of granuloma-
tous rosacea with dapsone. Hautarzt
2013; 64:226-8.
42. Lane JE, Khachemoune A. Use of
pulsed light to treat refractory gran-
ulomatous rosacea. Dermatol Surg
2010; 36(4):571-3.
43. Baglieri F, Scuderi G. Treatment of
recalcitrant granulomatous rosacea
with ALA-PDT: report of a case. Indi-
an J Dermatol Venereol Leprol 2011;
77(4):536.
44. Cunha PR, Rossi AB. Pimecrolimus
cream 1% is effective in a case of
granulomatous rosacea. Acta Derm
Venereol 2006; 86:71-2
45. Mitoma Ch, Takahara M, Furue M.
Severe granulomatous rosacea in a
boy succesfully treated with topical
azelaic acid. Indian J Dermatol 2015;
6(3):323.
46. Keri J. What´s new in acne and ro-
sacea? Semin Cutan Med Surg 2016;
35:103-6.
47. Schaller M, Schofer H, Homey B, et
al. Rosacea Management: Update on
general measures and topical treat-
ment options. J Dtsch Dermatol Ges
2016; 14:17-27.
48. Ali ST, Alinia H, Feldman SR. The
treatment of rosacea with topical
ivermectin. Drugs Today Barc 2015;
4:243-50.
Rosacea –one of the most frequent
grounds for medical consultations
in dermatology– is often charac-
terized by a persistent midface er-
ythema, visible blood vessels and
papules and pustules. Its diagnosis
requires one or more of the fol-
lowing findings, on the skin of the
convex areas of the face: flushing
(transitory erythema), persistent er-
ythema, papules, pustules and tel-
angiectases.1 Comedones are not
usually observed. One of its most
significant signs is the erythema on
the central part of the face, which
persists at least for three months
and does not include the periocu-
lar region. A classification may be
attempted, based on anatomo-clini-
cal criteria and in line with its clinical
characteristics. In this manner, four
main subtypes may be determined:
erythematotelangiectatic, papulopus-
tular, glandular or hyperplasic/phy-
matous and ocular.2
The histologic findings associated
with these subtypes is discussed be-
low.
ERYTHEMATOTELANGIECTATIC
ROSACEA (ETR)
An important and typical histolog-
ic alteration in ETR consists of the
existence of capillaries and dilated
venules, located on the superficial
dermis (Fig. 14-1). Capillaries often
have angled, irregular edges with
Chapter 14
Most common
histopathological
findings in
rosacea
José G. Casas
few visible endothelial cells. In many
cases, the presence of Demodex in
the follicular infundibula is consid-
ered an indicator of rosacea. There
is often a mild inflammatory cellu-
lar infiltrate with predominance of
leukocytes, a moderate edema on
the superficial dermis and scarce
plasmocytes. The pattern is usually
perivascular and interstitial. In cas-
es suggesting a differential diagno-
sis with lupus erythematosus, it is
important to exclude the edema-
tous alteration of the basal layer, as
well as the thickening of the subep-
idermal basal membrane; two fea-
160
tures that cannot be observed in
rosacea. 3
PAPULOPUSTULAR ROSACEA
(PPR)
Midface erythema is characteristic
of PPR and is accompanied by pap-
ules, pustules or by both. There are
no comedones, but there might be
telangiectases. A mixed inflammato-
ry cellular infiltrate can be observed
in the histology, along with numer-
ous plasmocytes, neutrophils and
occasionally, with eosinophils. These
alterations are more evident in other
rosacea subtypes and they are local-
ized both in the superficial and deep
strata. There is follicular and extrafol-
licular involvement. Neutrophilic clus-
ters surround the hair infundibulum,
very often correlating with the pres-
ence of Demodex.3 Solar elastosis is
also characteristic of this form and its
presence suggests the pathophysi-
ological role of ultraviolet exposure
and its association with skin damage
by way of free radicals.
GLANDULAR HIPERPLASTIC/
PHYMATOUS ROSACEA
This subtype is characterized by its hy-
pertrophic clinical aspect. It prevails
in men and its most frequent form is
the rhinophyma. Its most common his-
tologic features are: an enlargement
of the sebaceous glands, dilation of
the infundibulum and dermo-epider-
mal thickening with fibrosis. (Figs. 14-2
and 14-3).
OCULAR ROSACEA
The diagnostic of ocular rosacea is
mainly clinical. Biopsy is rarely per-
formed in routine clinical practice.
Yet biopsy may help where symp-
toms are atypical or when the dif-
ferential diagnosis with sarcoidosis,
lupus miliaris or lupus erythemato-
sus remains unclear. Inflammatory
infiltrate and vascular changes can
both be easily observed, charac-
terized and quantified under micro-
scope, using routine staining and
immunohistochemistry.3
Fig. 14-1. Rosacea. Dilatated venules. Leukocyte infiltration. Incipient solar elas- Fig. 14-2. Rhinophyma. Sebaceous hyperplasia. Dilated hair infundibula
tosis.

GRANULOMATOUS ROSACEA
Granulomas are frequently observed
in rosacea and they are not only re-
stricted to the midface area. They
appear like firm, symmetrically dis-
tributed lesions, from brownish red to
yellowish, in color. Under microscopic intermingled with lymphocytes. In se- [EDITOR´S NOTE: For further de-
examination, big granulomas can be rial sectioning, debris or fragments of tails on the classical forms, see Chap-
observed on the superficial reticular Demodex may appear, suggesting a ter 11 and for granulomatous rosacea,
dermis. They present a central cav- possible pathogenic role (Fig. 14-4). Chapter 13].
itation, surrounded by neutrophils
and numerous peripheral histiocytes,
161
Fig. 14-3. Rhinophyma. Area of superficial dermic fibrosis.
References
1. Crawford GH, Pelle MT, James WD.
Rosacea: I. Etiology, pathogenesis,
and subtype classification. J Am
Acad Dermatol 2004; 51:327-41.
2. Kaminsky A, Flórez-White M, Pique-
ro Martín J, et al. GILER. Informe
Fig. 14-4. Demodex in a hair infundibulum, with adjoining leukocyte infiltration.
de Consenso Ibero-Latinoamericano 3. Cribier B. Rosacea under the mi-
2016 sobre la clasificación clínica y croscope: characteristic histological
terapéutica de la rosácea (2016-Ibe- findings. J Eur Acad Dermatol Vene-
rian-Latin-american Consensus Re- reol 2013; 27:1336-43.
port on the Clinical and Therapeu-
tic Classification of rosácea). Med
Cutan Iber Lat Am 2016; 44(1): 6-10.
162
 „„ Chapter 15. Differential Diagnoses

Section 5 „„ Chapter 16. Demodicidosis

„„ Chapter 17. Perioral or Periorificial

Dermatitis

Differential Diagnosis „„ Chapter 18. Seborrheic

Dermatitis

„„ Chapter 19. Adult Acne

and Rosacea: A Diagnostic
Challenge

„„ Chapter 20. Morbihan

Disease
Rosacea and rosacea-like disorders
are one of the most frequent reasons
why dermatologists receive daily con-
sultations.1 Occasionally, it may be nec-
essary to carry out histopathological
studies of the lesions or certain labo-
ratory studies to correctly make the
diagnosis. However, in most cases, the
differential diagnosis between rosa-
cea and its “mimickers” will depend on
the combination of exploratory find-
ings and data from a complete clinical
history. Identifying the typical local
symptoms of rosacea, recognizing its
different forms of presentation and
acquiring a good understanding of the
course of the disease are three key
cornerstones in guiding the diagnosis.
The differential diagnosis of rosa-
cea-like disorders can be organized into
three large groups, depending on the
predominant clinical manifestation and
coexistence of extracutaneous symp-
toms (Table 15-1).2 In patients whose
leading sign is facial erythema (either
permanent [couperose] or transient
[in the form of flushing episodes]), the
differential diagnosis should include
the conditions described in Chapter
3. In these cases, if the clinical course
includes a rapid onset of systemic
symptoms (such as tachycardia, hyper-
tensive crisis, sweating, heat stroke or
diarrhea), other less frequent diseases
such as pheochromocytoma, mastocy-
tosis or carcinoid syndrome should be
ruled out.1,2
Chapter 15
Differential
Diagnoses
Lidia Maroñas-Jiménez, Elena González-Guerra,
Aurora Guerra-Tapia
CLASSICAL MIMICKERS
The following are the dermatoses
that most commonly pose difficulties
in the differential diagnosis of the pa-
tient with rosacea.
Systemic lupus erythematosus
(SLE). SLE is a chronic inflammatory
disease that typically leads to recur-
rent episodes of photosensitive ery-
thematous lesions at the malar level.
Approximately 50% of SLE patients
develop butterfly-wing erythema,
which may precede or occur together
with other clinical manifestations. This
form of lupus can be easily confused
with the ETR especially if there is no
additional systemic symptomatology.3
However, lupus skin lesions tend to be
better delimited on the outer borders
of the cheeks and display a purplish
tonality (Fig. 15-1).
164
Dermatomyoscitis (DM). This is an
inflammatory myopathy characterized
by varying degrees of proximal muscle
weakness associated with skin lesions.
The heliotrope rash –reddish purple
rash on or around the eyelids Got-
tron’s papules– discrete red papules
overlying the knuckles and elbows –
or the shawl sign– a widespread, flat,
reddened area that appears on the
upper back, shoulders, and back of the
neck–, are the most typical and easily
recognizable lesions of DM. Erythema
macularis violaceae (EMV) is classically
described in extended limbs or the up-
per third of the back. There are reports
of EMV with seborrheic distribution at
facial level (Fig. 15-2) indistinguishable
from rosacea.4
Seborrheic dermatitis (SD). This
is a very common chronic erythema-
Table 15-1. Rosacea Differential
Diagnosis
Predominance of Erythematotelangiectatic
Lesions (without Inflammatory Lesions)
Systemic lupus erythematosus.
Dermatomyositis.
Urticaria/angioedema.
Cases of photosensitivity.
Seborrheic dermatitis.
Allergic contact dermatitis.
With extracutaneous clinical manfestations:
pheochromocytoma, carcinoid syndrome,
polycythemiavera, mastocytosis.
Inflammatory Lesions Predominance (papule,
pustule and cystic-nodule type)
Acne: vulgaris, late in adult woman, cosmetic,
chloracne. Micropapular sarcoidosis
Acne-like eruptions induced by anti-EGFR
drugs, RAS/RAF/MEK/ERK inhibitors
and TK inhibitors.
Gram-Negative Folliculitis.
Perioral (periorificial) dermatitis.
Demodicidosis: pityriasis folliculorum, similar to
rosacea, to granulomatous rosacea and to
perioral dermatitis.
Lupus miliaris disseminatus faciei.
Rosacea-likedermatitis from calcineurin inhibitors.
Micropapular sarcoidosis.
Fibrous papules of the nose (face).
Sebaceous hyperplasias.
Lymphomas
Phymatous Lesions
Lupus pernio
Basal cell epitheliomas.
Basal cell carcinoma.
Angiosarcoma
Leonine facies (leprosy)
Fig. 15-1. Systemic lupus erythematosus.
tous scaly dermatitis, which produces
recurrent lesions in seborrheic areas
of the face, scalp and trunk. When
this condition is sever and persistent
could be associated with infection by
the human immunodeficiency virus.
DS is described as a frequent con-
dition in patients with neurological
disorders such as Parkinson’s dis-
ease. At the facial level it appears in
the form of macular erythema, with
grayish-white scaling on the surface,
affecting the nasolabial folds and fur-
rows (Fig. 15-3) as well as the centro-
facial region (interciliary [glabellar],
supraciliary and perinasal areas). DS
often affects extrafacial areas, such
as the scalp involving the hair im-
plantation line or more commonly
manifesting as a diffuse, fine desqua-
mation (dandruff). The retroauricular
area and the external ear could be
also involved. It is not unusually as-
sociated with psoriasis, producing
mixed forms known as sebopsoriasis,
a seborrheic-like psoriasis. Perinasal
erythema may be present in both SD
and rosacea.5 However, the tendency
of lesions to respect facial concave
areas, such as cheeks, chin or fore-
165
Fig. 15-2. Dermatomyositis.
head; the existence of extrafacial
involvement; and fine scaling should
lead to a SD diagnosis.6
Acne. To a greater or lesser extent,
acne vulgaris affects about 90% of
adolescents. It produces polymorphic
lesions that combine open and closed
comedones, papules, pustules and
nodular-cystic lesions in seborrheic
areas, such as the chest, upper third
of the back and face (Fig. 15-4).7 This
is the main differential diagnosis in
patients with papulopustular rosacea,
especially late forms in adult women,
chloracne, cortisol acne, and cosmetic
acne. As a general rule, rosacea lacks
comedones, it predominantly occurs
in the center-facial region, and it usu-
ally appears later in life than acne vul-
garis.8
Rosacea-like Demodicidosis. De-
modex folliculorum is a saprophytic
mite located in the pilosebaceous
unit and it is found in virtually all
of adult humans at a density of  5
mites per square centimeter of skin.9
An increase in the density of mites
in the skin, frequently associated

Fig. 15-3. Seborrheic dermatitis.
with factors such as the use of cor-
ticosteroids, HIV infection or various
disorders of the immune system, fa-
vors the transformation of the mite
into its pathogenic form, which leads
to the appearance of facial erup-
tions.10,11 It usually produces chronic
and recurrent conditions, especially
166
Fig. 15-4. Acne vulgaris.
among young women, with skin le-
sions such as pityriasis folliculorum
which is similar to rosacea (Fig. 15-5),
granulomatous rosacea and perioral
dermatitis. Pityriasis folliculorum
manifests as facial erythema, follicu-
lar plugs and a rough scaling which
gives the skin the appearance of
“sandpaper”. These are fine, whitish
scales located on the face, eyelids,
pinnas, and scalp. Rosacea-like de-
modicidosis is characterized by the
appearance of pruritic inflammatory
lesions, in the form of follicular pap-
ules, over an area of erythema and
scaling. It differs from classical rosa-
cea by its more sudden onset, rapid
progression and absence of flushing
episodes in response to vasoactive
stimuli. There may be ocular compro-
mise in the form of keratoconjuncti-
vitis or blepharitis. The histological
study of demodicidosis usually shows
a dense dermal, perivascular and
peripheral infiltrate, composed of
lymphocytes and mononuclear cells,
which are sometimes form granulo-
matous structures.12 A very high den-
sity of Demodex is usually found in
skin biopsy. Effective treatments for
Demodex mites include 5% perme-
thrin lotions, metronidazole 0.75%

Fig. 15-5. Demodicidosis similar to rosacea.
gel, ivermectin 1% cream, oral iver-
mectin 200 mg/kg weight.
Perioral (Periorificial) Derma-
titis (POD). This dermatitis can
be observed in both children and
adults.13 Among adults, female gen-
der predominates, primarily young
women of childbearing age. The
etiology of this entity remains un-
known. However, atopic diathesis,
as well as topical or inhaled use
of corticosteroids, are considered
predisposing factors.14 It appears in
the form of erythematous papules
and millimetric vesicles, with fine
superficial scaling arranged around
the oral area and, as a characteristic
feature, a lack of involvement of the
area immediately adjacent to the
167
lips. Particularly in children, there
may be some kind of extension over
the perinasal and periocular areas
(Fig. 15-6).15 At the histological level,
a preserved epidermis is frequent-
ly found together with a discrete
perivascular inflammatory infiltrate,
composed mainly of lymphocytes
and histiocytes. Oral tetracyclines
are the treatment of choice in most
cases, except in children under 8
years of age, in whom they are con-
traindicated due to the risk of dental
pigmentation and bone develop-
ment disorders. Topical corticoste-
Fig. 15-6. Periorificial dermatitis.
roids should be avoided, as they
are involved in the pathogenesis of
POD. Azelaic acid or metronidazole
are traditional topical treatments.
Good clinical response has been
reported following off-label use of
the topical calcineurin inhibitors (pi-
mecrolimus, tacrolimus). In patients
with POD and sensitive skin, several
authors recommend avoiding topi-
cal drugs during the first weeks of
treatment.
Gram-Negative Bacteria Follicu-
litis. This type of folliculitis often ap-
pears as a complication of prolonged
oral antibiotic treatments in patients
with acne. Typically, it appears as a
sudden resurgence of acne, with pap-
ulopustular lesions in which Klebsiella
spp or Proteus spp are isolated.13 The
management of this condition may
require several cycles of oral antibi-
otics, such as ampicillin and even oral
isotretinoin.
LESS FREQUENT MIMICKERS
Lupus Miliaris Disseminatus Faciei
(LMDF). This is a very rare chronic
inflammatory skin disorder, marked
by the appearance at the facial lev-
el of small asymptomatic erythem-
atous-brown or yellowish papules
(Fig. 15-7).16 It is usually located in the
central region of the face and is usu-
ally responsive to treatments used
on individuals with acne vulgaris and
rosacea, with which it shares several
characteristics.17 Lupus miliaris main-
ly affects men, is self-resolving over
a period of months or years, and as
a typical trait leaves residual scars
that can have very negative effects
in terms of aesthetic appearance.18,19
Several authors consider it a varia-
tion of granulomatous rosacea, while
others consider it an independent
entity. In any case, its pathogenesis is
unknown.20,21 Its histological identity
is defined by intense granulomatous
inflammation, with important central
caseation in absence of any detect-
able infection.
Fig. 15-7. Lupus miliaris disseminatus faciei.
Rosacea-like Appearance of Cuta-
neous Lymphomas. Skin involvement
due to B-cell lymphoproliferative disor-
ders may be primary (cutaneous origin)
or secondary (systemic origin). In both
cases, it appears as asymptomatic, mul-
tiple or solitary erythemato-violaceous
papules or nodules, asymmetrically
distributed. Although rosacea-like pre-
sentations are extremely uncommon,
there are publications reporting lym-
168
phomas and leukemias mimicking the
rosacea phymatous and granuloma-
tous variants.22-25
Acne-Like Eruptions are induced by
epidermal growth factor receptor in-
hibitors (anti-EGFR), RAS/RAF/MEK/
ERK signaling pathway inhibitors and
tyrosine kinase inhibitors. The use of
these drugs has been linked to the
occurrence of various dermatological
problems, such as dry skin, hypersen-
sitivity reactions, mucositis, parony-
chia, nail weakness, hair changes and
skin rashes.26 Acne-like reactions are
the most common adverse effect of all
(Fig. 15-8). They are made up of rath-
er monomorphic, sterile papules and
pustules, mostly distributed in the up-
per part of the body. These reactions
almost always affect the scalp, face
and upper third of the back.27 They are
sometimes accompanied by diffuse
erythema and facial telangiectases,
mimicking the papulopustular variant
of rosacea. On other occasions, they
display a fine, greyish-white scaling,
which requires a differential diagnosis
with seborrheic dermatitis. The erup-
tion typically resolves within a month
after cessation of treatment.28
Rosacea-like Dermatitis Induced
by Tacrolimus. Topical tacrolimus
and pimecrolimus are used off label
in certain inflammatory facial der-
matoses, such as perioral dermatitis
and seborrheic dermatitis, typical-
ly with good results.13 However, in
recent years, several publications
have described the development of
facial eruptions, such as rosacea-like
dermatitis, associated with the pro-
longed use of topical calcineurin
inhibitors (Fig. 15-9).29 While clinical
presentation may be non-distinguish-
able from rosacea-like demodicidosis,
periorificial dermatitis, and papu-
lopustular rosacea, the eruptions

Fig. 15-8. Acne-like eruption induced by cetuximab.
produced by the topical use of tac-
rolimus have fewer inflammatory
pustular lesions and a less involve-
ment of the naso-facial region.30 Fa-
cial flushing reactions associated
with the use of these drugs and al-
cohol consumption have also been
described.
169
References
1. Barco D, Alomar A. Rosácea. Ac-
tas Dermosifiliogr 2008; 99:244-
56.
2. González-Guerra E. Rosácea. Más
Dermatología 2007; 2:6-13.
3. Marzano AV, Lazzari R, Polloni I,
et al. Rosacea-like cutaneous lu-
pus erythematosus: an atypical
presentation responding to an-
timalarials. Acta Derm Venereol
2013; 93:106-107.
Fig. 15-9. Rosacea-like dermatitis induced by tacrolimus.
4. Okiyama N, Kohsaka H, Ueda N,
et al. Seborrheic area erythema
as a common skin manifestation
in Japanese patients with derma-
tomyositis. Dermatology 2008;
217(4):374-7.
5. Oge’ LK, Muncie HL, Phillips-Sa-
voy AR. Rosacea: Diagnosis and
treatment. Am Fam Physician.
2015; 92(3):187-96.
6. Napierkowski DB. Rosacea: Di-
agnosis and management. Nurse
Pract 2016; 41(4):8-13.
7. Titus S, Hodge J. Diagnosis and
treatment of acne. Am Fam Phy-
sician 2012; 86:734-740.
8. Baldwin HE. Is it acne or is it ro-
sacea? An important distinction.
Cutis 2012; 90(2):59-61.
9. Lacey N, Russell-Hallinan A, Pow-
ell FC. Study of Demodex mites:
Challenges and solutions. J Eur
Acad Dermatol Venereol 2016;
30(5):764-75.
10. Brutti CS, Artus G, Luzzatto L,
et al. Crusted rosacealike de-
modicidosis in an HIV-positive fe-
male. J Am Acad Dermatol 2011;
65:e131-e132.
11. Chovatiya RJ, Colegio OR. De-
modicosis in Renal Transplant
Recipients. Am J Transplant 2016;
16(2):712-6.
12. Hsu CK, Hsu MM, Lee JY. De-
modicosis: a clinicopathological
study. J Am Acad Dermatol 2009;
60(3):453-62.
13. Dessinioti C, Antoniou C, Katsam-
bas A. Acneiform eruptions. Clin
Dermatol 2014; 32(1):24-34.
14. Poulos GA, Brodell RT. Perioral
dermatitis associated with an in-
haled corticosteroid. Arch Der-
matol 2007; 143:1460.
15. Lipozenčić J, Hadžavdić SL. Peri-
oral dermatitis. Clin Dermatol
2014; 32(1):125-30.
16. Cymerman R, Rosenstein R,
Shvartsbeyn M, et al. Lupus milia-
ris disseminatus faciei. Dermatol
Online J 2015; 21(12).
17. Rocas D, Kanitakis J. Lupus miliaris
disseminatus faciei: report of a new
case and brief literature review.
Dermatol Online J 2013; 19(3):4.
18. Kang BK, Shin MK. Scarring of lupus
miliaris disseminatus faciei: treat-
ment with a combination of trichlo-
roacetic acid and carbon dioxide la-
ser. Dermatol Ther 2014; 27(3):168-70.
19. Uchiyama M, Tsuboi R. Lupus
miliaris disseminatus faciei in-
volving the scalp resulted in cic-
atricial alopecia. J Dermatol 2013;
40(9):760-1.
20. Van de Scheur MR, van der Waal
RI, Starink TM. Lupus miliaris
170
disseminatus faciei: a distinctive
rosacea-like syndrome and not a
granulomatous form of rosacea.
Dermatology 2003; 206:120-123.
21. Skowron F, Causeret AS, Pa-
bion C, et al. F.I.GU.R.E.: facial
idiopathic granulomas with re-
gressive evolution. is ‘lupus mil-
iaris disseminatus faciei’ still an
acceptable diagnosis in the third
millennium? Dermatology 2000;
201:287-289.
22. Barzilai A, Feuerman H, Quaglino
P, et al. Cutaneous B-cell neo-
plasms mimicking granulomatous
rosacea or rhinophyma. Arch
Dermatol 2012; 148(7):824-31.
23. di Meo N, Stinco G, Trevisan G.
Cutaneous B-cell chronic lym-
phocytic leukaemia resembling a
granulomatous rosacea. Derma-
tol Online J 2013; 19(10):2003.
24. Cruz Manzano M, Ramírez García L,
Sánchez Pont JE, et al. Rosacea-Like
Leukemia Cutis: A Case Report. Am
J Dermatopathol 2016; 38(8):e119-21.
25. Murad A, Fortune A, O’Keane C,
et al. Granulomatous rosacea-like
facial eruption in an elderly man:
leukaemia cutis. BMJ Case Rep
2016; 2016.
26. Rezaković S, Bukvić Mokos Z,
Paštar Z. Drug-Induced Rosa-
cea-like Dermatitis. Acta Derma-
tovenerol Croat 2016; 24(1):49-54.
27. Štulhofer Buzina D, Martinac I,
Ledić Drvar D, et al. Adverse
Reaction to Cetuximab, an Epi-
dermal Growth Factor Receptor
Inhibitor. Acta Dermatovenerol
Croat 2016; 24(1):70-2.
28. Rezaković S, Paštar Z, Bukvić
Mokos Z, et al. Erlotinib-induced
rosacea-like dermatitis. Acta Der-
matovenerol Croat 2016; 24(1):65-
9.
29. El-Heis S, Buckley DA. Rosa-
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pimecrolimus. Dermatol Online J
2015; 21(5).
30. Teraki Y, Hitomi K, Sato Y, et al.
Tacrolimus-induced rosacea-like
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ointment application. Dermatolo-
gy 2012; 224(4):309-14.
The mites of the genus Demodex
(from the Greek demos = fat and dex
= woodworm, wood rodent insect)
are the most frequent ectoparasites
in human skin. They live in the oily
secretion of pilosebaceous follicles,
where they feed on cellular proteins
obtained by destroying the follicular
epithelium1 and sebum components.
They predominate in areas where se-
baceous glands are prominent (nose,
forehead, cheeks, and chin) or where
there is a greater amount of sebum.
Most studies agree that the follicles
most frequently affected are those in
the nasolabial, nasal and palpebral re-
gions,2 or the temples.3 In exception-
al cases, they may be found in other
regions, such as the scalp,4 chest or
pubis,5 nipples,6 gluteal region or ex-
tremities.7,8 According to one study,
Demodex is not found in the scrotum
or male perineum because secretion
from the apocrine glands along with
the ammonium and iron content of
the area limit the growth of the mite.9
In veterinary medicine, Demodex
infestation is usually described as de-
modicidosis, demodectic mange, or
demodectic scabies. In humans, the
medical importance and pathogene-
sis of Demodex mites has been widely
discussed because only a few people
develop symptoms and signs of the
demodidicosis (although the vast ma-
jority of people host Demodex in their
skin), and it remains unknown whether
Chapter 16
Demodicidosis
Francisco Urbina
the mite’s presence provides any ben-
efit to the host. Demodex have been
linked to numerous disorders in the
literature, including rosacea, perioral
dermatitis, granulomatous perioral
dermatitis, follicular pityriasis, pustu-
lar folliculitis, pigmented folliculitis,
and blepharitis.
The demodicidoses, which are
also sometimes called demodicidosis
in human beings, without establish-
ing clearly which of the two terms is
the most etymologically appropriate,
would then constitute a group of dis-
eases marked by an extensive parasit-
ic infection by Demodex mites, which
are expressed in various clinical man-
ifestations that we will review below.
BIOLOGICAL CHARACTERISTICS
Among the various species of Demo-
dex that parasitize some animals, two
are found in humans, Demodex follic-
171
ulorum and Demodex brevis; the lat-
ter has humans as its only host. They
belong to class Arachnida, order Aca-
rina, family Demodicidae, hence the
term demodicidosis, which seems to
be the most appropriate. Both mites
are very similar: they have a spindle
shape of 0.3 to 0.4 mm long, with
four pairs of short legs located in the
front third of the body, allowing a very
minute amount of mobility (8-16 mm/
hour); each leg has a pair of claws with
which the mite is attached to the epi-
dermis and produces persistent and
progressive microabrasions. Certain
anatomical features allow differenti-
ation from other Demodex, with De-
modex folliculorum being relatively
longer and having a more rounded
opisthosoma (Fig. 16-1), as well as larg-
er eggs (Table 16-1). Demodex follicu-
lorum mites inhabit the pilosebaceous
follicles, while Demodex brevis mites
are more deeply located, towards the
sebaceous glands and ducts. Usually
three or more Demodex folliculorum
mites are found in a single follicle,
while Demodex brevis is usually more
solitary (one or at most two speci-
mens). The ratio Demodex brevis/
Demodex folliculorum in humans ac-
cording to sex is 1:4 in men and 1:10 in
women.10
In both species, male mites pre-
dominate over females, and adult
forms tend to prevail over larvae and
juvenile forms. Females tend to be
territorial, so they remain in their re-
spective follicles, while males move
over the skin surface in search of fe-
males to reproduce with and, it is pre-
sumed, to migrate and cause parasitic
infection of another host.11 Copulation
takes place at the level of the follic-
ular orifice, and occurs in darkness,
when they are most active. Bright light
makes them go deep into the follicle,
and their usual position is with their
head pointing into the orifice and
Fig. 16-1. Demodex folliculorum mite.
(Courtesy, Dr. Carlos Misad).
Table16-1. Main differences between Demodex folliculorum and Demodex wall and its subsequent dilation may dermatitis, Demodex presence has
brevis mites simply be the result of the long-term been attributed to prior use of topi-
parasite nutrition from follicular cells.3 cal corticosteroids, with a significant-
Characteristics Demodex folliculorum Demodex brevis ly higher density of mites in patients
Transmission of Demodex occurs thus treated.20 Detection of close to
Habitat Follicular infundibulum Sebaceous glands or ducts by direct contact, presumably from 40% in melanocytic nevi may be due
birth, although it has rarely been to a possible affinity of the mite for
Number 3-10 per follicle Usually solitary detected in children, which makes melanin.21 Conversely, a significantly
sense given the scarce production of lower density of Demodex mites has
Size Larger Smaller sebum at this age range. The reason been detected in melanoma patients
Male 280 m 166 m for its low frequency in patients with compared to healthy controls, leading
Female 294 m 208 m acne vulgaris, similar to that found in to the hypothesis that host defenses
Larva 283 m 105 m healthy population14 despite the abun- would act against both melanoma and
Protonymph 365 m 148 m dance of sebum, is unknown. This is the mite, or that the mite has a pro-
Nymph 392 m 165 m probably due to the fact that the mite tective effect against melanoma or
prefers to be away from the typical vice versa.22 Even more rarely, a strik-
Opisthosoma Long and rounded Shorter and sharp-pointed acne suppurations and that the alter- ing presence of Demodex mites was
7/10 of body 1/2 to 1/3 of body ations in the composition of the seba- described in cases of sebaceous ad-
ceous secretion among adolescents enoma23 and neutrophilic sebaceous
Male/female range 1:4.5 1:3,4 prevents its growth.15 No differences adenitis.24
were found in the degree of parasit-
Eggs In arrowhead, 105 ´ 42 m Oval, 60 ´ 34 m osis according to the type of acne, Finally, the most debated and
comedonal or inflammatory.16 Howev- questioned association has been,
er, a meta-analysis of what was pub- and currently is, with rosacea. Al-
tail protruding towards the surface FREQUENCY AND DISTRIBUTION lished regarding the acne/Demodex though some studies have shown
of the skin, with their body in parallel In all the studies where the frequen- relationship, mostly including publica- that patients with rosacea may have
with the hair shaft. Oviposition lasts 12 cy of Demodex mite infestation in hu- tions made in China, concluded that a greater facial infestation by Demo-
hours after copulation; eggs are de- mans was analyzed, it was shown that there is indeed a relationship, so it is dex mites, their participation as a
posited 60 hours later; the larva stage it progressively increases according suggested to consider the use of aca- causative agent, vector of other mi-
lasts 36 hours; the protonymph stage to the different age groups, up to ricides when a patient with acne does croorganisms or mere spectator tak-
lasts 72 hours; with nymph stage last- a prevalence that reaches 100% in not respond to usual treatments.17 ing advantage of the situation was
ing 60 hours, and adult state, 5 days.11 middle-aged or senior adults.12,13 Skin One study described a significant not clearly established. In one study,
The complete life-cycle is about 15 changes that tend to occur among positivity and density of parasitosis it was observed that a higher density
days. About half the mites at the out- the elderly include epidermal atrophy by Demodex compared to the control of Demodex mites was related to oily
let of the follicular orifice are dead, and solar elastosis, disorders which group in seborrheic dermatitis,18 while skin, regardless of the presence of
blocking the follicular opening, thus may determine certain follicular dila- in another no relationship was found; rosacea.25 The composition of sebum
reducing the possibility of new infes- tion and favour mite infestation. On no relationship has been shown with -with a profile of altered fatty acids in
tations.11 the other hand, damage to the follicle atopic dermatitis either.19 In perioral papulopustular rosacea rather than
172
a higher production- could influence
the growth of the mite.26 Its pres-
ence in the skin -initially considered
as that of a guest- has caused dif-
ferent theories which have changed
and been inconsistent over time. The
action of Demodex as a causative or
exacerbating agent of rosacea or as
a vector of other microorganisms
that would cause the inflammatory
phenomena of the disease is current-
ly being discussed,27 all aspects that
will be reviewed further on.
The distribution of the parasite is
universal and has been detected in
variable figures in different popula-
tions and ethnic groups according
to different studies, including Brazil,
72%,28 Mongolia, 51.5%,29 New Zealand,
19.3% (in the total sample but with an
increase from 8% to 75% according to
different age groups),30 Australian ab-
origines 66.6% in males and 80% in fe-
males,31 and Mexico, 27.3% -in the total
sample and over 65% in persons over
60 years of age.32 In a study carried
out in Chile based on eyelashes taken
from corpses, specimens of Demo-
dex folliculorum mites were detected
in different evolutionary stages, with
a frequency ranging from 55.5% in
those under 50 years of age to 82.6%
in those over that age.33
In a quantitative study34 carried
out to determine the density and dis-
tribution of Demodex mites on the
face by their extraction with 24 adhe-
sive tapes of 1.2 × 5 cm (6 cm2 each),
618 mites were obtained in a healthy
subject. The density of Demodex fol-
liculorum mites ranged from 1 to 6 per
follicle, while Demodex brevis mites
were found only occasionally and in
the form of isolated or unique speci-
mens. The distribution of mites varied
in number of specimens according to
the different regions of the face: 233
on the upper cheek, 153 on the mid-
dle cheek, 114 on the lower cheek, 78
on the chin, 59.5 on the forehead, 55
on the nose, 54.5 in the infraorbital
region, 49.5 in the perioral region and
45 in the nasal cleft. Other authors
also reported a higher likelihood of
the mite in samples obtained from
cheeks (70%) compared to those of
the forehead (46%) or chin (32%),35
while through a histopathological
study the mite was detected more
frequently on the temples.3
In rare cases, Demodex has been
described on the limbs: in a patient
with pretibial lesions associated with
lymphedema, in the form of an erup-
tion characterized by numerous red
papules of firm consistency,7 and in
rosacea patient with a similar though
milder eruption of lesions distribut-
ed on a forearm (Fig. 16-2).8 A case
was also described where Demodex
mites were detected by cytology
from a nipple discharge in a 56-year-
old woman.36
173
PATHOGENESIS
The ability of Demodex to block fol-
licles and sebaceous ducts, causing
epithelial hyperplasia and reactive hy-
perkeratinization has been proposed
as a possible pathogenic mechanism.
Demodex could also act as a possible
vector for bacteria37 or fungi,38 and
stimulate humoral and cellular im-
mune responses in the affected host
and even determine the formation of
granulomas.13 Various microorganisms
present in the Demodex microbiome
were described, mainly Staphylococ-
cus epidermidis, Proteobacteria and
Firmicutes,39,40 and also the gram-neg-
ative Bacillus oleronius,41,42 Bacillus
cereus43 and Bartonella quintana.44 It
is suggested that they may act as trig-
gers or enhancers of the inflammato-
ry response, in some manner that has
not yet been well defined.45 Anecdot-
ally, it has been said that Demodex
could be a vector transmitting leprosy. Fig. 16-2. Asymptomatic papu-
In recent years, Bacillus oleronius has loerithematous rash, on the left fore-
been the most studied microorganism arm of a rosacea patient. Demodex
associated with Demodex. B. oleronius folliculorum mites were detected
survives in two forms, vegetative and both on the forearm and face.
endosporic. After being consumed by
the Demodex mites, endospores ger- and other mediators of the inflamma-
minate into vegetative forms in their tory response, causing tissue damage
digestive tract and are presumed to around the pilosebaceous unit along
live in endosymbiosis with the mite, with the usual clinical manifestations.
thus making digestion easier, as in The antibiotics commonly used to
the case of termites. After the death treat rosacea (tetracycline, doxycy-
of the mite, two highly immunogenic cline, metronidazole, etc.) temporarily
antigens (proteins 62 kDa and 83 kDa) kill bacilli which, in turn, decreases the
are released, activating neutrophils metabolism of mites. There is a con-
comitant temporary reduction in the
number of lesions, which reappear
after treatment has ceased, as both
mites and bacilli reestablish coloniza-
tion ... thus starting the cycle all over
again.46,47
The finding of a higher density of
Demodex mites in face-related areas,
where basal cell carcinoma tumors
also develop, has led to the suspicion
of a relationship between the two
conditions, in which demodicidosis
would act as a cause of chronic follicu-
lar inflammation and contribute to the
carcinogenic process, also favoured
by the age-related immune decline,
in turn allowing an increase in the
number of mites.48 A greater range
of infestation was also described in
individuals with basal cell carcinoma
compared to squamous cell carcino-
ma, seborrheic keratosis, and trichi-
lemmoma,49 with significantly higher
frequency (71%) in basal cell carcino-
mas located in the nose.
Host immune status may also be
an important factor contributing to
parasite overgrowth. Eruptions with
numerous mite specimens were de-
scribed in patients with AIDS or dif-
ferent hematologic malignancies,50
as well as in subjects on long-term
treatment with topical51,52 or systemic51
corticosteroids,53 or with rosacea ag-
gravated by the use of topical corti-
costeroids.13 More recently, increased
mite populations were also observed
after the use of pimecrolimus,54-56 tac-
rolimus57 and erlotinib.58 However, in
a series of cases treated with cetux-
imab, it was ruled out that the ac-
ne-like eruption resulting from its use
may be related to an overgrowth of
Demodex mites.59
A study carried out on kidney
transplant recipients treated with
cyclosporine, azathioprine and pred-
nisolone, found no Demodex folliculo-
rum mites were detected.60 However,
Demodex infestation was noticed in
lesions in a more recent set of 4 kid-
ney transplant recipients who had
facial papules and pustules that had
appeared months to years after trans-
plantation: all of them were being
treated with tacrolimus and predni-
sone; three were also treated with
mycophenolate; and only one patient
received azathioprine in addition to
tacrolimus and prednisone.61
In individuals with chronic renal
failure, despite not having found sig-
nificant differences with respect to
the control group in relation to skin
disorders, a significant difference was
found in relation to eye disorders, es-
pecially of the blepharitis type.62 Sim-
ilarly, in two other studies performed
in patients undergoing dialysis due to
renal failure, a greater number of par-
asites was observed in the two stud-
ies compared to the control group.
174
This difference was more marked in
those whose renal failure was second-
ary to diabetes mellitus,63 while in the
other subjects without diabetes, a sig-
nificantly greater mite thickness was
detected.64
No major parasitosis by Demodex
were described in pregnant wom-
en compared to the control group
(non-pregnant women).65 In those with
polycystic ovarian syndrome (PCOS)
a significantly greater infestation was
reported compared to a healthy con-
trol group. No differences were found
in the levels of estrogen, FSH, or LH
among women with PCOS with or
without mites.66 In another area, no
relationship was detected between
the frequency of parasitosis due to
Demodex with metabolic syndrome in
women, but it was observed in those
who were overweight, with a higher
intake of fatty foods and who also had
high (diastolic) blood pressure.67
Significantly larger Demodex
folliculorum mite populations have
been described in patients with type
2 diabetes mellitus vs those without
diabetes. Moreover, increased mite
populations were also correlated
with higher percentage of HbA1c,
which reflects the blood glucose
level of the last three months. It was
therefore suggested that poorly-con-
trolled hyperglycemia may represent
an additional immune stimulus for
those with diabetes, which may re-
sult in larger populations of mites.68
Similarly, Gökçe et al.69 described
increased parasitosis by Demodex
mites in people with type 2 diabetes
with poor glycemic control (HbA1c
greater than 7%), compared to an-
other group of type 2 diabetes with
adequate glycemic controls and
maintenance of glycosylated hemo-
globin at less than 7%.
The impact of body mass index
(BMI) on the presence of Demodex
mites in different groups of obese
people has also been studied. There
was a significant difference between
the group with positive presence of
mites (BMI 35.7 ± 12.1 kg/m2) and the
group with no mites (BMI 29.2 ± 9.2
kg/m2), although another group with
normal weight showed a significant
positivity to the mite compared to the
control group.70 Thus, it is difficult to
make any definitive conclusion about
the relationship between BMI and
parasitosis at the moment.
As regards alcohol intake, a study
conducted on 102 students deter-
mined the frequency of infestation by
Demodex mites and analyzed its asso-
ciation with acne and other variables.16
The only significant factor found was
a higher prevalence (55.6%) of De-
modex mites in alcohol consumers.
It seems that alcohol drinkers had
some degree of immunosuppres-
sion and abandonment of self-care,
which allowed greater proliferation
of the mite.71 They also had a more
oily skin determined by the detection
of the amount of fatty acid ethyl es-
ters, which was higher among drink-
ers than among non-drinkers.72 An
alteration in the composition of the
cutaneous lipids in papulopustular ro-
sacea was demonstrated, with elevat-
ed levels of linoleic and myristic acids,
as well as decreased levels of long-
chain saturated fatty acids and mono-
unsaturated fatty acids.26 This sebum
composition could allow for over-
growth of the mite. Similarly, higher
pH levels and cholesterol esters were
described in the sebum composition
of patients with demodicidosis.73 At
the same time, with respect to alco-
hol intake, an interesting hypothe-
sis was formulated a couple of years
ago given the similarity of rosacea
patients’ redness with Asian flushing
syndrome produced by a genetic dis-
order of aldehyde dehydrogenase 2,
which induces vasodilation due to in-
adequate metabolism of alcohol acet-
aldehydes.74 Both Helicobacter pylori
-which generates acetaldehydes from
alcohol or carbohydrates- and anti-
bodies against proteins from Bacillus
oleronius from Demodex mites -which
would hinder enzyme performance
being unable to adequately metabo-
lize acetaldehydes- may be involved in
vasodilation and angiogenesis among
these patients.
IMMUNOLOGICAL STUDIES
On immunohistochemistry, follicular
infestation by Demodex folliculorum
mites in individuals with papulopus-
tular rosacea was associated with in-
tense peripheral infiltrates composed
largely of CD4 T lymphocytes, and
increased macrophages and Lang-
erhans cells. The authors suggested
that the stimulus and progression of
rosacea could be due to a delayed
hypersensitivity reaction, possibly
determined by follicular antigens re-
lated to mites, a reaction that would
stimulate the progression of rosacea
to the papulopustular stage.75
In a study to determine charac-
teristics of the immune response to
Demodex mites in patients with de-
modicidosis versus healthy controls,
a higher absolute CD95+ cell count
was observed in the former, as well as
a reduction in the absolute number of
CD3+, CD4+, CD8+ and CD16, and a
decrease in functional leukocytic ac-
tivity. No significant differences were
identified in the other T cell subpop-
ulations studied, circulating immune
complexes, serum complement levels,
phagocytosis index and anti-IgA, IgM
and IgG antibody values between the
two groups. The authors concluded
that the speed of lymphocytes to ac-
tivate apoptosis is directly correlated
with increase in the density of infesta-
tion by mites, suggesting a local immu-
nosuppression that facilitate survival of
175
mites in the skin of the infested host.76
In a subsequent study made by the
same authors, the immune response
in individuals with demodicidosis was
evaluated using monoclonal antigens
anti-CD3+, CD4+, CD8+, CD16, CD20
and CD95+, immunoglobulins, circu-
lating immunocomplexes, hemolytic
complement and functional activity
of neutrophils and leukocytes, com-
paring different groups according to
histocompatibility antigens (HLA A,
B, Bw and Cw). Patients without A2
phenotype were observed to have
lower functional leukocyte activity, less
CD8+, and higher IgA concentrations
compared to those with A2 pheno-
type; the former correlated with more
extensive and deeper papulopustular
forms of demodicidosis. Likewise, pa-
tients with phenotype Cw2 showed a
greater propensity to suffer demodici-
dosis, with a decrease in CD3+ and an
increase in phagocyte activity, accom-
panied by more severe clinical pictures
and with a greater density of infesta-
tion by Demodex mites.77
In conclusion, both an immu-
nodeficiency factor favoring mite
overgrowth and an abnormal skin re-
sponse may be involved in the forma-
tion of lesions. In some patients, a type
IV hypersensitivity response may be
generated as a defense mechanism
against the mite, clinically represent-
ed as papulopustules, while in other
patients, penetration of the mite in
the dermis would lead to persistent
immune stimulation and the forma-
tion of granulomas with giant cells.78
Sunlight and lack of facial cleans-
ing with soap and water, aggravated in
some cases by the use of oily moistur-
izing creams, may act as factors favor-
ing the increase in the number of mites
on the skin. Sunlight, in addition to its
local immunosuppressive effect at skin
level, promotes skin damage, with the
development of solar elastosis, vascu-
lar dilation and telangiectases, as well
as follicular dilation, all leading to a
hyperproliferation of the mite. In this
regard, it is worth mentioning the de-
scription of Demodex folliculitis after
phototherapy in a female patient with
psoriasis, who also had atrophic and
telangiectasic skin after prolonged
treatment with topical corticoste-
roids.79 In a study of this issue, the fre-
quency of demodicidosis was analyzed
in 45 patients undergoing treatment
with PUVA (12 cases) and narrow-band
UV-B (33 cases) for different diseases
versus controls.80 Thirteen cases in
the UV-treated group were diagnosed
with demodicidosis (8 of them with
evident clinical lesions) versus 3 cases
among controls. A significant differ-
ence was also detected based on the
phototherapy type, with higher rates
of demodicidosis in those receiving
PUVA (7 out of 12 cases) compared to
those treated with narrow-band UV-B
(6 out of 33 cases).
 DIAGNOSIS
The diagnosis of demodicidosis is
established by demonstrating high
quantities of Demodex mites in scaling
and follicular content along with vari-
ous clinical manifestations or forms
of disease presentation. The mite is a
usual parasite in normal skin and can
be present in healthy asymptomatic
adults with nocutaneous lesions, so
the term demodicidosis implies mor-
bidity accompanied by symptoms.
Skin biopsy and other non-inva-
sive methods are used to determine
the content of mites in the pilose-
baceous follicle and the horny layer.
Skin biopsy simply consists of ex-
tracting follicular material by scrap-
ing or compression and examining it
under a microscope after maceration
with 40% KOH. Another option is to
obtain tissue from stratum corneum
and superficial follicular content af-
ter adhering and removing a trans-
parent adhesive tape, followed by
microscopic examination. The most
commonly used method in publica-
tions is the so-called standardized
skin surface biopsy (SSSB).12,81 This
method uses a slide which has a pre-
viously drawn 11.5 mm diameter circle
in the middle providing a 1 cm2 exam-
ination area. At the time of the exam-
ination, a drop of cyanoacrylate glue
is placed on the glass sheet, which is
applied over the area of skin to be
assessed on the patient’s face, and
it is left there for one minute to dry. half the time of SSSB. The authors Dermoscopy and confocal micros-
Then it is gently removed, obtaining concluded that KOH saves time and copy have also been used to facilitate
a superficial part of the horny layer is easier for the technical personnel diagnosis. In 2010, the first series of
and the follicle content adhered to who collects the samples.84 However, demodicidosis cases was described in
the slide. After applying a couple in an earlier series of 37 cases, both a study of patients with various facial
of drops of immersion oil, a cover- methods resulted in the diagnosis of eruptions (n=72); dermoscopy showed
slide is placed over the slide and it demodicidosis in 23 cases, although a specific finding related to demodici-
is immediately examined under the SSSB detected higher averages of dosis (mite tails in follicular openings)
microscope. Finding more than 5 De- Demodex specimens than KOH.85 in 54 of the subjects (Fig. 16-3).86 Con-
modex mites per square centimeter
is considered abnormal; sometimes
tens to hundreds of them are found
in a single sample. Forton et al per-
formed this method twice in the
same area to avoid false negatives,
and found a frequency of demodi-
cidosis of 5.2%.78 They hypothesized
that conducting an isolated exam-
ination may lead to failures in the
detection of the mite.82 In a different
publication, Forton et al also estab-
lished that the optimal criteria for di-
agnosis is the finding of more than 5
mites/cm2 in the first sample or more
than 10 mites/cm2 in the second sam-
ple, with a 95.5% specificity for the
negative Demodex group and 98.7%
for the positive Demodex group.83
Another recent study compared
KOH scraping and preparation versus
SSSB and showed no significant differ-
ences in detection of mites between
the 2 methods in 100 patients (sam-
ples were taken from adjacent areas
of one cheek). KOH preparation time
was 6 times shorter than SSSB, with Fig. 16-3. Dermoscopy of demodicidosis showing a large number of mite tails
an interpretation process that took emerging from the surface of the skin (Courtesy, Dr. Orlando Alvarado).
176
focal microscopy,87 reflectance confo-
cal microscopy88-93 and confocal laser
scanning microscopy94,95 are very use-
ful for diagnosis and follow-up of pa-
tients after treatment, although their
cost does not allow their use as basic
technology or screening. Polymerase
chain reaction (PCR) has been eval-
uated for the detection of Demodex
mites in rosacea and revealed 5.7
times more mites in patients with ro-
sacea compared to healthy patients.96
CLINICAL FORMS
Human Demodex mite infestation
may be asymptomatic or produce
a broad spectrum of clinical mani-
festations, collectively referred to
as demodicidosis. In general, De-
modex-associated diseases may be
classified into three main groups:
pityriasis folliculorum, rosacea-like
demodicidosis and granulomatous
rosacea-like demodicidosis or de-
modicidosis gravis.97 Subsequently,
other forms of classification were
considered, none of has been uni-
versally accepted. Akilov et al.98
proposed a clinical-histological clas-
sification, in which they divided the
demodicoses into primary and sec-
ondary. The primary form would be
produced by Demodex folliculorum,
while in the secondary form Demo-
dex brevis would generally be pres-
ent. The primary form would be
associated with lesions affecting the
T zone of the face (erythema, scal-
ing and papulopustules) that appear Table16-2. Demodicidosis Forms of UU Papulopustular rosacea (37%)
suddenly in a previously healthy skin Presentation
and are accompanied by itching; UU Follicular eczematid (7%)
in the second form, lesions would Pityriasis folliculorum
symmetrically affect the cheeks and Rosaceiform demodicidosis UU Folliculitis (7%)
cheekbones on top of an underlying Demodicidosis gravis
disease such as acne, rosacea or peri- Pustular folliculitis UU With ocular manifestations (5%)
oral dermatitis, with itching appear- Demodicidosis in AIDS and immunosuppressed
ing later. Likewise, Chen and Plewig99 Pigmentous folliculitis by Demodex UU Hyperpigmentation (4%)
proposed a division into primary Blepharitis by Demodex
demodicidosis (which includes the Facial spinulosis UU Isolated inflammatory papule (1%)
spinulate form that would become Demodicidosis in children
a synonym of pityriasis folliculorum, Alopecia by Demodex The highest numbers of parasit-
papulopustular/nodulocystic variety, Demodicidosis of the external ear canal osis were detected in the cases of
the ocular and the auricular) and sec- pityriasis folliculorum (mean 61 mites/
ondary form produced by local or global entity, are follicular scales and cm2, range 4-396) and in the hyperpig-
systemic immunosuppression, or su- telangiectases, while the main sub- mented form of demodicidosis (mean
perimposed on pre-existing disorders jective symptoms consist of redness, 134 mites/cm2, range 45-276).78
(acne, rosacea, seborrheic dermatitis, dry skin and itching (Table 16-3). The
perioral dermatitis, etc.). Conversely, pattern of clinical presentation in one Pityriasis folliculorum
Forton et al.100 proposed to classify study78 was, ranked by frequency: Pityriasis folliculorum is a common
them as inflammatory and non-inflam- though poorly-understood disorder
matory demodicidosis. Pityriasis fol- UU Pityriasis folliculorum type (54%) characterized by diffuse facial ery-
liculorum is kept unchanged and it is
included as a separate entity to hon-
or the person who named it that way Table16-3. Clinical Manifestations in 83 Demodicidosis Cases78
in 1930. Forton et al. also remarked
that demodicidoses may appear in Subjective symptoms Objective symptoms
isolation or simultaneously with oth-
er conditions without any other caus- Flushing 46% Follicular scales 71%
ative relationship. Dry skin 30% Telangiectases 63%
Itching 29% Papules 40%
With no further attempt at classi- Tightness sensation 27% Erythema 35%
fication, the different clinical forms of Roughness sensation 24% Pustules 25%
presentation of demodicoses will be Hyper-reactive skin 23% Dilated follicular orifices 10%
reviewed in terms of their character- Burning sensation 12% Irregular skin 7%
istics (Table 16-2). The main clinical Stinging 1% Appearance of orange peel skin 6%
manifestations in demodicidosis, as a Hyper-seborrhea 1% Non-follicular scales 4%
177
thema and a slight follicular peeling
that gives the skin a frost-like appear-
ance and a sandpaper texture (Fig.
16-4 which has been compared to a
nutmeg grater (Fig. 16-5).101 In a study
analyzing the non-specific signs and
symptoms of demodicidosis, approx-
imately 65% of the cases consulted
about erythema and facial pruritus of
non-specific origin, 9.4% of the cases
consulted about erythema and pityri-
asiform scaling or acne-like eruptions,
6.3% about facial itching and 3.3%
about papulopustular lesions, gran-
ulomatous rosaceaform dermatitis
or perioral dermatitis.3 Typically, the
periocular regions (more protected
from the sun by the ciliary arches) are
not involved, giving patients the ap-
pearance of having been sunbathing
with sunglasses102 (Fig. 16-6) or as a
skier in snow (Fig. 16-7). Eruption oc-
curs in both sexes, although it is pre-
dominant in women.
History of use of fatty cosmetics,
use of cleansing creams and lack of
washing the face with soap and water
are often, though not consistently, re-
ported by patients.

Fig. 16-5. “Nutmeg grater” skin. (Courtesy, Dr. María Isabel Herane).

Patients may also report a burn- feeling of dryness or roughness which

ing sensation or itching (exacerbated
when exposed to the sun), perhaps
due to movement of mites deep-
er into the follicle on exposure to a
bright light like sunlight. The incre-
seased number of mites may also pro-
duce a feeling of tightness, dryness
or roughness in the affected areas
(Fig. 16-8); when studied by scanning
electron microscope, it can be seen
that the follicular scales belong to
numerous opisthosomes of Demodex
folliculorum which appear from follic-
Fig. 16-4. “Sandpaper” skin. ular orifices (Fig. 16-9),103 giving a false
178
leads patients to apply creams, there-
by promoting the growth of the para-
site. In a few cases, a histopathological
study of the lesions was carried out,
showing a hyperkeratotic epidermis
with a chronic inflammatory infiltrate
at the dermis and follicular orifices
that appear filled with mites.
Rosaceiform (Rosacea-like)
Demodicidosis
Rosaceiform demodicidosis, or rosa-
cea-like demodicidosis, is seen with er-
ythema, scaling, and papulopustules, a
 Fig. 16-9. Scanning electron microscopy, showing numerous opisthomas of De-
modex folliculorum mites protruding over the surface of the skin around a hair.
(Authorized by Wiley Publications: Crosti C et al. Demodectic infestation of
the pilosebaceous follicle. J Cutan Pathol 1983; 10: 257-261).

Fig. 16-6. Aspect of having been in
the sun with glasses.
Fig. 16-8. Dryness, roughness and
“tightness” in affected areas.
Fig. 16-7. Aspect of “skier in the snow.”
presentation that is clinically similar to
common rosacea (Fig. 16-10). Some dis-
tinctive features of the latter are small-
er and more superficial papulopustules,
follicullar scaling and absence of a histo-
ry of sun intolerance, persistent erythe-
ma or flushing, along with absence of
evident and center-facial telangiectases
(Fig. 16-11). The absence of comedones
differentiate it from acne vulgaris. In di-
agnosing rosaceaform demodicidosis,
patient report of sudden onset and fre-
quent asymmetrical or unilateral distri-
bution is also helpful (Figs. 16-12).104
179
Fig. 16-10. Papulopustules and scal-
ing on cheeks.
Demodicidosis gravis
This is a type of rosaceiform and
granulomatous demodicidosis char-
acterized by dermal granulomas
with central necrosis, composed of
foreign-body giant cells containing
remnants of phagocytosed mites105
and even intact mites with extrafol-
licular location, without displaying
any apparent follicle rupture.106 In
clinical terms, the presentation re-
sembles a granulomatous rosacea or
rosaceiform rash suggesting demod-
icidosis,107,108 with scaly papulopustu-
lar lesions distributed in the perioral
region, cheeks and eyelids (Figs. 16-
13 and 16-14).106
 Fig. 16-12. Unilateral distribution of lesions resembling those of rosacea.

Fig. 16-11. Small papulopustules and scaling, extrafacial compromise and ab-
sence of involvement in the center of the face (count of 50 mites of Demodex
folliculorum at scraping in self-medicated patient with topical corticoids)..

Fig. 16-13. Demodicidosis gravis.

It has the appearance of a gran-
ulomatous rosacea, with pap-
ulopustular or nodular lesions
located on the cheeks, perioral
region and eyelids, accompanied
by scaling. (Courtesy, Dr. Ximena Fig. 16-14. Papules and long-term recurrent scaling with unilateral distribution
Ancic). on eyelids and external angle after intermittent use of topical corticoids.
180
 A histopathological review of 53
cases of granulomatous rosacea found
that 10 of them had intact or frag-
mented Demodex mites, surrounded
by an intense inflammatory reaction
composed of histiocytes, giant cells,
and necrosis.109 Similarly, another clin-
ical and histopathological study of
granulomatous rosacea found that 9
out of 53 cases had Demodex mites in
follicular infundibulae.110 Granulomas
are formed by persistent reaction
to an antigen, and it was suggest-
ed that Demodex mites would play
some role in this regard. Most of the
T-lymphocytes present in granuloma-
tous infiltrates around fragments of
Demodex mites with extrafollicular
location were of the helper-inducer
T-type, which supports the hypoth-
esis regarding the involvement of a
cellular-type immune response in the
origin of this kind of lesion.111 The anti-
genic presentation would occur in the
epidermis or more likely in the dermis
after rupture of the follicular wall and
release of its contents, including the
mite, into the dermis thus inducing a
persistent immune reaction with gran-
uloma formation.
Pustular Folliculitis
This type consists of a pustular follicu-
lar eruption, moderately itchy, located
on the face or scalp. It may be accom-
panied by isolated erythematous pap-
ules and confluence of lesions forming
plaques (Fig. 16-15), usually localized
or unilateral (Fig. 16-16). The presence
of Demodex should be suspected
when a localized pustular folliculitis
does not respond to conventional
antibiotic treatment. Bacteriological
and mycological culture do not isolate
microorganisms, but examination of
follicular content reveals hundreds of
Demodex folliculorum.112 As an unusu-
al clinical case, an immunocompetent
patient was reported to have rapidly
developed a tuberous pustular tumor
on the chin; histopathological study
showed follicular cysts and chronic
granulomatous perifolliculitis with nu-
merous Demodex folliculorum mites.113
Demodicidosis in AIDS and
Immunosuppressed Individuals
In patients with AIDS,114-116 those who
are HIV positive117 or in immunosup-
pressed patients, the eruption of
Fig. 16-15. Plaques with pustules and
scabs located only on the forehead
after use of topical corticoids..
181
demodicidosis shows a more varied
morphology and, in addition to ery-
thema and scaling, papules, nodules
and pustules may be added, which are
usually itchy. In a series of 51 HIV-posi-
tive patients with itchy folliculitis, only
3.9% of cases originated from Demo-
dex mites. The most frequent causes
were eosinophilic folliculitis (45.1%),
bacterial folliculitis (41.2%) and Pity-
rosporum folliculitis (9.8%).119
Lesions in immunosuppressed indi-
viduals may extend beyond the face,
to the neck, trunk and extremities, al-
though asymptomatic cases have also
been described.120 Similar eruptions
were reported in other types of immu-
nosuppression, including lymphoblastic
leukemia,121-126 and chronic myelomono-
cytic leukemia in children,127 as well as
hematologic malignancies in adults such
as acute myelocytic leukemia, non-Hod-
gkin’s lymphoma, acute lymphocytic
Fig. 16-16. Papulopustules with unilat-
eral distribution and follicular scales.
leukemia, chronic lymphocytic leuke-
mia, and chronic myelocytic leukemia.
This suggests that, in the event of a
facial eruption in patients with these
diseases who are undergoing che-
motherapy, a possible demodicidosis
should be investigated.50 The absence
of a secondary cell-immunity or lym-
phocyte depletion in patients under-
going chemotherapy would favor mite
proliferation.121
A pustular folliculitis eruption on the
trunk was also described in a patient
with mycosis fungoides in the tumor
stage during full-body electron beam
treatment. This led to claim that basal
immunosuppression associated with
therapy favored parasite proliferation
and the development of folliculitis.128
A patient with pemphigus foliaceus
with a two-year course, treated with
mycophenolate mofetil, oral and top-
ical corticosteroid, and calcineurine
inhibitors, who developed numerous
pustules in both forearms, was similar-
ly described. The microscopic study
of a scraping of the lesions showed
numerous Demodex mites.129 A higher
density of mites than normal was also
reported in patients with skin erup-
tions who were receiving epidermal
growth factor receptor inhibitors.130
The relationship of mites with oth-
er types of cancer was also investigat-
ed. An interesting report mentioned
the case of a woman with breast can-
cer and a history of facial redness and
itching, in which high concentrations
of mites were detected on cheeks
(20/cm2) and forehead (15/cm2) before
the onset of chemotherapy. After the
first course of adriamycin, cyclophos-
phamide and 5-fluorouracil, facial red-
ness worsened, as did itching. A new
mite count was performed showing
50/cm2 on cheeks and 30/cm2 on the
forehead. In another publication in
which 101 patients with different can-
cers were analyzed in terms of infes-
tation frequency by Demodex mites,
the results were higher for breast
cancer (47.4%), followed by lung can-
cer (29.2%), gastrointestinal cancer
(18.5%) and urogenital cancer (16.7%),
and with a frequency of 76.2% for all
cases with cancer.132
Local immunosuppression induced
by the use of topical corticosteroids
was also reported with the appearance
of erythematotelangiectatic spots ac-
companied by itching and scaly follic-
ular papules on the neck and upper
trunk; scrapings from these lesions
showed Demodex folliculorum mites.51
In topical corticosteroid-induced ro-
sacea, a significantly greater increase
in mite count was observed (72.9
specimens on average) compared to
those in papulopustular rosacea (36.9
specimens), erythematotelangiectatic
rosacea (42 specimens) and healthy
controls (10.8 specimens).1 Similarly,
the increase in the number of Demo-
dex folliculorum mites in perioral der- palpebral rim can be seen in healthy
matitis was correlated to a significant people and with no eye discomfort
degree as a secondary phenomenon unlike when it occurs in those with
associated with topical corticosteroid blepharitis.135-137 However, a meta-anal-
treatment.20 In summary, any immu- ysis showed a statistically significant
nodeficiency status could result in an association between blepharitis and
increase in the number of mites and Demodex mites.138 In this situation,
lead to an inflammatory reaction or blepharitis most often affects the
impaired immune response. lower eyelid, perhaps due to great-
er proximity to the nose from where
Folliculitis by Pigmented Demodex mites migrate searching new follicles
This type of folliculitis consists of an Fig. 16-17. Folliculitis by pigmented to colonize. The finding of 4 or 5 mites
infrequent though distinctive variety Demodex. There are brownish hyper- per eyelash is considered an intense
of Demodex folliculorum disease char- pigmented macules located in the degree of parasitosis (Fig. 16-18), while
acterized by hyperpigmented brown area of the chin, submental region, the presence of 1 isolated mite every
lenticular macules which are clinically neck or chest. 10 eyelashes is not considered an in-
similar to pityriasis versicolor lesions festation. Demodex folliculorum is
(Fig. 16-17). Lesions are located espe- Demodex Blepharitis found with anterior blepharitis, while
cially on the chin area, although they As with other skin areas, the discovery Demodex brevis is found with pos-
may also extend to the neck or chest. of Demodex mites on the eyelashes or terior blepharitis, Meibomian gland
They are accompanied by dryness,
with or without fine scaling of the af-
fected areas, where the mite is de-
tected in high numbers; notably, the
elevated concentrations of mites are
not found in healthy neighbouring
skin.133 The histopathological study of
these lesions shows an increase in pig-
mentation of the basal layer, dilation of
hair infundibulae filled with keratin and
Demodex folliculorum mites increased
in number. In the dermis, capillary di-
lation and perivascular and peripheral
lymphohistiocytic mononuclear inflam-
matory infiltrate can be observed.134
Probably hyperpigmentation is pres-
ent as a secondary postinflammatory Fig. 16-18. Demodex folliculorum mites attached to an eyelash. (Courtesy, Dr.
phenomenon to mite parasitosis. Nancy Rivera).
182
dysfunction, chalazion and blepha-
roconjunctivitis.139 A study described
infestation frequencies of 20% in an-
terior blepharitis, 40% in Meibomian
gland dysfunction and 90% in mixed
blepharitis compared with 18% in the
healthy control group.140
In clinical terms, Demodex bleph-
aritis is characterized by erythema
of the palpebral margin accompa-
nied by itching or foreign body sen-
sation, ocular redness and watery
eyes.141 Typically, it is accompanied
by dry scabs or cylindrical scales,
which would be pathognomonic for
the infestation, at the base of eye-
lashes (Fig. 16-19).142 Such scabs or
scales can be warped or absent, or
show an easy depilation and loss of
resistance induced by edema and
follicular inflammation (Fig. 16-20).
Conjunctivitis, chalazion and gran-
uloma formation may also be ob-
served. Chalazion describes the
granulomatous inflammation of the
Meibomian glands, where Demodex
brevis mites were detected in their
center, surrounded by lymphocytes,
histiocytes and epithelioid cells. Re-
current chalazions are usually asso-
ciated with demodicidosis,143,144 as are
those cases involving recurrent pte-
rygium, especially conjunctival.145,146
Chalazion was also associated with
the origin of the so-called dry eye,
when the follicular blockage induced
by the mite affects the Meibomian or
Fig. 16-19. Demodex blepharitis. Er-
ythema and scaling of the palpebral
rims without other skin lesions.
Zeis glands, leading to a reduction
in the superficial lipid content of the
tear film.
The mite was the cause of chron-
ic blepharitis in 52%, 58% and 68%
of the cases studied in three publi-
cations in this regard,147-149 although
report found no difference with re-
spect to the control group.150 Demo-
dex blepharitis should be suspected
if there is persistent lack of response
to conventional treatments, including
topical and systemic antibiotics, top-
ical corticoids and antihistamines,151,152
both in adults and in pediatric pa-
tients.153 Likewise, it has been ob-
served that with age, the frequency
of parasitosis by Demodex mites in-
creases.148,151,150,154 Mites appear with
a frequency of around 25% until the
age of 20 and increase to 30% by the
183
Fig. 16-20. Demodex blepharitis.
There is erythema of the lower palpe-
bral rim, scaling and reduction of eye-
lashes. The cheekbone has erythema
and papulopustules.
age of 50 and 100% after 70.155 How-
ever, a separate study of patients with
seborrheic blepharitis did not show
significant variations with respect to
healthy controls.150
Mites may be mediators in the or-
igin of chronic blepharitis. A great-
er growth of gram-negative and
gram-positive bacteria was observed
in culture samples taken from the
conjunctiva147 or eyelids,156 show-
ing predominant growth of coagu-
lase-negative staphylococci in the
latter study. Mites may also cause mis-
alignment and falling eyelashes, or dis-
tichiasis, with possible irritation of the
cornea,157 or formation of punctiform
erosions, blepharokeratitis or corneal
ulcers.158 Finally, mites have been cited
as a possible cause of abandonment
of the use of contact lenses, with a
frequency of parasitosis of 92.86%
in patients with contact-lens intoler-
ance.159 Experimentally, exposure of
corneal epithelial cells to a protein
extract obtained from Bacillus olero-
nius from a Demodex mite produced
abnormal scarring, thus leading to a
possible relationship between eye-
lash parasitic load in patients with
ocular rosacea and the development
of corneal ulcers.160 This bacillus could
act as a copathogen in the develop-
ment of severe forms of blepharitis.161
Other corneal abnormalities in pa-
tients with Demodex blepharitis may
occur with superficial vascularization,
marginal infiltrates, phlyctenule-type
lesions, opacity and formation of nod-
ular scars.162
Study of local immunity in patients
with blepharoconjunctivitis due to
Demodex163 showed alterations con-
sisting of a decreased level of IL-4 in
the lacrimal fluid, a relatively smaller
number of CD3+ cells and a relative
increase in CD16+ lymphocytes in-
filtrating the palpebral conjunctiva.
A relative decrease of CD3+ and
CD4+ lymphocytes in the palpebral
conjunctiva was detected in older
patients, which would allow a great-
er invasion of mites and a greater
frequency of this type of condition
in elderly individuals. In cases com-
plicated with episcleritis or kerati-
tis, elevated levels of IgE in the tear
fluid were detected, together with a
decrease in the IgE/IL-4 range.163 An-
other study showed that Demodex in-
festation induced an increase in IL-17
levels, causing ocular and palpebral
inflammation,164 and mite eradication
was associated with a reduction of
inflammation and clinical improve-
ment.165 However, another clinical
study showed no difference in the
degree of infestation or symptom-
atology in immunodepressed individ-
uals compared to a healthy control
group.166 In HIV-positive patients, the
degree of mite infestation was cor-
related with CD4+ lymphocyte count,
with 95% ranges of Demodex mite in-
festation in patients with cell counts
of less than 200 cells/ml, 70% in the
range of 200 to 500 cells/ml, and
20% in those with cell counts above
500 cells/ml.167
Some interesting conditions that
should be included in this section
are a greater frequency of infesta-
tion by Demodex mites in eyelashes
of diabetic patients with proliferative
diabetic retinopathy,168 as well as in
patients with eyelid basal cell carci-
noma169 and in those with Behçet’s
disease.170
Facial Spinulosis
Facial spinulosis was described in
three patients with polycythemia ru-
bra vera. They presented with multi-
ple fine follicular and hyperkeratotic
spicules located on the cheeks,171,172
the temporal and frontal regions, and
the chin and ears.173 Another case was
reported in a patient with depression
and fibrocystic breast disease, also
with lesions on the cheeks.174 The his-
topathological study of the lesions
showed keratosic material and re-
mains of Demodex folliculorum mites
at the level of the follicular infundib-
uli (Fig. 16-21).174 For some authors
this process would be the same as
pityriasis folliculorum, which may or
may not be accompanied by baseline
erythema.99
Fig. 16-21. Facial Spinulosis, with whit-
ish and hyperkeratotic follicular ele-
ments forming protruding spicules.
184
Demodicidosis in Children
Despite its low frequency in child-
hood, there has been a report of de-
modicidosis in a series of 4 boys and 4
girls with immunocompetence, rang-
ing between 10 months and 5 years
of age. They consulted a physician af-
ter a facial eruption characterized by
erythema, variable edema and pap-
ulopustules.175 Two cases presented
clinical characteristics similar to pityri-
asis folliculorum, while the remaining
6 showed rosacea-like dermatosis. In
7 cases a parasitosis with abundant
Demodex folliculorum mites was
proven by skin scraping, and in one
case by histopathological study after
biopsy of the affected skin. The rea-
son for demodicidosis is unknown in
these cases. In another series of 17
cases of childhood demodicidosis,
which included 16 girls and 1 boy, all
Fig. 16-22. Demodicidosis in a girl with papulopustules and scaling. (Courtesy,
Dr. Ligia Araníbar).
HIV negative and aged between 1 and
14 years, 3 patients had immunosup-
pression by bone marrow transplanta-
tion, while the rest had no history of
previous use of oily creams or topical
corticoids; notably, 4 of the children
had a family history of rosacea. Le-
sions consisted of papules and pus-
tules located on cheeks and nose (Fig.
16-22), with little itching.176 In another
study on the prevalence of Demodex
mites in children with malnutrition or
malignancies, a frequency of 25% and
32.3%, respectively, was detected.177
Demodex Alopecia
It has been claimed that Demodex
mites may play some part in the devel-
opment of androgenic alopecia, per-
haps indirectly participating through
the follicular secondary inflammatory
response.178 The presence of mites on
the scalp has been correlated with
early alopecia and hair thinning, with
frequencies between 84% and 98% in
patients with androgenic alopecia.80,178
Very similar to canine demodicidosis,
human disease is clinically manifest-
ed by erythema, scaling and hair loss,
which determines alopecia.179 Micro-
scopic examination detects large num-
bers of mites in the affected follicles.
The histopathological study of scalp
in forensic autopsies showed about
30% parasitosis by Demodex folliculo-
rum or Demodex brevis mites, in both
sexes, predominantly in elderly per-
sons with dark complexion and bald
individuals.180 More than 70% of cases
showed chronic lymphocytic infiltra-
tion of scalp skin.180 However, a study
of males with androgenic alopecia did
not show significant differences in the
degree of Demodex infestation com-
pared to controls, although the vast
majority had greasy hair.181 Seborrhea
produced by androgenic stimulation
is likely the cause of mite overgrowth,
and is probably secondary to alope-
cia and not the cause. Similarly, the
results of a histopathological study
of 333 scalp biopsies indicated by al-
opecia or hair loss showed only 17 cas-
es (5.1%) with detection of Demodex
mites in at least one pilosebaceous
follicle, considered pathological in
only 4 cases, characterized by erythe-
ma, pustules and scaling, which sub-
sequently improved completely after
treatment with metronidazole.182
External Ear Canal
and Demodex
References in this regard are scarce.
The finding of Demodex mites in the
secretion of the external auditory
canal of school children who report-
ed itching in the area has been de-
scribed,183 as well as in patients who
had used topical corticosteroids due
to itching in the external auditory ca-
nal but not in the groups that had not
used corticosteroids or had no pruri-
tus (though in two other groups that
had not used them or in whom no
itching existed).184 In another isolated
case, a chronic, itchy otitis was de-
scribed, complicated by myringitis,
in which the biopsy of the eardrum
and the external auditory meatus
showed numerous Demodex mites
and a non-specific inflammatory re-
sponse.185
OTHER FORMS OF
PRESENTATION OR
DEMODICIDOSIS SIMULATING
OTHER PROCESSES
Isolated cases of demodicidosis with
other seemingly infrequent forms of
clinical presentation have scattered
reports.
Demodex Abscesses. Abscess due
to Demodex has been described in
isolated cases, with papular, pustular
and nodular lesions, leading to for-
mation of abscesses or supurative
conglomerates located on the face.
185
These abscesses were associated
with marked infestation by Demo-
dex mites, no growth of bacteria or
fungi in appropriate cultures and no
response to treatment with antibi-
otics, topical permethrin,186 lindane
or oral ivermectin.187 In both publi-
cations the patients improved after
use of oral metronidazole in differ-
ent doses and intervals. In another
case, an abscessed nodular form
-with unilateral lesions of preauric-
ular location- showed no change
after 10 days of oral metronidazole,
although it improved after the use
of oral ivermectin in conjunction
with topical treatment with 5% per-
methrin.188
Demodicidosis in Plaques. This
disorder was reported to affect one
cheek, with fat-like adherent plaques
that showed numerous Demodex
mites and a peripheral lymphocyte
infiltrate on biopsy.189 A second case
was characterized by erythematous
annular plaques also located on the
face.190
Crusted Demodicidosis. This type
of demodicidosis was reported both in
an immunocompetent girl, with itchy
lesions made up of yellowish-grey
plaques located on the dorsum of her
nose and cheeks,191 and in an HIV-posi-
tive woman, both with a history of pre-
vious use of topical corticosteroids in
the affected area.192
Demodicidosis with Polymorphic
Lesions. One case has been de-
scribed with papulovesicular and ur-
ticarial lesions located on the cheek
and forehead.193
Demodicidosis Mimicking Tinea
Favosa. This variant has been de-
scribed in a child with scalp, neck and
chest lesions of long-term develop-
ment. Eggs and adult specimens of
Demodex mites were detected under
microscopic examination.194
Demodicidosis Mimicking Basal
Cell Carcinoma. This variant was de-
scribed in a letter to the editor and
involved a patient with a skin-colored
papule on the nose with the clinical
appearance of a basal cell carcinoma
in the illustration. The histology did
not demonstrate the presence of a
carcinoma, but rather an infestation
by Demodex mites, although no histo-
pathological findings were described.
The authors reported having seen
another 3 similar cases that had un-
dergone surgery, without subsequent
tumor evidence. In borderline situa-
tions, they suggest searching for the
mite and making a therapeutic trial
before indicating surgery (Fig. 16-23,
personal case).195
Demodicidosis Mimicking Cuta-
neous Linfoma. This has been de-
scribed in two patients with indurated
facial papules, erythema and eyelid

Fig. 16-23. Confluent translucent pap-
ules, nasal dorsum, resembling a basal
cell carcinoma.
edema, eye congestion and histo-
pathological findings with presence
of Demodex mites and massive lym-
phocytic infiltrates with monoclonal
expansion of T cells, similar to those
in a lymphoma. Both improved after
the use of oral ivermectin and topical
crotamiton, or oral minocycline.196
Demodicidosis Mimicking Host
Vs. Graft Disease. This variant has
been reported in very few cases
which were characterized by the ap-
pearance of facial erythema in bone
marrow or pluri-potent cell transplant
recipients.197-200 The histological study
of facial skin biopsies showed varying
degrees of chronic perifolliculitis with
massive concentrations of Demodex
mites. The appearance of facial ery-
thema in the first 100 days after trans-
plantation may be a sign of graft vs.
host disease, and even longer latency
periods are accepted.199
Demodicidosis Mimicking Herpes
Zoster. This has been described in
two cases. The first case was a male
with a painful, erythematopustular
eruption located on the right side of
the face and extending to the scalp
in a zosteriform pattern. Scraping of
the pustules showed numerous De-
modex mites.201 The second case also
involved a male, with an itchy, burning
spot following the trigeminal upper
branches on the right side of the face,
plus small pustules and scaling; stan-
dardized biopsy of the skin surface
revealed a large number of Demodex
folliculorum mites.202
Demodicidosis Mimicking Lepro-
sy. Described in a 32-year-old male
with an erythematous and indurated
plaque on one cheek, this variant was
accompanied by hypoesthesia.203 An
initial biopsy showed non-specific in-
flammation. It was empirically treated
as unresponsive leprosy with lesion
worsening, and marked by edema,
erythema and follicular dilation of the
cheek. A second biopsy showed ac-
186
centuated follicular and perifollicular
lymphocytic infiltrates, along with De-
modex mites.
Demodicidosis Mimicking Se-
baceous Carcinoma. Described in
a 60-year-old male, with major right
blepharitis, thickening of the palpe-
bral rim with upper scar ectropion
and madarosis, this variant demon-
strated no response to conventional
treatments of blepharoconjunctivitis.
Biopsy ruled out malignancy and re-
ported follicle infestation by Demo-
dex mites and chronic inflammation.
Treatment with tea tree oil improved
blepharitis and ectropion.204
PATHOLOGY
The finding of Demodex mites in skin
biopsies showed variable frequen-
cies ranging from 10%3 to 13%,205
when considered together with sam-
ples taken from different parts of the
body, to 84%,155 in the case of biopsies
taken only from the eyelids. Likewise,
it was seen that, according to the
species considered, Demodex follic-
ulorum is more frequent on the face,
in comparison with Demodex brevis,
which was detected more frequently
on the neck and chest, according to
a study.3 The frequency of infestation
also varies according to age, with a
progressive increase as time goes
by,3 and also in relation to sex, since a
greater preponderance is observed
in males, with more noticeable dif-
ferences for Demodex brevis (5%
in males and 1% in females).3 In the
microscopic study, it was observed
that mites are more abundant in hair-
type pilosebaceous follicles -richer
in sebaceous glands- than in those
containing terminal hair. The affect-
ed follicles appear dilated, accom-
panied by a peripheral inflammation
composed of lymphohistiocyte infil-
trates and homogeneous and dense
eosinophilic material surrounding
the mites (Fig. 16-24), which appears
to be made up of follicular cells de-
stroyed by the former.3 Histophato-
logic analysis of folliculitis showed
mites were present in 42% of folli-
cles which appeared to be swollen,
contrasting with only 10% for those
showing no inflammation. In addi-
tion, 83% of follicles containing De-
modex mites were accompanied by
inflammation, suggesting that the
presence of the mite is associated
with folliculitis, even at small scale.206
The presence of an eosinophilic fol-
licular reaction in histology may be
found in the context of an eosinophil-
ic folliculitis in HIV-positive patients
where Demodex may contribute to
its pathogenesis; however, this was
also described in a healthy male with
recurrent itchy lesions on the face,
scalp and neck, who had eosinophil-
ic micro-abscesses in histology with
Demodex mites. The name “eosin-
ophilic follicular reaction” has been
proposed for this process.207
 Demodex mites are considered
pathologic in two instances: presence
in abnormally high quantities and de-
tection in the dermis. Similarly, it must
be assumed that in many processes
mites act as innocent observers rather
than pathogens.208 Comparative anal-
ysis on the frequency of infestation
by Demodex mites in different dis-
eases showed its higher prevalence
in rosacea (51%) compared to discoid
lupus (31%) or eczema (28%),209 while
in another study it appeared in 80%
of cases with rosacea and only in 30%
of controls on histology.210 Although
the role of Demodex mites in the
pathogenesis of rosacea is still un-
der discussion, they may play a role
in stimulating inflammatory or immu-
nospecific reactions, mechanically
blocking follicles, or participating as
vectors of bacteria.211 According to
one study, no differences were found
regarding the numbers of Demodex
mites in papulopustular rosacea com-
pared to the erythematotelangiectat-
ic type; in both studies perivascular
and peripheral lymphohistiocytic in-
filtrates, follicular spongiosis and exo-
cytosis of inflammatory cells towards
hair follicles were present, although
dermal inflammatory infiltration was
greater in the first form.212 It has
been suggested that an exaggerat-
ed immune response occurs when
the mites migrate to the dermis after
Fig. 16-24. Demodex folliculorum mites in a pilosebaceous follicle. (Courtesy, having eaten the epithelium, which in
Dr. Carlos Misad) turn causes the papules and pustules
187
typical of rosacea. This is in contrast
to pityriasis folliculorum, in which, al-
though the parasitic load is accentu-
ated, it clinically presents with scaling
and minimal or absent inflammatory
reaction. The author suggests that the
study of the immune traits of pityriasis
folliculorum would enable finding the
missing link between a first stage with
little immune reaction and rosacea.213
Although it is interesting as a working
hypothesis, the appearance of a rosa-
cea typically is not clinically preced-
ed by a stage of facial scaling, which
would have been noticed many years
ago. It is also likely that this pityriasis
folliculorum is more closely related
to the current recent year’s trend of
not using soap, (instead cleansing
with multiple commercial substitute
products) rather than with an immune
defect. An exception would be the
relationship between pityriasis and
the appearance and use for some
decades of topical corticosteroids
(whose arrival in various countries
was associated with the appearance
of the so-called “steroid rosacea” or
“steroid-induced rosacea”).
TREATMENT
Since the retrospective history of
lack of face washing was obtained in
several studies on demodicidosis,78,133
an initial therapeutic approach
should include twice daily washing
with soap and water, followed by dry-
ing with a towel, which would favour
the removal of mites by chemical and
mechanical action, respectively.78
Eyelids and eyelashes should also
be neatly cleaned. Various products
were used for the local treatment of
this condition, especially acaricides,
such as 1% lindane, 10% crotamiton
or 1% or 5% permethrin.214 Some au-
thors recommend the use of 10%
crotamiton in the morning and 10%
crotamiton plus 12% benzyl benzoate
in the evening, after washing the face
with soap and water, until a normal-
ization of the mite count is obtained,
which may take between 2 and 12
months.78 If necessary, it can be used
intermittently, 3 times a week. In a
publication comparing the efficacy
of different topical therapeutic alter-
natives (metronidazole 2%, perme-
thrin 1%, sulfur sublimate, lindane 1%,
crotamiton 10% and benzyl benzoate
10%) in 34 patients with demodicido-
sis, using standardized biopsy of the
skin surface, before, during and after
treatment, only benzyl benzoate and
crotamiton had demonstrated effi-
cact.215
In isolated cases, good results
have been achieved with use of oral
ivermectin alone216 or followed by
topical permethrin.217-220 Ivermectin
was used in single or repeated doses
of 200 mg/kg and topical permethrin
at 5%. However two initial weekly dos-
es of 200 mg/kg of oral ivermectin
used in conjunction with 5% topical
permethrin overnight resulted in no
improvement in a child with leuke-
mia. Two additional doses at the sixth
and seventh week were necessary to
achieve complete remission, which
was obtained gradually five weeks
later.221 Ivermectin is an antiparasitic
compound of the group of macrocy-
clic lactones known as avermectins,
which has been used in the treatment
of nematodes and ectoparasites in an-
imals and humans. It blocks the neuro-
transmission of gamma aminobutyric
acid (GABA) in parasites, selectively
inducing muscle paralysis and death.
The drug does not affect the synaps-
es of other neurotransmitters, such
as acetylcholine, noradrenaline or se-
rotonin, nor does it cross the blood-
brain barrier.222 Use of ivermectin in
humans is relatively safe, with good
tolerance and infrequent adverse ef-
fects. However, its use has not been
approved in children, pregnant wom-
en, or during breastfeeding. Ivermec-
tin has also been successfully used in
the treatment of scabies, lice, larva
migrans, miasis, filariasis, loiasis, and
onchocerciasis. Use is recommended
in doses of 200 mg/kg; occasionally
a second or third dose may be ad-
ministered at intervals of one to two
weeks. A few years ago a topical iv-
ermectin 1% cream was developed; in
this formulation, ivermectin has been
shown to havegood ranges of effec-
tiveness, safety and tolerance.223,224
Comparative study has shown iv-
188
ermectin to be more effective than
topical metronidazole at 0.75% in the
treatment of rosacea.225 It is believed
that its mechanism of action is primar-
ily determined by its antiparasitic and
anti-inflammatory activity through
reduction of neutrophil chemotaxis
and phagocytosis, inhibition of inflam-
matory cytokines and tumor necrosis
factor alpha.226
The use of skin peeling products
such as salicylic acid133 or topical ret-
inoids101 may also help or prevent the
development of follicular blockage
and promote the elimination of super-
ficial scales in demodicidosis.
Although one study showed that
Demodex folliculorum mites can sur-
vive in vitro in metronidazole con-
centrations of up to 1 mg/ml,227 in
some cases a good clinical response
was observed after application175 or
at least a partial improvement,121 ei-
ther due to a local anti-inflammatory
effect, suppression of bacterial flora
or some antiparasitic activity of a me-
tabolite of it against the mite.228 In a
group of five children with acute lym-
phoblastic leukemia who developed
Demodex folliculitis after chemother-
apy, none experienced improvement
after treatment with permethrin 5%
cream, while the use of topical metro-
nidazole helped reduce lesions in four
cases, although without complete
improvement.229 The comparison be-
tween the use of topical metronida-
zole and benzoyl peroxide gel plus
topical erythromycin in patients with
rosacea showed that the latter prod-
uct was more effective in reducing
mite count after a first examination;
in the second examination both were
equally effective.230
In one case the use of oral metroni-
dazole was not found to be effective,103
and in another publication, despite
improving the symptomatology and
clinical appearance of lesions after
eight months of use in three times a
day doses of 250 mg, oral metroni-
dazole did not reduce the number of
mites; however, crotamiton did impact
mite numbers.231 In another isolated
report, after 5 years of unsuccessful
treatments including repeated oral
ivermectin and topical application of
lindane, permethrin, and benzyl ben-
zoate, the use of oral metronidazole
in three times a day doses of 250 mg
over two weeks led to a prompt and
sustained improvement.187
For the treatment of Demodex
blepharitis, washing eyelashes and
eyelids with water and baby shampoo
is recommended, although the mite
has been shown to be resistant in vitro
to various antiseptic solutions, includ-
ing 75% alcohol, 10% povidone iodine
and 50% baby shampoos.232 Washing
the eyelids with 50% tea tree oil fol-
lowed by shampooing with the same
product was very effective, with a no-
ticeable reduction in mite count,232,234
as well as relief of itching.235 This com-
pound is obtained from a native Aus-
tralian plant (Melaleuca alternifolia)
that contains about 100 components,
of which terpinen-4-ol is the most ac-
tive ingredient in the elimination of
Demodex mites.236
Another useful topical treatment
is 1% mercury oxide ointment used at
bedtime, applied over the palpebral
rim and thickly coated eyelashes for
3 to 4 weeks. Good results were re-
ported after the use of 2% metronida-
zole gel, with reduction of symptoms
and reduction in mite count after one
month’s use, followed by absence of
detection after six months and no re-
currence after one year.237 Likewise,
the use of 4% pilocarpine gel has been
described; this treatment is thought
to inhibit the mobility and breathing
of the mite due to its muscarinic ef-
fect. Pilocarpine gel is associated with
both the reduction in the number of
mites and a significant improvement
in itchy eye.238 It should be used with
caution, as it may cause conjunctival
irritation, miosis and other adverse ef-
fects if it inadvertently spreads to the
surface of the eyeball.
Oral ivermectin -with a repeat dose
of 200 mg/kg per week- has shown
efficacy in the treatment of subse-
quent blepharitis, with reduction in
the number of mites and improve-
ment in evaluation parameters.239 Its
use (200 mg/kg repeated weekly)
combined with oral metronidazole
(250 mg three times daily for 2 weeks)
has been shown to be more effective
than the use of oral ivermectin alone
in patients with rosacea or previous
blepharitis.240 The recent pharmaceu-
tical appearance of topical ivermectin
may offer a new alternative if it is pre-
pared in an ophthalmic formulation.
In short, an optimal or completely
effective treatment for demodicidosis
has not yet been established, but we
do have the alternatives mentioned
and their combinations. As a first step,
it is reasonable to restrict use of all
types of oily creams or cosmetics and
to recommend daily cleansing of the
face with water and soap, or a good
soap substitute. Next, either choose
oral treatment with ivermectin or topi-
cal acaricides, such as 10% crotamiton,
5% permethrin or the newly formulat-
ed 1% ivermectin, which should be ap-
plied at night at bedtime, when mites
migrate to the follicular opening for
reproduction. In the morning, the use
of a gel or cream containing topical
metronidazole 0.75%, depending on
the type of skin, can be added, thus
obtaining an anti-inflammatory effect
targeting the lesions. The use of a mild
exfoliating agent can be also added
according to tolerance, a couple of
times a week, to promote the scaling
189
and removal of the dead mites locat-
ed in the follicle openings. Depending
on the degree of clinical resolution,
or through controls with mite count
of the affected areas, the application
of acaricide can be reduced to every
other day, or to 1-2 times per week as
a maintenance therapy if necessary.
The patient should be warned that
exposure to solar radiation will favor
the development of the process, so it
should always be avoided. In case of
unavoidable sun exposure, the use of
non-oily sunscreens, preferably in a
gel vehicle should be recommended.
Finally, it is worth mentioning the
exceptional use of photodynamic
therapy with methyl aminolevulinate
in a case of Demodex folliculitis in
scalp resistant to other therapies,241 as
well as the use of various other com-
pounds - such as camphor oil,242,243 dib-
utyl phthalate, 244,245 sodium dodecyl
benzene sulfonate,246 mud from the
Xiushan Sea247 and various Chinese
herbal extracts, especially Herba ta-
raxaci,248 Cortex phellodendri, Herba
taraxac and Herba agrimoniae.249
In the coming months and years, we
will surely be readers of numerous and
novel studies of various kinds (bacteri-
ological, immunological and therapeu-
tic, among others), about this strange
and tiny “Eighth Passenger” who slow-
ly gnaws us day after day, while at night
has sex in our own noses.
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1015.
Periorificial dermatitis (PD), is a
chronic dermatosis characterized by
non-itchy papules and pustules with
a perioral, perinasal and periorbit-
al distribution. Despite the scarcity
of publications available, PD occurs
quite frequently. This dermatitis main-
ly affects women between 16 and 45
years old. However, there have been
reports of some cases in men and in
children between 7 months and 13
years. In children, it is called childhood
granulomatous periorificial dermato-
sis (CGPD) to highlight it as a variant
of adult GPD.1-4 The use of the terms
“childhood perioral dermatitis” or
“childhood facial rash” in publications
relating to dermatitis in Afro-Caribbe-
an children has led to confusion, since
the publications make reference to
the same disease. Frumes and Lewis
described PD as photosensitive seb-
orrheic dermatitis in 1957, and in 1964,
Mihan and Ayres called it perioral
dermatitis. Its correct name would be,
periorificial dermatitis.5,6
PATHOGENESIS
Over the years, several factors have
been considered as sole etiological
agents, however, there are multiple
causative factors that must be consid-
ered in this disease. The pathogenesis
is not yet fully known; consequently,
it is considered as a disease of mul-
tifactorial etiology.1,7 The influence of
physical factors, like ultraviolet and
infrared radiation, have been includ-
Chapter 17
Perioral or
Periorificial
Dermatitis
Juan C. Diez de Medina
ed in its pathophysiology since its
first description when it was named
photosensitive seborrheic dermatitis.
Despite their resemblance and the de-
scription of some authors as a variant
of rosacea, the validation of a direct
relationship between PD and rosacea
has not been an easy task. In the biop-
sy samples included in the few avail-
able histopathological studies, there
seems to be no visible solar elastosis,
which distinguishes PD from rosacea.
However, in long standing cases, elas-
tosis may be evident. Regardless of
these differences and from the clini-
cal point of view, it seems undeniable
that both UVR and heat constitute
200
triggering and perpetuating factors
rather than defining factors.7-10
Several infectious agents have
been identified as etiological agents
of PD, among them: Demodex, Can-
dida Albicans and fusiform bacteria.
However, not a single paper exists
showing conclusive evidence of the
role of these microorganisms.1,11-15
Others have proposed an etio-
logical role to an endless number
of contact irritants, but patch trials
have been contradictory. Fluoride
contained in toothpaste was pro-
posed as a sole causative factor of
PD, but the result of patch trials was
were negative. A clinical trial eval-
uating discontinuation of fluoride
toothpastes did not show a direct
correlation with disappearance of
PD. The use of heavy moisturizing
creams, specifically those containing
Vaseline or paraffin, may cause follic-
ular occlusion or irritation. As a result
of this, the epithelial barrier be-
comes dysfunctional, leading to ede-
ma of the stratum corneum and an
increase in the transepidermal water
loss (TEWL). This process produces
a sensation of tightness and dryness
of the skin. Other skin irritants, like
some cosmetics, may be contributing
factors in the development of PD.7,8
Hormonal factors have been impli-
cated in the pathogenesis due to the
typical age of onset of PD, in women
during their reproductive years. More-
over, the association between PD and
hormonal triggering factors could in-
clude the n increase of this condition
within the pre-menstrual and men-
strual periods, its occasional appear-
ance during pregnancy, and the use
of oral contraceptives. Therefore, in
some patients, hormonal factors may
play an important role in PD.7,8,11
Undoubtedly, in a good number of
cases, glucocorticoids act as a major
triggering, perpetuating and even
causative factor. It is not unusual that
a facial contact dermatitis treated
with corticosteroids of mid or strong
potency evolves into PD. Not only
topical, but also inhaled and systemic
corticosteroids are clearly implicat-
ed. In recent years, the frequent use
of topical calcineurin inhibitors (tac-
rolimus and pimecrolimus) has also
been implicated in the appearance
of PD.1,3,4,7,8

CLINICAL MANIFESTATIONS
Patients typically present with a fa-
cial rash, affecting mostly the perioral
area, and sometimes the perinasal
and the periorbital regions. Some pe-
diatric cases also present perivulvar
involvement.16 The glabella and the
forehead are occasionally involved.
The rash is mainly symmetrical and in
the perioral zone, it ends a few milli-
meters off the vermilion border. The
severity of the clinical picture is vari-
able. It evolves through outbreaks
and in women, pre-menstrual exacer-
bation is not infrequent. The eyelids,
the perinasal or perioral areas may be
affected by a disseminated or isolated
rash. (Figs. 17-1 to 17-7) 1,3,8,9
The degree of itch associated with
PD is also variable, though it is usual-
ly mild; at times patients might com-
plain of irritation and a slight burning
pain. Others acknowledge discomfort
but the cosmetic impact is the pri-
mary reason to consult a physician.
The typical presentation may include
a variable erythema and papules in
Fig. 17-1. Erythematous papules of perioral distribution.
Fig. 17-2. Erythematous papules of perinasal distribution.
201
Fig. 17-3. Erythematous papules of
periorbital distribution.
irregular clusters, varying several
millimeters in size. Sometimes, papu-
lovesicular or papulopustular lesions
can also be observed, along with a
discrete flaking.1,7,8
HISTOPATHOLOGY
In general, and considering that the
clinical diagnosis is, almost always,
decisive, very few biopsies are per-
formed to diagnose PD. Moreover,
affected women -representing the
largest affected group- usually re-
ject this procedure. Research shows
a spectrum of results going from a
slight lymphohistiocytic, perivascu-
lar and perifollicular infiltrate, up to
occasional eczematous changes with
follicular spongiosis.
Fig. 17-4. Periorificial papulopustular dermatitis with glabellar involvement.
None of the special laboratory
stains are useful. Other cases pre-
sented a closer similarity with rosacea,
like uniform edema. The inflammatory
infiltrates could be lymphohistiocyt-
ic or sometimes only lymphocytic or
histiocytic, polymorphonuclear, or a
mixture of all of them; It is generally
perivascular and perifollicular or sar-
coid type granulomas. Finding gran-
ulomas is practically the rule in cases
related to the use of corticosteroids
(Figs. 17-8 and 17-9).1,8,18-20
DIFFERENTIAL DIAGNOSIS
In most cases, the PD diagnosis is
very clear; however, occasionally
certain pathologies with lesions of
similar localization may need to be
considered. Sebohrreic dermatitis
may simulate a PD and one must
search for papules to define a diag-
nosis. In children, perioral contact
dermatitis secondary to saliva (lick-
ing dermatitis) may lead to confusion
in the diagnosis. However, the age of
appearance and the clear irritating
reaction with scaly papular plaques
enables differentiation.21
Rosacea mainly affects the cheeks
and nose; telangiectases and flush-
ing also help to differentiate rosacea
from PD. However, in spite of the dif-
ficulties in verifying the diagnosis, it is Fig. 17-5. Girl with periorificial dermatitis involving the perioral, perinasal and
clinically evident that the boundaries periorbital areas.
202
 Fig. 17-7. The same 4 year old girl with Fig. 17-8. Histopathology. Inflammato-
perivulvar involvement. Extrafacial ry periadnexal infiltrates.
form of periorificial dermatitis.

Fig. 17-9. Histo-

pathology. Lym-
phohistiocytic in-
filtrates mapping
out the confor-
mation of granu-
lomas.

Fig. 17-6. A 4 year old girl with periorificial dermatitis.

203
between PD and rosacea are quite
diffuse. In certain cases, the diagnosis
is not easily defined, which leads us to
think that rosacea and PD may share
the same pathology.3,9,21
Acne is also part of the list of dif-
ferential diagnoses. However, besides
its distribution, acne lesions include
comedones, papules, pustules, nod-
ules and cysts; the presence of come-
dones rarely leaves room for a doubt
in the diagnosis What must be taken
into consideration is the overlap-
ping of clinical pictures, particularly
in patients suffering from acne, who,
whether by overmedication or by iat-
rogenesis, end up with PD superim-
posed on their acne.3,9,21
In the papular sarcoid, its mono-
morphism, distribution and espe-
cially its histology, determine a
definite diagnosis. As already men-
tioned above, it is worth consider-
ing that there are several reports
in which it is impossible to assert
whether PD or miliary lupus or papu-
lar sarcoid are being described. The
decision may be even more difficult
in the case of a child with childhood
granulomatous periorificial dermati-
tis (GPD).3,9.21
TREATMENT
Unquestionably, the therapy for PD
has many things in common with the
treatment of rosacea.
General measures
First and foremost, it is necessary to
cancel triggering contact irritants, as
well as topical, oral or inhalant cor-
ticosteroids. It is essential to avoid
vasodilating factors like; spicy food,
very hot water in hygiene, alcoholic
beverages or coffee.3,7,8,21 The use of
sunscreen, especially in children with
PD, constitutes the backbone of the
therapy.
Topical therapy
Given the result obtained with rosa-
cea, metronidazole 0.75% in cream
or gel is also the treatment of choice
for PD, since it has been proven to
be highly effective. Azelaic acid (15%)
is also very useful. Benzoyl peroxide
(2.5 and 5%), topical tretinoin and oth-
er retinoids have also provided good
results in a number of cases. From the
experience of the author and with no
detriment of their value, the down-
side of these topical agents would be
their irritant effect which can be par-
ticularly problematic in patients with
minimum threshold of tolerance.1,8,9,20-23
Compared to metronidazole, topi-
cal ivermectin (1%) in gel, has proven
greater effectiveness.24
It is essential to mention the cal-
cineurin inhibitors -pimecrolimus
and tacrolimus. While use of these
agents for PD is not yet approved
by the FDA, they can be very useful
to avoid the rebound effect caused
204
in patients, by the discontinuation of
corticosteroids used for long term.
However, it must be noticed that
these drugs are considered as trig-
gers of PD and of rosacea-like erup-
tions.8,25
Others prefer to taper cortico-
steroids, and in this way prevent the
rebound effect, instead of turning
to calcineurin inhibitors. If taper is
not possible and calcineurin inhibi-
tors are not considered appropriate,
corticosteroids may be discontin-
ued abruptly, but the patient must
be warned of the discomfort that
will likely occur over the short term.
Both approaches are valid, but dis-
continuing corticosteroids shall al-
ways be the overriding measure to
be considered.8,21
Systemic therapy
Tetracyclines are effective for the
treatment of PD like in rosacea. The
mechanism of action has not yet been
elucidated, but may be related to
anti-inflammatory effect. Among the
tetracycline antibiotics, doxycycline,
minocycline and lymecycline are most
often chosen for their similar effec-
tiveness.1,3,7-9,21
Macrolides may be used in chil-
dren less than 11 years old, in pregnant
or breastfeeding women and in aller-
gic or tetracycline intolerant patients.
Erythromycin may be used keeping in
mind that it is considered a Category
B medication for pregnancy. Newer
macrolides, like clarithromycin and
azithromycin, are also very effective
for PD. Prescribing macrolides for
PD has its detractors, because these
drugs very useful in other infectious
processes and it is important to pre-
serve their efficacy. Nonetheless,
macrolides certainly may be the best
choice for the group of patients men-
tioned above.
Overall, the benefits of antibiotics
in PD should be considered, but the
unlimited use of tetracyclines in pa-
tients prone to receive this drug, may
cause a bacterial resistance that must
also be contemplated.1,3,7-9,26,27
Oral isotretinoin is of great utility
in patients with refractory response
to medical treatment and in patients
with histology of granulomas.
PROGRESSION AND PROGNOSIS
Without treatment, the persistence of
PD may be variable. The average du-
ration may be 2 or 3 years, but PD may
persist up to 10 years. Its evolution is
episodic, with periods of exacerba-
tion. 1,7-9,21
Once an energetic and adequate
treatment has been established, the
prognosis is excellent. Most of the
series show that relapses very rarely
occur.3,8,9,21
References
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4. Laude TA, Salvemini JN. Perioral
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Seborrheic dermatitis (SD) –syn. sebor- at 40 to 60 years of age.2 The preva-
rheic eczema, Unna’s disease- is a com- lence of SD is up to 42%4 in infants,
mon, chronic, recurrent to persistant Chapter 18 whereas it is estimated at 1 to 3% of
erythematosquamous skin disease.1,2 the general adult population reach-

Seborrheic
It affects the seborrheic areas of the ing up to 7-10% in young adults.1,2,4
body including the scalp, face (naso- The peak incidence of the disorder is
labial folds, ears, and eyebrows), and at the 3rd to 4th decade of life. Men

upper part of the trunk (chest/prester-
nal region). Some patients with SD also
may present with inflamed erythema-
tous folliculitis (possibly caused by the
fungus Malassezia) and blepharitis.
SD is classified according to the age
of occurrence and the localization of
involvement in infantile and adult vari-
ants and pityriasis capitis (Table 18-1;
Figs. 18-1 a 18-7).
Absence of a standardized defini-
tion of SD has been an obstacle to
scientific investigation and a pos-
sible differentiation from pityriasis
capitis (dandruff).3 Pityriasis capitis
can be considered a mild form of
Dermatitis
Christos C. Zouboulis
SD, with scalp scaling and/or mild
to marked erythema of the nasola-
bial fold during times of stress. The
severity of SD varies. Some patients
experience only a mild flaking dan-
druff, whereas others demonstrate a
severe oily, scaling on the scalp, face,
and trunk.
EPIDEMIOLOGY
The incidence of SD peaks during two
age periods -in the first three months
of life and in adulthood with an apex
(3.0%) are more likely to be affected
than women (2.6%).5 No apparent dif-
ferences were observed in the inci-
dence of SD between ethnic groups.1,6
Compared with SD, pityriasis capi-
tis is much more common and affects
approximately 50% of the general
adult population worldwide.2,3 It is also
more prevalent in males than females.
It starts at puberty, reaches peak inci-
dence and severity at the age of about
20 years, and becomes less prevalent

Table 18-1. Classification of seborrheic dermatitis

Variant Age of occurrence Localization

Infantile seborrheic dermatitis (Figs. First 3 months of life Scalp

18-1 y 18-2)

Adult seborrheic dermatitis (Figs. Predominantly after puberty Face, scalp, retroauricular area,
18-3 a 18-6) chest and inguinal area

Pityriasis capitis (syn. dandruff, dia- Predominantly after puberty Scalp, face, inguinal area Fig. 18-1. Infantile seborrheic dermatitis. Honey-yellow scaling at the scalp of
per dermatitis) (Fig. 18-7) an infant. [Courtesy Dr. Ana Kaminsky].
206
 Fig. 18-3. Adult seborrheic dermatitis. Centrofacial erythema and scaling at
the nasolabial folds of an older male patient.

Fig. 18-4. Adult seborrheic dermatitis. Centrofacial erythema and scaling in

young female patients. [Courtesy Dr. Ana Kaminsky].

among people over 50. Incidence var-
ies between different ethnic groups,
being more common in dark skin pop-
ulations and less present in Asian ones.
ETIOLOGY AND
Fig. 18-2. Infantile seborrheic dermatitis. Disseminated papular erythema PATHOPHYSIOLOGY
and scaling at the face and scalp of a newborn child. [Courtesy Dr. Ana Ka- Despite its high prevalence, the eti-
minsky]. ology of SD is not well understood.
207
Major textbooks include SD in the
chapter of altered reactivity together
with atopic dermatitis and nummular
eczema or in the chapter of eczema-
tous eruptions.7,8 Various intrinsic and
environmental factors, such as seba-
ceous secretions, skin surface fungal
colonization, individual susceptibil-
ity, and interactions between these
 Fig. 18-6. Adult seborrheic dermatitis. Severe disseminated facial erythema
Fig. 18-5. Adult seborrheic dermatitis. Figurated centrofacial erythema and and scaling in a male patient with familial history of psoriasis (seborrhiasis).
scaling in a young female patient. [Courtesy Dr. Ana Kaminsky]. [Courtesy Dr. Ana Kaminsky].
208

Fig. 18-7. Pityriasis capitis in a 69-year old male patient.
factors, all may contribute to the
pathogenesis.1-6 Genetic, biochemical
studies and investigations in animal
models have only provided some in-
sight on the pathophysiology and
strategies for better treatment.
SD is likely a multifactorial skin
disease that develops due to both
endogenous and exogenous pre-
disposing factors. The influence of
androgens is suggested by the find-
ings that the disease is more com-
mon in men, can develop at puberty
(the age when sebaceous glands are
most active), and it affects sebaceous
gland-rich body areas.1,5 The casual
lipid composition of the skin surface
in males with SD differs from that of
unaffected controls.9
An infection with Malassezia can
also play a role in the pathogenesis
of SD. Louis-Charles Malassez (1842-
1909) first proposed the connection
between SD and fungi in 1874.10 Lipo-
philic yeasts of the genus Malassezia
(former Pityrosporum) are commen-
sals of the microbiota found on nor-
mal skin in 75-98% of healthy adults.
Malassezia possess the ability to me-
tabolize fatty compounds in sebum.
This family of yeasts causes pityria-
sis versicolor and Malassezia follicu-
209
litis and appears to also be involved
in the pathogenesis of common skin
disorders, such as psoriasis, and atop-
ic dermatitis.11 A direct causal link be-
tween Malassezia yeast and SD has
been proposed based on the distribu-
tion of Malassezia species on the skin
of lipid-rich anatomic locations, such
as the face, scalp, and trunk12 on the
presence of Malassezia in affected SD
skin, and on the therapeutic response
seen to antifungal agents.3 Improve-
ment of SD is accompanied by reduc-
tion in the yeast on the scalp, whereas
recolonization leads to disease recur-
rence.13-15 A causative link between
SD and Malassezia was further sup-
ported by the finding that patients
with dandruff who had responded to
nystatin relapsed when nystatin-re-
sistant Pityrosporum (Malassezia)
was reintroduced.16 Among the sev-
eral Malasezzia species recognized
to date, Malassezia restricta and
Malassezia globosa are considered
the most important pathogenic or-
ganisms in the development of SD.11,17-21
Several studies have shown disputing
results that may be associated with
the environmental conditions in dif-
ferent countries. Analyses of the com-
plete genome of Malassezia globosa
and the partial genome of Malassezia
restricta have presented gene encod-
ing enzymes of the lipase and phos-
pholipase families that could explain
the lipid dependency of the genus.19
It was proposed that lipases may be
related to the development of SD and
could be considered as virulence fac-
tors. These enzymes may provide the
ability to metabolize lipids and to in-
tegrate the fatty acids into the fungal
cell wall, and thus are very important
for yeast growth.22 However, not all
Malassezia globosa or Malassezia re-
stricta strains can be isolated from SD
suggesting that there may be specific
strain-determined phenotypic charac-
ters of different fungi that account for
their ability to cause disease.17
The exact mechanism by which the
skin lesions are induced remains un-
known. Neither the number of yeasts
nor their morphology are related to
the skin lesions.
Yeasts have been considered in
the past incidental to primary inflam-
matory dermatoses resulting in in-
creased cell turnover and epidermal
inflammation, e.g. in psoriasis.23,24 Evi-
dence used in favor of this “hyperpro-
liferative theory” included the failure
of patients with dandruff to respond
to topical amphotericin B and the re-
sponse to keratolytic and anti-inflam-
matory medications, such as salicylic
acid and corticosteroids.24 Psoriasis
shares some clinical characteristics
with SD. When both psoriasis and SD
are localized exclusively on the scalp
with no involvement of other skin
sites, a skin biopsy may not discrimi-
nate these two conditions.
 Since SD is more common in im-
munosuppressed patients, immune
mechanisms may be important in the
pathogenesis of the disease.25 In a
DBA/2 2C TCR transgenic mouse and
the loss of MPZL3 function in mouse
a localized inflammatory skin disease
on maturity, with striking skin scaling
similar to SD were detected.26,27 This
mouse does not have T-cell progenitor
thymocytes and are lymphopenic for
both CD4+ and CD8+ cells. Yeast-like
organisms were seen in affected hair
follicles, and the condition responded
to treatment with fluconazole. Hu-
moral as well as cellular immunity has
been studied in patients with SD with
conflicting results. With regard to cel-
lular immunity, a low CD4+/CD8+ ratio
was found in 68% patients,28 whereas
a normal ratio was found in all pa-
tients with SD in other studies.25,29 In
patients with SD, no specific defects
in T-cell function have been shown to
explain the link with HIV infection, nor
is there evidence of contact sensitiza-
tion.30 Malassezia yeast may reduce
the production of pro-inflammato-
ry cytokines which is related to the
presence of lipid-rich microfibrillar
layer surrounding yeast cells.31 High
amounts of lipids may prevent the
yeast cell from inducing inflammation
in consistence with their commensal
status. An altered lipid layer in SD
may explain the inflammatory nature
of the disease.32 Immunohistochem-
ical studies in patients with SD have
shown increased production of cyto-
kines such as interleukin (IL)-1a, IL-1b,
tumor necrosis factor-a, interferon-g,
IL-12, and IL-4 in the lesional skin com-
pared with non-lesional skin.33
Malassezia is a non-pathogenic
skin commensal that can undergo
transition to a pathogenic form un-
der favourable conditions.34 At high
concentrations, it reduces the protec-
tive barrier of the skin and affects the
control of inflammation.35 The pres-
ence of host susceptibility factors
associated with immune response
and inflammation could explain the
lack of correlation between the pres-
ence and number of yeasts and the
presence and severity of dandruff. In
a study using DNA microarrays, the
most striking feature of lesional dan-
druff scalp skin relative to normal was
the reciprocal expression of induced
inflammatory genes and repressed
lipid metabolism genes. Induced in-
flammatory genes were also enriched
in dandruff uninvolved skin, suggest-
ing the existence of predisposing fac-
tors associated with inflammation.36
The expression of the gene-encoding
fatty acid synthase, the rate-limiting
enzyme in fatty acid biosynthesis, was
diminished by nearly 50% in dandruff
lesional skin versus non-dandruff.37
Metabolites produced by Malasse-
zia species may play a key role. The
current hypothesis for SD/dandruff
pathogenesis associates individual
210
susceptibility with the penetration ing Parkinson’s disease,44 neuroleptic
of irritating Malassezia metabolites, induced parkinsonism,45 tardive dyski-
such as oleic acid, through a defective nesia,46 traumatic brain injury, epilepsy,
epidermal barrier.38 facial nerve palsy, spinal cord injury and
mood depression,47 chronic alcoholic
SD and dandruff have a strong pancreatitis,48 hepatitis C virus,49 and in
temporal correlation with sebaceous patients with congenital disorders, such
gland activity, with cradle cap after
birth, increased incidence throughout
the teens, between third and sixth
decades and then decreasing.39 How-
ever, seborrheic dermatosis patients
may have normal sebum production,
and individuals with excessive sebum
production sometimes do not devel-
op seborrheic dermatosis.40 These
findings suggest that while seba-
ceous glands activity strongly cor-
relates with seborrheic dermatosis
and dandruff, sebum production by it-
self is not a decisive cause. In addition
to the level of sebum production, ab-
normalities of lipid composition may
also play a role in SD development,
likely through a favorable milieu for
Malassezia growth.9 In patients with
SD, triglycerides and squalene were
reduced, but free fatty acids and cho-
lesterol were considerably elevated.41
COMORBID DISORDERS
The disorder is more prevalent in im-
munocompromised patients (Fig. 18-8), Fig. 18-8. 33-year old male patient
such as organ transplant recipients42 with centrofacial scaling at the na-
and patients with human immunodefi- solabial folds. Erythema is not visible
ciency virus infection (30-83%).9,43 SD since the patient is under systemic
is also associated with neurological dis- corticosteroids due to a systemic im-
orders and psychiatric diseases, includ- munological disease.
as Down syndrome.50 Furthermore,
seborrhea-like dermatitis may develop
in tumor patients,51 while SD of the face
may also develop in patients treated for
psoriasis with psoralene and ultraviolet
A (PUVA) therapy,52 with rates up to
83% compared with 1% to 3% seen in
the general population, suggesting that
the immune system is important in the
pathogenesis of the disease (Fig. 18-6).53
Patients with unilateral Parkinson-
ism may exhibit bilateral seborrhea.
In addition, the circulating a-melano-
cyte-stimulating hormone in patients
with Parkinson’s disease is elevated.54
Therefore, the underlying mechanism
of changes in skin sebum levels is
probably of endocrine origin.55,56 SD
often presents a seasonal pattern,
with increasing presentation during
the winter. Exposure to sunlight typ-
ically improves the disease however,
there are cases of disease develop-
ment subsequent to psoralen plus ul-
traviolet A treatment.57
Most cases of SD in HIV patients
are diagnosed with CD4+ T lympho-
cyte counts between 200 and 500/
mm3. Decreased CD4+ counts are of-
ten associated with worse forms of the
disorder.26 These observations suggest
that immunological defects may also
play a role in SD (Figs. 18-9 y 18-10).
Stress conditions could be a rea-
son of disease recurrence.58
Fig. 18-9. Severe adult seborrheic dermatitis at the perioral area and the nose
of a male patient with HIV infection. [Courtesy Dr. Ana Kaminsky].
DIFFERENTIAL DIAGNOSIS
The major differential diagnoses of
SD are facial and scalp psoriasis and
similarly localized atopic as well as al-
lergic contact dermatitis. Psoriasis of
the face represents a difficulty in the
differential diagnosis and seborrhiasis
(sebopsoriasis) is a term usually ap-
plied for overlapping conditions (Fig.
18-6).59 Atopic dermatitis and allergic
contact dermatitis are further diseas-
es, which belong to the differential di-
agnosis of SD.60-62 The disease belongs
to the reasons that can induce a red
face disease.58 Confocal microscopy
may support the differential diagnosis
of SD and psoriasis in the future.63
211
Further differential diagnoses that
may occur occasionally include facial
(perioral) candidiasis, impetigo, lichen
simplex chronicus, rosacea, discoid or
subacute cutaneous lupus erythema-
tosus and tinea capitis.
CLINICAL PICTURE
The use of varying terms such as
sebopsoriasis, SD, seborrheic ecze-
ma, dandruff, and pityriasis capitis
reflects the vast clinical spectrum of
SD and the controversy regarding its
etiology, being considered at times
a form of dermatitis, a precursor of
psoriasis or a fungal disease. Diagno-
sis remains a clinical one, based on
the characteristic clinical morpholo-
gy of erythema and scaling and the
distribution of lesions on the scalp,
nasolabial folds, eyebrows, postauric-
ular areas, and the sternum (Figs. 18-1
a 18-6). The distribution of lesions is
generally symmetrical. Pruritus may
occur. On the face, it is characterized
by erythematous areas with overly-
ing, non-adherent, yellowish greasy
scales. Scales are easily raised and
the surface underneath may ooze a
little, especially during the flare-up
periods. Patches locate in the nasal
folds, but easily spread to the sur-
rounding areas, glabella, and inner
part of the eyebrows and along the
frontal hairline (corona seborrhei-
ca). In infants, it may present as thick
white or yellow greasy scales on the
scalp; it is usually benign and re-
solves spontaneously.
Dandruff is restricted to the scalp,
and involves itchy, flaking skin without
visible inflammation. Flaking in SD
and dandruff is usually white-to-yel-
low (Fig. 18-7).
The histological picture shows
follicular plugging, shoulder paraker-
atosis and prominent lymphocytic
exocytosis and occasionally spon-
giosis.64 No immunohistochemistry
characteristic picture occurs. The di-
agnosis can be challenging in patients
with darker skin, but the same princi-
ples apply.
 TREATMENT
Although seborrheic dermatosis is a
chronic disease with no permanent
cure, a variety of treatment options
are available that can effectively treat
this condition. Therapy centers on the
control of acute flares and on main-
taining remission with long-term ther-
apy. Efficacy, ease of use, safety, and
compliance issues need to be consid-
ered when selecting a treatment to
provide the best clinical outcome. The
age of the patient is also an important
consideration (Tables 18-2-18-4).4,65-68
In a Cochrane database systematic
review of topical SD treatment, 51 stud-
ies with 9052 participants have been
included.65 Of these, 45 trials assessed
treatment outcomes at five weeks or
less after initiation of treatment, and
6 trials assessed outcomes over a lon-
ger time frame. 24 trials had funding
by pharmaceutical companies. Among
the included studies, 12 trials investi-
gated ketoconazole (patient number
n=3253), 11 ciclopirox (n=3029), 2 lithi-
um (n=141), 2 bifonazole (n=136) and one
clotrimazole (n=126) that compared
the effectiveness of these treatments
versus placebo or vehicle. Nine keto-
conazole (n=632) and one miconazole
trial (n=47) compared these treatments
versus corticosteroids. Fourteen stud-

Table 18-2. Evidence based treatment of seborrheic dermatitis (revised

from 67)

Evidence
Clinical recommendation rating References

Topical antifungal agents are the first-line therapy for acute and A 65-67; 69-111;
long-term treatment of seborrheic dermatitis of the face and 114-116; 123
body.

Topical corticosteroids are effective in treating seborrheic A 68-67; 117-122

dermatitis and should be used sparingly to avoid adverse
effects.

Topical calcineurin inhibitors are effective, well-tolerated A 66, 67, 118-128

Fig. 18-10. Disseminated facial erythema and minor scaling in a
male patient with adult seborrheic dermatitis and HIV infection.
[Courtesy Dra. Ana Kaminsky].
212
second-line treatments for seborrheic dermatitis (not approved
by EMA/FDA for this use).
A = consistent, good-quality patient-oriented evidence
Table 18-3. Treatments for scalp seborrheic dermatitis in adults and adolescents Table 18-4. Treatments for facial and body seborrheic dermatitis in adults
(revised from 67) and adolescents (revised from 67)

Compound Dose Common adverse effects Compound Dose Common adverse effects
Over-the-counter preparations Topical antifungals
Coal tar shampoo 2x/week Contact dermatitis, folliculitis, photosensi- Ciclopirox 0.77% gel or cream 2x/day for up to 4 weeks Burning, contact dermatitis, pruritus
tivity
Ketoconazole 2% cream, foam or gel 2x/day for 8 weeks, Burning, irritation, photosensitivity
Selenium sulfide shampoo 2x/week Alopecia, hair discoloration, irritation then as needed
Tea tree oil shampoo 1x/day Allergic contact dermatitis, irritation Sertaconazole 2% cream 2x/day for up to 4 weeks Contact dermatitis, tenderness,
xeroderma
Zinc pyrithione shampoo 2x/week Irritation
Topical calcineurin inhibitors*
Topical antifungals
Pimecrolimus 1% cream 2x/day Burning, headache, upper respiratory
Ciclopirox 1% shampoo 1x/day initially, later 2x/ Burning, contact dermatitis, pruritus
infection
week
Tacrolimus 0.1% ointment 2x/day Burning, influenza-like symptoms,
Ketoconazole 2% shampoo 1x/day initially, later 2x/ Irritation, pruritus, xeroderma
pruritus
week
Topical corticosteroids
Topical corticosteroids
Betamethasone valerate 0.1% cream 1-2x/day Hypopigmentation, skin atrophy,
Betamethasone valerate 0.12% 2x/day Hypopigmentation, pruritus, skin atrophy,
or lotion stinging, telangiectasia
foam stinging
Desonide 0.05% cream, foam, gel, 1-2x/day Burning, hypopigmentation, skin
Clobetasol 0.05% shampoo, al- each 2x/week, alternat- Burning, erythema, folliculitis, hypopigmentation,
lotion or ointment atrophy, stinging, upper respiratory
ternating with ketoconazole 2% ing medications, for up pruritus, skin atrophy
symptoms
shampoo to 2 weeks
Fluocinolone 0.01% cream, oil or 1-2x/day Burning, cough, dryness, fever, hy-
Fluocinolone 0.01% shampoo 1x/day Burning, dryness, hypopigmentation, skin
solution popigmentation, irritation, pruritus,
atrophy
rhinorrhea, skin atrophy
Fluocinolone 0.01% solution 1-2x/day Burning, cough, fever, hypopigmentation,
Hydrocortisone 1% cream or 1-2x/day Burning, hypopigmentation, pruritus,
pruritus, rhinorrhea, skin atrophy
ointment skin atrophy
Topical calcineurin inhibitors*
* off-label use.
Tacrolimus 0.1% ointment 2x/day Burning, influenza-like symptoms, pruritus
* off-label use

213
ies (n=1541) compared one antifungal
versus another or compared different
doses or schedules of administration
of the same agent versus one anoth-
er. Topical ketoconazole 2% treat-
ment showed a 31% lower risk of failed
clearance of rashes compared with
placebo [risk ratio (RR) 0.69, 95% con-
fidence interval (CI) 0.59-0.81, 8 stud-
ies, low-quality evidence) at 4 weeks
of follow-up, but the effect on side ef-
fects was uncertain because evidence
was also of very low quality (RR 0.97,
95% CI 0.58-1.64, 6 studies). Hetero-
geneity between studies was substan-
tial (I2=74%). The median proportion
of those who did not have clearance
in the placebo groups was 69%. Ke-
toconazole treatment resulted in a
remission rate similar to that of corti-
costeroids (RR 1.17, 95% CI 0.95-1.44, 6
studies, low-quality evidence), but oc-
currence of side effects was 44% lower
in the ketoconazole group than in the
corticosteroid group (RR 0.56, 95% CI
0.32-0.96, 8 studies, moderate-quality
evidence). Ketoconozale yielded a sim-
ilar remission failure rate as ciclopirox
(RR 1.09, 95% CI 0.95-1.26, 3 studies,
low-quality evidence). Most compari-
sons between ketoconazole and other
antifungals were based on single stud-
ies that showed comparability of treat-
ment effects.
Ciclopirox 1% led to a lower failed
remission rate than placebo at 4
weeks of follow-up (RR 0.79, 95% CI
0.67-0.94, 8 studies, moderate-quality
evidence) with similar rates of side ef-
fects (RR 0.9, 95% CI 0.72-1.11, 4 stud-
ies, moderate-quality evidence).
Clotrimazole and miconazole effi-
cacies were comparable with those
of corticosteroids on short-term as-
sessment in single studies. Treatment
effects on individual symptoms were
less clear and were inconsistent, pos-
sibly because of difficulties encoun-
tered in measuring these symptoms.
Evidence was insufficient to conclude
that dose or mode of delivery influ-
enced treatment outcome. Only one
study reported on treatment com-
pliance. No study assessed quality
of life. One study assessed the max-
imum rash-free period but provided
insufficient data for analysis.
One small study in patients with
HIV compared the effect of lithium
versus placebo on SD of the face, but
treatment outcomes were similar.
A more current systematic review
conducted as a critical analysis of the
selected 32 studies -encompassing 18
topical treatments for facial SD- by
grading the evidence and qualita-
tively comparing results among and
within studies.66 Pimecrolimus, being
the focus of 7 studies, was the most
commonly studied topical treatment
and an effective alternative to topical
antimycotic agents and corticoste-
214
roids. A non-steroidal anti-inflamma-
tory cream (Promiseb®), desonide and
mometasone furoate were also found
to be effective topical treatments
for facial SD, as they had the lowest
recurrence rate, highest clearance
rate, and the lowest severity scores
(e.g. erythema, scaling, and pruritus),
respectively. Ciclopirox olamine, ke-
toconazole, lithium (gluconate and
succinate), and tacrolimus were also
strongly recommended (level A rec-
ommendations) topical treatments
for facial SD, as they were consistent-
ly effective across high-quality trials
(randomized controlled trials).
Controversial emerging therapies
include keratolytic agents, pyrithione,
selenium sulphide, metronidazole, and
antimicrobial peptides as well as sys-
temic compounds.4,65-68
Topical urea is a known keratolyt-
ic129,130 and propylene glycol is used
as an excipient and has keratolytic ef-
fects. Lactic acid has keratolytic and
hydrating properties. All these agents
may inhibit the growth of bacteria and/
or fungi.131 A topical keratolytic-con-
taining urea, propylene glycol, and lac-
tic acid, applied daily for 4 weeks, was
assessed for the treatment of mild to
severe SD of the scalp in 88 patients,
in two randomized, double-blind, pla-
cebo-controlled, multicenter trials, and
significant improvement in erythema
and desquamation was shown.129
Pyrithione is a zinc ionophore, fa-
cilitating zinc transport across mem-
branes. Zinc pyrithione inhibits fungal
growth through increased cellular lev-
els of copper, damaging iron-sulphur
proteins that are essential for fungal
metabolism.37,110,132
Selenium sulfide has also been
used for SD treatment due to its
fungicidal activity to Pityrosporum
ovale and keratolytic effects. It is
available in various formulations, such
as shampoo, lotion, cream, foam, and
suspension. Orange-brown scalp
discoloration has been described in
children after the application of se-
lenium sulfide 1% shampoo for SD. It
was stated that this side effect should
be borne in mind and not be confused
with Langerhans cell histiocytosis.
This discoloration is reversible and
can easily be removed with an isopro-
pyl alcohol swab.107,108,119,133
A randomized controlled, blind-
ed study in 60 patients with facial
SD showed that metronidazole
0.75% gel applied for 4 weeks, had
similar efficacy (63% mean percent-
age decrease in clinical disease se-
verity scores) and safety profile to
ketoconazole 2% cream. The ratio-
nal of use of topical metronidazole
is its anti-inflammatory action via in-
hibition of free radical species and
subsequent oxidative tissue dam-
age.121,134
 For infantile SD, a moisturizer
containing 0.025% licochalcone was
compared with 1% hydrocortisone,
for 14 days, in a prospective, split-side,
double-blind study in 72 infants (ages
2 weeks to 1 year). These two treat-
ments showed similar response rates
(90%; P = 0.317). Licochalcone is an
extract from Glycyrrhiza inflata. It is
a natural product that has anti-inflam-
matory and antimicrobial effects.135
Antimicrobial peptides (AMPs)
are an emerging concept as an innate
defense mechanism of the epithelial
barrier. Cathelicidins and other cat-
ionic AMPs are active against Malas-
sezia furfur.136,137 Cecropin A (CA) and
magainin 2 (MA) are non-cytotoxic
AMPs acting via the formation of ion
channels, with subsequent disruption
of bacterial phospholipid bilayers and
eventual cell death. A modified syn-
thetic AMP, P5, which is a synthetic
CA-MA hybrid peptide analogue,
was studied against M. furfur in nor-
mal human keratinocytes. P5 showed
potent antifungal action, and it was
3-4 times more potent against Malas-
sezia furfur than ketoconazole or
itraconazole in vitro. Also, it had an-
ti-inflammatory properties, inhibiting
the expression of IL- 8 and Toll-like
receptor 2 in Malassezia furfur-in-
fected human keratinocytes, and
downregulating nuclear factor-kB
activation and intracellular calcium
fluctuation.34
Regarding systemic therapies, oral
antifungals have been used in selected
cases of extensive SD resistant to top-
ical therapies. Oral ketoconazole, 200
mg daily for 4 weeks, was effective for
SD of the scalp and body. Itraconazole
200 mg daily for 7-28 days has also
been shown to also be effective.138 An
advantage of itraconazole is the re-
ported reduced risk for hepatotoxic-
ity compared to ketoconazole.5 Pulse
itraconazole treatment has also been
shown to be effective.139 Because oral
terbinafine (a fungicidal allylamine) is
not effective for pityriasis versicolor,
a skin disease caused by Malassezia
species, this agent is not used for SD.
Isotretinoin 10 mg every 2nd day can
be used as alternative to oral antifun-
gal agents.140
IL-1a receptor (IL-1aR) and IL-18
have currently been shown to be in-
volved in seborrheic dermatosis ex-
acerbations. 141 Next to the IL-1aR
antagonist anakinra and the soluble
decoy rilonacept, the anti-IL-1a mono-
clonal antibody MABp1 and anti-IL-1b
canakinumab but also gevokizumab,
LY2189102 and P2D7KK, offer valid al-
ternatives to target IL-1.
Topical antifungals or topical corti-
costeroids are, therefore, the first line
treatment for seborrheic dermatosis
and are sometimes used in combina-
tion.65-68 Topical antifungals are used
in the treatment of seborrheic der-
215
matosis because of their ability to re-
duce Malassezia proliferation and the
subsequent inflammatory response.
Topical antifungals are safe to use for
all skin areas, even thin, sensitive skin,
and in infants.
Some therapies are better suit-
ed for treatment of the acute flare,
whereas others are more adaptable
for long-term maintenance therapy to
reduce the frequency and intensity of
exacerbations. Topical corticosteroids
should be reserved for the control of
acute flares. Topical corticosteroids
should be used in a limited body
area and for a short period of time,
with extra caution being paid when
treating children. Patients should be
advised to follow the application in-
structions and not to extend the du-
ration of treatment beyond what is
recommended, to avoid permanent
side effects such as skin atrophy and
telangiectasias.
Topical calcineurin inhibitors are
an effective alternative to topical an-
timycotic agents and corticosteroids
because of their immunomodulatory
and anti-inflammatory properties.66,142
A 2% shampoo formulation of keto-
conazole has been used successfully
as a prophylactic treatment to prevent
recurrence of the disease symptoms
and as maintenance therapy (once
weekly) to sustain clinical improve-
ment.83,143 More studies also may be
conducted to further evaluate topical
pimecrolimus and tacrolimus as a long-
term maintenance therapy for SD.
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Acne is not uncommon in adults, par-
ticularly adult females, and in this age
group can pose diagnostic challenges
in determining whether lesions are
due to acne or rosacea.
Along with the common form of
polymorphous juvenile acne, adult
female acne has been recently de-
scribed and defined. Literature
shows that this entity primarily af-
fects women over 25 but can also oc-
cur in women as young as age of 20
(i.e immediately post-adolescence).
It has the same characteristics in the
immediate post-adolescent patient
as acne observed in older women.
Being a well-defined entity, adult
acne should also be differentiated
from juvenile acne. The prevalence
of adult acne varies across studies,
depending on the population con-
sidered (general population includ-
ing men, women over 20 or over
25 years of age), between 41% and
54%.1-3 Up to 75% of black Senega-
lese women had adult acne when
analyzed in dermatologic consulta-
tions.4
According to age at onset, two
subtypes are distinguished: continu-
ous, an extension of adolescent acne
into adulthood, including possible
periods of remission, and the less
frequent late-onset,5 appearing in
around 25% of women after 20 years
of age.1,6
In contrast to adolescent acne, which
Chapter 19 is most typically located on the facial
T-zone, adult women have lesions lo-
Adult Acne cated on the U-zone (cheeks, chin, and
perioral area). In adults, nodules are
always found in the lower region of
and Rosacea:
the face (Fig. 19-2) and may exist when
there is no other inflammatory lesion
(papule or pustule). They are few in
number and can occur in periodic in-
A Diagnostic
flammatory outbreaks, which are quite
characteristic.
Challenge
There may be no comedones in
adult acne; if there are, their number
is typically lower than that of inflam-
matory lesions. These are generally
Mélanie Saint Jean, Brigitte Dreno mild (Fig. 19-3) to moderate (Fig. 19-
4) forms of acne.6 The traditionally
CLINICAL MANIFESTATIONS
The clinical profile of the female adult
with acne was recently determined
by a literature review7 and an interna-
tional prospective study including 374
patients.6
Two forms of clinical presentations
are possible. The first profile is close to
adolescent acne, and includes non-in-
flammatory (comedonal) lesions and
inflammatory lesions (with possible
nodules). This type of adult acne in-
volves the trunk in approximately 50%
of cases. The second clinical pattern
is the one classically described, and is
characterized by lesions predominant-
ly located on the mandible (Fig. 19-1). Fig. 19-1. Adult female acne with mandibular inflammatory lesions.
222
Fig. 19-2. Adult female acne. Form with nodules found in lower mid-face. Fig. 19-4. Mandibular rosacea. Moderate form.
used acne severity assessment scales
determine severity according to the
number of facial lesions;8 however, in
these patients significant neck com-
promise with few facial lesions may
be found. A scale specifically devot-
ed to female adults has been recently
developed, including mandible com-
promise severity.9 In a small number
of patients it may be severe acne (Fig.
19-5); however, no cases of acne fulmi-
nans or conglobata have been report-
ed among this population.
Hormonal Factors
A relationship between adult female
Fig. 19-3. Mandibular rosacea. Mild form. acne and hormonal factors has been
223
suggested, due to women report-
ing an increase of lesions around the
time of menstruation.1,10 Serum andro-
gen levels were studied among adult
women with acne, and the frequency
of abnormalities ranges from 17.6%6 to
86%.11,12 These results may be overesti-
mated because several studies include
women with irregular cycles or hirsut-
ism, while others are included women
who suffer from acne without any oth-
er clinical sign of hyperandrogenism. In
one study, sex hormone-binding glob-
ulin (SHBG) serum levels were nega-
tively correlated with the severity of
acne, possibly through an increase in
free testosterone levels.13 Conversely,

Fig. 19-5. Adult female acne. Severe diffuse form.
3 other studies showed no relationship
between abnormal serum androgen
levels and acne severity.11,14,15 In addition,
when comparing adult women with
acne versus a control population, high-
er serum dehydroepiandrosterone sul-
fate (DHEAS),12,14 d4-androstenedione,12
dihydrotestosterone (DHT),15 or free
testosterone can be observed.12,15 Final-
ly, serum DHEA sulfate, DHT and IGF-1
levels correlate positively with acne le-
sions counts.16
In practice, association of adult
acne with an underlying hormonal
cause is infrequent; however, cli-
nicians are justified in evaluating
patients for associated hyperandro-
genism clinical signs, such as hirsut-
ism, male type alopecia, weight gain,
amenorrhea or oligomenorrhea, and
infertility. If no signs of hyperandro-
genism or menstrual cycle disorders
are shown, no hormonal testing is
indicated. In fact, within the con-
text of adult female acne, hyperan-
drogenism occurs due to possible
hypersensitivity of androgenic re-
ceptors but not due to biological
hyperandrogenism.11 Adult male acne
is less frequent and more difficult to
estimate, because it is essentially lo-
cated on the back and is often asso-
ciated with hyperseborrhea.3
Acne as an Indicator of
Hormonal Imbalance (Biological
Hyperandrogenism)
In certain cases, acne is a symptom
of biological hyperandrogenism.
Androgens are synthesized in the
ovaries and adrenal gland from cho-
224
lesterol and progesterone. They may
also result from a peripheral con-
version from inactive precursors (in
the liver, muscles, and skin). D4-an-
drostenedione originates from the
ovaries and adrenal glands; dehy-
droepiandrosterone sulfate essen-
tially from the adrenal gland, and
17b-hydroxyprogesterone from the
ovary. Acne may be related to func-
tional hyperandrogenism; the most
commonly reported cases are poly-
cystic ovary syndrome and late-onset
21-hydroxylase deficiency.
Also, although more infrequent-
ly, tumor hyperandrogenism (ovar-
ian or adrenal tumor) and Cushing
syndrome may be present. In these
cases, acne is associated with other
symptoms, such as irregular and pain-
ful periods, obesity, hypertrichosis or
hirsutism. The association of these
signs with acne suggests a possible
hormonal imbalance and endocrine
studies are required: an ovarian ultra-
sound scan (transvaginal if possible)
and a laboratory study. Diagnostic
signs on the ultrasound scan include
an increase in the volume of the ova-
ries and a number of follicles greater
than.12 The laboratory study should
be performed early in the morning,
during the first part of the cycle (be-
tween the 3rd and 6th day) and two
months after all hormonal contracep-
tive treatment has been discontinued.
It includes determination of testoster-
one and 17-OH progesterone before
and after an ACTH test. Certainly,
SHBG and DHEAS can also be test-
ed. Normal testosterone levels and a
normal ultrasound scan enable a diag-
nosis of “idiopathic” hirsutism.
Induced Acne
Exogenous
Although cases of acne induced by
tar or chlorine have been reported,
it is advisable to systematically seek
the use of inadequate cosmetics or
acne-inducing drugs in adult women
during clinical assessment.
Cosmetic acne is caused by vege-
table oils or liquid paraffin (also called
petroleum jelly or Vaseline) found in
topical products, sometimes also by
the direct use of essential oils on skin
(Fig. 19-6). On the other hand, repeat-
ed friction or occlusion (helmet, back-
pack) can generate acne mechanica,
which is usually comedonic.17 The ex-
istence of lesions located in a limited
area or unilaterally on the face sug-
gests the need to look for an inducing
factor, such as friction.18
Iatrogenic
Some drugs, such as local or sys-
temic corticosteroids, tuberculostatics
(isoniazid, rifampicin) or even antiepi-
leptic drugs and lithium salts, can in-
duce acne-like lesions. These lesions
are monomorphic, most often inflam-
matory (papules, pustules) induced by
Fig. 19-6. Aggravated inflammatory acne from topical use of essential oils.
the inflammatory reaction developed
around the pilosebaceous follicle.
Comedones or microcysts are rare or
absent.
Acne Induced by Hormonal
Contraceptive Treatments
Most progestogens produce an ago-
nistic effect when they bind to andro-
gen receptors and become potentially
androgenic. They can induce or ex-
acerbate acne. Five progestogens
have antiandrogenic activity in vitro:
cyproterone acetate, chlormadinone
acetate, dienogest, drospirenone and
norgestimate.
Excoriated Acne
Often, excoriations (Fig. 19-7) caused
by continuous physical manipula-
tion are also found in acne lesions.
It may be the expression of an un-
derlying fragile psychic structure,
which should be taken into ac-
count in therapy. It may be difficult
to break the vicious cycle of exco-
riation, especially since untimely
manipulations are often associated
with inadequate cosmetology care.
It is worth educating patients about
the increased likelihood of scarring
after this type of repeated micro-
traumas.
225
Fig. 19-7. Excoriated acne.
DIFFERENCES BETWEEN ADULT
ACNE AND ROSACEA
The onset of rosacea is more fre-
quently observed after the fourth de-
cade. While there are pediatric forms,
these are exceptional.19 Rosacea fre-
quency increases with age and peaks
around 50, which in women roughly
corresponds to menopause.20 Occa-
sionally, there may be patients whose
condition began almost immediately
after the end of acne. Blush may ap-
pear after the age of 20, often on a
seborrheic background with closed
comedones; later the disease evolves
into an authentic rosacea.
In the erythematotelangiectatic
and papulopustular forms, there is
a clear female predominance, with
women comprising about 70% of
the cases.20,21 On the contrary, in the
hypertrophic form, particularly in
rhynophyma, there is a clear male
predominance with over 90% of cas-
es among men.
Another important difference with
adult acne is the type of skin. Rosacea
is predominantly found in subjects
with fair skin, blue eyes and blond hair.
Formerly known as the “disease of the
Scandinavian countries”, a frequency
gradient from northern to southern
Europe is noted. The more matt the
skin, the lower the risk of developing
rosacea. Adult acne can be observed
on any skin type.
Differential diagnoses of rosacea
with adult acne depend on its clinical
form.
Vascular Form or
Erythematotelangiectatic Rosacea
The vascular form of rosacea, the
earliest one, is typically marked by
three main elements which may
occur singly or all together: back-
ground erythema or erythrosis, and
telangiectases or couperose, two
permanent elements, and the par-
oxysmal vasomotor phenomenon or
flushing (Fig. 19-8).
Erythema in rosacea has character-
istic locations: it affects the mid-face
area, i.e. malar regions, in an invert-
ed triangle shape across the nose
and the center of the forehead and
chin. Symptomatically, the periocular
and perioral areas are not affected.
Rosacea-associated erythema disap-
pears during vitropressure. However,
some patients have raised areas, ac-
companied by a discrete edema or a
hard-edematous infiltration. This is
sometimes referred to as solid facial
edema.22 These forms correspond to
what Degos described as Morbihan
disease (see Chapter 20).
Telangiectases or couperose are
located in the malar regions, but
also on the nose, especially the nasal
wings. They very often extend over
the whole cheek and reach the man-
dible area. They may become fairly
large and profuse. Erythema worsens
over time, as well as telangiectases.
The whole face can be affected, in-
cluding the scalp in bald men. How-
ever, even in severe forms, unscathed
areas around the eyes and mouth per-
sist.
A mixed clinical pattern is more
frequently observed, where a back-
ground erythrosis and telangiectases
are associated, also known as the ery-
thematotelangiectasic state, or eryth-
rocouperose. Fig. 19-8. Erythematotelangiectasic rosacea.
In this vascular form, flushing par- Patients affected by this vascular ly associated with adult acne. In pre-
oxysmal phenomena are associated. form complain of abnormal skin sen- menopausal or menopausal women,
Flushing episodes may be very fre- sitivity, especially to heat.24 They often heat strokes and flushing are attribut-
quent, have no general signs and are poorly tolerate topical products, re- ed to this process. Telangiectases are
mainly triggered by changes in room gardless of their nature, because these most likely to occur in patients with
temperature or professional activ- products lead to feelings related to history of sun exposure.
ity, as well as by the consumption of skin tightness, burning or discomfort.25
hot drinks.23 Alcohol and spicy foods This can be objectified by the stinging Papulopustular Rosacea
can also trigger flushing in some test, which consists of measuring the Papulopustular rosacea (PPR) is the
people. Patients often complain of reaction after applying lactic acid.26 most classical form of rosacea, which
thermo-phobia and poorly cope with This test is positive in the vast majority in the past was referred to as the
high temperatures, particularly over- of patients with vascular rosacea. “state phase”.27 Usually in PPR there is
heated places, and notably saunas. a background of erythema and telan-
Likewise, physical activity frequently The diagnosis for this form of rosa- giectases includes papules and pus-
produces a very annoying facial flush- cea is mainly clinical. It is based on the tules. These are very small in size, not
ing and a feeling of warmth that leads topography of erythema, flushing and exceeding a few millimeters. Pustules
to limiting this type of activity. telangiectases. Flushing is very rare- can be follicular or extrafollicular (Fig.
226
19-9). Unlike acne, there are no com-
edonal lesions; therefore, presence/
absence of non-inflammatory lesions
is considered an essential differentiat-
ing diagnostic criterion. Inflammatory
lesions develop through successive
outbreaks, unpredictably, with phases
of spontaneous improvement. Con-
versely, erythema and telangiectases
are permanent. Triggering factors
of papules and pustules are not well
known. In most cases, papules and
pustules are confined to the areas af-
fected by erythema. However, some
specialists describe extrafacial lo-
cations, particularly in the cleavage.
The elements located on the back
and limbs are much more difficult to
include in the context of rosacea. As
these lesions are hardly ever sought
systematically, their actual prevalence
remains unknown. These characteris-
tics of extrafacial rosacea may be con-
fused with adult acne.
Occasionally, there are papulopus-
tular forms that are unilateral or with
a clear predominance on one side. In
severe untreated or neglected forms,
the number of lesions varies from iso-
lated elements to several hundreds.
The existence of an intense violet
erythema, with large telangiectases
beyond usual areas, should suggest a
diagnosis of steroid-induced rosacea.
It is an induced form or aggravated by
corticosteroid therapy, which is initially
Fig. 19-9. Papulopustular rosacea.
very effective in reducing erythema.
The chronic application of steroids, in-
cluding low potency ones, is responsi-
ble for aggravating and perpetuating
this clinical pattern. After some time
the corticosteroid no longer produces
227
a vasoconstrictive effect, cytes and polymorphonuclear cells.28
and the condition inex- The appearance of granulomatous
orably worsens. When- rosacea differs from granuloma in
ever there is an atypical sarcoidosis. A characteristic sign may
lesion, particularly on the be sometimes observed: the granulo-
eyelids and in contact ma bears a central hole (“sign of the
with the lips, the applica- Strasbourg hole”) surrounded by some
tion of a corticosteroid polymorphonuclear cells. Serial cuts
should always raise con- allow the identification of Demodex or
cerns. These very same their remains in this empty space. This
circumstances are also is a borderline granulomatous rosacea,
observed in adult acne. making diagnosis more complex.29
Another form of Mixed Facial Dermatosis
rosacea, such as the Seborrheic dermatitis, which accom-
granulomatous, is char- panies adult acne in most cases, and
acterized by the ap- rosacea are mainly distinguished by
pearance of multiple primary lesions; thus, in daily prac-
infiltrated chestnut red tice doubt frequently arises between
and yellowish papules these diagnoses. This is because signs
under vitropressure, not are combined with a background er-
seen in adult acne. This ythema, telangiectases and some
is quite infrequent, ac- papulopustules, which is suggestive
counting for less than of rosacea. However, seborrheic der-
10% of the cases. It is matitis also often causes scales on
sometimes referred to eyebrows, nasolabial folds and scalp.
as lupoid rosacea, which Finding some comedones is not un-
should not be confused common with seborrheic dermatitis.
with milliary lupoid. It This form of dermatosis may appear
is predominantly found more frequently in immunosuppressed
in women between 30 patients.30 The skin of patients with
and 50 years of age. seborrheic dermatitis is particularly
The papules are often profuse, larg- sensitive, and topical treatments are
er, and in some cases may affect the often very poorly tolerated. It should
eyelids or the contour of the mouth. also be noted that some patients on
The characteristic histological sign is oral medication may have acne-like
“non-necrotizing granuloma”, which is lesions; but these are typically easy to
made up of epithelioid cells, lympho- distinguish from adult acne.
Periorificial Dermatitis
As its name suggests, this condition is
located in the lower part of the face,
predominantly around the mouth. It
most often begins in the nasogenian
folds, and is characterized by papules
and pustules, often painful, that reach
the angles of the mouth. There is no
flushing and background erythema is
discrete. Periocular locations may also
be present, due to the application of
corticosteroids in that area. Steroid
therapy is one of the identifiable
causes, though not the most frequent.
The use of moisturizers, powders and
make-up bases is the main risk factor
for periorificial dermatitis.31 The histo-
logical presentation is very similar to
that of rosacea. And the primary dif-
ference with adult acne is history of
topical corticosteroid use, perhaps
due to situations unrelated to acne,
such as allergic contact reactions.
However, it may appear simultane-
ously.
Demodicidosis
Demodicidosis, less chronic than ro-
sacea, frequently appears in immu-
nosuppressed subjects, particularly
those infected with HIV or those on
immunosuppressive treatments or
chemotherapy. The onset is abrupt,
with multiple, often itchy, pustules.
Lesions often extend beyond the
typical areas of rosacea, particularly
extending past the jaw line towards
the neck. The biopsy shows numer-
ous Demodex, both in infundibula
and dermis, where they cause a vio-
lent granulomatous or neutrophilic
inflammatory reaction. Some authors
do not separate demodicidosis from
rosacea. Indeed, D. folliculorum plays
a role in rosacea, notably in the gran-
ulomatous forms, where this parasite
is often observed. Demodex is known
to trigger major inflammation when it
leaves its natural habitat, the infundib-
ulum, and activates innate skin immu-
nity. Demodex is a saprophyte of the
skin, especially present in seborrheic
areas, observable in acne. In rosacea,
its density is greatly increased in the
affected areas.32 Blepharitis may be
associated, confirming the diagnosis
of demodicidosis.
Other conditions with papular le-
sions that can cause confusion are
milliary lupoid and micropapular sar-
coidosis. Biopsy removes all doubts.
Hypertrophic Rosacea
This form is represented by rhinophy-
ma (Fig. 19-10). Erythema, telangiecta-
ses and a history of papulopustules in
the center-facial region are frequent.
Follicular orifices dilate, skin thickens
and small polypoid, pseudotumoral
formations appear. Fibrosis settles
progressively. There are several clin-
ical manifestations. Rhinophyma may
be erythematous, purplish, normal
skin color or yellowish in the case of
pronounced actinic elastosis. Signifi-
228
cant production of sebum
and presence of comedo-
nes should not confuse di-
agnosis.
Ocular Rosacea
The most common symp-
toms are burning and a for-
eign body sensation in the
eye, which is often slightly
red. Repeated conjunctivi-
tis, with persistent bulbar
telangiectases, may be the
initial form of rosacea. How-
ever, adult patients with
acne may have conjunc-
tival irritation, infectious
conjunctivitis, or any other
ophthalmic condition due
to many causes unrelated
to rosacea.
Particular Form of Fig. 19-10. Rhinophyma.
Rosacea: Facial Pyoderma
or Rosacea Fulminans forming plaques by coalescence. A
Facial pyoderma is described in Amer- purulent material drains from the
ican literature.33 Some authors believe plaques. Necrotic lesions may also be
it is a very severe form of abrupt onset present (Fig. 19-11). The affected areas
of rosacea in young women (average are the same as those of rosacea, so
age: 20-30 years), sometimes during the inclusion of this condition in the
pregnancy, and with no significant rosacea spectrum is often discussed.
history of acne. It often begins with Healing with no or minimal scarring is
an important seborrhea, occasion- possible.
ally associated with a dark purplish
erythema, predominantly in the cen- The only differential diagnosis is
ter-facial region. All of a sudden, very with acne fulminans, which also starts
large papules and pustules or deep abruptly and develops into necrotic
and painful nodules appear, at times lesions; however, unlike rosacea, it al-
 findings in type I are Enterobacter,
Klebsiella or Escherichia coli, and Pro-
teus in type II.

Complications in Adult Female

Fig. 19-11. Rosacea fulminans.
Acne: Scars
Acne scars are secondary lesions and
represent the final evolution of inflam-
matory lesions. In a large study of 374
adult women with acne, more than
59% displayed scars (Fig. 19-12).6 The
intensity of pigmentation is related to
phototype and sun exposure. Scars
are more marked when skin inflam-
mation is significant and of prolonged
evolution. However, the formation
of scars is not always related to the
severity of acne. In 50% of cases of
female acne, post-inflammatory pig-
mentation is observed, and erythema
in 40% of them.6 Fig. 19-12. Atrophic ice-pick scars.

most always occurs only among males.
Pseudo-acne fulminans, associated
with isotretinoin treatment and repre-
senting a Herxheimer phenomenon,
is reported in both sexes. A history of
isotretinoin use due to severe acne
makes diagnosis easier. Frequently,
systemic signs (temperature, arthral-
gias) are observed, though they are
not found in rosacea fulminans. There
is a long-term course of the disease,
as well as significant scarring.
Rosacea with nodular lesions may
look like acne conglobata. In bacteri-
al culture studies, the most frequent
The differential diagnosis is sim-
ple, as rosacea usually does not leave
scars or they are superficial. Post-in-
flammatory hyperpigmentation is
only seen in high phototypes and se-
vere rosacea.
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12. Vexiau P, Husson C, Chivot M, et
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acne alone compared with women
with acne and/or hirsutism. J Invest
Dermatol 1990; 94:279-283.
13. Borgia F, Cannavo S, Guarneri F, et
al. Correlation between endocrino-
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14. Seirafi H, Farnaghi F, Vasheghani-Far-
ahani A, et al. Assessment of andro-
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Am J Clin Dermatol DOI 10.1007/
s40257-017-0310-0.
Morbihan disease (MD) is an unusu-
al condition that was described by
Robert Degos in 1957 as a chronic
facial erythema and edema. Later, it
was named Morbus Morbihan (from
the Latin morbus, illness or disease).
Morbihan comes from the Breton Ar
Mor-Bihan, after the patient -a farmer
from the Brittany region- who enabled
the description of the clinical picture.1
However, there is a dispute concern-
ing who was the first to describe it. Ac-
cording to Veraldi et al., the first one
was Schimpf, who published four cas-
es between 1956 and 1960; neverthe-
less, no photos remain of these cases.2
Moreover, it has been asserted that
the histopathological images from
Schimpf’s cases included granulomas,
which are now known to be very rarely
present in Morbihan disease. Merklen
et al., called this condition “persistent
massive infiltration of the forehead,
with intense palpebral edema.” The
latter authors concluded by claiming
that the MD denomination is most
properly attributed to Gorin, as it
appeared in 1991, in Journées Derma-
tologiques de Paris. Gorin authored
several publications that attributed
this disease (MD) to different etio-
pathogenic factors.2 Conclusions that
may be drawn from the few published
cases are that MD affects persons of
both sexes with fair skin (of the Celtic
type of Northern Europe) and may oc-
cur most frequently in the population
of the French region of Brittany.3
Chapter 20
Morbihan Disease
Ana Kaminsky, Patricia Della Giovanna
There are very few recorded
cases in other skin types or color:
only one case in a black individual
and one in an Indian person.2 There
is also one case of a black Haitian
woman of 36 years old who had MD
associated with dermatosis neglec-
ta. Her history included 6 months
of slow-growing brown patches in
the center of the forehead, cheeks,
upper and lower eyelids and naso-
labial folds. These patches resulted
from the accumulation of keratin,
sebum and sweat. The patient had
had recurrent episodes of painful,
itchy, cheek edemas, which ham-
pered diagnosis. Once the hyper-
pigmented, hyperkeratotic lesions
were removed, the edema of the
cheeks worsened. This symptom to-
gether with histopathological study
led to the diagnosis of MD.4 Recent-
ly, Okubo et al. published 4 cases in
Japanese men, ranging in age from
32 to 67 years old.5
231
PATHOGENESIS AND
HISTOPATHOLOGY
The pathogenesis of MD is not well
understood. According to Marks, the
causes that might trigger the pro-
cess in predisposed individuals are:
deregulation of the skin blood flow,
poor local lymphatic drainage with
blood circulation slowdown or lym-
phatic stasis and vessel damage. This
is based on the observation that MD
starts with increasingly frequent re-
curring episodes and an acute serous
CLINICAL CHARACTERISTICS inflammation.3
MD is characterized by a persistent
edema and erythema on the two up-
per thirds of the face. Localized main-
ly on the forehead, glabella, eyelids,
nose and cheeks, the edema of MD
is a firm, solid, and non-pitting ede-
ma (Figs. 20-1 to 20-4). Intense edema
on both eyelids is a very important
clinical finding. (Figs. 20-5 to 20-8).6-9
The facial contour may be altered in
patients with very prominent facial
edema; others may experience nar-
rowed or diminished field of vision
with intense palpebral edema. The
subjective symptoms of MD are mild
or non-existent.
Laboratory parameters show no al-
terations that are specific to MD. MD
persists indefinitely, with no dispo-
sition to spontaneous regression. In
some circumstances treatment may
help, although no specific therapy is Fig. 20-1. Initial stages of Morbihan dis-
available. ease.
Fig. 20-2. Morbihan disease midface localization.
Histopathology is also variable,
but several authors report it can pro-
vide valuable clues. An increase in
the number of mast cells was detect-
ed and described by Jansen et al. as
granulomatous dermatitis with an in-
filtrate, consisting mainly of lympho-
cytes and histiocytes of periadnexal
distribution. A moderate fibrosis of
the dermis with abundant mast cells
may also be present. Histopatholog-
ical findings have shown solid per-
sistent erythema and edema, as well
as facial edema, associated with ro-
sacea and lymphatic dysplasia (Figs.
20-9 to 20-11). Histological study of
MD may show that persistent edema
results from lymphatic obstruction.10,11
Other authors have hypothesized
that the chronic inflammatory pro-
cess accompanying the disease leads
232
Fig. 20-3. Morbihan disease. Prominant midface edema of firm consistency.
to the destruction of the connective
tissue around the dermal lymphat-
ic vessels, particularly elastin. Over
time, there might be a weakness in
the integrity of the walls of these
vessels, leading to transudation of
liquids and posterior development
of lymphedema.12 The cutaneous
lymphatic system could play a role in
the expression of MD. There are hy-
potheses that some as-yet-unknown
factors may trigger excessive serous
exudation, ultimately altering drain-
age potential to the regional lymph
nodes of facial skin.
Wohlrab suggests that region-
al variations plus irritating contact
agents contribute to the induction
and localization of MD.11 However, in
rosacea this type of lymphedema is
found in very few cases.
Fig. 20-4. Morbihan disease. Exten-
sive involvement of the forehead,
eyelids, midface area and upper lip.
[Courtesy Dr Ricardo Pérez Alfonzo].
For Hu et al. MD is considered a
rare condition. These authors claim
that the histopathology of persistent
lymphedema is only documented in
very few cases, which include perifol-
licular fibrosis, as well as perifollicular
and perivascular infiltration of lympho-
cytes, histiocytes and neutrophils as-
sociated with stromal edema.8
DIAGNOSIS
So far, there are no clinical, histo-
pathological or laboratory elements
Fig. 20-5. Morbihan disease. Glabella and forehead involvement.
to define the pathogenesis of MD.
Some authors consider it a rare form
of rosacea and others, including our-
selves, perceive it as an independent,
ill-defined condition, with a distinc-
tive evolution and huge therapeutic
challenges.13-15 Ultrasonography is an
auxiliary method to demonstrate the
presence of lymphedema. This non-in-
vasive imaging technique, enables the
subclinical anatomical observation and
may help to solidify the diagnosis of
MD (Fig. 20-12) (see Chapter 23).
Bearing in mind the clinical aspects
and the histopathological findings, the
233
differential diagnosis must consider a
series of entities, including: sarcoid-
osis, pseudolymphomas, and Melkers-
son-Rosenthal syndrome (along with
its variants: systemic lupus erythema-
tosus, dermatomyositis, chronic actinic
dermatitis, foreign body granuloma,
orofacial granulomatosis, chronic con-
tact dermatitis and acute urticaria).
In the matter of immune contact
urticaria, it is interesting to high-
light the research of Wohlrab et al.,
who performed allergy studies in 6
patients affected by persistent ery-
thema and edema of the middle and
Fig. 20-6. Morbihan disease. Exten-
sive frontal and palpebral involvement.
upper third of the face which resem-
bled Melkersson-Rosenthal syndrome
and lymphedematous rosacea. These
authors stated that the French call
this clinical presentation MD. They
performed a series of patch tests plus
laser Doppler flowmetry and ultra-
sound (20-MHz) on skin affected by
immune urticaria induced by contact
with cosmetic components. They con-
cluded that the recurrent and possi-
bly subclinical inflammation caused
by contact urticaria, plus a decline in
the pre-existent lymphatic drainage
had an important role in the evolution
Fig. 20-7. Morbihan disease. Frontal
involvement and palpebral edema,
occluding the ocular opening.

Fig. 20-9. Morbihan disease. Initial stages with Fig. 20-10. Morbihan disease. Lymphohistiocytic periadnexal and
dermic edema and mild capillary vasodilation. perivascular dermatitis, with discrete superficial angiectases.

Fig. 20-8. Morbihan disease. Intense
palpebral edema, occluding the ocu-
lar opening.
of MD. Wohlrab et al. consider that
all patients with MD should undergo
allergy testing to detect non-obvious
contact immune urticaria, which may
retain and exacerbate MD.11
MANAGEMENT OF MD
A variety of treatments have been
used for patients with MD but they
are generally non-specific. Different
measures may be useful to help con-
trol of the condition, including anti-
234
biotics, antihistamines, and others.
High dose of antibiotics such as mi-
nocycline and doxycycline have been
used, as well as antihistamines, radi-
ation and interferon gamma -all with
unsatisfactory results. Oral predniso-
lone in combination with doxycycline
has been used with relative success.16
However, recently Okubo et al. re-
ported achieving very good results
with administration of doxycycline for
a prolonged length of time.5
Unlike thalidomide, which was con-
sidered a failure, good results were
obtained with metronidazoles. Clo-
fazimine was also attempted.
Isotretinoin was administered in a
dose of 0.1-0.2 mg/kg daily plus keto-
tifen (2 mg), resulting in the complete
resolution of facial lesions.17,18 Smith
et al. used isotretinoin in a total dose
of approximately 285 mg/kg (range
170-491 mg/kg). The entire duration
Fig. 20-11. Morbihan disease. Granulomatous dermatitis composed by epithe-
lioid granulomas with scarse lymphocytic crown and no central necrosis. Neg-
ative Ziehl Neelsen staining.
of the treatment varied from 10 to
24 months, with an average follow-up
time of 9 months (range 1-24 months).
In the 5 cases treated with this dose,
clinical improvement was not appar-
ent until 6 months into treatment, and
long-lasting results were observed. It
was considered a good option by the
authors, though the mechanism of ac-
tion is not yet known.19
Therapeutic trial has also been giv-
en to diuretics. Messikh et al. treated
3 men of 38, 66 and 76 years old, suf-
fering from MD and obtained good
results, like quenching the intense
palpebral edema in spans of two,
five and eight years, respectively. 20
These patients were treated unsuc-
cessfully with cyclines, antimalarial
drugs, danazol, corticosteroids and
isotretinoin. Two of these patients
improved after treatment with furose-
mide (60 mg/daily) and the third one
after treatment with spironolactone
(75 mg twice daily). These interven-
tions resulted in an almost complete
or complete regression of the edema,
though some secondary effects were
observed.20
235
Fig. 20-12. Morbihan disease. Color Doppler echotomography (nasal tip; right
side, longitudinal axis). Some thickening and a rather heterogeneous decrease
in the echogenicity of the dermis can be observed, with effacement of the
dermohypodermic junction. The anteriomedial segment of the right alar nasal
cartilage looks swollen and with an area of augmented echogenicity.(*) Notice
the enhancement of dermic and hypodermic vascularization, in the inside of
the cartilage. (Text and images, courtesy of Dr. Ximena Wortsman).
One final therapeutic alternative References
that has received attention is the re- 1. Degos R, Civatte J, Beuve-
section of the redundant tissue, while Méry M. Nouveau cas d’oedème
a group reported good cosmetic re- érythémateux facial chronique.
sults using blepharoplasty with CO2 Bull Soc Fr Dermatol Syph 1973;
laser.21 80:257.
In conclusion, MD is a very com- 2. Veraldi S, Persico MC, Fran-
plex, hard to treat disease that leads cia C. Morbihan syndrome. In-
to serious psychological problems dian Dermatol Online J 2013;
and reduction of self-esteem. 4(2):122-4.
3. Marks R. Rosacea: Hopeless hypoth-
eses, marvelous myths and dermal
disorganization. In: Marks R, Plewig G,
editors. Acne and related disorders.
London: Martin Dunitz; 1989. pp. 293-9.
4. Eber AE, Mlacker S, Verne S, et al. Mor-
bihan disease complicated by derma-
tosis neglecta: An unique presentation.
J Cutan Pathol 2017; 44(5):470-473.
5. Okubo A, Takahashi K, Akasaka T, et
al. Four cases of Morbihan disease
successfully treated with doxycy-
cline. J Dermatol 2017; 44(6):713-716.
6. Morales-Burgos A, Alvarez Del Man-
zano G, Sánchez JL, et al. Persistent
eyelid swelling in a patient with rosa-
cea. P R Health Sci J 2009; 28(1):80-2.
7. Lamparter J, Kottler U, Cursiefen C,
et al. Morbus Morbihan: A rare cause
of edematous swelling of the eyelids.
Ophthalmologe 2010; 107(6):553-7.
8. Hu SW, Robinson M, Meehan SA, et
al. Morbihan disease. Dermatol On-
line J 2012; 18(12):27.
9. Jansen T, Plewig G. The treatment
of rosaceous lymphedema. Clin Exp
Dermatol 1997; 22:57.
10. Jansen T, Regele D, Schirren CG, et
al. Persistent erythema and edema
of the face associated with rosacea
and lymph vessel dysplasia. Hau-
tarzt 1998; 49(12):932-5.
11. Wohlrab J, Lueftl M, Marsch WC. Per-
sistent erythema and edema of the
mid third and upper aspect of the face
(morbus Morbihan): evidence of hid-
den immunologic contact urticaria and
impaired lymphatic drainage. J Am
Acad Dermatol 2005; 52(4):595-602.
12. Nagasaka T, Koyama T, Matsumura K,
et al. Persistent lymphoedema in Mor-
bihan disease: formation of peri-lym-
phatic epithelioid cell granulomas as
a possible pathogenesis. Clin Exp
Dermatol 2008; 33(6):764-767.
13. Crawford GH, Pelle MT, James WD.
Rosacea: I. Etiology, pathogenesis,
and subtype classification. J Am
Acad Dermatol 2004; 51(3):327-41.
236
14. Elewski BE, Draelos Z, Dréno
B, et al. Rosacea global diversi-
ty and optimized outcome: Pro-
posed international consensus
from the Rosacea International
Expert Group. J Eur Acad Der-
matol Venereol 2011; 25(2):188-
200.
15. Kaminsky A, Flórez-White M,
Piquero Martín J, et al. GILER.
Informe de Consenso Ibero-Lati-
noamericano 2016 sobre la clasifi-
cación clínica y terapéutica de la
rosácea. Med Cutan Iber Lat Am
2016; 44(1):6-10. (2016-Iberian Lat-
in-american Report on the Clinical
and Therapeutic Classification of
rosacea).
16. Ranu H, Lee J, Hee TH. Therapeu-
tic hotline: Successful treatment of
Morbihan’s disease with oral pred-
nisolone and doxycycline. Dermatol
Ther 2010; 23(6):682-5.
17. Mazzatenta C, Giorgino G,
Rubegni P, et al. Solid persistent
facial oedema (Morbihan’s dis-
ease) following rosacea, success-
fully treated with isotretinoin and
ketotifen. Br J Dermatol 1997;
137:1020.
18. Jungfer B, Jansen T, Przybilla B, et
al. Solid persistent facial edema of
acne: successful treatment with
isotretinoin and ketotifen. Derma-
tology 1993; 187(1):34-7.
19. Smith LA, Cohen DE. Successful
long-term use of oral isotreti-
noin for the management of
Morbihan disease: A case se-
ries report and review of the
literature. Arch Dermatol 2012;
148(12):1395-8.
20. Messikh R, Try C, Bennani B, et al.
Efficacy of diuretics in the treat-
ment of Morbihan’s disease: three
cases. Ann Dermatol Venereol 2012;
139(8-9):559-63.
21. Bechara FG, Jansen T, Losch R, et
al. Morbihan’s disease: Treatment
with CO2 laser blepharoplasty. J
Dermatol 2004; 31(2):113-5.
Section 6
„„ Chapter 21. Dermoscopy

„„ Chapter 22. Confocal

Complementary Microscopy

diagnostic techniques „„ Chapter 23. Color Doppler

Ultrasound
Dermoscopy (or dermatoscopy) is a
highly useful non-invasive technique
for diagnosing pigmented lesions.
The hand-held dermoscope and
technical experience improve clini-
cal diagnosis by up to 30%.1 The first
dermoscopes included non-polarized
light and their use was mostly limited
to pigmented lesions. Over the years
and after the creation of new equip-
ment including polarized and non-po-
larized light, which allowed a clearer
observation of the vessels, diagnosis
of pink lesions also began. This wid-
ened the field of dermoscopy and
allowed a more precise recognition
of hypomelanotic/amelanotic melano-
mas, superficial non-pigmented basal
cell carcinomas and squamous cell
carcinomas, in situ and invasive, as
well as other benign pink lesions.2 In
recent years, the use of dermoscopy
in general dermatology, especially in
inflammatory conditions of the face,
has opened up a new field of study
and research.3,4 This chapter is main-
ly devoted to the dermoscopic mani-
festations of rosacea and some of its
differential diagnoses (demodicidosis,
seborrheic dermatitis and acne).
When examining pink lesions with
a dermoscope, it is important to stop
to observe vessels and assess three
aspects: morphology, pattern, and
distribution (Figs. 21-1 to 21-3).5 These
observations will be are particularly
important in assessment of rosacea.
ROSACEA
Chapter 21 Depending on the subtype, different
dermoscopic characteristics may be
Dermoscopy
observed.4
The erythematotelangiectasic sub-
type includes:
UU Polygonal or reticular linear ves-
sels: vessels with a straight linear
morphology, a specific polygonal
Horacio A. Cabo, Emilia N. Cohen Sabban distribution providing a reticulated
aspect and a monomorphic pattern.
These characteristic vessels are the
hallmark of rosacea (Figs. 21-2 a 21-7).6
UU Less frequent.
• Yellowish-white scales (Fig. 21-8).
• Dilated follicles (follicular plugs)
(Fig. 21-9).
 Associated or not with De-
modex (Fig. 21-10).
The papulopustular subtype (Figs.
21-11 to 21-16) includes:
UU Papules.
UU Pustules (even those clinically un-
detectable).
UU Polygonal vessels (less prominent).
Fig. 21-1. Vessel morphology with dermoscopy. There are two morphologies with UU Rosettes: These are whitish
dotted vessels and six with linear vessels. structures, only observable with
238
 polarized light dermoscopes, com-
posed of four bright white blood
cells symmetrically arranged, sim-
ilar to a four-leaf clover.7 They are
caused by the optical effect of po-
larized light reflected on follicular
openings filled with keratin.
UU Follicular Disorders.
• Comedones.
• Dilated follicles.
• Follicular plugs.
The phymatous subtype (Figs. 21-17
to 21-19) includes:
Fig. 21-2. Vessels may be distributed into 8 different patterns. One is randomized,
and the most frequent, and seven are specific and observed in different lesions. UU Structureless reddish-yellowish areas.
UU Follicular Disorders.
• Comedones
• Dilated follicles.
• Follicular plugs.
Differential Diagnoses (Rosacea
Mimickers)
Demodicidosis8,9
Demodicidosis may be found alone
or associated with rosacea. In the
first case, no polygonal vessels are
observed. Demodex can be detected
by the Standardized Skin Surface Bi-
opsy (SSSB) or the cyanoacrylate test
(Figs. 21-20 and 21-21). Dermoscopy al-
lows the observation of the following:
Fig. 21-3. Monomorphic or polymorphic pattern with dermoscopy, depending on UU White extensions protruding from
presence of one or more vessel types, respectively. the follicle (Demodex tails) corre-
239
sponding to the body of one or more
Demodex emerging through the fol-
licular orifice (Figs. 21-22 to 21-26).
UU Yellowish dilation of follicular open-
ings (Demodex follicular openings).
They refer to dilations of the follic-
ular orifice containing one or more
Demodex inside (Figs. 21-27 to 21-29).
Seborrheic Dermatitis
Together with rosacea, seborrheic
dermatitis is one of the most frequent
causes of red faces. The differential di-
agnosis between these two entities is
highly reliable with dermoscopy (Figs.
21-30 to 21-32). The following may be
observed with seborrheic dermatitis:
UU Focally distributed punctiform
vessels.
UU Yellowish scales.
Acne
Dermoscopes allow the observation
of the following (Figs. 21-33 to 21-35):
UU Papules.
UU Pustules (even those clinically un-
detectable).
UU Follicular Disorders.
• Comedones
• Dilated follicles.
• Absence of polygonal vessels.
Fig. 21-4. Erythematotelangiectatic ro- Fig. 21-5. Erythematotelangiectatic rosacea. Dermoscopy with polygonal or re- Fig. 21-6. Erythematotelangiectatic
sacea (clinical image). ticular linear vessels (vessels with straight linear morphology, with a diffuse po- rosacea (clinical image).
lygonal distribution producing a reticulated aspect and a monomorphic pattern.

Fig. 21-8. Erythemato-

telangiectatic rosa-
cea. Dermoscopic
image with yellow-
ish white scales
(white circle).

Fig. 21-7. Erythematotelangiectatic rosacea. Dermoscopy with polygonal linear

vessels (red circle) and follicular plugs (white arrows).
240
Fig. 21-9. Erythematotelangiectatic rosacea. Dermoscopic image, dilated folli- Fig. 21-11. Papulopustular rosacea (clinical image).
cles (follicular plugs) (white arrow).

Fig. 21-10. Erythematotelangiectatic rosacea. Dermoscopic image, polygonal Fig. 21-12. Papulopustular rosacea. Dermoscopic image, polygonal vessels (red
vessels (black circle); Demodex tail (white arrows). circle); pustules (white arrows).
241
Fig. 21-13. Papulopustular rosacea. Dermoscopic image, polygonal vessels (red Fig. 21-15. Papulopustular rosacea (clinical image).
circle); pustules (white arrows); papule (black arrow).

Fig. 21-16. Papulopustular

rosacea. Dermoscop-
ic image, polygonal
vessels (white cir-
cle); Demodex
tail (white arrow);
follicular plugs
(black arrow)

Fig. 21-14. Papulopustular rosacea. Dermoscopic image, pustules (white arrows).

242
Fig. 21-17. Phymatous rosacea (clinical image). Fig. 21-19. Phymatous rosacea. Dermoscopic image, dilated follicles (white arrow).

Fig. 21-18. Phymatous rosacea. Dermoscopic image, dilated follicles (black ar-
rows); pustule (white arrow). Fig. 21-20. Standardized skin surface biopsy (SSSB) or cyanoacrylate test.
243
Fig. 21-21. Standardized Fig. 21-23. Demodi-
skin surface biopsy cidosis (Clinical im-
(SSSB). Positive: age).
more than five
adult Demodex
per square
centimeter.

Fig. 21-24. Demodicidosis.

Dermoscopic image
showing Demodex
tails which belong
to the body of
one or more
Demodex
e m e rg i n g
through the
follicular or-
ifice (white
arrows).

Fig. 21-22. Dermoscopic image showing Demodex tails which belong to the
body of one or more Demodex emerging through the follicular orifice (white
arrows).
244
 B

Fig. 21-25. Demodicidosis. Clinical (A) and dermoscopic (B) image. Demodex Fig. 21-26. Demodicidosis. Clinical (A) and dermoscopic (B) image. Demodex
tails which belong to the body of one or more Demodex emerging through the tails which belong to the body of one or more Demodex emerging through the
follicular orifice (white arrows) are observed. follicular orifice (white arrows) are observed.

245
 B

Fig. 21-27. Dermoscopic image showing Demodex follicular openings. Dilated Fig. 21-28. Clinical (A) and dermoscopic (B) image. Dermoscopic image show-
follicular orifice containing one or more Demodex inside (white arrows). ing Demodex follicular openings. Dilated follicular orifice containing one or
more Demodex inside (white arrows).

246
Fig. 21-29. Dermoscop-
ic image showing mul-
tiple Demodex follic-
ular openings. Dilated
follicular orifice con-
taining one or more
Demodex inside (white
arrows).

247
Fig. 21-30. Differential di-
agnosis with dermosco-
py between seborrheic
dermatitis (A and B) with
white-yellow scales and
punctiform vessels, and
rosacea (C and D) with
polygonal vessels.

248
Fig. 21-31. Seborrheic dermatitis. Clinical (A) and dermoscopic (B) image show- Fig. 21-33. Acne. Clinical image.
ing locally distributed punctiform vessels (red arrow) and yellow scales (white
arrow). Fig. 21-34. Acne.
Dermoscopic
image showing
pustules (white
arrows) and
blackheads
(black arrows).

Fig. 21-32. Seborrheic dermatitis. Dermoscopic image showing focally distrib-

uted punctiform vessels (red arrow).
249
 5. Rosendahl C, et al. Prediction with-
out pigment: a decision algorithm for
non-pigmented skin malignancy. Der-
matol Pract Concept 2013; 4(1):9-59
6. Lallas A, Argenziano G, Longo K, et
al. Polygonal vessels of rosacea are
highlighted by dermoscopy. Int J
Dermatol 2014; 53:e325-e327.
7. Rubegni P, Tataranno DR, Nami N,
et al. Rosettes: Optical effects and
not dermoscopic patterns related to
skin neoplasms. Australas J Derma-
tol 2013; 54:271-272.
8. Friedman P, Cohen Sabban E, Cabo
H. Usefulness of dermoscopy in the
diagnosis and monitoring treatment
of demodicidosis. Dermatol Pract
Concept 2017; 7(1):6-35.
9. Segal R, Mimouni D, Feuerman H.
Dermoscopy as a diagnostic tool in
demodicidosis. Int J Dermatol 2010;
49:1018-23.

Fig. 21-35. Acne. Dermoscopic image showing various blackheads (white arrows).

CONCLUSIONS 2. Cabo H. Color Atlas of Dermoscopy.

Dermoscopy provides additional in-
formation to clinical examination.
Besides, it is a great aid not only for
diagnosis but also for monitoring the
therapeutic response in rosacea.
References
1. Cabo H. Dermatoscopía (2da Ed.)
Ediciones Journal. Dermatoscopia:
Fundamentos, técnica e instrumen-
tal. 2012 Chapter 3 : 15.
Jaypee Brothers Medical Publish-
ers. Why Use the dermatoscope.
2017. Chapter 1: 3.
3. Errichetti E, Stinco G. Dermoscopy
in general dermatology: A practical
overview. Dermatol Ther (Heidelb)
2016; 6(4):471-507.
4. Lallas A, Argenziano G, Apalla Z, et al.
Dermoscopic patterns of common facial
inflammatory skin diseases. J Eur Acad
Dermatol Venereol 2014; 28:609-14.
250
In rosacea and other related diseases
–such as perioral dermatitis and De-
modex folliculitis– the large number
of Demodex folliculorum can be of
great importance because, although
its pathophysiologic role remains
controversial, it is accepted that the
increase in Demodex mite density is
important for the course and severity
of the condition.1-4 Therefore, its study
is increasingly requested, despite the
fact that the techniques used (stan-
dardized skin-surface biopsy, direct
microscopic examination) are semi-in-
vasive and sometimes painful and
uncomfortable. Nevertheless, until
recently this has been the technolo-
gy available to guide the therapeutic
approach.5-7 Reflectance confocal mi-
croscopy is a non-invasive technique
which provides visualization of the
surface layers of the skin with a nearly
histologic resolution. It uses a diode
laser at a wavelength of 830 nm, with
a power less than 35 mW at tissue
level. It generates black and white im-
ages with a horizontal resolution of 2
mm, a vertical resolution of 5 mm and
depth of 200 to 250 mm (Fig. 22-1).
The test is painless, harmless and al-
lows visualization of structures in vivo
and in real time.8,9
Confocal microscopy is increasing-
ly used in the differentiation of pig-
mented skin lesions, non-melanoma
cancer and some inflammatory dis-
eases.10-15 The role of this technique in
Chapter 22
Confocal
Microscopy
Pedro Lobos
the diagnosis of fungal and parasite is often used in the diagnosis of tu-
infestations (tinea, scabies, larva mi- mor lesions of the skin and sometimes
grans, demodicidosis) has also been it is possible to visualize the parasite
investigated.16-18 Confocal microscopy in the pilosebaceous follicles of facial
Fig. 22-1. Reflectance confocal microscope and computer image showing a
sectioning of the skin in black and white. On the right side, there are images of
the left cheek skin for the study of Demodex sp.
251
lesions (Fig. 22-2). In recent years, the
use of confocal microscopy for the
detection and quantification of Demo-
dex in both rosacea and other related
diseases (pityriasis folliculorum, eye-
lid demodicidosis) has increased.20-24
The monitoring of the therapeutic re-
sponse in patients with rosacea using
this technique constitutes a new mo-
dality of in vivo study that also promis-
es to contribute to the knowledge of
the pathogenesis of this disease.
TECHNIQUE
During the month prior to confocal
microscopy testing, patients should
not have received any antibiotic
treatment, either systemic or topi-
cal. The facial region with the most
marked symptomatology should be
selected.21-23 In erythematotelangiec-
tatic rosacea (ETTR), select the area
where erythema is more severe; in
papulopustular rosacea (PPR), select
the area with the highest concentra-
tion of papulopustules. In general, the
most frequently chosen areas are the
cheeks, followed by the frontal and
nasal regions (Fig. 22-3).
At Clínica Las Condes (Santiago,
Chile), the reflectance confocal mi-
croscope (VivaScope 5000, Lucid.
Rochester, NY, USA) is used for the
test. With the device in the Vivablock
function, images of 5 × 5 mm are tak-
en, and 2 to 3 horizontal sections are
made, on average, in the epidermal

Fig. 22-2. Patient under study for facial pigmented skin lesions. The test shows Demodex folliculorum. On the left side,
3 parasites occupying a pilosebaceous follicle can be counted. On the right, 7 Demodex are occupying practically the
entire orifice of a pilosebaceous follicle.
area at different levels from 20 to 80
mm. The section yields 100 images
and each measures 500 × 500 mm.
The software reproduces and pastes
them to obtain a mosaic (Fig. 22-4).
Sattler et al.21 showed that the areas
of 8 × 8 mm and 5 × 5 mm are com-
parable in terms of number of mites.
Fig. 22-3. Patient with papulopustular
rosacea and prominent involvement
in the right cheek, the area where the
test is done.
252
Consequently, the smaller area is pre-
ferred, because it decreases the time
of exploration and subsequent inter-
pretation of the test. The images are
digitally stored for analysis. Those that
make up the mosaic can be enlarged
without losing sharpness, which fa-
cilitates the search for Demodex. In
some cases, the Vivastack function
can be used, which allows visualiza-
tion of the mite deep in the follicle,
because it generates multiple optical
slices in the selected area deep into
the skin. The test is completely pain-
less and does not cause any discom-
fort for the patient.
INTERPRETATION OF THE TEST
The number of follicles, the presence
of Demodex in follicles, and the num-
ber of parasites per follicle are as-
sessed. Demodex mites are seen as
small structures (6 mm in diameter)
with a very bright contour, located
inside the hair follicles. These struc-
tures are the posterior extremity of
the mites, since Demodex live with
their heads in the deep part of the
follicle and their tails located at the
surface.19 When the image is totally
horizontal, they appear as rounded,
shiny and grouped structures. If the
sectioning is more diagonal, they ap-
pear as lengthy cone-shaped struc-
tures,21 similar in appearance to those
obtained by skin scraping and with
the optical microscope with immer-
sion oil (Fig. 22-5).
Test Results
In general, Demodex sp are detected
more frequently and in greater num-
bers in patients with rosacea than in
control individuals, in whom Demo-
dex are scarce or absent. Sattler et
al.21 established the cut-off point to
report a test as positive with a sen-
sitivity of 84% (95% CI 65-94) and a
specificity of 72% (95% CI 52-86) in
the face of a follicle with 4 or more
mites, or that the area examined (5 ×
 Fig. 22-4. Single 500 × 500 mm image
where 3 follicles are evidenced, one
of them with 2 Demodex inside. To the
right, mosaic obtained by exploring a
surface of 5 × 5 mm where a total of
100 individual images are taken, and
then pasted to obtain the final image.
A large number of pilosebaceous fol-
licles are observed, and some of them
with Demodex.

Fig. 22-5. Horizontal sectioning show-

ing 3 mites inside a hair follicle. They
have a retractable cylindrical struc-
ture with a clear contour. On the right
side, a more oblique sectioning where
lengthy-structured cone-shaped mites
are evident and grouped inside hair
follicles.

253
5 mm) has an average of 0.3 mites per
follicle, demonstrating a sensitivity of
72% (95% CI 52-86) and a specificity
of 76% (95% CI 57-89) (Figs. 22-6 and
22-7); this is used in the report of the
tests at Clínica Las Condes. It should
be noted that, although infrequent,
there are cases in which despite be-
ing in the presence of a clear clinical
picture of rosacea, the presence of
Demodex is minimal or null; therefore,
positivity in the test is an important
factor in the therapeutic evaluation of
each patient.
DISCUSSION
Demodex is a permanent ectopara-
site of the human being that lives in
the follicular infundibulum (Demodex
folliculorum) or is located in the mei-
bomian and sebaceous glands (De-
modex brevis). They belong to the
class arthropods, subclass mites. They
measure 0.2 to 0.4 mm and their body
has a vermiform elongation. Their life
cycle is 14 to 18 days and their repro-
duction is sexual25 (Fig. 22-8). They are
especially present in the facial area
and eyelashes, in individuals of all age
groups, although their prevalence
increases with age26 and according
to the immune status, since they are
more frequent in immunocompro-
mised patients. They are related to
some skin diseases, especially rosa-
cea, seborrheic dermatitis, perioral
dermatitis, blepharitis, and chalazion.
Both the parasite and the associated
Fig. 22-6. Patient with papulopustular rosacea on
the right cheek. In a single Vivablock image (0.5
× 0.5 mm), 6 Demodex are observed inside a hair
follicle, sufficient criterion to report this test as
positive.
bacteria may play an important role in
facial dermatoses associated with this
mite.27 The relationship between De-
modex and rosacea was established
by Ayres in 1961,28 and Bonnar et al. or more mites per square centimeter advance, since it allows the study of
in 1993 who, for the first time, demon- must be found. This method is the diverse skin lesions (tumor, inflamma-
strated an increase in mite density most effective for determining the tory, parasitic ones) in vivo, in a fast,
in patients with rosacea.29 From then mite density31 and has been used for painless and harmless way. It also
on, interest in detection, density, and decades in multiple centers specializ- contributes to the knowledge of its
etiopathogenic role of mites has been ing in acne, rosacea, and related dis- disease pathophysiology, diagnosis
increasing. eases. However, direct microscopic and treatment results.24 The more
examination of skin scraping or ex- frequent use of confocal microsco-
Over time, several techniques pression with a curette is also wide- py in facial tumor lesions has made
have been developed for Demodex ly used in many centers, particularly it possible to indirectly appreciate
detection. The most commonly used in Chile, since it is fast, very low cost the tubular structures of Demodex
is the standardized skin-surface biop- and has good sensitivity, as corrobo- folliculorum within the hair follicle,
sy, originally described by Marks et rated by a recent publication by Yung described for the first time by Longo
al. in 1971.30 For the diagnosis of de- C, et al.32 The emergence of confocal et al. in 2012.19 Since then, there has
modicidosis, it was established that 5 microscopy is an important scientific been growing interest in centers that
254
Fig. 22-7. Patient with papulopustular roscaea
and with test reported as negative. Only 2 De-
modex were investigated in an area with more
than 120 pilosebaceous follicles. A panoramic
view of Vivablock (5 × 5 mm) is shown, where
dark spots corresponding to openings of pi-
losebaceous follicles can be seen. This image
is saved in bitmap format, which allows its en-
largement without losing resolution. The para-
site inside the follicle can be seen in detail.

have this technology for the diagnosis of skin

diseases associated with Demodex, as report-
ed in multiple scientific publications.

Confocal microscopy and standardized

skin-surface biopsy have been compared for
the detection of Demodex density. A porta-
ble VivaScope 3000 model was used (which
allows greater speed and plasticity than the
VivaScope 1500, especially on irregular or dif-
ficult-to-access surfaces). The results showed
that the confocal microscope was superior to
255
 of the technique only once or repeat-
edly in the same area can result in sig-
nificant differences in the number of
mites.33,34
Demodex infestation in the eyelid
is a frequent finding in patients with
posterior blepharitis; study of this an-
atomic region is usually performed
by removing eyelashes to detect and
count mites.35 The various species of
Demodex are associated with a large
number of ocular conditions, such
as blepharitis, meibomian gland dys-
function, recurrent chalazion and re-
fractory keratoconjunctivitis.36 Hence
the growing importance of their de-
tection and quantification. The emer-
gence of an efficient, fast and reliable
tool for the in vivo study of Demodex
infestation of the eyelid, with minimal
discomfort for the patient, is an im-
portant advantage in relation to eye-
lash removal or depilation. Besides,
confocal microscopy allows the study
of a large surface of the lower eyelid,
as well as all its structures, and can be
repeated as many times as required
to monitor responses to treatments.37
Fig. 22-8. Microscopic image of Demodex folliculorum inside a pilosebaceous In the study of ocular rosacea,
follicle with its cephalothorax in the deep part (a) and its lengthy abdomen which is estimated to occur in approx-
towards the outer surface (b) [courtesy Dr. Ivo Sazunic]. imately 50% of patients with rosacea,
the confocal microscope has also
the skin surface biopsy.23 However, higher densities than conventional ex made an important contribution, as
this comparison is difficult and the vivo techniques. In addition, the accu- diagnosis is often difficult in patients
results may not be realistic, since the racy of skin surface biopsy depends who do not have skin involvement.
examination is in vivo and shows much on the operator; further, performing Using the confocal microscope Ros-
256
tock Cornea Module, designed to
study the cornea, Liang et al.38 were
able to quantify Demodex in the low-
er eyelid, right cheek and back of the
hand in a group of patients with ocu-
lar rosacea. Their conclusion was that,
in patients with rosacea, the confocal
microscope is a useful, safe and ef-
fective tool to study corneal, meibo-
mian gland and pilosebaceous gland
alterations, as well as allowing in vivo
quantification of the parasite. All of
the above will contribute to the study
of the pathophysiology of the disease
and the evaluation of treatments.
Although the role of Demodex fol-
liculorum in facial and ocular rosacea is
not fully clear, clinical experience and
the outcome of specific treatments
have led to improvements (either par-
tial or complete) in cases where the
parasite was found in abnormally high
amounts. Brown et al.3 published a
case of acne rosacea in a 12-year-old
girl whose multiple biopsies showed
numerous mites. The patient respond-
ed completely only after treatment
with ivermectin, and there were no
recurrences in the long term. Abok-
widir et al.4 provided additional evi-
dence on the role of Demodex in the
pathogenesis of rosacea by evaluating
the efficacy of two topical antiparasit-
ic drugs in decreasing the severity of
papulopustular rosacea. Finally, Chang
et al.39 conducted a systematic review
and meta-analysis on the role of De-
modex infestation in rosacea. This re-
cently published study concluded that
it may have a pathogenic role both in
erythematotelangiectatic rosacea and
papulopustular rosacea.
The confocal microscope has also
been of great help in cases of very
rare Demodex facial diseases, such
as facial spinulosis. Pampin et al.40 de-
scribed a case of a 43-year-old woman
who was quickly and easily diagnosed
through the use of this instrument,
which allowed the detection of large
quantities of Demodex, making it pos-
sible to establish a timely and effec-
tive treatment.
The use of the confocal micro-
scope in the diagnosis of skin infec-
tions by various Demodex species,
and especially in rosacea, opens up
a fascinating field of study, as well as
being a simple, practical, and innocu-
ous way to facilitate the diagnosis and
follow-up of patients. Additionally,
the enthusiasm that this technique is
arousing in the field of ophthalmol-
ogy will undoubtedly help to under-
stand the mechanisms involved in
ocular rosacea and the specific role
of Demodex. As in many other med-
ical fields, the use of state-of-the-art
technologies is costly and difficult to
implement, especially in poor coun-
tries. This is the main disadvantage
of confocal microscopy. However,
proving its usefulness and favorable
cost-benefit ratio in the study of skin
diseases, over time, will make it more
accessible, thus contributing to the
development of medicine and im-
proving patient care.
References
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3. Brown M, Hernández-Martin A,
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13. Chan A, Busam K, Benvenuto-An-
drade C, et al. Reflectance confocal
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14. Ardigo M, Maliszewski I, Cota C, et
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15. Astner S, González S, González E.
Noninvasive evaluation of allergic
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16. Marcus R, Huzaira M, Anderson R.
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17. Longo C, Bassoli S, Monari P, et al.
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18. Purdy K, Langley R, Webb A, et al.
Cutaneous larva migrans. Lancet
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19. Longo C, Pellacani G, Ricci C, et
al. In vivo detection of Demodex
folliculorum by means of confocal
microscopy. Br J Dermatol 2012;
166:690-692.
20. Turgut A, Salih M, Esra A. Demodex
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21. Sattler EC, Maier T, Hoffmann VS, et
al. Noninvasive in vivo detection and
quantification of Demodex mites by
confocal laser scanning microscopy.
Br J Dermatol 2012; 167:1042-7.
22. Randon M, Liang H, El Hamdaoui M,
et al. In vivo confocal microscopy as
a novel and reliable tool for the diag-
nosis of Demodex eyelid infestation.
Br J Ophthalmol 2015; 99:336-341.
23. Turgut A, Gurel MS, Koku Aksu AE,
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Demodex mites. Skin Res Technol
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24. Sattler EC, Hoffmann VS, Ruzicka T,
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Demodex mites in patients with ro-
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Br J Dermatol 2015; 173:69-75.
25. Litwin D, Chen W, Dzika E, et al.
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and their relations with clinical type
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the diagnosis of Demodex eyelid
infestation. Br J Ophthalmol 2015;
99:336-341.
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Rosacea is a common inflammatory dis-
ease affecting the pilosebaceous units
and blood vessels.1 However, there is
limited information in the medical lit-
erature on the use or role of imaging
techniques in this condition. In the last
decade there has been a significant
advance in the use of color Doppler
ultrasound in dermatology, due to
the development of high-resolution
equipment with multichannel devices
and high-frequency transducers (≥ 15
megahertz) that allow high definition
observation of the skin layers and their
vascularization in vivo.2-4 The applica-
tions of ultrasound or color Doppler
ultrasound have been increasing over
time and today this imaging technique
is used in the study of multiple derma-
tological diseases, such as skin and nail
tumors, benign and malignant inflam-
matory diseases, vascular anomalies
and complications of cosmetic proce-
dures, among many others.2,3-5
Color Doppler ultrasound can pro-
vide subclinical anatomic information
to support diagnoses that cannot be
deduced from physical examination;
can aid in establishing the severity of
a disease; and may be used to monitor
the activity of that disease in a non-in-
vasive way.2 Like any imaging tech-
nique, ultrasound requires adequate
equipment and a trained medical
operator, who in this case must both
know the dermatological disease
and be trained in imaging.2 There are
Chapter 23
Color Doppler
Ultrasound
Ximena Wortsman
published guidelines about the condi-
tions required to perform ultrasound
imaging examinations.6 Unlike other
imaging techniques used in derma-
tology, such as dermoscopy, confo-
cal microscopy or optical coherence
tomography (OCT), ultrasound does
not present problems of penetra-
tion, since it allows observation from
the cutaneous surface to the cortical
bone margin without any problems.
Further, it allows panoramic visual-
izations of extensive body segments
- which can only be visualized in a lim-
ited fashion via histological studies -
while avoiding serial biopsies.2
This chapter describes the ultra-
sound characteristics of rosacea, ac-
cording to the author’s experience,
and the characteristics of differential
diagnoses that should be considered
259
in a patient with clinical signs sug-
gesting rosacea. The images shown
belong to the database of the Institu-
to de Investigación y Diagnóstico por
Imágenes en Piel y Tejidos Blandos
(IDIEP) from Santiago, Chile, and the
patients have provided their consent
to publish them.
ULTRASOUND
CHARACTERISTICS
Normal Skin
Normal skin of the face, the area most
often affected by rosacea, shows an
epidermis observed as a hyperechoic
(white) line, due to the keratin content
in the stratum corneum. The dermis is
thin on the face, measuring approxi-
mately 1.5 mm, and is visualized as a
hyperechoic band, less bright than
the epidermis with a tone determined
by collagen content. The hypodermis
has a hypoechoic aspect (grey) due to
the content of adipose tissue. Some
hyperechoic (white) linear bands are
detected among the fat lobules of the
adipose tissue. These bands corre-
spond to the fibrous septa (Fig. 23-1).2
Facial vascularization is mainly vi-
sualized by the facial artery and its
branches, and by the supraorbital
and supratrochlear arteries. In the
preauricular regions, the temporal ar-
teries flow, forking towards the head,
providing the frontal branches in the
area of the temples. Using currently
available equipment, ultrasound can
detect vessels of at least 0.1 mm in the
superficial hypodermic planes.7
In the nasal region, the upper and
alar nasal cartilages are observed as
symmetrical hypoechoic bands, one
on each side. The cartilage is not vas-
cularized, so there are normally no
vessels within these structures.7 In
the preauricular regions, the parotid
glands are observed as tenuously hy-
perechoic formations, and in the man-
dible regions they are visualized as
hypoechoic bands, with hyperechoic
septa of both masseter muscles.2,7 The
facial superficial muscle-aponeurot-
ic system, also called SMAS, is com-
posed of multiple hypoechoic and
hyperechoic bands, with muscular
component showing as hypoechoic
and aponeurotic or fascial component
as hyperechoic.7

Fig. 23-1. Ultrasound anatomy of normal skin.
Ultrasound Characteristics of
Rosacea
In rosacea, an epidermal and dermal
thickening and a decrease of the der-
mal echogenicity is observed, which,
particularly in the nasal region, be-
comes somewhat more heteroge-
neous and may push up the epidermis
in some sections. Decrease in dermal
echogenicity has been described in
other inflammatory conditions such as
morphea.8 In the author’s experience,
this heterogeneity is related to the
histological existence of sebaceous
hyperplasia.
The hypodermis in rosacea is more
echogenic (becomes whiter), which
has also been reported in other inflam-
matory disorders such as panniculitis.9-11
In addition, the hypodermis becomes
blurred and heterogeneous, which
correlates with the existence of lymph-
edema. Lymphatic ectasia also causes
diffuse thickening of the epidermis,
dermis, and hypodermis.9 The link be-
tween lymphedema and rosacea -re-
peatedly reported- is considered one
of the causes of phymatous rosacea.12-15
Case reports on Morbihan’s disease
often include lymphangiectasis and
histiocytic infiltrate within the lymph
nodes.12-14 Moreover, it has been sug-
gested that peri-lymphatic epithelioid
cell granulomas may play a role in rosa-
cea pathogenesis.15
Using color Doppler and the spec-
tral analysis of curves it is usually pos-
sible to detect a diffuse increase in
dermal and hypodermal vasculariza-
tion with a low speed arterial and ve-
nous vessel flow, which in the case of
arterial vessels reaches speeds with
260
maximum systolic peaks of  15 cm/
sec. This hypervascularization reflects
the degree of regional inflammation,
which together with thickness mea-
surements and the establishment of
changes in echogenicity of the skin
layers, may allow monitoring the util-
ity of a rosacea treatment in a non-in-
vasive manner.
In the nasal region it is not unusual
to observe thickening of the antero-
medial edges of both alar cartilag-
es, which may slightly increase their
echogenicity and develop internal
vascularization. These findings are ul-
trasound signs of chondritis and peri-
chondritis, which could contribute to
the development of phymatous rosa-
cea in the nasal region and the pinna.
However, this is still in need of further
research (Figs. 23-2 to 23-4).
The Utility of Ultrasound for
Differential Diagnosis
The most frequent differential diag-
noses of rosacea detected by ultra-
sound include secondary inflammatory
complications due to cosmetic fillers,
mainly because, for various reasons,
the patient does not disclose history
of filler injection to the dermatologist.
This information is difficult to obtain
from medical records, since patients
tend to consult in different centers
and with different professionals, med-
ical or not, so the records may not
exist. Ultrasound can detect cosmetic
fillers and identify those most com-
monly used, such as hyaluronic acid,
as well as others not approved by the
FDA, such as silicone oil.16 Some re-
ports mention that ultrasound is the
first-line diagnostic imaging method to
identify hyaluronic acid -pure, or asso-
ciated with lidocaine or other compo-
nents- and also silicone (pure or as oil),
polymethylmethacrylate, polyacryl-
amide, polycaprolactone, and calcium
hydroxylapatite.17-19 Each of these fillers
provides a characteristic ultrasound
appearance, so this technique is an im-
portant part of present-day algorithms
in managing cosmetic filler complica-
tions (Fig. 23-5).17,20,21
Another less common situation
where ultrasound can be helpful may
be facial vascular malformations, such
as nasal malformations, which may be
similar to a rhinophyma.22 Ultrasound
is the first-line diagnostic imaging
method in the case of suspected vas-
cular anomalies, because it differen-
tiates hemangiomas from vascular
malformations and discriminates be-
tween high-flow (arterial or arteriove-
nous) and low-flow (venous, capillary
or lymphatic) hemangiomas.2,23,24 This
differentiation is made with the color
Doppler, which allows the observa-
tion of hypervascularization and its
pattern; whereas with the spectral
analysis of curves, the type of flow (ar-
terial or venous) and its speed can be
established (Fig. 23-6).2,23
 A B C

D E

Fig. 23-2. (A to E). Rosacea. A, clinical photo. B-D, facial

color Doppler ultrasound. B and C, left cheek (transverse
axis). D and E, nasal tip region (transverse axis). Note
the increased thickness of epidermis, dermis and hypo-
dermis. The dermis is visualized with lower echogenicity
and the hypodermis, with increased echogenicity and a
blurred and heterogeneous appearance. With color Dop-
pler, on the cheek and nasal tip there is an increase in
superficial dermal and hypodermal vascularization (C and
E). Reference: C, nasal alar cartilage.

261
Fig. 23-3. (A-D) Rosacea. A B
A, clinical photo. B-D, fa-
cial color Doppler ultra-
sound. B and D, longitudi-
nal axis at the dorsum, and
D, transverse axis at the
tip of the nose. In B (grey
scale) and C (Doppler col-
or) epidermal, dermal and
hypodermal thickening is
observed, which predomi-
nates in the nasal tip (right
margin of the images) with
a dermis of lower echoge-
nicity and a hypodermis
of higher echogenicity,
somewhat heterogeneous
and blurred. C shows an
increase in dermal and
hypodermic vascularity in
the dorsum of the nose.
In D (Doppler color), note C D
the increase of vascular-
ization in the interior and
periphery of both alar car-
tilages.

262
A B Fig. 23-4. (A-C). Rosa- CONCLUSION
cea. A, clinical photo. Color Doppler ultrasound provides
B and C, facial color non-invasive anatomical informa-
Doppler ultrasound. tion useful in patients with rosacea,
B, transverse axis which can help in monitoring their
in nasal tip, and C, treatment. In addition, ultrasound
comparative trans- can be a good support to establish
verse axis in both differential diagnoses with disorders
cheeks. In B, note that can simulate rosacea or hinder
the dermal hyper- its treatment, such as complications
vascularization, hypo- of cosmetic fillers or vascular malfor-
dermic perichondrial mations among others.
and inside both nasal
alar cartilages. In C
a diffuse increase of
vascularization, der- References
mal and hypodermic, 1. Culp B, Scheinfeld N. Rosacea: A re-
is observed in both view. PT 2009 Jan; 34(1):38-45.
cheeks.
2. Wortsman X. Common applications
of dermatologic sonography. J Ul-
C trasound Med 2012; 31:97-111.

3. Echeverría-García B, Borbujo
J, Alfageme F. The use of ultra-
sound imaging in dermatolo-
gy. Actas Dermosifiliogr 2014;
105(10):887-90.

4. Mandava A, Ravuri PR, Konathan R.

High-resolution ultrasound imaging
of cutaneous lesions. Indian J Radi-
ol Imaging 2013; 23(3):269-77.

5. Wortsman X. Ultrasound in Der-

matology: Why, how and when?
Semin Ultrasound CT MRI 2013;
34:177-195.
263
 A B C

Fig. 23-5. (A-D) Silicone oil. A, patient on rosacea treatment for 6 months
with no results. B-D, facial color Doppler ultrasound. B, interciliary frontal
region (transverse axis, color Doppler). C, nasolabial fold and right peri-
oral region (grey scale), and D, longitudinal axis upper and lower lips (col-
or Doppler). In the ultrasound images (dermal and hypodermic planes of
the frontal, nasolabial and perioral regions, as well as in the dermal planes
and crossing the upper and lower orbicularis oculi muscle) hyperecho-
genic deposits are observed producing a “ snowstorm “ type reverbera-
tion artifact, compatible with silicone oil (*). In B, on the periphery of the
deposits, observe the reduction in dermal echogenicity and the increase
in blurred echogenicity of the hypodermis of the frontal interciliary re-
gion, as well as, in B and D, the increase in vascularization in the periphery
of the deposits.
264
 Fig. 23-6. (A-C), Nasal arteriovenous vascular malformation. A, clinical photo. Patient with ery-
A thematous and raised areas on the nasal dorsum. B and C, facial color Doppler ultrasound. B,
transverse axis, and C, longitudinal axis. They show intense dermal and hypodermic hypervascu-
larization, with vascular network in the nasal dorsum, of greater right paramedian amount and at
the expense of thick vessels. Spectral analysis of curves revealed arterial and venous flows.

B C

265
6. Wortsman X, Alfageme F, Roustan
G, et al. Guidelines for performing
dermatologic ultrasound examina-
tions by the DERMUS Group. J Ul-
trasound Med 2016; 35(3):577-80.
7. Wortsman X, Wortsman J, Carreño
L, et al. Sonographic anatomy of
the skin, appendages and adjacent
structures. In: Dermatologic Ultra-
sound with Clinical and Histologic
Correlations, Wortsman X, Jemec
GBE eds., 1st edition, Springer NY
2013 p15-35.
8. Wortsman X, Wortsman J, Sazunic
I, et al. Activity assessment in mor-
phea using color Doppler ultra-
sound. J Am Acad Dermatol 2011;
65:942-8.
9. Wortsman X, Carreño L, Morales
C. Inflammatory diseases of the
skin. In: Dermatologic Ultrasound
with Clinical and Histologic Cor-
relations. Wortsman X, Jemec GBE
eds., 1st edition, Springer NY 2013.
p73-117.
10. Maldonado Cid P, Rubio Flores C,
Prats Caelles I, et al. High-frequen-
cy ultrasound features in a case of
gouty panniculitis. Dermatol Online
J 2017; 23(6). pii:13030/qt33j2z14m.
11. Wortsman X. Sonography of derma-
tologic emergencies. J Ultrasound
Med 2017; 36(9):1905-1914.
12. Wohlrab J, Lueftl M, Marsch WC.
Persistent erythema and edema of
the midthird and upper aspect of
the face (morbus Morbihan): Evi-
dence of hidden immunologic con-
tact urticaria and impaired lymphat-
ic drainage. J Am Acad Dermatol
2005; 52(4):595-602.
13. Carlson JA, Mazza J, Kircher K,
et al. Otophyma: A case report
and review of the literature of
lymphedema (elephantiasis) of the
ear. Am J Dermatopathol 2008;
30(1):67-72.
14. Carruth BP, Meyer DR, Wladis EJ,
et al. Extreme eyelid lymphedema
associated with rosacea (Morbihan
Disease): Case series, literature
review, and therapeutic consider-
ations. Ophthal Plast Reconstr Surg
2017; 33(3S Suppl 1):S34-S38.
266
15. Nagasaka T, Koyama T, Matsumura
K, et al. Persistent lymphoedema
in Morbihan disease: formation
of perilymphatic epithelioid cell
granulomas as a possible patho-
genesis. Clin Exp Dermatol 2008;
33(6):764-7.
16. Wortsman X, Wortsman J, Orlandi
C, et al. Ultrasound detection and
identification of cosmetic fillers in
the skin. J Eur Acad Dermatol Ve-
nereol 2012; 26:292-301.
17. Wortsman X, Wortsman J. Polyacryl-
amide fillers on skin ultrasound. J
Eur Acad Dermatol Venereol 2012;
26:660-1.
18. Wortsman X. Identification and
complications of cosmetic fillers:
Sonography first. J Ultrasound Med
2015; 34(7):1163-72.
19. Wortsman X, Quezada N. Ultra-
sound morphology of polycaprolac-
tone filler. J Ultrasound Med 2017;
doi: 10.1002/jum.14327.
20. Wortsman X. Sonography of cos-
metic procedures. In: Dermatologic
Ultrasound with Clinical and His-
tologic Correlations, Wortsman X,
Jemec GBE eds , 1st edition, Spring-
er NY 2013. p373-399.
21. Cassuto D, Pignatti M, Pacchioni L,
et al. Management of complications
caused by permanent fillers in the
face: A treatment algorithm. Plast
Reconstr Surg 2016; 138(2):215e-27e.
22. Kayabasoglu G, Kaymaz R, Yil-
maz MS, et al. Rhinophyma-like
venous malformation of the nose.
Br J Dermatol 2014; 171(1):195-7.
doi:10.1111/ bjd.12896. Epub 2014 Jun
22. Erratum in: Br J Dermatol. 2015
Jan;172(1):307.
23. Peer S, Wortsman X. Hemangiomas
and vascular malformations. In: Der-
matologic Ultrasound with Clinical
and Histologic Correlations, Worts-
man X, Jemec GBE eds., 1st edition,
Springer NY 2013 p183-248.
24. Benzar I. A diagnostic program of
vascular tumor and vascular mal-
formations in children according to
modern classification. Acta Medica
(Hradec Kralove) 2017; 60(1):19-26.
 „„ Chapter 24. General Measures to
Section 7 Manage Rosacea

„„ Chapter 25. Topical Treatment

„„ Chapter 26. Systemic Treatment

Treatment „„ Chapter 27. Complementary
Treatments

„„ Chapter 28. Treatment

Guidelines
The objective of the treatment of
rosacea is to attenuate morbidity
and prevent complications. Medical
treatments depend upon the rosa-
cea subtype and include topical and
systemic agents, together with sup-
plementary management. However,
all treatment plans should be orient-
ed to the patient’s general well-be-
ing due to the considerable impact
that rosacea can have on quality of
life. Typically, rosacea evolves in cy-
cles, with episodes of remission and
relapse. Patients may be free of le-
sions for prolonged periods only to
relapse when exposed to different
exacerbating factors, like sun expo-
sure, emotional stress, hot or warm
weather, wind, heavy exercise, alco-
holic beverages, hot baths, as well as
very spicy or hot food. Most patients
suffer two to three yearly episodes;
consequently, a primary general
management strategy is to avoid
exposure to the above-mentioned
trigger factors. Being a chronic dis-
ease, rosacea often requires long-
term treatments; it is important for
patients to become aware of this fact
right from the beginning.
PATIENT EDUCATION
It is essential to provide rosacea pa-
tients with the adequate education
and information to help them to bet-
ter understand their condition and be
able to cope with the disease. First,
it is important to emphasize that ro-
Chapter 24
General Measures
to Manage Rosacea
Mercedes Flórez-White
sacea has a benign nature and does
not inevitably lead to the phymatous
variant. Patients should be educated
that rosacea is –at least for now– a
chronic, inflammatory and incurable
skin disorder that may be efficiently
controlled through long-term, phar-
macological or procedural interven-
tions. In addition, the patients must
be aware of the existence of sever-
al strategies that may improve their
symptoms.1-3
Avoiding triggering factors
Affected patients should avoid, as
much as possible, all the specific
triggering factors that induce facial
vasodilation including: sun exposure,
extreme temperatures (hot or cold),
excessive heating, steam rooms (sau-
na), very hot or spicy food, hot bev-
erages, products containing great
quantities of biogenic amines like
wine (especially red) or cheese. Also,
268
emotional factors, aggressive pro-
cedures (chemical peelings), certain
drugs and physical or psychological
stress. These provoking factors may
differ from one individual to anoth-
er: a specific trigger may cause an
outbreak in one patient but have no
effect whatsoever in another. There-
fore, it is very important to train
patients in identifying their trigger-
ing factors. In addition to these ex-
ogenous factors, certain mites, like
Demodex folliculorum, may cause
inflammation. Since these mites are,
by nature, permanent human ecto-
parasites, they cannot be eradicated,
so they must be controlled with anti-
parasitic drugs which shall be men-
tioned further on.1-5
DERMOCOSMETIC CARE
Proper skin care constitutes a key
element in the management of ro-
sacea by supporting adherence to
topical treatment. Due to the fact
that rosacea patients present with
an alteration of the skin barrier –as
evidenced by the increase in the
centrofacial transepidermal water
loss– it is convenient to use cleans-
ing and moisturizing products con-
taining lipids similar to those of the
skin barrier and free of soap, aggres-
sive surfactants, oils and additives or
preservatives.1,4,5 The cosmeceutical
management of rosacea is described
in another chapter.
GENERAL MEASURES FOR MILD
OCULAR INVOLVEMENT
In patients with ocular involvement,
basic care should include daily hy-
giene of the palpebral border via
cleansing the base of the eyelash-
es with a soft gauze compress and
lukewarm water. The purpose of
this practice is to remove the se-
cretion excessively produced by the
Meibomian glands. Furthermore, the
regular use of lipid based (gel) arti-
ficial tears is an option for manag-
ing dry eyes, a frequent problem in
patients with blepharitis caused by
rosacea.
PHOTOPROTECTION
There is strong evidence that sun
exposure is a triggering factor of
rosacea symptoms, through the ex-
pression of different inflammatory
chemokines, particularly cathelicidin
LL-37. In addition, solar radiation,
through ultraviolet radiation (UV)
and infrared radiation (IR), generate
reactive oxygen species (ROS). This
leads to the oxidative modification
of proteins and to lipid peroxidation,
thus intensifying skin inflammation.
Besides, UVB radiation may directly
activate keratinocyte receptors in-
volved in inflammation and pain in-
cluding the hydrocarbon receptors
or transient receptor potential vanil-
loid type-4 (TRPV4) ion channel. It
is also well known that exposure to
acute UV light acts as an exacerbat-
ing factor of rosacea by stimulating
innate immunity and contributing to
drain the antioxidant reserve in af-
fected skin. 1,7-10
Daily photoprotection, via the use
of physical means (for example, pro-
tective clothes, wide brim hats) and
the proper use of sunscreens, should
become part of the fundamental
management of rosacea. As men-
tioned above, acute exposure to UV
rays may stimulate vasodilation and
the innate immune responses, drain
the antioxidant reserves and exacer-
bate chronic clinical characteristics,
like fixed erythema and telangiecta-
ses. Habitual photoprotection reduc-
es these skin alterations that develop
over time. It is also useful for reduc-
ing the probability of a rosacea rash,
when acute exposure to sun light
reaches its triggering threshold. En-
vironmental heat can also induce ro-
sacea exacerbation independent of
exposure to solar radiation.1,5,11 There
are innumerable sun protection
products for daily use, including lo-
tions, creams, various make-up prod-
ucts and moisturizing creams.
To date, there is no consensus
concerning the ultimate, scientifical-
ly proven sun protection product for
the management of rosacea. Howev-
er, the ideal sun protector for these
patients should consist of a liquid
or aqueous gel, oil-free formulation,
with anti UVA and UVB protection,
a 30 or higher sun protection factor
(SPF) containing physical or inorganic
filters like zinc oxide and/or titanium
dioxide.1,11
On account of the ROS generat-
ed by solar radiation, there is a de-
crease in the activity of the systemic,
antioxidant defense system, with the
consequent oxidative stress induc-
ing the enhancement of inflamma-
tion in rosacea patients. Therefore,
the simultaneous use of sunscreens
and topical antioxidant agents, like
vitamins C, E and others, is also rec-
ommended.12
CONCLUSIONS
Identifying different triggering and
exacerbating factors is of fundamen-
tal importance for the treatment of
rosacea. Patients should learn how to
identify them, so that they may try to
269
eliminate them in the best way pos-
sible. Because rosacea worsens with
sun exposure, it is necessary to insist
on the use of photoprotection, with
adequate clothing and specifically
with wide brim hats. This goes togeth-
er with the daily use of a broad-spec-
trum sun protection containing
proper vehicles and ingredients for
sensitive and intolerant skin. The best
sunscreens are those containing zinc
oxide or titanium dioxide. The simulta-
neous use of topical antioxidants and
inorganic sun protectors, constitutes
one of the most important measures
in the management of rosacea.
References
1. Schaller M, Schöfer H, Homey B, et
al. Rosacea management: Update
on general measures and topical
treatment options. J Dtsch Derma-
tol Ges. 2016 Dec;14 Suppl 6:17-27.
2. Del Rosso JQ, Thiboutot D, Gallo R,
et al. Consensus recommendations
from the American Acne & Rosa-
cea Society on the management of
rosacea, part 1: A status report on
the disease state, general measures,
and adjunctive skin care. Cutis.
2013;92(5):234-240.
3. Two AM, Wu W, Gallo RL, et al. Ro-
sacea: Part II. Topical and systemic
therapies in the treatment of ro-
sacea. J Am Acad Dermatol 2015;
72:761-70.
4. Kaminsky A, Flórez-White M, Pique-
ro J, et al on behalf, of the Grupo Ibe-
ro-Latinoamericano de Estudio de la
Rosácea (GILER) (Iberian-latinamer-
ican Group for the study of rosacea)
– CILAD (Iberian-Latinamerican
School of Dermatology).Informe de
Consenso Ibero-Latinoamericano
2016 sobre la clasificación clínica y
terapéutica de la rosácea. (2016-Ibe-
rian Latin-american Consensus Re-
port on the Clinical and Therapeu-
tic Classification of rosacea) Med
Cutan Iber Lat Am 2016; 44 (1).
5. Schaller M, Almeida L, Bewley A, et
al. Rosacea treatment update: Rec-
ommendations from the global RO-
Sacea Consensus (ROSCO) panel.
Br J Dermatol. 2017 Feb;176(2):465-
47.
6. Vieira AC, Mannis MJ. Ocular ro-
sacea: Common and commonly
missed. J Am Acad Dermatol 2013;
69:S36-41.
7. Jones D. Rosacea, reactive oxygen
species, and azelaic acid . J Clin Aes-
thet Dermatol 2009; 2:26-30.
8. Moore C, Cevikbas F, Pasolli HA,
et al. UVB radiation generates sun-
burn pain and affects skin by activat-
ing epidermal TRPV4 ion channels
and triggering endothelin -1 signal-
ing. Proc Natl Acad Sci USA 2013;
110(34):E3225-34.
9. Del Rosso JQ, Gallo RL, Tanghetti E,
et al. An evaluation of potential cor-
relations between pathophysiologic
mechanisms, clinical manifestations,
and management of rosacea. Cutis
2013; 91(3 Suppl):1-8.
10. Wilkin JK. Erythematotelangiectat-
ic Rosacea and telangiectatic pho-
toaging: Same, separate, and/or
sequential? JAMA Dermatol 2015;
151:821-3.
270
11. Weinkle AP, Doktor V, Emer J. Up-
date on the management of rosa-
cea. Clin Cosmet Investig Dermatol
2015; 8:159-77.
12. Tisma VS, Basta-Juzbasic A, Jagan-
jac M, et al. Oxidative stress and
ferritin expression in the skin of
patients with rosacea. J Am Acad
Dermatol 2009; 60(2):270-6.

METRONIDAZOLE
Metronidazole is a synthetic nitro-
imidazole derivative and one of the
most commonly used drugs in rosa-
cea. Its mechanism of action in rosa-
cea is unclear. Its therapeutic action is
antibacterial and antiprotozoal, with
anti-inflammatory and immunosup-
pressive effects. Metronidazole inhib-
its the synthesis of nucleic acids and is
used in the management of infections
by protozoa and anaerobic bacteria.
In anaerobic microorgamisms, it is a
prodrug that is converted by pyruvate
ferredoxin oxidoreductase enzymes.
The nitro group of metronidazole is
reduced by ferredoxin –or by an anal-
ogous mechanism– and the resulting
metabolites disrupt the helical struc-
ture of bacterial DNA, inhibiting its
synthesis.
Chapter 25
Topical Treatment
Antiparasitic Drugs
María I. Herane
Topical metronidazole has been in versus a placebo and in comparison
the pharmacopoeia since the 1950s. with oral tetracycline.4-6
It is available in gel, cream or oint-
ment which is important because Antioxidant Effect
the type of vehicle used can have an There is evidence to suggest that
impact on efficacy and tolerability.1 the efficacy of metronidazole in ro-
It has an oxygen scavenging action, sacea is due to both its antimicrobi-
decreasing reactive species and in- al and anti-inflammatory actions. In
hibiting neutrophils.2 Topical appli- the pathophysiology of rosacea, the
cation of metronidazole to reduce inflammatory process includes the
redness in rosacea was studied by release of reactive oxygen species
Nielsen in the early 1980s.3 This au- (ROS) mediated by neutrophils. Some
thor demonstrated, as others would in vitro studies demonstrated that
confirm later, therapeutic efficacy in metronidazole interferes with the re-
the management of rosacea with a 1 lease of superoxide ions (O2–), hydro-
% metronidazole cream formulation gen peroxide (H2O2), and hydroxyl
271
radicals (OH–). This antioxidant ac-
tion, which is obtained by modulating
the activity of neutrophils and not by
direct oxidative sequestration, occurs
with both oral and topical administra-
tion. Rosacea-affected skin often has
additional damage from extrinsic and
intrinsic aging, which exacerbates
symptomatology and increases cellu-
lar oxidation. Metronidazole is used
to prevent and treat oxidative dam-
age, and helps manage it, both by de-
creasing the generation of ROS and
by inactivating pre-existing ROS lev-
els.7 An antiparasitic activity against
Demodex folliculorum has been sug-
gested; however, there is evidence
that these mites survive metronida-
zole solutions greater than 1 mg/ml, a
concentration much higher than that
achieved in vivo.8
Topical Use in Rosacea
Metronidazole is useful and safe in ro-
sacea and available formulations are
cosmetically well accepted. It can be
used as a cream, lotion or gel once a
day. A meta-analysis suggests that the
lotion may be the most effective for-
mulation. The maximum solubility of
the drug in water is 0.75%. Concentra-
tions of 1 % in cream have been devel-
oped, but once-daily application did
not show greater efficacy in reducing
papules, pustules and erythema, and
its higher cost makes it unsuitable.9
In a multicentre, randomized, split-
face, double-blind, controlled study,
treatment of papulopustular rosacea
(PPR), 0.75 % metronidazole gel re-
duced 65.1 % of papules and pustules
in eight weeks.10 Another multicentre,
double-blind study demonstrated a
significant improvement in papules
and pustules compared to vehicle
alone after three months of treatment.
In the latter study, the gel formulation
caused dryness and skin irritation.11
The gel had no effect on the telangi-
ectases.12
Nowadays, formulations may have
hydrosolubilizing agents to improve
tolerability. Patients who cannot tol-
erate the gel formulation can use the
cream, which is marketed at 1%. In an
open multicentre, phase IV study, 582
patients with PPR were prescribed
0.75 % metronidazole gel twice dai-
ly in the affected areas. After twelve
weeks, there was a progressive de-
crease in papules and pustules of up
to 71 %. The onset of improvement
in inflammatory lesions began after
four weeks of treatment (44%). The
average decrease in the erythema
parameter was 50% at twelve weeks.
Itching, burning, pain, or stinging sen-
sation improved by 25% at the end
of the study. Fifty-three percent of
patients reported fewer feelings of
shame and increased participation in
social activities.13
The 0.75 % gel has been shown
to maintain remission of papules
and pustules and provide longer
sustained disease-free intervals com-
pared to placebo. Dahl et al. conduct-
ed a study in patients with PPR who
had been successfully treated with
oral tetracycline and 0.75 % metroni-
dazole gel. Upon entering a second
randomized, double-blind phase, one
subgroup continued topical treat-
ment with 0.75% metronidazole gel
and another with metronidazole gel
vehicle. There was a 42% decrease
in relapses versus a 23% decrease
in the active versus control groups,
respectively. In addition, six months
after the complete suspension of
treatments, those in the first group
who had longer metronidazole treat-
ment had fewer inflammatory le-
sions and fewer erythema relapses
than the second subgroup (74 %
versus 55 %).14
272
Similar results were obtained in
comparative studies of 0.75 % met-
ronidazole gel and 1 % ivermectin
cream. After discontinuation of treat-
ments, ivermectin performed better
than metronidazole in terms of dis-
ease-free time and severity of relaps-
es; however, topical application of
both drugs exerted good anti-inflam-
matory activity.15
Adverse Effects
In general, the tolerability and safety
of topical metronidazole, whether in
gel, cream, or lotion, is similar in all
studies. Local adverse effects at appli-
cation sites have been reported with
more serious events being rare.11,12 The
most common adverse effects were
dermatitis and irritation at the appli-
cation site which usually occurred
at the start of treatment (first four
weeks).13
Oral Metronidazole
After oral administration, metronida-
zole is widely distributed through-
out most tissues. It is metabolized in
the liver, 60-80% is excreted in urine
and a smaller amount in faeces. Side
effects reported with oral metroni-
dazole include nausea, diarrhea, and
a metallic taste in the mouth. Hy-
persensitivity reactions, headaches,
dizziness, vomiting, glossitis, stomati-
tis, paresthesias and dark urine may
also occur. Occasionally, there may
be leukopenia, neutropenia and risk
of peripheral neuropathy or central
nervous system toxicity. A disulfiram
effect may occur if metronidazole is
used with the simultaneous intake of
alcohol. Its administration is formally
contraindicated in the first trimester
of pregnancy.
Oral metronidazole is occasional-
ly used in PPR, almost exclusively for
cases associated with demodicidosis
resistant to treatment or in combina-
tion with other therapies, such as oral
ivermectin or topical mercury oxide.16,17
IVERMECTIN
Ivermectin is an 80:20 avermectin B1a
to B1b mixture, which are macrocy-
clic lactones produced by the actino-
bacteria Streptomyces avermitilis. Its
broad antiparasitic spectrum has long
been known in animals and humans.
It has been used with good results in
onchocerciasis, strongyloidiasis, filari-
asis and infestations such as scabies
and lice. Ivermectin selectively binds
with high affinity to glutamate-gated
chloride channels in the nerves and
muscle cells of invertebrates. This
causes an increase in the permeability
of the cell membrane to chloride ions
and hyperpolarization of the nerve
or muscle cell. This hyperpolarization
results in paralysis and death of para-
sites, either directly or by causing the
worms to starve.1 Chloride channels
are not present in humans or other
vertebrates (Fig. 25-1).
 There is an increase in the De-
modex load (the normal value is five
parasites/cm2) in approximately 35%
to 50% of individuals with rosacea.
Ivermectin kills Demodex found in
the pilosebaceous unit of patients
with PPR. The resulting antigens
from the dead of the parasite, such
as chitin and beta-glucans, activate
toll-like receptors 2 (TLR-2) and
inflammasomes which are also in-
creased in rosacea.2 In addition to
its efficacy in eradicating Demodex,
ivermectin exerts anti-inflammato-
ry effects; it decreases cellular and
humoral immunity including neutro-
phil phagocytosis and chemotaxis; in
vitro, it inhibits the lipopolysaccha-
ride-induced production of pro-in-
flammatory cytokines such as TNF-a,
IL-1b, and IL-10. It also suppresses li-
popolysaccharide-induced secretion
of nitric oxide and PGE2 in macro-
phages, and reduces blastogenesis
and recruitment of immune cells and,
in some circumstances, the antibody
response (in animal models) for the
treatment of non-infectious diseases

↓ Pro-inflammatory cytokines + ↑ Anti-inflammatory cytokines = Anti-inflammatory effects

(TNF-α + IL-1β) (IL-10)

Presynaptic nerve ending Presynaptic nerve ending Presynaptic nerve ending

Glutamate Glutamate Glutamate

Avermectin Avermectin Avermectin

Cl– Cl– Cl–

– – –
Cl Cl Cl
Glutamate Glutamate Glutamate
binding site binding site binding site

Avermectin binding Avermectin binding Avermectin binding

site [glutamate-gated site [glutamate-gated site [glutamate-gated
chloride channels] chloride channels] chloride channels]
Fig. 25-1. Mode
of action of iv-
ermectin at the Motor neuron Motor neuron Motor neuron
level of chloride
channels in the
neuron.
Paralysis → Death
273
of the upper respiratory tract, such
as allergic asthma. Inflammatory
mechanisms appear to play a major
role in the development of inflamma-
tory rosacea lesions, such as papules
and pustules, as well as in related
vascular changes, such as erythema
and telangiectases. Skin with rosa-
cea is prone to Demodex infestation,
which exacerbates the inflammatory
phenomena described above. There
is evidence that avermectins, includ-
ing ivermectin, have bactericidal
properties against Mycobacterium
tuberculosis, even against multi-re-
sistant strains, and against Chlamyd-
ia trachomatis.3,4
Pharmacokinetic Properties
In patients with severe PPR, the ap-
plication of ivermectin 1% cream once
daily reaches stable plasma levels
after two weeks of treatment. Peak
plasma concentrations at steady state
are achieved approximately 10 hours
after application, with no drug accu-
mulation in long-term treatments of
more than 52 weeks.5 In vitro, ivermec-
tin is 99 % bound to plasma proteins,
mainly to serum albumin; binding to
red blood cells is not significant. It
is metabolized by cytochrome P450
(CYP3A4) to dimethyl and 4a-hy-
droxy-ivermectin, which also have not
been shown to accumulate after >12
weeks treatment. The pharmacoki-
netics of ivermectin has not been as-
sessed in patients with kidney or liver
damage. When ivermectin is applied
topically, in 1% cream for 28 days, its
half-life is prolonged to an average of
six days.
There have been no studies of drug
interactions for ivermectin 1% cream.
In vitro, inhibition of key cytochrome
iso-enzymes and induction of CY-
P1A2, 2B6, 2C9 or 3A4 have not been
observed; therefore, the likelihood of
interaction with drugs metabolized by
these enzymes is low. However, the
role of CYP3A4 in ivermectin metab-
olism must be considered, which is
why caution must be exercised when
administering the cream together
with CYP3A4 inhibitors, since plasma
levels of the drug may increase.5,6
Dosage and Administration
Ivermectin 1% cream is indicated for
the treatment of the inflammatory
lesions of rosacea. It is suggested to
apply a lentil-size amount of cream in
each affected area of the face night-
ly for 4 months. The cream should
be spread in a thin layer, avoiding
contact with lips, eyes and mucous
membranes. The application may be
repeated if necessary. If there is no
improvement after three months,
treatment should be discontinued.
The cream must be used within six
months after the tube is opened.
The excipients in the cream may
cause adverse effects such as irri-
274
tant dermatitis (cetyl and stearic
alcohol), allergic reactions (methyl pa-
rahydroxybenzoate and propyl para-
hydroxybenzoate), and local irritation
(propylene glycol).7
Ivermectin cream is not recom-
mended for use in children, although
recent studies of its use off-label have
shown good efficacy without adverse
effects.8 Due to the potential for tera-
togenicity demonstrated in animals,
ivermectin should not be used during
pregnancy; it is also not recommend-
ed during breastfeeding, because the
drug is excreted in breast milk.
The dosage does not require any
adjustment in elderly patients or in
patients with renal failure, although
caution is advised in patients with se-
vere liver damage.
Antiparasitic and Anti-
Inflammatory Action9
In recent studies, patients with mod-
erate to severe PPR (defined as an
IGA 3 score (IGA: Investigators
Global Assessment) of rosacea sever-
ity and a Demodex  density of 15/
cm2) were treated with ivermectin 1
% cream once daily for 12 weeks. The
results showed a significant decrease
in mite density at 6 and 12 weeks. At
the end of the same period, and at
the final week for toll-like receptor 4
(TLR4), reductions in gene expression
levels for LL-37, HBD3 and TNF were
relevant. Expression of LL-37 and a re-
duction in IL-8 was confirmed at the
protein level by immunofluorescence
staining. From the clinical perspec-
tive, there was therapeutic success in
16 of 20 patients (IGA  1).
Efficacy of Ivermectin 1 % Cream in
Rosacea
Initially, ivermectin cream was com-
pared to the vehicle in double-blind
studies. These 12-week studies were
performed on patients older than 18
years with PPR and an average of 31
to 33 baseline inflammatory lesions.
Phase III studies versus vehicle in-
cluded Study 1, in which 451 patients
received ivermectin and 232 vehicle,
and Study 2, in which 459 patients
received ivermectin and 229 vehi-
cle.10 The results of these two studies
demonstrated that in cases of mod-
erate to severe PPR, ivermectin 1 %
cream applied during the night was
efficacious. In Study 1, a decrease of
inflammatory lesions to total or almost
total clearance (IGA 0-1) was achieved
in 38.4 % versus 11.6 % observed with
placebo. In Study 2, slightly higher
numbers were obtained (40.1 % vs. 18.8
%, ivermectin and placebo, respec-
tively). In each group, the success rate
was significantly higher with ivermec-
tin than with vehicle after just four
weeks of treatment (p < 0.05). These
findings correlate with a reduction in
the number of inflammatory lesions in
those treated with the ivermectin 1 %
cream, with an absolute change from
baseline to week 12 of treatment of
–8.13 and –8.22 inflammatory lesions
in Studies 1 and 2, respectively. From
week 2, the mean reduction in inflam-
matory lesions was higher for those
treated with ivermectin 1 % cream and
reductions remained higher in the iv-
ermectin group until week 12 (76 % vs.
50 % in Study 1; 75 % vs 50 % in Study
2) (Fig. 25-2).

More patients considered the re-

sults to be excellent to good with the
use of ivermectin 1 % cream than with
placebo (69 % of patients treated vs.
38.6 % of the placebo group from
Study 1, and 66.2 % vs. 34.4 %, respec-
tively, from Study 2). Improvement
in the quality of life measured was
also significantly higher in ivermec-
tin-treated patients, both on the DLQI
(Dermatology Life Quality Index) and
on the rosacea-specific questionnaire
(HR-QOL).10

The third therapeutic study was

designed in patients with characteris-
tics similar to the patients in the piv-
otal studies but compared ivermectin
1% cream once daily at night versus
twice-daily metronidazole 0.75%
cream. It was a 16-week, randomized,
investigator-blinded, parallel-group
study conducted in 962 patients with Fig. 25-2. Change in percentage of inflammatory lesions in patients from pivotal studies 1 and 2..
moderate to severe PPR (478 patients
in the ivermectin 1 % group and 484
in the metronidazole 0.75 % group).11
275
At week 16, reductions from baseline
in inflammatory lesions (83 % vs. 73.7
%; p < 0.01) and erythema were sig-
nificantly superior in the ivermectin
1% cream group compared with the
metronidazole 0.75% cream group;
separation between the groups was
observed from week three. IGA suc-
cess (clear/almost clear) was also su-
perior in the ivermectin 1 % cream
group, and differences versus metro-
nidazole 0.75% cream were observed
from week six until the end of the
study. The differences in IGA success
between the two treatment regimens
were slightly more marked in patients
with severe PPR (82.5 % vs. 63 %)
compared to those with more mod-
erate PPR (85.4 % vs. 77.9 %). Total
clearance of lesions was statistically
significantly more likely in the iver-
mectin 1 % group (34.9 % vs. 21.7 % for
metronidazole) (p < 0.001). DLQI and
HR-QOL questionnaires results were
better in the group treated with iver-
mectin 1 % than in the group that re-
ceived metronidazole 0.75 % at study
end.11
Observational studies of patients
with PPR treated with ivermectin 1
% cream have shown a relative effi-
cacy in the resolution of the erythe-
matotelangiectatic component. The
greatest efficacy was observed in
moderate to severe PPR, with an im-
provement of up to 40 %. In mild PPR,
the improvement in erythema did not
exceed 9%. This may be explained by
the anti-inflammatory effect of the
drug in reducing erythema surround-
ing inflammatory lesions.12
Ivermectin 1 % Cream in Long Term
Studies
Two investigator-blinded studies –
with the same patients recruited for
the initial 12-week pivotal studies–
were extended by an additional 40
weeks to test ivermectin 1 % cream
over the long term in the treatment
of moderate to severe PPR. Patients
who were originally randomized to
receive the 1 % cream in Studies 1 and
29 continued to receive the same
treatment for another 40 weeks.
Patients originally randomized to re-
ceive vehicle switched to azelaic acid
15 % gel twice daily.10 The long-term
extension study showed that a high
proportion of patients who contin-
ued to use ivermectin 1 % once daily
maintained their improvement. After
52 weeks, these patients had IGA
success rates (clear/almost clear, IGA
0/ 1) of 71.1 % and 76 %, while in piv-
otal studies 1 and 2, the improvement
rates after 12 weeks were 38.4 % and
40.1 %, respectively. The continued
use of ivermectin 1 % cream in the
management of PPR was associat-
ed with an increase in improvement
without adverse effects.13 The azelaic
acid group achieved improvements
of 59.4 % and 57.9 % (IGA 0 to 1) after
40 weeks of treatment.
276
Ivermectin 1 % Cream in the
Maintenance of Remission
Patients who completed the com-
parative metronidazole study and
achieved complete or almost com-
plete remission (IGA 0 to 1), were
studied for an additional 36 weeks. In
case rosacea condition worsened to
reach mild to moderate levels (IGA 2
or higher), treatment with the same
previous medication was restarted. A
measurement was made of mean time
to first relapse, relapse rate, number
of days off treatment and adverse
effects. The group treated with iv-
ermectin 1 % cream achieved better
results as shown by the mean time to
first relapse (115 days vs. 85 days) and
in relapse rates at the end of the study.
The median number of disease-free
days was higher for ivermectin 1 %
cream ( 196 days vs. 169.5 days), and
the percentage of patients who expe-
rienced a related adverse event was
equally low in both groups.14
A study was conducted to evaluate
therapeutic success of PPR treatment
with ivermectin 1 % cream and time
to relapse in 1366 patients from con-
trolled studies and patients from un-
published phase 2 trials;10,11 this study
compared the IGA score before and
after treatment as well as DLQI re-
sults and patient’s assessment of im-
provement. In one trial, relapse time
was measured.11 At end of treatment,
more ‘clear’ than ‘almost clear’ sub-
jects had a clinically meaningful dif-
ference in DLQI (59% vs. 44%; p < .001)
and a final DLQI score of 0-1 indicat-
ing no effect on quality of life (84%
vs. 66%; p < .001). More ‘clear’ subjects
reported an ‘excellent’ improvement
in their rosacea (77% vs. 42%; p < .001).
The median time to relapse was more
than 8 months for ‘clear’ vs. 3 months
for ‘almost clear’ subjects (p < .0001).
Achieving an endpoint of ‘clear’ (IGA
0) vs. ‘almost clear’ (IGA 1) is associ-
ated with multiple positive patient
outcomes, including delayed time to
relapse. Therefore, it is advisable not
to discontinue treatment until an
IGA 0 score or a complete clearance
of the disease is obtained.15
Tolerability
Overall, in pivotal studies, ivermec-
tin 1% cream was very well tolerated
in-patients with moderate to severe
PPR. Adverse reactions were not re-
lated to severity and, in general, de-
creased with continuing treatment.
The most frequent adverse events
were burning sensation (study 1 in
4.2 % of the treated group vs. 7.8 %
of those who received vehicle treat-
ment) or itching and dry skin (in study
2, present in < 2 % of each group). No
adverse effects were serious, and it
was not necessary to stop treatment.10
In comparative studies with metro-
nidazole, adverse effects were similar
for both drugs. Some patients experi-
enced local irritation (0.6 % vs. 0.8 %)
and worsening of symptoms of local
tolerance, including stinging sensa-
tion, dryness, itching and burning (8.8-
11.1 % vs. 11.4-15.5 %).11
In the 40-week extension study,
there was no increase in adverse ef-
fects from long-term ivermectin 1 %
cream use. At week 52 of this study
there was a greater percentage of pa-
tients with local adverse effects was
detected in the group that used aze-
laic acid 15 % gel twice daily (62-82%
of patients in the ivermectin group
showed no symptoms of local irrita-
tion versus 35-47% of patients in the
group treated with azelaic acid 15 %
gel).13
Oral Ivermectin
Ivermectin is generally a safe drug for
oral use. There is extensive experi-
ence with its use, especially in tropi-
cal countries. In some Latin American
countries, the authorization for oral
use is restricted to specific indica-
tions, such as ectoparasitosis. In most
of these countries, the indication for
its use in PPR or in demodicidosis is off
label. Oral ivermectin is administered
in a single dose of 200 mg/kg of body
weight. It is contraindicated in cases
of hypersensitivity to any of its com-
ponents, pregnancy, and lactation.
Rises in transaminases have been ob-
served in 2% of treated patients, but
was not thought to be drug related ,
and leukopenia in 3% of those treated
with oral ivermectin. Rare adverse re-
actions have been reported, such as
headache, asthenia, abdominal pain,
anorexia, constipation, diarrhea, nau-
sea and vomiting, drowsiness, vertigo,
and urticaria.
Use of oral ivermectin as treatment
for PPR and demodicidosis is found in
occasional reports, usually in relation
to clinical cases which are refractory to
usual therapies.16,17 In patients with cu-
taneous demodicidosis, anterior bleph-
aritis by Demodex and therapeutic
resistance, the single drug treatment
(200 mg/kg in 2 doses separated by
one week) was compared with the
combined treatment of oral ivermec-
tin in the same dose and oral metroni-
dazole (250 mg three times daily for 2
weeks). The response to combined iv-
ermectin-metronidazole therapy was
better, as there was a complete remis-
sion in 71.6% compared to 45% among
those treated with oral ivermectin
only.18 In a recent publication,8 15 pedi-
atric patients with PPR or periorificial
dermatitis were treated with a single
dose of 200 to 250 mg/kg of oral iver-
mectin, while another group received
a compound of topical ivermectin 1%
in an oil-in-water base cream applied
once a day for 3 months. Good results
were recorded in 8 patients treated
with oral therapy and 6 treated with
topical therapy, with complete or al-
most complete clearance of lesions.
277
The overall response to oral or topical
ivermectin was 93% of patients; 21%
experienced relapses, and 80% re-
mained disease-free for a prolonged
observation period.8 Oral ivermectin
may be a therapeutic alternative in re-
fractory cases.
PERMETHRIN
Permethrin is a synthetic chemical
substance which is active against
nits, flies, mites, bedbugs, and other
arthropods. It belongs to the family
of compounds known as pyrethroids,
whose mechanism of action is neu-
rotoxicity due to prolonged activa-
tion of sodium channels which in turn
causes sustained depolarization. Per-
metrhin has no effect on the neurons
of mammals or birds, so its toxicity in
mammals is low, except for cats which
are affected in the central nervous
system and liver with serious damage
and even death. After extensive test-
ing in plants and animals to prove its
safety, permethrin has been formu-
lated for use against human ectopar-
asites. Although large studies show
low toxicity in mammals, in volunteer
studies, active permethrin could not
be detected in blood or urine.
Currently, permethrin is used in
the treatment of head lice and sca-
bies in adults and children over two
months. For these conditions, it is
used as a lotion or 1%-5% cream that
is applied to the affected areas. Ap-
plications are repeated two to three
times, as required by the persistence
of live parasites on clothes, combs
and other personal effects, in addition
to establishing a family treatment. Pa-
tients should be advised to avoid con-
tact with eyes, mouth, ears, nose and
vagina.1,2
Preliminary Use in Rosacea
Considering the possible role of De-
modex folliculorum in the pathophys-
iology of rosacea, scabicidal agents
such as crotamiton, lindane, and
permethrin could be options in the
management of rosacea and demodi-
cidosis. To the antiparasitic properties
of permethrin, some not well-known
anti-inflammatory properties are add-
ed.3 The use of permethrin in rosacea
dates back to 1995, when Signore and
Park4 conducted a pilot study in five
patients with rosacea and obtained a
moderate improvement on both sides
of the face. Patients were treated for
nine weeks with 5% permethrin cream
on one side of the face, and 0.75%
metronidazole gel on the other side.
The authors did not note a variation
in the population of Demodex follic-
ulorum.4 In a subsequent study, 1 %
permethrin cream was used; it was
applied every other day for 45 days
in 10-minute applications followed by
rinsing to remove the cream. The stan-
dardized skin-surface biopsy showed
a decrease in the density of Demodex
folliculorum, but the acaricidal action
of permethrin was not statistically sig-
nificant.5 The same authors suggest
testing permethrin 5% cream for the
management of rosacea. A newer
clinical trial (2004) in patients with
demodicidosis obtained a significant
decrease of Demodex folliculorum
after 15 to 30 days of applying per-
methrin 5% cream twice daily.6 Good
results were also reported in refracto-
ry demodicidosis with the association
of oral ivermectin and weekly applica-
tions of permethrin 5% cream.7
Clinical Trials of Permethrin in
Rosacea
Only two randomised controlled clin-
ical trials have been published for
permethrin 5% cream in the manage-
ment of rosacea signs and symptoms.
Kocak et al.8 randomly assigned 63
patients with PPR to receive perme-
thrin 5% cream, metronidazole 0.75%
gel, or placebo applied twice daily for
two months. In the group treated with
permethrin 5% cream, the decrease in
Demodex folliculorum was significant-
ly greater than that seen with metro-
nidazole 0.75% gel or placebo. After
60 days of treatment, the therapeutic
efficacy of permethrin and metroni-
dazole in the reduction of erythema,
papules, and pustules was similar. No
changes in telangiectases or phy-
mas were observed with either drug.
Compared to placebo, permethrin
5% cream was associated with great-
er reductions in erythema beginning
on day 15, of papules beginning on
day 45, and of Demodex, beginning
between days 15 and 30. Efficacy con-
tinued until day 60 when the study
ended. The decrease in pustules
was not considered significant until
day 60. Compared to placebo, met-
ronidazole showed a similar efficacy
to permethrin, although reductions
of Demodex began on day 45 of
treatment.8
In 2009, Mustafa et al. published an-
other randomized, double-blind study
in which they compared the efficacy
of azelaic acid cream, metronidazole
0.75% and permethrin 5%9 twice a day
for 15 weeks. The results showed an im-
provement and a reduction of inflam-
matory lesions with the three drugs,
but a greater effectiveness of azelaic
acid, except in the management of
erythema. All three formulations were
well tolerated, and adverse effects
were discrete, local and transient.
Permethrin 5% Gel in Rosacea
Permethrin 5% aqueous gel –formu-
lated for the research work of Raou-
finejad et al.–10 showed good results
in the management of Demodex fol-
liculorum and the signs and symp-
toms of PPR compared with placebo.
In a randomized, double-blind trial,
20 patients with PPR and > 5 mites/
cm2 were studied. Permethrin 5 % gel
was applied twice daily on one side
of the face and placebo on the other,
278
after cleaning with mild soap and ap-
plying filter and oil-free moisturizers.
Demodex density was assessed and
photographs were taken four times
during the 12 weeks of the study. After
12 weeks, the results showed a signifi-
cant decrease in Demodex density in
both groups; however, that reduction
was significantly greater in the group
treated with permethrin 5% gel. The
clinical presentation, in relation to
flushing, non-transient erythema, pap-
ules, pustules, burning sensation, and
dry skin improved in both groups but
more in the permethrin 5% gel group.
Permethrin was also significantly more
effective in reducing the number of
inflammatory lesions versus placebo.
However, the effects of permethrin on
erythema were not statistically signif-
icant. Neither permethrin 5% gel nor
placebo was effective in the manage-
ment of plaques, edema and granulo-
matous lesions. Patients reported in
both groups felt symptoms improved;
but medical assessment found a supe-
rior clinical improvement on the side
of the face treated with permethrin
5% gel (measurement by lesions score
and comparison of clinical photo-
graphs). Adverse effects were similar,
and mild, in both groups. However, in
two patients of the permethrin-treat-
ed group, a sensation of numbness
was detected. At the end of 12 weeks
of observation, the significant reduc-
tion in Demodex folliculorum and the
severity of signs and symptoms in both
groups, compared to baseline, suggest
the importance of hygiene, vehicle and
changes in lifestyle. The use of cleans-
ers alone can reduce mite density.
Decrease in the number of Demodex
occurred from the eighth week on in
both groups; however, it remained until
week 12 only in the group treated with
permethrin 5% gel, demonstrating
that the improvement in symptoms ac-
companies decrease in mites at week
12. The importance of Demodex in the
disease is established, and the period
of 12 weeks was sufficient for the treat-
ment of PPR with permethrin 5% gel.
Adverse Effects
Permethrin may cause side effects,
such as itching in the skin or scalp,
redness, numbness or tingling in the
treated areas, and sometimes micro-
papular and itchy rash. In more severe
cases, there may be a hypersensitivi-
ty reaction with breathing difficulties,
irritation, or severe pustular skin or
scalp rash. As an insecticide in cer-
tain crops, its indiscriminate effect,
without differentiating between crop
parasites and other insects, has been
debated, as it even affects aquatic life.
Traces of permethrin have been isolat-
ed in the breast milk of women living
in malaria-controlled regions, but it is
not known whether it harms infants.1,2
Topical use in pregnant women would
not be contraindicated as long as it is
beneficial to the patient, as systemic
absorption is minimal.
References
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antra-ivermectin cream. US pre-
scribing information 2014. http://
www. fda.gov.
6. Deeks ED. Ivermectin: A review in
rosacea. Am J Clin Dermatol 2015.
doi: 10.1007/s40257-015-0150-8.
7. Kim ES, Deeks ED. Ivermectin in ro-
sacea: A guide to its use in the EU.
Drugs Ther Perspect 2016; 32:357-62.
8. Noguera-Morel L, Gerlero P, Tor-
relo A, et al. Ivermectin therapy for
papulopustular rosacea and periori-
ficial dermatitis in children: a series
of 15 cases. J Am Acad Dermatol
2016; 76(3):568-9.
9. Schaller M, Gonser L, Belge K, et
al. Dual anti-inflammatory and anti-
parasitic action of topical ivermec-
tin 1% in papulopustular rosacea. J
Eur Acad Dermatol Venereol 2017.
doi:10.1111/jdv.14437.
10. Stein-Gold L, Kircik L, Fowler J,
et al. Efficacy and safety of iver-
mectin 1% cream in treatment of
papulopustular rosacea: Results
of two randomized, double-blind,
vehicle-controlled pivotal studies.
J Drugs Dermatol 2014; 13(3):316-
23.
11. Taieb A, Ortonne JP, Ruzicka T, et al.
Superiority of ivermectin 1% cream
over metronidazole 0.75% cream
in treating inflammatory lesions
of rosacea: A randomized, investi-
gator-blinded trial. Br J Dermatol
2015; 172:1103-1110.
12. Mendieta M, Landa N. Treatment
of rosacea with topical ivermec-
tin cream: a series of 34 cas-
es. Dermatol On line J. 2016; 22
(8). http:// escholarship.org/uc/
item/9ks1c48n.
13. Stein-Gold L, Kircik L, Fowler J, et
al. Long-term safety of ivermectin
1% cream vs azelaic acid 15% gel
in treating inflammatory lesions of
rosacea: Results of two 40-week
controlled, investigator-blind-
ed trials. J Drugs Dermatol 2014;
13(11):1380-6.
14. Taieb A, Khamis A, Ruzicka T, et
al. Maintenance of remission fol-
lowing successful treatment of
papulopustular rosacea with iver-
mectin 1% cream vs. metronidazole
0.75% cream: 36-week extension of
the ATTRACT randomized study.
JEAD-V2015;DOI:10.1111/jdv13537.
15. Webster G, Schaller M, Tan J, et al.
Defining treatment success in rosa-
cea as “Clear” may provide multiple
patient benefits: Results of a pooled
analysis. J Dermatol Treat 2017. doi:
10.1080/09546634.2017.1343435.
16. Forstinger C, Kittler H, Binder M.
Treatment of rosacea-like demodici-
dosis with oral ivermectin and top-
ical permethrin cream. J Am Acad
Dermatol 1999; 41:775-7.
17. Holzchuh FG, Hilda RY, Moskovici
BK, et al. Clinical treatment of oc-
ular Demodex folliculorum by sys-
temic ivermectin. Am J Ophthalmol
2011; 151:1030-4.
18. Salem Doaa AB, El-Shazly A,
Nabih N, et al. Evaluation of the
efficacy of oral ivermectin in
comparison with ivermectin-met-
280
ronidazole combined therapy in the
treatment of ocular and skin lesions
of Demodex folliculorum. Int J In-
fect Dis 2013; 17:e343-7.
Permethrin
1. https://es.m.wikipedia.org/wiki/
Permetrina. [Accessed on July 29,
2017].
2. http://www.iqb.es/cbasicas/farma/
farma04/p018.htm. [Accessed on
July 29, 2017].
3. Gabbianelli R, Falcioni ML, Nasuti
C, et al. Effect of permethrin insec-
ticide on rat polymorphonuclear
neutrophils. Chem Biol Interact
2009; 182(2-3):245-52.
4. Signore RJ, Park T. A pilot study of
5 percent permethrin cream versus
0.75 percent metronidazole gel in
acne rosacea. Cutis 1995; 56:177-79.
5. Forton F, Seys P, Marchal JL, et al.
Demodex folliculorum and topical
treatment: acaricidal action eval-
uated by standardized skin sur-
face biopsy. Br J Dermatol 1998;
138:461-66.
6. Karincaoglu Y, Bayram N, Aycan
O, et al. The clinical importance
of Demodex folliculorum present-
ing with nonspecific facial signs
and symptoms. J Dermatol 2004;
31:618-26.
7. Forstinger Ch, Kittler H, Binder M.
Treatment of rosacea-like demodi-
cidosis with ivermectin and topical
permethrin cream. J Am Acad Der-
matol 1999; 41:775-7.
8. Kocak M, Yagli S, Vahapoglu G, et al.
Permethrin 5% cream versus metro-
nidazole 0.75% gel in the treatment
of papulopustular rosacea. Derma-
tology 2002; 205:265-70.
9. Mustafa FF, El Harras MA, Gomaa
SM, et al. Comparative study of
some treatment modalities of rosa-
cea. J Eur Acad Dermatol Venereol
2009; 23:22-8.
10. Raoufinejad K, Mansouri P, Rajabi
M, et al. Efficacy and safety of per-
methrin 5% topical gel vs. placebo
for rosacea: a double-blind ran-
domized controlled clinical trial. J
Eur Acad Dermatol Venereol 2016;
doi:101111/jdv.13801.
The treatment of rosacea includes
topical, systemic and surgical thera-
pies, laser therapy, phototherapy and
preventive measures, each according
to the subtype of rosacea. Based on
our understanding of the pathogen-
esis of rosacea, azelaic acid has been
used in its treatment.1-4
PHARMACOKINETICS
Azelaic acid is a short linear chain
carboxylic acid of 9 carbon atoms
(HOOC-(CH2)7-COOH). Its molec-
ular weight is 188.22. It occurs spon-
taneously in nature by disruptive
oxidation of ricinoleic acid. In bio-
logical systems, it is generated by
fermentative omega-oxidation of un-
saturated fatty acids; in its pure state,
it is presented as monoclinic pris-
matic needles with a melting point
of 106.50 °C. Azelaic acid is applied
topically. After a single administra-
tion on human skin, in vitro, the drug
penetrates the stratum corneum (ap-
proximately 3 to 5 % of the applied
dose) and other layers of the skin (in
the epidermis and dermis, up to 10
% of the applied doses are found).
About 4 % of the dose is absorbed
systemically. Cutaneous metabolism
is negligible. Most of the drug that
passes into the systemic circula-
tion is eliminated unchanged, and a
small amount undergoes oxidation to
shorter chain dicarboxylic acids. The
elimination half-life of the drug from
the body is about 45 minutes after
Azelaic Acid
Jaime Piquero-Martín
an oral dose, and 12 hours after top-
ical administration, indicating limited
transdermal absorption. Azelaic acid
concentrations and urinary excretion
are highly dependent on food intake.
After topical administration, plasma
concentrations and urinary excretion
are not significantly different from
baseline concentrations. It is consid-
ered pregnancy category B.5-7
MECHANISM OF ACTION
The inclusion of azelaic acid in the
dermatological therapeutic armamen-
tarium is justified by its recognised
efficacy as a topical agent in the treat-
ment of acne, rosacea, and melanotic
hyperpigmentation disorders such as
melasma, post-inflammatory hyper-
melanosis and lentigo maligna. It has
many other potential applications in
human therapeutics. In vitro, an anti-
proliferative and cytotoxic action has
been demonstrated on multiple cell
lines derived from malignant mela-
nomas, lymphomas and leukemias,
without any inhibitory activity on lym-
phocytes, fibroblasts or melanocytes
derived from normal human skin. In
vivo, it also has some activity against
superficial spreading melanoma and
nodular melanoma. The antiprolifer-
ative and cytotoxic actions of azelaic
281
acid may be due to reversible inhi-
bition of a variety of oxidoreductive
enzymes including DNA polymerase,
tyrosinase, and mitochondrial en-
zymes of the respiratory chain. At the
cellular level, it causes mitochondrial
swelling and accumulation of cyto-
plasmic lipid droplets. The keratolyt-
ic action of azelaic acid may be due
to decreased synthesis of filaggrin.
By inhibiting this protein, azelaic acid
may normalize the keratinization of
the follicle and produce a reduction
in acne lesions. Azelaic acid does not
affect sebum excretion.8
Azelaic Acid in the Treatment of
Acne
For the treatment of acne vulgaris,
it is used in the form of 20 % cream
and 15 % gel. Because it is pregnancy
category B, it can be used in preg-
nant women. Its beneficial action in
the treatment of acne was initially
described by Nazarro-Porro et al.,
after an open clinical trial using a
cream containing 20 % of the drug.
Since then, multiple clinical trials
have been conducted to evaluate
its therapeutic efficacy, both abso-
lute (evaluation against vehicle) and
relative (comparative studies with
benzoyl peroxide, tretinoin, topical
erythromycin, oral tetracyclines and
oral isotretinoin), as well as to deter-
mine its side effects.
The efficacy of azelaic acid in
acne is attributed to its antibacteri-
al activity, its normalizing action of
keratinization and its anti-inflamma-
tory effect. The antimicrobial effect
is due to an inhibition of cellular
protein synthesis, although the ex-
act mechanism is not known. It has
a bacteriostatic effect against a
number of aerobic microorganisms,
especially Staphylococcus epider-
midis and Propionibacterium acnes,
present in large quantities on ac-
ne-prone skin. In high concentra-
tions, azelaic acid is a bactericide
against S. epidermidis and P. acnes.
By reducing the concentration of
bacteria present on the skin, the
associated inflammation decreases.
It also has oxygen free radical scav-
enging properties.9-12
Azelaic Acid in Skin Pigmentation
Disorders
Azelaic acid has an antityrosinase
effect on carboxylic acids; it com-
petitively inhibits tyrosine, which is
the key enzyme for melanogenesis
and, conversely, thyroxine reduc-
tase, which is involved in the biosyn-
thesis of deoxyribonucleic acids. It
especially acts on post-inflammato-
ry hyperpigmentation. Its efficacy
has been shown in melasma, after
its topical application on spots. The
drug reduces epidermal melanogen-
esis, which promotes the replace-
ment of abnormal melanocytes.
Hyperactive melanocytes are much
more susceptible to the effects of
azelaic acid than normal melano-
cytes.13-15
Azelaic Acid in Rosacea
Traditional topical agents in the
management of rosacea are metro-
nidazole 0.75% gel, which was ap-
proved in 1988, and azelaic acid 15%
gel, approved by the United States
Food and Drug Administration
(FDA) in December 2002. More
recently, alpha-adrenergic ago-
nists –brimonidine 0.33% gel, and
oxymetazoline 1% cream– were ap-
proved. On December 24th, 2012,
azelaic acid was approved for the
treatment of papulopustular rosa-
cea (PPR). The FDA approval note
says “the mechanisms by which
azelaic acid interferes with PPR le-
sions are unknown”.16,17
Mechanism in Rosacea
In vitro, this drug has an antioxidant
effect through the scavenging of
hydroxyl radicals, the inhibition of
radical-induced hydroxyls, as well
as the toxicity on neutrophils and
the inhibition of oxygen radicals re-
lease by these cells. It competitively
inhibits tyrosinase and enzymes of
the respiratory chain in abnormal
melanocytes. It has comedolytic ac-
tivity, with reduction of abnormal fol-
licular keratinization. None of these
mechanisms is compatible with the
pathophysiology of rosacea, so it is
thought that its action in this disease
would be exerted on the immune
response of cathelicidins and the in-
creased expression of toll-like recep-
tors 2 (TLR-2). New studies suggest
that the anti-inflammatory activity
of azelaic acid consists of reducing
cathelicidins.18
Efficacy in Rosacea
Azelaic acid 20% cream –initially
approved by the FDA for the treat-
ment of acne vulgaris in 1995– led to
an improvement of nearly 80%, even
higher than topical metronidazole;
however, side effects associated with
the cream led to a change in the
formula to 15% hydrogel. This for-
mulation was the first new therapeu-
tic option for the treatment of this
chronic disease in almost a decade.
The great innovation offered by it is
a novel combination of soluble and
micronized azelaic acid at 15%, which
allows a greater release of the drug
(up to 25%) and enhanced skin ab-
sorption. The newer product con-
tains a high percentage of water and
is free of alcohol, fats or perfumes,
having attractive and comfortable
cosmetic properties for the skin. The
15% formulation is effective, tolerable
and safe. Percutaneous penetration
282
of 15% gel is eight times higher than
that of 20% cream. Although only
approved for PPR, it has produced
statistically significant levels of facial
erythema reduction, so it can also be
used for patients with erythemato-
telangiectatic rosacea (ETTR).18,19 An
oil-in-water formulation in the form
of 15% ionized foam is in phase III of
research and has also proven effec-
tive.18
A phase III, randomized, vehi-
cle-controlled study demonstrat-
ed the effectiveness and safety of
azelaic acid 15% gel in 664 patients
with PPR. Improvements of about
50% in erythema and papules were
recorded, although 38% of patients
reported itching and transient burn-
ing sensation. In severe PPR, the
combined use of azelaic acid 15%
with oral doxycycline 40 mg pro-
duced significant improvement after
6 months.19,20
Applying azelaic acid twice a day
may cause burning and stinging sen-
sation. These effects are transient
even when patients have sensitive
skin; they may last a few weeks and
it is typically not necessary to dis-
continue the medication. The ad-
verse effects are not associated with
changes in the appearance of the
skin. Tolerability increases with the
use of gentlecleansers and emollient
creams.20-22
The results of two multicentre,
double-blind, phase III studies involv-
ing 664 patients, and one of the same
characteristics involving 251 patients,
show that azelaic acid 15 % gel has sig-
nificantly greater efficacy than current
treatments in reducing the number of
inflammatory papules and pustules, as
well as rosacea-associated erythema.
After only four weeks of treatment,
significant effects were observed and
progressive improvement continued
for 12 to 15 weeks.23 Side effects were
initial burning sensation after appli-
cation, itching, dryness, scaling and
–rarely– contact dermatitis and facial
edema. Other less frequent adverse
reactions (less than 1 %) were contact
dermatitis, erythema, rash, peeling,
dermatitis, and xerosis. Hyperpig-
mentation may occur in dark-skinned
individuals. Rare allergic reactions to
azelaic acid may also occur. Other oc-
casionally reported adverse reactions
include worsening of asthma, vitili-
go, depigmentation, appearance of
depigmented spots, hypertrichosis,
keratosis pilaris, and recurrent herpes
labialis.24,25
References
1. Powel F. Rosacea. N Engl J Med
2005; 352(8):793-803.
2. Two AM, Wu W, Gallo RL, et al. Ro-
sacea: Part I. Introduction, categori-
 zation, histology, pathogenesis, and
risk factors. J Am Acad Dermatol
2015; 72:749-58.
3. Tan J, Leyden J, Cribier B, et al.
Development and evaluation of a
rosacea screening instrument (Ro-
sascreen). J Cutan Med Surg 2016;
20:317-22.
4. Rebora A. The management of ro-
sacea. Am J Clin Dermatol 2002;
3(7):489-496.
5. Mayer-da-Silva. Ácido azelaico. In
Acné: Piquero-Martin J, Second
edition, Impresos Panamericanos
formas e impresos SA, Santa Fe, Bo-
gotá, 1995.
6. Azelaic acid 15% gel (finacea) full pre-
scribing information, Bayer Health-
Care Pharmaceuticals Inc Whippany,
New Jersey, 2014.
7. Azelaic acid 15% gel (finacea), NDA
21-470, Approved labeling. Cen-
ter for Drug Evaluation Research,
US Food and Drug Administration,
12/24/02.
8. Two AM, Wu W, Gallo RL, et al. Ro-
sacea: Part II. Topical and systemic
therapies in the treatment of ro-
sacea. J Am Acad Dermatol 2015;
72:761-70.
9. Nazarro Porro M. Azelaic Acid. J Am
Acad Dermatol 1987; 17:1033-1041.
10. Balina L, Graupe K, Piquero J. The treat-
ment of acne 20% azelaic acid cream
versus 4% hydroquinone cream. Int J
Dermatol 1991; 30:893-895.
11. Antonio JR. Ácido Azelaico. In: Acné
manejo racional. Piquero Martin J.,
Third edition, Impresos Corpográfi-
ca, Caracas, Venezuela 2000.
12. Cunliffe WJ. Azelaic acid review of
the role in acne. J Dermatol Treat
1993; 4(suppl):31-34.
13. Piquero-Martin J, Rothe de Arocha J,
Loker DB. Estudio clínico doble ciego
en el tratamiento del melasma entre
ácido azelaico versus hidroquinona.
Med Cuta Iber Lat Am 1988; 16:511.514.
14. Piquero Martin J. Melasma in Cen-
tral and South America. Clin Drug
Invest 1995; 10/supp(2)41-45.
15. Arellano-Mendoza I, Arias-Gomez
I, Barba Gomez JF, et al. Melas-
283
ma: Consenso del Grupo Mexica-
no para el Estudio de los Trastor-
nos Pigmentarios. Dermatología
CMQ2007; 5(2):112-122.
16. Gupta AK, Chaudry MM. Rosacea
and its management: An overview. J
Eur Acad Dermatol Venereol 2005;
19:273-285.
17. Yamasaki K, Gallo RL. Rosacea as a
disease of cathelicidins and skin in-
nate immunity. J Investig Dermatol
Symp Proc 2011; 15:12-5.
18. Del Rosso JQ, Kircik L. Update on
the management of rosacea: A
status report on the current role
and new horizons with topical aze-
laic acid. J Drugs Dermatol 2014;
13(12):101-7.
19. Carmichael AJ, Marks R, Graupe
KA, et al. Topical azelaic acid in the
treatment of rosacea. J Dermatol
Treat 1993; 4(suppl 1):S19-22.
20. Cordero A, Piquero Casals V,
Piquero Casals J, et al. Tratamien-
to tópico de la rosácea. In: Rosácea
y afecciones relacionadas. 1st ed.
Herane MI, Piquero Martin J. Im-
presos Rubel, Caracas, 2007.
21. Van Zuuren EJ, Fedorowicz Z, Car-
ter B, et al. Interventions for rosa-
cea. Cochrane Database Syst Rev
2015; 4:CD003262.
22. Maddin SA. A comparison of topical
azelaic acid 20% cream and topical
metronidazole 0,75% cream in the
treatment of patient with papulo-
pustular rosacea. J Am Acad Der-
matol 1999; 40:961-S.
23. Thiboutot D, Thieroff-Ekerdt R,
Graupe K. Efficacy and safety of
azelaic acid (15%) gel as a new
treatment for papulopustular rosa-
cea: results from two vehicle-con-
trolled, randomized phase III stud-
ies. J Am Acad Dermatol 2003;
48(6):836-845.
24. Del Rosso JQ, Gallo RL, Tanghet-
ti E, et al. An evaluation of poten-
tial correlations between patho-
physiologic mechanisms clinical
manifestation and management
of rosacea. Cutis 2013, 91(suppl3)
S1-S8.
25. Frampton JE, Wagstff AJ. Azelaic
acid 15% Gel In the Treatment of
Papulopustular Rosacea. Am J Clin
Dermatol 2004; 5(1):57-64.
For optimal medical management
of patients with rosacea whose clin-
ical manifestations tend to be recur-
rent and progressive, it is important
to take into account their percep-
tion in relation to viable therapeutic
strategies for their care.1,2 In general,
patients prefer to use topical treat-
ments, whether they are the best op-
tion or not, due to the chronicity of
the disease as well as concerns about
possible medical interactions and ad-
verse effects that some systemic ther-
apies may cause them.2,3 At present,
FDA-approved topical treatments
for the control of rosacea include
sodium sulfacetamide, azelaic acid,
metronidazole, and alpha-adrenergic
receptor agonists brimonidine and
oxymetazoline. The first three have
a IA level of evidence (evidence ob-
tained from meta-analysis of well-de-
signed randomised controlled trials).4
Unfortunately, despite the high level
of evidence, the use of these drugs
does not always guarantee a success-
ful outcome, and this is largely due to
the increased sensitivity in the skin of
patients with rosacea resulting from
skin barrier dysfunction.5
Likewise, the prompt clinical re-
sponse expected by the patient to
a treatment plays an important role
in his/her therapeutic adherence in
the short, medium and long term.
For this reason, it is important to
select the appropriate treatments
Sodium Sulfacetamide and Sulphur
Mildreth Cid
early on to avoid having to make
frequent changes in treatments due
to adverse effects, or having to use
compensatory multi-therapies for
suboptimal results.6 The latter can
be achieved by using well-tolerated
drugs that provide acceptable re-
sults without causing worsening that
leads to discontinuation of treat-
ment.7 If this objective is achieved,
other drugs that are more effective
but have a higher risk of hypersensi-
tivity may subsequently be consid-
ered, although in a staggered and
safe manner. The key to the success-
ful use of any topical treatment for
rosacea is its individualization, which
involves an adequate analysis of se-
bum production, degree of sensitivi-
ty, skin reactivity and daily exposure
to environmental triggers.8
For several decades, sodium sul-
facetamide and sulphur have played
an important role in the treatment
of rosacea and other dermatological
diseases, such as acne and seborrhe-
ic dermatitis.9,10 However, in the field
of modern dermatology, their use has
been increasingly disregarded due
to the poor cosmetic qualities asso-
ciated with the unpleasant smell of
sulphur. Even so, given the increase in
284
bacterial resistance rates caused by
the use of topical antibiotics and the
numerous reports of hypersensitivity
caused by the most commonly used
drugs for the control of rosacea, sul-
facetamide sodium and sulphur con-
tinue to be an attractive option for
the management of these patients.9,11
Thus, adequate effectiveness com-
bined with good tolerability continue
to make this combination a safe and
affordable resource.
The role of inflammation and an-
giogenesis in the etiology of rosacea
have gained special attention with the
study of cathelicidins, pro-inflamma-
tory antimicrobial peptides that are a
component of the innate immune sys-
tem.4,12 With these findings, the cur-
rent approach to rosacea treatments
has focused even more on those drugs
with clinical effectiveness in blocking
inflammatory processes. Among the
best-known topical treatments with
anti-inflammatory and antimicrobial
effects are sodium sulfacetamide and
azelaic acid. However, although the
level of effectiveness of both sodium
sulfacetamide and azelaic acid is high,
the use of the former has decreased
considerably, while that of the latter
has shown an important boom.5,13
So far, the exact mechanism of action
of sodium sulfacetamide remains un-
known, but a clear anti-inflammatory
effect occurs in the treatment of rosa-
cea, seborrheic dermatitis, and acne.7
COMPOUND COMPONENTS
Sodium sulfacetamide is a sulfonamide
with antibacterial activity. Physically, it
is an odorless, white, crystalline pow-
der with a bitter taste. It is soluble in
water, sparingly soluble in alcohol, and
practically insoluble in benzene and
chloroform. It exerts a bacteriostatic
effect against sulphonamide-sensitive
Gram-positive and Gram-negative mi-
croorganisms, commonly isolated from
secondary cutaneous pyogenic infec-
tions. It acts by restricting the synthe-
sis of folic acid required by bacteria for
growth, competing with para-amino-
benzoic acid.7,14,15
Sulphur, on the other hand, is
a keratolytic agent whose use has
been reported since the time of the
Pharaohs, around 1550 BC. Its role
in the management of rosacea was
first described by James Morris in
1855. As several dermatologists have
pointed out, it is interesting to see
how this substance has undergone
multiple cycles of use throughout
history, under different formulations,
and yet continues to be rediscovered
again and again. Its exact mecha-
nism of action in rosacea is not fully
known either, although a decrease
in the growth of skin bacteria, such
as Propionibacterium acnes, strepto-
cocci, and Staphylococcus aureus, as
well as in the formation of free fatty
acids, has been reported. It also has
antifungal and anti-Demodex prop-
erties.9
USE IN ROSACEA
In terms of effectiveness, some re-
ports on the formulation of sodium
sulfacetamide 10%-sulphur 5% in a lo-
tion vehicle have indicated favorable
findings. In a double-blind, controlled
study involving 103 patients pub-
lished by Sauder et al. in 1997, a 66 %
decrease in facial erythema and 65 %
decrease in inflammatory lesions was
reported, compared to 33 % and 44
%, respectively, in the control group,
after 4 weeks of treatment (p = 0.005).
At the eighth week, the decrease in
facial erythema amounted to 88 % vs.
31 % for placebo (p < 0.001).7
Another study, published by Leb-
wohl et al. in 1995 and included in a
meta-analysis by van Zuuren et al. in
2015, reported how the use of sodium
sulfacetamide 10% and sulphur 5% for
the treatment of rosacea was shown
to be superior in effectiveness and
tolerance to topical metronidazole. In
addition, it was mentioned that topi-
cal metronidazole is often irritating in
some patients, especially in those who
have previously been offered multiple
therapies or who have a severe hydra-
tion problem that predisposes to high
skin sensitization. However, the me-
ta-analysis catalogues this study with
a high risk of bias and concludes that
further study is required.16,17
Adverse Effects
The most commonly reported ad-
verse effects during the use of 10%
sulfacetamide sodium and 5% sulphur
are dryness, erythema, scaling, irrita-
tion at the application site and burn-
ing sensation. The frequency of these
signs and symptoms usually decrease
over time. Other more relevant ad-
verse effects are those linked to the
use of a sulfonamide, even if its use
is exclusively topical. The latter are
described as exceptionally rare and
include: Stevens-Johnson syndrome,
systemic lupus erythematosus, agran-
ulocytosis, acute hemolytic anemia,
purpura haemorrhagica, jaundice, and
drug-induced fever.14,18
The combined formula of sodium
sulfacetamide and sulphur is classi-
fied as category C for pregnant pa-
tients. As regards lactation, it is not
known whether the compound is
excreted in breast milk. It is recom-
mended for use in children aged 12
years and older.7,19
A proper understanding of the
vehicles available is important in
the process of selecting topical
therapies for rosacea. Vehicles can
285
hydrate the skin, generate anti-in-
flammatory effects, and help the
active substance to properly pene-
trate the skin. Others have a refresh-
ing and emollient effect, which is
undoubtedly a favorable tool during
rosacea management.8,20 At pres-
ent, sodium sulfacetamide 10%-sul-
phur 5% formulations are available
in multiple vehicles, such as lotions,
gels, creams, and dermal cleans-
ers. The best-known formulation on
the market is sodium sulfacetamide
10%-sulphur 5% in lotion, which is
applied twice daily. More recently,
the dermal-cleansing presentation
has been the most promoted vehi-
cle, since it is applied and removed
right away, which decreases the
patient’s discomfort at the smell of
sulphur.7,19 This latter presentation
is well tolerated and represents a
suitable option when it is necessary
to use it simultaneously with other
drugs, such as topical metronida-
zole or brimonidine, as good stan-
dards of effectiveness and tolerance
are achieved.15
In the United States, sodium sul-
facetamide 10% lotion had a ma-
jor prescription boom after its FDA
approval in 1996. Ten years later,
the presentation of sodium sulfac-
etamide 10%-sulphur 5% dermal
cleanser emerged, which had a high
commercialization in its early years
but subsequently dropped, after not
having received the necessary FDA
approvals. At present, similar formu-
lations can be found in the US market
that are not considered prescription
drugs, so the FDA warns about its
use.22 Despite this, the known effec-
tiveness of sodium sulfacetamide
10%-sulphur 5% is still valued by mul-
tiple dermatologists, who continue
to support its use.
In the latest meta-analyses pub-
lished in Cochrane (van Zuuren et
al., 2011 and 2015), two main obser-
vations are drawn as a conclusion.
The first one refers to how rosacea
is a dermatological condition with a
high impact on the patient’s quali-
ty of life, so this parameter must be
properly assessed during treatment.
The second confirms that there are
currently several treatment options
for rosacea, although it is not clear
which are the most effective.1,17 This
last statement proposes to reflect
on the importance of keeping the
door open to the various treatment
options that exist and work, whether
they are the newest or not. It is also
important to remember that sodium
sulfacetamide-sulphur is a drug com-
bination which, due to its scarce use
at present, is an attractive option for
multi-treated patients who are reluc-
tant to repeat previously used drugs;
it is also very useful for the manage-
ment of patients with simultaneous
seborrheic dermatitis.
References
1. Van Zuuren EJ, Kramer SF, Carter BR,
et al. Effective and evidence-based
management strategies for rosacea:
summary of a Cochrane systematic
review. Br J Dermatol. 2011; 165:760-81.
2. Haber R, El Gemayel M. Comorbid-
ities in rosacea: A systematic review
and update. J Am Acad Dermatol
[journal on the Internet]. 2017 Oct
26 [cited 2017 Nov 20]. doi: 10.1016/j.
jaad.2017.09.016. [Epub ahead of print]
3. Taub A, Garretson C, Kajmowicz N. An
open-label study of the tolerability of
sodium sulfacetamide 10%, sulfur 5%
emollient foam in rosacea patients with
a history of sensitivity to metronidazole.
J Am Acad Dermatol 2011; 64:AB50.
4. Two AM, Wu W, Gallo RL, Hata TR.
Rosacea: Part II. Topical and systemic
therapies in the treatment of rosacea.
J Am Acad Dermatol 2015; 72:761-70.
5. Williamson T, Lin W, Ogbonnaya A,
et al. Treatment patterns with top-
ical rosacea treatment. Val Health
2016; 19:A128.
6. Lingam P, Rademaker A, West P, et al.
Acne versus rosacea: Therapeutic re-
sponse impacts topical dermatologic
product usage – An observational study.
J Am Acad Dermatol 2014; 70:AB5.
7. Sauder DN, Miller R, Gratton D, et al.
The treatment of rosacea: the safety
and efficacy of sodium sulfacetamide
10% and sulfur 5% lotion (Novacet) is
demonstrated in a double-blind study.
J Dermatolog Treat 1997; 8:79-85.
8. Draelos ZD. Cosmeceuticals for ro-
sacea. Clin Dermatol 2017; 35:213-7.
9. McKay C, Keiron L, Snowden L, et
al. Sulphur for rosacea: Are we rein-
venting the wheel? J Am Acad Der-
matol 2012; 66:AB33.
10. Del Rosso JQ. The use of sodium sul-
facetamide 10%-sulphur 5% emollient
foam in the treatment of acne vulgaris.
J Clin Aesthet Dermatol 2009; 2:26-9.
11. Yentzer BA, Fleischer AB Jr. Chang-
es in rosacea comorbidities and
drug utilization over time. J Drugs
Dermatol 2010; 9:1402-6.
286
12. Gallo RL, Granstein RD, Kang S,
et al. Standard classification and
pathophysiology of rosacea: The
2017 update by the National Ro-
sacea Society Expert Commit-
tee. J Am Acad Dermatol 2017
Oct 28 [cited 2017 Nov 20]. doi:
10.1016/j.jaad.2017.08.037. [Epub
ahead of print]
13. Schaller M, Almeida LM, Bew-
ley A, et al. Rosacea treatment
update: Recommendations from
the global ROSacea COnsensus
(ROSCO) panel. Br J Dermatol
2017; 176:465-71.
14. Korting HC, Schöllmann C. Cur-
rent topical and systemic ap-
proaches to treatment of rosacea.
J Eur Acad Dermatol Venereol
2009; 23:876-82.
15. Wolf K, Silapunt S. The use of sodi-
um sulfacetamide in dermatology.
Cutis 2015; 96:128-30.
16. Lebwohl MG, Medansky RS, Rus-
so CL. The comparative efficacy of
sodium sulfacetamide 10%/sulphur
5% (Sulfacet-R) lotion and metro-
nidazole 0.75% (Metrogel) in the
treatment of rosacea. Geriatr Der-
matol 1995; 3:183-5.
17. Van Zuuren EJ, Fedorowicz Z.
Interventions for rosacea: a
bridged updated Cochrane sys-
tematic review including GRADE
assessments. Br J Dermatol 2015;
173:651-62.
18. Layton AM. Pharmacologic treat-
ments for rosacea. Clin Dermatol
2017; 35:207-12.
19. Pelle MT, Crawford GH, James WD.
Rosacea: II. Therapy. J Am Acad
Dermatol 2004; 51: 499-512.
20. Li V, Chowdhury M. Dermatological
pharmacology: topical agents. Med-
icine 2017; 41:327-9.
21. The United States Food and Drug
Administration (FDA). Exact-Rx
Inc 4/19/17 [cited 2017 Nov 20].
Available from: www.fda.gov/iceci/
enforcementactions/warninglet-
ters/2017/ucm554253.htm
Rosacea is a chronic, cyclic inflamma-
tory skin disorder affecting 10% of the
general population. Four subtypes of
clinical presentations have been de-
scribed so far, which may appear si-
multaneously or successively in the
same patient.1 Transient and non-tran-
sient erythema, the typical facial red-
ness that is key to diagnosis, occurs in
up to 85% of patients. It may be short-
term or long-term and take many
forms, including persistent or tran-
sient underlying erythema, triggered
by stimuli, or erythema associated
with individual inflammatory lesions
or telangiectases, triggered by vascu-
lar and inflammatory changes.2
Facial erythema is one of the fac-
tors that negatively affect quality of life.
The psychological impact of rosacea is
a weakening factor for patients, and
treating this component may contribute
to its improvement.3 It predominantly
occurs in the subtypes of erythemato-
telangiectatic rosacea (ETTR) and papu-
lopustular rosacea (PPR).4
Persistent erythema and episodic
redness are explained by vasomotor
skin responses which cause vessels to
dilate, both transiently and persistent-
ly.4,5 These manifestations are the result
of anomalies in the homeostasis of the
skin vasculature caused by hormonal,
neurological, thermal, and topical fac-
tors. Cutaneous circulation is regulated
by the secretion of local and systemic
Alpha-Agonists
Elda Giansante, Minerva Gómez F., Perla Meneses R.
catecholamines, which stimulate vascu-
lar adrenergic receptors. Alpha-adren-
ergic receptors cause vasoconstriction
and beta-adrenergic receptors cause
vasodilatation.6 The current model of
adrenergic receptors consists of 6 sub-
types a (a1A, a1a/c, a1B, a1D, a2A, a2B,
a2C) and 3 subtypes b (b1, b2, b3,) with
two other variants (a1L and b4). There
is a total of eleven receptors, all mem-
bers of the G-protein family, with their
signalling system of seven transmem-
brane domains.7 Vasoconstriction of
vascular smooth muscle is mainly me-
diated by the subtypes a1A and a1D.
Several studies have shown that a2A/D
and a2B are of particular importance in
arterial smooth muscle, and a2A/D and
a2C predominate in venous smooth
muscle.7
Diffuse central facial erythema is of-
ten persistent and not very responsive
to conventional topical and systemic
treatments.4 Medications to treat ro-
sacea are usually aimed at inflamma-
tory lesions.5 All patients have facial
erythema; however, this is still difficult
to treat and is a poorly addressed prob-
lem.5,8 The use of alpha-agonists –such
as brimonidine, oxymetazoline, and
xylometazoline– in the treatment of
rosacea-associated facial erythema is
287
currently under evaluation.4 Table 25-1
presents the drugs used and their re-
spective adrenergic receptor affinities.
Alpha-agonists target adrener-
gic receptors. These are found in the
smooth muscle sheath of the wall of
superficial cutaneous blood vessels,
where they modify the vascular tone.
After application of alpha agonists,
facial erythema decreases in one to
three hours, and this effect persists
with repeated use. Since capillaries
and telangiectases do not have a fully
formed smooth muscle layer, they do
not respond to stimulation by an ad-
renergic receptor.4
BRIMONIDINE
This drug is a selective a2a adrenergic
receptor agonist. It is a powerful con-
strictor of subcutaneous vessels of less
Table 25-1. Alpha-agonists and receptors4,6,9
Drug Affinity: ++
Brimonidine a2a
Oximetazoline a1a
Xylometazoline a1a
than 200 mm in diameter. It has anti-in-
flammatory properties by reducing
edema. Its specific action is exerted on
the smooth muscle of superficial and
deep dermal vascular plexuses, which
causes vasoconstriction and reduction
of superficial erythema in the areas
where it is locally applied.
Brimonidine was previously used
for the topical treatment of open-an-
gle glaucoma at doses of 0.1 % and
0.15 %, and was subsequently found
to be effective in controlling the diffuse
facial erythema of rosacea, through its
specific action on post-synaptic en-
dothelial a2 receptors.10 By acting on
a2a adrenergic receptors of veins and
arteries, it has an effect on both vas-
cular components of rosacea. In facial
erythema, its effect on veins is im-
portant, since one of the first vascular
anomalies of rosacea is the circulatory
alteration of facial angular veins. Stud-
ies using dynamic optical coherence
tomography show that it acts on up
to 42% of small-calibre arteries, while
Affinity: +
a1a, a2c
a2a
a2a
no effect is observed in larger-calibre
vessels with a depth of more than 0.33
mm. It also has anti-inflammatory
properties that can prevent mast cells
activation in ETTR. Besides, it decreas-
es arachidonic acid concentrations.10
In August 2013, brimonidine 0.33%
gel was approved by the FDA and, in
February 2014, by Health/Canada for
topical treatment of persistent facial
erythema of rosacea in adults of 18
years of age and older.11,12
Clinical trials have shown a reduc-
tion of facial erythema within only 30
minutes after application, with a max-
imum effect at six hours and a lasting
time of up to twelve hours. Approxi-
mately 80% of patients treated with
brimonidine tartrate 0.5% (equivalent
to brimonidine topical gel 0.33%) re-
ported improvement in erythema and,
as the effects wear off (10-12 h after
application), erythema returns to base-
line, with few adverse effects after four
weeks of daily use once a day.12
The drug is metabolized in the liver
and its main route of elimination is uri-
nary excretion.10
When researching about quality of
life in patients who used this medica-
tion and were not satisfied with their
appearance, it was found that, after 8
days of use, 28.3% reported they were
no longer embarrassed or worried
about their facial erythema and 36.9%
mentioned they were satisfied with
their appearance.12
Adverse Effects
After the first application, adverse
event rates ranged from 6% to 14%
among three different concentrations
of brimonidine tartrate (0.5 %, 0.18 %,
0.07 %). When the daily application fre-
quency was increased for 4 weeks, the
rates of adverse events ranged from
11% to 19% and were similar at all drug
concentrations. Adverse events are
mild, transient and limited to the skin.
The most common are flushing (10%),
erythema (8%), nasopharyngitis (5%),
skin burning sensation (4%), increased
intraocular pressure (4%), and head-
ache (4%). In the bibliography of revers-
ible adverse events, there are reports
of discomfort, irritation, burning, xero-
sis, itching, increased skin temperature
and worsening of erythema.13
In the post-marketing experience,
there were some reports that, in up to
20 % of patients,14,15 there was a grad-
ual worsening of erythema rather than
a return to baseline levels, which can
be expressed as:16,17
UU Paroxysmal erythema, which occurs
>6 hours after application and may
be greater than baseline erythema.
UU Increased recurrence of erythe-
ma, which occurs when the effect
288
wears off (10-12 h after application)
(paradoxical erythema).
UU Allergic contact dermatitis: red-
ness accompanied by other signs,
such as eczema and itching, sever-
al months after the start of therapy.
Paroxysmal erythema. It is de-
scribed as a temporary adverse re-
action. It occurs at the beginning of
therapy and decreases with regular
use of the drug. Adverse effects last 30
minutes to 3 hours. Many of these re-
actions disappear with continued use.
One hypothesis to consider is that the
cutaneous vasculature could get con-
ditioned to the use of the drug, just
like the skin conditioning to retinoids.15
Paradoxical erythema occurs after
the disappearance of the initial ery-
thema, and may be even more intense
than the initial one.13 In these patients,
a reduction of the initial erythema is
observed 1 to 6 hours after application
and then, it reappears more severe-
ly.17 It may even begin five hours after
the medication has been applied and
remain for up to 12 hours.13,19 It may
occur in places that were previously
free of erythema.18 It is usually accom-
panied by itching and burning sensa-
tion. This adverse effect worsens with
continued use of the drug.17-19
Allergic contact dermatitis to bri-
monidine is poorly described; however,
ophthalmic use does have reports of
itchy contact dermatitis and conjuncti-
val reactions, with rates of 14 to 26 %.20
Allergic contact dermatitis has been
demonstrated through patch testing
in patients who had been sensitized by
ophthalmic brimonidine and even in
patients without prior exposure.20-22
Mechanisms that may contribute
to the worsening of erythema are:9
UU Local inflammation and increased or
modified perivascular inflammato-
ry cells responding to brimonidine,
which results in an increased effect
of the drug so as to release mediators
and produce sustained vasodilation.
UU High concentration of brimoni-
dine in the skin. This can cause skin
barrier dysfunction and make high
concentrations of the drug enter
the endothelium and nerve end-
ings, leading to vasodilation.
UU Effects of abnormal saturation and
release of norepinephrine of sym-
pathetic nerve endings, due to the
action of brimonidine on a2 recep-
tors, with a reduced norepineph-
rine availability effect.
UU Genetic polymorphism that in-
creases brimonidine’s affinity for
the receptor, resulting in increased
smooth muscle responses and sus-
tained vasodilation.
 After 28 days of continued use,
there is no evidence of tachyphylaxis
or worsening of inflammatory lesions
or telangiectases. The population least
susceptible to adverse effects are men
(e.g., to episodic redness). In terms of
age, those younger than 40 had less ir-
ritation but a greater risk of redness.15
Brimonidine was the first effective
topical treatment for persistent erythe-
ma in rosacea, which is often difficult to
manage. It is suggested that patients be
instructed in the use of the drug –start-
ing with a very thin layer of medication–
and in the use of combined therapies
according to the clinical presentation.
Due to the mechanism of action, red-
ness usually recurs within 12 hours of
application; however, many patients
may experience an overall reduction in
baseline erythema after three months
of daily use of this drug.
OXYMETAZOLINE
Oxymetazoline is a sympathomimet-
ic with direct action on a1 adrenergic
receptors, of the imidazoline class. For
its vasoconstrictor effect, is used in the
treatment of allergic rhinitis. In January
2017, oxymetazoline 1% cream was
approved by the FDA for topical treat-
ment of persistent facial erythema due
to rosacea in adults.16 Its use as a topi-
cal therapy has been established, with
positive results in the subtypes of rosa-
cea with erythema. It also has anti-in-
flammatory properties, by inhibiting
the phagocytosis by neutrophils and
the activity of lipoxygenase 5 in the ara-
chidonic acid cascade, which increases
prostaglandin E2 (PgE2) concentrations
and decreases the levels of leukotriene
B4 (LTB4).23 Because it acts specifically
on smooth muscle receptors, it has no
effect on capillaries, telangiectases or
vessels without smooth muscle which,
for that reason, are not regulated by
the sympathetic nervous system. Un-
like brimonidine, oxymetazoline has
fewer constricting effects on vessels
with a diameter of less than 200 mm,
which are the most involved in the er-
ythema of rosacea. In subcutaneous
vessels, the vasoconstricting effect of
oxymetazoline is less powerful than
that of brimonidine.8,24,25
Within topical therapies, the use of
oxymetazoline 1% cream is suggest-
ed as a first-line topical treatment for
persistent facial erythema in rosacea.25
In case reports from adult patients,
aged 55 to 70 years, with persistent
facial erythema and rosacea-related
flushing, topical oxymetazoline 0.1%
solution applied once a day to the af-
fected areas reduced facial erythema
within one hour after application, and
a dramatic improvement was observed
within 2 to 3 hours. Continued use for
several months was associated with an
improvement in erythema without ep-
isodes of redness or flushing. Patients
experienced sustained effects with pro-
longed use of 8 and 17 months, with no
289
significant adverse effects.26 Other pub-
lication including adult patients with
ETTR, indicate that topical application
of oxymetazoline 0.05% solution once
daily (N = 2) reduced facial erythema
for several hours. Facial erythema de-
creased within the first 3 hours and the
effect was sustained for several hours
and days with repeated daily use. No
tachyphylaxis was observed with daily
application for 8 to 17 months.4
Adverse effects of adrenergic ag-
onists include loss of efficacy with
prolonged use (tachyphylaxis) and
possible rebound vasodilation. There
are no clinical reports of burning and
itching with the application of the
drug, which is well tolerated by pa-
tients. Published data regarding the
use of topical oxymetazoline for the
treatment of rosacea are limited, but
they suggest improvements in symp-
toms with chronic use of the drug.7
XYLOMETAZOLINE
Xylometazoline 0.05% solution causes
vasoconstriction in the tissues. It is a
sympathomimetic agonist of imidazo-
line which is used to treat allergic rhini-
tis and glaucoma. It acts selectively on
a1A adrenergic receptors and is partially
selective by a2A receptors. In addition
to causing vasoconstriction, there is ev-
idence that it may decrease pro-inflam-
matory cytokines at the skin level, as it
does in the upper respiratory tract by
inhibiting the migration of neutrophils,
which prevents the oxidative burst of
phagocytes and decreases the produc-
tion of proinflammatory cytokines.6,7
The application of this drug on the
skin and mucous membranes reduces
erythema, edema, itching and vascu-
lar congestion after three hours. It has
been successfully used in one patient
for 8 months for the treatment of ery-
thema and telangiectases of rosacea,
without adverse effects.6 Alpha-ag-
onists may help improve the quality
of life of patients with rosacea. These
drugs have a temporary effectiveness,
so it is necessary to educate patients
about their correct application.
Brimonidine and oxymetazoline
are approved by the FDA and rec-
ommended by the international con-
sensus of the rosacea expert group.
It is necessary to be familiar with and
warn patients about the beneficial ef-
fects of these drugs, their mechanism
of action, effectiveness time and relat-
ed adverse events.
References
1. Abokwidir M, Feldman S. Rosacea
management. Skin Appendage Dis-
ord 2016; 2(1-2): 26-34.
2. Del Rosso JQ, Gallo RL, Tanghetti
E, et al. An evaluation of potential
correlations between pathophysio-
 logic mechanisms, clinical manifes-
tations, and management of rosa-
cea. Cutis Cutan Med Pract 2013;
91(3):1-8.
3. Moore A, Kempers S, Murakawa G,
et al. Long-term safety and efficacy
of once-daily topical brimonidine
tartrate gel 0.5% for the treatment
of moderate to severe facial erythe-
ma of rosacea: Results of a 1-year
open-label study. J Drugs Dermatol
2014; 13(1):56-61.
4. Del Rosso, JQ. Management of fa-
cial erythema of rosacea: what is
the role of topical alpha-adrener-
gic receptor agonist therapy? J Am
Acad Dermatol 2013; 69(6 Suppl
1):S44-56.
5. Fowler, J Jr. New agents for the
treatment of erythematotelangiec-
tatic rosacea. Cutis 2014; 94(1):6-7.
6. Kim JH, Oh YS, Ji JH, et al. Rosacea
(erythematotelangiectatic type)
effectively improved by topical
xylometazoline. J Dermatol 2011;
38(5):510-3.
7. Shanler SD, Ondo AL. Success-
ful treatment of the erythema
and flushing of rosacea using
a topically applied selective al-
pha-1-adrenergic receptor agonist,
oxymetazoline. Arch Dermatol
2007; 143(11):1369-1371.
8. Moustafa FA, Sandoval LF, Feldman
SR. Rosacea: New and emerging
treatments. Drugs 2014; 74(13):1457-65.
9. Docherty JR, Steinhoff M, Lorton D,
et al. Multidisciplinary consideration
of potential pathophysiologic mech-
anisms of paradoxical erythema with
topical brimonidine therapy. Adv
Ther 2016; 33(11):1885-1895.
10. Piwnica D, Rosignoli C, de Ménon-
ville ST, et al. Vasoconstriction and
anti-inflammatory properties of the
selective a-adrenergic receptor ag-
onist brimonidine. J Dermatol Sci
2014; 75(1):49-54.
11. Gerber PA. Topical brimonidine
tartrate 0.33% gel effectively re-
duces the post-treatment erythe-
ma of daylight-activated photody-
namic therapy. Br J Dermatol 2016;
174(6):1422-1423.
12. Layton, AM, Schaller M, Homey B,
et al. Brimonidine gel 0.33% rap-
idly improves patient-reported
outcomes by controlling facial er-
ythema of rosacea: A randomized,
double-blind, vehicle-controlled study.
J Eur Acad Dermatol Venereol 2015;
29(12):2405-10.
13. Ilkovitch D, Pomerantz RG. Brimoni-
dine effective but may lead to sig-
nificant rebound erythema. J Am
Acad Dermatol 2014; 70(5):109-110.
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14. Gold LM, Draelos ZD. New and
emerging treatments for rosa-
cea. Am J Clin Dermatol 2015;
16(6):457-61.
15. Holmes AD, Waite KA, Chen MC, et
al. Dermatological adverse events
associated with topical brimonidine
gel 0.33% in subjects with erythema
of rosacea: A retrospective review
of clinical studies. J Clin Aesthet
Dermatol 2015; 8(8):29-35.
16. Tanghetti EA, Jackson JM, Belas-
co KT, et al. Optimizing the use
of topical brimonidine in rosacea
management: Panel recommen-
dations. J Drugs Dermatol 2015;
14(1):33-40.
17. Routt ET, Levitt JO. Rebound ery-
thema and burning sensation from
a new topical brimonidine tartrate
gel 0.33%. J Am Acad Dermatol
2014; 70(2):e37-e38.
18. Gillihan R, Nguyen T, Fischer R, et
al. Erythema in skin adjacent to area
of long-term brimonidine treat-
ment for rosacea: A novel adverse
reaction. JAMA Dermatol 2015;
151(10):1136-7.
19. Lowe E, Lim S. Paradoxical Erythe-
ma Reaction of Long-term Topical
Brimonidine Gel for the Treatment
of Facial Erythema of Rosacea. J
Drugs Dermatol 2016; 15(6):763-5.
20. Rajagopalan A, Rajagopalan B. Al-
lergic contact dermatitis to topical
brimonidine. Australas J Dermatol
2015; 56(3):235.
21. Swanson LA, Warshaw EM. Allergic
contact dermatitis to topical brimo-
nidine tartrate gel 0.33% for treat-
ment of rosacea. J Am Acad Derma-
tol 2014; 71(4):832-3.
22. Cookson H, McFadden J, White J, et
al. Allergic contact dermatitis caused
by Mirvaso(R), brimonidine tartrate
gel 0.33%, a new topical treatment
for rosaceal erythema. Contact Der-
matitis 2015; 73(6):366-7.
23. Elewski BE, Draelos Z, Dreno B, et al.
Rosácea - diversidad global y resultados
optimizados: propuesta de consenso
internacional del Grupo de Expertos
Rosácea Internacional. J Eur Acad Der-
matol Venereol 2011; 25:188-200.
24. Generali JA, Cada DJ. Oxymetazo-
line (topical): rosacea. Hosp Pharm
2013; 48(7):558-9.
25. Beck-Speier I, Oswald B, Maier KL,
et al. Oxymetazoline inhibits and
resolves inflammatory reactions in
human neutrophils. J Pharmacol Sci
2009; 110(3):276-84.
26. Oxymetazoline Cream (Rhofade)
for Rosacea. Med Lett Drugs Ther
2017; 59(1521):84-86.
Topical calcineurin inhibitors (TCIs)
are macrolactam immunomodulators
with anti-inflammatory properties
which inhibit the activation of T cells
in the inflammatory process.1,2 Since
2000, they have been indicated and
approved by the FDA only for the
treatment of atopic dermatitis in in-
dividuals over 2 years of age.3,4 How-
ever, they have been effectively used
in the off-label treatment of differ-
ent dermatological conditions, such
as lichen planus, psoriasis, vitiligo,
contact dermatitis, seborrheic der-
matitis, cutaneous lupus erythemato-
sus, perioral dermatitis and rosacea,
among others.3,5,6 Tacrolimus and pi-
mecrolimus are currently available
on the market.
MECHANISM OF ACTION
TCIs are natural anti-inflamma-
tory agents and that is their role
in the treatment of rosacea. They
primarily block the activation of T
cells, but have also been shown to
inhibit eosinophils, basophils, mast
cells, and Langerhans’ cells.5,7 The
mechanism of action is to inhibit
the activation and proliferation of
T lymphocytes, mainly CD4 cells.
When entering the T cell, the drug
binds to an immunophilin (FKB or
FK binding protein), macrophil-
in-12, to form an TCI-macrophilin-12
complex. This complex competi-
tively blocks calmodulin, prevent-
ing the activation of calcineurin,
mediators such as histamine, sero-
Calcineurin Inhibitors: tonin and b-hexosaminidase.2 It has
Tacrolimus and Pimecrolimus three times less affinity for the mac-
rophylin-12 receptor than tacrolimus
Mónica Rivera Jay-Lung and does not induce apoptosis of
the Langerhans’ cells.1
a calcium-dependent phosphatase PIMECROLIMUS
necessary for the activation of the Pimecrolimus is a semisynthetic de- PHARMACEUTICAL
nuclear factor of T cells.1 Calcineurin rivative of ascomycin, product of FORMULATIONS
inhibition blocks the inflammatory the fermentation of Streptomyces Tacrolimus: Protopic© and Cromus©
cascade produced in the skin by T hygroscopicus var. ascomyceticus, 0.03 % and 0.1 % ointment.
cells, and this avoids the expression with a molecular weight of 810 Da2,5
of inflammatory cytokines such as (Fig. 25-4). Within its anti-inflamma- Pimecrolimus: Elidel©, Rizan©, Isap-
IL-2, which are key in the regula- tory effect, it inhibits inflammatory lic© 1% cream.
tion of the proliferation and differ-
entiation of T cells, and others such
as IL-3, IL-4, IL-5, IL-10, IFN-gamma
and TNF-alpha. Thus, calcineurin
inhibition leads to decreased T cell
response to the presence of anti-
gens.5,8
TACROLIMUS
Tacrolimus is a macrolide, derived
from Streptomyces tsukubaensis,
discovered in 1984 when identified
in a soil sample in Japan. It has a
molecular weight of 822 Da2,5 (Fig.
25-3). Unlike pimecrolimus, the tac-
rolimus-macrophilin-12 complex af-
fects the differentiation of dendritic
cells. In addition, it has been found
to have an antifungal effect and im-
prove the epidermal barrier func-
tion.2 Tacrolimus inhibits the release
of histamine by mast cells and inter-
feres with the regulation of prosta-
glandin D2 synthesis. Fig. 25-3. Molecular formula of tacrolimus.
291

Fig. 25-4. Molecular formula of pimecrolimus.
EFFECTIVENESS
TCIs are effective in the treatment of
rosacea with a level of evidence III B7.
As a third-line treatment of papulo-
pustular rosacea (PPR), with a grade
of recommendation C, they reduce
erythema and inflammatory lesions.9
Pimecrolimus 1 % cream has been
used to treat both PPR and ETTR with
variable results.10 Karabalut et al. and
Weissenbacker et al. did not observe a
significant difference in the decrease
of lesions or the overall severity of ro-
sacea compared to vehicle alone.8,11
However, a significant improvement in
erythema was observed in Karabault’s
292
study.8 Tacrolimus 0.1 % ointment is
effective in the management of rosa-
cea;3 but may also cause rosaceiform
dermatitis when used for a long time,
especially in predisposed patients.12,13
Pimecrolimus has been shown to
be effective in managing steroid-in-
duced rosaceiform rash,14 while tac-
rolimus has been described by some
authors as having an aggravating
effect;14-16 improvement when com-
bined with minocycline has also been
reported.17 Pimecrolimus has been
used as an effective treatment for
papulopustular eruption related to
epidermal growth factor receptor in-
hibitors,18,19 as well as for granuloma-
tous rosacea.20,21 Koca et al. found that
pimecrolimus 1 % cream has the same
effectiveness in improving inflamma-
tory lesions of PPR as metronidazole
1 % cream.22
In general, TCIs are not approved
for the management of rosacea and
are considered a costly off-label treat-
ment. Their use should be reserved
only as an alternative treatment, after
failure of conventional treatment.20,23,24
ADVERSE EFFECTS
The cellular activity and pharmaco-
logical properties of TCIs give them a
high safety profile and great potential
for long-term use, unlike corticoste-
roids, due to T2 cell selectivity. Al-
though generally associated with few
adverse effects, the most common
is burning sensation, which is most
often transient and occurs during
the first 24 to 72 hours, but may per-
sist until 7 to 10 days of treatment.2,6
This side effect is less frequent with
pimecrolimus than with tacrolimus.18
Other adverse effects have also been
reported, such as transient erythema,
itching, and allergic contact dermati-
tis.6 Viral and bacterial infections are
rare,2,18 although there are some re-
ports suggesting an increased risk of
infection with tacrolimus treatment,
attributable to localized immunosup-
pression. However, there is lack of
clinical studies to confirm this.6
Even more rare is the effect de-
scribed by Lubbe et al. of the com-
bination of tacrolimus with alcohol,
which led to a worsening of erythema
in patients with rosacea within 5 and
10 min after ingestion.10
Since the initial case reported by
Bernard in 2003, 26 cases of rosa-
cea-like eruptions induced by topi-
cal tacrolimus have been reported.
Overgrowth of Demodex folliculorum
associated with localized immunosup-
pression, as well as the occlusive and
vasoactive properties of this drug, ex-
plain the development of this event.
Although pimecrolimus lacks vasoac-
tive and occlusive properties, cases of
rosacea-like eruptions have also been
reported with its use, and typically
occur in the first week of treatment.
This suggests that these eruptions
are a side effect that applies to all
TCIs.2,13,18,23
SAFETY
Both tacrolimus and pimecrolimus
penetrate the epidermis well and have
high lipophilicity that allows them to
remain in the dermis without spread-
ing to the subcutaneous vasculature
and systemic circulation. Systemic ab-
sorption is minimal, and the concen-
tration of the drugs after 48 hours is
similar; however, the greater permea-
bility of tacrolimus is partly due to the
fact that it has lower lipophilicity than
pimecrolimus.23
In 2005, the FDA issued a black box
warning on tacrolimus and pimecroli-
mus due to a possible carcinogenic
risk with topical use, but this has not
been clearly established. Despite the
lack of evidence, animals developed
lymphomas and skin cancer after
treatment with high systemic doses
of calcineurin inhibitors.2,4,6 Both the
CDA (Canadian Dermatology Associ-
ation) and the AAD (American Acade-
my of Dermatology) agree that there
is no evidence to support a higher in-
cidence of lymphomas in patients us-
ing these products than in the general
population. In addition, the clinical and
histologic pattern of the lymphomas
found is not compatible with that re-
lated to immunosuppression.6 Tacroli-
mus and pimecrolimus can be said to
be effective in the treatment of PPR
by decreasing inflammation and pap-
ules. They are the treatment of choice
for corticosterid-induced rosaceiform
eruption.
Long-term treatment with tacrolim-
us may lead to rosaceiform dermatitis
in patients who are prone to develop
it. Burning sensation and itching are
usually present at the beginning of
treatment and are transient, and this
should be communicated to the pa-
tient.
References
1. Anonymous. Topical use of cortico-
steroids and calcineurin inhibitors
is the key to effective treatment of
atopic dermatitis. Drugs Ther Per-
spect 2009; 25(3)10-13.
2. Cook B, Warshaw E. Role of topical
calcineurin inhibitors in the treat-
ment of seborrheic dermatitis. Am
J Clin Dermatol 2009; 10(2):103-118.
3. Lin A. Innovative use of topical cal-
cineurin inhibitors. Dermatol Clin;
2010; 28:535-545.
4. Werfel T. Topical use of pimecro-
limus in atopic dermatitis: Update
on safety and efficacy. JDDG 2009;
7:739-742.
293
5. Sárdy M, Ruzicka T, Kuhn A. Topical
calcineurin inhibitors in cutaneous
lupus erythematous. Arch Dermatol
Res 2009; 301:93-98.
6. Wong E, Kurian A. Off-label uses of
topical calcineurin inhibitors. Skin
Therapy Lett 2016; 21(1):8-10.
7. Two A, Wu W, Gallo R, et al. Ro-
sacea. Topical and systemic ther-
apies in the treatment of rosacea.
Part II. J Am Acad Dermatol 2015;
72(5):761-770.
8. Karabulut AA, Izol Serel B, Eksiog-
lu HM. A randomized, single-blind,
placebo-controlled, Split-face study
with pimecrolimus cream 1% for
papulopustular rosacea. J Eur Acad
Dermatol Venereol 2008; 22:729-
734.
9. Ballester MM. Rosácea y rinofima.
AMF 2013; 9(7):397-401.
10. Molina AL, Londoño A, Escobar
SM, et al. Guías clínicas para el
tratamiento de la rosácea. Rev
Asoc Colomb Dermatol 2012;
20(4):339-364.
11. Weissenbacher S, Merkl J, Hildeb-
randt B, et al. Pimecrolimus cream
1% for papulopustular rosacea: A
randomized vehicle-controlled dou-
ble-blind trial. Br J Dermatol 2007;
156:728-732.
12. Teraki Y, Hitomi K, Sato Y, et al. Tac-
rolimus-induced rosacea-like derma-
titis: A clinical analysis of 16 cases
associated with tacrolimus ointment
application. Dermatology 2012;
224:309-314.
13. Fujiwara S, Okubo Y, Irisawa R, et
al. Rosaceiform dermatitis associ-
ated with topical tacrolimus treat-
ment. J Am Acad Dermatol 2010;
62:1050-2.
14. Lee DH, Li K, Suh DH. Pimecroli-
mus 1% cream for the treatment of
steroid-induced rosacea: an 8-week
split-face clinical trial. Br J Dermatol
2008; 158:1069-1076.
15. Chu C-Y. An open-label pilot study
to evaluate the safety and efficacy
of topically applied pimecrolimus
cream for the treatment of ste-
roid-induced rosacea-like eruption. J
Eurol Acad Dermatol Venereol 2007;
21:484-490.
16. Hu L, Alexander C, Velez NF, et al.
Severe tacrolimus-induced gran-
ulomatous rosacea recalcitrant to
oral tetracyclines. J Drugs Dermatol
2015; 14(6):628-630.
17. Korting HC, Schöllmann C. Current
topical and systemic approaches to
treatment of rosacea. J Eurol Acad
Dermatol Venereol 2009; 23:876-
882.
18. El-Heis S, Buckley DA. Rosa-
cea-like eruption due to topical
pimecrolimus. Dermatol Online J
2015; 21(5).
19. Niikolau V, Stratigos A, Antoniou
C, et al. Pimecrolimus cream 1%
for the treatment of papulopustu-
lar eruption related to epidermal
growth factor receptor inhibitors:
A case series and a literature re-
view of therapeutic approaches.
Dermatology 2010; 220:243-248.
20. Gül U, Gönül M, Kiliç A, et al. A
case of granulomatous rosacea suc-
cessfully treated with pimecrolimus
cream. J Dermatolog Treat 2008;
19:313-315.
21. Weinkle A, Doktor V, Emer J. Up-
date on the management of rosacea.
294
Clin Cosmetic Invest Dermatol 2015;
8:159-177.
22. Koca R, Altinyazar C, Ankarali H,
et al. A comparison of metronida-
zole 1% cream and pimecrolimus
1% cream in the treatment of pa-
tients with papulopustular rosa-
cea: a randomized open-label clin-
ical trial. Clin Exp Dermatol 2009;
35:251-256.
23. Schaller M, Schöfer H, Homey B, et
al. Rosacea management: Update on
general measures and topical treat-
ment options. JDDG 2016; 14( Suppl
6):17-27.
24. Sehgal VN, Srivastava G, Dogra
S. Tacrolimus approved and unap-
proved dermatologic indications/Us-
es-Physician´s sequential literature
survey. Skinmed 2008; 7(2):73-77.

Systemic Treatment
The main pathophysiological com-
ponents that seem to be related to
rosacea are neurovascular dysregu-
lation and immune system activation
through the cathelicidin cascade, an
important pathway that is physio-
logically involved in innate immunity
and first-line antimicrobial defence.
Rosacea is not caused by a bacteri-
um. The use of systemic antibiotics
in dermatology is common for the
numerous conditions caused by bac-
terial infections. Antibiotics destroy
microorganisms, either by bacteri-
cidal action or by preventing their
reproduction (bacteriostatic action).
In 1968, Marks, in his work “Concepts
in the pathogenesis of rosacea,”
pointed out the probable action of
tetracycline in rosacea is anti-inflam-
matory rather than antibacterial.1-4
Chapter 26
Antibiotics
Jaime Piquero Martin, Jaime Piquero Casals
This chapter discusses antibiotics Mechanism of Action
and their mode of action in rosacea.5 Tetracyclines are bacteriostatic an-
tibiotics, although in high concen-
TETRACYCLINES trations they can be bactericidal. In
Tetracyclines are lipophilic molecules gram-positive and gram-negative
developed in the 1950s for their anti- microorganisms (either aerobic or
bacterial properties. They are part of anaerobic), they inhibit protein
a set of natural antibiotics (chlortetra- synthesis by binding to the 30S ri-
cycline, oxytetracycline, tetracycline) bosomal subunit. They act against
or semi-synthetic antibiotics (metha- Rickettsia sp, Coxiella burnetii, Bor-
cycline, demeclocycline, doxycycline, relia sp, T. pallidum, T. pertenue, Chla-
minocycline, lymecycline, rolitetracy- mydia sp, Mycoplasma, Helicobacter
cline and tigecycline) derived from pylori, Plasmodium sp, E. histolytica,
different species of Streptomyces.6-9 and some mycobacteria. In rosacea,
At present, they are known to have the efficacy of tetracycline is due to
important anti-inflammatory effects. its anti-inflammatory properties and
295
a direct effect on the vascular en-
dothelium. Tetracyclines have been
shown to exhibit multiple anti-inflam-
matory properties, some correlating
with therapeutic activity in rosacea,
such as inhibition of several MMPs
and inhibition of neutrophil chemo-
taxis.5,8,9 Inhibition of MMP activity
appears to relate to therapeutic ac-
tivity in rosacea. This inhibition leads
to a reduction in kallikrein 5 (KLK5)
activation which, in turn, is ultimately
followed by decreased production of
cathelicidin LL-37. In addition, mino-
cycline and doxycycline were found
to inhibit angiogenesis induced by
implanted tumors in the rabbit cor-
nea. Doxycycline and, to a lesser
extent, chemically modified tetra-
cyclines (CMT) inhibit the synthesis
of MMPs (MMP-8, MMP-9) by en-
dothelial cells during angiogenesis. Second-Generation Table 26-1. Types of Tetracyclines
Recent experimental data indicate Tetracyclines
that tetracyclines have antiapoptotic Second-generation tetracy- First Generation Second Generation Third Generation
properties. Intraperitoneal adminis- clines are minocycline, dox-
tration of minocycline, 12 hours be- ycycline (in its two forms: Oral Parenteral Oral Parenteral Oral Parenteral
fore or 3 minutes after a brain injury, doxycycline hydrate and
prevents neuronal cell death in mice, doxycycline monohydrate), Oxytetracycline Oxytetracycline Lymecycline Rolitetracycline Tigecycline
by inhibition of caspase-1 an Interleu- and lymecycline. These are Tetracycline Tetracycline Doxycycline Lymecycline
kin-1 converting enzyme (ICE) which similarly effective in rosacea. Chlortetracycline Minocycline Guamecycline Under investigation
cleaves the precursors of interleukin Minocycline and doxycycline Mepycycline Doxycycline
1b and interleukin 18 mediating neu- are tetracycline analogues Guamecycline Minocycline Omadacycline Omadacycline
ronal cell death. Prophylactic admin- and differ from the original Etamocycline Sarecycline Eravacycline
istration of doxycycline reduces the molecule in positions 5 and Clomocycline
severity of canine osteoarthritis. This 6 (doxycycline) (Fig. 26-1).10,15 Demeclocycline
effect is accompanied by inhibition Doxycycline –in formulations Methacycline
of chondrocyte proliferation and hy- of more than 50 mg with an- Penimocycline
pertrophy, and a reduction of MMP tibiotic activity– is the most Tyacycline
activity.10,11 In rosacea, the mechanism widely used tetracycline in Upper peripheral region
of action of tetracycline and its deriv- the United States in clinical studies day, although there are currently no CH3 OH N(CH3)2
atives likely encompasses inhibition on the treatment of patients with ro- controlled studies of the use of sec- OH
of angiogenesis, neutrophil chemo- sacea. Currently, 40 mg modified-re- ond-generation tetracyclines in stan- D C B A
taxis, pro-inflammatory cytokines, lease (MR) doses are being used, as dard doses in rosacea.7,10,12,16-18
and MMP-9.12-14 this dosage is considered to have O
OH
O
CONH2
OH OH
anti-inflammatory but not antibiotic Adverse Effects Lower peripheral region
TETRACYCLINE
Types of Tetracyclines activity. Lymecycline is a semi-syn- Cutaneous adverse events with
Tetracyclines are classified from first thetic tetracycline obtained from the tetracyclines may include photosen- CH3 OH N(CH3)2
to third generation according to their reaction of tetracyclines with formal- sitivity, skin discoloration, nail pig- H H OH

age. First-generation tetracyclines may dehyde and lysine which is done to mentation and onycholysis; alteration D C B A
be available for oral administration improve its pharmacokinetic proper- of the color of teeth in tooth devel-
(chlortetracycline), or oral and paren- ties. It is rapidly converted to tetracy- opment, hypersensitivity syndromes OH O OH
OH
O
CONH2

teral administration (oxytetracycline, cline, lysine and formaldehyde in the (fixed-drug eruption, lichenoid DOXYCYCLINE
tetracycline, demeclocycline, rolitetra- gastro-intestinal tract. In comparative eruptions, serum sickness type re-
N(CH3)2
cycline, clomocycline). Second-gener- studies with minocycline and doxy- actions, moderate exanthems, Ste- H H
N(CH3)2
OH
ation tetracyclines are methacycline, cycline for the treatment of acne, a vens-Johnson syndrome and Sweet’s
doxycycline, and minocycline. Glycyl- lower incidence of side effects was syndrome). Other complications may D C B A

cyclines are third-generation tetra- recorded with lymecycline. In rosa- OH CONH2

cyclines and are under investigation cea patients, lymecycline can be ad- Fig. 26-1. Chemical structure of tetra- OH O OH O
MINOCYCLINE
(Table 26-1).6,8 ministered in doses of 150-300 mg/ cycline, doxycycline and minocycline.6
296
include drug-induced lupus, psoria-
sis exacerbation, gram-negative fol-
liculitis (from long-term treatment
of acne), and oral and genital can-
didiasis.
Systemic adverse events of tetracy-
clines may include digestive manifesta-
tions, blood alterations, hepatotoxicity,
exacerbation of kidney disease and
neurological disorders (especially
by minocycline) and pseudotumor
cerebri (reported in patients with
acne treated with oral retinoids).
Mindful of the fact that these po-
tential adverse events are mostly
dose-dependent and that rosacea
treatments usually last several weeks
to months, the use of lower doses in
which anti-inflammatory action per-
sists has been considered.19-24
Drug Interactions
Tetracyclines enhance the effect of
oral anticoagulants, increase pro-
thrombin time and interfere with the
bactericidal activity of penicillins.
They can raise the levels of lithium,
theophylline and digoxin, and increase
the hepatic metabolism of anticonvul-
sants. Doxycycline and minocycline
are excreted in breast milk. Like oth-
er tetracyclines, they are known to
cause staining of teeth (yellow, grey,
brownish) during tooth development
(last trimester of gestation, neonatal
period and early childhood). The use
of tetracyclines and its derivatives
should be avoided in pregnant wom-
en, breastfeeding women, infants and
young children.10,25
Absorption
As they are more lipophilic, doxycy-
cline, minocycline, and lymecycline
are absorbed better than the other
tetracycline derivatives. This lipid sol-
ubility facilitates transport across the
lipid-rich membrane and allows better
penetration. The distribution in the
body is wide.
Unlike tetracycline, doxycycline
and minocycline can be adminis-
tered with food or dairy products
without decreasing their absorption.
For this reason, the incidence of gas-
tric disorders with minocycline and
doxycycline is reduced. Absorption
of doxycycline and minocycline may
be decreased by antacids, although
to a lesser extent than tetracycline.
Iron also inhibits the absorption of
doxycycline and minocycline, so they
should be administered 3 hours af-
ter ingestion of iron. Doxycycline and
minocycline have a longer half-life
than other tetracyclines, between 15
and 24 hours the former and 12 to 16
hours the latter. When a lower dose of
doxycycline, is prescribed to patients
classified as low absorbents, there is
a risk that certain factors will reduce
the gastrointestinal absorption of the
drug and, thereby, also its systemic
bioavailability.25-27
297
Doses
Tetracycline, 250-500 mg every 6-8 h
(1-2 g/day orally); chlortetracycline, 250-
500 mg every 6-8 h (1-2 g/day orally);
oxytetracycline, 250-500 mg every 6-8
h (1-2 g/day orally or by IV); methacy-
cline, 300 mg every 24 h; doxycycline,
50-100 mg every 24 h; minocycline,
50-100 mg every 24 h; lymecycline, 150-
300 mg every 24 h.
Subantimicrobial Dose (SD) Dox-
ycycline. Several authors have
demonstrated the efficacy of suban-
timicrobial dose doxycycline for the
treatment of acne, adult periodontitis
and rosacea. This dose (SD doxycy-
cline) exerts a potent anti-inflamma-
tory action, without an antimicrobial
effect, with MMP inhibitory activity
greater than minocycline, and better
long-term tolerability. Adverse effects
are minor (decreased gastritis, vagi-
nitis, photosensitivity) and the risk of
bacterial resistance, associated with
higher doses, is also reduced. The ef-
ficacy of SD doxycycline (20 mg BID)
was confirmed by Thiboutot et al.28 in
a phase III randomized, multicenter,
double-blind, placebo - controlled study.
A total of 134 patients with rosacea
received SD doxycycline (n=67) or
placebo (n=67) for 16 weeks. Those re-
ceiving SD doxycycline had a greater
average reduction in the total num-
ber of inflammatory lesions (papules,
pustules, and nodules) than those in
the placebo group (-6.7 versus -3.8,
p = 0.009). Reduction in erythema
was 50 % greater in SD-doxycy-
cline-treated patients compared
with those in the placebo group (p
= 0.082). At the end of the study, the
global severity score was significantly
lower in patients treated with SD dox-
ycycline than in the placebo group (p =
0.006) and 13.1% of doxycycline-treat-
ed patients had complete clearance
of disease compared with 1.5 % of
placebo patients (p = 0.014). Tolera-
bility was comparable between the
SD doxycycline and placebo groups.
It was concluded that SD doxycycline
(20 mg, 2 times/day) is effective and
safe and is a new therapy in the man-
agement of rosacea. Additional stud-
ies have demonstrated the efficacy of
SD doxycycline in the treatment of
papulopustular rosacea (PPR), both
as monotherapy and in combination
with topical therapy.29,30 The favorable
therapeutic results of SD doxycycline
support the hypothesis that antibiotic
activity is not necessary for the treat-
ment of rosacea, and that improve-
ment in signs and symptoms is more
likely to be due to anti-inflammatory
effects. In 2006, this formulation was
approved by the FDA for the treat-
ment of inflammatory rosacea lesions.
It provides 30 mg immediate-release
and 10 mg delayed-release beads of
doxycycline (Oracea™), with proven
pharmacokinetic and microbiological
profiles, without antibiotic action, but
still with anti-inflammatory effects.31-34
 A new tetracycline, sarecycline hy-
drochloride acts on the production
of cytokines, has anti-inflammatory
properties and is currently under in-
vestigation.
Other drugs with antibacterial ac-
tion, which have been used orally to
treat cutaneous rosacea, are men-
tioned in small studies or case re-
ports. They are macrolide derivatives
(e.g. azithromycin and clarithromycin)
and metronidazole.
MACROLIDES
Macrolide antibiotics are consid-
ered the second therapeutic line
in the management of rosacea, and
are used primarily in patients with
contraindications to tetracyclines. In
recent studies, second-generation
macrolides clarithromycin and azith-
romycin have been shown effective
in treating rosacea. They are bacte-
riostatic because they inhibit bacteri-
al protein synthesis by binding to the
broad-spectrum 50S ribosomal sub-
unit and have activity against multi-
ple gram-positive and gram-negative
bacteria. Macrolides also have an-
ti-inflammatory effects by inhibiting
the synthesis of proinflammatory cy-
tokines (IL-8, TNF-a), and reducing
matrix MMPs and leukocyte chemo-
taxis. A comparison of clarithromycin
versus doxycycline for the treatment
of rosacea was published in 1997.35,36
The authors stated that 6 weeks of
clarithromycin treatment was equiv-
alent to 8 weeks of doxycycline treat-
ment. After three years of follow-up,
patients treated with clarithromycin
required this drug for an average
of 10.2 weeks per year, while those
receiving doxycycline used it for an
average of 14.6 weeks. Bakar37 eval-
uated the therapeutic potential of
azithromycin in rosacea. Oral azi-
thromycin was administered in two
decreasing doses (500 mg/day, 3
consecutive days weekly for 4 weeks;
250 mg/day, 3 consecutive days week-
ly for 4 weeks; and finally, 500 mg
once a week for the last 4 weeks).
At the end of 12 weeks, there was
an 89 % decrease in inflammatory
lesions, a 75 % decrease in erythe-
ma, and a 53 % decrease in telangi-
ectases compared with basal values.
Improvement continued during the
4 weeks after treatment. Adverse ef-
fects were minimal and azithromycin
was well tolerated in most patients.
In 2005, Caputo published a study
on pulse therapy with oral azithromy-
cin in rosacea and perioral dermati-
tis. Twenty patients with moderate to
severe papulopustular rosacea and
another 20 with perioral dermatitis
were recruited. They were given azi-
thromycin in a dose of 500 mg/day,
3 consecutive days per week for 4
to 8 weeks. At the end of 8 weeks,
there was an improvement in 90 %
of patients with rosacea and 85 %
of patients with perioral dermatitis.
298
Two patients experienced gastralgia,
but neither had to suspend the treat-
ment.
Second-generation macrolides have
better bioavailability and lower gas-
trointestinal effects than erythromy-
cin. Controlled clinical studies are
necessary to determine their role
as initial and maintenance therapy
in rosacea. Clinical studies showing
comparative effectiveness with oth-
er drugs used in this disease are also
needed. It is advisable to evaluate
the cost/benefit ratio of second-gen-
eration macrolide treatment, as well
as to evaluate macrolide-induced
antibiotic resistance and possible
side effects (prolongation of QT in-
terval).35-41
METRONIDAZOLE
Although oral metronidazole was ini-
tially popularized as a treatment for
rosacea, mainly in Europe, data on its
use are limited and efficacy is only sup-
ported by a few small studies. Alcohol
intake should be completely avoided
during treatment with oral metronida-
zole as it can cause a disulfiram-type
reaction. Although rare, reports of
convulsions and neuropathy have di-
minished enthusiasm for this agent as a
commonly used therapy in rosacea.42-46
DAPSONE
Sulfonamides are synthetic antimi-
crobials derived from sulfanilamide.
They are bacteriostatic for gram-pos-
itive and gram-negative microor-
ganisms, although they are often
associated with the development of
microbial resistance. Sulfone has
antimicrobial and anti-inflamma-
tory properties. Its most common
oral use is in leprosy and –be-
fore the era of isotretinoin– in the
treatment of severe inflammatory
acne. Oral use has been limited
by serious adverse effects such as
agranulocytosis, neuropathy and,
mainly, hemolytic anaemia in congen-
ital glucose-6-phosphate dehydroge-
nase-deficient patients. Topical use
is hampered due to poor solubility of
the drug in aqueous vehicles.
Recently, dapsone 5 % gel was
developed, which has shown to be
effective and quick in the manage-
ment of inflammatory acne lesions.
It does not cause severe adverse re-
actions, only skin dryness and mild
erythema. It is well tolerated even
in glucose-6-phosphate dehydroge-
nase-deficient patients. Although its
oral effectiveness in rosacea has not
been proven, it has been used with
satisfactory results since the time
when its action against neutrophil
chemotaxis was appreciated.5
BACTERIAL RESISTANCE
The problem of microbial resistance
has been gradually increasing over
the last twenty years in virtually all
countries. It refers to the lack of
therapeutic response to when the
minimum inhibitory concentration
of the antibiotic is greater than that
reached in vivo, as a result of the ap-
pearance of resistant strains. In the
last fifty years, the use and abuse
of antibiotics, and the consequent
pressure that this has exerted on
the selection-survival processes of
microorganisms, has led to the ap-
pearance of many resistant bacte-
ria. At the same time, advances in
medicine have led to an increase
in the number of immunocompro-
mised patients, who currently suffer
from infections caused by normal-
ly harmless agents. In this way, in-
fections by bacteria resistant to a
large number of known antibiotics
develop in healthcare facilities all
around the world. Most recently,
strains resistant to antibiotics that,
until now, have been considered the
last bastion of antibacterial defence
have begun to appear. The rationale
for use of antibiotics is aimed at
the greatest benefit to the patient,
limiting the development of resis-
tant microorganisms and minimizing
treatment costs. In rosacea, relaps-
es when antibiotic treatment is sus-
pended are frequent; so, to prevent
them, it is advisable to administer
oral medication along with the top-
ical one, such as metronidazole gel
or cream, which is maintained when
antibiotics are discontinued.25,47
References
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al. Consensus recommendations from
the American Acne & Rosacea Society
on the management of rosacea, part 1:
A status report on the disease state,
general measures, and adjunctive skin
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2. McAleer MA, Lacey N, Powell FC. The
pathophysiology of rosacea. G Ital
Dermatol Venereol 2009; 144:663-671.
3. Del Rosso JQ. Advances in under-
standing and managing rosacea: part
2: The central role, evaluation, and
management of diffuse and persistent
facial erythema of rosacea. J Clin Aes-
thet Dermatol 2012; 05:26-36.
4. Marks R. Concepts in the pathogen-
esis of rosacea. Br J Dermatol 1968;
80:1 70-7.
5. Honeyman J. Antibióticos sistémicos.
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en Dermatología 1ra. ed. Caracas. Ed-
itorial Pentagráfica 3000 CA, 2015.
6. Spadin NA, Fleischmajer R. Tetracy-
clines: Non antibiotic properties and
their clinical implications. J Am Acad
Dermatol 2006; 54:260.
7. Maibach H. Second-generation tet-
racyclines, a dermatologic overview:
Clinical uses and pharmacology. Cu-
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8. Nelson ML, Levy SB. The history of
the tetracyclines. Ann N Y Acad Sci.
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9. Stockley IH. Antibiotics and anti-in-
fective agents. In: Stockley IH, eds.
Drug Interactions. 5th ed. London,
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10. Hanemaaijer R, Visser H, Koolwijk
P, et al. Inhibition of MMP synthe-
sis by doxycycline and chemically
modified tetracyclines (CMTs) in
human endothelial cells. Adv Dent
Res 1998; 12:114-8.
11. Fleischer AB Jr. Inflammation in
rosacea and acne: Implications for
patient care. J Drugs Dermatol 2011;
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12. Sneddon IB. A clinical trial of tet-
racycline in rosacea. Br J Dermatol
1966; 78:649-52.
13. Knight AG, Vickers CF. A follow-up
of tetracycline-treated rosacea with
special reference to rosacea kerati-
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14. Williams S, Wakisaka A, Zeng QQ,
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Dermatol Clin 2007; 25:122-135.
16. Golub LM, Lee HM, Ryan ME, et al.
Tetracyclines inhibit connective tis-
sue breakdown by multiple nonan-
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17. Del Rosso JQ. Anti-inflammatory
dose doxycycline in the treatment
of rosacea. J Drugs Dermatol 2009;
8:664-668.
18. Hermansson J. Rapid determina-
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in human plasma and urine using
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19. Sjolin-Forsberg G, Hermansson J.
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20. Pallett AP, Smyth EG. Tetracycline.
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21. Arrouy M, Cournut J. Clinical ex-
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derivative: Lymecycline in 97 severe
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22. Dupre A, Albarel N. Lymecycline
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23. Smith K, Leyden JJ. Safety of doxy-
cycline and minocycline: A system-
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24. Sloan B, Scheinfeld N. The use and
safety of doxycycline hyclate and
other second-generation tetracy-
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7:571-577.
25. Del Rosso JQ. Systemic therapy
for rosacea: Focus on oral antibiot-
ic therapy and safety. Cutis 2000;
66(suppl 4):7-13.
26. Leyden JJ. Absorption of minocy-
cline hydrochloride and tetracycline
hydrochloride. Effect of food, milk,
and iron. J Am Acad Dermatol 1985;
12(2, pt 1):308-312.
27. Valentín S, Morales A, Sánchez JL,
et al. Safety and efficacy of doxycy-
cline in the treatment of rosacea.
Clin Cosmet Investig Dermatol
2009; 2:129-140.
28. Thiboutot D. Efficacy and Safety of
Subantimicrobial-dose doxycycline
for the treatment of rosacea. Poster
presented at: 63 rd Annual Meet-
ing of the American Academy of
Dermatology; February 18-22, 2005;
New Orleans; P128.
29. Berman B, Zell D. Sub antimicro-
bial dose doxycycline: A unique
treatment for rosacea. Cutis 2005;
75(suppl 4):19-24.
30. Del Rosso J, Rosen T, Thiboutot D,
et al Status report from the scien-
tific panel on antibiotic use en der-
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and Rosacea Society. J Clin Aesthet
Dermatol 2016; 9(6):17-24.
31. Del Rosso JQ, Webster GW, Jack-
son M, et al. Two randomized phase
III clinical trials evaluating anti-in-
flammatory dose doxycycline (40
mg doxycycline, USP capsules) ad-
ministered once daily for treatment
of rosacea. J Am Acad Dermatol
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32. Fowler JF Jr. Combined effect
of anti-inflammatory dose doxy-
cycline (40-mg doxycycline, USP
monohydrate controlled-release
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33. Del Rosso JQ. Effectiveness
and safety of doxycycline 40 mg
(30-mg immediate-release and
10-mg delayed-release beads)
once daily as add-on therapy
to existing topical regimens for
the treatment of papulopustu-
lar rosacea: Results from a com-
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34. Thiboutot DM, Fleischer AB, Del
Rosso JQ, et al. A multicenter study
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15% gel as maintenance monother-
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648.
35. Torresani C, Pavesi A, Manara GC.
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in the treatment of rosacea. Int J
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36. Torresani C. Clarithromycin: A new
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37. Bakar O, Demircay Z, Gurbuz O.
Therapeutic potential of azithromy-
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38. Fernández-Obregón A. Oral use
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acne rosacea. Arch Dermatol 2004;
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39. Caputo R. Pulse therapy with azith-
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oral dermatitis: An open study.
Poster presented at: 63rd Annual
Meeting of the American Academy
of Dermatology, February 18-22,
2005; New Orleans.
40. Modi S, Harting M, Rosen T. Azith-
romycin as an alternative rosacea
therapy when tetracyclines prove
problematic. J Drugs Dermatol
2008; 7:898-899.
41. Akhyani M, Ehsani AH, Ghiasi M,
et al. Comparison of efficacy of
azithromycin vs. doxycycline in the
treatment of rosacea: A randomized
open clinical trial. Int J Dermatol
2008; 47:284-288.
42. PyeRJ, Burton JL. Treatment of
rosacea by metronidazole. Lancet
1976; 1(121):1-2.
43. Saihan EM, Burton JL. A dou-
ble-blind trial of metronidazole
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for rosacea. Br J Dermatol 1980;
102:443-5.
44. Coxon A., Pallis CA. Metronidazole
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Psychiatry 1976; 39:403-5.
45. Wienbren M, Perinpanayagam
RM, Camba L, et al. Convulsions
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with leukemia after treatment with
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46. Caro-Paton T, Carvajal A, Martin de
Diego J, et al. Is metronidazole tera-
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Pharmacol 1997; 44(2):179-82.
47. Nacha E. Tratamiento oral en la rosá-
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Martin J. Caracas: Impresos Creser,
2007.
Isotretinoin, a vitamin A analogue
drug, is orally effective in the treat-
ment of nodulocystic acne, keratiniza-
tion disorders and chemoprevention
of skin malignancies. Since the 1980s,
it has remained an option for the
treatment of acne, and is indicated
as early as possible considering the
psychosocial impact and the risk of
scarring.1 Isotretinoin is a potent inhib-
itor of the sebaceous glands and also
has anti-inflammatory properties via
modulation of the expression of toll-
like receptor-2 (TLR-2)2 and increas-
ing gene transcription mediated by
Fox O (Forkhead box class O), which
seems to explain the multiple effects
of this drug.3
Despite its efficacy, isotretinoin
can cause side effects in the skin
and mucous membranes: cheilitis,
xerophthalmia, conjunctivitis, nasal
dryness, epistaxis, irritant dermatitis.
Laboratory alterations may also be
observed, such as increased serum
levels of liver enzymes, increased
triglyceride and cholesterol levels,
increased levels of the LDL fraction
and reduced levels of the HDL frac-
tion.4-7 Teratogenicity is the most se-
rious and irreversible adverse effect.
Since isotretinoin crosses the placen-
ta, fetal exposure to this medication is
dose-independent and occurs at any
time of pregnancy, primarily in the
first trimester.8-10 Cases of depression,
suicidal ideation or suicide attempt
Oral Isotretinoin
Ediléia Bagatin
have been reported to be possibly
associated with oral isotretinoin in the
treatment of acne vulgaris. The inci-
dence varies from 1 % to 3 %, while
in the general population, it is esti-
mated at 1.6 % to 7.5 %, with an aver-
age of 3 %.11 More recently, however,
various studies have concluded that
oral isotretinoin improves or cures
the depressive symptoms which are
proven to be related to acne.12,13 Many
population-based studies have not
confirmed the association between
oral isotretinoin and depression; how-
ever, the recommendation to monitor
symptoms and, if necessary, request
a psychiatric evaluation and specific
treatment remains in effect. Such an
association has been considered rare
and idiosyncratic. There are no psy-
chiatric contraindications to this drug.
The occurrence of inflammatory bow-
el disease (IBD), particularly ulcer-
ative colitis, has been associated with
the use of oral isotretinoin. However,
population-based case-control stud-
ies concluded that this association
does not exist.14-16 A national study,
conducted in France in 2012, which
included a database of 47 million in-
dividuals, also found no link between
isotretinoin and IBD.17 On the contrary,
a case-control study conducted at the
301
Mayo Clinic discussed the hypothe-
sis of an inverse association, that is, a
protective effect of isotretinoin in the
intestine by its anti-inflammatory ac-
tion (inhibition of the Th17 response)
and immunomodulatory action (reg-
ulation of the balance between Th1/
Th2 responses and normalization of
exaggerated expression of TLR-2).18
Crohn’s disease has been reported
with the use of tetracyclines, particu-
larly doxycycline, and even with top-
ical treatments for acne, suggesting
that the causal factor is the disease
and not the therapeutic option.19,29
There seems to be a misunderstand-
ing about the true trigger. A recent
meta-analysis showed that there is no
increased risk of developing IBD after
exposure to isotretinoin.21
Clinical and laboratory monitor-
ing for the prevention and control of
side effects begins with the selection
of patients, through medical history,
complete physical examination and
complementary studies. At the be-
ginning of the drug’s use in the treat-
ment of acne, monthly re-evaluations
of plasma lipid levels and hepatic
transaminases should be carried out.
Considering that the proportion of
patients with laboratory alterations
is low, it is suggested to repeat the
examinations –blood count, hepat-
ic function and lipids– every 4 to 6
weeks during treatment and conduct
re-evaluations only in those with alter-
ations. Such behaviour significantly
reduces treatment costs.22-25
Some authors have reported the
benefit of low daily dose schedules
(0.3 to 0.4 mg/kg/day, 20 mg/day
or 20 mg on alternate days, 5 mg/
day) for the treatment of moderate
acne, achieving the same efficacy,
lower incidence of side effects, and
greater adherence to treatment.26-29
The efficacy of low doses seems to
have influenced the indication of oral
isotretinoin –despite being off label–
in other conditions, such as rosacea,
seborrhea, seborrheic dermatitis and
photoaging.30-33
The only oral treatment for rosa-
cea approved by the FDA in the Unit-
ed States is doxycycline in the form of
40 mg.34
Considering the multiple mech-
anisms of action of oral isotretinoin
which, like other retinoids, are de-
pendent on ligand and activation of
nuclear receptors as well as the inter-
action of these receptors with other
transcription factors, various off-label
indications of this drug have been
suggested and one of the most cited
is rosacea.33-35
 Most of the studies mentioned
below consider it a good treatment
option for moderate to severe forms
of papulopustular rosacea (PPR), ro-
sacea fulminans, and phymatous ro-
sacea. In case reports from 1980 and
1981, German authors suggested for
the first time use of oral isotretinoin
for severe rosacea, because of its
greater efficacy and longer remis-
sion period than conventional treat-
ments (high doses of tetracyclines,
metronidazole, etc.).36,37 These au-
thors used daily doses of 0.05, 0.5
or 1 mg/kg for 12 to 28 weeks, which
resulted in a regression of 50% of
inflammatory lesions in two weeks
and more than 95% in eight weeks.
Telangiectases and chronic conjunc-
tivitis showed little improvement.
Remission periods of more than 12
months were observed. Side effects
were mild (cheilitis and increased lip-
ids). Five years later, a 20-week mul-
ticenter study including 92 patients,
in which the same doses were admin-
istered, also found isotretinoin to be
highly efficacious in rosacea cases
which were refractory to other treat-
ments.38
In 1994, a randomized double-blind
study compared the treatment of se-
vere or recalcitrant rosacea with oral
isotretinoin 10 mg/day, topical treti-
noin 0.025% cream, and the com-
bined use of both oral isotretinoin
and topical tretinoin for 16 weeks,
followed by another 16 weeks of use
of tretinoin cream or placebo cream.
There was no difference between the
treatments. The conclusion was that
both treatments were beneficial and
it was not considered necessary to
combine them. Adverse events were
minimal and well tolerated. These
authors suggested that isotretinoin
might act on rosacea by decreasing
inflammation and suppressing seba-
ceous gland secretion.39 In the same
year, a Chilean author in a case series
report, used isotretinoin in patients
with severe rosacea for periods of 3
to 6 months, and obtained quick re-
mission of papules and pustules, im-
provement of ocular manifestations,
few side effects, and maintenance of
results for an mean of 14.8 months.40
Doses of 0.5 mg/kg/day to 1 mg/kg/
day had an immediate effect consist-
ing of reduction of papules and pus-
tules and considerable improvement
of erythema.41 A German random-
ized, double-blind, multicenter study
published in 2010, which included
573 patients with rosacea, compared
three different daily doses of isotreti-
noin (0.1, 0.3 or 0.5 mg/kg/day), dox-
ycycline (100 mg/day, for 14 days, and
then 50 mg/day), and placebo. After
12 weeks, the authors concluded that
isotretinoin 0.3 mg/kg/day dose was
more effective than placebo; its ef-
ficacy was equal to or even greater
than that of doxycycline (90% reduc-
tion of lesions versus 83% with dox-
302
ycycline) and it caused fewer side
effects than higher doses.42 Another
double-blind, placebo-controlled,
multicenter study involving 156 pa-
tients, compared isotretinoin (0.25
mg/kg/day) (n = 108) with placebo (n
= 48) for 4 months for the treatment
of PPR. The primary endpoint (90%
reduction in the number of lesions)
was observed in 57.4% of patients
treated with isotretinoin and 10.4%
of those treated with placebo. Re-
currence after 4 months occurred
in 58.3% of the 51 patients who were
subject to follow-up. The quality
of life score based on the Skindex
questionnaire showed significant im-
provement in patients treated with
isotretinoin. There was no difference
in adverse events. The authors sug-
gested that further studies should
investigate the value of a minimal ef-
fective isotretinoin dose to maintain
the remission.43
Oral isotretinoin combined with a
topical or oral corticosteroid has been
considered a treatment option for ro-
sacea fulminans, which, according to
some authors, is a very severe variant
of rosacea.44
In phymatous rosacea, there is hy-
perplasia of the sebaceous glands,
connective tissue, and blood vessels.
By suppressing sebaceous gland
activity and decreasing sebum pro-
duction, oral isotretinoin delays the
progression of this type of rosacea.41,45
A recent systematic review of ran-
domized and controlled studies treat-
ing patients with PPR, concluded that
low dose isotretinoin was considered
by both the participants (RR 1.23, 95
% CI 1.05 to 1.43) and researchers (RR
1.18, 95 % CI 1.03 to 1.36) to be slight-
ly more effective than doxycycline in
doses of 50-100 mg/day. There was
high quality evidence to support its
effectiveness, as well as that of topi-
cal brimonidine, azelaic acid and iv-
ermectin, and oral doxycycline for
rosacea.46-48
In 2016, the Iberian-Latin American
Group for the Study of Rosacea pub-
lished a treatment algorithm which in-
cluded isotretinoin in low daily doses
for the papulopustular and glandular
hyperplastic/phymatous subtypes.49
The use of daily doses of 0.3 mg/
kg for 16 weeks for moderate to se-
vere forms resistant to convention-
al treatments has been reported
more frequently, highlighting that
this is an off-label use.33 Low dosage
administration has been associat-
ed with efficacy, fewer side effects
and good adherence to treatment.
There is a need for rigorous clinical
and laboratory monitoring of ad-
verse effects, particularly teratoge-
nicity, as rosacea often affects adult
women of childbearing age.10 It is
worth remembering that existing
data in the literature on isotretinoin
adverse effects are related to the
treatment of acne in adolescents.4,5,7
A global consensus panel on the
diagnosis, classification and manage-
ment of rosacea –ROSacea COnsen-
sus (ROSCO)–, whose conclusions
were published in 2017, recommends
optimizing treatment according to the
phenotype of the clinical picture, since
no single therapeutic measure can
control all of the various characteris-
tics of rosacea. The authors placed oral
isotretinoin as a therapeutic option in
the severe PPR form and in the pres-
ence of clinically inflamed phymas.50,51
Most studies exclude ocular ro-
sacea and do not discuss ophthal-
mic adverse effects, despite being a
common complaint observed in up
to 50 % of patients. Although oral
isotretinoin has been considered as
part of the off-label treatment of PPR
and phymatous rosacea, the mecha-
nism of action of oral isotretinoin in
the management of this disease is
not yet fully known, even with new
knowledge about the complex etio-
pathogenesis of rosacea.34,50,52 There
are still no studies relating the role of
oral isotretinoin as a modifier of the
expression of skin biomarkers associ-
ated with rosacea, such as: VEGF and
CD 31, TLR-2, cathelicidins, TRPV-1,
and iNOS. The ideal dose and dura-
tion of treatment have not been es-
tablished either.
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microbials used to treat acne and
inflammatory bowel disease. Am J
Gastroenterol 2010; 105(12):2610-6.
20. Alhusayen RO, Juurlink DN, Mam-
dani MM, et al. Canadian Drug
Safety and Effectiveness Research
Network. Isotretinoin use and the
risk of inflammatory bowel disease:
A population-based cohort study. J
Invest Dermatol 2013; 133(4):907-12.
21. Lee SY. Does exposure to isotreti-
noin increase the risk for the de-
velopment of inflammatory bowel
disease? A meta-analysis. Eur J Gas-
troenterol Hepatol 2016; 28(2):210-6.
22. Sampaio SAP, Bagatin E. Experiên-
cia de 65 anos no tratamento da
acne e de 26 anos com isotretinoí-
na oral. A 65-year experience treat-
ing acne, including 26 years with
oral isotretinoin. An Bras Dermatol
2008; (34):361-367.
23. Zane LT, Leyden WA, Marqueling AL,
et al. A population-based analysis
of laboratory abnormalities during
isotretinoin therapy for acne vulgar-
is. Arch Dermatol 2006; 142:1055-7.
24. Lee YH, Scharnitz TP, Muscat J, et
al. Laboratory monitoring during
isotretinoin therapy for acne: a sys-
tematic review and meta-analysis.
JAMA Dermatol 2016; 152(1):35-44.
25. Shinkai K, McMichael A, Linos E.
Isotretinoin laboratory test monitor-
ing-a call to decrease testing in an era
of high-value, cost-conscious care.
JAMA Dermatol 2016; 152(1):17-9.
26. Agarwal US, Besarwal RK, Bhola K.
Oral isotretinoin in different dose
regimens for acne vulgaris: A ran-
domized comparative trial. Indian
J Dermatol Venereol Leprol 2011;
77(6):688-94.
27. Boyraz N, Mustak PK. Comparison
of the efficacies of intermittent and
continuous low-dose isotretinoin
regimens in the treatment of mod-
erate acne vulgaris. Int J Dermatol
2013; 52(10):1265-7.
28. Rademaker M, Wishart JM, Bir-
chall NM. Isotretinoin 5 mg daily
for low-grade adult acne vulgaris –
a placebo-controlled, randomized
double-blind study. J Eur Acad Der-
matol Venereol 2014; 28:747-54.
29. Dhaked DR, Meena RS, Maheshwari
A. A randomized comparative trial
of two low-dose oral isotretinoin
regimens in moderate to severe
acne vulgaris. Indian Dermatol On-
line J 2016; 7(5):378-85.
30. Bagatin E. Oral isotretinoin: The
most promising dermatological
off-label uses. Exp Rev Dermatol
2010; 5(6):617-26.
31. Bagatin E, Guadanhim LRS, Enokihara
MMSS, et al. Low-dose oral isotretinoin
versus topical retinoic acid for photoa-
ging: A randomized, comparative study.
Int J Dermatol 2014; 53:114-122.
32. Kamamoto CSL, Sanudo A, Hassun
KM, et al. Low-dose oral isotretinoin
for moderate to severe seborrhea/
seborrheic dermatitis: a random-
ized and comparative trial. Int J
Dermatol 2017; 56:80-85.
304
33. Nickle SB, Peterson N, Peterson M.
Updated physician’s guide to the
off-label uses of oral isotretinoin. J
Clin Aesthet Dermatol 2014; 7:22-34.
34. Del Rosso JQ, Thiboutot D, Gallo R,
et al. Consensus recommendations
from the American Acne & Rosacea
Society on the management of rosa-
cea, part 3: A status report on system-
ic therapies. Cutis 2014; 93(1):18-28.
35. Zouboulis CC. Retinoids–which der-
matological indications will benefit
in the near future? Skin Pharmacol
Appl Skin Physiol 2001; 14(5):303-15.
36. Nikolowski J, Plewig G. Rosacea.
Oral therapy with 13-cis retinoic
acid. Hautarzt 1980; 31(12):660-1.
37. Nikolowski J, Plewig G. Oral treat-
ment of rosacea with 13-cis-retinoic
acid. Hautarzt 1981; 32(11):575-84.
38. Hoting E, Paul E, Plewig G. Treat-
ment of rosacea with isotretinoin.
Int J Dermatol 1986; 25(10):660-3.
39. Ertl GA, Levine N, Kligman AM. A
comparison of the efficacy of top-
ical tretinoin and low-dose oral
isotretinoin in rosacea. Arch Derma-
tol 1994; 130(3):319-24.
40. Gajardo J. Severe rosacea treated
with oral isotretinoin. Rev Med Chil
1994; 122(2):177-9.
41. Gupta AK, Chaudhry MM. Rosacea
and its management: An overview. J
Eur Acad Dermatol Venereol 2005;
19(3): 273-85.
42. Gollnick H, Blume-Peytavi U, Szabó EL,
et al. Systemic isotretinoin in the treat-
ment of rosacea doxycycline-and place-
bo-controlled, randomized clinical study.
J Dtsch Dermatol Ges 2010; 8(7):505-15.
43. Sbidian E, Vicaut É, Chidiack H, et
al. A randomized-controlled trial of
oral low-dose isotretinoin for diffi-
cult-to-treat papulopustular rosacea.
J Invest Dermatol 2016; 136(6):1124-9.
44. Walsh RK, Endicott AA, Shinkai K.
Diagnosis and treatment of rosacea
fulminans: A comprehensive review.
Am J Clin Dermatol 2017 Jun 27.
45. Korting HC, Schöllmann C. Current
topical and systemic approaches to
treatment of rosacea. J Eur Acad Der-
matol Venereol 2009; 23(8):876-82.
46. van Zuuren EJ, Fedorowicz Z, Car-
ter B, et al. Interventions for ro-
sacea. Cochrane Database Syst
Rev 2015; (4):CD003262. doi:
10.1002/14651858. CD003262.pub5.
47. van Zuuren EJ, Fedorowicz Z. Inter-
ventions for rosacea: Abridged up-
dated Cochrane systematic review
including GRADE assessments. Br
J Dermatol 2015; 173(3):651-62.
 48. van Zuuren EJ, Fedorowicz Z. Inter-
ventions for rosacea. JAMA 2015;
314(22):2403-4.
49. Grupo Ibero-Latinoamericano de
Estudio de la Rosácea (GILER,
Iberian-Latin American Group for
the Study of Rosacea) – CILAD
(Iberian-Latin American Associa-
tion of Dermatology). Kaminsky A,
Zinc, a divalent cation, is an essential
micronutrient for humans, since it is
an essential component of more than
three hundred metalloenzymes and
two thousand transcription factors
that are needed for the regulation
of lipid, protein and nucleic acid me-
tabolism, and gene transcription. It is
involved in gene transcription at var-
ious levels, via histone deacetylation
reactions and via factors related to
zinc-dependent proteins, such as ste-
roid and thyroid hormone receptors.
Zinc also plays an important role in
maintaining the proper reproductive
function, immune status, and wound
repair via regulation of DNA and RNA
polymerases, thymidine kinase, and ri-
bonuclease. It maintains macrophage
and neutrophil functions, natural kill-
er cell activity, and complement activ-
ity. It activates natural killer cells and
phagocytic function of granulocytes
and stabilizes the plasma subcellular
membranes, especially the lysosomes.
Flórez White M, Piquero Martín
J, Herane MI, et al. Informe de
Consenso Ibero-Latinoamericano
2016 sobre la clasificación clínica
y terapéutica de la rosácea (2016 –
Iberian Latin-american Consensus
Report on the Clinical and Ther-
apeutical Classification of Rosa-
cea). Med Cutan Iber Lat Am 2016;
44(1):6-10.
Zinc Salts
María Herane
It inhibits the expression of integrins
by keratinocytes, modulates the pro-
duction of TNF-a and IL-6, and re-
duces the production of inflammatory
mediators like nitric oxide. It is also
proposed that it is toll-like-recep-
tor-mediated regulation of zinc ho-
meostasis which influences dendritic
cell function and immune processes.
Zinc has antioxidant properties. Su-
peroxide dismutase, an antioxidant en-
zyme, is zinc dependent. Zinc ions would
replace redox-active molecules, such as
copper and iron, and stimulate the syn-
thesis of free-radical scavenging metal-
lothioneins. It has been found useful in
preventing UV-induced damage and re-
ducing malignant diseases. In addition,
zinc has an anti-androgenic effect via
modulation of the activity of 5a-reduc-
305
50. Tan J, Almeida LMC, Bewley A,
et al. Updating the diagnosis,
classification and assessment of
rosacea: recommendations from
the global ROSacea COnsensus
(ROSCO) panel. Br J Dermatol
2017; 176: 431-8.
51. Schaller M, Almeida LMC, Bewley
A, et al. Rosacea treatment update:
tase types 1 and 2; in high doses, it com-
pletely inhibits in vitro enzyme activity.1,2
ZINC PHYSIOLOGY AND
DEFICIENCY STATES
An average adult weighing 70 kg
has a body zinc content of 1.4-2.3 g.
The highest tissue concentrations
(> 500 mg/g dry weight) are in the
prostate, seminal fluid, uveal tissue,
and skin. While about half of the to-
tal body zinc is in the bones, the skin
contains nearly 6% of total body zinc.
As movement of zinc across various
tissues is limited and there is no stor-
age depot, the continuous external
supply of zinc is important for meta-
bolic needs, growth, and tissue repair.
The recommended daily allowance
of zinc for an average adult male is 11
recommendations from the glob-
al ROSacea COnsensus (ROSCO)
panel Br J Dermatol 2017; 176:465-71.
52. Yamasaki K, Kanada K, Macleod DT,
et al. TLR-2 expression is increased
in rosacea and stimulates enhanced
serine protease production by ke-
ratinocytes. J Invest Dermatol 2011;
131(3):688-97.
mg, and it increases from 8 mg/d to up
to 12 mg/d in females during pregnancy
and lactation. It may be supplemented
as 10 mg/d during 1-10 years, 15 mg/d for
adolescents and adults, and 20-25 mg/d
during pregnancy and lactation. Some
animal foods –like meat, eggs, fish, and
oysters– are rich in zinc. Although ce-
reals and legumes contain a moderate
amount of zinc, only 20%-40% of the
ingested metal is absorbed. Its absorp-
tion is hampered by the presence of
phytates (cereals, grains), calcium, and
phosphates while chelating agents like
EDTA (ethylene diamino tetraacetic
acid) and animal proteins increase its
absorption from gut. Zinc is mainly ab-
sorbed from jejunum and distal duode-
num, and is excreted mainly through
faeces and, to a lesser extent, in urine.
Zinc deficiency is related to poor-so-
cioeconomic status, protein calorie
malnutrition, protein restricted and
vegetarian diets, anorexia nervosa, ex-
clusive parenteral nutrition, chronic
gastrointestinal diseases, infestations,
malabsorption syndromes, pancreatic
insufficiency, chronic renal failure, ma-
lignancies, infants on formula milk with
low zinc or parenteral alimentation, and
acrodermatitis enteropathica, which
causes poor availability or absorption
of zinc. Acute systemic deficiency is
characterized by diarrhea, mental ap-
athy, depression, acute alopecia and
dermatitis, mainly in the perioral area.2
ZINC IN DERMATOLOGY
The pathologies described are related
to systemic zinc depletion, but besides
them, many dermatological diseases
are treated with zinc preparations, ei-
ther topical or oral, with variable re-
sults. The usefulness of this element in
dermatology, either topically or orally,
covers a number of skin disorders such
as infections (warts, leishmaniasis, lep-
rosy, dermatophytosis), pigmentary
disorders (melasma), pre-neoplastic
lesions (actinic keratoses), neoplasias
(basal cell carcinomas), inflammatory
dermatoses (acne, rosacea, suppura-
tive hidradenitis, folliculitis decalvans),
hair disorders (alopecia), ulcers and
erosions, and oral lesions.1,3,4
Especially as zinc gluconate, it has
been used in the treatment of acne and
rosacea and provides excellent man-
agement of inflammatory lesions. The
therapeutic efficacy is mainly correlat-
ed with the preparation used. Those
available on the market are zinc acetate,
octoate, citrate, picolinate, ascorbate,
gluconate, and methionine-bound zinc.
New formulations dissolve better in the
stomach and are completely absorbed,
which enables to use lower doses with
better gastrointestinal tolerance.5
The bioavailability of zinc in oral
preparations is crucial to the thera-
peutic response. Picolinate and me-
thionine-bound zinc complex give
better results than commonly used
sulfate (Fig. 26-2).6 Effervescent glu-
conate preparations perform better
than sulfate and citrate, and even bet-
ter than tetracyclines in the manage-
ment of inflammatory acne lesions.
For therapeutic purposes, zinc may
be administered orally or parenterally,
either as sulfate (containing 22.5 mg
Zinc gluconate* = minocycline6
Zinc gluconate < minocycline7
Zinc picolinate/
Zinc gluconate
methionine-bound zinc
Fig. 26-2. Comparison of efficacy and bioavailability of zinc and its relationship
with tetracyclines and derivatives in acne.6
306
of elemental zinc/100 mg), acetate
(30 mg of elemental zinc/100 mg), ox-
ide (80 mg of elemental zinc/100 mg)
and gluconate (14.3 mg of elemental
zinc/100 mg).1 The recommended
dose of elemental zinc is 0.5-1 mg/kg/
day in children and 15-30 mg/day in
adults. In inflammatory diseases, such
as moderate to severe inflammatory
acne, papulopustular rosacea (PPR)
and suppurative hidradenitis, doses
of 300 mg/day or higher of oral zinc
sulfate or gluconate are used.
The anti-inflammatory effects of zinc
salts, via inhibition of TLR-2 expression
in keratinocytes, explain the action in
management of papules and pustules.
Zinc provides other advantages, such
as the reducting bacterial resistance
or restorating sensitivity of P. acnes
Zinc citrate/sulfate
†
ZnSO4 = oxytetracycline8
‡
ZnSO4/citrate < tetracycline9,10
to certain antibiotics, as demonstrat-
ed by adding zinc salts to resistant P.
acnes cultures. The absence of pho-
totoxic or photosensitive reactions,
plus a good safety profile in vulnerable
groups such as children and pregnant
women, and minor adverse effects are
additional advantages of zinc salts.7,8
In situations where isotretinoin or tet-
racyclines cannot be used, zinc can
be an alternative. Its use obviates the
problem of antibiotic overuse. The use
of retinoids, benzoyl peroxide and oral
zinc may be considered as an alterna-
tive in the management of inflammato-
ry acne lesions and PPR.5
Zinc in Rosacea
The efficacy and safety of orally admin-
istered zinc was evaluated in a small
number of research studies, with vari-
able results. In 2006, Sharquie et al.9
published a randomized, double-blind,
controlled study of 25 patients with PPR
and some with rhinophyma. The objec-
tive was to evaluate the efficacy and
safety of oral zinc sulfate (100 mg three
times daily for three months). At the end
of the study, a crossover of treatments
was performed in which patients from
the placebo group crossed over to re-
ceive zinc sulfate, and vice versa. In the
group of patients who completed the
study taking 300 mg a day of zinc sul-
phate from the beginning, the result was
a decrease in inflammatory lesions after
one month of treatment and a significant
level of improvement after 12 weeks. In
those who crossed over to placebo, the
average number of lesions began to rise
again after the fifth month, but always
at lower levels than the placebo group
before treatment. In the placebo group,
inflammatory lesions remained at high
levels for 3 months, but when crossing
over to zinc sulfate, improvement began
at the fourth month. Adverse effects
were minimal: 12% of patients receiving
zinc sulfate had gastritis.
Bamford et al.10 conducted a newer
randomized, double-blind, placebo-con-
trolled study in adults with PPR. Subjects
received 220 mg zinc sulfate (equivalent
to 50.8 mg elemental zinc) twice dai-
ly for 90 days. At the end of the study,
no statistically significant differences in
signs and symptoms improvement were
found between the placebo group and
the zinc-treated group, nor in the pa-
tient-referred quality of life (QoL) in-
dex. Blood zinc levels were higher in
the treatment group, as expected. This
group of authors states that the good
results of Sharquie’s work9 can be re-
lated to the lesion measurement scale
used, and to the fact that the crossover
did not include a period of therapeutic
suspension. In analysing both studies,
ethnic, dietary, and socioeconomic dif-
ferences are found that may create con-
fusion in the comparison.
Adverse Effects
In the usual doses, adverse effects are
minimal and are mainly related to the
digestive system: nausea, vomiting, and
mild epigastric pain. Newer formula-
tions, such as methionine-bound zinc
and gluconate, dissolve better in the
stomach and are also absorbed better,
which enables to use lower doses with
better tolerance. Systemic toxicity from
very high doses or prolonged use are
mainly at blood level due to copper
deficiency, sideroblastic anemia, and
neutropenia. It is observed with sulfate,
elemental zinc or gluconate. In animals,
at a dose of 1,250 mg/kg/day for 26
weeks, pancreatic alterations may devel-
op. In patients who took zinc gluconate
at a dose of 300 mg/day for 7 months
and 850 mg/day for 10 months, cases
of asthenia, anemia and leukopenia, and
copper deficiency were described.2
During pregnancy and lactation,
zinc supplements in doses lower than
75 mg/day did not led to anomalies,
congenital malformations, harmful
effects or fetal risk.5 In a study by
Dréno et al., more than 10,000 preg-
nant women and 2,000 breastfeeding
women were administered zinc gluco-
nate to treat acne and only 4 adverse
events were recorded, and their caus-
al relationship with zinc was doubtful.11
There is still room for research
on the use of zinc in dermatological
diseases in general, and inflammato-
ry pathologies in particular. Further
studies should be conducted for each
pathology individually. In rosacea, re-
307
search should aim to examine the effi-
cacy of zinc in the different subtypes
and determine whether there is ther-
apeutic efficacy –or not– and, if so, for
which subtype it is beneficial.12
References
1. Gupta M, Mahajan VK, Mehta KS, et
al. Zinc therapy in Dermatology: A re-
view. Dermatol Res Pract 2014; http://
dx.doi.org/101155/2014/709152.
2. Stephan F, Revuz J. Sels de Zinc en
dermatologie. Ann Dermatol Vene-
reol 2004; 131:455-60.
3. Bae YS, Hill ND, Bibi Y, et al. Inno-
vative uses for zinc in dermatology.
Dermatol Clin 2010; 28:587-97.
4. Sharquie KE, Noaimi AA, Al-Hashimy
SA, et al. Therapeutic evaluation of
2% tea lotion in comparison with 5%
zinc sulfate solution in the treatment
of acne rosacea. J Cosmet Dermatol
Sci Appl 2014; 4:60-5.
5. Sardana K, Garg VK. An observational
study of methionine-bound zinc with
antioxidants for mild to moderate acne
vulgaris. Dermatol Ther 2010; 23:411-8.
6. Sardana K, Chugh Sh, Garg VK. The
role of zinc in acne and prevention of
resistance: Have we missed the “base”
effect? Int J Dermatol 2014; 53:125-7.
7. Dréno B, Moyse D, Alirezai M, et al.
Multicenter randomized compara-
tive double-blind controlled clinical
trial of the safety and efficacy of
zinc gluconate versus minocycline
hydrochloride in the treatment of
inflammatory acne vulgaris. Derma-
tology 2001; 203:135-40.
8. Dréno B, Foulc P, Reynaud A, et al.
Effect of zinc gluconate on Propioni-
bacterium acnes resistance to eryth-
romycin in patients with inflammato-
ry acne in vitro and in vivo study. Eur
J Dermatol 2005; 15:152-5.
9. Sharquie KE, Najim RA, Al-salman
HN. Oral zinc sulfate in the treat-
ment of rosacea: A double-blind,
placebo-controlled study. Int J Der-
matol 2006; 45:857-61.
10. Bamford JTM, Gessert CH E,
Haller IV, et al. Randomized, dou-
ble-blind trial of 220 mg zinc sul-
fate twice daily in the treatment
of rosacea. Int J Dermatol 2012;
51:459-62.
11. Dréno B, Blouin E. Acné de la
femme enceinte et sels de zinc: Re-
vue de la littérature. Ann Dermatol
et Venereol 2008; 135:27-33.
12. Gessert Ch E, Bamford JTM, Haller
IV, et al. The role of zinc in rosacea
and acne: Further reflections. Int J
Dermatol 2014; 53:126-9.
In the mid-1970s, certain studies of
natural products showed that the
fermentation broth of Streptomy-
ces avermitilis, which is an actino-
mycete, improves Nematospiroides
dubuis infection in mice. By isolat-
ing the components of the broths
of that microorganism, avermectins
–16-membered lactone class deriv-
atives– were discovered.1 Ivermec-
tin is a semi-synthetic derivative of
avermectin, especially 22,23-dihy-
droavermectin B1, which has a high
in vitro antiparasitic bioactivity and
a high profile of safety and antipara-
sitic effectiveness in vivo.2 Ivermec-
tin is used to eradicate infestations
by endoparasites (nematodes) or
ectoparasites (arthropod insects
and mites). Since 1996, it has been
approved by the FDA for use in hu-
mans in the management of oncho-
cerciasis, filariasis, and intestinal
strongyloidiasis.
Ivermectin has a high bioavailabil-
ity, and is rapidly absorbed orally,
particularly when fasting; it is me-
tabolized in the liver and excreted
in faeces (98%) and urine (1%). It has
been found in minimal concentration
in breast milk.3 Four to five hours af-
ter ingestion in humans, ivermectin
reaches its peak plasma concentra-
tion levels, with a half-life of 57 hours.
It is metabolized in the liver through
the enzyme CYP3A4, disintegrating
into about 10 hydroxylated and de-
Oral Ivermectin
Gilberto Adame
methylated metabolites. Small quan-
tities are found at brain level, so it is
considered that it does not cross the
blood-brain barrier despite being
very liposoluble.1
The mechanism of action of iv-
ermectin is the selective binding to
specific neurotransmission receptors
that function in the peripheral motor
synapses of parasites.3 In this way, iv-
ermectin causes a tonic paralysis in
the parasites through glutamate-gat-
ed chloride channels which are
unique to invertebrates on muscle
and nerve cell membranes, causing
hyperpolarization. Because of its in-
ability to cross the blood-brain bar-
rier in mammals, ivermectin exhibits
a good safety profile in humans and
livestock.
Ivermectin is a macrocyclic lac-
tone, similar to macrolides, which,
unlike antibiotics, has little antibac-
terial and antifungal activity. But as
a macrolide lactone, it can modulate
host immune responses and sup-
press inflammatory responses via
inhibition of liposaccharide-induced
cytokine production.2 In veterinary
medicine, ivermectin is used for
the management of infestations by
308
various types of worms, larvae and
mites, including scabies. It is very
safe, as it acts on glutamate-gated
chloride channels, which are not ex-
pressed in mammals. It is also linked
to gamma-aminobutyric acid-gated
chloride channels, which are found
in arthropods and nematodes. In
humans, once administered, iver-
mectin causes a rapid decrease in
filariae in the skin and eyes. Larvae
are more affected than adult forms.
It is very effective against Ascaris
lumbricoides, Strongyloides ster-
coralis, and larva migrans caused by
Ancylostoma caninum. Other nema-
todes, such as Trichuris trichiura and
Enterobius vermicularis are partially
attacked; Ancylostoma duodenale
and Necator americanus are not af-
fected by ivermectin.
In humans, ivermectin has been
approved for the management of
onchocerciasis, lymphocytic filaria-
sis, intestinal nematode infections,
Loa-loa filarial disease (loiasis)5 with
skin tropism, Mansonella ozzardi,6 as-
cariasis, cutaneous larva migrans by
Ancylostoma caninum, larva migrans
currens by Strongyloides stercoralis,
scabies, in the treatment of scalp lice
(Pediculus capitis), and in demodici-
dosis and dermatitis by Cheyletiella
mites, in dogs, cats, and humans.4
Two mechanisms of resistance
to ivermectin are recognized, one
is the alteration of P-glycoprotein, a
membrane protein that transports
the drug across the membranes, and
the other is the alteration of chloride
channel receptors.4
USE IN HUMANS
Since 1980, it has been used to man-
age onchocerciasis or river blindness,
a disease caused by Onchocerca vol-
vulus, a parasite that breeds in the
host subcutaneous tissue and releas-
es a large number of microfilariae,
which move around the body, can
invade the eye and cause problems
from visual impairment to blindness.
A single oral dose of ivermectin 150
mg/kg weight or every 6 to 12 months
is recommended to decrease the
number of circulating filariae in adults
and children over 5 years of age from
endemic regions.1 When eliminated,
microfilariae produce a skin rash on
the trunk and extremities, with very
itchy lesions2 and subcutaneous nod-
ules (onchocercomas).3
In loiasis, a disease caused by the
bite of the horsefly which transmits
the causative agent, skin manifesta-
tions such as prurigo nodularis and
episodic angioedema on the upper
extremities (Calabar swellings) oc-
cur.3 In patients treated for Loa loa,
severe neurological reactions, such
as encephalopathy and coma, have
been observed.2 In lymphatic filari-
asis caused by Wucheria bancrof-
ti, lymphatic infestation by worms
causes elephantiasis and hydrocele.
Ivermectin is indicated in the treat-
ment of filariasis in adults, in oral
doses of 0.2 mg/kg weight. Results
improve when associated with al-
bendazole 400 mg. In Sarcoptes
scabiei mite infestation, oral iver-
mectin is considered first-line treat-
ment, along with topical application
of permethrin 5%.7,8 It is highly effec-
tive in crusted (or Norwegian) sca-
bies in HIV-infected patients, with
resolution after a single dose. Some
patients require a second dose cou-
pled with the use of topical benzyl
benzoate. Its management is con-
sidered to have great advantages
over topical scabicides, especially in
closed populations. Ivermectin has a
wide safety margin.
In demodicidosis, ivermectin acts
on Demodex folliculorum, the usual
skin commensal, which in immuno-
compromised patients causes dis-
seminated facial demodicidosis. It
has also been used in rosacea-like
papulopustular demodicidosis, to-
gether with topical permethrin 5 %.3
In rosacea, mite density is increased,
and it is thought that Demodex sup-
press the innate immune response of
the host to evade expulsion by ex-
pressing a Tn antigen. This antigen
is a carbohydrate coating known to
protect cancer cells and parasites
from immune surveillance.9 It is men-
tioned that an increase in the expres-
sion and recognition of the chitin
skeleton of mites by toll-like recep-
tors (TLR) may be the trigger for the
inflammatory response in rosacea.10,11
The presence of multiple mites, both
dead and alive, along with their skele-
tal disruption could release their gut
content including bacteria, such as
Bacillus oleronius or others, enzymes
and faeces, all within the follicular
canal. Contact with keratinocytes
triggers a type IV hypersensitivity re-
action or innate immune response.10,11
Also, tissue damage causes a Th2
and Th17 response as a result of neu-
trophil and macrophage activation.
Oral ivermectin is used in the treat-
ment of papulopustular rosacea (PPR)
and periorificial dermatitis (POD) in
children. Since 2014, cases of PPR and
POD treated with ivermectin doses
from 200 to 250 mg/kg orally and in
a water-based cream, have been re-
ported with good results.12
Therapeutic recommendations
for the treatment of demodicidosis
have not been standardized and,
although topical treatment is not
sufficient, several papers have been
published on the oral administration
309
of the drug. A study was conduct-
ed to evaluate the oral administra-
tion of ivermectin compared to oral
metronidazole and ivermectin in the
treatment of D. folliculorum asso-
ciated with blepharitis and skin le-
sions. In the first week, there were
no significant changes in the num-
ber of mites, but in the fourth week,
there was a significant decrease in
the study groups. However, at the
end of the study, the group using
oral ivermectin alone showed to-
tal clearance of blepharitis lesions.
Studies have shown that metroni-
dazole decreases inflammation, but
not the number of mites, as oral iv-
ermectin does.13
As already mentioned, ivermectin
has been used successfully in other
dermatoses, such as pediculosis and
cutaneous larva migrans.
Currently, oral ivermectin is used
in the management of various pa-
thologies in humans. In rosacea
and demodicidosis cases, it tends
to occupy a more prominent place
within therapeutics when there is
an increase in the number of De-
modex folliculorum and the disease
does not respond to usual therapy.
It is also indicated in blepharitis
by Demodex. All these indications
are off-label and further controlled
studies are required to verify their
use and effectiveness.
References
1. Loukas A, Hotez PJ. Quimi-
oterapia de las Helmintosis. In:
Brunton LL, Lazo JS, Parker KL.
Goodman & Gilman. Las bases
farmacológicas de la terapéuti-
ca. New York, McGraw-Hill 2007.
Pp. 1084-1087.
2. Kircik LH, Del Rosso JQ, Layton
AM, et al. Over 25 years of clin-
ical experience with Ivermectin:
An overview of safety for an in-
creasing number of indications. J
Drugs Dermatol 2016; 15(3):325-
332.
3. Dourmishev AL, Dourmishev LA,
Schwartz RA. Ivermectin: Pharma-
cology and application in derma-
tology. Int J Dermatol 2005; 44:981-
988.
4. Reynols HH, Elston DM, What’s Eat-
ing You? Cheyletiella Mites. Cutis
2017; 99(5):335-336.
5. Person RD. Loiasis at http://www.
merckmanuals.com/es-us/profes-
sional/enfermedades-infecciosas/
nematodos-gusanos-redondos/
loasis
6. Lima NF, Veggiani ACA, Dantur
MJ, et al. Mansonella ozzardi: A
neglected new world filarial nem-
atode. Pathol Glob Health 016 MY;
110(3):97-107.
 7. Salavastru CM, Chosidow O, Boffa
MJ, et al. European guideline for the
management of scabies. J Eur Acad
Dermatol Venereol 2017 Jun 22.
8. Ishii N, Asai T, Asahina A, et al. Guide-
line for the diagnosis and treatment
of scabies in Japan (third edition): Ex-
ecutive Committee of Guideline for
the diagnosis and treatment of sca-
bies. J Dermatol 2017 May 31.
Rosacea is a disorder characterized
by central facial erythema, telangiec-
tases, edema, papules and pustules.1,2
In particular, the erythematotelan-
giectatic subtype (ETTR) is charac-
terized by a persistent blushing and
flushing, which is usually very diffi-
cult to treat. Although not fully elu-
cidated, its pathogenesis appears
to be related to vascular dysfunc-
tion with vasodilation due to loss of
neurovascular regulation.1-4 In many
cases, the flushing symptoms per-
sist despite adequate control of in-
flammatory lesions. Currently, laser
therapies such as pulsed dye laser
(PDL) (590-595 nm), potassium-titan-
yl-phosphate (KTP) laser and intense
pulsed light (IPL) treatments have
had a significant beneficial effect on
facial erythema and telangiectases.
Pharmacological treatments that
modify the vascular smooth muscle
response to decrease vasodilation
will also be very useful.2,5-7
9. Moran EM, Foley R, Powell FC. De-
modex and rosacea revisited. Clin
Dermatol 2017; 35:195-200.
10. Forton FM. Papulo pustular rosacea,
skin inmunity and Demodex: Pityria-
sis folliculorum as a missing link. J Eur
Acad Dermatol Venereol 2012; 26:19-28.
11. Koller B, Muller-Wiefel AS, Rupec
R, et al. Chitin modulates innate im-
Beta-Adrenergic Blockers
Ricardo Pérez Alfonzo, María C. Isernia
Topical a2-adrenergic receptor
agonists, such as brimonidine tar-
trate, reduce persistent facial erythe-
ma in rosacea by vasoconstricting
dermal blood vessels.8,9 Locally ap-
plied, a1-adrenergic agonists such
as phenylephrine, naphazoline, tet-
rahydrozoline, oxymetazoline, and
xylometazoline are known for their
ability to eliminate skin flushing
and have been used as vasoconstrict-
ing agents for decades. Oxymetazo-
line hydrochloride, a known nasal
decongestant and potent vasocon-
strictor, is a synthetic imidazole-type
sympathomimetic agonist substance,
highly selective a1-adrenergic recep-
tor agonist and partially selective
a2-adrenergic receptor agonist. As
a 0.05 % solution, daily application
310
mune responses of keratinocytes.
PLoS One 2011;6, feb 24.
12. Noguera Morel L, Gerlero P, Tor-
relo A, et al. Ivermectin therapy
for papulopustular rosacea and
periorificial dermatitis in children:
A series of 15 cases. J Am Acad
Dermatol 2017; 76(3):567-569.
significantly reduces baseline ery-
thema in patients with rosacea.4,8-10
In 2017, the FDA approved a com-
mercial preparation of oxymetazo-
line hydrochloride 1 % in cream,
which exerts a rapid effect in reduc-
ing persistent erythema.10
Clonidine, an a2-adrenergic ag-
onist known as antihypertensive,
in doses of 0.05 mg twice daily
decreases peripheral sympathet-
ic discharge and improves redness
and flushing reactions in patients
with ETR. After a single dose of 15
mg, clonidine inhibits the flushing
induced by the ingestion of beer in
patients with rosacea. The sedation
effect may be a limiting factor for its
use.2,11-13
13. Salem Doaa AB, El-Shazly A, Nabih
N, et al. Evaluation of the efficacy of
oral ivermectin in comparison with
ivermectin - metronidazole com-
bined therapy in the treatment of
ocular and skin lesions of Demo-
dex folliculorum. Int J Infect Dis
2013; 17:e343-7.
Beta-adrenergic blockers are
used in the treatment of a variety of
cardiovascular disorders.4,8 Non-se-
lective beta-blockers decrease er-
ythema and flushing in rosacea by
inhibiting beta-adrenergic receptors
on the smooth muscles surrounding
blood vessels, leading to vasocon-
striction of these vessels.4,8
BETA-ADRENERGIC BLOCKERS
WITH POTENTIAL USE INETR
(TABLE 26-2)
Atenolol is a cardioselective be-
ta-blocker that acts on the heart’s b1
receptors. It is used as a cardiopro-
tective drug in cardiac arrhythmias
after a myocardial infarction. It has
been observed that oral atenolol, at
doses of 12.5-25 mg/day, reduces er-
ythema and flushing in patients with
ETR.4,7,8,17
Carvedilol, a non-selective be-
ta-adrenergic blocker, is indicated in
the treatment of mild to moderate
congestive heart failure. In addition
to its effect on the cutaneous vascu-
lature, the drug and its metabolites
are known for their potent antioxi-
dant effects (approximately 10 to 100
times more potent than a-tocoph-
erol, or vitamin E) and their anti-in-
flammatory properties, which may
explain its efficacy in the treatment
of ETR.3,14 Hsu, et al. studied 11 ETR
patients with normal blood pressure
(9 females and 2 males, aged 17 to
47 years, with a mean of 34.5 years)
who had been unsuccessfully treated
with doxycycline, topical corticoste-
roids, propranolol, clonidine, ondan-
setron, metronidazole, tacrolimus
and pimecrolimus, endoscopic tho-
racic sympathectomy with stellate
ganglion block, and pulsed dye la-
ser therapy in various combinations.
Carvedilol (3.125-6.25 mg, 2-3 times
daily) was added to the other drugs,
gradually increasing the daily dose
to 31.25 mg/day. All patients expe-
rienced significant clinical improve-
ment within 3 weeks (range 3-21 days,
mean 10.5 days), demonstrating that
low-dose carvedilol was effective in
treating ETR; moreover, it also al-
lowed other concurrent medications
to be tapered or even stopped.3,14
Nadolol and propranolol are also
non-selective beta-blockers used as an-
tihypertensives, antiarrhythmic agents,
and for the treatment of angina pec-
Table 26-2. Beta-adrenergic blockers with potential use inETR
Atenolol: cardioselective beta-blocker
Nadolol: non-selective beta-blocker
Propranolol: non-selective beta-blocker
Carvedilol: non-selective beta-blocker
toris. They may be effective in pa-
tients with rosacea associated with
severe erythema not responding to
conventional treatment. It has been
seen that both, at a dose of 20-40
mg 2-3 times daily can suppress er-
ythema in some patients, particular-
ly when the erythema is associated
with anxiety; however, frequent side
effects, such as hypotension and
bradycardia, limit their use.2,14,15 In
the treatment of ETR, propranolol
blocks the b2-adrenergic receptor
in the smooth muscle of the vascu-
lar wall. In addition, reactive oxygen
species released by local inflam-
matory cells, which contribute to
inflammation in rosacea, can be
controlled thanks to the antioxidant
properties of this drug.16 Propranolol
and doxycycline –as monotherapies
or in combination– have been evalu-
ated in patients with ETR and PPR.
The group of patients treated with
doxycycline (100 mg twice daily) ex-
perienced a dramatic improvement
between weeks 4 and 8. The group
treated with propranolol alone (30
311
OD, 12.5-25 mg day.
OD, 20-40 mg, 1-3 times a day.
OD, 10 mg, 3 times a day
OD, 3.125-6.25 mg, 2-3 times a day
mg/day) showed an especially rap-
id response in persistent flushing.
The combination group of doxycy-
cline (200 mg/day) and propran-
olol (30 mg/day) showed the best
result of the three groups: a rapid
improvement in the first 4 weeks
maintained throughout the 12-week
treatment period (significant reduc-
tion in flushing by 70% and papules
by 82%). The doxycycline group
showed a notably faster effect in the
handling of papules and pustules,
very useful in PPR, while proprano-
lol appears to be more effective in
ETR. The combined treatment, dox-
ycycline and propranolol, was effec-
tive both on persistent flushing and
on papules and pustules.16
In conclusion, the pharmacolog-
ical treatment of ETR forms, with
persistent flushing or blushing, by
administration of beta-adrenergic
blockers is reserved for recalcitrant
forms, in which topical therapy with
alpha-adrenergic receptor agonists
has not worked.17
References
1. Picardo M, Eichenfield LF, Tan J.
Acne and rosacea. Dermatol Ther
(Heidelb) 2017; 7:43-52.
2. Gupta AK, Chaudhry MM. Rosacea
and its management: An overview. J
Eur Acad Dermatol Venereol 2005;
19:273-85.
3. Hsu CC, Lee JY. Pronounced facial
flushing and persistent erythema of
rosacea effectively treated by carve-
dilol, a nonselective b-adrenergic
blocker. J Am Acad Dermatol 2012;
67:491-3.
4. Spoendlin J, Voegel JJ, Jick SS, et al.
Antihypertensive drugs and the risk
of incident rosacea. Br J Dermatol
2014; 17:130-136.
5. Taub AF. Treatment of rosacea with
intense pulsed light. J Drugs Derma-
tol 2003; 2:254-9.
6. Kassir R, Kolluru A, Kassir M. Intense
pulsed light for the treatment of ro-
sacea and telangiectasias. J Cosmet
Laser Ther 2011; 13:216-22.
7. Rebora A. The management of ro-
sacea. Am JClin Dermatol 2002;
3:489-96.
8. Abokwidir M, Feldman S. Rosacea
management. Skin Appendage Dis-
ord 2016; 2:26-34.
9. Jackson M, Knuckles M, Minni J, et al.
The role of brimonidine tartrate gel in
the treatment of rosacea. Clin Cosmet
Investig Dermatol 2015; 8:529-538.
10. Stuart D, Shanler SD, Ondo AL. Suc-
cessful treatment of the erythema
and flushing of rosacea using a topi-
cally applied selective alpha1-adrener-
gic receptor agonist, oxymetazoline.
Arch Dermatol 2007; 143:1369-1371.
11. Cunliffe WJ, Dodman B, Binner JG.
Clonidine and facial flushing in rosa-
cea. Br Med J 1977; 1:105.
12. Guarrera M, Parodi A, Rebora A, et al.
Flushing in rosacea: A possible mecha-
nism. Arch Dermatol Res 1982; 272:311-6.
13. Wilkin JK. Effect of sub depressor clon-
idine on flushing reactions in rosacea.
Change in malar thermal circulation in-
312
dex during provoked flushing reactions.
Arch Dermatol 1983; 119:211-4.
14. Hsu CC, Lee JY. Carvedilol for the
treatment of refractory facial flush-
ing and persistent erythema of rosa-
cea. Arch Dermatol 2011; 147:1258-60.
15. Wilkin JK. Effect of nadolol on flush-
ing reactions in rosacea. J Am Acad
Dermatol 1989; 20:202-5.
16. Park JM, Mun JH, Song M, et
al. Propranolol, doxycycline and
combination therapy for the
treatment of rosacea. J Dermatol
2014; 41:1-6.
17. Shinka K, Rosenbach M, Ahronowitz
I, et al. Rosacea Second edition. Ther-
apeutic Strategies in Dermatology.
Available at: https://www.derm101.
com/therapeu- tic/rosacea-2/.

Complementary Treatments
Skin with rosacea is more sensitive and
reacts easily to physical, psychic and
chemical stimuli from the environment.
This kind of skin is easily erythematous
and inflamed as a result of irritation or
allergy, which occurs more easily than
in normal skin.1 Rosacea patient’s skin
has special characteristics, such as vas-
cular reactivity and a higher degree
of sensitivity to chemical compounds.
Some other characteristics vary from
one patient to another, so the strate-
gy of management should arise from
a doctor-patient partnership. Some
external factors that redden the skin
with rosacea are sudden changes in
temperature, steam and heat, sun ex-
posure, cosmetics, beverages such as
red wine and spicy foods, certain med-
ications, chemical peels or laser skin
treatments, friction or massage, and
Chapter 27
Dermocosmetic Management – Skin care
Vanesa Piquero-Casals, Edgar La Rotha Higueras
emotional factors.1,2 The primary goals
of cosmeceuticals in patients with ro-
sacea is the control of facial erythema
as well as the prevention of exfoliation,
papules and pustules.
COSMETIC FORMULATIONS
Botanical and mineral molecules pre-
dominate in cosmetics, which are aimed
at reducing erythema. In fact, erythema-
totelangiectatic rosacea (ETR) is often
treated primarily with general skin care
optimization and cosmeceutical prod-
ucts which have ingredients to help
reducing inflammation. The selection
of the vehicle will depend on whether
313
or not there is an associated seborrheic
dermatitis. Typically, liquids or creams
free from potentially irritating or highly
concentrated substances are recom-
mended. Cosmetic treatment should
be maintained for prolonged periods,
as long as hypersensitivity reactions do
not appear, and the patient should be
counseled to avoid switching products
whenever possible. Fragrances and
preservatives should be avoided, as
they have the greatest irritant potential
in sensitive skin.2,3
Preservatives are an important
cause of intolerance reactions. Their
role is to limit bacterial prolifera-
tion, preserve the components from
decomposition by sunlight or high
temperature and avoid the oxidative
mechanisms that can modify the qual-
ity of the formulation. However, sensi-
tive skin with rosacea often reacts to
these ingredients. Fragrances, which
also contain molecules with irritant ca-
pacity, are responsible for 30% of the
causes of cosmetic contact dermatitis.
These substances contain between 10
and 300 ingredients, all of which are
known to cause irritant or allergic con-
tact dermatitis. Rosacea patients and
those with sensitive, intolerant or red-
dened skin should use hypoallergenic
formulations. Such formulations must
pass a series of tests proving their low
irritant potential and help ensure good
tolerability.3,4
 The patients with skin sensitive to
certain topical components should
receive instructions on the most suit-
able formulations and those that need
to be avoided. Perfumed products
are contraindicated; the use of sim-
ple cosmeceuticals containing as few
ingredients as possible is preferred.
The order in which the ingredients
are listed in the package leaflet indi-
cates the relative quantity. For exam-
ple, if perfume is scarce, it will be at
the bottom. In addition, the overall
ingredient list in a cosmetic product
suitable for rosacea patients should
not have more than ten substances.4,5
Types of Cosmetics and
Cosmeceuticals
Skin protection includes the following
types of cosmetic products: cleans-
ers, toners, make-up, emollients and
sunscreens.
Facial Cleansing
Facial cleansing consists of removing
dirt particles, secretions, pollution res-
idues and microorganisms from the
surface of the face. Because cleans-
ing products generally contain surfac-
tants or tensioactive agents, they are
the least tolerated by sensitive skin.
The skin care products selected for
facial cleansing should be gentle to
avoid skin irritation. Common soaps
are not well accepted due to their al-
kaline pH and should be replaced by
syndets (synthetic detergents), which
do not generate an alkaline reaction
when in contact with water; they tend
to rinse easily, produce a mild foam
while protecting the skin barrier func-
tion. Rosacea patients should avoid
sodium lauryl sulfate, instead choos-
ing micellar cleansing solutions which
are very soft and produce little foam.
If the skin is oily, diluted soaps such
as those used in pediatric patients are
recommended. On occasion, cleans-
ers with active components such as
sulphur and sodium sulfacetamide,
among others, may be indicated.6,7
Cleansers should be applied gently,
without rubbing, and rinsed with cool,
not hot water. Very vigorous or fre-
quent washing should be avoided (ad-
vise patients to cleanse only 1-2 times
a day) and soft cotton or soft paper
towels should be used for drying.1
In recent years, several emulsions
with good cosmetic appeal, greater
moisturizing power and low potential
for irritation have been introduced
to the market. However, even these
agents may produce irritation in pa-
tients with very sensitive skin.7 The
emulsions are applied with fingertips
or with a dampened cotton pad, with
soft movements and no friction. As
with syndets, cleansing with emul-
sions should be only carried out once
or twice a day.2
The removal of special or thera-
peutic make-ups, which are generally
314
adherent (in rosacea they are usually
green, to neutralize the erythematous
background), requires a special make-
up remover to minimize friction. For
eyelids requiring special care, gels
or lotions specifically formulated for
sensitive skin with sodium borate or
chamomile are used.8
Cosmetics for toning and thermal
waters
Toning lotions are generally liquid,
transparent or translucent, and whose
vehicle contains water and often alco-
hol or propylene glycol. Facial toning
lotions or toners can perform cleans-
ing, astringent and decongestant
functions. In patients with rosacea,
toning lotions with an alcoholic vehi-
cle, as well as those containing men-
thol, eucalyptus or camphor should
be avoided.
Replacement of a toning lotion by
thermal waters is a widespread com-
plementary treatment, and it is very
well accepted by patients. This is due
to its simple application and the ef-
fectiveness in generating freshness,
and reduction of inflammation signs
and heat induced by vasodilation. The
patient should be advised to spray
thermal water whenever they feel
burning, heat and inflammation with
erythema. During walks or outdoor
activities, and also during physical ac-
tivity, it is recommended to spray the
face to reduce flushing.1 The use of
cold chamomile water after cleansing
can also be suggested, thus signifi-
cantly reducing cost.
Sunscreens
It is very important for patients with
rosacea to avoid sun exposure and
physicians should advise patients to
use broad-spectrum sunscreens. In
general, the continuous use of a sun-
screen with an SPF 30 or higher is
recommended. Chemical filters are
poorly tolerated by patients with rosa-
cea, as they absorb UV radiation and
transform it into heat energy, which
can result in facial flushing and vaso-
dilation. Therefore, the use of physi-
cal, mineral sunscreens containing
titanium dioxide or zinc oxide is pre-
ferred, including tinted formulations
and those containing silicones. These
sunscreens reflect UV radiation and
prevent vasodilation, which improves
facial erythema and prevents epi-
sodes of flushing.7,9
Excessive exposure to solar radi-
ation is known to cause skin cancer,
aging, collagen damage, and vaso-
dilation. In patients with rosacea, it
also exacerbates erythema, which
worsens the crisis and may accel-
erate progress to more advanced
stages.7 Sunscreens can be divided
into chemical or organic UVB or UVA
protectors (para-aminobenzoic acid
derivatives, salicylate or cinnamate
derivatives, benzophenone series, an-
thranilate derivatives and others) and
physical or inorganic protectors (tita-
nium dioxide, zinc oxide, magnesium
oxide, kaolin, iron oxide, red petrola-
tum). Lately, sunscreens of natural ori-
gin may be found in the market. They
contain ingredients that have a low
filtration capacity, but the potential
to produce sensitivity reactions is low.
Belonging to this group are glycolic
extracts, chamomile, coffee, cayenne,
cotton, aloe, helichrysum, frangula,
and hypericum among others.10
Table 27-1 shows the recommend-
ed ingredients used in sunscreen for
sensitive skin with rosacea. In patients
with rosacea, sunscreens contain-
ing Parsol 1789 are an alternative to
chemical filters. Sunscreens contain-
ing Octyl salicylate and PABA should
be specifically avoided. Products
suitable for use in rosacea patients
should provide efficient protection
yet be formulated in a very light, fra-
grance free, oil-in-water (O/W) emul-
sion or gel base with the least amount
of preservatives. Additional caution
should be taken with solid products
that have a water-resistant effect, as
they are often difficult to apply and in-
volve friction. 2,10,11
Cosmetic camouflage: makeup
concealer
Makeup is a very important factor for
these patients. It allows them to join
work or social activities without the
Table 27-1 Recommended ingredients used in sunscreens for sensitive skin with rosacea
Organic filters Organic filters
(Chemical) UVA (Chemical) UVA - UVB
Octylmethoxycinnamate Avobenzone 1% to 5%
2% to 10 %
Menthylanthranilate
3.5% to 5%
Benzophenone-3
2% to 6%
Mexoryl SX 1% to 4%
stigma of a red face, thus having a
healthy psychological effect. In cases
of important facial erythema, applying
a green fluid concealer on the skin fol-
lowed by an opaque, fluid foundation
of the right color for each complex-
ion provides an excellent cosmetic
appearance. One of the agents that
gives the green color to the makeup
is chromium oxide powder, a mineral
pigment (Cr2O3) used as a natural
colorant. It is extracted from esko-
laite, although at present most of it is
produced by synthesis.
In patients with rosacea, fluid, sil-
iconized and hypoallergenic foun-
dations are recommended. They are
315
Inorganic (Physical)
sunscreens – UVA-UVB
Micronized zinc oxide 10% to
25%
Micronized titanium dioxide 8%
to 25%
suitable for oily skin being oil-free, and
more moisturizing for dryer skin. Fluid
bases with silicones are non-comedo-
genic, they are easy to spread, are
non-irritating and they give the skin
a silky smooth appearance . Formula-
tions with few ingredients and chemi-
cals should always be preferred.
Cosmetic powders have few ad-
ditives and preservatives and can
be used on seborrheic skin. Caution
should be taken to clean the skin sur-
face thoroughly before applying.12,13
Mica, the basic component of this
type of makeup, is usually found in ig-
neous rocks, such as granite and met-
amorphic rocks. The most abundant
Other
Soy protein: moisturizer
Coenzyme Q10 + Vitamin E:
Antioxidant
Barley, chamomile: Anti-inflammatory
Immucell (Saccharomyces cerevisiae):
Stimulates skin defenses
Silicones: To make it water resistant
varieties of mica, a silicate, are biotite
and muscovite. Mica powder gives
makeup a smooth, fine texture, better
adhesion and color and protection
against UV rays. It can be mixed with
water and glycerol or incorporated in
creamy emulsions. Another ingredi-
ent often used in makeup is bismuth
hexachloride; however, this could ag-
gravate rosacea skin due to its poten-
tial to cause inflammation and itching.
As far as possible, makeup formula-
tions should be natural and chemicals
should be avoided.14
Eyelid cosmetics must be carefully
selected. A pencil is preferable to a
liquid eyeliner. Pencils are made from
waxes and contain fewer preserva-
tives and pigments. Preservative pig-
ments and latex in liquid eyeliners can
aggravate ocular rosacea.15 Eyeshad-
ows should preferably be pale, earthy
colors, and not be glittery or pearly.
Mascara should be hypoallergenic. Ex-
perience indicates that black is the col-
or that produces the least reactions,
while red tones most induce them.12
Emollient and moisturizing cosmetics
There are many reports supporting
the importance of moisturizing the
skin of rosacea patients. Evidence
shows that improving the skin barrier
function reduces rosacea flares, de-
creases erythema and desquamation
and improves skin tone. Moisturizing
can also help to reduce inflammato-
ry lesions and after 24 to 48 weeks
may have a beneficial impact on facial
telangiectases. Cosmeceuticals that
help prevent redness and skin intoler-
ance in rosacea may act as mucilages
by providing a protective layer on the
skin and minimizing barrier damage.
These include aloe vera and prickly
pears or cactus tuna, which, present-
ed in the form of emollients, promote
skin flexibility, confer better texture
and reduce the feeling of dryness or
tension. A function of the emollient
product is the replacement of the
permeability barrier components; this
is how they reduce irritation. Adding
ingredients such as panthenol (Vita-
min B5) helps to restore the stratum
corneum, giving the skin softness,
smoothness, relief from the feeling
of tension and greater flexibility.15,16
The preferred cosmetic form is emul-
sion because it is easy to spread.
Emollients should be applied without
massaging and in a thin layer to avoid
occlusion. Water-in-oil (W/O) emul-
sions are suitable for very dry skin.
This type of vehicle usually contains
mineral or petrolatum oils, which pro-
vide them with a greasy feel; they are
semi-occlusive and can be cosmeti-
cally unacceptable. Emollient emul-
sions with fluid vehicles of oil in water
(O/W) are lighter, evaporate quickly
and give a fresh sensation. However,
they can sometimes aggravate the
perception of tension in sensitive skin
due to the hygroscopic action of their
active constituents.
The choice of the right vehicle for
the type of skin is crucial. Emollient
products indicated for sensitive skin
with rosacea must meet the condi-
tions mentioned above: few preser-
vatives, fragrance-free and colorless,
with silicones or dimethicones.14
Cosmeceutical substances to reduce
facial flushing
Facial erythema is a consequence of
inflammatory factors involving prosta-
glandins and cyclooxygenases which
lead to vasodilation and lymphocyte
recruitment. Consequently, cosme-
ceuticals intended to reduce flushing
316
must have anti-inflammatory, vaso-
constricting and skin barrier strength-
ening (moisturizing) properties. Some
of the components with anti-inflam-
matory effect, known as natural, are
bisabolol and allantoin. Bisabolol is
obtained from German chamomile
(Matricaria recutita), a volatile oil. Al-
lantoin is obtained naturally from the
root of Symphytum officinale or by
synthesis through the alkaline oxida-
tion of uric acid. Both drugs reduce
facial flushing and are included in
many cosmeceutical formulations.16
There are water-attracting protein
substances such as collagen, elastin,
hyaluronic acid, placenta extract and
ceramides. Collagen and elastin are
high molecular weight proteins, which
is why their penetration into the skin
layers is difficult; however, they can
absorb water and thus improve the ap-
pearance of the skin although they can-
not replace the collagen fibers found
in the dermis. Hyaluronic acid is the
basic component of the amorphous
intercellular matrix of the dermis and
it acts as a cement for dermal constitu-
ents. Hyaluronic acid is an excellent hy-
groscopic agent (water trapper), which
is why it is increasingly being used in
moisturizing compounds.
Among the cosmeceuticals added
to emollient products that prevent
transepidermal water loss (TEWL)
recommended for sensitive skin are
wheat germ extract (Triticum vul-
gare), sericin, which forms a film with
keratin, quinetins and ceramides. The
latter derive from fatty acids; they
represent 50% of the lipids of the
stratum corneum and are widely used
in cosmetic creams for their skin bar-
rier repair properties.16-18
Polyunsaturated oils are essential
fatty acids. They are precursors of the
synthesis of prostaglandins, through
the collection of free radicals, and the
regeneration of tissues. These include
evening primrose, borage, jojoba and
rosehip.
Among the regenerators are
cephalins (lipid regenerators), cera-
mide 3 (regenerates the lipid barrier),
glycoproteins (cellular regenerator
with phagocytic activity), Saccharomy-
ces lysate (activates and reactivates
cell regeneration, stimulates cellular
respiration) and glycosaminoglycans
(healing-regenerating). As mentioned
before, some mucilages, such as
those obtained from prickly pear or
from aloe, create a protective film on
the skin and contain water, mucopo-
lysaccharides, amino acids, glycosides
with anti-inflammatory properties im-
proving also the skin barrier function.
Panthenol or provitamin B5, a
pantothenic precursor component
of coenzyme A is another relevant
cosmeceutical substance for rosacea
due to an ability to improves the bar-
rier function. It is essential for cellular
metabolism and participates in the
biosynthesis of fatty acids and gluco-
neogenesis. Panthenol also increases
the amount of fatty acids on the skin
surface.2
Vitamin B3 (niacinamide or nico-
tinamide) is also worth mentioning.
It is an essential vitamin precursor of
endogenous enzyme cofactors. This
vitamin induces an increase in the
production of lipids and proteins, re-
ducing facial erythema and increasing
resistance to irritants, besides having
anti-inflammatory properties.2,3
Polyphenols such as green tea (Ca-
mellia sinensis), derivatives of ginkgo
biloba and St. John’s wort (Hypericum
perforatum), which are widely used
to reduce redness due to their an-
ti-inflammatory properties, are also
photoprotective as they reduce car-
cinogenic activity induced by solar
radiation. This is very useful in condi-
tions such as rosacea.4
Another cosmeceutical substance
that has been successfully used in
rosacea is licochalcone or licorice,
which is obtained from Glycyrrhiza
inflata. It is very well tolerated; and
its beneficial properties were shown
in a comparative study between
this cosmeceutic and metronidazole
gel.4,16,18
In-Office Dermocosmetic
Procedures on Sensitive Skin
Dermocosmetic procedures may also
be used to improve aesthetics in rosa-
cea. Peeling is a controlled irritation
of the skin. Peels can reach different
skin depths and may be followed by
healing processes. In sensitive skin,
peelings are only recommended in
specific cases; they must be very su-
perficial and carried out by specialists
with the strictest control.19
Glycolic acid or other alpha hydroxy
acids, such as mandelic acid, in concen-
trations of 20 to 35% can be applied
every 3 to 4 weeks. The acid should
not remain in contact with the skin for
more than 3 to 5 minutes. It causes ery-
thema, which lasts 1 to 4 days, followed
by fine scaling. After peeling, an alka-
line cream or gel mask is applied, cold
if possible to improve patient comfort
and minimize irritation.20-23
Masks. Masks have been in use for
many years and can provide a signifi-
cant beneficial psychological impact.
Masks are used in cosmetic dermatol-
ogy in different conditions. They are
generally plastic and flexible pastes
which are applied on the face. The
mask composition is adapted to the
skin conditions and masks can reduce
the inflammation and redness, may be
emollients, or refreshing. Creamy vehi-
cles or gels are preferred due to ease
of application and removal, as well as
317
for their non-occlusive and refreshing
properties. Masks are applied at the
end of a cosmetic treatment. They may
be indicated as a complement to medi-
cal treatment, either to reduce the heat
feeling of flushing or as a complement
to a procedure. For example, gauze
masks soaked in chamomile infusion,
gelled masks with active substances
acting on vasodilation, centella asiatica
(Gotu Kola), witch hazel, chestnut and
other botanicals may be used.19
In wet, viscous or creamy masks,
solvents do not evaporate but instead
remain on the skin fresh and malleable.
Wet masks are useful in erythematous
skin, because they combine emollient
and decongestive properties. They
are removed with compresses damp-
ened in water or in emollient lotions,
without friction.15
For patients with facial redness,
some authors such as Cordero4 also
recommend natural frozen yogurt
masks twice a week for 20 minutes,
afterwards removed with moistened
cotton. In general, the effect of the
mask is immediate. The surface of the
skin looks smooth, soft and paler, an
effect that patients highly appreciate.2
In the case of patients with rosacea,
it is necessary to avoid cosmetological
procedures with devices that rise the
skin temperature and release heat or
steam (heat masks, vaporization, etc.).3
Corrective cosmetics: ingredients
used in sensitive skin
The following are the most relevant
active ingredients for rosacea.
Depigmenting agents include arbu-
tin, a glycosylated derivative of hydro-
quinone obtained from different plant
species, such as uva ursi leaves, morus
nigra and pear bark. Like hydroqui-
none, arbutin inhibits tyrosinase. Kojic
acid, a substance produced by the Koji
yeast (Aspergillum oryzae), native to
Japan, inhibits melanogenesis through
its binding to catecholase, the main
protein fraction of the tyrosinase com-
plex. Azelaic acid is obtained from the
lipophilic fungus Pityrosporum ovale. It
competitively inhibits tyrosinase and
the concentrations used range from
15 to 20%. Licorice extract contains
glabridin, which reduces pigmenta-
tion by inhibiting melanin formation.
It is anti-inflammatory and antioxidant.
Other depigmenting agents that may
be suggested for their low irritation or
sensitization capacity are alpha-arbutin,
Melfade™ J (Centerchem, Pentafarm,
Gigawhite™ (Centerchem), adenine,
aluminum silicate, Azeloglycina™ (potas-
sium azeloyl diglycinate, Sinerga), Skin
Whitening Complex, saxifrage (Sarmen-
tosa saxifrage), blackberry (Morus alba),
skullcap root (Scutellaria baicalensis),
grape juice (Vitis vinifera), Aloesin
(Aloe or Aloe vera), beta-sitosterol
escin, green tea (Camellia sinensis),
chamomile (Matricaria recutita), flavo-
noids (genus Citrus), paper mulberry
(Broussonetia kasinoki and B. papyrif-
era), beta carotenes and extract of the
emblic fruit (Phyllantus emblica).12
Vitamins that can be incorporated
into cosmeceuticals include vitamin A
(palmitate), retinoids (retinaldehydes),
rosehip oil, vitamin E (d-alpha-tocoph-
erol), vitamin B5 (panthenol), vitamin
C (ascorbic acid, magnesium ascorbyl
phosphate), vitamin H (biotin), nicotin-
ic acid and provitamin B (pantothenic
acid). Within the group of vitamins, ret-
inol stands out in low concentrations
(0.005%) in creams or emulsions; but
its lower penetration capacity makes
its recommendation limited. However,
retinaldehyde, derived from retinol, is
considered an intermediate metabo-
lite in vitamin A metabolism and its use
could be beneficial, as appropriate.12
Another useful vitamin in patients with
sensitive skin is ubiquinone or coen-
zyme Q10. It is found in all living cells
within mitochondrial membranes. It has
antioxidant properties and good tissue
penetration, characteristics that have
widely increased its use in recent years
in anti-aging cosmetic preparations.
Alpha-hydroxy acids (glycolic, lac-
tic, malic, mandelic, tartaric, citric and
pyruvic acids) are compounds derived
from several plants. Glycolic acid is de-
rived from sugar cane, malic acid from
apples, tartaric acid from grapes and
citric acid from lemons. Lactic acid also
belongs to this group, although it is de-
rived from whey. These acids can all be
used in low concentration on sensitive
skins. Glycolic acid in concentrations
not exceeding 8% and at pH 4.5 to 5.5
can be used as a good moisturizer.12
Antioxidants come from plant ex-
tracts such as aloe, green tea, laven-
der, chamomile, calendula, jojoba oil,
tea tree oil, and aromatic oils derived
from eucalyptus, camphor, mint, and
jasmine.11 Aloe vera is widely used in
cosmetics to make creams, soaps and
shampoos. Mucilage is obtained from
the leaves of the plant, as a colorless
gel containing 99.5% water and a
complex mixture of mucopolysaccha-
rides, amino acids and minerals.
Other antioxidant free radical scav-
engers include vitamin E, mannitol, uric
acid, albumin, edelweiss (Leontopo-
dium alpinum) and ubiquinone (Q10);
reducers such as glutathione, vitamin
C and vitamin A; enzymes such as su-
peroxide dismutase, catalase, glutathi-
one peroxidase, oxidoreductases and
collagenase; metal chelating agents,
such as transferrin or lactoferrin; and
hydrogen donors, such as flavonoids
(lipid peroxidation), green tea and Thy-
mus vulgaris extract.
Kinetin, a synergistic combina-
tion of n-6-furfuryladenine, alpha-li-
poic acid and ascorbyl magnesium
phosphate, is another plant-derived
318
antioxidant substance that may be facial redness in rosacea. However,
recommended. Also relevant is ide- the marketing blitz favoring the use
benone, a potent antioxidant consid- of these products and the turnover
ered an intelligent drug, and green among the population has increased
tea, which contains caffeine, tannin, the incidence of allergy, irritation and
theophylline, theobromine, methylxan- sensitivity. There is a suitable product
thine, adenine, nucleotides (adenine, for each type of skin, also taking into
guanine and cytosine), quercetin, chlo- account the degree of sensitivity of
rophyll, xanthophyll, carotene, vitamin the skin. It is necessary to advise pa-
B, catechins, vitamins C and E, flavo- tients with rosacea about use of these
noids, polysaccharides and fluoride.15 products and to do so we present
here some tables with indications on
Other active ingredients capable general, special, food, medicine, envi-
of stimulating cell growth are Saccha- ronmental and local care (Tables 27-2
romyces lisate, Colostrum whey, lipo- to 27-5). Guidance should focus on
peptides, polypeptides and elements the use of cleansers, photoprotectors,
with Cu, Mn, Se, Zn and Au. They have moisturizers, cosmeceutical active
a moisturizing, repairing, protective substances and facial masks. Cleans-
effect against UV radiation and pro- ing should be carried out with prod-
mote healing.16 ucts that respect the skin’s natural
balance, without altering it, that are
Cosmeceutical products play a key capable of removing all traces of dirt
role in the control and treatment of and make-up in a gentle way. If deep-
Table 27-2. General treatment considerations for rosacea
Avoid everything which may cause skin redness (spicy foods, red wine, sudden changes in temperature,
steam, saunas, steam baths, plentiful meals, stress, heat, sun, medicines such as aspirin, inadequate
cosmetics, among others).
Spray thermal water in case of redness and take it on outdoor walks and physical activities.
Select the right cleaner, moisturizer and photoprotector following the recommendations in the tables
below.
Avoid frequent rotation of cosmeceutical products; once tolerance has been achieved, keep it over time.
Use specific topical and systemic medications for the type of rosacea.
Including dermatological treatments, such as pulsed light, lasers, masks (with firm neutral yogurt) may
be helpful.
Use hypoallergenic, non-comedogenic products for sensitive or intolerant skin.
Table 27-3. Recommendations on topical ingredients Table 27-4. Recommendations on photoprotectors

Give preference to botanical and mineral products. Select sunscreens with A and B ultraviolet filters.
Avoid common allergens and irritants. Give preference to hypoallergenic products. Physical filters are better tolerated (titanium dioxide and zinc oxide).
Avoid menthol, alcohol or ethanol, eucalyptus or cloves, hammamelis water among ingredients. Photoprotectors must contain protective silicones (dimethicone or cyclomethicone).
If solvents are necessary, choose high glycols, as polyethylene glycol, which do not penetrate the stratum Choose a soft makeup base that is easy to apply. select a formulation of sun protectors with A and B
corneum. ultraviolet filters.
Avoid anionic surfactants such as sodium lauryl sulfate. Use syndets or micellar solutions. Avoid water-resistant photoprotectors and thick makeup bases, which are difficult to apply or remove
Choose preservatives with low sensitizing potential (paraben-free). If possible, they should contain without irritating agents.
silicones or dimethicones. Preferably use oil-free sunscreens.
Avoid fragrances and oils.
Add natural calming or anti-inflammatory agents to the formula. Choose formulas with few ingredients
and high quality. protect the skin and correct the skin ucts mainly derived from plants and
Do not use scrubs or harsh cleansers or rub the skin (gentle cleansing). barrier deficit present in rosacea. Be containing few chemical ingredients
cautious with peelings, which can be should be selected, predominantly
replaced by moisturizers or soothing physical barriers. The education of
Table 27-5. Recommendations on cosmetics masks applied in the doctor’s office, or patients in skin care and treatment is
very superficial chemical substances of paramount importance.
Select cosmetics that are easily removable with water. Avoid waterproof cosmetics. in some specific cases, without using
Use recently purchased cosmetics (discard old ones). steam or microdermabrasion. Once General disease control requires
Select cosmetics with no chemical photoprotectors. or twice a week, it is also advisable to not only cosmeceutical products, but
Select cosmetics with no more than 10 components. apply an anti-inflammatory mask and also topical and oral medications that
Make-up preferred: Cream/powder or liquid, silicone-based (cyclomethicone, dimethicone) foundations. to use thermal waters. must be duly prescribed. In addition,
Green foundations/concealers neutralize redness. light therapies, lasers and even botu-
Avoid nail polish (especially intense or redcolors). In sensitive skin, extreme caution linum toxin, are daily showing greater
Recommend black eyeliners and eyelash mascara. should be taken when using creams benefits in this disease.
Choose light and earth-colored eye shadows and pencil eyeliner (avoid brushes). with fruit acids (AHA) and retinoids,
among others. Although they have a References
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er cleansing is required, exfoliants Physical sunscreens with titanium worsen sensitivity. Tolerance testing en la rosácea. In: Piquero-Martin J,
should not include scrubs, as these dioxide and zinc oxide should contain and risk/benefit assessment are re- Herane MI. Rosácea y afecciones
would mistreat the epidermis. Those a siliconized vehicle. With cosmetics, quired. Women with this type of skin relacionadas. Creser Publicidad
containing micro-particles should be use light makeup bases and loose should use specific hypoallergenic 2013 ed. 2007, Caracas.
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fully remove dead cells. Select syn- tector. In addition, green camouflage pidic film and soothe redness. Prop- 2. Costa A. Tratado Internacional de
det-type cleaners that do not contain may be advised to neutralize redness. er care of sensitive skin will enhance Cosmecéuticos. Rio de Janeiro:
sodium lauryl sulfate or include it in Emollients and moisturizers should be its resistance to external irritation, Guanabara Koogan, 2012.
very low concentrations. lightweight and applied twice daily to thus improving its appearance. Prod-
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 3. Perez Atamoros F, Enriquez Merino
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6. Kligman AM. Human models for
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José L. López Estebaranz
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signs, such as erythema, flushing and
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Recently, light systems have begun
to be used in the treatment of active
forms of rosacea. The type of laser and
light source to select depends on the
type of lesion and target.
TREATMENT OF THE VASCULAR
COMPONENT
For the treatment of the vascular
component of rosacea, vascular lasers
and light sources have been used to-
gether with topical treatments.3 The
vascular component is made up of
fine telangiectases, from 0.1 to 1 mm
in diameter, and facial erythema, for
which both lasers and light sources
are the preferred treatments. The tar-
get in this type of lesion is the blood
vessel, whose primary chromophore
is oxyhemoglobin. The main oxyhe-
moglobin absorption peaks are in
the range of visible light at 542 and
577 nm. Lasers emitting at this wave-
length will produce photocoagulation
in the blood vessels, destroying them,
which also contributes to a reduction
of the associated flushing. The most
commonly used lasers for the removal
of rosacea vascular lesions are potas-
sium titanyl phosphate (KTP), pulsed
dye laser (PDL), neodymium yttrium
aluminum garnet (Nd:YAG), 960-980
nm diode and intense pulsed light
(IPL) systems being PDL, KPT and
IPL the most widely used.4 The char-
acteristics of these light systems are
shown in Table 27-5. Lasers in the in-
frared spectrum, such as diodes and
Nd:YAG, are used to treat deeper or
larger caliber vascular lesions. In all
cases, the treatment has to be adapt-
ed to the size of the vessels, to the
skin phototype and to the patient’s
willingness to tolerate transient pur-
pura. In general, the thinnest vessels
and erythema are the most difficult to
eradicate. Shorter pulses and higher
energy densities or fluences are re-
quired.
Pulsed dye lasers (PDL), 585-595 nm
The initial PDL lasers were 575-585
nm and emitted short pulses that last-
ed microseconds. At present, the lat-
est models allow lengths greater than
595 nm and longer pulses, up to tens
of milliseconds (msec). Traditionally,
PDL sessions have been used every
3-4 months to effectively eliminate er-
ythema and telangiectases. Using 585
nm PDL and 450 microsecond pulses,
more than 75% of vascular lesions are
eliminated after 3 sessions. The pa-
rameters commonly used are spots
of 7-10 mm, pulses of 6 msec and flu-
ences of 6-9 J/cm2 with cooling of the
epidermis. Lower energies are used
with larger spot sizes.5 The higher
the chromophore (hemoglobin), the
lower the fluences needed. In high
phototypes, lower fluences and lon-
ger pulse durations are required to
avoid causing adverse effects to the
epidermis. Logically, the parameters
can vary and be adjusted according
to the type and brand of the device
used. Telangiectases can also be elim-
inated using purpuric or subpurpuric
parameters, depending on the pa-
tient’s preferences. In general, pulses
of 6 msec or greater are subpurpuric,
while pulses of 1.5 to 3 msec produce
purpura. These latter parameters are
generally more effective and fewer
sessions are required. In vascular le-
sions, the optimal endpoint of a treat-
ment with these laser systems is to
objectively lighten the lesions, or to
321
create a bluish tone of coagulation or
purpura. The larger the diameter of
the vessels, the greater the pulse du-
rations and fluences should be.
Often the vessels located in the
nostrils are more difficult to eradi-
cate or haver erythema that recurs
more easily. In a study on patients
with nasal telangiectasias resistant
to treatment with PDL or KTP, using
a PDL of 595 nm and long pulses of
40 msec and double passes, total
lightening was achieved in 55% while
in the remaining 45% the reduction
was more than 80%.6
The background erythematous
component may be treated with short
pulses and variable fluences before
or after removing telangiectases. It is
important to apply cold pads or packs
after treatment in order to reduce the
subsequent inflammation.
KTP Lasers (532 nm)
This type of laser, with a 532 nm wave-
length which selectively targets he-
moglobin enables the treatment of
capillary vessels and telangiectases
with minimal generation of purpura.
However, it is less effective in deeper
and thicker vessels, and it is necessary
to take extreme caution in dark pho-
totypes due to the risk of epidermal
damage and post-treatment depig-
mentation. In a split-face study com-
paring KTP and PDL lasers (n=15), 85%
of the vascular lesions were lightened
after 3 sessions with the KTP laser
compared to 75% with the PDL laser.7
Nd:YAG Laser (1.064 nm)
Although less specific for hemoglobin,
the Nd:YAG laser is effective for the
treatment of larger and deeper vas-
cular lesions, such as reticular veins
or refractory nasal veins. The risk of
post-treatment scarring is greater with
this type of laser and energy densities
should be conservative. In a study in-
volving 15 patients with facial telangi-
ectases treated on days 1 and 30 with
a Nd:YAG laser (fluences: 120 to 170 J/
cm2; pulse duration: 5 to 40 msec; spot
size: 3 mm), 73% (11/15) showed moder-
ate improvement on days 0 to 30, and
80% improvement at three months
post-treatment.8 More recently, a ma-
jor or excellent improvement was re-
ported in 50% of 66 patients with ETR
and PPR. Better results were seen in
ETR than in PPR, and in mild or mod-
erate rosacea compared with severe
disease. This laser is administered in
sessions every 3 to 4 weeks with 2 - 3
mm spot, fluences from 100-160 J/cm2
and pulses from 15-20 msec.9 Results
were divergent in two split-face stud-
ies performed to compare PDL and
Nd:YAG lasers in rosacea; one found
superior efficacy with 595 nm PDL
along with more pain while the oth-
er showed better results on the side
treated with Nd:YAG (the difference
did not reach statistical significance).10,11
Table 27-6. Lasers and light sources used to remove the vascular component ing rosacea in general. It has been similar efficacy rates.15 According to
of rosacea proven effective in the elimination Sum Lim et al., higher efficacy rates
of telangiectases, erythema and were obtained among patients un-
Fluence Range (pulse even in papulopustular inflammato- der 40 years of age and those with
Laser type Wavelength range duration) ry lesions (Figs. 27-2 and 27-3).12,13 In more intense lesions in 50 ETR pa-
one study, 34 patients with ETR (er- tients treated with IPL (4 sessions
Pulsed dye 585-595 nm 2-7 J/cm2 1-40 msec ythema, flushing and telangiectases) every 3 weeks).16 Using an IPL and
KTP 532 nm 1-6 J/cm2 1-8 msec were treated with IPL (filter 560 nm, bipolar radiofrequency system in 21
Diode 960-980 nm 100-400 J/cm2 5-200 msec fluences 24 to 32 J/cm2). After 4 ses- patients with rosacea, Taub et al. ob-
Nd: YAG 1.064 nm 100-160 J/cm2 15-10 msec sions, an average reduction of 39% tained an improvement in telangiec-
IPL 500-1.200 nm 5-35 J/cm2 Pulses Single, Double, erythema on the cheeks and 22% on tases, erythema and flushing after 3
Triple, msec the chin was achieved, and IPL was to 4 sessions.17
associated with minimal adverse ef-
Diode lasers (960-980 nm) a steeper learning curve than lasers. fects.14 IPL was compared with the There are multiple IPL devices
Diode lasers are similar to Nd:YAG la- IPL is probably the most effective PDL laser in a split face study of pa- available in the market, all with very
sers but have a slightly lower risk of and useful light treatment for treat- tients with ETR (n=29). IPL provided variable parameters.
post-treatment scarring. Diode lasers
have very variable spots that allows
treatment of linear capillary vessels
(even those that are more resistant
and deeper) in a fashion similar to
Nd:YAG (Fig. 27-1).

Intense Pulsed Light (IPL) Systems

Unlike lasers, IPLs are light systems
that emit polychromatic light that is
not coherent with wavelengths rang-
ing from 500 to 1,200 nm. Filters are
used to block the lower part of the
light spectrum. For the treatment of
vascular lesions, filters in the range
of 550 to 570 nm are usually used.
IPL can emit single, double or triple
pulses within the millisecond range.
The application spots are larger
than those of lasers, allowing faster
treatment and greater depth. IPL
are very versatile systems but have Fig. 27-1. Facial telangiectases after a 980 nm diode laser session.
322
 Combined Treatments
Vasoconstrictors, such as brimoni-
dine gel 0.33, are being used before
applying lasers and IPL systems in
order to remove erythema prior to
the treatment of capillary vessels and
telangiectases. This approach has
been associated with greater effec-
tiveness and fewer local adverse ef-
fects. Pre-treatment with brimonidine
also produces less inflammation and
post-treatment edema and allows for
more selectivity.18
TREATMENT OF
PAPULOPUSTULAR LESIONS
AND ROSACEA ACTIVE FORMS
Fig. 27-2. Facial telangiectases and erythema in a patient with ETR. Before and WITH LIGHT SOURCES
after 3 sessions of IPL (filter 570 nm, double pulses and fluences of 16 J/cm2).. The effect of laser and light sourc-
es on papulopustular inflammatory
forms may be mediated by the re-
modeling and reorganization of al-
tered dermal connective tissue, as
well as by the inhibition of inflam-
matory mediators.19 The elimination
of Demodex folliculorum, which de-
stroys hair follicles, has also been
suggested as a possible mechanism.
This has been observed mainly with
lasers of longer lengths (Nd:YAG)
and with IPL.9 Papulopustular rosa-
cea has been treated with Nd:YAG,
IPL and pulsed dye lasers, with vari-
able results and always less efficacy
than reported in erythematotelangi-
ectasic forms. PDL lasers have little
Fig. 27-3. Active rosacea grade II lesions, together with erythema and telangi- effect on the inflammatory compo-
ectases, after IPL treatment. nent.20
323
Photodynamic therapy and light
systems involving red and blue light
have also been used on inflammato-
ry lesions of rosacea with variable
results.21 A case of granulomatous
rosacea resistant to conventional
therapy has been described which
responded well to 6 sessions of pho-
todynamic therapy with ALA 20%
and irradiation with light of 400-700
nm (630 nm filter).22
Recently, a system called biopho-
tonic therapy which uses red and
blue light together with a photo-
converting gel for the treatment of
moderate and severe forms of acne
and its scarring sequelae was suc-
cessfully introduced.23 Biophoton-
ic therapy has also been used with
good results in the treatment of ro-
sacea inflammatory forms (personal
communication).
TREATMENT OF PHYMATOUS
LESIONS
Phymatous rosacea is character-
ized by hyperplasia of the seba-
ceous glands and connective tissue.
This rosacea type is more frequent
among males, unlike the other forms
of rosacea. Phymas cause an import-
ant morphological and aesthetic al-
teration and may cause important
health and physical appearance
changes. They often have a psycho-
social impact and reduce patients’
quality of life.
 Rhinophyma is the most frequent
phymatous form, but phymas can also
affect the chin, cheeks, pinna and
forehead. There is no evidence that
any oral or topical treatment is effec-
tive in resolving or eliminating estab-
lished phymatous forms of rosacea.
For this reason, ablative procedures
are used to eliminate hyperplastic
tissue. Before the existence of lasers,
therapy relied on dermabrasion, cryo-
therapy, electrotherapy and surgical
excisions. The disadvantages of these
procedures are prolonged post-op-
erative recovery and adverse effects
which occur frequently and can be
long-lasting.24 Along with technolog-
ical development and the introduc-
tion of lasers in medicine, they began
to be used in this disease. The first la-
ser applied in the ablative treatment
of phymas was argon, an ablative la-
ser that causes coagulation but is not
very selective and thus could easily Fig. 27-4. Rhynophyma before and seven days after treatment with CO2 laser treatment.
leave permanent problems. The most
commonly used lasers at present are Light sources and laser systems are and active rosacea flares. New forms 2. Van Zuuren EJ, Fedorowicz Z, Car-
the 10,600 nm CO2 laser and the increasingly used procedures for the of light, such as biophotonic therapy, ter B, et al. Interventions for rosa-
2,940 nm Er:YAG.25 The appearance various symptoms and clinical signs of are being introduced. cea. Cochrane Database Syst Rev
of fractional ablative CO2 lasers has rosacea. They are very useful and are 2015; 4:CD003262.
reduced the possible side effects of often the only procedures with effica-
these systems (hyperpigmentation, cy. IPL systems and vascular lasers are 3. Mansouri Y, Goldenberg G. Devices
hypopigmentation and abnormal essential and very effective in the elim- References and topical agents for rosacea man-
scars) with excellent results (Fig. 27- ination of vascular alterations, while 1. Wilkin J, Dahl M, Detmar M, et al. agement. Cutis 2014; 94(1):21-25.
4). Surgical excision and subsequent the ablative CO2 and erbium systems Standard classification of rosacea:
fractional CO2 laser application also are the best system for eliminating Report of the National Rosacea So- 4. Clark SM, Lanigan SW, Marks R. La-
provides excellent results with few phymatous forms. IPL and Nd:YAG sys- ciety expert committee on the clas- ser treatment of erythema and tel-
adverse effects; in addition, this strat- tems have been successfully applied sification and staging of rosacea. J angiectasia associated with rosacea.
egy can be implemented rapidly.26 to papulopustular lesions of rosacea Am Acad Dermatol 2002; 46:584-7. Lasers Med Sci 2002; 17(1):26-33.
324
5. Bernstein EF, Kligman A. Rosacea
treatment using the new generation,
high-energy, 595 nm, long pulse-du-
ration pulsed dye laser. Lasers Surg
Med 2008; 40(4):233-239.
6. Madan V, Ferguson J. Using the
ultra-long pulse width pulsed dye
laser and elliptical spot to treat re-
sistant nasal telangiectasia. Lasers
Med Sci 2010; 25(1):151-154.
7. Uebelhoer NS, Bogle MA, Stewart B,
et al. A split-face comparison study
of pulsed 532 nm KTP laser and 595
nm pulsed dye laser in the treatment
of facial telangiectasias and diffuse
telangiectatic facial erythema. Der-
matol Surg 2007; 33(4):441-448.
8. Darradet DM, Hussain M, Goldberg
DJ. Millisecond 1064 nm neodymi-
um:YAG laser treatment of facial tel-
angiectases. Dermatol Surg 2003;
29(1):56-58.
9. Say EM, Gokan G, Gokdemir G.
Treatment outcomes of long-pulsed
Nd:YAG laser for two different sub-
types of rosacea. J Clin Aesthet
Dermatol 2015; 8(9):16-20.
10. Alam M, Voravutinon N, Warycha
M, et al. Comparative effectiveness
of nonpurpuragenic 595nm pulsed
dye laser and microsecond 1064nm
neodymium:yttrium-aluminum gar-
net laser for treatment of diffuse
facial erythema: A double-blind ran-
domized controlled trial. J Am Acad
Dermatol 2013; 69(3):438-443.
11. Salem SA, Abdel Fattah NS, Tan-
tawy SM, et al. Neodymium yttri-
um aluminum garnet laser versus
pulsed dye laser in erythemato-tel-
angiectatic rosacea: Comparison of
clinical efficacy and effect on cuta-
neous substance (P) expression. J
Cosmet Dermatol 2013; 12(3):187-194.
12. Schroeter CA, Haaf-von Below S,
Neuman HAM. Effective treatment
of rosacea using intense pulsed
light systems. Dermatol Surg 2005;
31:1285-1289.
13. Svyatenko T, Starostina O. New op-
portunities of IPL-therapy in com-
plex treatment of the rosacea vas-
cular forms. Georgian Med News
2015; 243:62-66.
14. Papageorgiou P, Clayton W, Nor-
wood S, et al. Treatment of rosacea
with intense pulsed light: Signifi-
cant improvement and long-last-
ing results. Br J Dermatol 2008;
159(3):628-632.
15. Neuhaus IM, Zane LT, Tope WD.
Comparative efficacy of nonpur-
325
puragenic pulsed dye laser and
intense pulsed light for erythema-
totelangiectatic rosacea. Dermatol
Surg 2009; 35:920-928.
16. Lim HS, Lee SC, Won YH, et al. The
efficacy of intense pulsed light for
treating erythematotelangiectatic
rosacea is related to severity and
age. Ann Dermatol 2014; 26(4)491-5.
17. Taub AF, Devita EF. Successful
treatment of erythematotelangiec-
tatic rosacea with pulsed light and
radiofrequency. J Clin Aesthet Der-
matol 2008; 1(1):37-40.
18. Micali G, Gerber PA, Lacarrubba
F, et al. Improving treatment of er-
ythematotelangiectatic rosacea
with laser and/or topical therapy
through enhanced discrimination of
its clinical features. J Clin Aesthet
Dermatol 2016; 9:30-39.
19. Adamic M, Troilius A, Adatto M, et
al. Vascular lasers and IPLs: Guide-
lines for care from the European
Society for Laser Dermatology
(ESLD). J Cosmet Laser Ther 2007;
9:113-124.
20. Berg M, Edström DW. Flashlamp
pulsed dye laser (FPDL) did not
cure papulopustular rosacea. La-
sers Surg Med 2004; 34:266-268.
21. Katz B, Patel V. Photodynamic ther-
apy for the treatment of erythema,
papules, pustules, and severe flush-
ing consistent with rosacea. J Drugs
Dermatol 2006; 5:6-8.
22. Baglieri F, Scuderi G. Treatment of
recalcitrant granulomatous rosacea
with ALA-PDT: Report of a case.
Indian J Dermatol Venereol Leprol
2011; 77:536-536.
23. Antoniou C, Dessinioti C, Sotiriadis
D, et al. A multicenter, randomized,
split-face clinical trial evaluating the
efficacy and safety of chromophore
gel-assisted blue light photothera-
py for the treatment of acne. Int J
Dermatol 2016; 55(12):1321-1328.
24. Sadick H, Goepel B, Bersch C, et
al. Rhinophyma: Diagnosis and
treatment options for a disfiguring
tumor of the nose. Ann Plast Surg
2008; 61:114-20.
25. Madan V, Ferguson JE, August PJ.
Carbon dioxide laser treatment of
rhinophyma: A review of 124 pa-
tients. Br J Dermatol 2009; 161:814-8.
26. Kassir R, Gilbreath J, Sajjadian A.
Combination surgical excision and
fractional carbon dioxide laser for
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Plast Surg 2012; 1(1):36-40.
Rosacea is a chronic inflammatory
condition that manifests n the con-
text of an altered innate immune
response. It is characterized by hy-
perreactivity and hypersensitivity of
the skin to different stimuli, which
trigger the appearance and per-
sistence of facial erythema, telangi-
ectases, papules and inflammatory
pustules, the latter with intermittent
episodes of exacerbation and remis-
sion that affect the quality of life of pa-
tients.1 Treatment includes avoiding
triggers, skin care, photoprotection
and restoration of the skin barrier,
as well as topical and systemic medi-
cation. Besides light therapy such as
intense pulsed light and lasers, com-
plementary treatment includes the
use of chemical peels, cauterization
of telangiectases and, more recently,
the still unapproved (off label) use of
botulinum neurotoxin.1,2
CHEMICAL PEEL
This technique removes different lay-
ers of skin by applying a caustic or cor-
rosive chemical agent for therapeutic
and cosmetic purposes. There is sci-
entific evidence that chemical peels
have several therapeutic effects on
the skin: anti-aging, depigmenting,
comedolytic, antibacterial, sebaceous
secretion modulator and photocar-
cinogenesis preventive.3 Due to the
mentioned effects, chemical peeling
is indicated for the management of fa-
cial wrinkles, facial photoaging, active
Other Complementary Treatments
Carlos Montenegro
acne and rosacea, hyperpigmenta-
tion (such as melasma and secondary
inflammation), multiple actinic kera-
toses, actinic cheilitis, xanthelasma,
seborrheic keratoses, flat warts and
atrophic scars, among others.3 There
are several types of chemical peels,
from the most superficial, which in-
volves only the stratum corneum, to
the deeper peels that reach the re-
ticular dermis (Table 27-7). Several
chemical agents are also used, de-
pending on the condition and the
desired depth (Table 27-8). Chemical
peels are not often recommended
owing to the inflammatory nature of
rosacea. However, its use has been
reported. Peeling is indicated in re-
calcitrant PPR and PR. The most fre-
quently used chemical agents are
salicylic, lactic, glycolic and mandelic
acids, in concentrations that produce
only superficial or very superficial ex-
foliation.3,4
Table 27-7. Chemical Peel
Classification
Very Superficial: stratum corneum
Superficial: up to basal layer
Medium: up to papillary dermis
Deep: up to reticular dermis
326
Salicylic Acid
Salicylic acid is a lipid-soluble be-
ta-hydroxy acid that has been used
for more than two thousand years to
treat various skin disorders. Its abili-
ty to exfoliate the stratum corneum
makes it a good agent for superficial
chemical peels. It is a dermolytic, i.e.,
it breaks the intercellular junctions
(desmosomes).5 The main indications
for salicylic acid peels are acne vul-
garis, papulopustular and hyperplas-
tic rosacea, melasma, photodamage,
freckles and lentigines. Several sci-
entific studies show that peeling with
salicylic acid is effective and safe in
all Fitzpatrick skin phototypes.5 Apart
from its exfoliating effect, salicylic
acid has analgesic, anti-inflammatory
and antimicrobial properties; it also
stimulates fibroblasts, leading to an
improvement of the vascular compo-
Table 27-8. Agents for Chemical
peels in Rosacea
Very Superficial Superficial
Salicylic acid (10%) Salicylic acid (20-30%)
Glycolic acid (20%) Glycolic acid (30-50%)
Lactic acid (2%) Lactic acid (5-10%)
Mandelic acid (20%) Mandelic acid (50%)
nent of rosacea. Three to four peels
using 20-30 % salicylic acid are sug-
gested at intervals of 3-4 weeks for
ETR and 2-3 peels of the same con-
centration for RPP.3-5
Glycolic Acid
Glycolic acid is a water-soluble al-
pha-hydroxy acid that easily pene-
trates the skin, as it has the lowest
molecular weight of all alpha-hydroxy
acids. Commercial peeling formula-
tions are partially neutralized (higher
pH) in buffered or esterified solutions.
These formulations are available in var-
ious concentrations which range from
20% to 70%. The higher the concen-
tration and the lower the pH, the more
intense the exfoliation. In general, gel
formulations require longer penetra-
tion time and are easier to control.6
In 2009, Fabbrocini classified glycolic
acid chemo-exfoliations as very super-
ficial (30%-50%, applied for 1-2 min-
utes), superficial (50%-70%, applied
for 2-5 minutes) and medium depth
(70%, applied for 3-15 minutes).7 Chem-
ical peel with glycolic acid has anti-in-
flammatory, keratolytic and antioxidant
effects. Histological and histochemical
studies show that glycolic acid peels
increase dermal glycosaminoglycans
and collagen production through a di-
rect effect on fibroblast proliferation.8
Lactic Acid
Lactic acid behaves similarly to glycolic
acid, but its higher molecular volume re-
sults in lower penetration and less irrita-
tion. Because it is better tolerated, lactic
acid peeling is recommended for sen-
sitive skins. Lactic acid keeps the horny
layer healthy and well formed, increases
hydration at dermal and epidermal level,
increases dermal thickness by hydration,
and favors the increase of collagen and
the production of glycosaminoglycans
essential for the formation of hyaluron-
ic acid and the retention of humidity.8,9
Lactic acid peels are indicated in the
management of papulopustular rosacea
and can be used in 2% concentration by
applying 1 to 2 layers the first time, and
increasing the layers every 2 weeks.9,10
Mandelic Acid
Mandelic acid (MA) is an alpha-hy-
droxy acid, with a molecular size larger
than that of glycolic acid. It produces
less irritation than GA, is antiseptic and
erythema is predictable and gradual.
Mandelic acid peeling improves the
general condition of the skin and is rec-
ommended for acne and mild papulo-
pustular rosacea. It can be used in 30%
to 50% liquid or gel formulation.9,10
CAUTERIZATION OF
TELANGIECTASES
Cauterization is a clinical term that re-
fers to the burning of a part of the body
in order to destroy altered tissue. Facial
telangiectases, commonly known as
“spider veins,” are small, visible, super-
ficial vascular dilations. Their caliber
ranges from 0.1 to 1 mm. The thickness
of the epidermis varies from 0.05 to 0.3
mm; the epidermal layer lacks vascular-
ization as blood and lymphatic vessels
settle at dermal level. Facial telangiec-
tases can appear as an isolated entity or
in the context of another dermatolog-
ical process, such as rosacea, immune
diseases, or also associated with hepa-
topathies or other disorders. On the
face, telangiectases mainly affect the
cheeks, as well as the dorsum and flaps
of the nose. Morphologically, they can
be linear or spider-shaped, and may
appear in any region of the body and
at any age. Telangiectases are benign
lesions with a very good prognosis, but
those with facial location have a great
aesthetic impact.11
According to their clinical aspect,
telangiectases are subclassified in three
types: a) arboreal, b) spider (formed with
a central point), and c) linear or simple.11
The pathophysiological basis of these
lesions could be neo-angiogenesis in-
duced by factors such as anoxia, chem-
ical substances, physical factors and
infections. However, its etiopathogene-
sis is often multifactorial involving both
genetic and environmental factors.11 Ac-
cording to the guide for the treatment
of rosacea prepared by the the Iberi-
an-Latin American Group for the Study
of Rosacea (Grupo Ibero-Latinoameri-
cano de Estudio de la Rosácea, GILER),
the cauterization of telangiectases is
suggested as one of the complementa-
ry treatments of ETR.12
327
Electrocauterization
According to a clinical study conduct-
ed between 2009 and 2014 on 25 pa-
tients, hand cautery is a safe, effective,
and low-cost tool for the treatment of
superficial telangiectases and small
lesions.13 In that study, a hand cautery
was applied to each telangiectatic
vessel, using a 30 G tip. This led to a
temporary heat elevation of ~ 800 °C
for milliseconds, using low- current (1-2
A) energy conversion. The complete
vessel cauterization was performed by
repeated applications of the tip along
the full length of the visible vessel. The
procedure did not require local anes-
thesia and was well tolerated by the
patients. In most cases a single session
was enough to remove the telangiec-
tatic vessel; however, sometimes 2 or
3 consecutive sessions were needed,
with a 3- week interval. Immediately af-
ter treatment, an ice patch was used to
cool the area, and an antibiotic cream
containing fusidic acid with hydrocor-
tisone was applied to the skin for 1 to
3 days to minimize bruising and ery-
thema.13 The following results were ob-
tained. Twenty-two out of 25 patients
(88%) reported a complete resolution
of telangiectases performed with man-
ual cauterization. In 5 patients (20%), a
single application achieved complete
resolution of the lesions and in 10 pa-
tients (40%) re-treatment was required
after 3 weeks. Four patients (16%) re-
quired 3 consecutive treatments, of
whom 2 ( 8%) showed slight improve-
ment and one patient (4%) did not im-
prove at all. No major complications
were associated with this procedure;
two patients developed a white scar
which became inconspicuous after 3
months. Minor complications included
skin irritation and edema immediately
after treatment which were resolved
in 2-3 days without intervention. The
main risks associated with hand cau-
tery are punctiform scars, small white
skin scars or texture changes, as well
as the possibility of recurrence.13
BOTULINUM NEUROTOXIN
Botulinum toxin is the exotoxin of the
anaerobic, spore-forming microorgan-
ism Clostridium botulinum. It is a dou-
ble-stranded polypeptide consisting of
a light chain of 50 kD and a heavy chain
of 100 kD joined by a disulfide bridge.
So far 8 serotypes have been identi-
fied, named from A to G. The sero-
types are functionally and structurally
similar, and their amino acid sequences
have a high degree of homology. Types
A, B, E and F are the main serotypes
affecting humans. Type A is the most
powerful, and its effects are long-last-
ing, making it the most widely used for
therapeutic purposes. It is a powerful,
highly specific neuromuscular inhibitor,
which produces chemical denervation
by blocking the release of acetylcho-
line in the motor end-plate.14,15
The efficacy of botulinum neurotox-
in type A (BNTA) was examined in sev-
eral patients with recalcitrant rosacea.
Two Caucasian patients received in-
tradermal injections with BNTA micro-
drops, 0.5 cm apart, into the glabella or
cheeks. The total dose was 10 to 11 units.
Patients reported an improvement in
symptoms within 2 weeks of treatment
and the effects lasted up to 4 months.
Two Korean patients underwent two
intradermal BNTA treatment sessions
with an interval of one week. The total
dose of BNTA in the 2 sessions was 50
units for the first patient and 40 units
for the second patient. In each session,
the cheeks, chin and supraciliary region
were injected. The improvement of ro-
sacea facial erythema was evident one
week after the second treatment and
lasted for three months. The only side
effect reported was mild pain during
injection.14,15 Dayan et al. carried out a
study in 13 patients with rosacea who
had an intradermal injection of botuli-
num toxin A in each cheek, with a dose
of 8 to 12 U per cheek. The result was
a reduction in flushing, erythema and
inflammation within one week. The
effect persisted for three months and
there was no side effect. The authors
suggest that the mechanism at work
is related to a neurogenic component
associated with vascular dysfunction,
inflammation and sebaceous activity.
Botulinum toxin chemical denervation
appears to interfere with normal ace-
tylcholine signaling pathways and may
provide symptomatic relief to patients
with severe facial flushing. Because ro-
sacea is a chronic condition that is dif-
ficult to control and requires ongoing
treatment, toxin may be an innovative
option.16-18 The results of these small but
important pilot studies suggest that in-
tradermal injections of BNTA are safe
and effective in reducing persistent
flushing and erythema. Randomized,
controlled and larger studies are need-
ed to determine the optimal dose and
duration of effect. More research is also
needed to elucidate the mechanism by
which BNTA works in rosacea.16-18
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al. Glycolic acid treatment increases
type I collagen mRNA and hyaluron-
ic acid content of human skin. Der-
matol Surg 2001; 27(5):429-433.
9. Chemical peels and retinoids
http:// www.internationalrosacea-
foundation.org/peels_retinoids.php
consulted 03.03.2018.
10. Fischer TC, Perosino E, Poli F, et al.
Chemical peels in aesthetic derma-
tology: An update 2009. J Eur Acad
Dermatol Venereol 2010; 24(3):281-92.
11. Insua E. Tratamiento de telangiecta-
sias faciales. Revista Panamericana
de Flebología y Linfología 2009; 14(2).
12. Kaminsky A, Flórez-White M, Pique-
ro J, et al. Grupo Ibero-Latinoameri-
cano de Estudio de la Rosácea (Ibe-
rian-Latin American Group for the
Study of Rosacea, GILER) – Colegio
Ibero-Latinoamericano de Derma-
tología (CILAD, Iberian-Latin Ameri-
can College of Dermatology). Report
of the 2016 Iberian-Latin-American
Consensus about clinical and thera-
peutic classification of rosacea Med
Cutan Iber Lat Am 2016; 44(1):6-10.
13. Liapakis I, Englander M, Sinani R,
et al. Management of facial telangi-
ectasias with hand cautery. World J
Plast Surg 2015; 4(2):127-133.
14. Park K, Hyun M, Jeong S, et al.
Botulinum toxin for the treatment
of refractory erythema and flush-
ing of rosacea. Dermatology 2015;
230:299-301.
15. Yuraitis M, Jacob CI. Botulinum
toxin for the treatment of facial
flushing. Dermatol Surg 2004;
30(1):102-104.
16. Dayan S, Pritzker R, Arkins J. A new
treatment regimen for rosacea: On-
abotulinumtoxin A. Journal of Drugs
Dermatology 2012; 11(12):e76-79.
17. Bloom BS, Payongayong L, Mourin
A, Goldberg DJ. Impact of intra-
dermal abobotulinumtoxin A on fa-
cial erythema of rosacea. Dermatol
Surg 2015; 41(Suppl 1):S9-16.
18. Schlessinger J, Gilbert E, Cohen J,
Kaufman J. New Uses of Abobot-
ulinumtoxinA in aesthetics. Aesth
Surg J 2017; Vol 37(S1) S45-S58.
“Phyma” is a Greek word that defines
an edema, inflammation or protuber-
ance. It may appear in several areas
of the face: nose (rhinophyma), chin
(gnatophyma), forehead (metophy-
ma), eyelids (blepharophyma) or ears
(otophyma). It is a less common type
of rosacea, probably caused by a
sequel of chronic edema, increased
associated connective tissue, hy-
pertrophy of the sebaceous glands
as a result of rosacea and a chronic
inflammatory process.1,2 Although
these are benign lesions, physio-
logical, cosmetic, and psychological
aspects may be compromised in af-
fected patients.3 Rhinophyma is the
most common type of rhinophyma
and is associated with distortion and
obstruction of the nasal cavity, as
well as progressive disfigurement
leading to depression and anxiety.4
Consequently, treatment has a pos-
itive impact on patients’ quality of
life. In the early stages this may be
clinical and burgeoning phymas may
respond to oral antibiotics or oral
isotretinoin. However, in more ad-
vanced cases and in the final man-
agement of phymas, the best option
is surgical treatment aimed at remov-
ing hyperplastic sebaceous glands
and the consequent normalization
of the contour of the compromised
areas.2,3,5,6
Surgical treatment can be divid-
ed into two main groups: complete
Surgical Treatment of Phymas
João R. Antonio, Carlos R. Antonio, Lívia Arroyo Trídico
excision or incomplete excision fol-
lowed by re-epithelialization from the
remaining glandular epithelium. In-
complete excision techniques include
cryosurgery, dermabrasion, laser ab-
lation, and electrosurgery.2,7 Surgical
treatment options will be described
below, and since the vast majority of
phymas are rhinophymas, the tech-
niques will be described in this clinical
form; however, the same surgical op-
tions may be used on phymas in other
locations.
SURGICAL TECHNIQUES
Complete Excision
Surgical treatment is performed
through tissue excision with a scal-
pel. This allows the nose to be
sculpted in a controlled manner, a
large amount of sebaceous tissue to
be removed and the tissue removed
to be preserved for histopathologi-
cal examination as needed.8 Several
techniques for complete excision
with a scalpel are described in the
literature. In 1845, Johann Friedrich
Dieffenbach described cross or el-
liptical cuts in a vertical direction, on
the dorsum and nasal tip, and hor-
izontal cuts in the alar region. Lat-
er in 1851, Bernard von Langenbeck
carried out the excision of the nasal
329
skin up to the cartilaginous struc-
ture, allowing healing by secondary
intention. In 1912, Wood reported
total skin excision, followed by skin
grafting of the nasal defect second-
ary to treatment.7 The main limita-
tion of complete excision is heavy
bleeding, which reduces visualiza-
tion of the surgical field and makes
it difficult to control the depth of
excision and the local contour with
a flat surgical scalpel.8 Several tech-
niques of complete excision with a
scalpel are currently described, but
are generally associated with other
therapeutic options for controlling
bleeding.
Incomplete Excision
Incomplete excision consists of the
superficial removal of hypertrophic
tissues leaving the base of the seba-
ceous follicles, in order to support lo-
cal re-epithelialization.
Cryosurgery
Cryosurgery is performed in ses-
sions of 2-3 cycles of 15-30 seconds,
with a minute interval between cy-
cles. Sessions can be repeated ev-
ery 2 weeks. During application,
patients’ eyes should be protect-
ed with glasses. The results can be
observed after three or more ses-
sions, according to the intensity of
the rhinophyma.9 Among the main
advantages of cryosurgery to treat
rhinophyma are minimal bleeding,
discrete pain, no need for anesthe-
sia, preservation of nasal cartilage
and low recurrence rate. Disadvan-
tages include possible alterations
in local pigmentation, scarring, and
poor control of nasal depth and
contour. This surgical option is most
recommended for patients who are
not candidates for more invasive
surgical options, it has been asso-
ciated with good cosmetic results,
and is minimally invasive.10,11
Electrosurgery
Electrosurgery causes thermal tis-
sue damage through a high fre-
quency current, vaporizing the
tissue and allowing the surgeon to
maintain his/her visual field during
the procedure, so as to control tis-
sue destruction.12 The objective of
radiofrequency is to restore the
natural or acceptable shape of the
nose; therefore it is important to
observe the patient’s photos be-
fore the development of the gland
hypertrophy. The great advantage
of electrosurgery is the long-lasting
results and the absence, in the au-
thors’ experience, of recurrences af-
ter this surgical option. In addition,
it is a low-cost technique with excel-
lent aesthetic results.
 The electrosurgery procedure is
very painful. Therefore, the infraorbit-
al branch is blocked with tumescent
local anesthesia. The authors use ra-
diofrequency equipment with a sharp
round-ended tip in cut pattern and low
blend in power 3 (Fig. 27-5). The epi-
dermis and papillary dermis are com-
pletely removed, causing exulceration
with exposure of the dermis. This fa-
vors reepithelization, originating from
the remaining adnexa, by creating
migratory flows of keratinocytes and
melanocytes, and a new synthesis of
collagen and elastic fibers along with Fig. 27-6. Epidermis and papillary der- Fig. 27-7. Before treatment. Fig. 27-8. One week after electrosur-
neoformation of vessels and nerves mis removal to induce exulceration. gery treatment.
(Fig. 27-6). In the postoperative period,
an occlusive dressing with gauze and
paper adhesive tape is placed, which
must be changed daily. Total re-epithe-
lialization usually takes place within 15
to 20 days (Figs. 27-7 to 27-15).

Fig. 27-9. One month after electro- Fig. 27-10. Before treatment. Fig. 27-11. One month after electro-
surgery treatment. surgery treatment.
Fig. 27-5. Use of electrosurgery with
sharp round-ended tip.
330
Fig. 27-12. Before treatment.
Dermabrasion
Dermabrasion is used to improve the
nasal contour and the natural shape of
the nose. It is usually complementary
to other techniques to improve the fi-
nal result.13 The technique is quick and
precise; however, it produces consid-
erable bleeding.14 The authors used
“water sandpaper” to perform derm-
abrasion at the same surgical time as
electrosurgery, in order to optimize
results.
Laser
This treatment of rhinophyma con-
sists of the application of ablative
lasers to induce photothermolysis
that electrosurgery produces and
offers a discrete homeostasis, with
Fig. 27-13. One month after electro-
surgery treatment..
precise and gradual reduction of
tissue layer by layer. The results are
excellent; complications are scarce,
and both precision and healing are
optimal. Its greatest inconvenience
is that it requires a lot of time, as
the vascularization of the phyma
and the depth of the surgical site
hinder the rapid vaporization of the
tissue. Only a thin layer of tissue is
removed/steamed at each step of
the CO2 laser.13,14,16 Other laser op-
tions for treating rhinophyma have
been described, for example, the
non-ablative diode and pulsed la-
sers (Pulsed Dye Laser). Its rationale
is associated with the blood vessel
attraction and the probable vascular
etiology of this disease.1,17
331
Fig. 27-14. Before treatment.
surgery treatment.
Although there are several options
for the surgical treatment of phymas,
no technique is shown to be better
than another in terms of its advantag-
es so as to supersede the others. All
of them have both positive and neg-
ative aspects. Therefore, ideally, the
combination of techniques should be
individualized in each case in order to
obtain best results.
References
1. Moreira A, Leite I, Guedes R, et al.
Surgical treatment of rhinophyma
using carbon dioxide (CO2) laser
and pulsed dye laser (PDL). J Cos-
met Laser Ther 2010; 12(2):73-6
Fig. 27-15. Two months after electro-
2. Tüzün Y, Wolf R, Kutlubay Z, et al.
Rosacea and rhinophyma. Clin Der-
matol 2014; 32(1):35-46.
3. Rordam OM, Guldbakke KKS. Rhi-
nophyma: Big problem, simple solu-
tion. Acta Dermatol Venereol 2010;
11:188-89.
4. Kassir R, Gilbreath J, Sajjadian A.
Combination surgical excision and
fractional carbon dioxide laser for
treatment of rhinophyma. World J
Plast Surg 2012; 1(1):36-40.
5. Gupta AK, Chaudhry MM. Rosacea
and its management: An overview. J
Eur Acad Dermatol Venereol 2005;
19:273-285.
6. Elliot RAJ, Ruf LE, Hoen JG. Rhino-
phyma and its treatment. Clin Plast
Surg 1980; 7:277-288.
7. Karacor-Altuntas Z, Dadaci M, Ince
B, et al. A new surgical technique of
rhinophyma (gull-wing technique). J
Craniofac Surg 2015; 26(1):e28-30.
8. Prado R, Funke A, Bingham J, et al.
Treatment of severe rhinophyma us-
ing scalpel excision and wire loop tip
electrosurgery. Dermatol Surg 2013;
39(5):807-10. doi: 10.1111/ dsu.12193.
Epub 2013 Apr 5. Erratum in: Derma-
tol Surg 2013; 39(10):1556.
9. Kempiak SJ, Lee PW, Pelle MT. Rhi-
nophyma treated with cryosurgery.
Dermatol Surg 2009; 35(3):543-5.
10. Redett RJ, Manson PN, Goldberg
N, et al. Methods and results of rhi-
nophyma treatment. Plast Reconstr
Surg 2001; 107(5):1115-23.
11. Hsu CK, Lee JY, Wong TW. Good
cosmesis of a large rhinophyma af-
ter carbon dioxide laser treatment.
J Dermatol 2006; 33(3):227-9.
12. Erisir F, Isildak H, Haciyev Y. Man-
agement of mild to moderate rhi-
332
nophyma with a radiofrequency. J
Craniofac Surg 2009; 20(2):455-6.
13. Lian TS, Thompson RW. Manage-
ment of rhinophyma. Int J Head
Neck Surg 2016; 7(3):188-191.
14. Faris C, Manjaly JG, Ismail-Koch
H, et al. Rapid treatment of rhino-
phyma with powered microdebrid-
er. Case Rep Otolaryngol 2013;
2013:621-639.
15. Singh S, Peterson JD, Friedman PM.
Management of mild to moderate
rhinophyma using ablative fraction-
al photothermolysis. Dermatol Surg
2013; 39(7):1110-3.
16. Baró CJ, Gómez R, Serrat A. CO2
laser for the treatment of rhinophy-
ma. Acta Otorrinolaringol Esp 2015;
66(1):61-2.
17. Apikian M, Goodman GJ, Roberts
S. Management of mild to mod-
erate rhinophyma with a 1,450nm
diode laser: report of five patients.
Dermatol Surg 2007; 33(7):847-50.
The variety of the clinical manifesta-
tions of rosacea enables its classifi-
cation according to the predominant
lesions. These can be facial erythe-
ma, transitory or persistent; telangi-
ectases, and inflammatory papules
and pustules. In most cases, these le-
sions develop on a sensitive skin type,
along with other signs or symptoms,
such as dryness, scaling, edema,
plaques and glandular hypertro-
phy (phymas), and occasionally also
ocular compromise. These special
features, isolated or combined, are
what determine the classical forms
of rosacea: erythematotelangiectatic
(ETR), papulopustular (PPR), glandu-
lar hyperplasia/phymatous (PR), and
a fourth form, the ocular (OR) –which
is rarely the only expression of rosa-
cea– as an initial form of presentation
or as an occasional appearance in the
course of the other forms. To these
four classic forms, also called sub-
types, the rosacea study group of the
Colegio Ibero-Latinoamericano de
Dermatología (GILER, Iberian-Latin
American Group for the Study of Ro-
sacea) incorporates, as special forms,
infantile and extrafacial rosacea,
since their characteristics – age of
presentation and location – provide
them with enough specificity to do
so. While there is some discussion as
to whether granulomatous rosacea is
a form of rosacea, GILER considers
that it shares some clinical and his-
tological aspects with rosacea and
created. This guide is based on multi-
Chapter 28 ple studies in worldwide literature re-
garding the action of different drugs
(in topical formulations or for system-
Treatment
ic administration), the occasional use
of surgical techniques, and some pro-
cedures that, supported by state-of-
the-art technologies, may contribute
Guidelines
to alleviate some signs and symptoms.
The guide published in 2016 has
been updated based on the most
recent findings and conclusions. Nu-
merous publications have been thor-
Grupo Ibero-Latinoamericano de estudio de la Rosácea oughly examined, including Cochrane
evidence-based studies and reviews,
(GILER)* evidence to determine the effective-
ness and appropriateness of treat-
Iberian-Latin American Group for the Study of Rosacea ments -whatever their types and the
circumstances of their use- to which
therefore includes it as a variant. In corresponding to different forms of the GILER group’s experience with
all cases, the extent of lesion involve- presentation can be observed in the the Delphi method has been added
ment defines the degree of severity same patient. Consequently, it is im- (Fig. 28-1).
as mild, moderate or severe. possible to develop a treatment algo-
rithm that may lead in a predefined The treatment is complemented
Rosacea does not follow a se- order of steps to adopting the ap- with other care options and sugges-
quential course and, in addition, the propriate behavior in each case. For tions to prevent or improve situations
simultaneous development of lesions this reason, a therapeutic guide was that do not depend on drugs. GILER
includes them in two categories: gen-
* Chapter Acne, Rosacea and Related States of the Colegio Ibero-Latinoamericano de Dermatología (CILAD Ibe- eral care and dermocosmetic care.
rian-Latin American College of Dermatology). General care includes guidelines,
Coordinators: Ana Kaminsky (Argentina), Mercedes Flórez White (Colombia, USA), Jaime Piquero Martín suggestions or indications to patients.
(Venezuela), María Isabel Herane (Chile) y Juan Carlos Diez de Medina (Bolivia). The two most important general care
Members: Nélida Raimondo (Argentina), Edileia Bagatin (Brazil), Denise Steiner (Brazil), Emilia Zegpi (Chile), recommendations are avoidance of
Mónica Rivera (Colombia), Floribeth Madrigal (Costa Rica), Aurora Guerra (España), Diego del Ojo (España), triggers and protection during sun
Gilberto Adame (Mexico), Isabel Arias-Gómez (Mexico), Leonel Fierro-Arias (Mexico), Minerva Gómez (Mex- exposure. As both measures are part
ico), Jorge Moreno (Mexico), Luz Cantilo (Nicaragua), Lourdes Bolla (Paraguay), Roxana Maciel (Paraguay), of the medical practice, they will not
Betty Sandoval (Peru), Manuel del Solar (Peru), Elda Giansante (Venezuela), Ricardo Pérez Alfonzo (Venezuela). be developed in this guide.
333
Fig. 28-1. Treatment Guidelines (GILER).
334
 A special comment is needed
about dermocosmetic care, due to
its great therapeutic importance. The
term cosmetic began to be used in
the 18th century. It originates in the
Greek word kosmetikós, which means
“related to ornamentation”, and is
synonymous of makeup. It is current-
ly considered to include skin care as
well. In the 1980s, Albert Kligman in-
troduced the term cosmeceuticals in
order to classify cosmetic products
with active ingredients that modify a
biological response. In the Webster’s
dictionary, this term is defined as a
cosmetic preparation that has phar-
maceutical properties.
As a result of a greater under-
standing of the pathophysiology of
rosacea, especially as regards the
skin barrier, the role of sunlight, and
the effect of free radicals, knowledge
has spread in recent years about the
effect of these skin care products as
a complementary treatment for rosa-
cea in combination with conventional
therapy. These include cleansers and
moisturizers for sensitive skin, whose
ingredients improve the skin barrier;
335
sunscreens, especially physical ones,
with cosmetically acceptable formula-
tions; and cosmeceuticals with anti-in-
flammatory or antioxidant properties,
which have been found beneficial in
the treatment of rosacea.
The U.S. Food and Drug Adminis-
tration (FDA), which regulates cos-
metics, defines them –in agreement
with other government agencies– as
“a substance intended to be applied
to the human body for cleansing,
beautifying, or altering appearance,
without affecting the structure of the
body or its functions.” Consequently,
cosmetics, in combination with med-
icines, promote good therapeutic re-
sults by restoring or reinforcing the
skin’s barrier and protection.
While this guide represents a select-
ed summary of a large “library” aimed
at the treatment of rosacea, it is nothing
but the expression of the current state-
of-the art. Therefore, in no way does it
seek to establish a final and unchange-
able knowledge, it is subject to opinion
and, like all scientific knowledge, will be
modified and perfected in the future.
 „„ Chapter 29. Rosacea Comorbidities
Section 8
„„ Chapter 30. Neurogenic Rosacea

„„ Chapter 31. Rosacea and

Pregnancy
Specials Considerations „„ Chapter 32. Rosacea and
Skin Color

„„ Chapter 33. Rosacea and

Diet

„„ Chapter 34. Quality

of Life
Rosacea is a chronic skin entity ex-
tensively studied around the world.
It is characterized by four well-de-
fined subtypes, and is triggered by
the action of different environmental
factors (ultraviolet light, temperature
changes, seasonings, alcohol, as well
as mites and bacteria on the skin).
Although for many years it has been
associated with a series of systemic
symptoms and signs, the possible cor-
relation between rosacea and comor-
bidities is a recent approach.1 There is
definitely little evidence in this regard.
However, rosacea has been associ-
ated with depression, hypertension,
dyslipidemia, coronary artery disease,
allergies (airborne allergens, food), re-
spiratory diseases, gastroesophageal
reflux and gastrointestinal diseases;
metabolic disorders, urogenital dis-
eases, hormonal imbalance in women,
and other associations of lower inci-
dence, such as migraines, neurolog-
ical or musculoskeletal diseases, and
drug allergies.2
The analysis of rosacea subgroups
by severity reveals a dose-response
effect linking severity and comorbidi-
ty prevalence. When mild PPR is com-
pared with moderate to severe forms,
the latter are strongly associated with
hyperlipidemia, hypertension, meta-
bolic and cardiovascular diseases, and
gastroesophageal reflux. This charac-
teristic remains after adjusting by sex
and age.2
Chapter 29
Rosacea
Comorbidities
María I. Herane
Observational studies allow ex-
amination of these associations;
however, it should be noted that
associations can be explained by
shared lifestyles and genetic pre-
disposition. Some authors have
been researching the hereditary
factor in rosacea. A recent study
has found a strong familial predis-
position. 3 Other studies, in iden-
tical twins, suggest that half the
risk of developing rosacea and as-
sociated comorbidities are due to
genetic factors. 4 A recent genome
analysis has identified a rosacea
risk locus that was also associated
with type I diabetes mellitus (DMI)
and celiac disease. Several studies
have found shared genetic regions
in autoimmune disorders such as
rheumatoid arthritis, celiac disease,
multiple sclerosis and DMI. It can
therefore be inferred that rosacea
337
may be associated with autoim-
mune disorders.5
Associations between rosacea and
chronic systemic diseases might be es-
tablished on the basis of as-yet unclear
complex pathophysiological connec-
tions. Such a relationship is thought to
involve inflammatory conditions, such
as inflammatory cytokines, as well as
metabolic, immune and endocrine al-
terations. Associations between ro-
sacea and diseases involving barrier
tissues, such as the upper airways or
respiratory tract, and the gastroin-
testinal and urogenital epithelial -col-
onized by a diverse and site-specific
flora- lead to the suspicion that dysbi-
osis may be an additional pathogenic
factor in rosacea. A recent study ob-
served an increased risk of death due
to gastrointestinal diseases (mainly
liver disease) in patients with rosacea.6
In this chapter we will review the
main diseases that have been related
to rosacea.
UU Migraines
UU Neurological disorders/Depres-
sion
UU Gastrointestinal diseases
UU Cardiovascular risk
UU Autoimmune diseases/Metabolic
syndrome
UU Other
ROSACEA AND MIGRAINES
This relationship was first described
in 1976 in a small study of 137 cases in
which the association was found in
44% of patients with rosacea.7 A Swed-
ish study of 809 employees found that
27% of patients with rosacea experi-
enced migraines compared to 13% of
controls.8 In contrast, Spoendlin et al.9
found a slightly higher risk of develop-
ing rosacea in women with migraine.
Other authors only find this associ-
ation among women, and Berg and
Liden describe a significant increase
in co-occurrence of rosacea and mi-
graine in postmenopausal women.10
Migraine prevalence varies ac-
cording to ethnicity. The incidence
is higher among Caucasians (20%)
than among African Americans (16%),
which may be related to genetic vul-
nerability.11 A study on Saudi women
with skin type 4 and diverse ethnic
origins also shows low incidence of
migraine (16%).12 Egeberg et al. re-
cently expanded the study group to
a cohort of more than 4 million, of
whom 49,475 patients had rosacea
and a very high prevalence of mi-
graines, especially women. This risk
markedly increased in women over
50 years of age (7.3% reference pop-
ulation vs. 12.1% in patients with rosa-
cea).13 This study does not establish
any differences between the subtype
of rosacea (ETR, PPR or phymas) and
the prevalence of migraines. How-
ever, patients with ocular rosacea
presented 69% increased risk of
migraine, while the risk did not in-
crease in phymatous forms.13 In gen-
eral, no differences are found among
patients suffering migraines with or
without aura.9,13
The basis for the co-occurrence
of migraines and rosacea is unknown
and the association remains unclear.
However, vascular abnormality is cen-
tral to the pathophysiology of both
disorders. Patients with ETR often
have repeated episodes of prolonged
flushing on the affected facial skin;
several studies have shown an in-
crease in vascular endothelial growth
factor and receptors for vasoactive
intestinal growth factor in patients
with rosacea.14 In flushing, as well as
in rosacea exacerbation, there are
various triggers, such as physical ex-
ercise, exposure to ultraviolet light,
extreme hot or cold temperatures,
and intake of spicy foods and hot bev-
erages. Various migraine triggers are
also rosacea triggers, like stress and
alcohol. Further research is needed
to determine whether these triggers
occur simultaneously in rosacea and
migraine.
ROSACEA AND NEUROLOGICAL
DISORDERS/DEPRESSION
There is a prominent correlation
between rosacea and neurological
diseases such as multiple sclerosis,
Parkinson’s disease and dementia
caused by Alzheimer’s disease. Ac-
cording to one hypothesis, these
diseases may occur together in ge-
netically predisposed individuals. In
addition, it is possible that intestinal
microbiota and gastrointestinal tissue
barriers may play a role in this associ-
ation.6,15,16
The pathogenic role of psycho-
genic factors in rosacea has been
widely discussed. The disease is
associated with specific changes in
personality structure, such as feel-
ings of anxiety, guilt, and shame.17
Given the facial component, and the
noticeable and unpleasant changes
occurring in the affected facial skin
areas, rosacea has a deep negative
338
effect on self-esteem (negative ef-
fect in 75%) and is reported to cause
feelings of shame and frustration
(70% of cases). As a result, many pa-
tients experience a poor quality of
life. Depression and anxiety preva-
lence is higher in patients with rosa-
cea than in healthy controls. Recent
studies do not suggest a general
psychogenic etiology of rosacea. A
new subtype, neurogenic rosacea,
was described in 2011; this type af-
fects a small subgroup of patients
who do not respond to treatment
and suffer from a high degree of
neurological and neuropsychiatric
disorders including depression18
(see Chapter 30).
Simultaneous depression may
be mainly attributed to cosmetic
changes in these patients. However,
both entities have a strong inflam-
matory component and an immune
system compromise. In the USA, a
study by Gupta et al. examined da-
tabases to explore the comorbidity
of rosacea and depression in 13.9
million consultations on rosacea
between 1995 and 2002. Of those
13.9 million, 1.04% had psychiatric
comorbidity, of which 70% were de-
pressive disease.19 A Danish study
shows that rosacea is associated
with an increased risk of depression
or anxiety disorders, and the clinical
presentation depends on the sever-
ity of rosacea.20
ROSACEA AND
GASTROINTESTINAL DISORDERS
Comorbidity associations between
rosacea and gastrointestinal (GI) dis-
orders are controversial. The main as-
sociations that have been investigated
are with celiac disease (CeD), inflam-
matory bowel disease (IBD) -including
Crohn’s disease (CD) and ulcerative
colitis (UC)-, increased prevalence of
Helicobacter pylori (HP), small intesti-
nal bacterial overgrowth (SIBO), and
irritable bowel syndrome (IBS).21 A re-
cent study shows that there is a signifi-
cant association with CeD, IBD, CD, and
UC, but not with either SIBO or IBC.21
Different hypotheses have been made
about the interrelationship between
rosacea and GI disorders. Firstly, the
leading role of infectious agents in the
pathophysiology of rosacea as well as
in GI disorders has been a major source
of suspicion. For example, while intesti-
nal resident bacterial flora has been as-
sociated with the pathogenesis of IBD,
oral metronidazole appears to be effec-
tive in improving the symptoms of IBD
and also rosacea.22 Secondly, the as-
sociation between rosacea and IBD is
plausible when considering the genet-
ic overlap between the two diseases in
the histocompatibility class II complex
encoded gene HLA-DRB1*0.3:0.1.23
In addition, the association between
rosacea and CeD is consistent with a
recent study of the enlarged genome,
which shows that both conditions share
a locus of genetic risk.23
Helicobacter pylori and Small
Intestine Bacterial Overgrowth
A high prevalence of H. pylori and SIBO
is observed in patients with rosacea;
however, there is no risk of new clini-
cal presentations related to H. pylori
or SIBO overgrowth in patients with a
marked rosacea. In a recent study, 90
patients with rosacea and an identical
number of controls were examined -by
H. pylori antigen determination and
respiratory function test- to detect H.
pylori and SIBO. Significantly higher
levels of H. pylori were observed in
patients with rosacea than in controls,
but no significant differences were
found in SIBO prevalence. This differ-
ence may be because the respiratory
function test detects bacteria only in
the first 90 centimeters of the small
intestine; consequently, levels may be
underestimated.24
The role of H. pylori and other in-
testinal bacteria in the pathogenesis
of rosacea is still controversial. Early
studies on the association of H. pylori
and rosacea showed H. pylori gastri-
tis in 84% of 31 patients. Symptoms
of rosacea disappeared or improved
in all cases after metronidazole treat-
ment.25 Further observations suggest
lack of seropositivity for H. pylori
among patients with rosacea and con-
trols.26,27 In 1999, Bamford, et al con-
ducted a randomized, double-blind,
placebo-controlled study in which
no differences were found in H. pylo-
ri prevalence between patients with
rosacea and controls. However, there
was a marked improvement in rosa-
cea symptoms after treatment, un-
related to H. pylori infection. These
authors conclude that H. pylori is not
a major factor determining the infec-
tion, severity or extent of rosacea.28
Subsequent studies are controversial
and many keep reporting this associ-
ation, as well as good response to H.
pylori eradication versus symptomatic
improvement of rosacea.29-33
H. pylori infection increases the
production of lipopolysaccharides,
platelet activation factor, and several
cytokines, such as IL-8, IL-1, and TNF-a,
as well as ammonium due to the high
activity of urease and other enzymes.
It also increases the production of va-
soactive substances such as histamine,
prostaglandins, leukotrienes and cyto-
kines. These substances may contrib-
ute to the inflammation of the gastric
mucosa and cause gastritis, peptic ul-
cer, MALT lymphoma and even gastric
cancer. However, these vascular me-
diators are only found in strains of H.
pylori producing a specific cytotoxin,
CagA (cytotoxin-associated gene A)
and VacA proteins (vacuolant-associat-
ed gene A). Studies in which patients
with rosacea were compared with
control subjects of similar age and sex
have shown that 67% of patients with
rosacea when infected with H. pylo-
ri were also detected CagA (32% in
339
controls) and in 75% were detected
antibodies against that toxin. In addi-
tion, this group of patients had elevat-
ed levels of TNF-a and IL-8. After the
eradication of HP infection, rosacea
symptoms disappeared (in 51 out of
53 cases) while TNF-a and IL-8 levels
returned to normal.34 El-Khalawany et
al. showed that 72% of rosacea cases
and dyspeptic symptoms were H. py-
lori positive for VacA, CagA, or IceA
alleles, versus 46.3% of controls. Thir-
ty-one cases of rosacea were PPR and
18 ETR. Gastric ulceration was higher
in PPR (38.7%) than in ETR (11.1%) and
controls (12%). In addition, a signifi-
cantly greater inflammatory reaction
was observed in PPR (74.2% of cases).
The genotypic study on H. pylori VacA
was more recognizable in PPR (54.8%)
than in ETR (22.2%). Eradication of H.
pylori was observed in 55.6% of cases
of PPR, while in ETR it was 17.6%. Ap-
parently, in PPR the influence of H. py-
lori is higher and this is due to the fact
that certain more aggressive strains
increase the inflammatory response,
both in the gastric mucosa and in the
skin lesions.35 A recent meta-analy-
sis reported a weak relationship be-
tween rosacea and H. pylori infection
and the efficacy of H. pylori treatment
on rosacea symptoms, although it did
not reached statistical significance.
Whether there is a pathogenic link be-
tween the two conditions, or whether
H. pylori infection represents a bridge
to other factors, is still unknown.36
Inflammatory Bowel Disease IBD and
its two subtypes, UC and CD, are thought
to be triggered by an innate aberrant
immune response to certain stimuli,
which leads to gastrointestinal neuro-
genic inflammation. UC and CD appear
at the skin level with various lesions, as
erythema nodosum and pyoderma gan-
grenosum, and with inflammatory dis-
eases like psoriasis. Some cases of IBD
patients developing rosacea have been
described. Studies reveal the associa-
tion of IBD and high risk of developing
psoriasis, rosacea and atopic dermatitis.
Rosacea may have a high prevalence in
patients with IBD (2.2 times higher than
in controls).6 These findings were cor-
roborated in a recent study involving a
Korean population which confirmed the
association between IBD, UC and CD
with an increased risk of inflammatory
skin diseases.37
In a population study of 80,957 ro-
sacea patients and an equal number
of controls, Spoendlin et al38 reported
that history of UC was associated with
an increased risk of rosacea (odds ra-
tio [OR] 1.65) that was even higher in
cases of short course (less than 2 years
of disease history). In cases of CD, the
OR was 1.49 and was not correlated
with the duration of the disease. How-
ever, the assessment of the severity of
IBD shows an increased risk of rosa-
cea when UC and CD are in phases
of increased activity, i.e., of increased
gastrointestinal inflammation.
 In the treatment of rosacea with
tetracyclines, it is important to con-
sider the possible association of this
antimicrobial substance with IBD.
A study based on the analysis of
data from over 96,000 patients with
IBD, found that history of rosacea in
previous years and use of oral tet-
racyclines was not associated with
increased risk of UC. However, rosa-
cea was significantly associated with
CD, especially when rosacea had
been diagnosed long before. The
use of tetracyclines was associated
with increased risk of CD and UC,
which was greater in cases of more
prolonged antimicrobial use.39
Oral corticosteroids are a common
therapy for IBD and cases of steroid ro-
sacea have been reported. However, it
should be noted that steroid-associated
rosacea is mainly caused by topical cor-
ticosteroids. A recent study found no
association between oral steroid ther-
apy and rosacea.39 It is therefore sug-
gested that the association between
rosacea and IBD may be partly caused
by the use of oral corticosteroids or
oral tetracyclines. However, it is worth
noting the strong association between
the onset of UC and CD after the initia-
tion of rosacea, as well as the increased
baseline prevalence in both conditions.
In a study conducted in Denmark
on patients with rosacea, there was
an increased risk of death (95%) due
to GI diseases, mainly primary liver
disease. Although this does not es-
tablish a causal relationship, the find-
ings should be taken into account and
perhaps considered to increase in risk
factors such as alcohol consumption
and long-term tetracycline courses.6
Gastroesophageal Reflux Disease
(GERD)
A significant association was found be-
tween GERD and rosacea, which was
more prominent with more severe ro-
sacea (OR 4.6, 95% IBS 1.6-13.2, p < 0.1)
irrespective of the use of doxycycline.2
ROSACEA AND
CARDIOVASCULAR RISK
Rosacea has been significantly associat-
ed with cardiovascular (CV) comorbidi-
ties such as dyslipidemia, hypertension,
coronary artery disease, alcohol con-
sumption and nicotine addiction.2,40,41
Chronic inflammation in rosacea is an
immune process in which cathelicidins
and dermal serinoproteases, such as
the stratum corneum tryptic enzyme
present at elevated levels in rosacea
lesions, play a role. It is currently ac-
knowledged that atherosclerosis is
not simply a passive accumulation of
blood lipids on the vessel wall, but a
dynamic inflammatory process that
begins with vascular endothelial acti-
vation, leukocyte migration, and lipid
oxidation, leading to plaque destabi-
lization and thrombosis. Since athero-
sclerosis is an inflammatory process,
340
patients with other inflammatory dis-
eases such as rheumatoid arthritis and
especially severe psoriasis have an in-
creased incidence of atherosclerosis.
In recent years it has been shown
that cathelicidin peptides are also
found in plaques of atherosclero-
sis.42,43 An association of human
cathelicidin gene expression with
cardiovascular risk was subsequently
reported.44 Serinoproteases have also
been found to play a role in the entire
atherosclerosis process; inhibition of
serinoproteases with viral inhibitors
prevents plaque progression.45
Duman et al. reported that total
cholesterol >200 mg/dL, LDL >130
mg/dL, and C-reactive protein (CRP)
>0.8 mg/L, plus a family history of pre-
mature CV disease, alcohol and to-
bacco consumption were significantly
more common in the rosacea patient
group than in the age- and sex-ad-
justed control group.46 A Taiwanese
study of cardiovascular comorbidities
shows that dyslipidemia, coronary ar-
tery disease, and hypertension were
significantly associated with rosacea.
A higher prevalence of comorbidities
was observed in male patients than
in female patients. This study lacked
adjustment for important risk factors,
such as smoking and alcohol abuse.47
An extensive retrospective study
by Dosal et al reviewed the relation-
ship between use of oral tetracyclines
in patients with rosacea and decrease
in vascular episodes.48 Patients treat-
ed with oral tetracycline had a more
favorable odds ratio than those who
did not receive the antimicrobial. It is
suggested that the anti-inflammatory
properties of tetracyclines may have
beneficial side effects on the CV sys-
tem of elderly rosacea patients. It re-
mains unclear whether the observed
effect was due to the use of tetracy-
cline or an improvement associated
with systemic treatment of rosacea.
Tetracyclines are known to inhibit
MMP activity, so it could be assumed
that treatment of one disease may
benefit both the skin and CV system.
MMP2 and MMP9, inhibited by tetra-
cyclines, are enzymes capable of de-
grading the basement membrane of
capillaries. Tetracyclines are effective
in significantly reducing the incidence
of acute myocardial infarction, appar-
ently by inhibiting MMPs and sup-
pressing inflammatory mediators that
protect atherosclerosis plaques from
rupture. Doxycycline also showed de-
fensive capacity of the integrity of the
capillary wall and connective tissue,
as it reduces hypersensitivity to vaso-
dilator stimulation, prevents capillary
effusion, and inhibits cytokines in-
volved in inflammation and erythema.
It is known that 90 days of low doses
of modified doxycycline release may
lower CRP for more than two years in
postmenopausal women.49
 A recent study used a database
with over 21 million living patients to
determine, via logical regression, the
association between rosacea, psoria-
sis and atopic dermatitis with the risk
of CV disease in one year. Compari-
son with controls of equal sex and
age found no association between
these three diseases.50 Another study
conducted in Denmark, on a popula-
tion of 4,948 patients with rosacea, at-
tempted to determine the risk of CV
disease (myocardial infarction, stroke,
major CV episodes, and death from
CV and other events). The result was
the absence of association between
rosacea and increased risk of severe
CV events or death. The flaw of the
study is that it was conducted on the
basis of clinical histories of patients
diagnosed with rosacea at the hospi-
tal level, which may represent only a
limited group of patients with severe
disease.51 However, recent informa-
tion suggests that there would be no
differences in CV risk factors among
the different subtypes of rosacea.46
Since systemic inflammation often
crosses the border between skin dis-
ease and internal disease, it may rea-
sonably be inferred that patients with
rosacea should be screened for CV risk
factors and treated if appropriate, that
rosacea is an independent risk factor
for CV disease, and that treatment of
rosacea should be aimed at managing
skin involvement and systemic disease.52
Spoendlin et al. made an interest-
ing contribution on the use of anti-
hypertensive drugs and the risk of
triggering rosacea. A case-control
study conducted on 53,927 patients
with rosacea and an equal number of
controls exposed to antihypertensive
drugs showed that calcium channel
blockers do not trigger rosacea. The
use of beta-blockers is associated
with a slight decrease in the relative
risk of developing rosacea; but this ef-
fect may be greater in cases of ETR
alone. Neither angiotensin-convert-
ing enzyme inhibitors nor angiotensin
receptor blockers altered the risk of
rosacea in the population studied.53
ROSACEA, AUTOIMMUNE DISEASES
AND METABOLIC DISORDERS
Rosacea shares risk loci of develop-
ing autoimmune diseases, such as
type I diabetes mellitus (DMI) and ce-
liac disease. A recent genome study
identified 90 genetic regions associ-
ated with DMI, celiac disease, multi-
ple sclerosis and rheumatoid arthritis.
Research on the possible association
between rosacea and these diseases
was recently made available. Egeberg
et al. studied 6,759 patients with rosa-
cea. After adjusting for smoking and
socioeconomic status, patients with
rosacea were determined to have a
significant increase in odds ratio for
DMI (OR 2.59, 95% IBS 1.41-4.73), ce-
liac disease (OR 2.03, 95% IBS 1.35-
3.07), multiple sclerosis (OR 1.65, 95%
341
IBS 1.20-2.28) and rheumatoid arthri-
tis (OR 2.14, 95% IBS 1.82-2.52). These
associations were observed mainly
among women. In males the associa-
tion was only statistically significant in
rheumatoid arthritis.54
There are recent descriptions of
cases of Sjögren’s syndrome and oc-
ular rosacea. Both conditions can lead
to xerophthalmia, conjunctival hyper-
emia and blepharitis. If center-facial
erythema and flushing are added, the
criteria for defining the two entities
are met. The association may confuse
diagnoses, as their symptoms are sim-
ilar, but treatments differ.55
Similar factors, such as increased
levels of cathelicidins LL-37, endo-
plasmic reticulum stress, inflammato-
ry cytokines, and oxidative stress are
present in the pathogenesis of rosa-
cea and metabolic disorders. Howev-
er, the pathophysiological connection
between these diseases has not been
fully established yet.56
UK studies of patients with ad-
vanced diabetes under control with
oral hypoglycemic agents and insu-
lin find no increased risk of rosacea
in the patients studied.57 This may be
explained by the fact that patients
with all types of diabetes were admit-
ted. When the study focuses on type
1 diabetes mellitus (5-10% of diabetes
cases) there is a significant association.
Belli et al. find statistical significance
between rosacea and insulin resis-
tance and cardiovascular risk factors;
therefore, they recommend conduct-
ing appropriate research. The rosacea
group had significantly higher rates
of insulin resistance, high glucose lev-
els, total cholesterol, and high systolic
and diastolic blood pressure.56 Recent
studies consider cholesterol levels to
be the best parameter for predicting
metabolic disturbance in patients with
rosacea.58
OTHER DISORDERS
Rosacea and Chronic Rhinosinusitis
There are many publications outlining
occasional observations of patients
with a history of recurrent sinusitis,
perioral dermatitis, atopic diathesis
and rosacea worsening, or associa-
tions with sinusitis and migraines.7,59,60
A study in Saudi Arabia, involving 28
patients with rosacea and signs and
symptoms of chronic rhinosinusitis
(CR) (posterior nasal drip, anosmia, fa-
cial sensitivity, headaches) =compared
with a control group. Radiological evi-
dence of CR was found in 67.9%, while
in the control group only 4%. The mean
IgE concentration was similar in both
groups (225.4 kU/l and 223.1 kU/l).61 The
subgroup study of rosacea showed
that patients with rosacea and CR had
a more severe ETR than those with ro-
sacea alone. In addition, ETR severity
was significantly correlated with the
existence of atopic disease (bronchial
asthma, allergic rhinitis with or without
allergic conjunctivitis). Among patients
with rosacea with or without radiolog-
ical evidence of CR, no significant dif-
ferences in IgE levels were observed.
Comparative studies of subgroups did
not show important differences be-
tween skin types, severity of PPR, exis-
tence of atopic disease or migraine. In
both subgroups the severity of ETR and
PPR was not related to the duration of
the disease. Aggravating factors such
as sun exposure, heat, dust and sweat
were more significant in the CR group
with radiological evidence. Apparent-
ly, in rosacea there would be a tissue
interaction, mediated by cathelicidins
and anatomical proximity, between the
mucous blanket of the paranasal sinus-
es and the overlying skin.
The association between CR and
rosacea is manifested by severe ETR.
However, some evidence suggests
the convenience of requesting a clini-
cal and radiological study of the para-
nasal sinuses in this group.61
The use of potent corticosteroids
via inhalation, or by subsequent drain-
age and subsequent exhalation or nasal
runoff in the face, with nasal spray inhal-
ers, may be the cause of steroid rosa-
cea and perioral dermatitis. The cause
for halogenated corticosteroids exac-
erbating rosacea is unknown. They can
induce skin atrophy, with the develop-
ment of erythema and telangiectases
due to topical use; but the way in which
they generate papules and pustules
does not have a simple explanation.
They appear to allow the proliferation
of bacteria in the pilosebaceous unit or
an increase in Demodex, which triggers
the inflammatory cascade leading to
the exacerbation of the disease.62
Facial Dystonia and Rosacea
Benign essential blepharospasm (BEB)
and hemifacial spasm (HFS) belong to a
spectrum of focal movement disorders,
which cause involuntary, spasmodic,
eyelid and facial muscle contractions.
In a study of 140 patients (87 with BEB
and 53 with HFS), about 15% had rosa-
cea (prevalence 1.34% in the general
population) (p < 0.001). Of the total
number of patients, 21 had rosacea and
facial dystonia. In patients with rosacea
and facial dystonia, dry eye and tear in-
stability often coexist and can lead to
palpebral tonic contractions as well
as exacerbation of rosacea. Studies
suggest that neurogenic inflammation
and altered vasoregulation, combined,
contribute to the pathogenesis of rosa-
cea. It is also suggested that the same
inflammatory pathways of the immune
type act in both entities.63
A possible association between ro-
sacea and increased risk of developing
thyroid and basal cell carcinomas was
described.64 In addition, a prospective
study65 found a relationship between
rosacea and increased risk of glioma.
342
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cea, use of tetracycline, and risk of
 incidental inflammatory bowel dis-
ease in women. Clin Gastroenterol
Hepatol 2016; 14(2):220-5.
40. Tan J, Berg M. Rosacea: Current
state of epidemiology. J Am Acad
Dermatol 2013; 69:527-35.
41. Li S, Cho E, Drucker AM, et al. Alcohol
intake and risk of rosacea in US women.
J Am Acad Dermatol 2017; 76(6):1061-7.
42. Ciornei CD, Tapper H, Bjartell A, et al.
Human antimicrobial peptide LL-37 is
present in atheroesclerotic plaques
and induces death of vascular smooth
muscle cells: A laboratory study. BMC
Cardiovasc Disord 2006; 6:49.
43. Edfeldt K, Agerbeth B, Rottenberg
ME, et al. Involvement of the antimi-
crobial peptide LL-37 in human ath-
eroesclerosis. Arterioescler Thromb
Vasc Biol 2006; 26:15551-7.
44. Benachour H, Zaiou M, Samara A, et
al. Association of human cathelici-
din (h-CAP-18/LL-37) gene expres-
sion with cardiovascular disease risk
factors. Nutr Metab Cardiovasc Dis
2009; 19:720-8.
45. Bot I, van Berkel T, Biessen EA. Vi-
ral serine protease inhibitors as
anti-atheroesclerotic therapy. Curr
Opin Investig Drugs 2007; 8:729-35.
46. Duman N, Ersoy Evans S, Atakan N.
Rosacea and cardiovascular risk fac-
tors: a case control study. JEADV
2014; 28:1165-69.
47. Hua TCh, Chung PI, Chen YJ, et al.
Cardiovascular comorbidities in pa-
tients with rosacea: A nationwide
case-control study from Taiwan. J
Am Acad Dermatol http;//dx.doi.
org/10.1016/j.jaad.2015.04.028.
48. Dosal JR, Rodríguez GL, Penzon
CF, et al. Effect of tetracyclines on
the development of vascular dis-
ease in veterans with acne or rosa-
cea: A retrospective cohort study. J
Invest Dermatol 2014; 134(8):2267-9.
49. Meier CR, Derby LE, Jick SS, et al.
Antibiotics and risk of subsequent
first-time acute myocardial infarc-
tion. JAMA 1999; 281(5)427-31.
50. Marshall VD, Moustafa F, Hawkins
SD, et al. Cardiovascular disease
outcomes associated with three
major inflammatory dermatologic
diseases: A propensity-matched
case control study. Dermatol Ther
(Heidelb) 2016; 6:649-58.
51. EgebergA, Hansen PR, Gislason GH,et
al. Assessment of the risk of cardiovas-
cular disease in patients with rosacea.
J Am Acad Dermatol 2016; 75:336-9.
344
52. Dosal J, Keri J. Rosacea and cardiovas-
cular disease: Is there an association? J
Am Acad Dermatol 2015; 73:308-9.
53. Spoendlin J, Voegel JJ, Jick SS, et
al. Antihypertensive drugs and the
risk of incident rosacea. Br J Derma-
tol 2014; 171:130-6.
54. Egeberg A, Hansen PR, Gislasom
GH, et al. Clustering of autoimmune
diseases in patients with rosacea. J
Am Acad Dermatol 2016; 74:667-72.
55. Dos Santos-Neto LL, Santos An-
drade EH, Yamakawa PE, et al. As-
sociation of Sjögren’s syndrome
and rosacea: a diagnostic challenge.
APLAR J Rheumatol 2007; 10:140-2.
56. 56 . Belli AA , Ozbas Gok S, Akbara
G, et al. The relationship between
rosacea and insulin resistance and
metabolic syndrome. Eur J Derma-
tol 2016; 26 (3):260-4.
57. Spoendlin J, Voegel JJ, Jick SS, et al.
Risk ofrosacea in patients with diabetes
using insulin or oral antidiabetic drugs. J
Invest Dermatol 2013; 133:2790-3.
58. Belli AA, Asude K, Ozbas Gok S.
Can hematologic parameters be an
indicator of metabolic disorders ac-
companying rosacea? Acta Derma-
tovenereol Croat 2017; 25(2):145-50.
59. Dirschka T, Tronnier H, Folster-Holst
R. Epithelial barrier function and
atopic diathesis in rosacea and peri-
oral dermatitis. Br J Dermatol 2004;
150:1136-41.
60. Saberi A, Nemati S, Shakib RJ, et
al. Association between allergic rhi-
nitis and migraine. J Res Med Sci
2012; 17:508-12.
61. Al Balbeesi AO. Rosacea and
chronic rhinosinusitis: A case con-
trolled study. Med Princ Pract
2014; 23:511-6.
62. Egan CA, Rallis TM, Meadows KP, et
al. Rosacea induced by beclometha-
sone dipropionate nasal spray. Int J
Dermatol 1999; 38:131-41.
63. Khan TT, Donaldson J, Hesse RJ.
Facial dystonias and rosacea: Is
there an association? Orbit 2014;
33(4):276-9.
64. Li WQ, Zhang M, Danby FW, et al.
Personal history of rosacea and risk
of incident cancer among women in
the US. Br J Cancer 2015; 113:520-3.
65. Egeberg A, Hansen PR, Gislason
GH, et al. Association of rosacea
with risk for glioma in a Danish na-
tionwide cohort study. JAMA Der-
matol 2016; 152:541-5.
In 2011, Scharschmidt et al. de-
scribed 14 patients with rosacea and
prominent neurological signs. These
authors considered this to be a new
subtype of rosacea and called it neu-
rogenic rosacea. A high percentage
of these patients had neurological
(43%) or neuropsychiatric (50%)
conditions, such as complex region-
al pain syndrome or reflex sympa-
thetic dystrophy, essential tremor,
depression, and obsessive-compul-
sive disorders. In addition, they re-
ported important symptoms such
as burning and itching, and exhibit-
ed signs of erythema and flushing,
sometimes with edema, telangiecta-
ses and papules. Triggers included
heat, sunlight, hot showers, stress,
exercise, alcohol consumption, and
spicy foods, among others.1
Scharschmidt et al theorized that
neuronal dysregulation could contrib-
ute to rosacea pathogenesis through
various mechanisms, such as vaso-mo-
tor instability, release of proinflam-
matory neuropeptides and neuronal
injury, all of which causing intense
dysesthesias in these patients.1
In 2013, Cabet et al. reported a
case of an 80-year-old patient who
had suffered left facial paralysis five
years before skin lesions appeared.
The patient characteristically showed
unilateral diffuse facial erythema,
telangiectasias and papulopustules.
Piccolo et al., referring to a case of
unilateral rosacea located at the site
Chapter 30 of facial paralysis, commented that
Cabet’s publication is an example of
Neurogenic
a broader concept, which is the “im-
munocompromised district” (ICD)
since it fully meets the criteria defin-
Rosacea*
ing it.3 The ICD concept, developed
and disseminated in 2009 by Ruoc-
co et al., defines a cutaneous site of
locoregional immune dysregulation
due to the existence of an obstacle in
the normal flow of immunocompetent
cells through lymphatic channels or
Ana Kaminsky, María I. Herane to the interference of the signals that
neuropeptides and neurotransmitters
There was a mild malar erythema area corresponding to the facial pa- send to the membrane receptors of
on the right side, the area not com- ralysis. These authors also suggest- these cells. This regional destabiliza-
promised by paresis. Symptoms in- ed that dysregulation of neuronal tion of the neuro-immuno-cutaneous
cluded flushing on the affected area receptors and mediators could play system would explain how heteroge-
and burning sensation, which were an important role in the pathophys- neous factors can transform a skin
worsened by various stimuli such as iology of rosacea, as they may pro- district into a site where the emer-
spicy foods, hot drinks, stress, sun mote vasodilation, edema, fibrosis, gence and confinement of a variety
exposure and cosmetics. The his- and inflammation. In their opinion, of conditions are stimulated. It should
topathological study of the lesions this complexity is likely to stem from be noted that the term “immunocom-
showed superficial perivascular and the fact that the rosacea process is promised” indicates a generic alter-
periadnexal lymphoplasmacytic infil- multifactorial, marked by import- ation of the immune response and not
trate, mild edema with fibrosis and ant pathophysiological mechanisms necessarily its decrease.4-6 The ICD
dilated capillaries but no Demodex. ranging from changes in cutaneous becomes a particularly sensitive site
With these clinical and histological blood flow to an increased innate for further outbreaks of opportunistic
data, Cabet et al. diagnosed rosacea immune response and neurogenic infections, tumors and confined im-
with intensification in the unilateral inflammation.2 mune disorders.
* [Authors’ Note] We have included neurogenic rosacea as a comorbidity, as it is a subgroup of rosacea associated with In line with this concept, the patho-
neurological or psychiatric disorders. However, there is no general agreement on this important issue. genesis of neurogenic rosacea is based
Other prominent colleagues believe that neurogenic rosacea is the result of a very special vascular alteration, due to the
influence on flushing exerted by the nervous system. It would consequently be a well-defined entity that should be included on neuronal dysregulation. Through a
among the variants of rosacea. variety of mechanisms such as vaso-
This difference has not yet been settled and, as is the rule in medicine, the solution will only come from greater experience
gathered in scientific research. motor instability, release of pro-inflam-
345
matory neuropeptides and neurologic
injury, this could contribute to the ap-
pearance of dysesthesias.
Piccolo et al. introduce the novel
concept of the “neuroimmunocuta-
neous system”, which encompasses
the physical, chemical and functional
links between the skin, nervous sys-
tem and immunity.7 In addition, they
observe that the appearance of uni-
lateral rosacea where facial paralysis
formerly occurred is not mere coinci-
dence. Conversely, the appearance of
rosacea strictly confined to the neu-
rologically damaged area would be a
possible local consequence of a dys-
regulation, with an associated neuro-
logical mediator.7
ASSOCIATED DISEASES
Besides neurological or neuropsychiat-
ric phenomena, headaches, Raynaud’s
phenomenon, rheumatic diseases such
as lupus erythematosus, rheumatoid
arthritis, fibromyalgia, mixed connec-
tive tissue diseases and psoriatic ar-
thritis are described, all diseases also
associated with different subtypes of
rosacea. Some authors point out that
patients with rosacea have a signif-
icant increased risk of neurological
conditions, such as migraine, depres-
sion, regional pain syndromes, and gli-
oma.8 Apparently, this association may
be due to an increased expression of
extracellular matrix metalloprotein-
ases, which is seen both in the above
mentioned diseases and in rosacea,
raising suspicions as regards common
pathogenic mechanisms.9
Treatment
The range of symptoms may differ
in the same individual, which affects
the choice of the optimal therapeutic
strategy.1,7 According to the original
proposal put forward by Scharschmidt
et al. the treatment must aim at the
predominant symptom.1
Patients with prominent vaso-
motor symptoms, flushing and tel-
angiectases respond to vasoactive
medications, such as beta blockers,
alpha1-adrenergic blockers, and cal-
cium channel blockers. Lasers and
light therapies have also proven ef-
fective in this group of patients. In a
recent publication, the use of pulsed
dye laser (PDL) in a case of refractory
neurogenic rosacea resulted in 50%
improvement on symptoms and 30%
improvement of erythema. PDL re-
duces the levels of substance P and
the calcitonin gene-related peptide,
as well as neuropeptides that modu-
late skin pain.10
Schram et al. reported a success-
ful outcome of endoscopic thoracic
sympathectomy in the eradication of
facial flushing.11 Dayan et al. adminis-
tered multiple intradermal injections
(8 to 12 units per affected cheek) of
droplets (0.05) of botulinum toxin A,
346
in a dilution of 100 units in 7 cm3 of
physiological saline. The symptoms
of erythema and flushing improved,
which was attributed to an action on
the probable neurogenic component
of vascular dysfunction, inflammation
and sebaceous hypersecretion.12
Other researchers also used bot-
ulinum toxin in cases of flushing re-
fractory to all other treatments. There
was a sustained improvement (sever-
al months) without adverse effects;
these instances suggest that more
studies are needed to discern the
mechanism of action.13,14
Patients with inflammatory le-
sions, such as mild papules and pus-
tules, or edema, may respond to
traditional topical therapies. System-
ic antibiotics and antimalarial agents
may be useful in refractory cases.1
Those with disproportionate dyses-
thesias reaching levels of flushing or
inflammation are the most difficult
group to treat. Focus should be made
on treating the chronic pain syndrome
and neuropathic itch. In this regard,
the most effective drugs are neurolep-
tics (gabapentin, pregabalin), tricyclic
antidepressants and antidepres-
sants that act on pain (duloxetine).
N-methyl-d-aspartate receptor an-
tagonists (memantine), systemic an-
tibiotics and topical formulations with
ketamine or capsaicin may also be use-
ful. Laser and pulsed light should be
used with caution because of the ex-
treme sensitivity to heat and sunlight
of the treated skin.1
Diagnosis
The literature on neurogenic ro-
sacea is very limited. Suspicion is
well-founded in patients with rosa-
cea who refer to burning or pain as
the predominant and disproportion-
ate symptom of flushing. In these
cases, the coexistence of neuro-
logical or neuropsychiatric prob-
lems needs further investigation, as
treatment contributes to the reduc-
tion of the symptoms of the cutane-
ous disease.15
Differential Diagnosis
In cases of unilateral localization or in
which rosacea is more exacerbated,
differential diagnosis should be made
with unilateral demodicidosis. This
demodicidosis typically manifests
with clinical lesions very similar to
those of rosacea; it is hemifacial and
is characterized by the increase of the
Demodex folliculorum parasite in the
pilosebaceous follicles concentrated
in the facial seborrheic areas. In de-
modicidosis, eruption is characterized
by dryness, follicular scaling, superfi-
cial vesicles and pustules. Response
to treatment specific to demodicido-
sis, with oral or topical ivermectin or
permethrin, confirms diagnosis (see
Chapter 16).16
References
1. Scharschmidt TC, Yost JM, Truong
SV, et al. Neurogenic rosacea: A
distinct clinical subtype requiring
a modified approach to treatment.
Arch Dermatol 2011; 147(1):123-126.
2. Cabet J, Serrão V, Lestre S. Unilat-
eral rosacea in a patient with Bell’s
palsy. J Dermatol 2013; 40:403-404.
3. Piccolo V, Ruocco V, Russo T, et al.
Unilateral rosacea in patients with
facial nervepalsy: A mere example
of immunocompromised district. J
Dermatol 2013; 40(10):850.
4. Ruocco V, Brunetti G, Puca RV, et
al. The immunocompromised dis-
trict: A unifying concept for lymph-
oedematous, herpes-infected and
otherwise damaged sites. J Eur
Acad Dermatol Venereol 2009;
23:1364-1373.
5. Ruocco V. The immunocompro-
mised district: How the pieces of
the puzzle gradually fell into place.
Clin Dermatol. 2014; 32(5):549-52.
6. Caccavale S, La Montagna M, Cac-
cavale T. Isoscartopic response: An-
other facet of the immunocompro-
mised cutaneous district. Indian J
Dermatol 2016; 61(2):219-20.
7. Piccolo V, Russo T, Bove D, et al.
Segmental immune disorders re-
sulting from neurologic injuries.
Clin Dermatol 2014; 32:628-632.
8. Woo YR, Lim JH, Cho DH, et al. Ro-
sacea: Molecular mechanisms and
management of a chronic cutane-
347
ous inflammatory condition. Int J
Mol Sci 2016;17(9).
9. Egeberg A, Hansen PR, Gislason
GH, et al. Association of rosacea
with risk for glioma in a Danish na-
tionwide cohort study. JAMA Der-
matol 2016, 152:541-545.
10. Wessman BS, Miller DD, Goldfarb N,
et al. Neurogenic rosacea successful-
ly treated with pulsed dye laser fol-
lowing failed medical management. J
Am Acad Dermatol 2017; AB 177.
11. Schram AM, James WD. Neurogen-
ic rosacea treated with endoscopic
thoracic sympathectomy. Arch Der-
matol 2012; 148:270-1.
12. Dayan SH, Pritzker RN, Arkins JP. A
new treatment regimen for rosacea:
Onabotulinumtoxin A. J Drugs Der-
matol 2012; 11(12):e76-9.
13. Bloom BS, Payongayong L, Mourin
A, et al. Impact of intradermal abo-
botulinumtoxin A on facial erythe-
ma of rosacea. Dermatol Surg 2015;
41(Suppl 1):S9-16.
14. Park KY, Hyun MY, Jeong SY, et al. Bot-
ulinum toxin for the treatment of refrac-
tory erythema and flushing of rosacea.
Dermatology 2015; 230(4):299-301.
15. Parkins GJ, Maan A, Dawn G. Neu-
rogenic rosacea: An uncommon and
poorly recognized entity? Clin Exp
Dermatol 2015; 40(8):930-1.
16. Pallotta S, Cianchini G, Martelloni E,
et al. Unilateral demodicidosis. Eur
J Dermatol 1998; 8(3):191-2.
During pregnancy, a series of signifi-
cant metabolic, hormonal, behavioral,
and morphological changes occur in
women; these can influence the evo-
lution of different nosological pro-
cesses.1,2 Rosacea is a chronic and
inflammatory skin disease, whose
etiology and pathophysiology is not
well known.3 Clinical manifestations
–erythema, telangiectases, papules,
pustules, and edema (mainly cen-
ter-facial)– fluctuate due to different
stimuli.4 Medical literature about ro-
sacea and pregnancy is scarce; most
references are devoted to therapeu-
tic suggestions.
EPIDEMIOLOGY
Rosacea occurs most frequently be-
tween the ages of 30 and 50, with
a female predominance (except for
phymatous rosacea, which in 90 %
of the cases affects males), mostly
among the Caucasian population,
although there are more frequent
reports of the papulopustular type
in the male sex.3,5,6 In Latin America
(data from Mexico), official figures re-
port that about 70 % of pregnancies
are among women aged 20-34, 15 %
in the 35-39 age group, and 1.5 % be-
tween the ages of 45 and 49. At old-
er ages, the proportion of more than
two children per pregnancy increas-
es.7 According to data released by the
World Health Organization (WHO),
it is estimated that 78 % of pregnant
women have access to a qualified
Chapter 31
Rosacea and
Pregnancy
Leonel Fierro-Arias, Aline Armas-Vázquez
perinatal health care system,8 a fact
that may increase the number of di-
agnoses of diseases concurrent or
exacerbated in the process, such as
certain dermatoses. A recent study
on rosacea conducted in Colombia
indicated a prevalence of 2.85 % (the
highest reported in Latin America),
with a predominance in women (76
%), and a maximum incidence be-
tween the ages of 41 and 50.9
ETIOLOGY AND PATHOGENESIS
Pregnancy and menstruation can ex-
acerbate rosacea due to hormonal
changes that predispose to increased
vascularity of the skin.3,10 Some stud-
ies have described a probable rela-
tionship between pyoderma faciale
and certain hormonal changes, such
as those that occur during pregnan-
cy.6,11 “Pyoderma faciale” or “rosacea
fulminans,” a disorder that usually af-
348
fects women, is triggered by stress,
use of oral contraceptives, psycholog-
ical events, and pregnancy in young
women. It is characterized by the
acute and sudden onset of coalescing
nodules and draining sinuses in the
face, compromise of the general state
and, frequently, seborrhea. One case
of complication of pyoderma faciale
and stillbirth was described, but the
cause of death was not precisely es-
tablished.
During pregnancy, the activity of
the sebaceous and eccrine glands
increases, but that of the apocrine
sweat glands decreases, which iden-
tifies a hormonal change at the func-
tional, chemical, and metabolic levels.12
During the third trimester of preg-
nancy, there is a modification of the
estrogenic function and its pituitary
stimulus, increasing sebaceous secre-
tion. Similarly, during lactation, hyper-
function of the pilosebaceous unit will
is influenced by increased prolactin
secretion. Consequently, there may
be implications in the pathogenesis of
entities such as acne or rosacea.13
In 2000, IE Aydingöz et al.14 investi-
gated the possible influence of preg-
nancy on the increase of Demodex
folliculorum and the corresponding
relationship to conditions such as ro-
sacea. The result showed that there
was no significant difference between
non-pregnant and pregnant women
in rates of mite infestation.
CLINICAL FEATURES
During pregnancy, the classic rosa-
cea clinical subtypes occur: erythe-
matotelangiectatic, papulopustular,
phymatous, and ocular rosacea. The
granulomatous variant and other
forms –whose inclusion among ro-
sacea variants is debatable– such as
pyoderma faciale, may also occur.4,9,15,16
The course of rosacea during preg-
nancy is unpredictable.12 It has been
assumed that the clinical manifesta-
tions of dermatosis may worsen and
even begin in patients with no history
of them during pregnancy.17 Erythe-
ma, flushing episodes, and papules
and pustules may increase or be ex-
acerbated, and may become difficult
to manage due to difficulties in ad-
ministering oral medications to these
patients.18
Differential Diagnosis
Some differential diagnoses of rosa-
cea during pregnancy are:
1. Spider angiomas or telangiecta-
ses due to physiological vascular
changes, specifically estrogenic
vasodilation, which may appear
or be exacerbated during this
stage.19
2. Vasomotor instability can cause
flushing or sudden transient ery-
thema of pregnancy.20
3. Pregnancy acne. During the third
trimester of pregnancy, there is an
increase in the function of the se-
baceous glands due to estrogenic
influence (some authors consider
it a variant of pruritic folliculitis of
pregnancy). It occurs in the form
of follicular papules and is accom-
panied by intense itching.19,21 This
entity resolves spontaneously, usu-
ally one to two months following
delivery.19
4. Systemic lupus erythematosus may
appear, with malar rash and isolated
or confluent papules, but no pus-
tules.22
5. Photodermatitis or polymorphous
light eruption of pregnancy, which
is exacerbated by exposure to solar
radiation and has skin manifesta-
tions similar to rosacea.22
6. Seborrheic dermatitis (SD), due to
its morphology, can clinically simu-
late a papulopustular inflammatory
picture; but topography is almost
always different, with lesions more
frequently found in the scalp, eye-
brows, glabella, periauricular re-
gion, and nasolabial folds22,23 Unlike
rosacea, SD is scaly and itchy; how-
ever, it has been reported that in up
to 26 % of cases both dermatoses
can coexist.23
7. Demodicosis is difficult to distin-
guish from some forms of rosa-
cea.23 It is necessary to remember
that the parasite that causes it is a
co-participant in the inflammatory
process in the cutaneous alteration
of rosacea.
TREATMENT DURING
PREGNANCY
The treatment of rosacea should
be selected according to the clini-
cal signs and symptoms of rosacea.24
However, it is important to remember
that most of the available medications
are contraindicated in pregnancy.3
FDA categories related to the use
of drugs in pregnancy are as follows:
Category A: no risk in pregnancy.
Category B: no evidence of risk
in humans and remote possibility of
fetal damage (either because con-
349
trolled studies in pregnant women Table 31-1. Topical medications in
show no risk despite adverse findings rosacea and pregnancy
in animals, or because no studies have
been conducted in humans but the FDA
studies conducted in animals show no Drug Category
fetal risk).
Azelaic acid I B
Category C: the risk cannot be Benzoyl peroxide I C
ruled out and there is a possibility Clindamycin I B
of fetal damage, although the ben- Erythromycin I B
efits may outweigh the risks (lack of Metronidazole I B
well-controlled studies and lack of Retinoids CI C
animal studies, or animal studies have Salicylic acid CI C
not demonstrated fetal risk). Brimonidine CI B
Ivermectin CI C
Category X: use in pregnancy is
prohibited due to fetal risk. I: indicated, CI: Contraindicated.
Retrieved and adapted from Bechstein SK, Ochsendorf
Topical Treatment. Topical thera- F. Akne und rosazea in der schwangerschaft. Hautarzt.
peutic options for rosacea that are 2017;68:111-119.
available and permitted during preg-
nancy are: azelaic acid, metronidazole, since only 4 % of the applied dose is
clindamycin and erythromycin.12,25 The systemically absorbed.27 Use of clin-
general characteristics of these drugs damycin has implications for bacterial
and others recently included in rosa- resistance; thus, it would only be used
cea management are described be- in selected cases and not as a mono-
low. The indications and categories therapy. Clindamycin is a pregnancy
of topically applied drugs for rosacea, category B antimicrobial. Erythromy-
as well as their category during preg- cin 2 %, in gel or solution, can also be
nancy, is shown in Table 31-1. used, as well as fusidic acid gel for oc-
ular rosacea.
The formulations for cutaneous
application of azelaic acid and clin- Metronidazole also has antibacte-
damycin do not only have antibacte- rial and anti-inflammatory properties.
rial but also anti-inflammatory effects; It is not recommended for oral or par-
they are applied every 12 hours and enteral administration because of its
can be used safely during pregnan- possible mutagenic effects (cleft lip
cy.26 Azelaic acid is in category B, and palate) and, during the first tri-
mester, vaginal administration is not
recommended either. Formulations
for topical application to skin have no
disadvantages.26 Although there are
few controlled clinical studies, metro-
nidazole is included in category B2, so
its use should be restricted to cases
where it is particularly necessary. In
contrast, recent documents mention
oral metronidazole as a therapeutic
option for papulopustular rosacea
in pregnancy, in doses of 200 mg in
twice daily.17
Salicylic acid is category C and its
systemic absorption varies between
9 % and 25 %. In the third trimester
of pregnancy, women should avoid
use of salicylic acid over large areas
for prolonged periods, or under oc-
clusive dressings, because this may
cause early closure of the fetal ductus
arteriosis and oligohydramnios.27 The
use of salicylic acid or topical phenols
in any concentration should be avoid-
ed due to the possibility of systemic
absorption.17 Some authors suggest
the prescription of benzoyl peroxide;
however, it is not approved by the
FDA for the treatment of rosacea and
is considered to be category C for
pregnancy.23
Topical retinoids, such as tretinoin
(retinoic acid) and adapalene, are cat-
egory C drugs, while tazarotene is in
category X. Absorption of the former
is minimal; however, some studies find
a risk of teratogenicity if used in the
first trimester of pregnancy.27 Other
references indicate that there is no
clear evidence that topical retinoids
cause congenital malformations,
spontaneous abortions, low birth
weight, or prematurity, as is the case
with oral isotretinoin.28
Ivermectin is an antiparasitic drug
that is available in 1 % cream, 6 mg
tablets, and drops. It is mainly indicat-
ed for papulopustular rosacea.29 It is
classified pregnancy category C30,
although teratogenicity has not been
demonstrated in humans.31 The Amer-
ican Academy of Pediatrics (AAP)
considers the use of oral ivermectin
during lactation possible in cases of
scabies and head lice, when topical
therapy is not effective, since the
dose absorbed by the infant is only
0.98 %.32 In general terms, ivermectin
should be considered a contraindicat-
ed drug for rosacea, since there are
no controlled clinical studies of its use
in pregnant women.
Brimonidine is a novel and selec-
tive alpha-2 adrenoceptor agonist,
which is used topically as a gel for
the treatment of persistent facial er-
ythema in patients with rosacea. It
is recommended for people over 18
years in concentration of 0.33 %. Its
mechanism of action is the reduction
of erythema through direct vasocon-
striction. It is classified as category B
350
for pregnancy; however, there are no
studies showing conclusive results of
its use in this situation. In animal stud-
ies, brimonidine was shown to cross
the placental barrier.33
Topically administered calcineurin
inhibitors, such as tacrolimus and pi-
mecrolimus, are associated with min-
imal systemic absorption because
the molecular size prevents total
penetration. There are no conclusive
studies of the use of these immuno-
modulators and their safety during
pregnancy; however, when no oth-
er therapeutic options are available,
they can be administered on small
surface areas. Oral tacrolimus has
been associated with prematurity and
low birth weight, and its safety during
lactation is controversial.31 With both
topical and systemic formulations the
transmission to breast milk is said to
be minimal or almost non-existent;
but since there are no studies yet to
prove this, manufacturers contraindi-
cate use of these drugs during lacta-
tion.32 Both are pregnancy category C
drugs.31
Oxymetazoline is a vasoconstric-
tor, an alpha-1 adrenergic receptor
agonist, and an alpha-2 adrenergic
receptor partial agonist. Cream for-
mulations have been proposed as an
option for the treatment of moderate
to severe facial erythema in rosacea,
although reports of studies on its in-
dication are still pending.34 Formula-
tions of this drug for other conditions
are not recommended for use during
pregnancy. It has been categorized as
A, B, C, D and X for pregnancy, de-
pending on the vehicle and the route
of administration.
Oral Treatments. Among the oral
medications for the treatment of pap-
ulopustular rosacea during pregnan-
cy are the following options:
1. Systemic erythromycin in a dose
of 250 to 1,000 mg/day. Erythro-
mycin is a recommended antimi-
crobial agent during lactation and
in patients under twelve years of
age, and is an option when there
is intolerance or allergic sensitivity
to other medications.3 However,
erythromycin is associated with
gastrointestinal adverse effects,
which represent its primary draw-
back. 17,29
2. Clarithromycin in a dose of 250 mg
every 12 hours.17 Clarithromycin is
a macrolide antibiotic that acts at
the level of the 50 S-subunit in ri-
bosomes.
3. Azithromycin in a dose of 500 mg
three times per week. Azithromycin
it is another good alternative for
the treatment of rosacea in preg-
nancy and it appears to be better
tolerated than erythromycin. A re-
 cent report proposed the use of
this broad-spectrum antibiotic as a
treatment for pyoderma faciale in
pregnant patients because azithro-
mycin produced a complete clinical
response at twelve weeks with no
relevant side effects or disturbanc-
es during labor.35 It is not associated
with risk of miscarriage or congeni-
tal malformations.36
These three drugs are used during
pregnancy when the use of tetracy-
clines is contraindicated.23,37
The following therapeutic options
are available to treat pyoderma fa-
ciale in pregnant patients:
1. Azithromycin in a 3-day per week
schedule for 8 weeks; then one
day per week for another 4 weeks,
in combination with topical metro-
nidazole.17 It is important to note
that although some references
suggest metronidazole as part of
the basic therapy in pregnancy, the
FDA indicates that the drug pass-
es into the bloodstream in very
low amounts after being applied
to the skin –whether in lotion, gel,
or cream– and its absolute safety
has not been proven. Its prescrip-
tion is left to the consideration of
the physician, if he/she considers it
essential for the treatment of the
case. Metronidazole is classified
as pregnancy category B, and in
animal studies, no teratogenicity
or embryotoxicity was reported,
although it crosses the placental
barrier and enters the fetal circula-
tion. Its safety in pregnancy is not
sufficiently documented.38
2. Erythromycin in a dose of 2 g/day
plus oral prednisone (35 to 40 mg/
day) or oral amoxicillin combined
with erythromycin or topical met-
ronidazole.17,27 With this last combi-
nation, improvement is generally
observed after 10 days of treatment.
Some authors suggest that oral
erythromycin plus systemic steroids
is the treatment of choice for pyo-
derma faciale;12 however, it should
be noted that these drugs may
cause intrauterine growth retarda-
tion.36 The literature acknowledg-
es oral isotretinoin in combination
with prednisone as the treatment of
choice for pyoderma faciale in the
absence of pregnancy.11
Antimicrobials of the tetracycline
family are contraindicated in preg-
nancy and during lactation (category
D drugs) because they can damage
tooth enamel with color changes
and growth retardation, and cause
alterations in bone tissue as well as
maternal hepatotoxicity.39 Although
doxycycline is a category D drug, it
may be administered at imminent risk
to maternal and fetal health; howev-
er, its prolonged-release formulation
351
should be discontinued if pregnancy Table 31-2. Systemic medications
is confirmed. The need for controlled in rosacea and pregnancy
studies to determine the actual tera-
togenic effect of this substance has FDA
been suggested.40 Drug Category
Isotretinoin is contraindicated during Azithromycin I B
pregnancy in all of its formulations and Clindamycin CI B
routes of administration. Due to its Cephalexin CI B
important teratogenic effects, it is in- Erythromycin I B
cluded in category X.3,41,42 Steroids I (rosacea C
(prednisone) fulminans)
Table 31-2 shows the indications Tetracyclines CI D
and categories of oral drugs for rosa- Retinoids CI C
cea during pregnancy. Metronidazole I B
OFFICE PROCEDURES I: indicated, CI: Contraindicated
For pregnant patients with erythe- Retrieved and adapted from Bechstein SK, Ochsendorf
matotelangiectatic rosacea, intense F. Akne und rosazea in der schwangerschaft. Hautarzt.
pulsed light is a therapeutic alterna- 2017;68:111-119.
tive.17 It consists of the application of
intense pulses of non-coherent light um aluminum garnet) laser is the one
over a range of wavelengths from that has provided greater benefits in
500 nm to 1200 nm (visible spectrum). patients with non-inflammatory con-
It is useful in various dermatological ditions. Fractionated CO2 and Erbi-
processes and has recently been re- um:Yag (yttrium-aluminum-garnet) are
ported to be useful in the ophthal- used in phymatous cases.
mologic therapeutic arsenal for the
treatment of meibomian gland dys- Surgical approaches include abla-
funtion.43 Thus, it could be an option tion of prominent tissue, dermabrasion
for patients with ocular rosacea. and electrosurgery, essentially for cases
with phymas at different levels.44 Frac-
Other physical mechanisms that tional radiofrequency by micro-nee-
should be considered as therapeutic dles is a novel technique consisting
options for these patients are differ- of the application of a bipolar energy
ent types of lasers; among them, the discharge directly into the dermis,
pulsed dye, krypton and long pulsed without causing epidermal damage.
(1,064 nm) Nd:Yag (neodymium-yttri- In some reports, it is considered an
option to reduce inflammation in rosa-
cea and an opportunity for safe treat-
ment in pregnant patients.45
QUALITY OF LIFE
Recently, relevance has been given to
studies that assess the impact of der-
matoses on the patient’s existence and
social interaction. As with other skin al-
terations that occur or are exacerbated
during pregnancy –and which clearly
affect the quality of life of patients–46 it
should be noted that the exacerbation
of rosacea skin manifestations could
have an impact on the emotional state
during pregnancy, or possibly even
contribute to postpartum depression.
Proper understanding of the various
skin manifestations during pregnancy
will allow the physician to improve the
quality of life of these patients.13
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3. Tüzün Y, Wolf R, Kutlubay Z, et al.
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6. Layton AM. Dermatological caus-
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7. Information available at: http://
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who.int/ gho/maternal_health/en/
(accessed on June 15, 2017)
9. Rueda LJ, Motta A, Pabón JG, et
al. Epidemiology of rosacea in
Colombia. Int J Dermatol 2017;
56(5):510-13.
10. Picardo M, Eichenfield LF, Tan J.
Acne and Rosacea. Dermatol Ther
(Heidelb) 2017; 7(Suppl 1):43-52.
11. de Morais e Silva FA, Bonassi M,
Steiner D, et al. Rosacea fulminans
in pregnancy with ocular perfora-
tion. J Dtsch Dermatol Ges 2011;
9(7):542-3.
352
12. Yang CS, Teeple M, Muglia J, et al.
Inflammatory and glandular skin
disease in pregnancy. Clin Dermatol
2016; 34(3):335-43.
13. Urasaki MBM. Skin physiological
alterations perceived by pregnant
women attended at public health
services. Acta Paul Enferm 2010;
23(4):519-25.
14. Aydingöz IE, Dervent B, Güney
O. Demodex folliculorum in
pregnancy. Int J Dermatol 2000;
39(10):743-5.
15. Layton AM. Pharmacologic treat-
ments for rosacea. Clin Dermatol
2017; 35(2):207-212.
16. Tan J, Berg M. Rosacea: Current
state of epidemiology. J Am Acad
Dermatol 2013; 69(6S1):S27-35.
17. Bechstein SK, Ochsendorf F. Akne
und rosazea in der schwanger-
schaft. Hautarzt 2017; 68(2):111-119.
18. Machet L, Vaillant L. Piel y embara-
zo. EMC Dermatología 2017; 51(1):1-8.
19. Vora RV, Gupta R, Mehta MJ, et al.
Pregnancy and skin. J Family Med
Prim Care 2014; 3(4):318-24.
20. Tunzi M, Gray GR. Common skin
conditions during pregnancy. Am
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21. Huerta M, Avilés JA, Martínez D, et
al. Embarazo y piel. Med Integral
2003; 41(2):79-87.
22. Wayne B, Pelletier AL. Rosacea:
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looked, condition. Am Fam Physi-
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23. Troielli P, González FM, Ríos JM, et
al. Actualización y recomendaciones
para el diagnóstico y tratamiento de
la rosácea en Latinoamérica. Med
Cutan Iber Lat Am 2016; 44(S1):S7-S26.
24. Schaller M, Almeida LM, Bewley A, et
al. Rosacea treatment update: Rec-
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Pregnancy. J Am Acad Dermatol
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32. Butler DC, Heller MM, Murase JE.
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and early childhood-time to rebuild
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with systemic medications for acne.
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Clinical and histologic effects of
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Rosacea is more frequent among
fair-skinned individuals. Although
the higher incidence in people of
Celtic and northern European origin
suggests that there may be a genet-
ic component, genomic association
studies have not been able to identify
it. Conversely, patients with rosacea
have an increased expression of a va-
riety of genes with roles in the innate
and adaptive immune systems.1-3
FAIR SKIN
The overall prevalence of rosacea
in phototypes I and II is higher than
among darker skin types. In these indi-
viduals, rosacea prevalence varies ac-
cording to the geographic region and
type of population, and it is believed
to range from 1% to 22%. Among Eu-
ropean countries, the prevalence is
2.2% in Germany, 2.7% in Ireland, 10%
in Sweden and 22% in Estonia. In the
United States, prevalence has been
reported to be 8.3%.1,4-6
Diagnosis and classification of ro-
sacea are based on clinical character-
istics. In fair skin, flushing, persistent
erythema as well as telangiectases
are more easily detected than in dark-
er skins. Papules, pustules, phymas
and ocular disorder may be equally
evident both in fair and dark skins.
SKIN OF COLOR
Although rosacea is most frequently
described in fair-skinned individu-
Chapter 32
Rosacea and Skin
Color
Mercedes Flórez-White
als, recent publications indicate that
it can be observed in other photo-
types, though much less frequently.
It was found that in dark-skinned
patients the diagnosis is less fre-
quent even though the reason for
consultation was the same. This
finding suggests a possible underdi-
agnosis in dark skin. However, fewer
consultations for rosacea does not
necessarily indicate that the disease
is less common in these patients.
Under-diagnosis may be the result
of the difficulty in recognizing the
typical characteristics of rosacea,
such as the erythematous back-
ground and telangiectases, due to
the darker pigmentation in people
with phototypes V and VI; in this
population, papules and pustules
may lead to a misdiagnosis of adult
acne. In general, dermatology texts
354
do not emphasize that rosacea may
develop on black skin. Most studies
report very few cases of rosacea in
dark phototypes. Disparity among
phototypes may also be caused
by sampling bias, as no large-scale
prospective general population sur-
veys have been conducted in dark-
skinned populations.1,6-11
A study published by Al-Dabagh et
al. in 2014 has also shown that the dis-
ease is underdiagnosed in black pa-
tients. When analyzing the NAMCS
(National Ambulatory Medical Care
Survey) database from 1993 to 2010 to
determine the ethnic and racial distri-
bution of patients with rosacea, only
2% were black; 2.3% were Asian and
3.9% were Latin American. However,
skin colour was not explicitly reported
in the last two groups.6
As already mentioned, rosacea is
observed in all skin types and all con-
tinents. It is not uncommon in Turkey,
Lebanon and Iran, nor is it in Tunisia,
where a retrospective study on 244
patients diagnosed with rosacea was
conducted. In this study, published
by Khadel et al. in 2010, no reference
is made to the patients’ skin photo-
types. However, an analysis of their
photographs showed that 93% had
dark brown skin, dark hair and dark
eyes, and only 7% had fair skin and
light eyes with blond hair.11
In 2016, Dlova and Mosam pub-
lished an eight-year retrospective
study to describe clinical and histo-
logical features of skin in South Afri-
can patients with phototypes V and
VI. Out of the 6,700 patients analyzed,
15 (0.2%) -14 women and 1 man- had a
primary diagnosis of rosacea. Nine
patients had skin-colored papules,
without pustules or telangiectases,
four had erythema and telangiecta-
ses, some had phymatous lesions and
one had an ocular lesion. In most pa-
tients with papular lesions, the histo-
logical characteristics were those of
epithelioid granuloma, some of them
with caseous necrosis which was neg-
ative for acid-alcohol resistant bacilli.
The authors concluded that rosacea
continues to be underdiagnosed in
patients with black skin because
the classical characteristics can be
masked by skin pigmentation, and
that rosacea should be considered in
the differential diagnosis of patients
with phototypes V and VI with facial
papules.12
Al-Balbeesi and Halawani pub-
lished a study in which they included
50 Saudi Arabian women with photo-
types IV-VI: 40% had skin phototype
IV, 18% phototype V and 21% photo-
type VI. The purpose of the study
was to determine the characteristics
of rosacea in women with dark skin in
that country. They found that only 18%
had a family history of rosacea, which
is a low percentage compared to that
reported in fair-skinned patients. Fur-
ther, the authors reported erythema
and telangiectases were difficult to
determine due to skin colour. The
distribution of lesions in dark-skinned
individuals was center-facial, similar
to rosacea in fair skins. Extrafacial
lesions were observed in 14% of the
patients, located in the ears, upper
thorax and the back. Unlike acne, no
hyperpigmentation or hypopigmen-
tation secondary to inflammation was
seen in patients with papulopustular
rosacea. Alexis had also reported this
finding, and has hypothesized that the
severity of inflammation or inflamma-
tory mediators are different in both
diseases.7,13 Exacerbating factors in
the Arabian study were found sun ex-
posure (72%), heat (44%), dust (52%),
sweat (6%) and the use of cosmetics
(4%). Eye symptoms were identified in
64% of the Arabian subjects -a high-
er percentage than previously pub-
lished in other groups- and the need
to differentiate ocular rosacea from
allergic conjunctivitis was identified,
since both diseases may coexist and
have very similar signs and symptoms.
The difference is that IgE can be de-
tected in the tears of patients with al-
lergic conjunctivitis. Migraine history
was also reported by 16% of Arabian
subjects with rosacea, which is a low-
er percentage than that observed by
other researchers.13
Lazaridou et al. published a study
of 100 patients with rosacea from
northern Greece. Most were wom-
en and half were between 51 and 70
years old. Two thirds had skin pho-
totypes I and II; this was unlike the
general population of Greece which
mostly has skin phototypes III and IV.
About 73% of subjects reported that
their rosacea worsened with exposure
to sunlight; this was correlated with
the histological finding of solar elas-
tosis which has also been observed
by other authors. Finally, Lazaridou
demonstrated a strong pathogenic
correlation between Demodex follic-
ulorum and rosacea.14
When consulting the different
medical search engines about the
epidemiology of rosacea and skin col-
or in Latin America, only one study
by Rueda LJ et al. was found, which
355
was conducted in Colombia and pub-
lished in the International Journal of
Dermatology in 2017. These research-
ers reported that 76% of patients with
rosacea had Fitzpatrick phototypes
II and III, 12% had phototype I, 11%
had IV, and 1% had V. No rosacea was
found in patients with phototype VI.15
CONCLUSIONS
Rosacea is a chronic disease observed
on all continents. Recent epidemiolog-
ical data show that its prevalence is
undoubtedly higher than reported to
date (more than 10% of adults in some
countries). Although it is more frequent
in patients with Fitzpatrick phototypes
I and II, it can also be found in individ-
uals with skin phototypes V or VI. The FFig. 32-1. Erythematotelangiectatic
general consensus is that the disease rosacea in a patient with phototype III.
is underdiagnosed in this skin type. It is
extremely important to learn to distin-
guish clinical features in patients with
phototypes IV to VI. Erythema may be
absent or purplish. The darker the skin,
the harder to observe telangiectases.
However, the papulopustular elements
and functional signs are very similar to
those observed in light skins (Figs.32-1
to 32-3). Several authors have deter-
mined that dark-skinned patients are
more likely to develop phymatous and
granulomatous rosacea (Figs. 32-4 to
32-6).12,16,17 Patients with dark skins likely
Fig. 32-2. Papulopustular rosacea in a
patient with phototype III. (Courtesy,
Juan Carlos Diez de Medina)
Fig. 32-3. Papulopustular rosacea with
plaques in a patient with phototype IV.
(Courtesy, Juan Carlos Diez de Medina)
are not adequately represented in clin-
ical studies due to the preconceived
notion that rosacea occurs only in indi-
viduals with fair skin. This preconcep-
tion and the challenge in recognizing
clinical signs, such as erythema and
telangiectases, may contribute to the
underdiagnosis of rosacea in darker
skinned individuals. Rosacea should be
considered in the differential diagno-
sis in a patient with dark skin who has
facial flushing, heat, eye symptoms or
papulopustular elements, and absence
of comedones. This will avoid many
mistakes in diagnosis due to confusion
between rosacea and adult acne.
Fig. 32-4. Papulopustular rosacea
with a granulomatous component in a
patient with phototype IV. (Courtesy,
Juan Carlos Diez de Medina)
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Fig. 32-5. Papulopustular rosacea in a
Caribbean patient with phototype IV.
4. Woo YR, Lim JH, Cho DH, Park HJ.
Rosacea: Molecular Mechanisms
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Feldman SR. Rosacea in skin of col-
or: Not a rare diagnosis. Dermatol
Online J. 2014 Oct 15;20(10)
Fig. 32-6. Hyperplastic rosacea in
patient with phototype IV. (Courtesy,
Juan Carlos Diez de Medina)
7. Alexis AF. Rosacea in patients with
skin of color: Uncommon but not
rare. Cutis. 2010 Aug;86(2):60-2.
8. Rosen T, Stone MS. Acne rosacea
in blacks. J Am Acad Dermatol
1987;17:70-3
9. Wollina E, Verma SB. Rosacea and
rhinophyma - not curse of the Celts
but Indo Eurasians. J Cosmet Der-
matol. 2009 Sep;8(3),234-5
10. Tan J, Almeida L, Bewley A et al.
Updating the diagnosis, classifica-
tion and assessment of rosacea:
 Recommendations from the glob-
al ROSacea Consensus (ROSCO)
panel. Br J Dermatol 2017; 176:
431–8.
11. Khaled A1, Hammami H, Zeglaoui
F, et al. Rosacea: 244 Tunisian cas-
es. Tunis Med. 2010 Aug;88(8):597-
601.
12. Dlova NC, Mosam A. Rosacea in
black South Africans with skin pho-
totypes V and VI. Clin Exp Derma-
tol. 2017 Aug;42(6):670-673.
13. Al-Balbeesi AO, Halawani MR. Un-
usual features of rosacea in Saudi
females with dark skin. Ochsner J.
2014;14(3):321-7.
14. Lazaridou E, Apalla Z, Sotiraki S, et al.
Clinical and laboratory study of rosa-
cea in northern Greece. J Eur Acad
Dermatol Venereol 2010, 24:410–414
357
15. Xie HF, Huang YX, He L, et al.
An observational descriptive
survey of rosacea in the Chi-
nese population. PeerJ. 2017 Jul
7;5:e3527.
16. Bae YI, Yun SJ, Lee JB, et al. Clinical
evaluation of 168 Korean patients
with rosacea: The sun exposure cor-
relates with the erythematotelan-
giectatic subtype. Ann Dermatol.
2009 Aug;21(3):243-9.
17. Sanchez J, Somolinos AL, Almodóvar
PI, et al. A randomized, double-blind,
placebo-controlled trial of the com-
bined effect of doxycycline hyclate
20-mg tablets and metronidazole
0.75% topical lotion in the treatment
of rosacea. J Am Acad Dermatol.
2005;53:791-797.
While the role of diet in the prevention
and treatment of diseases has been
the basis of various publications and
research, medical education has long
regarded it with scepticism or direct-
ly denied it. There is little evidence of
the influence of diet in relation to flare-
ups or exacerbation of rosacea. In a
survey of 1,066 patients with rosacea,
9-13 % reported worsening with alco-
hol, spices, hot (mainly caffeinated)
drinks, tea, marinated meats, some
cheeses, and certain fruits and vegeta-
bles. Other foods, such as citrus fruits
and tomatoes, were also reported to
be triggers. The U.S. National Rosacea
Society, after a survey of more than
three thousand patients, found the
most common trigger to be red wine,
followed by hard liquors and beer, cay-
enne pepper (36 %), red pepper (34
%), black pepper (18 %), white pepper
(9 %) and paprika (9 %).1,2
ALCOHOL
Alcohol impairs the vasomotor center
of the brain, inducing peripheral va-
sodilation and affecting the immune
system. Cutaneous vasodilation and
pro-inflammatory effects contribute
to the redness and flushing that ex-
acerbate rosacea. In addition, alcohol
intake causes elevated temperature
and may induce catecholamine re-
lease, leading to bradykinin-induced
facial vasodilation. It also induces cell
cycle activators, which may contribute
to epidermal hyperproliferation in ro-
Chapter 33
Rosacea and Diet
Isabel Arias
sacea. The epidemiologic association
between alcohol intake and rosacea
is inconsistent. In an epidemiological
study which included 82,737 women
with 14 years of follow-up (from 1991
to 2005), 4,945 cases of rosacea were
identified. Compared with non-drink-
ers, excess alcohol intake was associ-
ated with an elevated risk of rosacea in
a dose-dependent fashion (p < 0.0001).
The alcoholic beverages associated
with the highest risk of rosacea were
white wine and liquors, which sug-
gestively lack anti-inflammatory com-
ponents (flavonoids) that are present
in red wine. However, red wine was
shown to contain more histamine and
other inflammatory factors (such as
resveratrol) which may also contribute
to flushing among rosacea patients.3
OMEGA-3 (w-3) AND OMEGA-6
(w-6) FATTY ACIDS
The role of omega fatty acids in the
management of rosacea is a novelty.
358
Supplements and foods containing
an abundance of these fatty acids are
used in ophthalmology to treat dry
eye, also in topical application with
alpha-linolenic acid w3. To treat ocu-
lar rosacea, flaxseed oil –rich in w3– is
recommended.4
PREBIOTICS AND PROBIOTICS
Prebiotics are non-digestible carbohy-
drates (oligosaccharides) that stimulate
the growth of probiotic bacteria in the
gut. They are found in garlic, artichoke,
peas, leeks, berries, bananas and kiwis.
Probiotics such as lactobacilli, bifido-
bacteria and enterococci, generate
host benefit by improving symptoms of
lactose intolerance, diarrhea, and irrita-
ble bowel syndrome. They also prevent
inflammatory bowel disease.
Skin benefits have been reported
in patients with acne and rosacea who
take probiotics daily. The effect, which
would be associated with the so-called
“gut-brain-skin axis,” is one reason why
they are considered supplementary
therapy. Probiotics protect the intes-
tine, which is a barrier that prevents
the inflammation that triggers acne
or rosacea. The use of topical probiot-
ics to inhibit bacteria and parasites as
well as for antimicrobial and soothing
properties is under investigation. Stud-
ies with probiotics in acne show 80 %
clinical improvement as they reduce in-
flammation by reducing the release of
inflammatory cytokines and CD8 cell
recruitment. They also activate T-regu-
latory cells, which could be extrapolat-
ed to rosacea.
Topical probiotics (Streptococcus
thermophilus) increase the produc-
tion of ceramides, which helps to re-
cover the barrier function. They also
decrease cutaneous sebum content.7
The role of stress in rosacea is due
to its impact on digestion. Stress al-
ters the intestinal wall due to bacterial
overgrowth, gastrointestinal passage
disorder, and altered intestinal barrier
function. Constipation is associated
with increased intestinal permeability
and causes decreased concentration
of healthy bacteria, such as lactobacil-
li and bifidobacteria.5-7 The role in the
management of rosacea of probiotics
from yogurt, kefir, miso, and certain
fermented foods such as sour cab-
bage, soy tempeh, and Korean kimchi
is currently under investigation.
 VITAMIN B
Vitamins of the B complex, such as
B2 (riboflavin), B6 (pyridoxine), and
B12 (cyanocobalamin) can exacer-
bate acne vulgaris or trigger an ac-
neiform rash, which is more common
in women than in men. Clinically,
this rash tends to appear as dissem-
inated papules and pustules on the
face (especially on the forehead and
cheeks). Cases of rosacea fulminans
were also described following the
administration of vitamin B; in most
of the cases, the reactions were dose
dependent. Vitamin B–triggered
rosacea does not usually respond
satisfactorily to standard rosacea
treatments, but it does improve rap-
idly on withdrawal of the offending
vitamin supplement. B-complex vita-
mins are added to many foods, such
as boxed cereals, cereal bars, cook-
ies, milk, packaged bread and others.
In the case of vitamin B-triggered
rosacea, intake of B-supplemented
food should be limited or, even bet-
ter, discontinued. In conclusion, the
role of vitamin B derivatives should
be considered when analysing possi-
ble pharmacological causes of rosa-
cea onset or exacerbation.8
MICROBIOTA
Patients with rosacea may be at high
risk of co-morbidity with gastrointes-
tinal disorders such as intestinal dys-
plasia with absence of microvilli and
inflammatory bowel disease (IBD)
(including Crohn’s disease and ulcer-
ative colitis, which involve portions
of the intestine with high concentra-
tions of bacteria), so it is necessary to
collect data regarding the existence
of gastrointestinal symptoms. There
is a controversy regarding the as-
sociation of Helicobacter pylori and
rosacea. Remission of rosacea symp-
toms has been observed with a diet
rich in coarse wheat bran and high in
fluid consumption. Since such effect
appears after reduction in the gut
transit time, the change in intestinal
bacteria is thought to be responsible
for plasma kallikrein-kinin activation
related to neurogenic inflammation
in rosacea.9 One of the functions of
the digestive system is to maintain a
physiological immune response. Con-
sequently, a gastrointestinal infection
or alteration of the enteric microbiota
by dietary patterns, connects met-
abolic processes with insulin resis-
tance, obesity, and fatty liver disease.
An imbalance in intestinal microecol-
ogy may be associated with derma-
toses induced by an overstimulated
immune system.
ALKALINE DIET
Dairy products and sugar have been
implicated as rosacea triggers. How-
ever, findings about the impact of
alkaline or acidic diets are controver-
sial. Some dietary factors modulate
the activity of the intestinal alkaline
phosphatase (IAP) enzyme, whose
359
role in inhibiting the inflammatory
response to intestinal bacteria sug-
gests a mechanism that associates
the intestinal pathologies with the
typical skin inflammation of rosacea.
Analysis of alkaline phosphatase ac-
tivity is routinely performed in blood
samples. If decreased, the acute
symptoms of rosacea can be treat-
ed with oral IAP supplementation
and dietary modification to naturally
increase IAP activity.10 IAP is a mem-
brane-dependent enzyme expressed
at the brush border of intestinal vil-
li. Its function is to dephosphorylate
and detoxify lipopolysaccharides
(LPS or endotoxins) from the surface
of gram-negative bacteria in the di-
gestive tract, thus inhibiting inflam-
mation and promoting tolerance to
normal gut flora. If not detoxified,
LPS induces the transcription of cy-
tokines, such as tumor necrosis fac-
tor alpha (TNF-a), which have local
intestinal and systemic action. In IBD,
irritable bowel syndrome and celiac
disease, there are elevated levels of
TNF-a and interleukin-1-beta.
The use of systemic antibiotics in
rosacea reduces the burden of bac-
teria and carries LPS in the intestine.
This reduces local and systemic in-
flammatory effects. Systemic met-
ronidazole, a first-line treatment of
rosacea, is also prescribed for IBD and
Crohn’s disease as it increases IAP ac-
tivity and reduces TNF-a levels.
The optimal pH for IAP activity in
vitro is in the range of 9-10; but so is
the physiological pH of 7.5 in the in-
testine, using LPS as a substrate. The
typical western diet causes metabol-
ic acidosis; an alkaline diet improves
IAP activity, which decreases inflam-
mation in rosacea. There are several
dietary factors that modulate IAP
activity. It is inhibited by phytates
found in grains and legumes, and by
phenylalanine from artificial sweet-
eners. Short-chain fatty acids (butyr-
ate), derived from the fermentation
in the gut of dietary fibre or ingest-
ed directly from butter, increase IAP
activity. Fish oil has the same effect
in the intestinal brush border, gut
lumen and serum. The mechanism
is an increased transcriptional rate
and high enzyme secretion via the
hormone cholecystokinin, which is
released in response to oil feeding.
IAP is also activated by dietary zinc
and vitamin A. Vitamin A analogues,
such as isotretinoin, increase IAP ac-
tivity by a mechanism not yet known.
There are at least 4 alkaline phos-
phatase isoforms in serum. Further
studies are underway to attribute en-
zyme activity specifically to the intesti-
nal isoform, either by electrophoretic
or chromatographic separation of the
isoforms, or by measuring changes in
enzyme activity in response to inhib-
itors acting differentially on the iso-
forms. The hypothesis is that IAP is a
central mediator of the inflammatory
symptoms of rosacea, either by oral
supplementation or by dietary modi-
fication.
The endogenous acid production
of foods is estimated by their protein
and potassium content, as in meats,
dairy products and cereal grains that
are poor in potassium. In turn, potas-
sium-rich foods, such as fruits, veg-
etables and nuts, are alkaline, while
legumes have a neutral pH.
In addition to an alkalizing diet,
some foods promote IAP activity,
such as zinc-rich oysters, orange veg-
etables rich in beta-carotene (pro-vi-
tamin A), and oil-rich cold-water fish.
Conversely, other foods inhibit IAP
activity, such as phytates, found most-
ly in whole grains, legumes, seeds and
nuts (Table 33-1).10 Phytic acid is a che-
lator of several nutritionally important
minerals, such as calcium, magnesium,
iron, and zinc. When a mineral binds
to phytic acid it becomes insoluble,
precipitates and will not be absorbed
in the intestines. This process may
contribute to mineral deficiencies in
people whose diets are based on veg-
etables with phytates.11
Probiotic lactobacilli and other spe-
cies of endogenous digestive micro-
flora are an important source of the
enzyme phytase, which catalyses the
release of phosphate from phytate and
the hydrolysis of complexes formed
by metallic ions or phytates and other
cations. This makes them more soluble,
which ultimately improves and facili-
tates their intestinal absorption. Probi-
otics also promote the colonization of
the gastrointestinal tract by beneficial
gram-positive bacteria, which decreas-
es the overgrowth of gram-negative
bacteria containing LPS. They also
reduce inflammation in irritable bowel
syndrome by limiting intestinal bacteri-
al overgrowth.
Artificial sweeteners are also a
source of phenylalanine, while cheeses
and processed meats promote an ele-
vated renal acid load, inhibiting IAP.
Table 33-1. Dietary recommendations to promote IAP activity
Oysters
Pumpkin, sweet potato, carrots
Herring, mackerel, salmon and sardines
Butter
Dietary fibre
Fresh fruit and vegetables
Beverages and probiotic foods Lacto-fermented
Decrease consumption of:
Phytates
Artificial sweeteners
Processed meats and cheese
Translated from Whitehead J. Intestinal alkaline phosphatase: The molecular link between rosacea and gastrointestinal dis-
ease? Medical hypotheses. Elsevier 73(2009):1019-1020.
360
Other foods that trigger or ag-
gravate rosacea are also consid-
ered, all of which contain histamine.
For example, vanilla, chocolate, soy
sauce, onion, garlic, curry, mustard,
vinegar and chili (or pepper) –which
also contains capsaicin–flavonoids,
vitamin B1, and B2.12,13 Due to drug
interactions, caution should be ex-
ercised when administering medica-
tions based on lavender, chamomile,
and liquorice to decrease the symp-
toms of rosacea.
FOOD TEMPERATURE
Food temperature can aggravate ro-
sacea. There are studies that have
quantitatively shown the skin sen-
IAP Activators
Rich in zinc
Rich in betacarotene
Source of fishoils
Source of butyrate
It forms butyrate by fermentation in the intestine
Negative acidic renal load
Probiotic gram + bacteria IAP inhibitors
Soaking and cooking of grains and legumes
Source of phenylalanine
Elevated acidic renal load
sitivity of some rosacea patients to
heat, especially in those with the
papulopustular rosacea subtype. The
triggers of rosacea are hot beverag-
es, in addition to heat coming from
the environment and from doing ex-
ercise.14
In the doctor’s office, patients ask
about what diet to adopt and are
often frustrated because dermatol-
ogists do not guide them. However,
clinicians should keep in mind that
providing reliable medical infor-
mation can help minimize patients
seeking information from internet
sources that may or may not be cor-
rect.15 However, what may aggravate
some patients’ condition may not ag-
gravate others. The metabolic effect
of the diet as a whole may be more
relevant than the effect of individu-
al foods.10 Dietary modification in
rosacea is part of the treatment and
should be considered an additional,
safe, and inexpensive measure.
References
1. Keri J, Rosenblatt A. The role of diet
in rosacea and acne. J Clin Aesthet
Dermatol 2008; 1(3):22-26.
2. Divya SA, Sriharsha M, Narotham
RK, et al. Role of diet in dermatolog-
ical conditions. J Nutrit aFood Sci
2015; Vol 5(issue 5):400.
3. Suyun Li BA, Eunyoung Cho,
Drucker AM, et al. Alcohol intake
and risk of rosacea in US women. J
Am Acad Dermatol 2017; 76(6):1061-
1067.e2
4. National Rosacea Society. (n.d.)
Rosacea Triggers Survey. Ac-
cessed at http://www. rosacea.
org/patients/materials/triggers-
graph.php.
5. Bowe WP. Could probiotics be the
next big thing in acne and rosacea
treatments? AAD NEWS releases
30 January 2014. Schaumberg, IL,
USA. (Feb. 3, 2014).
6. Bowe WP. Probiotics in acne and ro-
sacea. Cutis 2013; 92:6-7.
7. Baquerizo Nole K, Jim E, et al. Pro-
biotics and prebiotics in derma-
tology. J Am Acad Dermatol 2014;
71(4):814-821.
8. Martín JM, Pellicer Z, et al. Rosacea
triggered by vitamin B complex sup-
plement. Actas Dermosifilogr. 2011
Apr; 102(3):223-4. [Article in Spanish]
9. Chun-Ying W, Yun-Ting Ch, Cha-
oKeui J, et al. Risk of inflammatory
bowel disease in patients with ro-
sacea: Results from a nationwide
361
cohort study in Taiwan. J Am Acad
Dermatol 2017; 76:911-917.
10. Whitehead J. Intestinal alkaline
phosphatase: The molecular link
between rosacea and gastrointes-
tinal disease? Med Hypotheses.
2009;73:1019-1020.
11. Hurrell RF. Influence of vegetable
protein sources on trace element
and mineral bioavailability. J Nutri-
tion 2003; 133(9):2973-7.
12. Allevato M, Donatti L. Rosácea.
Acta Terapéutica Dermatológica
2004;27:6
13. Aguirre Hernández E, Muñoz Ocotero
V. El chile como alimento. Revista Cien-
cia.amc.edu.mx. 2015. pp.1-23 (http://
www.revistaciencia.amc.edu. mx/imag-
es/revista/66_3/PDF/Chile. pdf)
14. Guzman-Sanchez DA, Ishiuji Y, Patel
T, et al. Enhanced skin blood flow
and sensitivity to noxious heat stim-
uli in papulopustular rosacea. J Am
Acad Dermatol 2007; 57(5):800-805.
15. Allinia H, Moradi Tuchayi S, Farhangian
ME, et al. Rosacea patients seeking
advice. Qualitative analysis of patient’s
posts on a rosacea support forum. J
Dermatol Treat 2016; 27(2):99-102.
Rosacea is a chronic inflammatory
disease, mainly affecting the central
part of the face (malar area, nose
and forehead). It is characterized by
flushing, erythema, telangiectases
and episodes of inflammation, with
formation of papules and pustules,
and possible ocular involvement. Its
pathogenesis, which is as yet poorly
clarified, encompasses intrinsic fac-
tors such as genetic susceptibility,
vascular matrix degeneration and
pilosebaceous unit abnormalities1
as well as extrinsic factors (trigger-
ing and aggravating factors such as
heat, climatic variation, sun expo-
sure, alcohol abuse, spicy foods, and
emotional stress). From the clinical
point of view, rosacea is classified into
four different types, which can occur
simultaneously: erythematotelangiec-
tatic, papulopustular, phymatous, and
ocular rosacea.
The prevalence of rosacea is
higher in fair-skinned populations
of northern and eastern European
descent where it has been estimat-
ed to be around 2-10 %.2,3 U.S. stud-
ies indicate a prevalence of 5 %. 4
Rosacea is more common in women
than in men, in a 3:1 female to male
gender ratio, and occurs mainly in
adults aged 30 to 60 years. Only
the phymatous form -due to the hy-
perplasia of the sebaceous glands
located in the nose- is more fre-
quent in men.
Chapter 34
Quality of Life
Denise Steiner
The primary impact of rosacea on
quality of life involves the social as-
pect. Because rosacea exclusively
affects the face, it has a significant
impact on self-esteem and self-confi-
dence. Symptoms such as flushing, er-
ythema and episodes of inflammation
generate feelings of anxiety and em-
barrassment, which in turn cause the
patient to avoid social activities. Mild
social avoidance often evolves into
more severe conditions, such as social
phobia and depression.5,6 Historically,
flushing and rhinophyma have been
associated with alcohol abuse and
poor hygiene, which has increased
the social stigma of rosacea.7-9
The number of patients with psy-
chological alterations and loss of qual-
ity of life is often underestimated by
dermatologists. Compared with acne,
there have been many fewer studies
on the impact of rosacea on quality
of life (seven-fold fewer).10 In a survey
362
conducted on 400 patients, the Na-
tional Rosacea Society found that 75
% had low self-esteem, while 70 % felt
embarrassed or frustrated.11
Reasons why dermatologists un-
derestimate or minimize the impact
of rosacea include insufficient prepa-
ration to properly address this issue
during medical training and frustra-
tion at the lack of results from avail-
able treatments. However, it should
be noted that the impact on the qual-
ity of life is not directly correlated to
the severity of the condition, patients
with severe rosacea may not report
a large impact on quality of life while
others with mild disease may indicate
a great impact. Many times, erythema
due to telangiectases is more embar-
rassing than ocular rosacea.
Few studies have compared quality
of life before and after rosacea treat-
ment. In general, treatment improves
quality of life; therefore, correct and
complete evaluation from a clinical
and quality of life point of view can
improve clinical and psychological
symptoms are improved, particularly
when the approach is tailored to the
patient’s concerns and desires.12-23
ASSESSMENT
All patients with rosacea should un-
dergo a comprehensive, detailed
and individual assessment, primari-
ly because –as indicated above– the
psychological impact may not direct-
ly correlate with disease severity.
The important items to be evaluated
are sex, age, habits, profession, so-
cial and cultural aspects. There are
several quality of life questionnaires
that are useful in this process. Some
are specific for rosacea, others for
dermatology, and others also for
health in general (Table 34-1).23-27 It is
important to be trained in the use of
these tools and always use the same
with a patient. The RosaQoL is a
questionnaire specifically designed
to evaluate the impact of rosacea
on quality of life. It was developed
and validated in 2007, on the ba-
sis of Skindex-29.28 It consists of 21
questions divided into three groups:
symptoms, functional disability, and
emotional disability over the last
four weeks. The possible answers
are: never, rarely, sometimes, often
and always. It is the most specific
and ideal instrument for monitoring
Table 34-1. Quality of Life Questionnaires The Skindex is a dermatology-spe- ed to each of the 24 facets that make
cific questionnaire that evaluates the up the original instrument. Although
Rosacea-specific worsening of symptoms, psychoso- it is used less frequently than oth-
Rosacea Quality of Life (RosaQoL) cial aspects and emotional state. It ers, it has the advantage of allowing
Used in dermatology was developed to detect changes to compare a variety of pathologies
Dermatology Life Questionnaire Index (DLQI) throughout the time, as well as differ- from different countries.
Dermatology Quality of Life Scales (DQoLS) ences among patients. The 29-ques-
Dermatology Specific Quality of Life Instrument (DSQL) tion version –more refined than the IMPACT ON QUALITY OF LIFE
Skindex (Skindex, Skindex-29, Skindex-16) 61-question version– combines easier While the number of studies using
Used throughout the health arena administration with improved psycho- these questionnaires to evaluate the
EuroQoL (EQ-5D) metric properties. It is the most wide- impact of rosacea on quality of life is
Short Form Health Survey (SF-12 y SF-36) ly used version in different countries. relatively small, it is possible to draw
World Health Organization Quality Of Life-100 (WHOQOL-100) Skindex yields a final score ranging certain conclusions from existing
World Health Organization Quality Of Life-BREF (WHOQOL-BREF) from 0 to 100: the higher the result, data. Rosacea has a mild to moder-
the worse the negative impact on ate impact on quality of life,3,12,13,15,30-32
quality of life. which is not directly proportional to
a patient with rosacea. The Derma- it is an excellent tool for monitoring the medical severity of the condition
tology Life Quality Index (DLQI) the impact of skin disease on the The WHOQOL-100 is a gener- but varies with the clinical form. Ap-
is a dermatology-specific quality of quality of life, and ideal for compar- ic questionnaire, developed by the propriate treatment can result in im-
life evaluation method. It was devel- ative studies between rosacea and World Health Organization (WHO), provement in quality of life.12-23
oped in 1994 in the United Kingdom other skin diseases. with the purpose of providing differ-
and has proven valid and reliable for ent cultures with the same evaluation The greatest improvements in
various skin diseases; in addition, the The Short-Form (SF) is a gener- system. It consists of one hundred quality of life are generally seen in the
DLQI has validated translations in ic instrument for quality of life as- questions referring to six domains: female sex; only one study showed a
several languages.29 DLQI consists of sessment. It is validated worldwide physical, psychological, level of inde- more significant impact on men.30 And
10 questions, to be answered in the for all types of diseases. The SF-36 pendence, social relations, environ- although assessment by age group
form of multiple choice, that assess consists of 36 questions grouped ment and spirituality/religiousness/ was not conclusive, it seems that the
the psycho-social damage of skin dis- into 8 domains: functional capaci- personal beliefs. The answers vary most extreme age groups also have a
ease and the impact on the patient’s ty, physical aspects, pain, general from “Not at all” (1) to “Extremely” (5). higher impact on quality of life.18,30,33
quality of life during the last seven state of health, vitality, social as- These domains are divided into 24 fac-
days. The result varies from 0 to 30; pects, emotional aspects, and men- ets, each consisting of four questions. DLQI makes it possible to compare
the higher the score, the greater the tal health. The answers give a score In addition to the 24 specific facets, different skin diseases. In one study,
disability presented. DLQI is often from 0 to 100, from the worst gen- the instrument has a twenty-fifth fac- rosacea scores ranged from 4 to
used to monitor a number of chron- eral state of health to the best. It is et consisting of general quality of life 17.3; however, it should be noted that
ic dermatoses, mainly psoriasis and easy to apply and has low specifici- questions. The WHOQOL-BREF is a there was only one score (17.3) greater
atopic dermatitis. It is the most wide- ty. There is also a version consisting short version of the WHOQOL-100 than 10 among 11 patients evaluated.
ly used questionnaire in dermatolo- of 12 questions, the SF-12, of even with 26 questions: two general quality This range of scores is similar to the
gy. Although not specific for rosacea, simpler application. of life questions and the others relat- ranges found in other dermatoses. In
363
psoriasis, DLQI scores range from 1.7
to 18.2; in atopic dermatitis from 6 to
8.5;32 in chronic urticaria from 3.9 to
10.9; in lower limb ulcer from 5.5 to 7;
in melasma from 3.5 to 11.5; in occupa-
tional contact dermatitis from 3.8 to
6.7; in pruritus from 1 to 10.5; and in vit-
iligo from 4.8 to 15. Psoriasis and acne
are the dermatoses with the highest
number of studies and have been
more heavily considered than other
systemic diseases.34
Three studies compared DLQI
among the different forms of rosacea
and the results were as follows: erythe-
matotelangiectatic scores ranged from
2.8 to 4 - 6; papulopustular scores were
4.9 to 6 - 7, and phymatous scores were
3.6 to 5.6 - 6).31 The impact on the quality
of life was also evaluated when rosacea
was associated with anxiety, and values
were higher (4.05 to 4.67 - 6).30
Administration of SF-36 to patients
with rosacea showed a worsening of
quality of life in all subgroups: func-
tional capacity, physical aspects, pain,
general state of health, vitality, social
aspects, emotional aspects and men-
tal health.33
In addition to the specific medical
questionnaires, a perception survey
was conducted via the Internet, where
1,000 people compared photos of
women with and without rosacea.35
Women with rosacea were perceived
as more insecure, not as healthy, less
intelligent and less successful than
women with healthy skin.
Treatment and Quality of Life
Rosacea can be treated using mono-
therapy or combined therapy. Topical
therapy options include brimonidine,
azelaic acid, ivermectin, and metroni-
dazole. In oral therapy, doxycycline and
isotretinoin have been more effective
than tetracycline and metronidazole.
Laser and light therapies are also useful,
but scientific evidence is scarce. When
quality of life is evaluated post-treat-
ment, questionnaires show significant
improvement in quality of life scores
with different therapies.36 In an eval-
uation of 308 patients with rosacea,
before and after various treatment mo-
dalities, both topical and oral (oral anti-
microbials, isotretinoin, sun protection
and associations), the DLQI showed
an improvement of 6.93 ± 5.18 for 4.36
± 4.82.15 After 56 days of topical treat-
ment with 10 % sodium sulfacetamide +
5 % sulphur emollient foam, Trumbore
et al.16 reported an improvement in the
RosaQoL (1.17 to 6 for 0.9 to 6). Baldwin
evaluated doxycycline monotherapy
versus doxycycline in combination with
topical therapy for 12 weeks, and report-
ed improvement in quality of life in both
treatment groups.18 Stein et al. demon-
strated an improvement in the quality
of life by both DLQI and RosaQoL after
using 1 % ivermectin versus control.19 In a
study of 583 patients with mild to mod-
364
erate rosacea treated with azelaic acid
as monotherapy or in combination with
oral or topical treatments, the Investi-
gator Global Assessment mean score
decreased from 3.52 to 2.1. Patients with
combined therapy showed better re-
sults. Regardless of the therapy, all the
components of RosaQol showed an im-
provement during the treatment.17
Although there are few studies, a
statistically significant improvement
in quality of life has been shown with
pulsed dye-laser.12-14 For this reason,
this laser is considered an important
therapeutic option, mainly for erythe-
ma in the telangiectatic form.
Other laser and intense pulsed
light treatments may be used to com-
plement topical or oral therapy, po-
tentially boosting anti-inflammatory
activity, although these light therapies
have limited effect on diffuse facial er-
ythema and telangiectases.37
The impact of corrective make-
up on self-esteem was evaluated in
a prospective study including rosa-
cea along with several other derma-
toses. Among 63 female patients, 10
with rosacea, the DLQI was evaluated
after one month of makeup use and
showed an improvement in the qual-
ity of life.21
Another way to measure the qual-
ity of life of patients with rosacea are
the questionnaires that evaluate how
much a patient is willing to pay for full
cure or guaranteed symptom control.
These values can be absolute or relat-
ed to a percentage of the monthly in-
come. More than 50 % of patients with
rosacea would be willing to pay up
to 10 % of their monthly income. The
values were higher than in other der-
matoses, such as blistering diseases,
fungal infections, herpes zoster, warts,
lupus erythematosus, and vitiligo.5
CONCLUSION
Rosacea is a common pathology in
a dermatologist’s daily life. Given
that severe symptoms are rare, it is
often underestimated. Despite the
few studies conducted on this issue,
its impact on the quality of life is im-
portant, as it impairs self-esteem and
can evolve to more serious conditions
such as depression. It is important
for the dermatologist to evaluate the
patient correctly, especially through
the use of questionnaires, in order to
identify the causal factors and treat
them in the best possible way.
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