4 Bollous

Understanding
Dermatology
Volume 1
Autoimmune and Inherited
Bullous Diseases
Ahmad Kamel, MD
U n derstanding
D erm atology
Series
S eco n d E d itio n
Volume 1
Autoim m une an d Inherited

Bullous Diseases
L ecture N otes for P o stg ra d u a te D erm atology S tu d en ts
Board and Fellowship Review
A h m ad Kamel, MD
2017
Understanding Dermatology Series
Ahmad Kamel, MD
Volume 1
Autoimmune and Inherited Bullous Diseases
First edition © 2015

Second edition © 2017
^. <u o / y o v j
978 - 977 - 90 - 4807 - 9 :

Dedication
To my little family:
My wife, Yomna.
My son, Omar.
The jo y o f my life.
Acknowledgm ents
I would like to thank all staff members at Dermatology, Andrology and
Venereology department, Faculty o f medicine, Al-Azhar University who first
taught, and are still teaching, me the science, practice and passion of
dermatology.
Also, I would like to express my gratitude for my colleagues and readers
of the first edition whose encouragement and comments helped greatly to
improve this edition.
Preface to the Second Edition
The main content, format and organization of this edition is maintained
as was in the first edition. However, certain changes have been done in this
edition to improve both the content and the quality of the book including:
• Updating the contents according to the latest literature published in 2017.
• Highlighting the topics frequently encountered in board and fellowship
exams. Throughout the text, these are highlighted with MCQ.
• Adding more MCQs for exam training.
I hope this work will continue to be useful for both clinicians and
dermatology students preparing for their exams.
A h m a d K am el, M D
C airo, E gypt
2017
Preface to the First Edition
Dermatology is a continuously expanding medical specialty. In addition
to clinical dermatology, many other specialties are included within the broad
scope of dermatology such as dermatopathology, phototherapy, light and laser
therapy, cosmetic and surgical dermatology.
Aim of “U nderstanding D e rm atology” series
Despite the broad scope of dennatology, undergraduate medical students

curricula at most medicine faculties do not allocate enough hours for
dermatology. On the other hand, most dermatology “textbooks” are actually
“reviews of literature” that necessitate some sort of “previous” knowledge in the
field of dermatology to understand these textbooks. Graduate doctors intending
to specialize in the field of dermatology find it very difficult to start reading from
these textbooks mainly due to the discrepancy between their “actual” knowledge
in dermatology and the knowledge “required” to understand these books.
“Understanding dermatology” series aims at “bridging” this gap by

providing a simplified step-by-step approach to the common dermatologic
conditions as well as the basic knowledge in dermatology.
Features of “Understanding D e rm atology” series
In order to achieve its main aim, “Understanding Dermatology ” series has

been written with certain features to help readers understand dennatology in
better and easier ways. These features are
• A step-by-step guide through basic and clinical dermatology: the series
takes into consideration the logic order of presenting information starting
with the essential knowledge to understand the topic before dealing with main
topic. It is highly recommended that the reader should read each volume
in orderly fashion and not to jump into subjects in the middle o f the text.
• Reader-friendly text format: the series has been written in large enough
easy-to-read fonts. The most important or key points were written in bold.
• High-quality images and illustrations: to illustrate the clinical and histo-
pathological features of diseases, pathogenesis cascades and treatment
algorithms.
• Reference to latest updates in dermatology: throughout the text, the reader
will find references to the latest articles published in dennatology journals.
• At-a-glance chapter summaries: at the end o f each chapter, the reader will
find a brief and concise summary of the main points in the chapter (this is
good for pre-exam revision or rapid recall of information).
• MCQs and essay questions fo r self-assessment: at the end of each volume,
this section will help the reader test how much information he/she gained.
Scope and limitations of “Understanding
D e rm atology" series
In medical practice, books are not the only tool. Readers should attend
clinical rounds and gain enough training in clinical dermatology to enhance their
diagnostic, intervention and therapeutic skills. Books only give the basic
knowledge that should be “applied” in practice.
Moreover, ‘‘Understanding Dermatology'” series is intended mainly for

post-graduate diploma and master degrees students. Doctors preparing for
MD degrees should enhance their knowledge by referral to more detailed
textbooks and recent updates in dermatology literature.
Finally, I hope this work will be useful for junior dermatologists and
help them better understand and practice dermatology.
A h m a d K am el, M D
Cairo, E gypt
2015
Reader guide
Icons used in this book series and their
meaning
Throughout the book, the reader will find many different icons with
pieces of information next to them. Icons tells you the nature of these information
and how to benefit form them.
Clinical # Helpful tips

application Useful hints
Tells you how to delp-T^ highlighting important
apply basic knowledge Tips. points in the subject or
in clinical practice. " : maki ng them clearer.
Advanced
Com pare and information
Detailed information,
contrast
mostly o f academic
Highlights the main
interest. Junior
difference between
dermatologists reading
similar topics.
the book for the first
time can skip this.
Chapter
Study plan 0 sum m ary
Tells you how to study
a certain topic or
chapter in an
organized fashion.
V
D
A brief and concise
summary of the main
points in the chapter
(good for pre-exam
revision).
Controversial Literature
issue reference
Clarifies certain Tells you where to find
debates regarding detailed and updated
classification and information about the
management o f skin M topic in dermatology
diseases. journals.
Th e author
Ahmad Kamel, MD
Lecturer,
D erm atology, A ndrology and V enereology departm ent
Faculty o f m edicine, A l-A zhar U niversity
• MD dermatology, venereology and andology (2014) - Al-Azhar University.

• Diploma o f Medical Application of Laser in dermatology (2012) - National
Institute of Laser Enhanced Sciences (NILES), Cairo University.
• MSc dermatology, venereology and andology (2010) - Al-Azhar
University.
• MBBCh (2006) - Al-Azhar University.
Correspondence information:
Suggestions, comments or criticisms are truly appreciated and welcomed at
• Email: dr_akamel@hotmail.com
• Facebook: Ahmad Kamel
List of abbreviations
A2ML1 Alpha-2-macroglobulin- EBS-MP EBS with mottled
like-1 protease inhibitor pigmentation
ABSIS Autoimmune bullous skin EBSS EBS superficialis
disorder intensity score ECP Extracorporeal photopheresis
ACE Angiotensin converting EDF European Dermatology Forum
enzyme ELISA Enzyme-linked
AD Autosomal dominant immunosorbent assay
ANA Antinuclear antibodies EM Electron microscopy
AR Autosomal recessive EM Erythema multiforme
BM Basement membrane EOR Endoplasmic reticulum
BMZ Basement membrane zone overload response
BP Bullous pemphigoid G6PD Glucose-6-phosphate
BPAG1 Bullous pemphigoid dehydrogenase
antigen 1 GFD Gluten-free diet
BPAG2 Bullous pemphigoid GSE Gluten-sensitive enteropathy
antigen 2 GVHD Graft-versus-host disease
C Complement HD Hemidesmosome
Ca2+ Calcium HHD Hailey-Hailey Disease
CBDC Chronic bullous disease of HHV Human herpesvirus
childhood HLA Human leucocyte antigen
CD Celiac disease HPV Human papillomavirus
CD Cluster o f differentiation HSV Herpes simplex virus
CLAS Congenital localized absence ICS Intercellular space
o f skin idp inner dense plaque
CP Cicatricial pemphigoid IEN Intra-epidermal neutrophilic
DD Darier Disease IF Immunofluorescence
DD Differential diagnosis Ig Immunoglobulin
DDEB Dominant DEB IIF Indirect IF
DEB Dystrophic EB IVIG Intra-venous
DH Dermatitis herpetiformis immunoglobulins
DIF Direct IF JEB Junctional EB
dm dense midline JEB-H JEB Herlitz
DM Dowling-Meara JEB-nH JEB non-Herlitz
DP Desmoplakin K14 Keratin 14
Dsc Desmocollin K5 Keratin 5
Dsg Desmoglein KIF Keratin intermediate filaments
EADV European Academy of KS Kindler syndrome
Dermatology and Venereology LABD Linear IgA bullous
EB Epidermolysis bullosa dermatosis
EBA Epidermolysis bullosa LAD Linear IgA disease
acquisita LD Lamina densa
EBS EB simplex LDH Lactate dehydrogenase
LL Lamina lucida
MMP Matrix metalloproteinase SERCA2 Sarco(endo)plasmic
Mn2+ Magnesium reticulum Ca2+ ATPase type 2
NaCI sodium chloride SH Sulphydryl (Thiol)
NC16A Non-co.llagenous 16A SLD Sub-lamina densa
odp outer dense plaque SLE Systemic lupus erythematosus
PA Plasminogen activators SPCA1 human secretory pathway
PA Pyloric atresia Ca2+/Mn2+ ATPase protein 1
PDAI Pemphigus disease area SSS Salt-split skin
index SSSS Staphylococcal scalded skin
PG Pemphigoid gestationis syndrome
PG Plakoglobin TEM Transmission electron
PNP Paraneoplastic pemphigus microscopy
PP Plakophilin TEN Toxic epidermal necrolysis
PUVA Psoralen-UVA TG2 Tissue transglutaminase
RDEB Recessive DEB TG3 Epidermal transglutaminase
ROS Reactive oxygen species Th Helper T-cells
SCC Squamous cell carcinoma UPR Unfolded protein response
SCPD Subcorneal pustular UV Ultraviolet
dermatosis
Contents
Introduction to Bullous Diseases
Chapter 0 What you should know before studying bullous
diseases
Pem phigus fam ily
Part 1 The intra-epiderm al autoim m une bullous 10
diseases
Chapter 1 Introduction to Pemphigus Family 11
Chapte 2 Pemphigus Vulgaris 15
Chapte 3 Pemphigus Vegetans 25
Chapte 4 Pemphigus Foliaceus 26
Chapte 5 Pemphigus Foliaceus Variants 30
Chapte 6 Paraneoplastic pemphigus (PNP) 32
Chapte 7 Immunoglobulin A (IgA) Pemphigus 36
Chapte 8 Drug-induced Pemphigus 39
Pemphigus appendix 41
Pem phigoid fam ily
Part 2 The sub-epiderm al autoim m une bullous 46
diseases
Chapter 9 Introduction to Pemphigoid Family 47
Chapter 10 Bullous pemphigoid (BP, Pemphigoid) 54
Chapter 11 Cicatricial pemphigoid (CP) 62
Chapter 12 Epidermolysis bullosa acquisita (EBA) 69
Chapter 13 Dermatitis herpetiformis (DH) 73
Chapter 14 Linear IgA bullous dermatosis (LABD) 84
Chapter 15 Bullous SLE 90
D arier D isease and H ailey-H ailey D isease
Part 3 94
The intra-epiderm al gen etic bullous diseases
Introduction to Darier Disease and Hailey-Hailey
Chapter 16 Disease (HHD)
95
Chapter 17 Darier Disease 98

Chapter 18 Hailey-Hailey Disease (HHD) 109
E piderm olysis B ullosa
Part 4 118
The sub-epiderm al gen etic bullous diseases
Chapter 19 Epidermolysis Bullosa (EB) 119
Appendices 131
Self-assessm ent 133
Understanding Dermatology
C h a p te r
Introduction to Bullous
Diseases
What you should know before studying
bullous diseases 0
W hat are bullous diseases?
Bullous diseases, also called “vesiculo-bullous or blistering diseases”, are
diseases characterized clinically by blisters i.e. vesicles (if small) and / or
bullae (if large) (Fig 0.1).
(a) (b)
Fig 0.1 Examples of some bullous diseases, (a) herpes zoster, (b) bullous pemphigoid, and (c)
porphyria cutanea tarda.
W here in the skin m ay blisters o c cu r?

Blisters in the skin may occur
1. in the epidermis (in this case, called intra-epidermal) due to defects in the
adhesion between keartinocytes (Fig 0.2 a) or
2. below the epidermis (in this case, called sub-epidermal) due to defects in
the proteins of the basement membrane zone (dermo-epidermal
junction) (Fig 0.2 b).
Fig 0.2 Levels of blisters in the

skin, (a) intra-epidermal (b) sub-
epidermal.
• In the epidermis, keratinocytes are held together by structures

called desmosomes.
Bullous Diseases
M ec h an ism s a n d c a u s e s of skin blistering

There are 2 main mechanisms by which skin blisters may occur:
1) Immunological (antibody- mediated):

Autoantibodies attack structural proteins in the skin resulting in blisters. This
group of disorders is called “im m unobullous” or “autoim m une bullous”
diseases. Autoantibodies may attack
a) the desmosomal proteins (that mediate cell-to-cell adhesion in the
epidermis) O impaired adhesion o f epidermal cells “keratinocytes” to
each other ■=> intra-epidermal blisters. This results in a group of
diseases collectively called “pemphigus”, or
b) the basement membrane proteins (that mediate cell-matrix “epidermal-
dermal” adhesion in the skin) <=> impaired adhesion of the epidermis to
the basement membrane ^ sub-epidermal blisters. This results in a
group of diseases collectively called “pemphigoid”.
• Autoimmune blistering diseases (i.e. pemphigus and

pemphigoid) are treated mainly with immunosuppressive
agents (e.g. systemic steroids) that decrease production of
autoantibodies.
2) Non-immunological:
Skin blistering is mediated by mechanisms other than autoantibodies.
Examples of these mechanisms / causes include:
a) Genetic: due to inherited defects in the synthesis and / or modification

o f structural proteins in the skin resulting in blisters. Again, these
defects may affect
• the desmosomal proteins ■=> intra-epidermal blisters as in Darier’s
and Hailey-Hailey diseases, or
• the basement membrane proteins O sub-epidermal blisters as in
epidermolysis bullosa (EB).
* ■1 V # EB is a collective term including a group of disorders
. iru characterized by blistering of the skin and mucosaefollowing
y mild mechanical trauma. Therefore, the alternative term is
* : mechanobullous diseases.______________________________
b) Traumatic e.g. friction / rubbing blisters.
c) Infections:
•
Bacterial e.g. bullous impetigo.
•Viral e.g. herpes simplex, herpes zoster and varicella.
d) Inflammatory e.g. eczema and insect bites.
e) Metabolic e.g. porphyria cutanea tarda.
f) Drug reactions
2
• NOT all bullous diseases are immunobullous (i.e. pemphigus

or pemphigoid). Bullous diseases may be caused by a variety of
'Tips. other causes such as insect bites and bullous impetigo.
S tu d y plan
• In this volume, we are going to study only the autoimmune and
genetic blistering diseases, whether intra-epidermal or sub-
epidermal (Fig 0.3).___________________________________
Bullous diseases
Autoimmune Genetic
i
Infra- Sub-epidermal
Intra-
Sub-epidermal epidermal
epidermal Epidermolysis
Pemphigoid Darier's and bullosa
Pemphigus
family Hailey-Hailey
family diseases (some types) ,
F ig 0.3 A utoim m une and genetic blistering diseases.
Table 0.1 A u to im m u n e and genetic Level of blister

blistering diseases. Intra-epidermal |! Sub-epidermal
Mechanism Autoimmune Pemphigus family Pemphigoid family
of blister Darier's disease Epidermolysis bullosa
Genetic
formation Hailey-Hailey disease (some types)
Diagnosis of a uto im m une, g e n e tic and

o th e r bullous diseases
Diagnostic approach to a case o f skin blistering includes the triad of (1) history
taking, (2) examination, and (3) investigations.
1) History faking;
• Age of onset:
o Since birth —> EB.
o Middle age —* pemphigus,
o Elderly —>pemphigoid.
• Family history: positive in EB.
• Relation to trauma—►EB.
• Drug intake: e.g. ACE inhibitors (drug-induced pemphigus).
• Symptoms:
o Asymptomatic.
o Pruritus —>bullous pemphigoid / dermatitis herpetiformis,
o Painful erosions —►oral pemphigus / Hailey-Hailey disease.
3
Bullous Diseases
2) Exam ination:
• General examination:
■ General condition —>poor in oral pemphigus.
G Associated symptoms / systemic affection.
• Local examination:
n Skin: examine the blisters for
o Flaccid / tense,
o Small / large.
o On normal / erythematous skin,
o Contents (clear fluid / blood / pus),
o Distribution (site and symmetry),
o Configuration e.g. annular in IgA pemphigus,
o Healed blisters (scarring / post-inflammatory hyper- or hypo-
pigmentation).
• In pemphigus, blisters are flaccid (because they are relatively

superficial in the epidermis) and rupture easily before
reaching a large size.
« In pemphigoid, blisters are tense (relatively deep below the
epidermis) and may reach a large size before they rupture.
■ Mucosa: oral, conjunctival, nasal, genital etc (predominant mucosal

affection in cicatricial pemphigoid).
■ Others: e.g. nail and teeth affection (in Darier’s disease and EB
dystrophica respectively).
3) Investigations:
• Detection o f skin blister:
o Skin biopsy for routine histopathology.
o Cytologic examination (Tzanck smear).
• Detection o f autoantibodies (in autoimmune bullous diseases):
o Immunofluorescence (IF),
o Enzyme-linked immunosorbent assay (ELISA),
o Immunoprecipitation and immunoblotting.
• Investigations fo r genetic blistering diseases (i.e. EB):
o Transmission electron microscopy (TEM).
o Immunofluorescence antigenic mapping (see later, page 8).
Routine histopathology
• Site o f biopsy: early small intact vesicle. The whole v
vesicle should be biopsied. A small portion o f the intact 1 e Blister :j I
skin should be included in the biopsy specimen (Fig 0.4).
•S Small intact whole vesicle —>to determine level of \
blistering.
S Early —►to avoid secondary bacterial infection Fig 0 4 site of skin
(changes the nature of inflammatory infdtrate). b iopsy for routine
histology.
4
• Ruptured blisters or excoriated lesions are of little value and

should not be sampled.
• Punch biopsies done through the center of a large blister are of
little value.
Tip* • In patients with only oral lesions (e.g. oral pemphigus), a
biopsy specimen should be obtained from the active border of
a denuded area because intact blisters are rarely encountered.
• Diagnostic clues in a histopathology specimen o f a bullous lesion include:

1. the level of the blister (Fig 0.5):
o intra-epidermal —>■e.g. pemphigus,
o sub-epidermal —>e.g. pemphigoid.
Intra-epidermal blisters (i.e. pemphigus) are further subdivided into

• supra-basal (deep)
uelp-Cul • intra-spinous
Tip* • intra-granular or sub-corneal (superficial)
vk Different types ofpemphigus have different levels o f blisters.
2. the mechanism o f blister formation e.g. acantholysis —>pemphigus.

3. the nature of the inflammatory infiltrate (Fig 0.5):
o eosinophils, neutrophils or minimal infiltrate.
(a) (b) (c)

Fig 0.5 Different levels of blisters and types of inflammatory infiltrates in different bullous
diseases, (a) intra-epidermal, supra-basal with eosinopils (pemphigus vulgaris) (b) intra-epidermal,
sub-comeal with neutrophils (IgA pemphigus) (c) sub-epidermal with eosinopils (bullous
pemphigoid) .
Immunofluorescence (IF)
* Definition: a method to detect
pathogenic autoantibodies
whether they are
1. bound to their target
antigens in the skin or
2. circulating freely in the Fig 0.6 General principle of IF
blood (before reaching and
binding their target antigens in the skin). IF may also detect
complement.
• General principle: IF uses anti-antibodies labeled with fluorescent dye
and examined under fluorescent (UV) microscope —»■fluorescence.
5
Bullous Diseases
» Types: there are 2 main Pathogenic autoantibodies

types o f IF (Fig 0.7): circulating in the blood
o direct IF (DIF) and
o indirect IF (IIF)
D irect IF (DIF)
> Detects pathogenic auto #
antibodies in vivo bound
to their antigens in the
patients’ skin or mucous V
membranes. Pathogenic autoantibodies
> Sample: peri-lesional skin bound to their target
or mucous membrane antigens in the skin
MCQ. Why peri-lesional
and not lesional skin? the
immune deposits are
degraded in blistered skin,
and DIF may be falsely
negative.
> Steps: Add anti-antibodies
labeled with fluorescent
dye and examine under
fluorescent microscope 5 ml serum or Peritesional skin for
(ONE step). dotted feood direct
for indirect immnofluorescece
immunofluoresoencs
Indirect IF (IIF)
> Detects pathogenic auto
antibodies circulating
freely in the blood.
> Sample: blood sample —►
serum. j Substrata
> Steps: (TWO steps)
1. Add serum to a substrate
-------------------- =4
(e.g. human skin, monkey
esophagus or rat bladder).
2. Add anti-antibodies
labeled with fluorescent
dye and examine under
fluorescent microscope.
• Interpretation o f I F test:
1. Type o f immune-reactants
deposited:
• Immunoglobulins
(Igs) e.g. IgG or IgA.
• Complement e.g. C3. F ig 0.7 Steps o f the 2 types o f IF test
2. Site o f immune-reactants deposition
6
IF is positive only in autoimmune bullous diseases. It is

U&lp^ul negative in genetic and other non immune-mediated bullous
Tip?- diseases.
« Findings o f IF test in autoimmune buttons diseases'

1. In pemphigus, pathogenic autoantibodies are precipitated on
the surface of keratinocytes (because they attack desmosomes
found on the cell surface) (Fig 0.8 a).
2. In pemphigoid, pathogenic autoantibodies are precipitated in a
linear pattern along the basement membrane (BM) (because
they attack structural proteins of the BM) (Fig 0.8 b).
(a) (b)
Fig 0.8 Findings of IF testing in pemphigus (a) and pemphigoid (b).
Substrates for IIF staining:

• Monkey esophagus is more sensitive for pemphigus vulgaris.
UpAp-vul • Normal human skin or guinea pig esophagus is better for
Tip?- pemphigus foliaceus.
• Rat bladder is used to detect paraneoplastic pemphigus MCQ.
Site o f biopsy:
• Routine histopathology: early small intact vesicle.
• DIF: peri-lesional normal skin or mucous membrane.
D IF versus IIF :
DIF IIF
Sample Peri-lesional skin Serum
Detects Bound to their target Free, in the
autoantibodies antigen, in the skin circulation
Steps 1 step only 2 steps
Invasiveness Invasive Minimally invasive
Enzyme-linked immunosorbent assay (ELISA)

• Technique:
The patient’s serum is tested on ELISA plates pre-coated with recombinant
antigens. Thus, specific antibodies can be detected.
7
Bullous Diseases
• Advantages:
1. Antigen-specific.
2. Measure for disease activity: ELISA titers demonstrate parallel
fluctuations with disease activity and are useful in monitoring disease
activity, planning schedules for tapering corticosteroids, and predicting
flares or relapses before there is clinical evidence.
The most important and routinely employed investigations are:

• Routine histopathology
• Immunofluorescence (IF)
• ELISA
• Electron microscopy (EM)________________________
Immunoblotting and immunoprecipitation:

1. Immunoblotting is a qualitative test to identify which
autoantigen(s) is involved, (a) Molecules in a skin protein
extract are separated by gel electrophoresis, (b) The protein
pattern is electrophoretically transferred to a membrane filter,
(c) The filter is immersed in diluted patient serum, (d) Bound
IgG is visualized by staining. Antigens become visible as
purple bands (identified by apparent molecular weight).
a gg| b c d
■p
2. Immunoprecipitation: The patient serum is incubated with

protein G-coupled beads. Protein G specifically binds IgG in
the serum, (a) Patient IgG bound to beads is added to
radioactive labeled protein extracts, (b) The IgG on the beads
bind the disease-causing antigen(s). (c) The beads are spun
down by centrifugation, (d) The supernatant containing the
other skin proteins is removed, (e) The antigen(s) is visualized
by gel electrophoresis followed by immunoblotting.
8
S tu d y plan
In this volume, there are 4 main parts:
• Part 1. Pemphigus family
• Part 2. Pemphigoid family
• Part 3. Darier's and Hailey-Hailey diseases
• Part 4. Epidermolysis bullosa
C h a p te r s u m m a ry
D
B ullous diseases
0 Bullous “Blistering” diseases are characterized clinically by blisters (vesicles and
bullae).
0 Blisters in the skin may be intra-epidermal or sub-epidermal.
0 In the epidermis, keratinocytes are held together by desmosomes.
0 There are 2 main mechanisms by which skin blisters may occur:
1. Immunological (antibody- mediated) o “immunobullous” or “autoimmune
bullous ” diseases:
0 intra-epidermal blisters ■=>“pemphigus family”.
0 sub-epidermal blisters ■=>“pemphigoid family”.
2. Non-immunological: mediated by mechanisms other than autoantibodies
e.g. genetic, traumatic, infections, inflammatory, metabolic or drugs.
0 Genetic bullous diseases are due to inherited defects in the synthesis and/or
modification of structural proteins in the skin:
1. intra-epidermal blisters ^ Darier’s and Hailey-Hailey diseases.
2. sub-epidermal blisters o epidermolysis bullosa.
0 Diagnostic approach to a case of skin blistering includes the triad of history
taking, examination and investigations.
0 History taking should include age of onset, family history, drug intake and
symptoms (asymptomatic, pruritus or pain).
0 General examination should include general condition, associated symptoms and
systemic affection.
0 Local examination should include both the skin and mucosae
0 Skin blisters should be examined whether flaccid / tense, small / large, on normal
/ erythematous skin, contents (clear fluid/blood/pus), distribution, configuration
and healing sequlae (scarring/post-inflammatory hyper- or hypo-pigmentation).
0 Examination of mucosa should include oral, conjunctival, nasal, genital and
other mucosal sites.
0 Other sites to be examined include nail and teeth.
0 The most important investigations are histopathology, IF, ELISA, and EM.
0 Routine histopathology of early small intact vesicle should determine the level
of the blister, the mechanism of blister formation and the nature of the
inflammatory infiltrate.
0 IF detects pathogenic autoantibodies whether bound to their target antigens in
the skin (direct IF) or circulating freely in the blood (indirect IF). It gives
information about type and site of deposition of immune-reactants (Igs and
complement).
0 ELISA tests patient’s serum for specific antibodies (disease activity monitoring).
9
Part 1
i
Pemphigus
family
The intra-epidermal autoimmune bullous
diseases
C h a p te r
Introduction to
Pemphigus Family
The intra-epidermal autoimmune bullous
diseases 1
W hat is pem phigus?
Pemphigus is NOT a single disease. Instead, the term “pem phigus” refers to a
group of chronic autoimmune blistering diseases that are
1. caused by autoantibodies directed against the cell surface of keratinocytes
(desmosomes), resulting in the loss o f cell-cell adhesion of keratinocytes (a
process called acantholysis) and blister formation (Fig 1.1).
2. characterized clinically by blisters (i.e. vesicles and bullae) affecting the
skin and mucous membranes (the term “pemphigus” stems from the Greek
“pemphix”, meaning blister or bubble).
'3. characterized histologically by intra-epidermal blisters (clefts).
4. characterized immunopathologically (immunofluorescence, IF) by
presence of skin-bound and circulating autoantibodies (IgG and other
types) directed against the cell surface of keratinocytes.
Kera+inocyte
F ig 1.1 P ath ogen esis o f p em phigus. A utoantibodies attack desm osom es resulting in
acantholysis and intra-epiderm al blister form ation.
• Desmosomes are cell-cell junctions on the keratinocyte cell

surfaces of composed of proteins called “cadherins” (calcium-
dependent cell-cell adhesion molecules). Cadherins include
Pelp-Cul desmogleins (Dsg) and desmocollins (Dsc). Other desmosomal
proteins include plakoglobin, plakophilin and desmoplakin (see
Tip^ later, pages 131-132).
• In different types of pemphigus, autoantibodies attack
different member(s) of the cadherin family.
u
Bullous Diseases
W hat a re th e ty p e s of p e m p h ig u s?
Members in the pemphigus family are classified into major types (or forms),
subtypes and variants (Table 1.1).
Table 1.1 Members of the pemphigus family

Types Subtypes Variants
s’ > mphigus vegetans
■ Mucosal-dominant
Pemphigus*
btypes:
1) Pemphigus type
ere ■=>Neumann
vulgaris ■ Muco-cutaneous
type
a o> Hallopeau type
calized variant
■Herpetiform
signs
2) Pemphigus
;•7hematosus
foliaceus
at f "demic variant ^
/ T y . selvagem
3) Paraneoplastic
pemphigus (PNP)
■ Sub-corneal
pustular dermatosis
(SCPD)-like type
4) IgA pemphigus
■ Intra-epidermal
neutrophilic (IEN)
type
5) Drug-induced
pemphigus
*Herpetiform Pemphigus: a clinical variant o f pemphigus foliaceus (most
patients) or pemphigus vulgaris (the remainder of cases).
The classification scheme of pemphigus adopted in table 1.1

is used for simplification and represents the author’s opinion.
It is NOT a universally accepted classification. Different
authors may use different classification schemes.__________
12
S tu d y plan
In studying different types of pemphigus, the following points
should be fulfilled:
1. Subtypes and/or variants of this type (if present),

2. Pathogenesis: target protein(s) in desmosomc,
3. Epidemiology:
• Incidence / prevalence.
• Type o f patient: age / sex / race (geographical distribution).
4. Clinical picture:
• General condition.
• Symptoms.
• Signs: skin / mucosa lesions.
UPlt>Cui • ' n pemphigus, blisters are flaccid upture easily and usually
heal without scarring (why?).
T ip s ---------------------------------------------------------------------------------
5. Histopathology:
In pemphigus, histopathology reveals

1. Intra-epidermal cleft. Level of cleft differs by type of
pemphigus e.g. supra-basal (pemphigus vulgaris) or sub
uelpTAl corneal (SCPD-like IgA pemphigus).
T ip s 2. Acantholytic cells (rounded-up cells).
3. Inflammatory infiltrate, usually eosinophils (however, certain
types of pemphigus may have different types of infiltrates)
6. IF (DIF, IIF):
UpicTul * Pemphigus, IF shows intercellular IgG autoantibodies (IgA

y in IgA pemphigus) ± C3 on the cell surface of keratinocytes.
Tips- ----------------------------------------------------------------------------------
7. Other investigations e.g. ELISA.

8. BB: Three questions for the DD:
1. Is it immuno-bullous?
a) Differentiate pemphigus from non-
immune bullous diseases. 2. Is it pemphigus?
3. Which type?
b) Differentiate pemphigus from
pemphigoid.
c) Differentiate between different types of pemphigus.
9. Prognosis.
10. Treatment.
13
Bullous Diseases
gf
C h a p te r su m m a ry
g P e m p h ig u s
0 Pemphigus refers to a group of chronic autoimmune blistering diseases

that are
1. caused by autoantibodies directed against desmosomes resulting in
acantholysis.
• In different types of pemphigus, autoantibodies attack different
member(s) of the desmosomal proteins.
2. characterized clinically by blisters affecting the skin and mucous
membranes.
3. characterized histologically by intra-epidermal blisters.
4. characterized immunopathologically (immunofluorescence, IF) by
intercellular IgG autoantibodies ± C3 on the cell surface of
keratinocytes.
0 Pemphigus family is classified into types, subtypes and variants.
0 The 5 main types of pemphigus are:
1. Pemphigus vulgaris
• 2 subtypes: mucosal-dominant / muco-cutaneous
• 1 variant: pemphigus vegetans
■ 2 subtypes: Neumann (severe) / Hallopeau (mild)
2. Pemphigus foliaceus
• 2 variants: localized (pemphigus erythematosus) / endemic (Fogo
selvagem)
f t Herpetiform Pemphigus: a clinical variant of pemphigus foliaceus
or pemphigus vulgaris.
3. Paraneoplastic pemphigus (PNP)
4. IgA pemphigus
• 2 subtypes: SCPD-lilce / IEN
5. Drug-induced pemphigus
C h a p te r
Pemphigus Vulgaris
Definition
• Pemphigus vulgaris is the commonest and main type o f pemphigus. It is a
chronic autoimmune intra-epidemal blistering disease o f the mucosa
and skin characterized by flaccid blisters and erosions due to
autoantibodies attacking the desmosomal proteins.
S u b type s
1. Mucosal-dominant subtype (mucosal erosions - minimal or no skin
involvement).
2. Muco-cutaneous subtype (mucosal erosions + skin blisters and erosions).
V a ria n ts
• Pemphigus vegetans.
P athogenesis (ta rg e t p ro te in in the desm osom e)

• Mucosal-dominant type: desmoglein 3 (Dsg 3) IVtCQ.
• Muco-cutaneous type: desmoglein 3 (Dsg 3) + desmoglein 1 (Dsg 1).
Distribution of Dsg 1 and Dsg3 in the skin and mucous membranes

MCQ
(a) In the skin:

• D sgl is expressed throughout the epidermis, but more intensely in the
superficial layers.
• Bsg3 is expressed in the lower portion of the epidermis (basal and supra-
basal layers) (Fig 2.1 a).
(b) In the mucosa:

• D sgl and Dsg3 are expressed throughout mucosa (but D sgl is expressed at
a much lower level than Dsg3) (Fig 2.1 b).
15
Bullous Diseases
(a) (b)
Fig 2.1 Distribution of Dsgl and Dsg3 in the skin (a) and mucosa (b).
Desmoglein compensation theory

• If one desmoglein is present in enough amounts, it can compensate for the
loss of the other.
Application of desmoglein compensation theory in determining the

level of blistering in pemphigus vulgaris subtypes
a) Mucosal-dominant subtype: affection o f Dsg3 only —►
• In the skin: Dsgl compensates (NO skin lesions).
• In the mucosa: Dsgl CAN’T compensate ^ mucosal lesions
(;theoretically, the whole thickness of mucosa should be affected).
b) Muco-cutaneous subtype:
• Affection of BOTH Dsg3 and Dsgl —►affection of both skin and
mucosa (theoretically, the whole thickness o f skin / mucosa should be
affected).
In pemphigus vulgaris, theoretically, the whole thickness of

skin and/or mucosa should be affected by blistering. However,
actually only the supra-basal level is affected. Why?
There are 2 possible explanations:
1. Cell-cell adhesion in the basal and supra-basal layers might be
weaker than in other parts of the epidermis / mucosa (fewer
desmosomes).
2. Autoantibodies, which penetrate from the dermis, might have
better access to the lower part of the epidermis.
E p id e m io lo gy
• Incidence / prevalence: rare (variable worldwide, ranging from 0.05 to
2.7 per 100 000 per year).
• Age: middle-aged (mean age o f onset o f disease is 50 to 60 years).
o may also affect the elderly and children (juvenile pemphigus
vulgaris).
• Sex: affects men and women equally.
• Race (Geographical distribution): all over the world (higher incidence
in Ashkenazi Jews).
16
C linica l picture
G eneral condition:
® Poor general condition (due to affection of
mucosa! “ora!” lesions and poor nutrition).
Sym ptom s:
_ , . . . „ , Fig 2.2 O ral erosions in pem phigus
• Oral lesions are painful. vulgaris (Bologniciy 2012)
• Skin lesions may be asymptomatic or rarely pruritic.
Mucous membrane lesions: (Fig 2.2)

• Present in essentially all patients.
• Painful erosions of the oral mucosa (intact blisters are rare, because they
are fragile and break easily). This may result in decreased oral intake o f
fo od or liquids (poor general condition).
• Other mucosal sites may be involved e.g. throat (hoarseness and difficulty
in swallowing), esophagus, conjunctivae, nasal mucosa, vagina, penis, anus
and labia.
Skin lesions: (Fig 2.3)

9 Present in 50 - 70 % of the patients.
® Flaccid, thin-walled, fragile, easily ruptured
blisters (on normal-appearing or erythematous
skin) —*■painful erosions that ooze and bleed easily
—> become partially covered with crusts.
® Lesions can occur anywhere on the skin surface
with a predilection for the scalp, face, neck, upper
chest and back.
9 Fluid within the bullae is initially clear but may
become hemorrhagic, turbid, or even purulent
(pus).
® Fleal with hyperpigmented patches without Fig 2.3 Pem phigus vulgaris:
flaccid blisters and erosions
scarring.
(Bolognia, 2012).
Special diagnostic signs:

Nikolsky sign:
• Firm sliding pressure or rubbing with a finger on normal-looking skin
will separate epidermis from dermis, producing blister/erosion (due to
absence of cohesion within the epidermis).
® Indicates active disease.
® Positive also in toxic epidermal necrolysis (TEN).
Asboe-Hansen sign (indirect Nikolsky, Nikolsky II sign, bulla-spread
phenomenon):
9 Gentle pressure on an intact bulla forces the fluid to spread under the
skin away from the site o f pressure (spread of bullae).
17
Bullous Diseases
H isto p a th o lo gy
• Site o f biopsy: early small intact vesicle. The whole vesicle should be
biopsied.
* Histopathologicalfindings:
1. Intra-epidermal blister just above the basal cell layer (supra-basilar).
Basal cells maintain their attachment to the basement membrane via
hemidesmosomes (appearance of a “row of tombstones”) (Fig 2.3 b).
2. Loss of cell-cell adhesion o f keratinocytes (acanttiolysis) —* rounded-
up (acantholytic) keratinocytes are seen in the blister cavity (supra-
basilar acantholysis) (Fig 2.3 a).
3. Inflammatory cells: eosinophils (in the blister cavity and the dermis).
(a) (b)
Fig 2.3 Histopathology of pemphigus vulgaris, (a) supra-basilar blister with acantholytic cells and
eosinophils (b) row of tombstones.
• In most types of pemphigus, the inflammatory infiltrate is

formed mainly of eosinophils. Flowever, there are exceptions
-pips. to this rule (see later in the text).________________________
Im m u no flu o re sce n ce
Site o f biopsy:
• Direct IF (DIF): peri-lesional normal
skin or mucous membrane.
• Indirect IF (IIF): blood sample —<■
serum.
Findings: (type o f immune-reactants and site Fig 2.4 IF in pem phigus vulgaris.
o f deposition)
• DIF: IgG ± C3 on the keratinocyte cell surfaces (inter-cellular) (Fig 2.4).
This pattern is referred to as “chicken wire appearance” MCQ.
• IIF: circulating IgG better detected on Monkey esophagus.
18
IgG deposition is seen in up to 100% of patients with active

pemphigus vulgaris.
IgM deposition is not found.
Direct IF is the most reliable and sensitive diagnostic test for
Tips- all forms of pemphigus. If the direct IF is negative, the
diagnosis of pemphigus should be seriously questioned.
In IF of pemphigus, unlike IgG, complement (C3) deposition is

not necessarily observed (±). Why?
• This is probably because the dominant subclass of IgG is IgG4
which does not fix complement.
Methods for detection o f autoantibodies in pemphigus:

1. IF (direct IF and indirect IF)
2. Enzyme-linked immunosorbent assay (ELISA)
Tips- Immunoprecipitation
4. Immunoblotting
Differentia! Diagnosis
A. The differentia! diagnosis of mucosal (oral) lesions:
1. Acute herpetic stomatitis
2. Aphthous stomatitis
3. Erythema multiforme or Stevens-Johnson syndrome
4. Lichen planus
5. Systemic lupus erythematosus
6. Mucous membrane (cicatricial) pemphigoid
• The differential diagnosis of mucosal (oral) lesions in

delpTwl pemphigus vulgaris includes any skin disease with oral
Tip?- (mucosal) erosions or ulceration.
B. The differential diagnosis of cutaneous lesions:

1. Other forms o f pemphigus
2. Sub-epidermal immuno-bullous diseases e.g. bullous pemphigoid
3. Non-immune bullous diseases e.g.
• Erythema multiforme
• Elailey-Hailey disease
• Transient acantholytic dermatosis (Grover’s disease)_____________
• Demonstration of IgG autoantibodies directed against the cell
surface of keratinocytes by IF (or any other method) is the gold
standard for the diagnosis of pemphigus, and can
Tips- differentiate pemphigus from other vesiculobullous or pustular
diseases.
19
Bullous Diseases
Prognosis
Causes o f death in pemphigus vulgaris
• Before the use of systemic corticosteroids, pemphigus vulgaris was
usually a fatal disease; most patients died within 2-5 years o f the onset of
the disease because large areas of the skin lost their epidermal barrier
function, leading to the loss of body fluids or to secondary bacterial
infections.
• After the introduction of systemic corticosteroids and
immunosuppressive agents, prognosis has greatly improved BUT
morbidity, and occasional mortality, is still present due to complications of
therapy.
T re a tm e n t
Strategy and goals of therapy:
Because pemphigus is caused by pathogenic autoantibodies, therapy must aim
to reduce autoantibody production (in addition to suppression of
inflammation).
Lines of treatm ent:
(A) Topical treatment

• Topical corticosteroids (for localized mild lesions. They are rarely
effective alone).
• Topical antibiotics.
• Topical immunomodulators (e.g. tacrolimus).
(B) Systemic treatment

The 2 main lines of systemic treatment in pemphigus vulgaris are systemic
corticosteroids and immunosuppressive (corticosteroid-sparing) agents.
Systemic corticosteroids:
• The mainstay of therapy for pemphigus MCQ.
• Oral prednisone (standard treatment): 1 mg/kg/day (usually 60 mg/day).
• Intra-venous pulse therapy: Methylprednisolone 1 gram /day (over a
period of 2-3 hours, with continuous cardiac monitoring) for 3-5
consecutive days - Used for severe cases.
Immunosuppressive agents:
• Used for their corticosteroid-sparing effect to reduce the side effects of
the corticosteroids (with the goal o f therapy to control the disease with the
lowest possible dose of corticosteroids).
• When combined with corticosteroids —* early control o f the disease and
an increased percentage o f clinical remissions (Table 2.1).
20
• In some patients, especially those who are elderly with limited

disease or those in whom corticosteroids are contraindicated,
immunosuppressive agents alone may be used.
• In young patients, the potential increase in malignancies that
might be associated with the use of these drugs must be taken
into account.
T able 2.1 Im m unosuppressive (C orticosteroid-sparing) agents

D rug Dose M ajo r side effects
2^1 mg/kg/day
Azathioprine
(100-300 mg/day) Nausea, myelosuppression (dose-
Mycophenolate dependent)
2-3 g/day
mofetil
1-3 mg/kg/day Hemorrhagic cystitis, sterility and
Cyclophosphamide
(50-200 mg/day) leucopenia
Cyclosporine 5 mg/kg/day Nephrotoxicity and hypertension.
Nausea, vomiting, hepatotoxicity,
Methotrexate 7.5-20 mg/week
myelo-suppression, teratogenicity.
Rituximab 375 mg/m2 once Progressive multifocal
weekly for 4 weeks leukoencephalopathy
Others
High-dose IVIG “intra-venous immunoglobulins”
• A blood product prepared from pooled plasma
• It has immune-modulatory effects when used in a high dose (400
mg/kg/day for 5 consecutive days)
• Effective and safe for steroid-resistant pemphigus
Plasmapheresis
• Quickly reducing the titers of circulating autoantibodies
• Used for severe pemphigus unresponsive to a combination of prednisone
and immunosuppressives (1-2 times per week)
Extracorporeal photopheresis (ECP): 2 days per month
• Rituximab is an anti-CD20 monoclonal antibody. It’s a potent

B-cell-depleting agent resulting in a decline in IgG (including
HfilpA'ul anti-desmoglein) autoantibodies. CD20 is a transmembrane
glycoprotein specifically expressed on B cells (but its
Tip£ expression is lost upon plasma cell differentiation). Used for
refractory pemphigus.
How to m onitor the therapeutic response?

• Clinically: (1) number of new blisters per day and (2) rate o f healing of
lesions. If NO new lesions for 2 weeks —►clinical remission.
• Titer o f circulating auto-antibodies: determined by indirect IF or ELISA.
• Once clinical remission is obtained, changes in the titer of circulating
autoantibodies are helpful in adjusting the dose of prednisone.
21
Bullous Diseases
• The use of pemphigus severity indices e.g. PDAI (pemphigus

disease area index) and ABSIS (autoimmune bullous skin
disorder intensity score) provides a means of standardizing the
assessment of disease extent in patients with pemphigus.
The choice of therapy:

The choice of therapy is dependent on ...
1. Severity of the disease at presentation.
• M ild cases —» systemic corticosteroids alone.
• Moderate to severe cases —> combination o f systemic corticosteroids
+ immunosuppressive agents.
2. Patient-related factors (e.g. age, general health, and associated medical
illnesses such as diabetes, hypertension, or tuberculosis).
• For patients in whom corticosteroids are contraindicated,
immunosuppressive agents are used alone.
3. Drug-related factors (e.g. action onset, efficacy, adverse effects, and
cost).
A lgorithm of therapy: (Fig 2.5)

• Unless there is an absolute contraindication, the initial therapy of
pemphigus vulgaris is systemic corticosteroids whether
A alone —> for mild cases, or
A in combination with immunosuppressive agents —> for ...
o moderate to severe cases.
o mild cases not responding to systemic corticosteroids alone or if
serious adverse effects develop.
• If there is an absolute contraindication for systemic corticosteroids,
immunosuppressive agents may be used alone.
F ig 2.5 A lgorithm for treatm ent o f pem phigus vulgaris.
22
If complete remission is achieved with the combined therapy:

• the dosage of the immunosuppressive drug is maintained.
• prednisone is slowly tapered (5 - 10 mg every 2 weeks)
• when a dose of 5-10 mg/day prednisone is reached, careful tapering of
the immunosuppressive drug.
• If there is no recurrence, the patient undergoes a maintenance regimen
of 5 mg prednisone daily or every other day for several years.
• Choice of a specific immunosuppressive agent depends on the

severity of the case. A usual practice is to begin with
azathioprine or mycophenolate. Other choices are reserved for
more severe or refractory cases.
The regimen adopted here for tapering protocol and

maintenance therapy is NOT universally agreed upon. There
is a great variation among clinicians regarding tapering
doses and durations and whether to use a maintenance
regimen or not. As a general rule, steroid tapering should
be performed with small dose decrements and slowly to
avoid relapses and this should be tailored according to
case. It is always the clinician judgment that determines
these variables based upon individual case approach._____
P em phigus tre atm e n t guidelines 2014

According to European Dermatology Forum (EDF) and the European Academy of
Dermatology and Venereology (EADV).
F irst-line treatm en t
• Predniso(lo)ne
> Initially 0.5 mg to 1.5 mg/kg/day.
> Taper by 25% reduction in biweekly steps and at <20 mg/d more slowly.
> Add proton pump inhibitors/H2 blockers, vitamin D and calcium.
Second-line treatm en t (in refractory disease or in case of contraindications to
glucocorticoids)
• Azathioprine or
• Mycophenolate mofetil or
• Mycophenolic acid
T h ird -line tre a tm e n t (in refracto ry disease or in case of contraindications to
im m unosuppressants)
• Anti-CD20 monoclonal antibody (rituximab)
• Intravenous immunoglobulins
• Immunoadsorption
• Cyclophosphamide
• Dapsone
• Methotrexate
H For further details, refer to Hertl et al. Pemphigus. S2 Guideline for diagnosis and
treatment-guided by the European Dermatology Forum (EDF) in cooperation with
the European Academy of Dermatology and Venereology (EADV). JEADV 2014.
23
Bullous Diseases
P e m p h ig u s vu lg a ris
0 The commonest and main type o f pemphigus.

0 Chronic autoimmune intra-epidemal blistering disease of the mucosa
and skin.
0 2 main subtypes:
A Mucosal-dominant subtype (mucosal erosions + minimal or no skin
involvement - target antigen: Dsg 3).
☆ Muco-cutaneous subtype (mucosal erosions + skin blisters and erosions
- target antigen: Dsg 3 + Dsgl).
0 1 variant: pemphigus vegetans.
0 Affects the middle-aged o f both sexes with higher incidence in the Jewish.
0 Poor general condition (due to mucosal “oral” lesions and poor nutrition).
0 Oral lesions are painful while skin lesions may be asymptomatic or
pruritic.
0 Mucous membrane lesions are present in essentially all patients (erosions
- intact blisters are rare).
0 Skin lesions: flaccid, thin-walled, fragile, easily ruptured blisters —>
painful erosions that ooze and bleed easily —* become partially covered
with crusts.
0 Nikolsky sign: firm sliding pressure or rubbing with a finger on normal-
looking skin will separate epidermis from dermis, producing blister/erosion
(indicates active disease).
0 Asboe-Hansen sign (indirect Nikolsky, Nikolsky II sign, bulla-spread
phenomenon): gentle pressure on an intact bulla forces the fluid to spread
under the skin away from the site of pressure (spread of bullae).
0 Histopathology (early small intact): supra-basilar cleft with acantholytic
cells and eosinophils.
0 Immunofluorescence:
☆ DIF: IgG ± C3 on the keratinocyte cell surfaces (inter-cellular).
IIF: circulating IgG better detected on Monkey esophagus.
0 Differential Diagnosis:
☆ The differential diagnosis of mucosal (oral) lesions: e.g. acute
herpetic stomatitis, aphthous stomatitis, erythema multiforme, Stevens-
Johnson syndrome...
A The differential diagnosis of cutaneous lesions:
o Other forms of pem phigus
o Sub-epidermal im m uno-bullous diseases e.g. bullous
pemphigoid
o N on-im m une bullous diseases e.g. erythema multiforme
0 Treatment: systemic corticosteroids ± immunosuppressive agents (e.g.
azathioprine).
24
C h a p te r
Pemphigus Vegetans
3
Definition
• A rare vegetative variant of pemphigus vulgaris. It is a reactive pattern of
the skin to the autoimmune insult of pemphigus vulgaris.
S u b type s
1. Severe ri> N eum ann type
2. Mild ri> Hallopeau type
C lin ica l p ictu re (Fig 3.i)

• Flaccid blisters (as pemphigus vulgaris) that
become erosions and then form fungoid
vegetations or papillomatous proliferations.
• Common sites: intertriginous areas and on the
scalp or face.
Fig 3.1 Pemphigus vegetans.
• The affected skin is easily secondarily infected E xtensive vegetating
which explains the foul smelling. papillom atous lesions.
• Supra-basilar acantholysis (as pemphigus vulgaris).
o Papillomatosis and acanthosis.
• Characteristically, there is intense
inflammatory cell infiltrate (reactive)
containing numerous eosinophils, and
intraepidermal microabscesses (Fig 3.2).
Differential Diagnosis
• Hailey-Hailey disease.
• Pemphigoid vegetans.
Fig 3.2 Histopathology of
• Blastomycosis-like pyoderma. pemphigus vegetans. N ote the
• Pyodermatitis-pyostomatitis vegetans. m arkedly acanthotic epiderm is.
Tre a tm e n t as pemphigus vulgaris.
25
Bullous Diseases
C h a p te r
Pemphigus Foliaceus
4
S u b ty p e s ■=>n o n e
V a ria n ts
1. Localized (Sporadic) variant Pemphigus erythematosus
2. Generalized (Endemic) variant ■=> Fogo selvagem
P athogenesis (ta rg e t prote in in desm osom e)

• Desmoglein 1 (Dsg 1) “refer to Fig 2.1”
o In the skin: Dsg3 functionally compensates for the impaired Dsgl in
the lower part of the epidermis ■=> superficial blisters
o In the mucosa: cell-cell adhesion is mainly mediated by Dsg3 =>
NO blisters in the mucous membranes
Epidem iology
• Incidence / prevalence: generally, less common than pemphigus vulgaris
• Age and sex: as pemphigus vulgaris
C lin ica l p icture

General condition:
• Good (generally, patients with pemphigus foliaceus are not severely ill).
Symptoms:
• Burning and pain in association with the skin lesions.
Mucous m em brane lesions:

• NO clinically apparent mucosal involvement (even with widespread
cutaneous disease).
• It is extremely rare, if ever, for patients with pemphigus

foliaceus to develop mucosal involvement (in contrast to the
extensive oral lesions in pemphigus vulgaris).____________
26
Skin lesions:
• Well-demarcated scaly, crusted cutaneous erosions, on an erythematous
base.
o NB. Because the vesicle is so superficial and fragile, only the
resultant crust and scale are seen.
• Seborrheic distribution (face, scalp and upper trunk MCQ) (Fig 4.1).
• Nikolsky sign is present in pemphigus foliaceus.
(a) (b)
Fig 4.1 Pemphigus foliaceus. (a) Scaly, crusted erosions widely distributed on the back, (b) As the
disease progresses, the lesions become confluent
H isto pa th o lo gy
Site o f biopsy: early blisters.
Histopathological findings: (Fig 4.2)

• Acantholysis in the upper epidermis,
within or adjacent to the granular layer
• Sometimes the blister cavity contains
numerous acute inflammatory cells, F ig 4.2 H istop ath ology o f pem phigus
particularly neutrophils. foliaceus. C lefting in the upper
spinous and granular layers o f the
• Eosinophilic spongiosis can be also
epiderm is w ith acantholytic cells
seen in very early lesions of detaching from the ro o f o f the blister.
pemphigus foliaceus.
® The dermis shows a moderate number o f inflammatory cells, among which
eosinophils are often present.
NB. Histopathlogical differential diagnosis:

• These superficial blisters are histologically indistinguishable from those
seen in staphylococcal scalded skin syndrome (SSSS) or bullous
impetigo, because D sgl is targeted in both diseases.
Im m u no flu o re sce n ce (aspemphigusvulgaris)

• DIF: IgG ± C3 on the keratinocyte cell surfaces (inter-cellular) (Fig 2.4).
This pattern is referred to as “chicken wire appearance”.
• IIF: circulating IgG better detected on Monkey esophagus.
Autoantibodies specific to Dsgl are demonstrable by ELISA.
27
Bullous Diseases
Differential D iagnosis
• Other forms of pemphigus
• Bullous impetigo: because the lesions of pemphigus foliaceus may become
secondarily infected, the finding of bacteria does not confirm a diagnosis
of bullous impetigo.
• Subcorneal pustular dermatosis (SCPD)
• Seborrheic dermatitis
• Subacute cutaneous lupus erythematosus
> Demonstration of IgG autoantibodies against epidermal cell surfaces

is essential for separating these disorders from the pemphigus family
Prognosis
• The disease may stay localized for years or it may rapidly progress in some
cases to generalized involvement and an exfoliative erythroderma.
• Pemphigus foliaceus had a better prognosis (than pemphigus vulgaris),
except for the occasional acute cases with generalized involvement.
Pemphigus foliaceus is the commonest type of pemphigus that

may present erythroderma. Erythroderma refers to generalized
erythema and scaling affecting > 90% of body surface area.
T re a tm e n t
• Localized disease >=> does not necessarily need systemic therapy. Super-
potent topical corticosteroids are sufficient to control the disease.
• Active and widespread disease treatment is similar to that for
pemphigus vulgaris (systemic therapy).
• Dapsone can also be used when neutrophils are dominant histologically.
28
D
P e m p h ig u s fo lia ce u s
0 Less common than pemphigus vulgaris

0 Target antigen: desmoglein 1 (Dsg 1)
o In the skin ■=>superficial blisters
o In the mucosa --> NO blisters
0 Good general condition
0 2 main variants: Localized (pemphigus erythematosus) and Endemic
(Fogo selvagem).
0 Skin lesions: Well-demarcated scaly, crusted erosions, on an
erythematous base in seborrheic distribution (face, scalp and upper
trunk)
0 Histopathology: acantholysis in the upper epidermis (within or adjacent
to the granular layer)
0 Differential Diagnosis: other forms of pemphigus, bullous impetigo,
subcomeal pustular dermatosis (SCPD), seborrheic dermatitis, subacute
cutaneous lupus erythematosus.
0 Prognosis: The disease may stay localized for years or it may rapidly
progress to generalized involvement (erythroderma)
0 Pemphigus foliaceus had a better prognosis (than pemphigus vulgaris),
except for the occasional acute cases with generalized involvement
0 Treatment
W Localized disease ■=> super-potent topical corticosteroids
W Active and widespread disease ■=> systemic therapy (as pemphigus
vulgaris)
A When neutrophils are dominant histologically ^ Dapsone
29
Bullous Diseases
C h a p te r
Pemphigus Foliaceus
•
Variants
There are 2 main variants of pemphigus foliaceus:

5
1. Localized (sporadic) variant O Pemphigus erythematosus
2. Endemic (generalized) variant O Fogo selvagem
• Moreover, herpetiform pemphigus may be a clinical variant of pemphigus
foliaceus (most patients) or pemphigus vulgaris (the remainder of patients).
P em p h ig u s e r y th e m a to s u s
(S e n e a r-U s h e r Syndrom e)
@ The localized variant of pemphigus foliaceus
$ Affects middle-aged and older patients
• Typical scaly and crusted lesions of Fig 5.1 Pemphigus
pemphigus foliaceus appear in the malar erythematosus. E rythem atous
region of the face and in other ''seborrheic" plaques w ith scale-crust and
areas (Fig 5.1). erosions on the nose and m alar
area o f the face.
Sim ilar to lupus erythematosus (LE) ...
1. Clinically: affects malar region, induced by UV exposure.
2 . Immunologic ally: IgG and C3 deposition on cell surfaces of
keratinocytes and at the BMZ (lupus band test).
3. Serologically: circulating antinuclear antibodies (ANA).
Pemphigus erythematosus is not related to LE. The clinical

p£lp-£u^ findings do not meet the criteria for systemic LE as published
Tips- by the American College of Rheumatology.
The nature of the “lupus-band phenomenon” in pemphigus

erythematosus was disclosed by Oktarina et al., 2012. The
granular BMZ depositions located below the lamina densa
consist of IgG, complement, and the shed Dsg 1 ectodomain. It
was hypothesized that shedding of the Dsgl ectodomain was the
result of UV-induced apoptosis.
f Oktarina DAM, Poot AM, Kramer D, Diercks GFH, Jonkman
MF, Pas HH. The IgG “lupus-band” deposition pattern of
pemphigus erythematosus: association with the desmoglein 1
ectodomain as revealed by 3 cases. Arch Dermatol.
2012;148:1173-8.
30
Fogo S e lva ge m mcq

• Endemic in certain regions of Brazil [pemphigus brasiliensis). In rural
Brazil, the ratio of pemphigus foliaceus to pemphigus vulgaris is 17:1).
• Affects young adults and children (unlike sporadic pemphigus foliaceus,
which is a disease of mostly middle-aged and older patients).
• Affects both sexes and all races.
• Caused by an environmental factor(s).
A More common in rural areas MCQ (the incidence gradually decreases as
the area is developed).
A Majority of patients live close to rivers and within the 10-15 km flying
range of black flie s (Simulium spp.) MCQ, which may be the vector
that precipitates the disease.
A There is also a high frequency of hematophagous insects (bedbugs
and kissing bugs) in the homes o f patients with fogo selvagem.
A Frequently occurs in genetically related family members, although it is
not contagious (to date, spread by blood products or body fluids has not
been documented).
• Patients are clinically, histologically and immunopathologically similar to
patients with sporadic pemphigus foliaceus.
• The burnt appearance/burning sensation, especially on sun exposure, gives
the disease its popular name, fogo selvagem, Portuguese for “wild fir e ”.
• Histologic changes of pemphigus foliaceus and its 2 variants

(pemphigus erythematosus and fogo selvagem) are identical.
• Other areas with endemic pemphigus foliaceus:
1. In Tunisia, endemic areas are also rural MCQ. and patients are
mostly women. The use o f traditional cosmetics was
suggested as a risk factor.
Tip£ 2. Colombia: ( 1) Indian tribes in the southern areas o f the
Amazonian and Orinoquian forest regions and (2) gold-mining
regions of El Bagre.
3. Tanzania.
H erpetiform P em p h ig u s
• A clinical variant of pemphigus foliaceus (most patients) or pemphigus
vulgaris (the remainder of cases).
• It is remarkable itchy (which is uncommon for pemphigus) condition that
clinically resembles dermatitis herpetiformis (DH).
• Clinically —> arcifonn and annular erythematous urticarial plaques and
vesicles that present in a herpetiform arrangement (grouped vesicles on
an erythematous base).
• Histologically —►eosinophilic spongiosis and subcorneal.
• IF —> IgG ± C3 on the keratinocyte cell surfaces (inter-cellular). The
target antigen is D sgl (in most cases) and Dsg3 (in the remainder).
31
Bullous Diseases
C h a p te r
Paraneoplastic
pemphigus (PNP)
6
Definition
• PNP is a rare type of pemphigus (3-5 % o f all pemphigus cases ) associated
with underlying neoplasms (whether malignant or benign).
P athogenesis
Underlying neoplasms:
• PNP is associated with underlying neoplasms, both malignant and benign.
• The most commonly associated neoplasms are...
☆ Non-Hodgkin lymphoma (40%)
% Chronic lymphocytic leukemia (30%)
A- Castleman’s disease (10%): a very rare lymphoproliferative disorder
% Malignant and benign thymomas (6%)
V Sarcomas (6%)
Y Waldenstrom’s macroglobulinemia (6%)
• Non-Hodgkin lymphoma and chronic lymphocytic leukemia

MCQ together account for two-thirds o f patients.___________
Pathogenesis (target proteins)

Polymorphic - targets many antigens (BOTH in desmosome and BMZ).
☆ Desmoglein 3, 1
☆ Desmoplakin I, II
A Envoplakin / Periplakin: the demonstration of antibodies to both
envoplakin and periplakin is most sensitive and specific MCQ.
☆ BPAG1 (bullous pemphigoid antigen 1)
☆ Plectin
A A2ML1 (alpha-2-macroglobulin- like-1 protease inhibitor)
Neoplastic cells may produce these autoantibodies themselves or may

stimulate B cells to do so.
32
C lin ica l picture

• Intractable severe stomatitis
o The most constant clinical feature of PNP.
o Usually the earliest presenting sign,
o Erosions and ulcerations that affect all surfaces
of the oropharynx and characteristically extend
onto the vermilion lip (Fig 6.1).
F ig 6.1 PN P. Severe
o Extremely resistant to therapy, stom atitis extending onto
o After treatment, it is the one that persists. the verm ilion lip w ith
• O ther mucosal affection erosions and hem orrhagic
o Most patients also have a severe pseudo crusts.
membranous conjunctivitis, which may progress to scarring and

obliteration of the conjunctival fomices.
o Esophageal, nasopharyngeal, vaginal, labial and penile mucosal lesions
may also be seen.
• Cutaneous findings
o Polym orphic. May present a s....
1. erythematous macules, flaccid blisters and erosions (resembling
pem phigus vulgaris)
2. tense blisters (resembling bullous pemphigoid)
3. erythem a m ultiforme-like lesions
4. lichenoid eruptions (resembling lichen planus)
The variety o f clinical manifestations of PNP is attributed to the

balance between the cellular and humoral response.
• A cellular autoimmune reaction produces more lichenoid
clinical features.
• The humoral autoimmune reaction leads to more pemphigus
and pemphigoid- like clinical manifestations.____________
• Systemic affection:
o Some patients with PNP develop bronchiolitis obliterans, which
can be fatal as a result of respiratory failure
* Cutaneous lesions:
Considerable variability (polymorphism) - a combination o f histologic
features (sometimes in the same specimen)
1. pemphigus vulgaris-like A supra-basilar acantholysis
2. erythema multiforme-like ^ individual keratinocyte necrosis with
lymphocytes within the epidermis
3. lichen planus-like ■=>basal cell liquefactive degeneration or a band-like
dense lymphocytic infiltrate in the upper dermis
33
Bullous Diseases
• Biopsy specimens of the severe ulcerative stomatitis:

Non-specific changes of inflammation (but the perilesional oral epithelium
shows supra-basilar acantholysis)
!m m u n of 8u ©r e s c e n c e
• DIF: Intercellular and subepidermal IgG.
• IIF: rat bladder is used to detect paraneoplastic pemphigus MCQ.
PNP is a polymorphic disease

p&ip-ful • Immunologically: targets many antigens.
• Clinically: different clinical presentations.
Tip^ • Histopathologically: combination o f histologic features.
O th er in v e stig a tio n s
1. To detect the occult underlying neoplasm e.g.
☆ CT scan of the chest, abdomen and pelvis
A complete blood count
A flow cytometry
A lactate dehydrogenase (LDH)
V serum protein and immunofixation electrophoreses
2. To detect bronchiolitis obliterans:
A A chest X-ray or CT scan obtained at the onset of bronchiolitis
obliterans may be normal.
A Pulmonary function tests will show small airway obstruction that does
not reverse with bronchodilators.
Differential D iagnosis
Cutaneous lesions:
• pemphigus vulgaris
• erythema multiforme or Stevens-Johnson syndrome
• lichen planus
• mucous membrane (cicatricial) pemphigoid
• graft-versus-host disease (GVHD)
M ucosal lesions (stomatitis):
• persistent HSV infection
• other viral infections
• stomatitis due to chemotherapy (limited in duration, 7-14 days)
• Severe intractable stomatitis MCQ that extends onto the

vermilion lip is a key clinical feature in differentiating PNP
from most cases o f pemphigus vulgaris or cicatricial
pemphigoid.___________________________________________
P ro g n o sis
• Overall, the prognosis of PNP is poor due to
(1) underlying neoplasm(s),
(2) underlying bronchiolitis obliterans, and/or
(3) its resistant nature to treatment.
• Patients with resectable tumor have the best prognosis and mostly survive.
T r e a tm e n t
• Benign tumors (e.g. thymomas or localized Castleman’s disease) ^
surgical excision.
• Malignant neoplasms tumor-specific chemotherapy.
• Cutaneous lesions respond more rapidly to therapy, in

contrast to the stomatitis, which is generally refractory to most
forms o f treatment.
• Types of pemphigus with both intercellular and

subepidermal IgG on DIF:
(1) Pemphigus erythematosus.
(2) Paraneoplastic pemphigus.
35
Bullous Diseases
C h a p te r
Immunoglobulin A (IgA)
Pemphigus
Definition
• IgA pemphigus is a special type of pemphigus characterized ...
1. immunopathologically by the presence o f IgA autoantibodies (rather
than IgG).
2. histologically by neutrophils infiltrate (rather than eosinophils).
3. clinically by pus-filled blisters (i.e. pustules) in annular configuration
with pruritus.
4. therapeutically by response to dapson. Sneddon-Wilkinson’s disease
is similar to IgA pemphigus
SPD type but without MCQ
S u b type s detectable IgA depositions in
• IgA pemphigus is divided into 2 subtypes the skin (i.e. non-immune).
depending on the level of intra-epidermal
pustule (i.e. histopathologically):
1. Snb-corneal pustular dermatosis (SCPD)-like type: pustules are
located sub-corneally in the upper epidermis MCQ.
2. Intra-epidermal neutrophilic (IEN) type: supra-basilar pustules
involving the lower or entire epidermis.
V a ria n ts none
P athogenesis (ta rg e tp ro te in in desm osom e)

1. SCPD type: desmocollin 1 (expressed in the upper part of the epidermis).
2. IEN type: still unknown target antigen (?).
E p id e m io lo gy
• Age: usually occurs in middle-aged or elderly.
C lin ica l picture :

General condition: relatively good.
Symptoms: pruritus is often a significant symptom.
Mucous membrane lesions: mucous membrane involvement is rare.
36
Skin lesions: (in both types of IgA pemphigus)

• Flaccid vesicles or pustules on either
erythematous or normal skin
• Pustules coalesce to form an annular or
circinate pattern with crusts in the center of the
lesion (,sunflower-like configuration of pustules)
• Most common sites of involvement are the axilla
and groin, but the trunk and proximal
extremities can also be involved
F ig 7.1 IgA pem phigus.
H istopatholo gy P ustules coalescing into
annular or circinate
Intra-epidermal pustule containing neutrophils
p attern w ith crusts.
• SCPD type: pustules are located sub-comeally
in the upper epidermis.
• IEN type: supra-basilar pustules involving the lower or entire epidermis.
F ig 7.2 H istop ath ology o f IgA pem phigus. Left: SCPD type, right: IE N type.
immunofluorescence
• Direct IF: IgA deposition on cell surfaces o f epidermal keratinocytes.
• Indirect IF: circulating IgA autoantibodies.
Differential Diagnosis
• Pemphigus foliaceus
• Linear IgA bullous dermatosis
• Dermatitis herpetiformis
• Bullous impetigo
• Pustular psoriasis
• Subcorneal pustular dermatosis (SCPD, Sneddon-Wilkinson
disease): the clinical and histologic features of the SCPD-like type of
IgA pemphigus and classic SCPD are indistinguishable (immunologic
evaluation is essential to differentiate the two diseases).
Demonstration o f IgA autoantibodies is essential for separating

these other disorders from IgA pemphigus.
Tips-
37
Bullous Diseases
Prognosis
• Most cases run a chronic indolent course.
T re a tm e n t
• Dapsone is the drug of choice MCQ (it suppresses functions of neutrophils)
☆ Dose: 25-125 mg/day.
hr A clinical response usually occurs within 24-48 hours
A If dapsone is not well tolerated, sulfapyridine and acitretin are useful
alternatives.
☆ If those drugs are not effective, consider low- to medium-dose
prednisone, photochemotherapy (PUVA) or colchicine
• In disorders characterized by IgA antibodies, © the

inflammatory infiltrate is made up of neutrophils and clinically
VlelpAul there are © pustules (with or without © annular configuration
and © pruritus). Therapeutically, these disorders respond to ©
Tip?- dapson. Examples include IgA pemphigus, linear IgA
bullous dermatosis and dermatitis herpetiformis.__________
Superficial pemphigus is a histopathological term referring to any

type of pemphigus affecting superficial layers of epidermis. This
pelp-Cul includes:
T ip^ 1. Pemphigus foliaceus (and its variants).
2. IgA pemphigus (SCPD type).__________________________
38
C h a p te r
Drug-induced Pemphigus
(DIP)
8
Definition
• Pemphigus induced or exacerbated by drugs.
Pathogenesis
Causative drugs:
• Thiol drugs: drugs containing a sulphydryl (-SH, thiol) group e.g.
penicillamine and captopril
• Non-thiol drugs: e.g.
o other A C E inhibitors (e.g. enalapril ...)
o angiotensin II receptor blockers (e.g. candesartan, telmisartan ..)
o calcium channel blockers (e.g. nifedipine)
o antibiotic (e.g. penicillins, cephalosporins)
o others (e.g. chloroquine, hydoxychloroquine, rifampicin,
montelukast and interferon)
o radiotherapy
How these drugs induce pemphigus:

• Thiol drugs:
1. Both penicillamine and captopril contain sulfhydryl (-SH) groups
interact with the sulfhydryl groups in D sgl and Dsg3 =>
A the interaction modifies the antigenicity of the desmogleins
autoantibody production, or
A the interaction directly interfere with the adhesive function of the
desmogleins
2. Thiol drugs increase the activity of plasminogen activators.
• N on-thiol drugs:
An active amide group in the molecule of non-thiol drugs may be
responsible for inducing disease.
• A great proportion of dmgs implicated in inducing pemphigus

are anti-hypertensive drugs (ACE inhibitors, angiotensin II
receptor blockers and calcium channel blockers).
39
Bullous Diseases
C lin ica l features

• Pemphigus foliaceus or pemphigus erythematosus are the most
common patterns o f pemphigus induced by drugs.
• Drug-induced pemphigus vulgaris and pemphigus vegetans are rare.
• Pemphigus foliaceus is seen more commonly than pemphigus vulgaris
(4:1).
• Most patients with drag-induced pemphigus have circulating

autoantibodies with the same antigenic specificities as in
"p;p5. other forms of pemphigus.____________________________
P rognosis
• Most, but not all, cases of drug-induced pemphigus go into remission after
the offending drug is discontinued.
• In drug-induced pemphigus (DIP), the autoimmune disease

was not present before exposure to the putative drag, whereas
in drug-triggered pemphigus (DTP), the autoimmune process
was already programmed and only facilitated by the drag
MCQ.
• Timely withdrawal of the culprit drug will often result in full
resolution in DIP, whereas in DTP, this is generally not the
case.
• Pathogenesis of DIP is not completely known, but probably

comprises endogenous (genetic) and exogenous (drugs) factors.
Immunologic acantholysis may start with biochemical events
resulting in neoantigen formation and autoantibody production.
Thiol-associated drags and immune modulators could also
directly interfere with the immune system resulting in release of
forbidden B cell clones.
• Contrary to the latency time in most other cutaneous adverse
drag reactions, latency between start of new medication and
onset of the reaction can be up to several months.____________
40
P em phigus appendix
® The following section contains additional and updated
information about pemphigus. It is mainly o f interest to those
preparing for their MD degree.___________________________
Detailed aetio-pathogenesis of pemphigus (vulgaris):

(1) Genetic predisposition:
Evidence for the genetic basis o f pemphigus includes:
• Few familial cases have been reported.
• The presence of low titers of anti-Dsg antibodies in healthy relatives
o f patients with PV (as high as 70% in some studies).
• Association o f pemphigus with certain class II HLA alleles (strong
association with HLA DRB1*04 and *14 alleles and with BQB1*0503
and *0302). Dsg 3 polymorphisms have been observed in association
with HLA class II pemphigus susceptibility alleles. Some class I HLA
genes have been implicated in PV including HLA A10 and HLA B38.
• Association with other non-HLA genes e.g. immunoglobulin heavy
chain and pemphigus relevant cytokine genes e.g. interleukin 10 (IL-10).
(2) Environmental factors:
Possible triggers in pemphigus development include:
1. Diet: garlic has been proposed as a trigger for disease development and
has been shown to induce acantholysis in vitro (controversial).
2. Organophosphate pesticides block the acetylcholine breakdown
pathway and so may lead to acetylcholine accumulation with resulting
loss of cell-cell adhesion in the epidermis. Pesticides implicated in
contact pemphigus include glycophosate and di-hydro-di-phenyl-tri-
chlor-ethane.
3. Role of black flies (Simulium spp.) in the development o f the endemic
form of pemphigus foliaceus, fogo selvagem (see before, page 31).
4. Smoking may have a protective or beneficial role in pemphigus.
Human keratinocytes have both nicotinic and muscarinic receptors for
acetylcholine and these receptors may play a role in regulating
keratinocyte cell-cell adhesion.
(3) Autoimmunity:
Pemphigus is characterized by the presence o f IgG autoantibodies
against Dsg 3 ± D sgl (see before - page 15) resulting in acantholysis.
• Mechanisms by which autoantibodies induce acantholysis:
1. Steric hindrance by anti-Dsg antibodies. Binding of autoantibodies to
Dsgs spatially interferes with the adhesive interaction of Dsgs between
cells (direct inhibition).
2. Protease activation: IgG causes release o f plasminogen activator.
3. Disruption of intra-cellular signaling pathways (a transient increase in
intracellular calcium and/or inositol 1,4,5-triphosphate, activation of
protein kinase C, phosphorylation of Dsg, endocytosis of Dsg3).
41
Bullous Diseases
4. Apoptosis: pemphigus antibodies can trigger secretion o f factors from

keratinocytes which are involved in apoptosis such as Fas ligand.
Apoptosis is seen late in the development of pemphigus lesions, after
acantholysis. The term “apoptolysis” has been proposed to explain
acantholysis and keratinocyte damage in pemphigus.
The suggested series of events includes (1) binding of autoantibodies to
pemphigus antigens, (2) epidermal growth factor receptor activation, (3)
initiation o f cell death cascades, (4) basal cell shrinkage, (5) degradation
of structural proteins, and (6) apoptosis of acantholytic cells.
• Other “non-Dsg” antigenic targets in pemphigus:
> Some patients have active pemphigus with intercellular antibodies
detectable on DIF/IIF but have negative Dsg antibodies as assessed by
specific ELISA assays.
> One explanation for this is that in some patients there may be significant
non-Dsg targets. Antibodies against desmocollins, plakoglobin, E-
cadherin and acetylcholine receptors have been reported.
> Acetylcholine receptor antibodies are found in up to 85% of
pemphigus patients. These antibodies may weaken desmosomal
junctions by inducing phosphorylation of adhesion molecules and
prevent desmosomal reassembly.
Neonatal pemphigus:
• In pregnant women with pemphigus, autoantibodies cross the placenta
and bind to the fetal epidermis.
• Neonates develop blisters if the mother has pemphigus vulgaris, but very
rarely if she has pemphigus foliaceus.
> The distribution of Dsg3 within neonatal epidermis is unlike that in
adult epidermis; it is found on the surface of keratinocytes throughout
the epidermis, which is similar to its distribution in mucous
membranes (neonatal skin is bathed in amniotic fluid).
> Pemphigus foliaceus sera containing only anti-Dsgl IgG cannot induce
blisters in neonatal skin.
• Neonates of mothers with pemphigus vulgaris may have a transient
disease caused by maternal IgG that crosses the placenta. As maternal
antibody is catabolized, the disease subsides.
Unusual (Atypical) clinical presentations of pemphigus vulgaris:

1. Isolated crusted plaque on face or scalp
2. Paronychia
3. Foot ulcers
4. Dyshidrotic eczema or pompholyx
5. Macroglossia
Disorders associated with pemphigus:

• PV may be associated with other autoimmune diseases, particularly
thyroid disease, rheumatoid arthritis and type 1 diabetes.
• PNP occurs in association with hematological malignancy (page 32).
42
Some details about some pemphigus therapies:

Plasmapheresis:
• Plasmapheresis is exchanging patient plasma by fresh-frozen plasma or
human albumin.
• It aims at removing harmful antibodies from the circulation.
• Drawbacks / hazards:
1. “Rebound” to the antibody “vacuum”: massive antibody depletion
triggers a burst of new antibody production (feedback mechanism).
Plasmapheresis should be followed by short cycles (“pulses”) of
conventional treatment with high doses of steroids and
immunosuppressants (in particular cyclophosphamide).
2. Risk of infection.
3. Risk of hypotension, bradycardia, and deep venous thrombosis (DVT).
4. In addition to removing pathogenic pemphigus antibodies, it also
removes a wide range of protective immunoglobulins, albumin, and
clotting factors (i.e. non-specific).
Immuno adsorption:
• Selectively trapping the pathogenic autoantibodies out o f the body while
returning protective antibodies and other plasma components to the patient
(only removing immunoglobulin).
• It is done using filtering membranes rich in sulphydryls (-SH groups).
• Immunoadsorption has replaced plasmapheresis in the treatment of
pemphigus. It is associated with a lower rate o f adverse events like
infections and allergic reactions.
Intravenous immunoglobulin (IVIG):

• Dose: 400 - 600 mg/kg (total: 2 g / kg) for 3-5 consecutive days (cycle).
• It neutralizes and slows down the production of circulating pemphigus
autoantibodies (through negative feedback).
• Advantages: safe, effective / Disadvantages: expensive.
• Side effects: expensive, dyspnea, tachycardia, abdominal pain.
Azathioprine:
• Dose: 1-3 mg/kg/day. Start first week with 50 mg/day to detect
idiosyncratic reactions (and in case stop immediately), and then raise to
desired dose.
• It is metabolized through 3 different pathways. One of them is thiopurine
methyltransferase (TPMT). The TPMT pathway can have variable
activity based upon genetic polymorphisms and its activity should be
monitored prior to treatment.
> High TPMT activity (>19 U): normal dose (up to 2.5 mg/kg/day).
> Intermediate TPMT activity (13.7-19 U): up to 1.5 mg/kg/day.
r Low TPMT activity (5-13.7 U): lower dose (up to 0.5 mg/kg/day).
> Very low TPMT activity (<5 U): azathioprine is contraindicated.
43
Bullous Diseases
Observation points (Endpoints) of disease (pemphigus) activity:
Early observation points:

1. Baseline: the day that therapy is started by a physician.
2. Control of disease activity (disease control): the time interval from
baseline to the time at which new lesions cease to form and established
lesions begin to heal.
> It is the beginning o f the consolidation phase (see below).
> It is on the order of weeks, although it may be shorter.
3. The end of the consolidation phase: the time at which no new lesions
have developed for a minimum of 2 weeks and the majority
(approximately 80%) of established lesions have healed.
> At this point, begin to taper corticosteroid doses.
Late observation points:

1. Complete remission: absence o f new and/or established lesions for at
least 2 months. Complete remission may be:
> off therapy: the patient is off all systemic therapy.
> on therapy: the patient is receiving minimal therapy (< 10 mg/day of
prednisone or the equivalent) and/or minimal adjuvant therapy.
2. Partial remission: the presence of transient new lesions that heal within
one week without treatment for at least 2 months.
> Partial remission off therapy: the patient is off all systemic therapy.
> Partial remission on minimal therapy: the patient is receiving minimal
therapy, including topical steroids.
3. Relapse/Flare: the appearance of 3 or more new lesions a month that do
not heal spontaneously within 1 week, or the extension o f established
lesions, in a patient who has achieved disease control.
4. Treatment failure (Failure of therapy): failure to control disease activity
(i.e. relapse/flare) with full therapeutic doses o f systemic treatments. There
is (1) continued development of new lesions, (2) continued extension of old
lesions, or (3) failure o f established lesions to begin to heal despite 3 weeks
of therapy on 1.5 mg/kg/day prednisone equivalent with or without any of
the following agents: cyclophosphamide 2 mg/kg/day for 12 weeks,
azathioprine 2.5 mg/kg/day for 12 weeks (if TPMT level is normal),
methotrexate 20 mg/week for 12 weeks, or mycophenolate mofetil 3
gm/day for 12 weeks.
44
Therapeutic lines of pemphigus-classification according to

mechanism of action:
PR O D UC TIO N OF
DESM OGLEIN CIRCULATING AN TIBO D Y-M ED IA TED
D ESM O G LE IN -R EA C TIV E
IM M UNOGENICITY
AN TIBO D IES
AN TIBO D IES T$> APO PTO LYSIS
I
Avoid: Corticosteroids P lasm apheresis Corticosteroids
* thiol drugs
Azathioprine Im m unoadsorption Gold
- spiced foods
- bu rns a n d sunb urns C yclo p h o sp h a m id e Te tra cyclines (? )
- hot food a n d be verage s
M ycop h en ola te mofetil Nicotinam ide
Tre at coexisting IVIg Pyridostigm ine

herpetic infections Rituxim ab Ep id e m a l Grow th
G old Facto r
Pim ecrolim us
Nicotinam ide
Proteom ics-derived
Pyridostigm ine
desm oglein peptide
Pemphigus phenotype transition:

• Transformation between the subtypes o f pemphigus vulgaris (PV) and
pemphigus foliaceus (PF) is rarely reported in the literature.
• A shift from PV to PF is more common than, vice versa, a shift from PF to
PV.
• The disease period before transition may vary between 1-20 years.
• Shift from PV into PF is accompanied by disappearance of anti-Dsg 3
and autonomous reappearance o f anti-Dsg 1.
• Antibody profiles in observed PF shifts into PV revealed antibody profile
transition from anti-Dsg 3 - / Dsg 1 + to anti-Dsg 3 + / Dsg 1 +
• The mechanism for such an acquisition of new autoantibodies has been
termed “epitope spreading” or “epitope shift”.
• Tissue damage caused by an autoimmune or inflammatory skin disease
exposes a previously sequestered antigen normally undetectable by the
immune system, leading to the production o f autoantibodies against the
exposed protein components and formation of another autoimmune skin
disease.
• Transition into bullous pemphigoid have been reported.
45
Part 2
n sfe m m m m
Pemphigoid
family
The sub-epidermal autoimmune bullous
diseases
C h a p te r
Introduction to
Pemphigoid Family ^
The sub-epidermal autoimmune bullous
diseases
W hat are basem ent m em branes (B M s)?

Basement membranes (BMs) are specialized structures located between cells
and their underlying stroma or between different cell types.
• Functions of basem ent m em branes:

1. Act as permeability barriers for cells and macromolecules.
2. Attachment o f cells.
3. Templates for tissue repair.
4. Cell migration.
5. Influence differentiation, morphogenesis and apoptosis o f epithelial
cells.
Lo ca tio n s of BM s in the skin

1. At the interface of the epidermis and dermis (the epidermal basement
membrane, basement membrane zone ‘B M Z ’)
2. Around the dermal microvasculature.
Epiderm al ba sem ent m em brane (B M Z )

* Origin / Embryology of the BMZ:
BMZ is comprised o f proteins derived from:
1. Epidermal basal keratinocytes (of ectodermal origin), and
2. Dermal fibroblasts (of mesodermal origin).
• U ltra-structure of the BMZ:

o BMZ is a highly-complex ‘adhesion unit’ that is comprised of proteins,
o Transmission electron microscopy identified 4 sub-regions (layers or
laminae) in the BMZ (the ‘laminated’ model).
• Think of BMZ as a multi-layered structure composed of 4

layers (regions or laminae). Each layer is made of different
components, each of which is composed of various proteins
(antigens).
BMZ = layers & components ^ proteins (antigens)
47
Bullous Diseases
Epidermis
(A) Layers (regions or laminae) o f
BM Z:
BMZ is formed o f 4 layers (Fig 9.1):
Basal
keratinocvtes
1. Lower portions o f basal
Lamina lucida (LL) ^
keratinocytes
2. Lamina lucida (LL): electron- Lamina densa (LD)
lucent area Sub-lamina densa (SLD)

3. Lamina densa (LD): BM proper
Dermis
4. Sub-lamina densa (SLD)
Fig 9.1 Layers of BMZ
(B) Components o f BM Z; (Fig 9.2)
L L o w er p o rtio n s o f b a s a l k e ra tin o c y te s
• the cytoskeleton (keratin intermediate filaments, KIFs).
• hemidesmosomal (HD) plaques:
o small (<0.5pm) electron-dense units on the basal plasma membranes
• plasma membranes of basal keratinocytes.
2. L a m in a lu c id a (L L ):
•anchoring filaments ■=> small delicate (thread-like) strands (filaments)
connecting HDs to the underlying lamina densa (LD).
3. L a m in a d e n sa (L D ): electron-dense, somewhat granular matrix.
4. S u b -la m in a d e n sa (S L D ):
• anchoring fibrils ■=> looping elements that originate and end in the
underside of LD. Act as attachment sites for fibrillar proteins in the
papillary dermis
• anchoring plaques
• filamentous proteins of the papillary dermis (interstitial collagens)
Epidermis
Keratin intermediate
filaments (KIFs)
Basal
keratinocvtes
Lamina lucida (LL)

{ Hemidesmosome (HD)
Plasma membrane
Anchoring Filaments
Lamiua densa (LD) ^

Anchoring fibrils
Anchoring plaques
Sub-lamina densa (SLD ).
Interstitial collagens
Dermis
Fig 9.2 Components of BMZ
48
(C) Proteins (Antigens) o f BM Z: (Fig 9.3, Table 9.1)
KIFs
Hemidesmosome
Pfasma membrane
Basal KC
Lamina lucida Lamlnfn 5
*1 *
Lamina densa
Anchoring fibrils) ' '*** VIt C°"OS,n

F ig 9.3 Proteins (Antigens) of BMZ (9 p rotein s are shown in blue circles and ovals)
Layer Component(s) Antigen(s)

Keratin intermediate • Keratin 5 (K5)
filaments (KIFs) • Keratin 14 (K14)
Lower portions of basal
• Plectin
keratinocytes Hemidesmosome
• Bullous pemphigoid
(HD)
antigen 1 (BPAG1)
Lamina lucida (LL) HD-anchoring antigen 2 (BPAG2)
filament complexes • Integrin subunit a6
• Integrin subunit (34
• Type IV collagen
Lamina densa (LD)
LL-LD interface • Laminin 5
Sub-lamina densa (SLD) Anchoring fibrils • Type VII collagen
BMZ is a highly-complex ‘adhesion unit’ that preserves the

integrity of the skin. KIFs attach to HDs on the basal plasma
membranes of KCs. HDs connect to the underlying LD by
anchoring filaments. The LD is tethered to the papillary dermis
T ip s by anchoring fibrils. In other words, proteins of BMZ act as a
continuous chain of proteins that link epidermis and dermis.
49
Bullous Diseases
Synonyms:
• Bullous pemphigoid antigen 1 BP230
• Bullous pemphigoid antigen 2 ■=!>BP 180; type XVII collagen
• Laminin 5 ^ epiligrin, laminin-332
• Type VII collagen => the epidermolysis bullosa acquisita
antigen; long collagen_______________________________
Adhesion proteins of the BMZ are affected in 2 clinical situations:

1. Acquired disorders in which auto-antibodies attack these
proteins (i.e. immune-bullous) ^ pemphigoid family.
2. Inherited (Genetic) disorders in which there are mutations in
the genes encoding these proteins (i.e. mechano-bullous) =>
epidermolysis bullosa (EB) family.
• Both 2 groups of disorders are characterized by sub-epidermal
blisters (Fig 9.4).____________________________________
Disorders affecting adhesion proteins in BMZ
_________ y ________
Acquired Inherited (Genetic)
Auto-antibodies against these Mutations in genes encoding
proteins these proteins
(Immunobullous) (Mechanobullous)
>1
'Pemphigoid' family 'EB' family
F ig 9.4 Disorders affecting adhesion proteins in BMZ
M em bers of the 'P em p higoid ' fa m ily (6 )

1. Bullous pemphigoid (BP)
Variant Pemphigoid gestationis (PG)
2. Cicatricial pemphigoid (CP)
3. Epidermolysis bullosa acquisita (EBA)
4. Linear IgA disease (LAD)
5. Dermatitis herpetiformis (DH)
6. Bullous systemic lupus erythematosus (Bullous SLE)
50
S tu d y plan
In studying different members of pemphigoid family, the
following points should be fulfilled:
1. Definition: autoimmune sub-epidermal/ sub-epithelial blistering disease.

2. Pathogenesis (i.e. target protein(s) in BMZ).
3. Epidemiology:
• Incidence / prevalence.
• Type of patient: age / sex / race (geographical distribution).
3. Clinical picture:
• General condition.
• Symptoms.
• Signs: skin / mucosa lesions.__________________________________
In pemphigoid family,
• skin blisters are tense, do not rupture easily, may reach large
sizes and usually heal with scarring (why?).
• mucosal lesions are usually rare (except in cicatricial
pemphigoid where mucosae are preferentially affected).
T ip s • general condition is generally good due to..
1. rarity of mucosal affection.
2. tense blisters make fluid loss and barrier dismption less severe.
4. Histopathology.
In pemphigoid, histopathology reveals sub-epidermal cleft.
Inflammatory infiltrate is usually eosinophils (however, certain
members of pemphigoid family may have different types of
infiltrates).
5. IF (DIF, IIF).
In pemphigoid, IF shows linear IgG autoantibodies (IgA in

linear IgA bullous dermatosis) ± C3 along the epidermal
T ip s BM.
g g |p Ig g a §g mSigdm
6. Other investigations:
(a) Salt-split skin (SSS) IF technique:
• Salt-split skin (SSS) is a special technique of IF in which salt-split
normal human skin is used as a substrate.
• In this procedure, normal human skin is incubated in 1M (1 mol/L)
sodium chloride (NaCl) at 4°C for 48-72 hours to split it at the level of
the lamina lucida (the weakest point in BMZ) and create an artificial
cleft (Fig 9.5). The specimen is then processed in the same manner as
conventional IF.
51
Bullous Diseases
1M ,
NaCl'
Intact skin
Split at LL (*) R oof IF Floor IF
F ig 9.5 Salt-split skin (SSS) im m unofluorescence technique
• SSS technique is used to distinguish between sub-epidermal blistering

conditions with similar immunofluorescence findings (linear deposition
at BMZ). It detects the site o f immune deposits w hether...
1. in the epidermal side (roof) o f the split,
2. in the dermal side (floor) o f the split, or
3. both (Fig 9.5)
SSS technique can be used for DIF (where the specimen is

patient’s perilesional skin) or IIF (where the specimen is salt-
Tip& split normal human skin)._____________________________
(b) E L ISA : detects autoantibodies against specific antigens.
7. DD.
a) Differentiate between different members of pemphigoid family.
b) Differentiate pemphigoid from pemphigus.
c) Differentiate pemphigoid from non-immune bullous diseases.
8. Prognosis.
qeip-ful Generally speaking, pemphigoid has a better prognosis (in

comparison to pemphigus)._________________________
T ip s
9. Treatment.
Generally speaking, pemphigoid is treated with potent topical

qeipfwl corticosteroids (in localized cases). Systemic corticosteroids
may be used in generalized or refractory cases.___________
Tips
52
P e m p h ig o id fa m ily
D
0 Basement membranes (BMs) are located between cells and their

underlying stroma or between different cell types.
0 Basement membranes (BMs) act as permeability barriers and help for cell
attachment, tissue repair and cell migration.
0 The epidermal basement membrane (basement membrane zone ‘BMZ’)
is comprised o f proteins derived from both the epidermal basal
keratinocytes (ectodermal) and dermal fibroblasts (mesodermal).
0 BMZ is composed of 4 sub-regions (layers or laminae). Each layer is
made of different components, each o f which is composed of various
proteins (antigens). This is called the ‘laminated’ model'.
Layer Component(s) Antigen(s)

Keratin intermediate • Keratin 5 (K5)
fdaments (KIFs) • Keratin 14 (K14)
• Plectin
Hemidesmosome
Lower portions of basal • Bullous pemphigoid
(HD)
keratinocytes antigen 1 (BPAG1)
Plasma membranes
of basal
keratinocytes.
Lamina lucida (LL) HD-anchoring antigen 2 (BPAG2)
filament complexes • Integrin subunit a6
• Integrin subunit (34
• Type IV collagen
Lamina densa (LD)
LL-LD interface • Laminin 5
Anchoring fibrils • Type VII collagen
Anchoring plaques
Sub-lamina densa (SLD)
Interstitial collagens
of papillary dermis.
0 Adhesion proteins o f the BMZ are affected in 2 clinical situations:

1. Acquired disorders in which auto-antibodies attack these proteins (i.e.
immune-bullous) ■=>pemphigoid family.
2. Inherited (Genetic) disorders in which there are mutations in the genes
encoding these proteins (i.e. mechano-bullous) ■=>epidermolysis
bullosa (EB) family.
A Both 2 groups of disorders are characterized by sub-epidermal
blisters.
53
Bullous Diseases
Bullous pemphigoid
(BP, Pemphigoid)
Definition
Bullous pemphigoid (BP, pemphigoid) is the most common autoimmune sub-
epidermal blistering disease of the skin.
P athogenesis (ta rg e t p ro te in s in B M Z )
• Autoantibodies
Autoantibodies in BP are directed against 2 autoantigens:
1. Bullous pemphigoid antigen 2 (BPAG2, BP180)
Autoantibodies against this autoantigen are present in
almost all cases of BP.
2. Bullous pemphigoid antigen 1 (BPAG1, BP230)
Autoantibodies against this autoantigen are present in a
significant portion of, but not all, cases of BP. Fig 10.1 Auto
antigens in BP.
Characteristic o f these 2 autoantigens are shown in Fig 10.1 and summarized in
Table 10.1
BPAG1 BPAG2
Site Cytoplasmic protein (HD) Trans-membrane protein
Molecular weight 230 kDa 180 kDa
Shape Globular Rod with a tail (J-shaped)
A large collagenous extra
Nature Non-collagenous protein cellular domain (collagen type
XVII) + non-collagenous parts
• Mechanism of blister formation

Binding o f autoantibodies to their target antigens ■=>complement activation
activation products C3a and C5a ■=>mast cells (MC) to degranulate ■=>
pro-inflammatory mediators recruitment o f inflammatory cells (mainly
neutrophils and eosinophils) o liberation of proteases “e.g. neutrophil
elastase, gelatinase B (MMP-9) and plasminogen activators (PAs)” and
reactive oxygen species (ROS) ■=>degrade extracellular matrix proteins ■=>
subepidermal blister.
54
Detailed structure of the extracellular

domain of BPA G 2 “ectodomain” NC-16A
A Shaped like a rod with a tail (J-shaped).

A Long molecule: spans the LL ■=>inserts
into the LD ■=>loops back through the
LD into the LL
A Composed o f 15 collagenous sub-
domains (light-colored in Fig 10.2) +
intervening non-collagenous sequences
(dark-colored in Fig 10.2)
A NC16A domain (thel6th non-
collagenous domain) is the first
extracellular segment of BPAG2 Fig 1# 2 Co|lagen x v || ^
(adjacent to the trans-membrane ecto-domain shedding,
portion). It’s the immune-dominant
epitope. _______________________________________________________
• In BP, autoantibodies are directed specifically against the non-
collagenous NC16A domain (the immunodominant region)
and additional antigenic sites. The presence of several
antigenic sites throughout BP180 and BP230 is called ‘epitope
spreading phenomenon’. This phenomenon may also occur in
other sub-epidermal autoimmune-mediated blistering diseases.
Moreover, in the course of these diseases, it is possible to detect
autoantibodies directed against additional antigens, the so-
called “intermolecular epitope spreading phenomenon”.
Epidem iology
• Age: affects the elderly (onset > 60 years) (also affects children rarely).
• Sex: more common in men than in women.
• While BP affects the elderly and is more common in men,

pemphigus vulgaris affects the middle-aged with equal sex
distribution.
Clinical Features
(A) N o n -b u llo u s (p ro d ro m a l) p h a se : (Fig 10.3)
• Non-specific signs and symptoms
• Symptoms: pruritus (range from mild to severe
intractable)
• Signs: urticarial lesions (+ excoriated, Fig
eczematous and/or papular lesions) l'rm annular urticarial plaques.
• This stage may persist for several weeks or months (before the appearance
of bullous lesions) and may remain as the only sign of the disease
55
Bullous Diseases
While BP may present with severe pruritus, pemphigus

vulgaris is usually asymptomatic (non-pruritic).______
W
mSm
7
(B) Bullous phase:

Skin lesions = vesicles and bullae (Fig 10.4)
• Tense
• On apparently normal or erythematous skin
• Contain a clear fluid (occasionally, blood-tinged
fluid)
• Up to 1-4 cm in diameter {large)
Fig 10.4 BP, bullous
• Residual post-inflammatory hyper- and hypo-
stage: tense bullae on
pigmentation (rarely, milia) erythematous and normal
• Persist for several days ^ rupture <=> eroded and skin with erosions.
crusted areas
• Symmetrical distribution (flexural aspects of the limbs and lower trunk)
* • While BP presents with large tense bullae, pemphigus

vulgaris usually presents with flaccid bullae and erosions.
M ucous membrane affection:

• Uncommonn
• Oral cavity (10-30%)
• Eyes, nose, pharynx, esophagus and anogenital region (rarely)
• While BP rarely affects mucous membranes, ALL patients

with pemphigus vulgaris present with mucosal (oral) lesions
# which may be the only manifestation (mucosal-dominant
pemphigus).______________________________________
Clinical variants:
1. Gestational pem phigoid (pemphigoid gestationis, herpes gestationis, HG):
• This variant MCQ occurs during pregnancy (2nd or 3rd trimester usually)
• Peri-umbilical and abdominal region —»• pruritic papular and urticarial
lesions ■=> vesicles and bullae (may become generalized)
2. Dyshidrosiform pemphigoid: palmoplantar involvement mimicking
dyshidrotic eczema (vesicles and bullae)
3. Lichen planus pemphigoides (LPP): a combination of clinical, histological,
and immunological features o f both lichen planus (LP) and BP (volume 2).
4. Childhood BP: lesions are similar to those of adults
5. Vulvar childhood pemphigoid: involvement of the genital area / perineum
6. Pemphigoid nodularis: mimicking prurigo nodularis
7. Erythrodermic BP: presenting as erythroderma
56
8. Pemphigoid vegetans: intertriginous vegetating plaques

9. Localized:
• pretibial area (pretibial pemphigoid)
• around stomas (peristomal)
• within sites of irradiation
• confined to a paralyzed limb
» distal end of amputated limb (stump pemphigoid)
10. Vesicular pemphigoid: dermatitis herpetiformis-like / grouped small tense
blisters ______________________________________________________
Anti-p200 pemphigoid
• A special type of pemphigoid first described in 1996.
• Patients tend to be younger than in BP. An association with
psoriasis was seen in about 30 % of reported cases (see below).
© Auto-antibodies from the patients’ sera did not react to any
known autoantigen of the skin, but reacted to a 200-kDa
protein (p200) from dermal extracts.
• In 2009, Dainichi et al identified the 200-kDa protein as
gamma 1 (yl) chain of laminin and renamed the disease as
anti-laminin y 1 pemphigoid.
H Dainichi T, Kurono S, Ohyama B, et al. Anti-laminin gamma-1
pemphigoid. Proceedings of the National Academy of Sciences
of the United States of America. 2009;106(8):2800-2805._____
Associated Diseases
1. Internal malignancies:
® Increased frequency of certain cancers (e.g. digestive tract, urinary
bladder, lung) and lymphoproliferative disorders.
• Probably related primarily to the older age o f the patient.
• Patients with BP should be followed-up with age-related

cancer screening tests recommended for the general
population._____________________________________
2. Autoim m une disorders:

© e.g. inflammatory bowel disease, rheumatoid arthritis, Hashimoto’s
thyroiditis, dermatomyositis, lupus erythematosus and autoimmune
thrombocytopenia.
• These associations reflect a genetically determined susceptibility to
develop autoimmune diseases.
3. Skin diseases:
• e.g. psoriasis (anti-p200 pemphigoid) and lichen planus (LPP).
• The bullae may be localized to the psoriatic plaques.
• It has been speculated that a chronic inflammatory process at the
dermal-epidermal junction results in the exposure of antigens to
autoreactive T lymphocytes, leading to a secondary immune response
(in case of lichen planus, it is called lichen planus pemphigoides).
57
Bullous Diseases
4. Neurological disorders:
• e.g. Parkinson's disease, dementia, psychiatric disorders (unipolar and
bipolar disorders), stroke and multiple sclerosis.
• Neuronal variants of BP230 are expressed in the central and peripheral
nervous systems.
Drug-induced bullous pemphigoid

• Triggering drugs include diuretics (e.g. furosemide), analgesics (e.g.
phenacetin), D-penicillamine, antibiotics (e.g. amoxicillin,
ciprofloxacin), potassium iodide, gold and captopril.
• The mechanisms by which drugs trigger the development o f BP remain
not fully understood. It is likely that the drugs act as triggers in patients
with an underlying genetic susceptibility by either modifying the
immune response or altering the antigenic properties of the
epidermal BMZ.
• In all patients with BP, a careful drug history is mandatory to exclude
the triggering effect of a drug, since its prompt discontinuation may
result in rapid improvement.
• Reproduction of BP lesions following drug re-challenge has been
observed with some drugs (e.g. furosemide), not with others.
• NB. BP may also be triggered by trauma, burns, radiotherapy or UV
irradiation (PUVA).
• In the non-bullous phase: eosinophilic spongiosis and/or dermal
infiltrates of eosinophils (Fig 10.5).
• In the bullous phase (early small intact vesicle): sub-epidermal blister
with eosinophils (Fig 10.6).
^ '.w a s mm,*
Fig 10.5 BP, non-bullous phase, hosinophils within the Fig 10.6 BP, bullous phase. Sub
dermis and the epidermis (eosinophilic spongiosis). epidermal blister with eosinophils.
NB. In BP, electron microscopy revealed that sub-epidermal blister occurs at

the level o f the LL
58
Direct IF: (peri-lesional, uninvolved skin)
• Deposits of IgG (less frequently, IgA or
IgE) and/or C3 along the epidermal BM
(fine, linear, continuous) (Fig 10.7)
Salt-split skin (SSS) indirect IF: Fi§ 10 7 DIF fmdinss in BP-

. , ^-1 j' 1 • j „ Linear deposits at the BMZ.
• Autoantibodies bind to ■=>
A the epidermal side (typically) (Fig 10.8) WHY??
A both the epidermal and dermal sides (less frequently) WHY??
Differential diagnosis
Non-bullous phase (non-specific)
• urticaria
• allergic urticarial reactions
• urticarial drug reactions
• urticarial vasculitis
• contact dermatitis Fi§ 10,8 IIF usin§ salt-split
human skin in BP. Circulating
• arthropod reactions autoantibodies bind to the epidermal
side (roof) of the salt-induced split.
B ullous phase
• Other sub-epidermal immunobullous disorders
• The pemphigus group
• bullous arthropod bites
• Stevens-Johnson syndrome
• bullous drug eruptions
• pompholyx
• pseudoporphyria or porphyria cutanea tarda
• In children T bullous impetigo, inherited epidermolysis bullosa, bullous
mastocytosis
• These disorders can be differentiated from BP based on clinical

history and findings, histopathologic features and IF findings.
Tips.
Prognosis
• BP is a chronic disease characterized by spontaneous exacerbations and
remissions. The majority of patients finally go into clinical remission with
treatment.
59
Bullous Diseases
T reatm ent
M ild and/or localized disease:
• Superpotent topical corticosteroids

• Topical immunomodulators (e.g. tacroli us)
• Nicotinamide + minocycline or tetracy*; le
• Erythromycin, penicillins
® Dapsone, sulfonamides
Extensive / persistent cutaneous disease:
• Superpotent topical corticosteroids

• Oral corticosteroids (Prednisone 0.5-1 kg day usually controls the
disease within 1 or 2 weeks then progressively tapered over a period of
6-9 months)
• The ‘steroid-sparing’ agents:
o Azathioprine
o Mycophenolate mofetil
o Methotrexate
o Cyclophosphamide
o Chlorambucil
o Rituximab
o IVIg
o Plasma exchange
Tetracyclines, Erythromycin, and Nicotinamide in BP:

• Non-immunosuppressive agents.
• Can be used as adjuvant therapy, especially in patients (1) who
respond only partially to corticosteroid therapy or who develop
adverse effects, (2) with mild or moderate disease, (3) older
patients and children (these agents do not cause major adverse
effects).
• Mechanisms o f action: anti-inflammatory effect. Tetracyclines
inhibit chemotaxis of neutrophil and eosinophils and block the
action o f certain metalloproteases.
• Dose: tetracycline 2 g/d combined with niacinamide 2 g/d._____
60
B u llo u s p e m p h ig o id (B P )
D
0 BP is the most common autoimmune sub-epidermal blistering skin disease.
0 A utoantibodies are directed against 2 autoantigens: BPAG2 (BP180,
collagen type XVII) and BPAG1 (BP230).
0 Autoantibodies against BPAG2 are directed specifically against the non-
collagenous NC16A dom ain (the immunodominant region).
0 BP usually affects the elderly (onset > 60 yrs) men.
0 C utaneous features:
o Non-bullous (prodromal) phase: p ru ritu s and u rticarial lesions,
o Bullous phase: tense vesicles and bullae, on apparently normal or
erythematous skin up to I-4 cm in diameter (large).
0 M M affection is uncom m on to rare.
0 Clinical variants: gestational, childhood, vulvar childhood, localized,
dyshidrosiform, palmoplantar, vesicular, pemphigoid nodularis,
erythrodermic, lichen planus pemphigoides and pemphigoid vegetans.
0 Associated Diseases: internal malignancies (related to the older age o f the
patient), autoim m une disorders, skin diseases and neurological disorders.
0 D rug-induced BP: triggering drugs include diuretics (e.g. furosemide),
analgesics (e.g. phenacetin) and antibiotics (e.g. amoxicillin,
ciprofloxacin)....
0 BP may also be triggered by trauma, bums, radiotherapy or UVR (PUVA).
0 Histopathology:
o Non-bullous phase: eosinophilic spongiosis and/or dermal
eosinophils.
o Bullous phase: sub-epiderm al blister with eosinophils
0 In BP, EM revealed that sub-epidermal blister occurs at the level of the LL.
0 Im m unofluorescence:
o Direct IF : linear deposits o f IgG and/or C3 along the epidermal
BMZ.
o Salt-split skin (SSS) indirect IF : autoantibodies typically bind to the
epiderm al side (roof).
0 Differential diagnosis:
o Non-bullous phase (non-specific): urticarial dermatoses,
o Bullous phase: other sub-epiderm al immunobullous disorders, the
pem phigus group and non-autoim m une bullous disorders.
0 Prognosis: BP is a chronic with exacerbations and remissions. The majority
o f patients finally go into clinical rem ission w ith treatm ent.
0 Treatm ent:
o M ild and/or localized disease: Superpotent topical corticosteroids,
o Extensive / persistent cutaneous disease: Oral corticosteroids
(Prednisone 0.5-1 mg/kg/day) ± steroid-sparing agents e.g.
Azathioprine, Mycophenolate m o fetil,.....
61
Bullous Diseases
Cicatricial pemphigoid
(CP)
S yn o n ym s
• Mucous membrane pemphigoid 1. Mucosa
• Desquamative gingivitis 2. Scarring
• Ocular pemphigus 3. Chronic
• Scarring pemphigoid
Synonyms give an idea about the main clinical features of CP:

• Mucous membrane pemphigoid <^>affects mainly the
U& lpAul mucosa.
• Desquamative gingivitis / Ocular pemphigus O the 2 most
Tips commonly affected mucosal sites are oral (gingival) and eye.
• Scarring pemphigoid ■=>heals with scarring.
Definition
• CP is a rare autoimmune sub-epithelial blistering disorder characterized by
1. predominant involvement of the mucosae (may affect the skin),
2. tendency towards scarring and
3. chronic and progressive course (may result in serious local
complications e.g. atrophic scarring and fibrosis of the conjunctivae
and blindness).
Pathogenesis (ta rg e t p r o te in s in B M Z )
• CP can be separated into 4 subgroups according to the reactivity of
patients’ autoantibodies (i.e. their target antigens) (Fig 11.1):
1. Anti-laminin 5 (Anti-epiligrin) CP: Five antigens:

1. Laminin-5
• Target antigen is laminin 5 (laminin 332, epiligrin). 2. Integrin a6
2. Ocular CP: 3. Integrin p4
• Target antigen is p4 subunit o f a6p4 integrin. 4. BPAG1
• Pure or predominant ocular disease. 5. BPAG2
■tjU m • Affection o f a6 subunit —►oral pemphigoid.

#4 • Affection of 34 subunit —>ocular involvement.
Tips --------------------------------
62
3. A nti-B P antigen m ucosal pem phigoid:

• Target antigens are BP180 ± BP 230 (same as BP).
• The antigenic regions targeted on BP180 are located on its distal C-
terminal portion, which ultrastructurally extend into the LD region.
• Lesions affect both mucosae and the skin.
4. The fourth subgroup is rather heterogeneous. It includes patients who

have variable involvement of mucosae without involvement o f the skin (it
is as yet unclear whether injury occurs as a result of an autoantibody-
mediated response to proteins o f the epithelial basement membrane).
Autoantigens are marked by red stars (*).
E p id e m io lo gy
• Incidence / Prevalence: rare (annual incidence in Western Europe of
approximately 1-5 cases per million).
• Age: affects the elderly (between 60 and 80 years).
• Sex: Women are affected more often than men (estimated ratio 1.5-2 : 1).
C lin ica l Features

M ucous m em brane lesions:
• The 2 most frequently involved sites are oral and conjunctival
mucosae.
• However, any mucosal site may be affected e.g. external genitalia,
anus, upper aerodigestive tract and esophagus.
63
Bullous Diseases
(1) Oral involvement:

• -85% of patients (often without skin
lesions, may be the only site).
• Lesions often involve the gingiva, buccal
mucosa and palate.
☆ gingiva —» erosive (desquamative)
gingivitis 'A erythema and erosions of
the gingival margins (Fig 11.2).
Fig 11.2 CP. Erythema and
A palate —> chronic erosions (Fig 11.3). erosions of the gingival
® Small intact blisters are rarely observed margins (desquamative or
(transient vesicles). erosive gingivitis).
® Variable associated pain.
• After healing, lesions may lead to white,
reticulated striations, resembling LP.
• Chronic inflammation may lead to
periodontal ligam ent damage and loss of
teeth.
(2) Conjunctival involvement (Ocular CP):

• Common (frequently the only site affected). Fig 11.3 CP. Chronic erosions
• Non-specific chronic conjunctivitis on the hard palate.
(burning, soreness, foreign body sensation,
mucus production) ■=> subepithelial
conjunctival fibrosis & scarring o may
result in blindness (Fig 11.4).
(3) Other mucosal sites:

Nasopharyngeal involvement o crusted
ulcerations, epistaxis, fibrous adhesions,
airway obstruction.
Pharyngeal involvement ■=>ulcerations, Fig 11.4 CP. Eye involvement
dysphagia. (fibrous tracts, partial or
incomplete symblepharon).
© Laryngeal involvement ■=>hoarseness, loss
of speech, life-threatening stenosis (potentially serious, requires
tracheostomy).
Esophageal disease ■=>erosions of the esophageal mucosa (strictures,
stenosis, dysphagia, weight loss).
Cutaneous lesions:
• The skin is involved in 25-30% of patients (generally limited).
• The most frequently involved sites are the scalp, face, neck and upper
trunk.
• Lesions typically present as erythematous plaques 'A recurrent blister
formation and erosions A atrophic scarring.
64
m
• BP commonly affects the skin, rarely the mucosa (non-
jk
< scarring).
1
• CP commonly affects the mucosa, rarely the skin (scarring).
B ru n s tin g -P e rry p em p h ig o id : a variant o f CP - a triad of

1. skin lesions ■=> limited to head and neck
2. on the scaip, the scarring o cicatricial alopecia
3. mucosal involvement A absent or m inim al
• CP should not be regarded as a clinical entity, but rather as a

“disease phenotype” shared by a heterogeneous group of
blistering diseases, with predilection for the mucosal surfaces.
H isto p a th o lo gy (intact vesicle)

• Sub-epiderm al or sub-epithelial blister without acantholysis.
® A mixed infiltrate composed primarily of mononuclear cells.
• O lder lesions A fibrosis in the upper dermis.
• EM A cleavage occurs within the LL.
im m u n o flu o re sce n ce
D ire c t IF : (peri-lesional, uninvolved skin)
• IgG and/or C3 along the epithelial BMZ (fine, linear, continuous).
• DIF of mucosae are more frequently positive than those of skin.
S a lt-sp lit skin (SSS) in d ire c t IF : Autoantibodies bind to a
A the epiderm al roof (most patients).
A the derm al side (anti-lam inin 5 CP).
The histo pathologic and DIF features of CP and BP are often

similar. Moreover, SSS IIF of CP (except anti-laminin 5 CP)
shows epidermal staining pattern as BP. These findings may
preclude the diagnosis of CP and make it difficult to distinguish it
from other scarring auto-immune sub-epidermal bullous diseases
(e.g. EBA). Additional investigative tools may be used to resolve
this issue:
• ELISA utilizing recombinant proteins (e.g. BP180, laminin 5)
® Indirect IF microscopy using “knockout” skin substrates
(substrates deficient in specific BMZ proteins) or the computer-
aided FOAM (fluorescence overlay antigen mapping)
technique.
• Immunoelectron microscopy.
65
Bullous Diseases
differential diagnosis
1. Other sub-epidermal autoimmune bullous diseases e.g. BP, EBA and
linear IgA bullous dermatosis
2. Intra-epidermal autoimmune bullous diseases e.g. pemphigus
vulgaris
3. Non-autoimmune bullous diseases
These disorders can be differentiated from CP based on clinical

I history and findings, histopathologic features and IF findings.
T ip i
'1
4. Oral lesions of CP (as the only manifestation of the disease):

Should be differentiated from..
• oral lesions of pemphigus vulgaris.
• erosive lichen planus.
5. End-stage scarring conjunctival lesions:
• severe chronic infectious conjunctivitis.
• ocular pseudo-pemphigoid (due to ophthalmologic preparations
e.g. pilocarpine, idoxuridine, guanethidine, P-blockers).
• late stages of Stevens-Johnson syndrome and toxic epidermal
necrolysis
6. Generalized skin eruption of CP (rare):
• BP (prominence of mucosal lesions and scarring favors the
diagnosis of CP).
Prognosis
• CP is a chronic, potentially devastating disease.
o The most important complication is impairment of vision due to
ocular involvement,
o It can also lead to weight loss as well as respiratory, sexual or
urinary complications.
• o Even with localized involvement, this disease can have a major
negative impact on quality of life,
o Patients with anti-laminin 5 (332) autoantibodies have an increased
relative risk for solid organ carcinomas, especially
adenocarcinomas.
• However, CP is a rarely fatal disease.
o Life-threatening complications, due to severe laryngeal, tracheal
or esophageal disease, are rare.
66
Tre a tm e n t: (depends upon the extent and severity o f the disease)
M ild to m oderate disease: Potent topical corticosteroids

☆ Oral lesions:
o topical corticosteroids (mouthwashes, topical preparations in a gel or
occlusive base)
o good hygiene
o tetracycline mouthwashes
V Nasal, pharyngeal or esophageal disease: corticosteroid sprays and
inhalers
Systemic medications:
Indicated fo r ^
N severe ocular, laryngeal or esophageal involvement.
N oral or cutaneous disease unresponsive to topical therapy.
Include ■=>
• Dapsone (50-150 mg/day) ■=>first-line therapy for oral & cutaneous
lesions (± mild ocular disease).
• Cyclophosphamide (1-2 mg/kg/day) ■=>treatment o f choice for rapidly
progressive or severe ocular disease (alone, in combination with oral
corticosteroids or as pulse therapy).
o Such regimens are effective in resolving severe conjunctival
inflammation and preventing recurrences and scarring.
• Combination of prednisone and cyclophosphamide or mycophenolate (2
g/day) >=> significant esophageal or laryngotracheal involvement.
• Other therapies: sulfapyridine, minocycline, a combination of tetracycline
and niacinamide, topical tacrolimus, topical or systemic cyclosporine,
azathioprine, thalidomide, methotrexate, subconjunctival mitomycin, IVIg
and TNF-a inhibitors such as etanercept, and rituximab.
Surgical therapy:
• Indications: severe scarring involving the eye, larynx, esophagus or
genitalia.
• Should be done when the disease is fully controlled by medical therapy.
• For ocular disease, surgical intervention includes comeal grafts, allograft
limbal transplantation, amniotic membrane transplantation, and
tarsorrhaphy.
• Systemic corticosteroids alone are insufficient therapy for CP,

and they are less effective for mucosal than for cutaneous
disease.
67
Bullous Diseases
C ic a tric ia l p e m p h ig o id (C P )
□
0 CP is a rare autoimmune sub-epithelial blistering disorder characterized
by mucosal involvement (may affect the skin), scarring and chronic and
progressive course.
0 Target antigens in the BMZ may include laminin 5 (epiligrin, laminin
332), p4 subunit of o.6p4 integrin, BP180 and / or BP230.
0 CP affects the elderly (60 - 80 years) and is more common in women.
0 Clinical Features:
o Mucous membrane lesions:
o Oral: erosive (desquamative) gingivitis,
o Conjunctival (Ocular CP): non-specific chronic conjunctivitis,
o Other mucosal sites e.g. nasopharyngeal, laryngeal, esophageal
o Cutaneous lesions: less common, limited, commonly affects the scalp,
face, neck and upper trunk (erythematous plaques ■=> blistering >=>
scarring).
o Brunsting-Perry pemphigoid: a triad o f skin lesions (head and neck),
cicatricial alopecia on the scalp and absent / minimal mucosal
involvement.
0 Histopathology (intact vesicle): sub-epidermal or sub-epithelial blister with
mixed infiltrate and fibrosis (in older lesions).
o DIF: IgG and/or C3 along the epithelial BMZ (fine, linear, continuous),
o SSS IIF: Autoantibodies bind to the epidermal roof (most patients) or
the dermal side (anti-laminin 5 CP).
o Other sub-epidermal autoimmune bullous diseases
o Intra-epidermal autoimmune bullous diseases e.g. pemphigus vulgaris
o Non-autoimmune bullous diseases
o Oral CP: oral lesions of pemphigus vulgaris, erosive lichen planus,
o Scarring conjunctival lesions: severe chronic infectious conjunctivitis.
0 Prognosis: CP is a chronic, potentially devastating disease (impairment of
vision, weight loss, respiratory, sexual or urinary complications and
negative impact on quality o f life). However, CP is a rarely fatal disease.
0 Treatment: (depends upon the extent and severity of the disease)
o M ild to moderate disease ^ Potent topical corticosteroids
o Severe cases or unresponsive to topical therapy ■=> systemic medications
e.g. Dapsone, Cyclophosphamide (alone, in combination with oral
corticosteroids), other immunosuppressive drugs,
o Surgical therapy for correction of severe scarring,
o Systemic corticosteroids alone are insufficient therapy fo r CP.
68
C h a p te r
Epidermolysis bullosa
acquisita (EB A ) 12
Synonym s
• Acquired EB (to distinguish it from hereditary EB).
Definition
• EBA is a rare acquired, sub-epidermal immuno-bullous disease.
P athogenesis (target proteins in BMZ)

• Type V II collagen MCQ (anchoring fibrils) in the SLD.
Epidem iology
• Incidence / Prevalence: EBA is one of the rarest sub-epidermal bullous
diseases (annual incidence in Western Europe is ~ 0.25 per million).
• Age: EBA usually occurs in adults (have been reported in children, may
occur at any age).
Clinical F e a tu re s
EBA has 2 main clinical presentations: patients may present with features of
either:
(1) M echano-bullous “Non-inflam m atory” disorder (resembling
dystrophic EB) ■=> the classic presentation (Fig 12.1a)
• acral blisters (may be serous or less frequently hemorrhagic) with
subsequent erosions.
• appear within non-inflamed skin / on areas of scarring.
• localized to trauma-prone areas e.g. elbows, knees, dorsal aspects of
hands, feet and toes.
• heal with atrophic scarring, milia and hyper- or hypopigmentation.
• acral involvement may be mutilating O ‘mitten’ deformity of the
digits, syndactyly, nail dystrophy and complete nail loss.
(2) Im muno-bullous “Inflam m atory” disorder (indistinguishable from
BP, CP)
• BP-like ■=> widespread vesicles and bullae, involving intertriginous
and flexural areas, heal without milia or atrophic scars (Fig 12.1b).
• CP-like ^ including the Brunsting-Perry pemphigoid phenotype with
scarring alopecia.
69
Bullous Diseases
• During the course of the disease, the clinical features can

convert from one variant to another or, alternatively, a mixture
of inflammatory and non-inflammatory features may coexist.
Mucous m em brane involvement is variable

• Erosions and intact vesicles may be seen in the mouth; larynx and
esophagus (may lead to dysphagia and laryngeal stenosis) (Fig 12.1c).
• Ocular involvement / blindness is reported in the CP-like phenotype.
Fig 12.1 Clinical features of EBA (a) Mechanobullous presentation. Milia and scarring that favors
sites of trauma overlying joints, in association with skin fragility, (b) Inflammatory BP-like
presentation. Bullous and erosive lesions, (c) Multiple erosions of the palate reminiscent o f mucous
membrane (cicatricial) pemphigoid.
Childhood EBA:
• Clinical features have substantial overlap with those observed in childhood
BP and linear IgA bullous dermatosis.
Associated diseases:
• A number of systemic diseases have been described in association with
EBA, including inflammatory bowel disease, myeloma, rheumatoid
arthritis, systemic lupus erythematosus, thyroiditis and diabetes mellitus.
• Inflammatory bowel disease MCQ. particularly Crohn’s disease, is the
most frequently associated condition. Type VII collagen is also expressed
in the basement membrane o f intestinal epithelium.____________________
U Thrash, B., Patel, M., Shah, K. R., Boland, C. R., & Menter, A. (2013). Cutaneous
manifestations of gastrointestinal disease: part II. J Am Acad Dermatol, 68(2),
21 l.e211-233.

• Sub-epidermal cleavage.
o In the BP-like or CP-like variants ■=> mixed inflammatory infiltrate of
neutrophils, eosinophils or lymphocytes (Fig 12.2 a),
o In the mechanobullous, non-inflammatory lesions ■=> minimal-to-
absent cellular infiltrate (Fig 12.2 b).
• EM demonstrates that cleavage occurs within the SLD zone.
70
(a) (b)
Fig 12.2 Histopathological features of EBA Sub-epidermal blister (a) Inflammatory type: mixed
inflammatory infiltrate, (b) Non-inflammatory type: minimal inflammatory infiltrate.
Direct IF : (peri-lesional, uninvolved skin)
• IgG along the epithelial BMZ
(broad, linear, continuous).
Sait-split skin (SSS) indirect IF:
• Autoantibodies bind to the dermal side Fig 12.3 IIF utilizing SSS in
(floor) (Typical - WHY?) (Fig 12.3). EBA. A uto-antibodies react w ith
the derm al side (floor) o f the
b lister (arrow s).
• The mechanobullous type of EBA: DD with inherited EB (mild dominant
dystrophic type).
A EBA ■=> lack of a family history, late onset, positive direct IF findings.
• The inflammatory type of EBA: DD with BP or CP (including
Brunsting-Perry pemphigoid)
A indirect IF (with salt-split skin as a substrate) “not conclusive”
A ELISA is “diagnostic”
• The involvement of the hands: DD with porphyria cutanea tarda
(excluded by porphyrin studies).
• Bullous SLE: clinical and histologic differences.
T re a tm e n t
• The treatment of EBA is difficult and often unsatisfactory (EBA is a
chronic disease that is often refractory to many treatment modalities).
• The 2 main lines of treatment are:
1. Systemic corticosteroids
2. Standard immunosuppressive agents e.g. azathioprine, methotrexate,
mycophenolate mofetil, cyclophosphamide, colchicine, Dapsone, Gold,
IVIg, Cyclosporine and Extracorporeal photochemotherapy.
(S ® • Mechano-bullous EBA resembles dystrophic EB:
UnlrT'ul (1) clinically: acrally-distributed blisters precipitated by trauma,
\ (2) target antigen: collagen VII,
(3) histopathology: sub-epidermal blister with minimal infiltrate.
71
Bullous Diseases
E p id e rm o lys is b u llo s a a c q u is ita
o (E B A )_______________________________
0 EBA is a rare acquired, sub-epidermal immuno-bullous disease.

0 Target antigen: Type VII collagen (anchoring fibrils) in the SLD.
0 EBA usually occurs in adults (also in children, may occur at any age).
0 Clinical Features: 2 main clinical presentations:
• Mechano-bullous “Non-inflammatory : resembling dystrophic EB
acral blisters and erosions, within non-inflamed skin, localized to
trauma-prone areas (elbows, knees, dorsal aspects o f hands, feet and
toes) and heal with atrophic scarring, milia and hyper- or
hypopigmentation.
• Immuno-bullous “Inflammatory”: resembling BP or CP
A BP-like ■=> widespread vesicles and bullae, involving intertriginous
and flexural areas.
A CP-like
0 Mucous membrane involvement:
o Erosions and intact vesicles in the mouth; larynx and esophagus,
o Ocular involvement and blindness (in the CP-like phenotype).
0 Associated diseases: inflammatory bowel disease (particularly Crohn’s
disease) is the most frequently associated condition. Others include
myeloma, rheumatoid arthritis, systemic lupus erythematosus, thyroiditis
and diabetes mellitus.
0 Histopathology (intact vesicle): Sub-epidermal cleavage.
o In the BP-like or CP-like variants *=>mixed inflammatory infiltrate,
o In the mechanobullous, non-inflammatory lesions 'A minimal-to-
absent infiltrate.
o Direct IF: IgG along the epithelial BMZ (broad, linear, continuous),
o SSS indirect IF: Autoantibodies bind to the dermal side (floor).
o The mechanobullous type o f EBA O DD with inherited EB.
o The inflammatory type o f EBA 'A DD with BP or CP.
o The involvement o f the hands ‘A DD with porphyria cutanea tarda,
o Others e.g. Bullous SLE.
0 Treatment:
o Systemic corticosteroids
o Standard immunosuppressive agents e.g. azathioprine,
methotrexate, mycophenolate mofetil, cyclophosphamide,
colchicine, Dapsone ....
72
C h a p te r
Dermatitis herpetiformis
(DH) 13
S yn o n ym s
• Duhring's disease MCQ
o DH was first described by D r Louis Duhring at the University of
Pennsylvania in 1884. It was the first skin disease described by an
American dermatologist.
Definition
• DH is a cutaneous manifestation o f gluten-sensitive enteropathy (GSE) /
celiac disease (CD)
• Gluten-sensitive enteropathy (GSE), also known as Celiac

disease (CD) or celiac sprue, is a chronic disorder of the
digestive tract characterized by an inability to tolerate gluten (a
family of grain proteins commonly found in wheat, rye, and
barley), but not oats.
• Gliadin is the alcohol-soluble fraction of gluten and it is the
antigenic component.
• When CD patients ingest gliadin, an immunologically
mediated inflammatory response occurs in their intestinal
mucosa.
• The spectrum of intestinal involvement ranges from minimal
infiltration of the lamina propria by lymphocytes (with normal
villi), to minimal atrophy of the jejunum accompanied by intra-
epithelial lymphocytic infiltrates, to total villous atrophy o f the
small intestine, resulting in maldigestion and malabsorption.
Association between DH and GSE:

• On small bowel biopsy, over 90% of DH patients have evidence of a GSE:
o The enteropathy is often patchy and may require multiple small bowel
samples for diagnosis i.e. DH is associated with GSE in virtually all
cases.
o Intestinal symptoms CD occur in only 20% of DH patients.
• Both the skin disease and the intestinal disease:
o respond to gluten restriction
o recur with institution of a gluten-containing diet (i.e. a regular diet)
73
Bullous Diseases
P a th o g e n e s is
• The following factors contribute to the pathogenesis of DH:
1. Genetic predisposition
2. Environmental factors (Triggers)
3. Immunologically-mediated inflammatory response
(1) Genetic predisposition:

• Association with HLA genes MCQ:
o HLA associations (in genetically susceptible individuals) are the same
for patients with CD and DH and include:
■ HLA DQ2 (in 90% of CD and DH patients)
■ HLA DQ8 (in the remaining DH patients)
• HLA molecules (on the surface of dendritic antigen-presenting

cells) interact with T-cell receptors. Specific HLA genes in
Helpful genetically susceptible individuals (mentioned above) provide
• > the antigenic specificity that processes the gliadin antigen.
Association with non-HLA genes:

• Less than 50% of the genetic predisposition in CD and DH is
due to specific HLA genes. Genomic searches for non-HLA
genes are currently underway.
• A susceptibility locus for CD (on chromosome 4q27) has been
proposed and includes the genes for IL-2 and IL-21._________
(2) Environm ental factors (Triggers)

• Monozygotic twins, one with DH and the other with CD, have been
reported, indicating that environmental factors (in addition to genetic
factors) play a role in the development of CD and/or its extra-intestinal
manifestation, DH.
• The major environmental factor involved in triggering the disease is
exposure to gluten MCQ.
• Iodide is another important trigger in DH.
o Ingestion o f iodide can lead to worsening o f DH.
o Topical application o f iodide onto the normal skin o f DH patients
produces lesions that are histologically identical to spontaneous lesions.
Iodide stimulates neutrophil infiltration into the skin.
• DH patients should avoid fish rich in iodine contents (e.g.

Shellfish) and iodized salt._________________________
74
(3) Im munologically-m ediated inflam m atory response

The following sequence of events represents the proposed immuno-
pathogenesis o f CD and DH.
(D Gastrointestinal processing o f dietary gluten: (Fig 13.1 a)

• Ingestion o f gluten - conta in in g grains (e.g. wheat) —►digestion —>gliadin
peptides —>transported intact across the mucosal epithelium o f the
intestinal mucosa (i.e. absorbed).
• Within the lamina propria, tissue transglutaminase (TG2):
(1) de-am idates glutam ine residues (within gliadin) are —>glutam ic acid.
(2) becomes covalently cross-linked to gliadin peptides (isopeptidyl bonds
are formed between gliadin glutam ine and TG2 lysine residues).
Wheat
Plasma cell
TG 2-specific
1 B cell
Gliadin
\
t
Gf lumen J
Q U I T*D j*' -Lamina propria

Th2
cytokines
-Endomyslum
(connective
Smooth muscle tissue sheath)
Cross-linking
A Deamidation
Inflammatory cell activation, e

1 matrix metalloproteinases
1
0
II M aSSS
C - N — (CHz)4—
I Villous atrophy and
H Isopeptidyl bond
crypt hyperplasia
(a) (b)
Fig 13.1 Pathogenesis of DH (a) Gastrointestinal processing of dietary gluten (e.g. wheat,
barely and rye), (b) Gastrointestinal immune response.
The transglutaminase (TG) family includes 9 different types of

proteins expressed in various cell types. Two are relevant in DH:
(1) Tissue transglutaminase (TG2): widely distributed in the
human body. A cytoplasmic calcium-dependent enzyme that
catalyzes cross-linkage between glutamine and lysine residues
leading to stabilization of the cytoskeleton.
(2) Epidermal transglutaminase (TG3): first described Sardy et al
in 2002 - present in keratinocytes - it maintains the stratum
corneum’s integrity (by cross-linking epidermal proteins).
75
Bullous Diseases
® Gastrointestinal im m une response: (Fig 13.1 b)

• Deamidated gliadin peptides —►uptaken by dendritic antigen-presenting
cells —►bind to HLA-DQ2 or -D Q 8 molecule on the surface of these cells
—» presented to helper CD4+ T cells —>
(1) Stimulation of B cells —>differentiate into plasm a cells —>produce IgA
antibodies to multiple antigens including gliadin, gliadin cross-linked
to TG2, TG2 and epidermal transglutaminase (TG3).
(2) Production o f T hl cytokines and matrix metalloproteinases (MMPs)
that cause mucosal epithelial cell damage —>■villous atrophy.
• The pathogenic autoantibodies in both CD and DH are mainly

of the IgA class. IgG can be found (important inpatients with
'TloS. ! gluten sensitivity and IgA deficiency).
Why auto-antibodies develop against TG3?

• Continuous exposure to gliadin (in gluten) —>epitope
spreading —>■development of IgA anti-TG3 antibodies (in
patients who already have IgA anti-TG2 antibodies). There is
64% structural homology between TG2 and TG3 molecules.
Anti-TG2 antibodies may, by cross-reaction, recognize TG3.
• Epitope spreading (i.e. formation of IgA anti-TG3 antibodies)
requires time and continued exposure to gluten (this explains
why DH presents at a later age than symptomatic CD “which
often manifests in childhood”). This is more likely to occur in
patients with less severe, relatively asymptomatic intestinal
involvement (this explains why patients with CD have more
severe intestinal disease than patients with DH).
• Evidence for this theory includes the higher prevalence of IgA
anti-TG3 antibodies in adults than in children with CD (i.e.
developing later in the evolution of the disease)._____________
(® Circulating im m une response:

• Both IgA anti-TG2 and IgA anti-TG3 circulate in the bloodstream.
® Progression o f skin pathology:

• When IgA anti-TG3 antibodies reach the dermis —> complex with TG3
antigens (which have been produced by keratinocytes and then have
diffused into the dermis) —>IgA/TG3 immune complexes are formed
locally within the papillary dermis —> neutrophil chemotaxis from the
circulation into the dermal papillae (with formation of neutrophilic micro
abscesses) —> degranulation of neutrophils —» proteases —>proteolytic
cleavage of the lamina lucida —» sub-epidermal blister formation.
• TG2 is the main antigen in CD, TG3 is the antigen in DH.

• Serum from patients with CD react against TG2 and TG3,
whilst those of patients with DH react mainly against TG3.
76
TG3 is not a basement membrane antigen:

• In normal subjects, TG3 is found in more superficial
epidermal keratinocytes, and NOT in the dermo-epidermal
junction, the main site of IgA deposits.
• There are two hypotheses to explain this phenomenon.
1. After a trauma, keratinocytes might release TG3 that would
then deposit in the basement membrane.Circulating
antibodies would bind to these autoantigens forming the
disease’s characteristic deposits in that site.
2. A second hypothesis is the possibility that keratinocytes would
release TG3 into the blood stream, where it would form
immune complexes with IgA, which would then deposit in the
dermal papillae
H Clarindo et al. Dermatitis herpetiformis: pathophysiology,
clinical presentation, diagnosis and treatment. An Bras
Dermatol. 2014; 89(6): 865-77).
E p id e m io lo gy
• Incidence and prevalence: DH is a relatively rare condition.
• Age: the mean age o f presentation is during the third and fourth decades
(30 to 40 years old), but it varies widely from infancy to the geriatric
population (2 to 90 years).
A DH is rare in adolescents and prepubescent children.
• Sex: more common in males (male to female ratio 1.5:1 to 2:1).
A In children with DH, there is a female predominance.
A Interestingly, the opposite is tme of the prevalence of CD, with female to male
ratios ranging from 2:1 to 4:1
• Fam ilial incidence may be present.
• Race: DH occurs most commonly in people of northern European origin
(Europe and the United States)
A DH is very rare among Asians and African Americans.
A DH in children is more common in Mediterranean countries (possibly
related to differences in diet or to a genetic predisposition)

Cutaneous lesions:
• Symptoms: intense pruritus (leads to secondary excoriation and crusting).
• Signs (Lesions): (Fig 13.2)
o Primary lesions: pleomorphic - urticarial plaques, papules and
vesicles. Grouped or “herpetiform” papulo-vesicles on an erythematous
base are characteristic,
o Distribution: bilateral and symmetric.
o Sites: extensor surfaces (elbows, extensor forearms, knees and back),
buttocks and scalp MCQ.
Bullous Diseases
(a) (b) (c)

Fig 13.2 C linical features o f D H (a) Excoriated papules on elbows, (b) Vesicles and
erosions on knees, (c) papulovesicles on the upper back, neck and scalp.
• The primary lesions of DH (papules and vesicles) are often

absent and replaced by erosions and excoriations (because it’s
a highly pruritic condition). Even if only hemorrhagic crusts or
secondary changes from scratching are present, the diagnosis
should be suspected on the basis of the distribution of lesions.
• Mucosal involvement in DH is rare.
(1) Autoim m une disorders:

• Common
A Autoimmune thyroid disease
Hypothyroidism is the most
(Hashimoto’s thyroiditis)
common autoimmune
A Insulin-dependent diabetes mellitus condition associated with DH.
• Uncommon: pernicious anemia
• Rare
A Addison’s disease A Systemic sclerosis (scleroderma)
A Autoimmune chronic active A Sjogren’s syndrome
hepatitis A Systemic lupus erythematosus
A Alopecia areata A Vitiligo
A Myasthenia gravis A Sarcoidosis
(2) Malignancies:
• Enteropathy-associated T-cell lymphoma (Adhering to a gluten-free diet
protects against lymphoma in DH patients).
• A small intact vesicle —> sub-epidermal clefts
with collections o f neutrophils MCQ within
dermal papillae (Fig 13.3).
• I f a small, intact vesicle is not available, an ,. , .4** ' 'em i
area o f erythema should be biopsied. Areas of Fig 13.3 H istopathological
features o f DH.
erythema will show dermal papillary edema
and neutrophil infiltration associated with a superficial perivascular
lymphocytic infdtrate.
78
In disorders characterized by IgA antibodies, the inflammatory

infiltrate is made up of neutrophils.______________________
T ip s
Direct IF : (Fig 13.4)
• Optimal biopsy site: normal-appearing
skin immediately adjacent to a lesion
(peri-lesional).
• Findings: Granular IgA MCQ deposits
localized to dermal papillae. Fig 13 4 DH _ m F. Granular IgA
deposition along DEJ.
Indirect IF:
• Negative. IgA/TG3 immune complexes are formed locally within the
papillary dermis.
O th e r investigatio ns
• Serologic tests: circulating IgA antibodies against gliadin, endomysium,
tissue transglutaminase (TG2) and epidermal transglutaminase (TG3) MCQ.
• Genetic testing to determine a patient’s HLA type is useful in cases where
DH cannot be excluded.
• A small bowel biopsy if clinical signs o f G I disease or malignancy are
evident on physical examination
• Screening for other associated autoimmune diseases especially thyroid
disease (thyroid stimulating hormone and anti-thyroid peroxidase antibody
titers). Measuring o f fasting blood glucose level for diabetes is also
recommended. Screening for other autoimmune connective tissue diseases
should be done, if clinically indicated (suspicious symptoms, such as joint
pain or photosensitivity).
• The endomysium is the connective tissue covering the smooth

muscle layers of the esophagus, stomach and small intestine,
-pjps, ; The endomysial antigen has been identified as TG2.________
• Other sub-epidermal immune-bullous diseases:
o Bullous pemphigoid (BP)
o Linear IgA bullous dermatosis (LABD)
0 Table 14.1 (page 87) outlines the clinical and histologic features
that help differentiate DH from LABD and BP.
79
Bullous Diseases
o Bullous lupus erythematosus LE

0 Presents with urticarial papules and vesicles on an erythematous
base and a histologic picture similar to LABD and DH. However,
the patients have clinical and serologic findings of systemic
lupus erythematosus.
• Erythema multiforme (EM): characterized clinically by target lesions that

are often acral in distribution and show vacuolar degeneration and
epidermal necrosis histologically; also there are no IgA deposits at the
BMZ.
• Other differential diagnoses include urticarial vasculitis, scabies and

arthropod bites.
Tre a tm e n t
• In disorders characterized by IgA antibodies, the inflammatory
infiltrate is made up of neutrophils and these disorders respond
to dapson MCQ.________________________________________
The mainstays of DH treatment are the gluten-free diet and drug therapy with
sulphones (dapsone or other sulphones)
G luten-free diet (G FD )
• A Gluten-free diet includes corn, rice and oats. Patients should AVOID
wheat, barley and rye (Table 13.1).
• Because several months of GFD therapy are needed for a response,
concurrent suppression of symptoms with dapsone is usually necessary
• With a prolonged GFD, IgA in the skin decreases and eventually
disappears, but with the reintroduction of gluten, IgA deposits and skin
disease return.
• Unfortunately, the GFD is inconvenient and unacceptable to some patients.
• Minor fluctuations in disease severity are related to oral gluten intake.
Dapsone (4',4' di-amino-di-phenyl- sulfone)

• Pruritus of DH is relieved within 48-72 hours o f instituting dapsone.
• Lesions abruptly recur within 24-48 hours of discontinuation of therapy.
• Dapsone has no effect on the intestinal pathology
• Initial daily dosages: 25-50 mg in adults - 0.5 mg/kg in children (after
screening for glucose-6-phosphate dehydrogenase “G6PD” deficiency)
o Initiation o f therapy with higher doses may precipitate severe
hemolysis and cardiac decompensation in susceptible individuals.
• Average maintenance dose in adults on a normal diet is 100 mg daily.
• Dapsone has anti-inflammatory properties and inhibits neutrophil
recruitment and local neutrophil- mediated tissue injury.
80
• The skin lesions and pruritus of DH respond slowly toa gluten-

free diet but are rapidly responsive to oral dapsone.
• Patients who adhere to a strict GFD are often able to be weaned
off dapsone within several months, and may subsequently
restart for brief periods as needed to control flares.
• If patients are intolerant to dapsone, therapy with
sulfapyridine should be considered. The initial dose of
sulfapyridine is usually 500 mg three times a day and it can be
safely increased to 2 g three times a day. Adequate fluid
intake and alkalinization of the urine minimizes the risk of
nephrolithiasis. Other sulphones may be used as sulfasalazine
and sulfamethoxypyridine.___________________________
O ther lines of treatm ent
• Potent and super-potent topical steroids (e.g. clobetasol propionate) have

a role by locally decreasing the associated pruritus. Topical steroids should
not be used as monotherapy for DH but rather in conjunction with
systemic treatments, and only during the acute stage of the disease.
• Systemic corticosteroids are generally not effective in DH.
• Antihistamines may play a limited, adjunctive role to control DH-
associated pruritus.
• Empirical therapies (uncontrolled studies and case reports): cyclosporine,
colchicine, heparin, tetracycline, and nicotinamide.
P rognosis
• DH is usually a lifelong condition. However, the course may wax and
wane. A spontaneous remission may occur in up to 10% of patients, but
most clinical remissions are related to dietary gluten restriction.
81
Bullous Diseases
D e rm a titis h e rp e tifo rm is (D H )
D
0 DH is a cutaneous manifestation o f gluten-sensitive enteropathy (GSE) /
celiac disease (CD)
0 Pathogenesis:
• Genetic predisposition: association with certain HLA genes (HLA
DQ2 and HLA DQ8).
• Environmental factors (Triggers):
■ Exposure to gluten (wheat, barley and lye).
■ Ingested or topically-applied iodide (fish rich in iodine e.g.
shellfish and iodized salt)
• Immunologically-mediated inflammatory response
© G astrointestinal processing of dietary gluten:
Ingestion of gluten-containing grains (e.g. wheat) —>■digestion —>
gliadin peptides. Tissue transglutaminase (TG2) de-am idates
glutamine residues (within gliadin) and becomes covalently cross-
linked to gliadin peptides.
© Gastrointestinal immune response:
Deamidated gliadin peptides —» uptaken by dendritic antigen-
presenting cells —>presented to helper CD4+ T cells —> stimulation o f B
cells —»plasma cells —» IgA antibodies to multiple antigens (gliadin,
gliadin cross-linked to TG2, TG2 and epidermal transglutaminase
“TG3”).
© Circulating immune response:
Both IgA anti-TG2 and IgA anti-TG3 circulate in the bloodstream.
© Progression of skin pathology:
IgA anti-TG3 antibodies reach the dermis —* complex with TG3
antigens (produced by keratinocytes and diffused into the derm is) —►
IgA/TG3 immune complexes —>neutrophil chemotaxis —>proteases —>
proteolytic cleavage of the lam ina lucida —> sub-epiderm al blister
formation.
0 Epidemiology:
• Incidence and prevalence: rare condition.
• M ean age of presentation: 3rd and 4th decades (30 to 40 years old)
• Sex: more common in males
• Race: people of n o rth ern E uropean origin (Europe and the US)
• Symptoms: intense pruritus
• Skin lesions: pleomorphic -g ro u p e d or “herpetiform” papulo-vesicles
on an erythematous. Bilateral and symmetric affecting extensor
surfaces (elbows, knees and back), buttocks and scalp.
• Associated diseases: (1) Autoimmune disorders: Hashimoto’s
thyroiditis, insulin-dependent D M , (2) GIT T-cell lymphoma
82
0 Histopathology (intact vesicle): Sub-epidermal clefts with collections of

neutrophils within dermal papillae.
• DIF: Granular IgA deposits localized to dermal papillae.
• IIF: NEGATIVE.
0 Other investigations:
• Serologic tests: IgA antibodies against gliadin, endomysium, TG2 and
TG3.
• Genetic testing to determine a patient’s HLA type
• A small bowel biopsy
• Screening for associated autoimmune diseases especially thyroid
disease
• Other sub-epidermal immune-bullous diseases: BP, LABD, bullous
LE
• Urticarial vasculitis, scabies and arthropod bites.
0 Treatment:
• A Gluten-free diet (corn, rice and oats). AVOID wheat, barley and rye.
• Dapsone (25-50 mg up to 100 mg daily in adults).
• Adjunctive therapy: potent and super-potent topical steroids ±
antihistamines (to control the associated pruritus).
T a b l e 13.1 Diet in derm atitis herpetiform is MCQ.

Food items allowed Food items to avoid
• Rice, rice flour • Wheat
• Corn, com flour • Rye
• Pure oat • Barley
• Soya bean • Millet
• Fresh vegetable • Canned food item (preservatives)
• Fresh Fruits • Instant coffee and instant tea
• Fresh brewed coffee • Noodles
• Apple cider • Spaghettis
• Custards • Macaroni
• Yogurt • Ice cream cones
• Salt • Packed rice mix
• Pepper • Shampoo containing wheat germ oil
• Coconut • Dental adhesive and tooth paste containing
• Pure chocolate offending grains
• Fish rich in iodine contents (Shellfish)
• Iodized salt
H Anwar MI et al. Guidelines for the management of dermatitis herpetiformis.
Journal o f Pakistan Association o f Dermatologists 2013; 23 (4): 428-435.
83
0 Histopathology (intact vesicle): Sub-epidermal clefts with collections of

neutrophils within dermal papillae.
• DIF: Granular IgA deposits localized to dermal papillae.
• IIF: N EG A TIV E.
0 Other investigations:
• Serologic tests: IgA antibodies against gliadin, endomysium, TG2 and
TG3.
• Genetic testing to determine a patient’s HLA type
• A small bowel biopsy
• Screening for associated autoimmune diseases especially thyroid
disease
• Other sub-epidermal immune-bullous diseases: BP, LABD, bullous
LE
• Urticarial vasculitis, scabies and arthropod bites.
0 Treatment:
• A Gluten-free diet (corn, rice and oats). AVOID wheat, barley and rye.
• Dapsone (25-50 mg up to 100 mg daily in adults).
• Adjunctive therapy: potent and super-potent topical steroids ±
antihistamines (to control the associated pruritus).
Table 13.1 D iet in d e rm a titis h e rp e tiform is MCQ.

Food items allowed Food items to avoid
• Rice, rice flour • Wheat
• Corn, com flour • Rye
• Pure oat • Barley
• Soya bean • Millet
• Fresh vegetable • Canned food item (preservatives)
• Fresh Fruits • Instant coffee and instant tea
• Fresh brewed coffee • Noodles
• Apple cider • Spaghettis
• Custards • Macaroni
• Yogurt • Ice cream cones
• Salt • Packed rice mix
• Pepper • Shampoo containing wheat germ oil
• Coconut • Dental adhesive and tooth paste containing
• Pure chocolate offending grains
• Fish rich in iodine contents (Shellfish)
• Iodized salt
H Anwar MI et al. Guidelines for the management of dermatitis herpetiformis.
Journal o f Pakistan Association o f Dermatologists 2013; 23 (4): 428-435.
83
Bullous Diseases
C h a p te r
Linear IgA bullous
dermatosis (LABD) 14
S yn o n ym s
In adults:
© Linear IgA dermatosis (LAD)
• Linear IgA disease (of adults)
In children:
• Chronic bullous disease of childhood (CBDC) MCQ
• Benign chronic bullous dermatosis o f childhood
• Linear IgA disease of childhood
The name of the disease gives a hint about its main characteristics:
• Linear ■=> auto-antibodies are deposited in a linear pattern
along the BMZ (i.e. targeting BMZ proteins resulting in sub-
epidermal cleft).
T ip s . IgA*> auto-antibodies are of the IgA class (rather than IgG
as in most other sub-epidermal immune blistering diseases).
Definition
• LABD is an autoimmuno sub-epidermal blistering disease.
P athogenesis (target proteins in BMZ)

• Based upon the site of IgA deposition (identified by immune-electron
microscopy), there are 2 types of LABD:
(1) Lamina lucida (LL) type of LA BD (majority o f cases)
© Target antigen is BP antigen 2 (BPAG2; BP180)

• It’s the same as BP but the antigenic specificity differs (Fig 14.1):
o In BP, IgG antibodies bind the MCW-1 region o f the NC16 domain
■=>near the trans-membrane portion of BPAG2.
o In LABD, IgA antibodies bind the LABD97 region o f the NC16
domain ^ more toward the carboxy terminus ■=>near or within the
collagenous domain o f BPAG2 (i.e. more deep towards the dermis).
(2) Sub-lamina densa (SLD) type o f LABD

® Target antigen is type VII collagen (anchoring fibrils) “as in EBA”
84
COOH
1 t
49
NC16A 1 T 1 1 1 ..... ' A . ' . - l
i i
MCW-1 LABD97
BP bullous pemphigoid □ = collagenous domain

NC non-collagenous
MCW-1 epitope that autoantibodies bind in BP
LABD97 cleaved ectodomain that autoantibodies bind in linear IgA bullous dermatosis
Fig 14.1 Cleavage ectodomains of BPAG2. COOH, carboxy terminus; NH2,amino
terminus; TM, transmembrane region.
E p id e m io lo gy
• Age and sex: LABD occurs in both adults and children.
o In adults, the average age of onset is after 60 years of age (with
slight female predominance),
o Childhood LABD occurs at a mean age o f 4.5 years.

C u ta n e o u s lesions: (Fig 14.2)
A In adults, the clinical findings may resemble those o f DH or BP
• Vesiculobullous lesions in a herpetiform arrangement on erythematous
and/or normal-appearing skin.
• Some patients present with expanding annular plaques, while others
have lesions that are scattered and asymmetric.
• An isomorphic response (Koebner phenomenon) has been reported
(e.g. lesions appearing at previous sites o f adhesive tape).
A In children, the cutaneous features may be clinically unique
• Annular erythema and blisters (often referred to as a crown of jewels).
• In flexural areas, particularly the lower trunk, thigh and groin.
Fig 14.2 Clinical features of LABD (a) Annular and polycyclic plaques of the trunk, (b) Bullae,
erosions and erythematous patches, (c) Circumferential and linear vesicles and bullae.
85
Bullous Diseases
Mucous m em brane involvement:

• LABD may present as a variant of mucous membrane (cicatricial)
pemphigoid, with oral, nasal, pharyngeal and esophageal lesions.
• Involvement o f the tracheo-bronchial mucosa (in severe cases).
• The ocular form of LABD is clinically indistinguishable from ocular
mucous membrane pemphigoid.
There are reports of the association of LABD with various disorders such as:
1. G astrointestinal diseases e.g.
• Gluten-sensitive enteropathy (incidence ranges from 0 to 24%)
“LABD skin lesions may improve on a gluten-free diet”
• Ulcerative colitis (LABD remits after colectomy), Crohn’s disease
• Gastric hypochlorhydria
2. A utoim m une diseases e.g. systemic lupus erythematosus, dermatomyositis,
thyrotoxicosis, autoimmune hemolytic anemia, rheumatoid arthritis, and
glomerulonephriti s.
3. M alignancies e. g. B-cell lymphoma, chronic lymphocytic leukemia, and
carcinoma of the bladder, thyroid, colon and esophagus.
4. Infections e.g. varicella zoster virus, antibiotic-treated tetanus, and upper
respiratory infections.
• These associations (e.g. the infectious agents) may play a role

in the initial stimulation of the IgA mucosal immune system.
Drug-associated LABD:
• LABD has been associated with many drugs, with vancomycin being one
of the more common inducers.
• Other implicated drugs include penicillins, cephalosporins, NSAIDs
(e.g.diclofenac), phenytoin, sulfonamide antibiotics (sulfamethoxazole),
captopril and other ACE inhibitors.
• These drugs may stimulate the immune system to produce an IgA class
antibody in a predisposed individual.
• Drug-induced LABD usually remits within 2-6 weeks o f drug cessation.

• Sub-epidermal blister which neutrophils in the underlying dermis (with /
without eosinophils. Eosinophils can become more numerous over time).

infiltrate is made up of neutrophils._______________________
T ip s
86
Direct IF: (peri-lesional, uninvolved skin)
• Linear IgA deposition along the BMZ (possibly
also IgG) MCQ (Fig 14.3).
Indirect IF:
• Circulating antibodies of the IgA class can be
demonstrated in 60-70% of LABD sera.
Fig 14.3 LABD - DIF. Linear
Salt-split skin (SSS) indirect IF : !8A deposition at b m z .
Circulating IgA class anti-BMZ antibodies from the
• Lamina lucida type o f LABD —> adhere to the epidermal side (roof).
• Sub-lamina densa type of LABD —> adhere to the dermal side (floor).
• Patients with both IgA and IgG at the BMZ demonstrate binding to the
epidermal side (roof).
• The classification of cases demonstrating both IgG and IgA

along the BMZ is problematic. Some authorities include only
those patients with IgA as the sole BMZ immunoglobulin
under the term LABD and categorize all others as BP. Others
categorize patients with both IgG and IgA along the BMZ on
the basis of the predominant immunoglobulin on DIF.
• Distinguishing the SLD form of LABD from EBA is made on
the basis of the class of immunoreactant (can be problematic).
• Adult LABD is often confused with DH and BP (Table 14.1).
Table 14.1 Characteristics that differentiate DH, LABD and BP.

DH LABD BP
HLA-DQ2 >90% 30% Normal (20%)
Enteropathy >90% Rare None
Cutaneous Grouped papules and Small vesicles Large tense bullae
lesions small vesicles and/or large bullae
Distribution Extensor surfaces, Similar to DH or Trunk, extremities,
symmetrical BP ± mucosal surfaces
Histology Subepidermal bulla, Subepidermal bulla, Subepidermal
neutrophilic infiltrate neutrophilic bullae, eosinophilic
(papillary tips) infiltrate infiltrate
Direct IF Granular IgA in Linear IgA at Linear IgG and C3
dermal papillae BMZ, possibly also at BMZ
IgG
Indirect IF Negative Linear IgA at BMZ Linear IgG at BMZ
Response to Excellent Good, may require Minimal to
Dapsone systemic steroids moderate
87
Bullous Diseases
• LABD secondary to drugs may have a toxic epidermal necrolysis-like or

morbilliform presentation. Routine microscopy plus DIF can allow a
distinction.
Tre a tm e n t
infiltrate is made up of neutrophils and these disorders respond
'-pips, to dapson.___________________________________________
• Oral dapsone MCQ (adults: 1 0 0 -3 0 0 mg daily, children: 1-2 mg/kg daily)

or sulfapyridine (The majority of patients have a clinical response within
48-72 hours and have been controlled by dapsone alone).
• It may be necessary to add oral prednisone (in doses up to 40 mg daily) to
achieve complete control of the disease.
• It has been observed that cases in which both IgG and IgA
deposits are present in the BMZ are those that are likely to
Tips- require additional therapy with systemic corticosteroids.
• O ther treatm ent lines:

A Steroid-sparing agents: e.g. mycophenolate mofetil, azathioprine and
IVIg (in patients who do not respond to a combination of prednisone
and dapsone or in patients with severe disease).
A Empirical therapy: Antibiotics e.g. dicloxacillin, erythromycin,
tetracycline (in those >9 years o f age), and trimethoprim-
sulfamethoxazole)
f#U LL type
LABD
SLD type
BPAG2 (BP 180, collagen Type VII collagen
Target antigen
XVII) (anchoring fibrils)
Salt-split skin (SSS)
Epidermal side (roof) Dermal side (floor)
indirect IF
88
Lin e a r IgA bullous derm atosis
o B
L
)D
A
(____________________________
0 LABD is an autoim m uno sub-epiderm al blistering disease.
0 Target antigen:
• LL type ■=> BP antigen 2 (BPAG2; BP 180)
• SLD type ‘A type VII collagen (anchoring fibrils)
0 Epidemiology: LABD occurs in both adults (> 60 years old) and children
(mean age o f 4.5 years).
• Skin lesions: vesiculo-bullous lesions on erythematous and/or normal-
appearing skin in an n u lar distribution (in children, referred to as a
‘crown of jewels').
• M ucous m em brane involvement may be present e.g. oral, nasal,
pharyngeal and esophageal lesions.
• Associated diseases: gastrointestinal (e.g. gluten-sensitive enteropathy),
autoimmune (e.g. SLE), malignancies (e.g. lymphoma and leukemia)
and infections (e.g. varicella zoster virus). These associations act as the
initial stim ulation of the IgA production.
• D rug-associated LABD: especially vancomycin, usually rem its
w ithin 2-6 weeks of drug cessation.
0 H istopathology (intact vesicle): sub-epidermal blister which neutrophils.
• DIF: Linear IgA deposition along the BMZ (possibly also IgG).
• IIF: circulating anti-BMZ antibodies of the IgA class.
• SSS IIF:
o LL type of LABD —> antibodies adhere to the epiderm al side
(roof).
o SLD type of LABD —►antibodies adhere to the derm al side
(floor).
• A dult LABD: derm atitis herpetiform is (DH) and BP.
• D rug-induced LABD: toxic epiderm al necrolysis or m orbilliform
eruption.
0 Treatment:
• Oral dapsone or sulfapyridine ± oral prednisone.
• Steroid-sparing agents: e.g. mycophenolate mofetil, azathioprine and
IVIg (in non-responsive or severe cases).
• E m pirical therapy: Antibiotics e.g. dicloxacillin, erythromycin,
tetracycline and trimethoprim-sulfamethoxazole.
89
Bullous Diseases
C h a p te r
Bullous SLE
15
S yn o n ym s
• Vesiculo-bullous SLE.
• Bullous eruption of SLE
Definition
• An autoimmuno sub-epidermal blistering condition, often
transient, that occurs in the setting o f SLE.
Pathogenesis (ta rg e t p ro te in s in B M Z )
• Autoantibodies are directed against collagen VII (anchoring
fibrils).
o This eruption may represent the concurrence o f lupus with
an autoimmune blistering disease due to autoantibodies to a
component of the BMZ.
Clinical Features
• The condition occurs only in patients with SLE.
• Affects young adults, mainly women.
• Urticarial papules, tense vesicles and bullae on an erythematous
base.
• Widespread blistering.
• All cutaneous sites may be involved.
• Mucosal lesions are uncommon.
• Post-inflammatory hyperpigmentation may occur.
• The occurrence of the bullous eruption is NOT related to flares

of the systemic disease.________________________________

• Sub-epidermal blister which neutrophils.
90
• Occasionally, neutrophilic infiltrate accumulates within the

UftlpCul dermal papillae resulting in microabscesses resembling DH.
• Another histopathological DD is LABD {sub-epidermal
Tips- blisters with neutrophils).____________________________
D irect IF: (peri-lesional skin)
• Linear bands of IgG, IgA, IgM and C3 in the BMZ.
Salt-split skin (SSS) indirect IF:

• Circulating antibodies adhere to the dermal side of split skin.
O ther causes of blistering in SLE patients:
• Photosensitivity
• Acute cutaneous lupus
• Drug eruption
O ther sub-epiderm al blistering diseases e.g. bullous pemphigoid or

epidermolysis bullosa acquisita.
uMt>PuI * The histopathology and immunopathology (IF) will

Ls ,, distinguish bullous SLE from these disorders.
Tp S J ----------------------------------------------------------------------------------------------------------------
Prognosis
• Most patients have a transient eruption.
T re a tm e n t
• Some patients may respond to systemic steroids used to control their SLE.
• Dapsone is very effective as first-line treatment (also in steroid-resistant
cases).
• Other therapies e.g. methotrexate and rituximab.
Bullous Diseases
B ullous SLE
0 Synonyms: Vesiculo-bullous SLE, Bullous eruption of SLE.
0 Autoimmuno sub-epidermal blistering disease that occurs in SLE patients.
0 Target antigen: type VII collagen (anchoring fibrils).
0 Clinical Features: tense vesicles and bullae in SLE patients (young
adults, mainly women).
0 Histopathology (intact vesicle): sub-epidermal blister which neutrophils.
• DIF: Linear bands of IgG, IgA, IgM and C3 in the BMZ.
• SSS IIF: circulating antibodies adhere to the dermal side of split skin.
• Other causes of blistering in SLE patients: Photosensitivity, Acute
cutaneous lupus and Drug eruption.
• Other sub-epidermal blistering diseases e.g. bullous pemphigoid or
epidermolysis bullosa acquisita.
0 Treatment:
Dapsone is very effective as first-line treatment.
• Subepidermal blisters with neutrophils:

1. LABD
2. DH
3. Bullous SLE
• Sub-epidermal autoimmune diseases targeting BPAG2:

1. BP —>NCI6A, proximal
2. LABD (LL type) ->NC16A, distal
3. CP —>■distal C terminal
• Sub-epidermal autoimmune diseases targeting type VII

collagen (anchoringfibrils):
1. EBA
2. LABD (SLD type)
3. Bullous LE
92
• Pemphigus vulgaris versus Bullous pemphigoid.
Pemphigus vulgaris Bullous pemphigoid

Level of blister Intra-epidermal Sub-epidermal
Target antigen Dsg3 ± Dsgl B PA G 2± BPAG1
Age Middle-aged Elderly (> 60 years)
Sex Equal More common in men
Symptoms Asymptomatic Pruritic
Skin blisters Small, flaccid Large, tense
Mucosal affection Always (100%) Rare (10-30%)
Histopathology Intra-epidermal blister with Sub-epidermal blister
eosinophils, acantholytic cells with eosinophils
IF Around keratinocytes Linear at BMZ
General condition Poor Good
Treatment Systemic treatment is Topical treatment
necessary may be enough
IF patterns in pemphigoid family:

• The linear deposition of immune reactants at BMZ can be
separated into 2 main pattern:
1. n-serrated pattern: seen in blistering diseases with binding
above the lamina densa with antibodies against hemi-
desmosomal components e.g. bullous pemphigoid.
2. u-serrated pattern: points to a sub-lamina densa binding
diseases caused by autoantibodies against type VII collagen,
e.g. epidermolysis bullosa acquisita MCQ.
• Of note, dermatitis herpetiformis shows a granular IgA
deposition along the epidermal basement membrane zone.
n-serrated pattern u-serrated pattern
93
Part 3
p g fe, ■ SB m ■
Darier Disease
and Hailey-
m S ■ m mm* m
Hailey Disease
The intra-epidermal genetic bullous diseases
Some clinicians don’t consider Darier and Hailey- Hailey

diseases as bullous diseases. However, these two conditions
are included here in bullous diseases because (1) both are
characterized histologically by acantholysis and supra-
basilar clefts, (2) there is a vesiculo-bullous variant of
Darier disease, and (3) the primary lesion in Hailey-
Hailey disease is a flaccid vesicle, which ruptures with
subsequent vegetations.______________________________
S tu d y plan
• Both Darier and Hailey- Hailey diseases share many
similarities regarding aetiopathogenesis, histopathology,
complications and management. It’s useful to study both
conditions simultaneously in a comparative approach.
Introduction to Darier C h a p te r
Disease (DD) and Hailey-
Hailey Disease (HHD)
The intra-epidermal genetic bullous
diseases
16
Introduction
• Both Darier and Hailey- Hailey diseases share many similarities regarding
aetiopathogenesis, histopathology, complications and management. It’s
useful to be familiar with these similarities before studying the two
diseases.
• In addition, certain basic knowledge in cell (keratinocyte) biology is
crucial for understanding the pathogenesis o f these two diseases.
Role of ca lc iu m (C a 2+) in k e ra tin o cyte s

adhesion
• Keratinocytes are held together by complex cell-cell junctions called
desmosomes formed of a group of proteins (desmosomal proteins).
• Desmosomal proteins are synthesized in association with the endoplasmic
reticulum (ER) (where they are folded and processed) then transported to
the Golgi apparatus for further processing before being transported to
the cell membrane.
• The translation, translocation, folding, processing, maturation and transport
of desmosomal proteins are regulated by the levels of luminal Ca2+ and
Mn2+ in the ER and the Golgi apparatus.
The assembly of desmosomes has been studied in vitro in the

presence of both high and low levels of extracellular Ca2+.
• In low Ca2+ conditions, desmosomes are not assembled, but
desmosomal proteins continue to be synthesized and stored in
the ER.
• Following a Ca2+ shift to physiological levels, desmosomal
proteins are gradually transported to the cell membrane, where
they form mature desmosomes.
i For further details, please refer to Dhitavat J et al. Calcium
pumps and keratinocytes: lessons from Darier's disease and
Hailey-Hailey disease. Br J Dermatol. 2004;150(5):821-8.
95
Bullous Diseases
C a lciu m pum ps in k e ra tin o cyte s

In keratinocytes, there are two calcium pumps of clinical relevance (Fig 16.1):
1. The sarco(endo)plasmic reticulum Ca2+ ATPase type 2 (SERCA2) that

catalyses the transport o f calcium (Ca2+) from the cytosol into the lumen of
the endoplasmic reticulum (ER).
2. The human secretory pathway Ca2+/Mn2+ ATPase protein 1 (SPCA1)

that is found in the Golgi apparatus and supplies it with both Ca2+ and
manganese (Mn2+).
96
G e n e tic defects in D arier and H a ile y-

H a ile y Diseases
• Both Darier and Hailey-Hailey diseases are inherited in autosomal
dominant (AD) manner and are caused by mutations in Ca2+ pumps MCQ
inside keratinocytes.
• Darier disease is caused by mutations in ATP2A2 gene

encoding SERCA2 in the ER.
• Hailey-Hailey disease is caused by mutations in ATP2C1 gene
encoding SPCA1 in the Golgi apparatus._________________
In both diseases, defective Ca2+ filling of ER and Golgi apparatus results in:
1) Impairment of desmosome assembly and transport resulting in
acantholysis.
2) Accumulation of unfolded (unprocessed) protein resulting in apoptosis
(idyskeratosis).
• In Darier and Hailey-Hailey diseases there is both acantholysis

and apoptosis (dyskeratosis) and this is collectively referred to
Tips. as acantholytic dyskeratosis.
D a rie r a n d H a ile y -H a ile y
D d ise a se s
0 Keratinocytes are held together by desmosomes (formed of desmosomal
proteins).
0 Desmosomal proteins are synthesized, folded and processed within the
ER, transported to the Golgi apparatus for further processing and then
transported to the cell membrane.
0 Translation, translocation, folding, processing, maturation and transport of
desmosomal proteins is dependent on luminal Ca2+ and Mn2+ levels in the
ER and the Golgi apparatus.
0 In keratinocytes, there are two calcium pumps:
1. The SERCA2 —>transports Ca2+ from the cytosol into the lumen of ER.
A Mutations in SERCA2 gene —>Darier disease.
2. The human SPCA1 —> transports Ca2+ and Mn2+ from the cytosol into
the lumen o f the Golgi apparatus.
A Mutations in SPCA1 gene —>■Hailey-Hailey disease.
0 BOTH Darier and Hailey-Hailey diseases are characterized by acantholysis
and apoptosis (dyskeratosis) i.e. acantholytic dyskeratosis.
Bullous Diseases
Darier Disease
S yn o n ym s
• Darier-W hite disease.
• Keratosis follicuiaris.
• Dyskeratosis follicuiaris.
P athogenesis
M ode of inheritance:
• Autosomal dominant (AD).
Genetic defect:
• Mutations in the ATP2A2 gene on chromosome 12q24.1 which encodes
the sarco/endoplasmic reticulum calcium ATPase type 2 (SERCA2).
SERCA2
• A member of a family of ion pumps which maintain high
calcium concentration in the ER. It has 3 isoforms:
1. SERCA2a (expressed in cardiac and smooth muscle).
2. SERCA2b (more widely expressed, including in epidermis).
3. SERCA2c (a less common third isoform).
• Although both SERCA2a and SERCA2b isoforms are found
in the epidermis, SERCA2b is the major product and its
dysfunction alone can produce Darier disease. SERCA2b
isoform displays the highest Ca2+ affinity._______________
• Norm al physiology:
> SERCA2 actively transports Ca2+ from the
cytosol into the endoplasmic reticulum (ER)
lumen (Fig 17.1). In keratinocytes, adequate
Ca2+ filling of ER is crucial for normal
processing and folding o f desmosomal proteins
and their trafficking (transport) to the cell
surface.
• Pathophysiology in Darier disease: Fig 17.1 Role ofSERCA2

> Defects in Darier disease are summarized in in keratinocytes.
(Fig 17.2).
98
F ig 17.2 P athophysiology in D arier disease.
0 0 • In Darier disease there is both acantholysis and apoptosis

(dyskeratosis) i.e acantholytic dyskeratosis.
rtftlpUul . ATP2A2 (SERCA2) mutations were identified in (1) Darier
'Tips disease, (2) Linear acantholytic dyskeratotic epidermal naevi
%,—»™t anc[ (3 ) Acrokeratosis verruciformis of Hopf.
Ep id e m io lo gy
• Incidence / prevalence: uncommon.
• Age of presentation: 6 - 2 0 yrs (peak onset during puberty “ 11-15 yrs”).
• Sex: Men and women are equally affected.
• Seasonal variation: Darier disease shows exacerbation during summer.

Symptoms:
• Most patients complain moderate itching.
• Disfigurement and malodor are distressing and may lead to social
isolation.
E xacerbating factors (associated with worsening of the disease):

• The disease frequently worsens in summer due to
o UV irradiation (Darier disease has been experimentally-induced in
uninvolved skin by UV radiation),
o Sweating, heat and occlusion (evidence: lesions occur primarily on
covered areas and flares often develop without UV exposure e.g.
after long airplane flights).
• Lithium carbonate MCQ (used to treat bipolar affective disorders can
provoke skin lesions in patients with Darier disease).
• A small subset of female patients report premenstrual exacerbations.
99
Bullous Diseases
Skin lesions:
(1) Papules
• The primary lesions are keratotic, crusted, red to brown papules with
‘seborrheic’ distribution (scalp- especially its margins, face, lateral
aspects o f the neck and upper trank) (Fig 17.3 a).
• Lesions tend to become confluent and may form papillomatous masses.
• Despite its initial description as follicular dyskeratosis, the

papules in Darier disease are NOT exclusively limited to a
(peri)follicular location. In fact, areas devoid of follicles, such
as palms, soles, and the oral mucosa, may be affected.
• Keratotic papules may be admixed with small (2-3 mm)
hypomelanotic macules, sterile vesicles or bullae (DD:
herpetic infection ‘Kaposi's varicelliform eruption’).
Occasionally, these lesions may be the predominant feature.
(2) Lesions on dorsa o f hand and fe e t (50% o f patients) (Fig 17.3 b)

• Flat-topped, skin-colored or brownish, 2-4-mm papules (similar to flat
warts) on the dorsal aspects of hands, feet, and less often forearms and legs.
(3) Palmoplantar affection:
• Keratotic papules, keratin-filled depressions (Fig 17.3 c).
• Subtle changes can be detected by obtaining finger or palm prints (show
interruption o f the dermatoglyphic pattern).
(4) Guttate leukoderma
® Small (2-3 mm) hypomelanotic macules most commonly in patients with
darkly pigmented skin (Fig 17.3 d).
(5) Intertriginous (flexural) lesions (axillae, groin and the inframammary
area)
• Mild flexural involvement is present in most patients. Macerated,
fungating masses are seen with malodor (a frequent and distressing
associated finding).
• Rarely, these lesions are the predominant finding (misdiagnosis o f HHD)
(Fig 17.3 e).
N ail ch an g es: (Fig 17.3 f)

• Longitudinal red and/or white lines MCQ.
• Longitudinal ridging and Assuring.
• Wedge-shaped subungual hyperkeratosis.
• Brittle nails ^ tend to break distally forming V-shaped notches.
O ra l m a n ife sta tio n s (1 5 % - 5 0 % ): (Fig 17.3 g)

• Painless whitish papules affecting the palate (the most common site of
involvement) followed by the gingiva, buccal mucosa and tongue.
100
Fig 17.3 C linical features o f D arier disease (a) crusted papules at the hairline on the face
and in the posterior auricular area, (b) m ultiple flat-topped papules on the dorsal aspect o f the
hand, (c) keratotic papules and keratin-filled depressions on the palm s, (d) guttate
leukoderm ain darkly pigm ented skin, (e) involvem ent in the groin, (f) alternating longitudinal
red and w hite streaks w ith notching o f the free edge o f the nail plate, (g) w hitish papules on
the palate, (h) T ype 1 segm ental D arier disease (papules along B lasch k o ’s lines), (i) K ap o si’s
varicelliform eruption (m ultiple hem orrhagic crusts o f a sim ilar size).
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Bullous Diseases
Clinical subtypes:
(1) Acral hemorrhagic type
• Red to blue-black, irregularly shaped, sharply demarcated macules on the
palms and soles and the dorsal aspects o f the hands. Lesions represent
hemorrhage into acantholytic vesicles (intra-epidermal hemorrhage).
(2) Segm ental types 1 and 2 (Table 17.1)
• In segmental types, lesions are distributed along Blaschko’s lines.
Table 17.1 Types of segmental Darier disease

Type 1 segmental Darier Type 2 segmental Darier
More common Less common
Unilateral along Blaschko's lines. Patients with generalized Darier
Age of onset, severity and histologic disease have a linear streak with
findines within the streaks do not increased severity
differ from those of generalized
Darier disease (Fig 17.3 h)
Results from a post-zygotic Occur when patients with Darier
mutation in the ATP2A2 gene disease also have a post-zygotic
during embryogenesis (mosaic inactivating mutation in the other
pattern of skin involvement) allele o f the same gene (second hit)
causing more severe manifestations
in a mosaic distribution
C o m p lica tio n s
© In fectio n s: the keratotic and papillomatous lesions are prone to
secondary infection with:
• Bacteria, yeasts or dermatophytes ■=> vegetating malodorous lesions with
exacerbation o f both the disease and the odor. Oral antibiotic treatment of
secondary bacterial infections may be indicated.
• Viral infections (uncommon) ■=> widespread skin infections with human
papillomaviruses (HPV) and human herpesviruses (HHV)
Kaposi’s varicelliform eruption MCQ (Fig 17.3 i)

• Rapid cutaneous spread of a superimposed herpes simplex
viral (HSV) infection.
• It is a potentially serious complication that must be suspected
when there is a sudden onset of multiple vesicular and crusted
hemorrhagic lesions of a similar size accompanied by fever
and malaise. Immediate systemic antiviral therapy e.g.
acyclovir, valacyclovir is necessary to control this complication.
• Immunologic studies in patients with Darier disease have

shown NO consistent abnormalities. Thus, the increased
frequency of local infections is a local phenomenon probably
caused by the disruption of the epidermal barrier.________
102
® Oral salivary glands;

• Obstruction of salivary gland ducts (by Darier-like histologic changes)
with painful swelling.
CDNeuropsychiatric disorders:
• Disfigurement and social isolation (associated with severe skin
diseases) lead to psychiatric and social morbidity.
• Darier disease has been associated with various neuropsychiatric
conditions e.g. epilepsy, intellectual impairment and mood disorders
(major depression, suicide attempts and bipolar disorder). These
findings, however, are not consistently observed.
® Ocular complications:
• Comeal ulcerations or staphylococcal endophthalmitis (very rare).
© Malignant transformation:
• Cutaneous or mucosal squamous cell carcinomas (SCC) arising in sites
chronically affected by Darier disease
• Malignant transformation is a rare event and may be related to

infection with oncogenic types of HPV or changes in
keratinocyte adhesion and proliferation secondary to
SERCA2 haploinsufficiency, which has been associated with
SCC of the skin and upper gastrointestinal tract in mice.______
Histopathology
(1) There are two main histologic features in
Darier disease: acantholysis and
dyskeratosis (i.e. acantholytic
dyskeratosis) (Fig 17.4)
• Acantholysis: supra-basilar cleft (due
to a disturbance in cell adhesion).
• Dyskeratosis: nuclear condensation and
perinuclear keratin clumping (due to
apoptosis o f keratinocytes). Two types
of dyskeratotic cells are observed.
T able 17.2 T y p e s o f d y s k c r a to tic c e lls in D a r ie r d is e a s e

‘Corps ronds’ ‘Grains’
Acantholytic enlarged keratinocytes in Small oval cells in the stratum
the malpighian (spinous) layer. granulosum / corneum.
Darkly staining and partially Intensely eosinophilic cytoplasm
fragmented nuclei surrounded by a composed of collapsed keratin
clear cytoplasm and encircled by a bundles containing shrunken
bright ring of collapsed keratin bundles. parakeratotic nuclear remnants.
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Bullous Diseases
(2) The epidermis overlying acantholytic and dyskeratotic foci: thickened

with papillomatosis and hyperkeratosis.
(3) The superficial dermis: mild/moderate peri-vascular inflammatory
infiltrate.
• “Grains” are likely derived from “corps ronds” i.e. they
represent different stages of the same pathologic process (but
formal proof of this has not been provided).
• Diagnostic histologic changes in Darier disease are often focal.
necessitating a careful search during slide examination.
• Histopathoiogical differential diagnosis: Grover’s disease.
■"pips. The two conditions can be histologically indistinguishable
V Grover's disease: more acantholysis, less dyskeratosis —»• fewer
‘corps ronds’ or ‘grains’
F Darier disease: more pronounced, more widespread and
follicularly based.
Diffe ential diagnc s

Severe seborrheic derm atitis:
• Darier disease is distinguished by positive family history, involvement of
acral skin, nails and oral mucosa, and characteristic histologic findings.
DD of D arier disease with mainly flexural (intertriginous) affection:

1. Pemphigus vegetans (Hallopeau type): older age / histology shows
acantholysis with eosinophils / DIF shows typical intercellular pattern of the
pemphigus group / antidesmoglein antibodies detected by ELISA.
2. Hailey-Hailey disease (HHD) (may be difficult to distinguish clinically
intertriginous Darier disease): palmoplantar papules, longitudinal
erythronychia, distal notching of the nails, mucosal lesions and prom inent
dyskeratosis and acantholysis histologically are characteristic of Darier
disease.
3. Blastomycosis-like pyoderma (Pyoderma vegetans): a neutrophilic
infiltrate, NO acantholysis and negative DIF.
Acrokeratosis verruciform is of Hopf

• Autosomal dominant (AD) disorder.
• Clinically indistinguishable from Darier disease (BOTH are characterized
by flat-topped wart-like papules on the dorsal aspects of the extremities).
• There is a debate whether it is a separate entity or an allelic forme fruste
(French, incomplete form ) of Darier disease (underlying ATP2A2 mutation
detected in some but not all patients with acrokeratosis verruciformis).
• Histologically, this condition lacks acantholysis and dyskeratosis.
G rover’s disease (transient acantholytic dermatosis)

• In Grover’s disease, the pruritic crusted papules are not confluent, and they
typically develop after occlusion and/or sweating.
104
Prognosis
• Darier disease follows a chronic course without spontaneous remission.
• Disease severity can fluctuate, with some patients reporting improvement
and others deterioration over time.
T reatm ent
General measures
• Light-weight clothes and sunscreen (to prevent aggravation due to heat,
sweating and sun exposure).
• Daily skin care:
A Antimicrobial cleansers / washes (to prevent malodorous bacterial
colonization).
A Intermittent use of antibiotics and antifungal agents (for treating
malodor due to microbial colonization and mild secondary infections).
A Keratolytic emollients (to reduce scaling and irritation).
Topical therapy
• Topical retinoids
• Topical 5-fluorouracil (1% or 5%) may be effective.
• Retinoid-associated irritation is common, can be reduced by:

S alternate-day application
S liberal use of emollients
■S combination therapy with mid-potency topical corticosteroids
• Topical corticosteroids are usually less effective as
monotherapy than are topical retinoids.
• Calcipotriene (calcipotriol) had NO clear benefit.
Systemic therapy
(1) Systemic retinoids (isotretinoin and acitretin):
• Advantages: very effective (significant improvement and control of the
disease in approximately 90% of patients).
• Disadvantages: their use is limited by their side effects (i.e.
teratogenicity) and patients relapse after cessation of therapy.
• Systemic retinoids should be prescribed only in patients with

severe disease unresponsive to topical therapy.
• Contraception is mandatoiy for women of childbearing
potential (because of the teratogenic potential).
• Individual dose titration is important to ensure maximal
therapeutic effect with minimal dose-related side effects.
• Intermittent therapy to prevent exacerbations during the
summer months is a useful approach.
• In predominantly bullous or intertriginous lesions, oral
retinoids may aggravate the disease (not recommended).
105
Bullous Diseases
(2) Oral contraceptives:

• Can alleviate symptoms in female patients with premenstrual
exacerbations.
(3) Cyclosporine:
• Reported to be effective especially in severe cases (not responding to oral
retinoids) or in patients who cannot tolerate oral retinoids.
Surgical therapy
Indications: focal recalcitrant lesions (particularly in the flexural and gluteal
areas)
Modalities:
• Excision followed by split-thickness grafting.
• Dermabrasion
• Laser removal (CO 2 or erbium: YAG - Pulsed dye laser)
• Photodynamic therapy
• Destructive treatment must include the follicular

infundibulum (to prevent recurrence)
• Caution is necessary to avoid scarring, particularly in body
areas at risk for hypertrophic scar or keloid formation (erbium:
YAG laser is better the CO2 laser).______________________
106
D
D a rier Disease
0 Synonyms: Darier-W hite disease, (Dys)Keratosis follicularis.
0 Pathogenesis:
• M ode o f inheritance: Autosomal dominant (AD).
• Genetic defect: Mutations in the ATP2A2 gene which encodes SERCA2.
A Mutations in SERCA2 ■=>inadequate filling of the ER Ca2+ stores ■=>
disturbed folding of desmosomal proteins ■=>
1. Reduced trafficking of desmosomal proteins to the keratinocyte cell
membrane ^ Failure of keratinocyte adhesion A acantholysis.
2. Accumulation of unfolded proteins in the ER 'A induction of
apoptosis (dyskeratosis) i.e acantholytic dyskeratosis.
0 Epidemiology
• Age o f presentation: 6 - 2 0 yrs (peak onset during puberty “ 11-15
yrs”).
• Sex: Men and women are equally affected.
• Seasonal variation: Darier disease shows exacerbation during summer.
• Symptoms: moderate itching, disfigurement and malodor.
• Exacerbating factors: summer season (UV irradiation, sweating, heat
and occlusion), lithium carbonate and premenstrual flares in some
females.
• Skin lesions:
1. Keratotic papules with ‘seborrheic’ distribution (scalp margins,
face, lateral aspects of the neck and upper trunk).
2. Flat-topped, skin-colored or brownish papules (similar to flat warts)
on the dorsal aspects of hands, feet.
3. Palmoplantar affection: keratotic papules, keratin-filled depressions.
4. Guttate leukoderma in patients with darkly pigmented skin.
5. Intertriginous (flexural) lesions: macerated fungating masses.
• Nail changes: longitudinal red lines, V-shaped notches, longitudinal
ridging and Assuring and wedge-shaped subungual hyperkeratosis.
• Oral manifestations: painless whitish papules affecting the palate.
• Clinical subtypes:
1. Acral hemorrhagic type: Red / blue-black macules on palms/soles.
2. Segm ental types 1 and 2: lesions are distributed along Blaschko’s
lines
☆ Type 1 : more common, unilateral lesions along Blaschko's lines.
Severity does not differ from generalized Darier disease.
A Type 2: less common. Patients with generalized Darier disease have
a linear streak with increased severity.
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Bullous Diseases
0 Complications:
1. Infections: secondary infection with bacteria, yeasts, dermatophytes or
viruses (HPV, HHV).
• Kaposi’s varicelliform eruption: superimposed HSV infection. A
serious complication. Sudden onset of multiple vesicular and
crusted hemorrhagic lesions o f a similar size accompanied by fever
and malaise. Immediate systemic antiviral therapy is necessary
2. Oral salivary glands: Obstruction with painful swelling.
3. Neuropsychiatric disorders:
• Psychiatric and social morbidity due to disfigurement and social
isolation.
• Epilepsy, intellectual impairment and mood disorders (not consistent).
4. Ocular complications: Corneal ulcerations or staphylococcal
endophthalmitis (very rare).
5. Malignant transformation: Cutaneous or mucosal SCC in sites
chronically affected by Darier disease (rare - may be related to infection
with oncogenic types o f HPV).
0 Histopathology: Acantholytic dyskeratosis

• Acantholysis: supra-basilar cleft
• Dyskeratosis: nuclear condensation and perinuclear keratin clumping.
Two types: Corps ronds (spinous layer) and grains (stratum comeum).
• The epidermis is thickened with papillomatosis and hyperkeratosis.
• The superficial dermis shows peri-vascular inflammatory infiltrate.
• Diagnostic histological changes are focal (follicularly based).
• Severe seborrheic dermatitis.
• DD of Darier disease with mainly flexural (intertriginous) affection:
Pemphigus vegetans (Hallopeau type), Hailey-Hailey disease (HHD)
and Blastomycosis-like pyoderma (Pyoderma vegetans).
• Acrokeratosis verruciformis of Hopf: clinically indistinguishable from
Darier disease (flat-topped wart-like papules on the dorsal extremities).
0 Prognosis: Darier disease follows a chronic course without spontaneous
remission (disease severity fluctuates over time).
0 Treatment:
• General measures: Light-weight clothes, sunscreen, antimicrobial
cleansers, antibiotics and antifungal agents and keratolytic emollients.
• Topical therapy: retinoids, 5-fluorouracil (1% or 5%).
• Systemic therapy: Systemic retinoids (isotretinoin and acitretin, severe
disease unresponsive to topical therapy), Oral contraceptives (female
patients with premenstrual exacerbations) and Cyclosporine.
• Surgical therapy (for focal recalcitrant lesions particularly in the
flexural and gluteal areas): Excision with grafting, Dermabrasion, Lasers
(CO 2, erbium: YAG or PDL), Photodynamic therapy (PDT).
108
C h a p te r
Hailey-Hailey disease
(HHD)
18
S yn o n ym s
• Familial benign chronic pemphigus.
• It’s useful to study Hailey-Hailey disease in comparison with

Darier disease.
Pathogenesis
Mode of inheritance:
• Autosomal dominant (AD).
Genetic defect:
• Mutations in the ATP2CA MCQ gene on chromosome 3q21 which encodes
the Golgi-associated human secretory-pathway Ca2+/Mn2+-ATPase
isoform 1 (hSPCAl).
IfiH i \hjjv' * Darier disease is caused by mutations in the ATP2A2 gene on

chromosome 12q24.1 which encodes the sarco/endoplasmic
L Jig Jj reticulum calcium ATPase type 2 (SERCA2).
• Normal physiology:
hSPCAl transports Ca2+ and Mn2+, and it sequesters Ca2+ within the Golgi
lumen.
Normal Golgi Ca2+ levels are required for complete processing of proteins
through the Golgi apparatus.
® Pathophysiology in HHD:
hSPCAl dysfunction ^ interfering with intracellular Ca2+ signaling A
depletion of Ca2+ within the Golgi lumen <=> impaired processing of
desmosomal proteins (required for normal cell-to-cell adhesion) A
acantholysis. Dyskeratosis is minimal or absent.
• In Darier disease there is both acantholysis and dyskeratosis.
109
Bullous Diseases
Epidemiology
• Age of initial presentation: 2nd or 3rd decade (may be delayed until the 4th
or 5th decade).
• Seasonal variation: HHD shows exacerbation during summer.
Clinical Features
Symptoms:
• Painful erosions and crusting (may interfere with physical activities).
• Pruritus (itching).
• Malodor (psychosocial distress).
• In Darier disease there is NO pain.
Exacerbating factors (associated with worsening of the disease):

• The disease frequently worsens in summer due to
o U Virradiation (UVB radiation suppresses ATP2C1 mRNA expression),
o Sweating and heat.
• Friction induces new lesions (due to abnormal cell-cell adhesion in the
epidermis).
• Microbial colonization / secondary infections: staphylococcal infection
acantholysis and may lead to severe and widespread blistering.
• Darier disease shows flares with drugs (e.g. lithium

carbonate) and during premenstrual exacerbations._________
Skin lesions:
Site
• Intertriginous sites: axillae, groin, lateral aspects o f the neck and perianal
region (less frequently scalp, antecubital and popliteal fossae and trunk).
• Infra-mammary and vulvar lesions are common in women (occasionally
present with isolated vulvar disease).
Lesions (Fig 18.1)
• Primary lesion is a flaccid vesicle on erythematous or normal-appearing
skin —>ruptures easily —> macerated or crusted erosions —> spread
peripherally —> circinate border with crusts and small vesicles —> chronic,
moist, malodorous vegetations and painful fissures. Healing occurs
without scarring leaving post-inflammatory hyperpigmentation.
• In Darier disease, the primary lesions are keratotic, crusted, red
to brown papules with ‘seborrheic’ distribution (scalp
margins, face, lateral aspects of the neck and upper trunk).
110
Nail changes:
• Asymptomatic, longitudinal white bands in the fingernails (longitudinal
leukonychia) in patients with limited or atypical disease.
• Darier disease is characterized by longitudinal red lines

affecting nails.
Mucous membrane manifestations:

• Involvement o f the buccal, vaginal or conjunctival mucosa is rare.
• In Darier disease, oral mucosa is affected in up to 50% of

cases (painless whitish papules)._____________________
(a)
Fig 18.1 Clinical features of HHD (a) Chronic
sub-mammary lesion with erosions (b)
Erythematous, eroded plaque in the axilla. Note
the flaccid vesicles at 2 and 7 o’clock.
(b)
Clinical subtypes:
Segm ental types 1 and 2 (Table 18.1)
• In segmental types, lesions are distributed along Blaschko’s lines.
Table 18.1 Types of segmental HHD

Type 1 segmental HHD Type 2 segmental HHD
Only a few cases have been reported. Rare.
Unilateral along Blaschko's lines. Patients with generalized HHD
Age o f onset, severity and histologic disease have a linear streak with
findings are similar to the classic increased severity and earlier onset.
HHD.
Caused by a heterozygous post- Due to post-zygotic inactivation of
zygotic mutation in an otherwise the normal ATP2C1 allele (loss of
normal embryo, resulting in a mosaic heterozygosity) leading to more
distribution o f disease. severe disease in a mosaic pattern.
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Bullous Diseases
Unlike the classic HHD, the affected segments in type 2

segmental HHD display acantholysis within adnexal
structures, which might make it impossible to eradicate foci of
blistering using superficial surgical methods.________________
C o m p lica tio n s
® Infections:
• Colonization and secondary bacterial, fungal and viral infections —►
disease exacerbation and persistence.
o Vegetating lesions/malodor suggest bacterial and/or fungal overgrowth
o Topical ± systemic antimicrobial agents may be required to induce a
clinical remission.
o Recalcitrant intertriginous lesions have been described in association
with HSV infections (diagnosis confirmed by direct fluorescent
antibody assays, viral cultures or PCR-based testing of infected
keratinocytes BUT skin biopsy may be required),
o Kaposi’s varicelliform eruption due to HSV (see chapter 17) is a rare
complication of HHD.
© M alignant transform ation:

• Cutaneous SCC may develop within chronic lesions of HHD in the
anogenital region (impairment of the structural integrity of the epidermis
may predispose patients to infection with oncogenic strains of HPV).
• In Darier disease, in addition to infections and malignant
transformation, there are oral salivary glands, ocular and
neuropsychiatric complications.
(1) Acantholysis WITHOUT
dyskeratosis.
• Acantholysis:
o Supra-basilar cleft —»■dermal
if s f U f
papillae are lined by a single layer
of basal cells and protrude into the
blister cavities —►referred to as
Fig 18.2 Histopathology of HI ID.
“villi”. Acantholysis beginning in the
o More widespread within the suprabasilar area and extending
epidermis, throughout the epidermis.
o Incomplete or partial —> groups of
acantholytic cells “dilapidated brick wall” (Fig 18.2).
• Dyskeratosis:
o Acantholytic dyskeratotic “necrotic” keratinocytes (i.e. “corps ronds
and grains) are uncommon or rare.
112
(2) The epidermis show epidermal hyperplasia, parakeratosis and focal crusts
(in more chronic lesions).
(3) The superficial dermis shows moderate peri-vascular lymphocytic
inflammatory infiltrate.
In Darier disease, acantholysis is focal (not widespread),

complete and with dyskeratosis (corps ronds and grain).
Histopathological DD
• Grover’s disease (histologically indistinguishable from HHD):
distinguished clinically.
• Pemphigus vulgaris (eosiophilic infiltrate and positive DIF).
> DD of lesions confined to the axillae o r groin: intertrigo, candidiasis.
> DD o f isolated perianal maceration: irritant dermatitis.
> DD of vulvar involvement: lichen simplex chronicus.
> DD of vegetating intertriginous lesions: pemphigus vegetans
(Hallopeau type): positive DIF of perilesional skin.
Inverse psoriasis:
• Lesions have sharper borders, fewer erosions and less crusting.
• Additional sites o f involvement and associated signs e.g. nail pitting.
Darier disease
The cutaneous features of HHD and DD disease may overlap (for example,
DD with predominantly flexural affection may mimic HHD). However,
• the two disorders have different patterns of distribution that are easily
distinguished.
• certain features e.g. V-shaped notches in the distal edge of the nail,
eiythronychia, and oral papules favour the diagnosis of Darier disease.
• genetic analysis can establish the diagnosis.
_____________________________________________________________
these clinical differential diagnoses, histologic
, .B|| examination of affected skin is often the key to the diagnosis.
T ip s ------------------------------------------------------------------------------------
Prognosis
• The clinical course in an individual patient is difficult to predict (BOTH
complete remissions and flares are common).
o Some patients report attenuation of the disease at an older age,
whereas others state that there is no change or worsening with aging.
• Life expectancy is not altered.
113
Bullous Diseases
Tre a tm e n t
General measures
• Wearing lightweight clothes (to avoid friction and sweating).
® Management of colonization/secondary bacterial, fungal, viral infections:
o Prevented with antimicrobial cleansers.
o Treated with appropriate topical and/or systemic antimicrobial agents.
Topical therapy
• Corticosteroids: effective treatment and are often combined with topical
antimicrobials and cleansers.
• Other topical preparations e.g. tacrolimus, cyclosporine, 5-fluorouracil,
calcitriol and tacalcitol.
• Improvement of axillary HHD after chemodenervation of sweat glands
with botulinum toxin has been observed.
• Early use of corticosteroids can improve developing lesions.

• When the disease is refractory to topical preparations, it may
respond to intra-lesional corticosteroids.
• To minimize the potential side effects of topical corticosteroids
in intertriginous zones (e.g. atrophy, striae, telangiectasias),
S the lowest potency that is effective should be used
■/ these medications can be applied intermittently
S steroid-sparing agents can be substituted e.g. tacrolimus
• In Darier disease, topical corticosteroids are not very

» effective.
S u rg ica l therapy
Indications: disease unresponsive to general measures and topical treatments.
Modalities:
• Wide excision and grafting (successful but aggressive - has been
replaced by more superficial ablative techniques).
Systemic therapy
With the exception of antimicrobial agents for superadded infections, there is
NO evidence to support the use of any systemic therapy in HHD.
• Oral retinoids are not clearly effective.
• There are only anecdotal reports of severely affected individuals
improving with the use of immunomodulatory drugs, e.g. prednisone,
methotrexate, dapsone and alefacept.
1 Darier disease, oral retinoids (isotretinoin and acitretin) are
ery effective (significant improvement and control of the
isease in approximately 90% of patients).__________________
114
• Superficial ablative techniques (dermabrasion, laser removal -

CO2 or erbium: YAG, photodynamic therapy with 5-
aminolevulinic acid) remove diseased epidermis and their
dermal niche of fibroblasts to the level of the mid-dermis.
Re-epithelialization (from the spared adnexal structures)
occurs within 7-14 days.
H a ile y -H a ile y D ise a se (H H D )
D
0 Synonyms: Familial benign chronic pemphigus.

0 Pathogenesis:
• M ode o f inheritance: Autosomal dominant (AD).
• Genetic defect: Mutations in the ATP2CA gene which encodes hSPCAl.
A hSPCAl transports Ca2+ and Mn2+ and sequesters Ca2+ within the
Golgi lumen.
A hSPCAl dysfunction ■=>depletion of Ca2+ within the Golgi lumen
^ impaired processing of desmosomal proteins ■=>acantholysis
(with minimal / NO Dyskeratosis).
0 Epidemiology
• A ge o f presentation: 2nd or 3rd decade (may be delayed until the 4th or
5th decade).
• Seasonal variation: HHD shows exacerbation during summer.
• Symptoms: Painful erosions, Pruritus (itching) and Malodor
(psychosocial distress).
• Exacerbating factors: summer season (UV irradiation, sweating and
heat), friction, microbial colonization and secondary infections
staphylococcal).
• Skin lesions: Flaccid vesicles, macerated or crusted erosions,
malodorous vegetations and painful fissures in intertriginous sites e.g.
axillae, groin, lateral aspects of the neck and perianal region.
• Nail changes: Asymptomatic, longitudinal white bands in the
fingernails (longitudinal leukonychia).
• Mucosal manifestations: Involvement o f the buccal, vaginal or
conjunctival mucosa is rare.
• Clinical subtypes:
Segm ental types 1 and 2: lesions are distributed along Blaschko’s lines
A Type 1: unilateral lesions along Blaschko's lines. Age of onset and
severity does not differ from generalized HHD.
A Type 2: Patients with generalized HHD have a linear streak with
increased severity and earlier onset.
115
Bullous Diseases
0 Complications:
1. Infections: Colonization and secondary bacterial, fungal and viral
infections —►disease exacerbation and persistence.
• Kaposi’s varicelliform eruption: superimposed HSV infection. A
rare complication of HHD.
2. Malignant transformation: Cutaneous SCC may develop within
chronic lesions of HHD in the anogenital region (infection with
oncogenic strains of HPV).
0 Histopathology: Acantholysis WITH minimal / no dyskeratosis.

• Acantholysis: Supra-basilar cleft, widespread and partial —»
dilapidated brick wall.
• The epidermis: epidermal hyperplasia, parakeratosis and focal crusts.
• The superficial dermis: moderate peri-vascular lymphocytic infiltrate.
• DD of lesions confined to the axillae or groin: Intertrigo - Candidiasis.
• DD of isolated perianal maceration: Irritant dermatitis.
• DD of vulvar involvement: Lichen simplex chronicus.
• DD of vegetating intertriginous lesions: Pemphigus vegetans
(Hallopeau type).
• Inverse psoriasis
• Darier disease
• Prognosis: The clinical course is difficult to predict (BOTH complete

remissions and flares are common). Life expectancy is not altered.
0 Treatment:
• General measures: Lightweight clothes - Management of
colonization and secondary bacterial, fungal and viral infections
(antimicrobial cleansers and topical and/or systemic antimicrobial
agents).
• Topical therapy: Topical or intra-lesional corticosteroids, botulinum
toxin (for axillary HHD) and others (e.g. tacrolimus, cyclosporine, 5-
fluorouracil, calcitriol and tacalcitol).
• Surgical therapy (for disease unresponsive to general measures and
topical treatments): Excision with grafting, Dermabrasion, Lasers (C02,
erbium: YAG), Photodynamic therapy (PDT).
• Systemic therapy: with the exception of antimicrobial agents for
superadded infections, there is NO evidence to support the use of any
systemic therapy in HHD. Oral retinoids are not clearly effective.
116
Darier disease versus Hailey-Hailey disease.

BOTH are AD, exacerbating in summer, chronic
Darier disease Hailey-Hailey disease

Synonym Darier-White disease, Familial benign chronic
(Dys)Keratosis follicularis pemphigus
Defect ATP2A2 / SERCA2 ATP2CA / hSPCAl
(Endoplasmic reticulum) (Golgi apparatus)
Age of onset 6 - 2 0 years (relatively early) 2nd - 3rd decade (relatively late)
Symptoms Itching Pain
Site Seborrheic area Intertriginous sites
Lesions Keratotic papules Vesicles, erosions, vegetations
Nail Longitudinal red lines, Longitudinal white bands
V-shaped notches
Mucosa Papules / palate Rare
Complications Infections Infections
Oral salivary glands
Neuropsychiatric
Ocular
Malignant transformation Malignant transformation
Histopathology Acantholytic dyskeratosis Acantholysis,
Minimal/no dyskeratosis
DD Seborrheic dermatitis Intertrigo
Treatment General measures General measures
Topical Topical
Systemic Surgical
Surgical Systemic (least)
117
Part 4
Epidermolysis
Bullosa
The sub-epidermal genetic bullous diseases
Although epidermolysis bullousa (EB) is classified as sub

epidermal disorder(s). The reader should notice that aone
majory type of EB (EB simplex) is actually intra-
epidermal blistering disease._______________________
Epidermolysis Bullosa Chapter
(EB)
The sub-epidermal genetic bullous
diseases
19
Synonyms:
A Inherited EB / EB hereditaria.
* ^he designations “inherited” and “hereditaria” are used to

differentiate EB from acquired EB (EB acquisita) - page 69.
.
Definition
• EB is NOT a single disease BUT a group of clinically distinctive disorders
(at least 30 phenotypes) with common features:
1. Genetic transmission: ALL forms o f EB are inherited (AD or AR).
• EB results from mutations within the genes encoding for any of at
least 15 structural proteins (within the BMZ or within the
epidemris) (Fig 19.1; Fig 9.3, page 49):
2. Blister formation:
3. Mechanical fragility of the skin: development o f blisters following
minor or insignificant trauma or traction to the skin. Inherited EB is
the prototypic mechano-bullous disease.
Classification
• EB is classified into 3 major forms (types) according to the ultra-structural
level of defective protein (and consequently the blister) (Fig 19.2):
1. E B sim plex (EBS): within the epidermis. It’s further subdivided into
basal and supra-basal subgroups (based on site of blister within the
epidermis).
2. Junctional E B (JEB): within the lamina lucida (LL) MCQ o f DEJ.
3. Dystrophic E B (DEB): within the sub-lamina densa (SLD) MCQ of the
uppermost papillary dermis.
• Each of the 3 major forms of EB has many variants

(subtypes).
q&lp-Tul • Kindler syndrome was added to the EB classification in 2008
as a fourth major form of EB. Blistering occurs in multiple
T ip s levels within and/or beneath the BMZ, rather than within a
discrete plane, as occurs in all other EB types._____________
119
Bullous Diseases
EB type Mutated protein
Transglutaminase 5
EBS suprabasal Plakoglobin

Platephilin 1
Desmoplakin
Keratin 5 /14, piectin, BP230,

EBS basal exophilin S, kindlin-X
Integrin a6p4, integrin a3,

Lamina iucida collagen XVII, laminiri 332
Sub-lamina densa
Collagen VII
Fig 19.1 A schematic representation of location of specific mutated proteins and the level in
which blisters develop in different EB types; KS = Kindler syndrome (Fine et al, 2014).
(a) (b) (c) (d)

Fig 19.2 Ultra-structure level of blister formation in EB. (a) Normal intact skin (b) EBS:
lowermost portion of basal keratinocytes (c) JEB: LL region (d) DEB: SLD region.
Study plan
While studying the 3 major forms (subtypes and variants) of EB,
you should highlight the following points (Table 19.1):
• Blister level.
• Mode of inheritance (AD or AR), defective protein.
• Extent (generalized, localized), severity.
• Associated features (if present)._______________________
120
Table 19.1 Major forms and subtypes of EB M C Q .
M ajor Subtypes Mode of Defective

in h e rita n c e
form New name Old / Other names protein(s)
S u p ra
-b a sa l Superficialis Unknown
Localized W eber-C ockayne
Koebner
Generalized
Generalized other
intermediate K5, K14
Non- Dowling-Meara
AD
Generalized Dowling-Meara
severe Herpetiformis
With mottled
Oh K5
S pigmentation
<Z)
& with muscular Plectin
PP PP
W dystrophy m cq MCQ
Plectin
With nvloric
«6p4
atresia (PA)
AR integrin
K14
EBS-AR K14
Autosomal BPAG1
EBS-AR P230
recessive (BP230)
EBS-AR exophilin 5
Exophilin 5
Generalized Laminin-5
Herlitz MCQ
severe MCQ
PP N
W
• pH Laminin-5
p «h Generalized non-Herlitz
es - Collagen
s intermediate Other
o § AR XYII
SJ
O
0 With pyloric a6p4 MCQ
o atresia MCQ integrin
Collagen
Localized
Localized
XVII
Cockayne-T ouraine
Generalized
'W and Pasini
0
cs Localized
n s
(e.g. acral, AD
w
• pH
ao pretibial,
£ Q Collagen
o
a pruriginosa,
VII
nails only)
o Generalized
Q Hallopeau Siemens
"oB
CB severe
o
w AR
<u Generalized non-Hallopeau-
pp intermediate Siemens
Kind er S AR Kindlin-1
NB. There are many other subtypes o f EB. The most important subtypes are
shown in bold.
121
Bullous Diseases
• There are many other subtypes of EB in addition to those

mentioned in Table 19.1 and new subtypes are still being
reported. Due to the rarity of these subtypes and the scope
limitation of this book, these subtypes were not mentioned.
The reader is referred to detailed reviews and textbooks,
fj An excellent and updated review is Fine et al. Inherited
epidermolysis bullosa: Updated recommendations on diagnosis
and classification. J Am Acad Dermatol 2014;70:1103-26.
C lin ica l features Clinical features o f EB:

1. Cutaneous
• General
(1) C utaneous Findings • Specific
2. Extra-cutaneous
General cutaneous features: 3. Malignancies
All forms of inherited EB are characterized by
• Mechanically fragile skin, skin blisters and erosions: minimal traction on
the skin leads to blister formation (blisters can be induced by rotating a
pencil eraser on intact skin)
• Scarring (almost always atrophic): can occur in any type or subtype o f EB
but mostly in subtypes characterized by disruption of the basement
membrane zone (particularly the lamina densa). It occur in only 15% of
patients with localized EBS and in almost every patient with RDEB.
• Other cutaneous findings: dystrophic or absent nails, milia, and scarring
alopecia of the scalp.
Specific cutaneous features:

Some cutaneous features and the distribution o f the skin lesion may help in
the classification o f EB subtypes (Table 19.2, Fig 19.3).
Table 19.2 Helpful cutaneous findings in patients with EB.

EB type / subtype Characteristic features Distribution
Superficial peeling of the
EBS superflcialis (EBSS)
skin, no blistering
EBS, localized Palms and soles
EBS-generalized severe Palmo-plantar Grouped (herpetiform) -
(Dowling-Meara “DM”) keratoderma arcuate or polycyclic
EBS with mottled Reticulated
pigmentation (EBS-MP) hypeipigmented macules
JEB-H. Excessive or exuberant Symmetric - periorificial,
granulation tissue axilla, neck, upper back
“Inversa” subtypes of JEB intertriginous areas (e.g.
and RDEB axillae, inguinal creases)
Pretibial DEB Exclusively on the shins
122
W (f)
Fig 19.3 Clinical features of EB (a) and (b) localized EBS: bullae on the toes and plantar
surfaces, (c) and (d) Dowling-Meara EBS: grouped blisters on an erythematous base with
hyperkeratosis of the soles, (e) JEB, Herlitz: blisters on the elbow and large areas of denuded
skin (axilla and groin), (f) severe generalized RDEB: “mitten” deformities of the hands MCQ.
(2) Extra-cutaneous Findings
• The same molecular defects that affect the skin in patients with
EB may also affect other tissues with an epithelial lining or
surface, including the eye, oral cavity, and gastrointestinal
and genitourinary tracts. This can result in blisters, erosions,
ulcers and/or scarring.
Tips • Extra-cutaneous involvement occurs most frequently in
RDEB and (to a lesser extent) JEB. Special types of EBS may
have extra-cutaneous involvement (EBS-MD and EBS-PA).
• Eyes: corneal blisters, ulcers, scarring and ectropion formation (repeated

blistering of the external eye can result in neovascularization and
blindness).
® Oral cavity: microstomia.
® Teeth: enamel hypoplasia (all subtypes of JEB - pitting of the surfaces of
teeth), excessive caries and premature loss of teeth (if untreated).
• Respiratory: trachea-laryngeal stenosis (possible fatal airway obstruction).
123
Bullous Diseases
• Cardiac: dilated cardiomyopathy (selenium or carnitine deficiency).

• Gastro-intestinal: esophageal strictures, pyloric atresia (JEB-PA and EBS-
PA), chronic malabsorption (involvement of the small intestine),
malnutrition / failure to thrive (may lead to death) and severe constipation
(involvement of the large intestine).
• Genitor-urinary: urethral meatal stenosis, hydroureter, hydronephrosis and
chronic renal failure.
• M usculoskeletal: pseudosyndactyly (digits become totally fused and
encased by scar tissue - “mitten” deformities o f the hands and feet),
osteoporosis or osteopenia (vertebral crush fractures in severe cases) and
muscular dystrophy (EBS-MD - plectin deficiency).
• Bone marrow: severe multi-factorial anemia (due to iron deficiency and
chronic inflammation)._____________________________________________
• Severe caries likely result from impaired clearance of food
from the mouth and poor dental hygiene due to intraoral injury
and scarring, ankyloglossia and microstomia.
• Renal failure may result from untreated outflow obstruction,
glomerulonephritis or secondary systemic amyloidosis.
Nephrotic syndrome (due to altered expression of laminin in
renal basement membranes) has been reported in JEB-H.
• Although it was common in the past, potentially lethal bacterial
sepsis is now relatively rare in inherited EB, due to improved
wound care and the availability of broad-spectrum antibiotics.
(3) C utaneous M alignancies

M ultiple cutaneous SCCs:
• A major complication o f EB. The leading cause of death in EB at or after
mid-adolescence (within 5 years o f the diagnosis of the first SCC).
• Occur almost exclusively in RDEB (especially severe generalized form)
and rarely in patients with JEB.
• Arise in chronic non-healing wounds or hyperkeratotic lesions.
• Criteria:
0 Clinically: indistinct borders (difficult to be completely excised
surgically with tendency to recur locally).
0 Histologically: well differentiated.
0 Frequently metastasize.
0 Unresponsive to chemotherapy or radiotherapy.
& Melanoma:
• Occurs in small number o f children with RDEB (severe generalized form)
EB nevi: large, irregularly-shaped, darkly pigmented

melanocytic nevi that develop in children with EB especially JEB-
nH. Clinically resemble melanoma but they are histologically and
biologically benign. A large size from the onset (rather than a
relatively slow horizontal expansion) differentiates it from
melanoma.
124
Investigations
(1) Light microscopy:
• It has NO role in the diagnosis of EB - it may be difficult to distinguish
between lower intra-epidermal and sub-epidermal blister formation and it is
impossible to differentiate between intra-lamina lucida (i.e. JEB) and sub
lamina densa (i.e. DEB) types.
• Supra-basal forms o f EBS (due to desmoplakin, plakophilin or plakoglobin
deficiency) share the histologic finding o f acantholysis.
• The two diagnostic tests that are routinely employed are

1. transmission electron microscopy (TEM)
2. immunofluorescence antigenic mapping
® Either approach may serve as the gold standard for the non-
molecular diagnosis of inherited EB.
(2) Transmission electron microscopy (TEM):

• Distinguishes among the four major EB types by defining the
ultrastructural level of blister formation.
• Can assess specific structures, e.g. basilar tonofilaments, hemi-
desmosomes, sub-basal dense plates, anchoring filaments, anchoring fibrils.
(3) Immunofluorescence antigenic mapping:

* Aim: to determine the level of blister formation.
* Method: staining the dermal-epidermal zone using antibodies against BMZ
components (structural proteins).
A Anti-keratin 14 antibody —» stains the cytoplasm o f basal epidermal
cells.
A Anti-BP230 antibody —»• stains the lower surface o f basal cells
(containing hemidesmosomes).
A Anti-laminin-1 antibody —> stains the upper lamina lucida.
A Anti-type IV collagen antibody —> stains the lamina densa.
* Interpretation:
A EB simplex: ALL antibodies (EXCEPT antikeratin) stain only the base
of the split.
A Junctional EB:
> Anti-keratin, anti-BP230 and anti-laminin-1 antibodies stain the roof.
> Anti-type IV collagen staining is on the floor.
A Dystrophic EB: ALL antibodies stain only the roof of the split.
m -----------------------------------------------------------------------------------------------------------------
• The aim of immunofluorescence antigenic mapping is NOT to
AAlp-£u^ look for reduced expression of skin antigens. It’s mainly
T ip^ used to determine the level of blister formation.
s®.
125
Bullous Diseases
(4) Molecular diagnosis:

• Important for the prenatal and pre-implantation diagnosis of EB (first
trimester DNA testing for couples at risk of having affected children).
• Useful for genetic counselling and prognosis.
• Determines whether a patient has a dominant or recessive form o f DEB.
Differential diagnosis______________________
• Although it is difficult to determine the subtype of inherited EB on the basis of
clinical findings alone, the diagnosis of EB is usually straightforward in anyone
beyond early childhood. Clues to the diagnosis are (1) early onset, (2) positive
family history and/or (3) relation to trauma._____________________________
(1) DD in neonates or young infants:

Diagnosis of EB in neonates or young infants may be difficult. DD o f blisters
and erosions in neonates or young infants includes:
r Genetic diseases e.g. bullous congenital ichthyosiform erythroderma or
incontinentia pigmenti (vesicular stage).
> Traumatic blisters e.g. sucking blisters.
> Infectious diseases e.g. herpes simplex, staphylococcal scaldedskin
syndrome, bullous impetigo).
> Tumors e.g. bullous mastocytosis.
> Autoim m une blistering diseases e.g. pemphigus or herpes gestationis,
acquired transplacentally.
> Metabolic disorders e.g. acrodermatitis enteropathica.
(2) DD of EBSS:
> Peeling skin syndrome.
> Bart syndrome: coexistence of any type o f EB and congenital localized
absence of skin (CLAS; aplasia cutis congenita).
Currently, there are NO specific

Treatm ent therapies available for any form of
(1) General preventive measures: inherited EB. Treatment is mainly
• Prevention o f mechanical trauma: preventive and symptomatic.
S Padding over bony prominences.
S Soft / loose-fitting clothing and shoes.
• Prevention o f infection:
■S Bathing or soaking with 0.005% sodium hypochlorite (0.5 cup
household bleach [6% sodium hypochlorite] in a full standard bathtub)
or 0.25% acetic acid (1 part white vinegar [5% acetic acid] to 20 parts
water) may help to reduce bacterial colonization.
S Antibiotics should be used judiciously, with avoidance o f chronic
treatment with topical mupirocin or oral antibiotics.
• Management o f symptomatic plantar hyperhidrosis in E B S patients:
Topical application o f aluminum chloride hexahydrate.
S Injection of botulinum toxin A.
126
(2) Skin dressing:

As a general rule, only non-adhesive dressings should be applied to EB skin
e-g-
• Vaseline-impregnated gauze (cheap - suitable for non-infected
wounds).
• Soft silicone dressings.
• Silver-impregnated dressings (for heavily colonized or infected
wounds - avoid long-term application to minimize systemic silver
absorption).
• Tissue culture-derived artificial skin bioequivalents (for chronic
recalcitrant ulcers).
(3) M onitoring for / m anagem ent of long-term complications of EB:

This requires a multidisciplinary approach. Examples include:
• Esophageal strictures: dietary modification (soft foods/purees, caloric
supplementation), balloon dilatation and surgical intervention (in severe
and recalcitrant cases).
• Anemia due to iron deficiency and chronic inflammation: iron
supplementation (oral or IV), erythropoietin or blood transfusion (if
hemoglobin < 7-8 g/dl and/or symptomatic).
• Cutaneous SCC: excision ± skin grafting.
(4) Systemic therapies:

• Phenytoin: inhibits collagenase.
• Tetracycline for EBS
• Thalidomide and cyclosporine for symptomatic relief in DEB
pruriginosa.
• Systemic retinoids: long-term treatment with low-dose systemic
retinoids may help to prevent the development of SCCs in RDEB
patients (but may increase mechanical fragility and blistering of the
skin).
(5) F u tu re and trial therapies:

• Gene therapy: gene transfer into keratinocytes from affected
individuals.
• Intra-dermal injection o f human type VII collagen or normal
allogeneic fibroblasts into non-healing wounds in RDEB patients.
• Bone marrow-derived stem cell transplantation.
127
Bullous Diseases
Chapter summary
E p id e rm o lys is B u llo s a (E B )
D
0 Synonyms: Inherited EB / EB hereditaria
o to differentiate EB from acquired EB (EB acquisita).
0 Definition: EB is NOT a single disease BUT a group of clinically

distinctive disorders with common features:
1. Genetic transmission: ALL forms of EB are inherited (AD or AR). EB
results from mutations within the genes encoding structural proteins
(within the BMZ or the epidermis).
2. Blister formation:
3. Mechanical fragility of the skin: development o f blisters following
minor or insignificant trauma / traction to the skin (i.e. mechano
bullous disease).
0 Classification: according to the ultra-structural level of the blister:

1. EB simplex (EBS): within the epidermis.
a) basal subgroup
b) supra-basal subgroup
2. Junctional EB (JEB): within the lamina lucida (LL).
3. Dystrophic EB (DEB): within the sub-lamina densa (SLD).
4. Kindler syndrome: multiple levels of blister (mixed).
A Each o f the first 3 major forms of EB has many variants (subtypes).
0 Clinical features:
1. Cutaneous Findings
• General cutaneous features: all forms o f inherited EB are characterized
by
■S Mechanically fragile skin, skin blisters and erosions
■S Atrophic seaming
S Dystrophic or absent nails, milia, and scarring alopecia of the scalp.
• Specific cutaneous features:
■S EBS superficialis (EBSS): superficial peeling of the skin - NO
blistering
•S EBS, localized : mainly affection of palms and soles
•S EBS-generalized severe (Dowling-Meara “DM”): Palmoplantar
keratoderma. Lesions are grouped (herpetiform) - arcuate or polycyclic
2. Extra-cutaneous Findings (most frequently in RDEB)

• Eyes: corneal blisters, ulcers, scarring and ectropion
• Oral cavity: microstomia.
• Teeth: enamel hypoplasia, excessive caries and premature loss of teeth
• Respiratory: tracheolaryngeal stenosis (fatal)
128
• Gastro-intestinal: esophageal strictures, pyloric atresia, chronic

malabsorption, malnutrition / failure to thriveand severe constipation
• Cardiac: dilated cardiomyopathy.
• Genitor-urinary: urethral meatal stenosis, hydroureter, hydronephrosis
and chronic renal failure.
• Musculo-skeletal: pseudosyndactyly, osteoporosis or osteopenia and
muscular dystrophy
• Bone marrow: severe anemia
3. Cutaneous Malignancies: Multiple cutaneous SCCs - Melanoma
Major Subtypes Mode of Defective

form New name Old / Other names in h e rita n c e protein(s)
S u p ra
-basal Superficialis Unknown
Localized Weber-Cockayne
Koebner
Generalized
Generalized other
intermediate K5, K14
X Non- Dowling-Meara
AD
ft Generalized Dowling-Meara
S severe Herpetiformis
Basal
tfi
With mottled
CQ K5
w pigmentation
with muscular
Plectin
dystrophy
AR Plectin
With nvloric
«6p4
atresia (PA)
integrin
Generalized
CQ TQ
3J Herlitz Laminin-5
W severe
N
”3 •H Laminin-5
a 3u Generalized non-Herlitz
V AR Collagen
c intermediate Other
XVII
s
l“9
a With pyloric a6p4
atresia integrin
Dominant
CQ Cockayne-T ouraine
W Generalized AD
and Pasini
2 Collagen
o Generalized V II
S-
Hallopeau-Siemens
95
>> X severe
o
O
u
AR
0) Generalized non-Hallopeau-
Of intermediate Siemens
Kind er S AR Kindlin-l
129
Bullous Diseases
0 Investigations:
• Light microscopy: MO role in the diagnosis of EB.
• Transmission electron microscopy (TEM): distinguishes the four
major EB types and can assess specific structures within the DEJ.
• Immunofluorescence antigenic mapping: determine the level of
blister formation through staining the dermal-epidermal zone using
antibodies against BMZ components (structural proteins) and detecting
the pattern o f staining (floor and/or roof o f the split).
• Molecular diagnosis: important for the diagnosis, prenatal and pre
implantation diagnosis - useful for genetic counselling and prognosis.
Z TEM and immunofluorescence antigenic mapping are the gold
standard for the non-molecular diagnosis o f inherited EB.
0 Differential diagnosis: Clues to the diagnosis of EB are early onset,

positive family history and/or relation to trauma.
• DD in neonates or young infants:
Z Genetic diseases e.g. bullous congenital ichthyosiform erythroderma
or incontinentia pigmenti (vesicular stage).
Z Traumatic blisters e.g. sucking blisters.
Z Infectious diseases e.g. herpes simplex, staphylococcal scaldedskin
syndrome, bullous impetigo).
Z Tumors e.g. bullous mastocytosis.
Z Autoimmune blistering diseases e.g. pemphigus or herpes
gestationis, acquired transplacentally.
Z Metabolic disorders e.g. acrodermatitis enteropathica.
• DD of EBSS: Peeling skin syndrome.
0 Treatment: NO specific treatment - preventive and symptomatic.

1. General preventive measures:
Z Prevention of mechanical trauma: padding over bony prominences,
soft / loose-fitting clothing and shoes.
Z Prevention of infection: bathing or soaking with 0.005% sodium
hypochlorite or 0.25% acetic acid, antibiotics.
Z Management of plantar hyperhidrosis: topical application of
aluminum chloride hexahydrate, injection of botulinum toxin A.
2. Skin dressing: non-adhesive dressing e.g. vaseline-impregnated gauze, soft
silicone dressings.
3. Monitoring for and management of long-term complications of EB: e.g.
esophageal strictures (soft foods, balloon dilatation and surgical
intervention), anemia (iron supplementation or blood transfusion),
cutaneous SCC (excision ± skin grafting).
4. Systemic therapies: e.g. Phenytoin (inhibits collagenase), Tetracycline,
Thalidomide and cyclosporine (DEB pruriginosa), Systemic retinoids.
5. Future and trial therapies: e.g. gene therapy, Intra-dermal injection of
human type VII collagen or fibroblasts, Bone marrow-derived stem cell
transplantation.
130
Appendices
D iagn o stic features of pem phigus
Types / variants of pem phigus
j Vulgaris / Para
i Foliaceus Erythematosus IgA
|! vegetans neoplastic
Blister
Suprabasal Subcomeal Suprabasal Subcomeal
level
Dsg3, DPI,
DP2,
Target Dsg3 ± BP230,
Dsgl Dscl
antigen Dsgl envoplakin,
periplakin,
others
| DIF IgG ± C3 at ICS IgG ± C3 at ICS + BMZ IgA at ICS
IgG at ICS, IgG at ICS,
IgG at ICS ±
IIF monkey IgG at ICS rat IgA at ICS
ANA
esophagus bladder
ICS = intercellular space, ANA = anti-nuclear antibodies, DP = desmoplakin.
S tru c tu re of desm osonie

• Desmosomes are inter-cellular adhering junctions that maintain cohesion
of epithelial cells (e.g. keratinocytes in the skin epidermis).
• By electron microscopy, desmosomes appear as small, electron-dense
structures that link keratin intermediate filaments (within the cytoplasm)
to the plasma membrane and to the adjacent cell. The whole desmosome
is a symmetrical junction of two adjacent cells with central intercellular
space.
Ultra-structural components
o f the desmosome:
1. An electron-dense band
next to the plasma
membrane (outer dense
plaque, odp).
2. A less dense band (inner
dense plaque, idp).
3. A fibrillar area (keratin intermediate filaments, kif)
4. A thin electron-dense midline (desmoglea or dense midline, dm).
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Bullous Diseases
Structural proteins o f the desmosome: Three families o f proteins:
Family Members Location

1. Desmosomal Desmogleins (Dsg)
cadherins Desmocollins Trans-membrane components
(Dsc)
2. Armadillo Plakoglobin (PG)
Cytoplasmic components
proteins Plakophilins (PP)
3. Plakins Desmoplakin (DP)
Intercellular space
m Diimogltm (Dig)
C J Dismocollin (Die)
® Plaksgtebin (PQ)
O Plakophtiln (PP)
O Disrneplakln (DP)
132
Self-assessment
P art 1: MCQs e v a lu atio n
S tudy plan
Source of these MCQs:
• Previous dermatology exams at various Egyptian Universities.
• CME articles in dermatology journals.
• American board of dermatology review questions.
Tips to make the utmost benefit from these MCQs:
• Start answering these MCQs only after you finish studying the
whole volume.
• Set a time to finish these MCQs (1 minute per question). This
will help you get accustomed to your final exam.
• Discus your answers with your colleagues and always ask your
tutors about difficult questions.___________________________
1) IgA is the predominant antibody in immune complex associated with

a) Pemphigus vulgaris
b) Dermatitis herpetiformis.
c) Bullous pemphigoid
d) Erythema multiforme
2) A skin biopsy for direct immunofl uorescence should preferably be

taken from
a) Lesional bullous skin
b) Peri-lesional erythematous skin.
c) Peri-lesional non-inflamed skin
3) A u-serrated linear staining along the basal membrane zone can be

observed in
a) Bullous pemphigoid
b) Epidermolysis bullosa acquisita.
c) Anti-p200 pemphigoid
4) Using monkey esophagus as a substrate, pemphigus is characterized

by:
a) A linear pattern along the basement membrane
b) An epithelial cell surface staining in a chicken wire pattern.
c) Both patterns can be observed
5) The substrate of choice for testing for paraneoplastic pemphigus is:

a) Monkey esophagus
b) Rat bladder.
c) Salt-split skin
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Bullous Diseases
6) In pemphigus vulgaris, the acantholytic cells are derived from

a) Stratum granulosum
b) Stratum spongiosum.
c) Stratum basale
d) Dermis
7) What is the expression pattern of D sgl and Dsg3 in the epidermis?

a) Dsgl and Dsg3 are expressed in all layers o f the epidermis
b) Dsgl and Dsg3 are expressed in the basal and granular layer of the
epidermis
c) Dsg3 is expressed in the basal and suprabasal layers, while D sgl
expression decreases from the upper to the lower layers of the
epidermis.
d) D sgl expression decreases from the basal to the upper layers o f the
epidermis, while Dsg3 expression decreases from the upper to the lower
layers of the epidermis
8) The most common histologic pattern seen in dermatitis herpetiformis

a) Sub-epidermal blister with lymphocytes and eosinophils
b) Sub-epidermal blister with neutrophils in dermal papillae.
c) Sub-epidermal blister with confluent epidermal necrosis
d) Cell-poor sub-epidermal blister
e) None of the above
9) The most common histologic pattern seen in bullous pemphigoid

a) Sub-epidermal bulla with eosinophils usually the predominant cells.
b) Sub-epidermal blister with neutrophils in dermal papillae
c) Sub-epidermal blister with confluent epidermal necrosis
d) Cell-poor sub-epidermal blister
10)Patients with mucosal dominant PV have antibodies directed against

a) Desmoglein 1
b) Desmoglein 3.
c) Desmogleins 1 and 3
11) First-line treatment of pemphigus is

a) Superpotent topical corticosteroids
b) Systemic corticosteroids.
c) Azathioprine
d) Rituximab
12) Which localization of lesions is more likely to be present in a

pemphigus foliaceus patient?
a) Abdomen
b) Feet
c) Upper trunk.
134
13) The most prevalent area for endemic pemphigus is

a) Rural.
b) Urban
c) None
14)Which autoantibodies are most sensitive and specifi c for PNP?

a) Antibodies to both envoplakin and periplakin.
b) Antibodies to BP230
c) Antibodies to desmoglein 3
d) Antibodies to A2ML1
15) Which of the following results confirm the diagnosis PNP?

a) Serum IgG binding to monkey esophagus
b) A dual ICS and BMZ IgG deposition pattern in patient skin
c) Serum IgG binding to rat bladder urothelium.
d) Positive anti-desmoglein 3 IgG serum antibodies by ELISA
e) Serum IgG binding to the roof o f salt-split skin
16)DIF finding characteristic of paraneoplastic pemphigus is

a) Linear IgG along the BMZ
b) Linear IgA along the BMZ
c) Intercellular epidermal IgG with granular linear complement along the
BMZ.
d) Granular IgA in dermal papillae
17) Pemphigus affects primarily:

a) young boys
b) males
c) females middle-aged persons
d) persons of European origin.
18)The following histological findings are characteristic of Darier’s disease

except
a) Hyperkeratosis and parakeratosis
b) Spongiosis.
c) Acantholytic dyskeratosis resulting in corps ronds and grains
d) Suprabasilar acantholysis with formation of clefts
e) Sparse superficial lymphocytic infiltrate
19) Ultra-structural level of skin cleavage or blister formation in

epidermolysis bullosa simplex is
a) Intra lamina lucida
b) Sub lamina lucida
c) Within lower half o f basal basilar keratinocytes.
d) Dermal
135
Bullous Diseases
20) In which autoimmune bullous disease do the autoantibodies target

anchoring fibrils?
a) Immunoglobulin A pemphigus
b) Epidermolysis bullosa acquisita.
c) Bullous pemphigoid
d) Mucosal pemphigoid
e) Dermatitis herpetiformis
21)PNP patients are characterized clinically by:

a) A severe stomatitis.
b) The combination of flaccid and tense blisters
c) Lichenoid plaques
22) Which is not a subtype of IgA pemphigus?

a) Subcorneal pustulosis dermatosis type
b) Intraepidermal neutrophilic IgA dermatosis type
c) Sneddon-Wilkinson’s disease.
23) Which form of IgA pemphigus is characterized by erythematous skin

lesions with tiny superficial pustules, particularly in the intertriginous
areas?
a) SPD-type.
b) IEN-type
c) Both types
24)First-line treatment of IgA pemphigus is?

a) Dapsone.
b) Systemic corticosteroids
c) Azathioprine
25) Which one of the following statements about bullous pemphigoid is not
true
a) Large tense blisters on erythematous base
b) It commonly starts with itching
c) The BP antigen 230 is intra-cellular and localized to the dense plaque
d) Niklosky’s sign is positive.
26) Regarding epidermolysis bullosa acquisita (EBA), which of the

following is not true
a) EBA may clinically resemble bullous pemphigoid
b) EBA is caused by autoimmunity to type VII collagen
c) Autoantibodies to the EBA antigen bind to the epidermal portion of
sodium chloride-separated normal human skin.
d) The presence of scarring and milia is more commonly observed in EBA
than in bullous pemphigoid
136
27) Topical steroids should be considered in the treatment of

a) localized pemphigoid.
b) ocular pemphigoid
c) pemphigus vulgaris
d) epidermolysis bullosa acquisita
e) dermatitis herpetiformis
28)Drug-induced pemphigus:
a) In drug-induced pemphigus (DIP), the autoimmune disease was not
present before the drag exposure.
b) In drag-triggered pemphigus (DTP), the autoimmune disease was not
present before the drag exposure
c) In drag-triggered pemphigus (DTP), the autoimmune process will be
stopped after suspension of the culprit drag
29) The ideal substrate for direct immunofluorescence in the evaluation of

bullous diseases is
a) early vesicle
b) late vesicle
c) erythematous patch
d) border o f erosion
e) normal skin adjacent to vesicle.
30)Sub-epidermal blisters with eosinophils are present in the following

except
a) Darier disease.
b) Bullous pemphigoid
c) Pemphigoid gestationis
d) Certain arthropod reactions
e) Some bullous drag reaction
31) Sub-epidermal blisters with neutrophils are present in the following

except
a) Dermatitis herpetiformis
b) Pemphigus vegetans.
c) Cicatricial pemphigoid
d) Linear IgA bullous dermatosis
e) Bullous lupus erythematosus
32)Fogo selvagem is a form of:

a) pemphigus erythematosus
b) pemphigus vulgaris
c) paraneoplastic pemphigus
d) lupus erythematosus
e) pemphigus foliaceus.
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Bullous Diseases
33)The most common malignancy associated with paraneoplastic

pemphigus is:
a) follicular dendritic cell sarcoma
b) thymoma
c) bronchogenic squamous cell carcinoma
d) non-Hodgkin’s lymphoma.
e) myeloblastic leukaemia
34) Which protein is a structural component of the hemidesmosome?

a) Integrin a6p4.
b) Type IV collagen
c) Laminin 332
d) Type VII collagen
35) Which protein is a structural component of the lamina densa?

a) BP230
b) Laminin 332.
c) Integrin a6(34
d) BP 180
36)Detection of circulating anti-desmoglein 1 antibodies alone is

pathognomonic of:
a) pemphigus vulgaris
b) pemphigus foliaceus.
c) pemphigus erythematosus
d) drug-induced pemphigus
e) paraneoplastic pemphigus
37)Detection of circulating anti-desmoglein 1 and anti-desmoglein 3

antibodies is pathognomonic of:
a) pemphigus vulgaris.
b) pemphigus foliaceus
c) pemphigus erythematosus
d) fogo selvagem
e) paraneoplastic pemphigus
38)Anti-desmoglein 1 antibodies are detected in each of the following

diseases except:
a) pemphigus foliaceus
b) fogo selvagem
c) pemphigus vulgaris
d) paraneoplastic pemphigus
e) lichen planus pemphigoides.
138
39)Dapsone is least effective in

a) linear immunoglobulin A disease
b) dermatitis herpetiformis
c) pemphigus vulgaris.
d) epidermolysis bullosa acquisita
e) immunoglobulin A pemphigus
40)Pemphigus vegetans:
a) is confined to the scalp
b) is confined to the buccal mucosa
c) is a form of pemphigus vulgaris.
d) never occurs in the axillae
e) responds easily to therapy
41)Suppression of antibody production is most important in the

management of
a) epidermolysis bullosa acquisita
b) bullous pemphigoid
c) pemphigus vulgaris.
d) dermatitis herpetiformis
e) linear immunoglobulin A disease
42) Which of the following diseases should not be treated with

glucocorticoids as a first-line agent?
b) Pemphigus foliaceus
c) Dermatitis herpetiformis.
d) Bullous pemphigoid
e) Paraneoplastic pemphigus
43)What area is most likely to be affected in a patient with dermatitis

herpetiformis (DH)?
a) Digits
b) Elbows.
c) Occiput
d) Palms and soles
e) Periumbilical
44)In patients with severe mucosal pemphigoid, first-line therapy includes

a) systemic glucocorticoids alone
b) cyclophosphamide alone
c) cyclosporine alone
d) a and b in combination.
e) a and c in combination
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Bullous Diseases
45)A 60-year-old gentleman presents with 30-pound weight loss, severe

oral and ocular erosions, and erythematous skin patches and erosions.
Histologic examination reveals suprabasal acantholysis. Direct
immunofluorescence reveals deposition of immunoglobulin G around
epidermal cells. Indirect immunofluorescence performed with monkey
esophagus reveals antibodies against the epithelial cell surface. The
next step is to
a) treat with prednisone
b) treat with prednisone and cyclophosphamide
c) perform further serum studies
d) perform malignancy work-up
e) both c and d.
46) The combination of tetracyclines and niacinamide is most helpful in the

treatment of
a) limited bullous pemphigoid.
b) oral pemphigus vulgaris
c) linear immunoglobulin A disease
d) dermatitis herpetiformis
e) pemphigus foliaceus
47)Direct immunofluorescence testing of perilesional skin from a patient

with DH is most likely to reveal granular deposition within the dermal
papillae composed of which of the following classes of antibodies?
a) IgA.
b) IgD
c) IgE
d) IgG
e) IgM
48) In addition to maintaining a gluten-free diet, which food should you tell
DH patients to avoid?
a) Bananas
b) Chocolate
c) Red meats
d) Shellfish.
e) Strawberries
49)As an adjunctive agent, dapsone is most likely to be effective in the

treatment of which form of pemphigus?
b) Pemphigus foliaceus
c) Immunoglobulin A pemphigus.
d) Benign familial pemphigus.
e) Paraneoplastic pemphigus.
140
50)DH patients should be screened for which of the following conditions?

a) Congestive heart failure
b) Hypertension
c) Polymyositis
d) Renal failure
e) Thyroid disease.
51) Which of the following is true regarding corticosteroid use in

pemphigus vulgaris:
a) most patients can be controlled with a dose of 0.5-1 mg/kg/day
b) corticosteroids reduce the inflammatory process and autoantibody
production.
c) high doses of prednisone are associated with a shorter period for disease
remission and low relapse rates
d) the prednisone dosage can be tapered 2-3 weeks after initiation of
treatment
e) the prednisone tapering may proceed rapidly until withdrawal
52)PuIsed intravenous corticosteroid therapy:

a) is quite safe with only mild side effects
b) is most often preferred to the oral route o f administration
c) has the goal to quickly achieve disease remission.
d) is used as first line therapy
e) can be used at any age
53)Each of the following statements is correct regarding adjuvant drugs

except:
a) they are given in combination with corticosteroids
b) their use is recommended if serious adverse effects of corticosteroids
appear
c) their use is indicated if steroids cannot be tapered because of repeated
exacerbations of disease activity
d) there are no prospective, controlled studies to demonstrate the benefits
of adjuvant drugs in pemphigus
e) adjuvant drugs are the mainstay of therapy for pemphigus.
54) Which sentence is not correct?

a) immunosuppressive drugs are the most common form of adjuvant
therapy for pemphigus
b) the co-administration of corticosteroids and azathioprine has resulted in
complete remission rates of 28^45% and mortality rates of 1.4-7%
c) azathioprine and cyclophosphamide are usually given from the
beginning of treatment, together with corticosteroids.
d) immunosuppressive drugs act as steroid sparing agents
e) cyclophosphamide appears to be the most efficacious
immunosuppressive drug for pemphigus
141
Bullous Diseases
55)Each of the following statements is correct regarding treatment of

pemphigus except:
a) cyclosporin is always beneficial as monotherapy.
b) the advantage of mycophenolate mofetil is its favourable side effect
profile
c) methotrexate has recently been re-evaluated at a low weekly dose with
favourable results
d) gold is an attractive adjuvant for female patients in their reproductive
years
e) dapsone is preferred for the treatment o f pemphigus foliaceous
56) Each of the following statements is correct regarding treatment of

pemphigus except:
a) rituximab, binds to transmembrane CD20, reduces circulating B cells
and prevents their maturation into all antibody-secreting plasma cells
b) rituximab has been used at a dose of 375 mg/m2 weekly for 4 weeks
c) patients on rituximab should be closely monitored for infectious
complications
d) the risk-benefit ratio of rituximab use is very well established.
e) rituximab should be applied to patients who are refractory to
conventional treatment regimens
57)Which statement regarding pemphigus is not correct?

a) mucous membranes are most often affected first and may precede skin
lesions by months
b) the lesions heal with scarring.
c) pemphigus vegetans tends to occur more frequently in intertriginous
areas
d) fogo selvagem is clinically, histologically and immunopathologically
indistinguishable from pemphigus foliaceous
e) the most common malignancy associated with paraneoplastic pemphigus
is non-Hodgkin lymphoma
58) A review of systems in a patient with DH is most likely to reveal

symptoms related to which organ system?
a) Cardiovascular
b) Gastrointestinal.
c) Musculoskeletal
d) Psychiatric
e) Respiratory
59)Which disease or syndrome is associated with EBA?

a) Atopic syndrome
b) Neoplasia
c) Inflammatory bowel disease.
142
60) The most important characteristics on DIF in LABD is

a) IgA deposition in epithelial cell surface pattern
b) Linear IgA deposition along the EBMZ.
c) Granular IgA deposition along the EBMZ
d) Granular IgA deposition in dermal vessels
61)First-line treatment of LAD is

a) Superpotent topical corticosteroids
b) Systemic corticosteroids
c) Dapsone.
d) Rituximab
62) What is the trigger of DH?

a) Gluten.
b) Gliadin
c) Reticulin
d) Drugs
63) Which HLA loci are associated with DH and CD?

a) HLA-DQ8
b) HLA-B51
c) HLA-DQ2
d) (a) + (c) are correct.
64)Which are the typically involved areas on the body in DH?

a) Backside of the body.
b) Mucosal surfaces
c) Palms and soles
d) Front side o f the body
65)First-line medication of DH is:

a) Systemic corticosteroids
b) Gluten-free diet
c) Doxycycline
d) Dapsone.
66)Mutations in calcium transporters cause which pair of diseases?

a) Erythrokeratodermia variabilis and progressive symmetric
erythrokeratodermia
b) Lamellar ichthyosis and nonbullous congenital ichthyosiform
erythroderma
c) Refsum syndrome and Sjogren-Larsson syndrome
d) Chondrodysplasia punctata and CHILD syndrome
e) Darier’s disease and Hailey-Hailey disease.
143
Bullous Diseases
67)Patients with Darier”s disease are at increased risk for:

a) Kaposi”s varicelliform eruption.
b) Melanoma
c) Decreased life span
d) Basal cell carcinoma
e) Lipid abnormalities
68)What medication may exacerbate Darier's disease?

a) Phenytoin
b) Lithium.
c) Oral contraceptives
d) Anti-malarials
e) Corticosteroids
69)Underlying defect for Hailey-Hailey disease is

a) ATP2A2
b) ATP2C1.
c) BPAG1
d) BPAG2
e) Collagen type 17
70) A patient that has Darier's disease has skin findings of hyperkeratotic
papules in the seborrheic areas and has nail findings with:
a) Alternating red and white longitudinal bands.
b) Long nails
c) Horizontal parallel ridges
d) Longitudinal fissures
e) Com
71) Which of the following conditions is worsened by ingestion of lithium?

a) Darier’s Disease.
b) Hailey-Hailey Disease
c) Haim-Munk syndrome
d) Hereditary lymphedema (Nonne-Milroy disease)
e) Epidermolytic hyperkeratosis
72) What is the most likely nail findings in a patient who has an autosomal
dominant disease with keratotic papules and cobblestoning of the oral
mucosa?
a) Koilonychia
b) Red and white longitudinal bands
c) Melanonychia
d) H alf and half nails
e) Pincer nails
144
73) Which is allowed in the gluten-free diet?

a) Wheat
b) Potato.
c) Rye
d) Barley
74)Epidermolysis bullosa with muscular dystrophy is caused by mutations

in which of the following?
a) Keratins 5 and 14
b) Plectin.
c) Loricrin
d) Collagen 7
e) Collagen 17
75)In biopsies from blisters in patients with junctional epidermolysis

bullosa, the split is found in the:
a) Basal cell layer o f the epidermis
b) Lamina lucida.
c) Lamina densa
d) Squamous cell layer of the epidermis
e) None o f the answers are correct
76)Junctional epidermolysis bullosa with pyloric atresia is associated with

mutations in:
a) The alpha-6 subunit of integrin
b) The beta-4 subunit o f integrin
c) Both subunits o f integrin can have mutations causing this type of
junctional epidermolysis bullosa.
d) Plectin
e) Laminin 5
77) Dystrophic epidermolysis bullosa is associated with mutations in

collagen VII. Trauma or friction induced blistering in these patients
have a plane a splitting in the:
a) Sublamina densa.
b) Stratum spinosum
c) Lamina lucida
d) Stratum basale
e) None of these answers are correct
78) Which type of epidermolysis bullosa is associated with mitten

deformities of the hands?
a) Dominant dystrophic
b) Recessive dystrophic.
c) Weber-Cockayne
d) Herlitztype
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Bullous Diseases
79)Patients with junctional epidermolysis bullosa have been found to have

mutations in:
a) Laminin 5
b) Bullous pemphigoid antigen 2
c) Collagen 17
d) BP 180
e) All o f the answers are correct.
80) Epidermolysis bullosa simplex is caused by blistering in which

structure?
a) Granular layer keratinocyte
b) Spinous layer keratinocyte
c) Basal layer keratinocyte.
d) Lamina densa
e) Sublamina densa
81) Which type of epidermolysis bullosa simplex is associated with early

death?
a) Weber-Cockayne
b) Generalized (Koebner)
c) Dowling-Maera.
d) Ogna variant
e) Non-Herlitz variant
82)Antibodies against type VII collagen are seen in:

a) Epidermolysis bullosa simplex
b) Pemphigus erythematosus
c) Cicatricial pemphigoid
d) Epidermolysis bullosa acquisita.
e) Bullous pemphigoid
83) Circulating autoantibodies to type XVII collagen are most

characteristic of which disease?
a) Epidermolysis bullosa accquisita
b) Herpes gestationis.
c) Pemphigus vulgaris
d) Pemphigus foliacious
e) Paraneoplastic pemphigus
84)The vector of fogo selvagem may be:

a) Triatoma
b) Simulium.
c) Cimex
d) Omithodorus
e) Mus
146
85)Patients with Duhring's disease are most likely to have:

a) Mutations in plectin
b) Mutations in laminin 5
c) Mutations in transglutaminase 1
d) Antibodies to transglutaminase 3.
e) Antibodies to BPAg2
86)Direct immunofluorescent studies in chronic bullous disease of

childhood is most likely to show:
a) Iga depostion in the superficial blood vessels
b) Linear IgG at the basement membrane
c) Linear IgA at the basement membrane.
d) Granular IgG
e) Linear C3 at the basement membrane
87)The primary autoantigen in pemphigoid gestationis is

a) Desmoplakin
b) BPAG1
c) BPAG2.
d) Plakoglobin
e) Anchoring fibrils
88)Papillary dermal deposits of IgA and a papillary dermal infiltrate of

neutrophils is diagnostic of:
a) Sweet's syndrome
b) Leukocytoclastic vasculitis
c) Dermatitis herpetiformis.
d) Linear IgA dermatosis
e) Bullous pemphigoid
89)Which association is incorrect?

a) Epidermolysis bullosa acquisita : inflammatory bowel disease
b) Dermatitis herpetiformis : small bowel lymphoma
c) Paraneoplastic pemphigus : Castleman’s
d) Herpes gestationis : menopause.
e) Porphyria cutanea tarda : hemochromatosis
90) Which neoplasm is the most common cause of paraneoplastic

pemphigus?
a) Thymoma
b) CLL
c) Castleman's disease
d) Retroperitoneal sarcoma
e) Non-Hodgkin's lymphoma.
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Bullous Diseases
Part 2: Written questions

Study plan
Source of these questions:
• Previous dermatology exams at various Egyptian
Universities.
Tips to make the utmost benefit from these questions:
• Start answering these questions only after you finish
studying the whole volume.
• Answering these questions will help you identify the
topics mostly encountered in written exams.
(A) Al-Azhar University Master degree

-
November 2016 exam

• Dermatitis herpetiformis is a skin disorder associated with gluten sensitive
enteropathy.
o What is the etiopathogenesis o f the disease?
o Describe the clinical picture and the differential diagnosis,
o How can you manage this case?
• Give short account on: steroid pulse therapy.
• Compare: pathology of pemphigus vulgaris versus bullous pemphigoid.
November 2015 exam

• Write a summary o f direct and indirect immuno-fluorescence and target
antigens in autoimmune bullous diseases with sub-epidermal blistering.
May 2015 exam

• What is the most important test(s) for the diagnosis of the following
diseases? Dermatitis herpetiformis.
• Give short account on the following:
o The most important diagnostic criteria in mucous membrane
pemphigoid (cicatricial pemphigoid),
o Dermo-epidermal junction structures.
November 2014 exam

• Write the target antigens in immunobullous disorders.
• DH is a chronic blistering disease. Define it; mention briefly its clinical,
histopathological, DIF features, its associated disorders and treatment.
• Darier’s disease is a genodermatosis. Mention in short mode of
transmission; clinical and histopathological features and its treatment.
April 2014 exam

• Give a short account on: steroid pulse therapy.
• Compare between: linear IgA bullous dermatosis and bullous pemphigoid.
148
November 2013 exam

• What are the important nail changes in the following skin diseases?
o Epidermolysis bullosa dystrophica
April 2013 exam

• Basement membranes are specialized structures located between
different cell types. On this statement mention:
■ The functions of the basement membranes.
■ The representative ultra-structural sub-regions o f the BMZ.
• A 30 years old male patient complaining of malodourous skin lesions
with mild itching. The condition started 10 years ago without remission
and worsens in summer. On examination, the lesions are multiple
keratotic and crusted brownish papules and plaques favour seborrheic
areas involving the trunk, the face and the lateral aspects of the neck
with palmoplantar affection. Cobblestone papules on the palate are
present.
■ What is your provisional diagnosis and pathogenesis o f this condition?
■ What are the histopathological criteria?
■ What are the lines of treatment?
• Discuss the diagnostic criteria for: Epidermolysis bullosa acquisita (EBA).
November 2012 exam

• Compare: Pemphigus vulgaris vs. paraneoplastic pemphigus.
• IgA deposits can be seen in different sites of skin by direct
immunofluorescence in some skin diseases. What are these diseases? And
what are the sites of IgA deposition in each?
April 2012 exam

• Compare clinically and histologically between:
■ Darier’s disease vs. epidermodysplasia verruciformis.
• Mention the major diagnostic clinical criteria of the following:
■ Senear-Usher syndrome.
■ Epidermolysis bullosa acquisita.
• Pemphigus vulgaris is an immunobullous disease characterized by
mucosal and cutaneous lesions
■ Describe the structure o f desmosome.
■ What are the basic principles of desmoglein compensation theory?
■ Apply this theory to explain the pathogenesis o f cutaneous lesions in
muco-cutaneous pemphigus vulgaris.
■ What are the side effects of azathioprine?
November 2011 exam

• Mention the defect in the following diseases: Junctional epidermolysis
bullosa.
149
Bullous Diseases
• A 40 years old female presented with recurrent blistering eruption with

erosions affecting skin, eyes and oral mucosa. The lesions healed with
scar formation. The patient was suspected to have mucous membrane
pemphigoid.
■ How to confirm the diagnosis?
■ What is the aetiopathogenesis of this condition?
■ W hat’s the differential diagnosis?
■ What is the treatment o f this disease?
• Give the common nail finding in the following diseases: Darier’s disease
A p ril 2011 exam

• Dermatitis herpetiformis is a skin disorder associated with gluten-
sensitive enteropathy.
■ What is the aetiopathogenesis of this disorder?
■ Give the clinical picture and the differential diagnosis?
■ What are the treatment options of this condition?
• What are the most important nail changes in the following diseases:
■ Darier’s disease ■ Epidermolysis bullosa
dystrophica
N ovem ber 2010 exam
• Compare between the following diseases:
■ Bullous pemphigoid and epidermolysis bullosa acquisita
(B) A l-A zh a r U n iversity—D ip lo m a d eg ree (Dermatoiogy/Basic sciences)
A p ril 2017 exam

• Female patient 55 years old presented with erythema and crustations all
over the body with superficial bullae. The provisional diagnosis was
pemphigus foliaceus.
o How to confirm the diagnosis?
o What are the different types o f pemphigus?
o How can you manage this case and what is the prognosis?
A p ril 2015 exam

• Compare between the following in a table:
* Bullous pemphigoid and epidermolysis bullosa acquisita

• Define and give example for each of the following: acantholysis.
• Write the histopathology o f each of the following: pemphigus vulgaris.
• Discuss structure o f hemidesmosome with drawing.
A p ril 2014 exam

• Give short account on: basement membrane zone (structure &
histopathology).
150
• Pemphigus vulgaris is a serious acute or chronic bullous autoimmune

disease.
■ Describe the clinical picture.
■ Discuss the pre-treatment investigations.
■ Give short account on the treatment of newly diagnosed case.

• Enumerate the differential diagnosis o f the following diseases:
* Darier’s disease.
• Compare histopathological features of: pemphigus and bullous pemphigoid.
A p ril 2013 exam

• What is the systemic first line therapy (with reference to drug doses and
side effects) of the following? Dermatitis herpetiformis.
• Differentiate between intra-epidermal autoimmune bullous diseases as
regards histopathological and immunofluorescence findings.

• What are the therapies o f the following diseases with reference to drug
doses: Pemphigus vulgaris
• Compare between: Hailey-Hailey disease and pemphigus vegetans.
• Define and give one example for each of the following: acantholysis.
• A 20 years old man presented with yellow to brown dirty itchy greasy
hyperkeratotic papules behind ears of 3 years duration. The lesions are
associated with longitudinal bands and notching of free edge of nail
plate.
■ What is the most likely diagnosis?
■ Describe the histopathology picture?
■ What is the differential diagnosis o f this case?
A p ril 2012 exam

• A 24 years old woman presents with small intensely itchy blisters on
her elbows, extensor aspects of forearms, scalp and buttocks. Some of
the blisters are de-roofed and present as erosions. She has been treated
for chronic diarrhea.
■ What is your diagnosis?
■ How can you investigate this case?
■ How can you treat this condition?
• What is the first line therapy of each o f the following diseases (mention
doses and side effects)? Cicatricial pemphigoid.
• Compare between:
■ pemphigus vulgaris and bullous pemphigoid (clinical picture).
• Write the histopathological picture o f each of the following diseases:
Dermatitis herpetiformis.
151
Bullous Diseases

• A 35 years old male suffering from painful oral ulcerations for the last
3 months developed flaccid bullae containing clear fluid over the trunk
& proximal parts of his extremities one week age. The bullae developed
on both normal & erythematous skin. They rupture easily with painful
erosions.
■ What is the most likely probable diagnosis?
■ How can you confirm your diagnosis?
■ How can you manage this patient?
• Write the histopathological criteria of each of the following diseases:
■ Darier’s disease.
• What is the cause of bulla formation and site of clefts of each of the
following diseases?
■ Bullous pemphigoid
■ Pemphigus vulgaris
• How can you differentiate histologically between?
■ Hailey-Hailey disease and pemphigus vulgaris.

• Compare between: Pemphigus vulgaris and paraneoplastic pemphigus.
• What is the systemic first line therapy with reference to drug doses and side
effects of the following? Dermatitis herpetiformis.
• Describe the structure o f basement membrane zone with drawing.
• Levels o f blisters in mechanobullous diseases, with drawing.
A p ril 2008 exam

• Mention the site of clefts (bullae) in each of the following diseases?
■ Bullous pemphigoid.
■ Pemphigus vulgaris.
■ Dermatitis herpetiformis.
(C) Banha University-Master and Diploma degrees

M ay 2014 exam
• Give an account about the clinical and histopathological features of
pemphigus vulgaris.

• Give an account on Darier’s disease.
• Give a short account on pulse intravenous steroid administration.
M ay 2012 exam
• Discuss immunopathology of immunobullous diseases.
M ay 2010 exam
• Discuss the demro-epidermal junction and related diseases.
152
• Give an account about bullous pemphigoid: pathology, clinical features and

treatment.
May 2010 exam

• Differentiate between intra-epidermal autoimmune bullous diseases as
regards histopathological and immunofluorescence findings.
• What is the systemic first line therapy of choice (with reference to drug
doses and side effects) in the following conditions? Dermatitis
herpetiformis.
• Define the following terms and mention two diseases in which each occurs:
Niklosky sign.
November 2009 exam

• As regards vesiculo-bullous disorders.
■ Discuss with illustration the microstructure o f the epidermal basement
membrane zone (BMZ).
■ Specify the types of epidermolysis bullosa and discuss epidermolysis
bullosa dystrophica as regards aetilogy, clinical picture and therapy.
May 2009 exam

• Give an account on the pathogenesis, clinical types, clinical and
pathological differential diagnosis, investigations and treatment o f a case of
bullous pemphigoid.
November 2008
• A 31 years old female patient presented with an itchy papulo-vesicular
eruption on the extensor surfaces of her upper limbs and scalp.
Microscopic picture of a skin biopsy showed sub-epidermal vesicle with
neutrophilic infiltration of the dermal papillary tips.
■ What is the suggested diagnosis?
■ What are the expected immuno-fluorescence findings? Discuss how they
can differentiate the condition from other immunobullous dermatoses.
May 2008 exam

• Give an account on aetiology, clinical picture, histopathology, differential
diagnosis, investigations and treatment o f Darier’s disease.
May 2007 exam

• Describe the immuno-fluorescence findings (direct and indirect) in
autoimmune vesiculo-bullous diseases.
November 2006 exam
• Describe the etiopathogenesis and clinical picture of all varieties of type VII
collagen related epidermolysis bullosa.
• Discuss etiopathogenesis, clinical picture, diagnosis and treatment of
paraneoplastic pemphigus.
153
Bullous Diseases
M ay 2006 exam
• What is acantholytic dyskeratosis? Mention two diseases in which this
phenomenon occurs and their histopathological differentiating points.
(E) Menoufia University-Master and Diploma degrees

O ctober 2016 exam
• Discuss blistering diseases of the basement membrane zone and dermis.
(F) Suez canal University-Master and Diploma degrees

O ctober 2016 exam
• Give an account on the following: dermatitis herpetiformis.
154
/
Series
L ecture Notes for P o stg rad u ate

D erm atology S tudents
S A step-by-step guide through

basic and clinical dermatology
S Reader-friendly text format
S High-quality images and
illustrations
S Reference to latest updates in
dermatology
S At-a-glance chapter summaries
S Tips for board and fellowship
exams
S MCQs and short-essay questions
for self-assessment

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Understanding

Autoim m une an d Inherited

Board and Fellowship Review

First edition © 2015

978 - 977 - 90 - 4807 - 9 :

Aim of “U nderstanding D e rm atology” series

Despite the broad scope of dennatology, undergraduate medical students

“Understanding dermatology” series aims at “bridging” this gap by

Features of “Understanding D e rm atology” series

In order to achieve its main aim, “Understanding Dermatology ” series has

Moreover, ‘‘Understanding Dermatology'” series is intended mainly for

Clinical # Helpful tips

• MD dermatology, venereology and andology (2014) - Al-Azhar University.

Chapter 17 Darier Disease 98

W here in the skin m ay blisters o c cu r?

Fig 0.2 Levels of blisters in the

• In the epidermis, keratinocytes are held together by structures

M ec h an ism s a n d c a u s e s of skin blistering

1) Immunological (antibody- mediated):

• Autoimmune blistering diseases (i.e. pemphigus and

a) Genetic: due to inherited defects in the synthesis and / or modification

• NOT all bullous diseases are immunobullous (i.e. pemphigus

Table 0.1 A u to im m u n e and genetic Level of blister

Diagnosis of a uto im m une, g e n e tic and

• In pemphigus, blisters are flaccid (because they are relatively

■ Mucosa: oral, conjunctival, nasal, genital etc (predominant mucosal

• Ruptured blisters or excoriated lesions are of little value and

• Diagnostic clues in a histopathology specimen o f a bullous lesion include:

Intra-epidermal blisters (i.e. pemphigus) are further subdivided into

2. the mechanism o f blister formation e.g. acantholysis —>pemphigus.

(a) (b) (c)

» Types: there are 2 main Pathogenic autoantibodies

IF is positive only in autoimmune bullous diseases. It is

« Findings o f IF test in autoimmune buttons diseases'

Substrates for IIF staining:

Enzyme-linked immunosorbent assay (ELISA)

The most important and routinely employed investigations are:

Immunoblotting and immunoprecipitation:

2. Immunoprecipitation: The patient serum is incubated with

• Desmosomes are cell-cell junctions on the keratinocyte cell

Table 1.1 Members of the pemphigus family

The classification scheme of pemphigus adopted in table 1.1

1. Subtypes and/or variants of this type (if present),

In pemphigus, histopathology reveals

UpicTul * Pemphigus, IF shows intercellular IgG autoantibodies (IgA

7. Other investigations e.g. ELISA.

0 Pemphigus refers to a group of chronic autoimmune blistering diseases

P athogenesis (ta rg e t p ro te in in the desm osom e)

Distribution of Dsg 1 and Dsg3 in the skin and mucous membranes

(a) In the skin:

(b) In the mucosa:

Desmoglein compensation theory

Application of desmoglein compensation theory in determining the

In pemphigus vulgaris, theoretically, the whole thickness of

Mucous membrane lesions: (Fig 2.2)

Skin lesions: (Fig 2.3)

Special diagnostic signs:

• In most types of pemphigus, the inflammatory infiltrate is

IgG deposition is seen in up to 100% of patients with active

In IF of pemphigus, unlike IgG, complement (C3) deposition is

Methods for detection o f autoantibodies in pemphigus:

• The differential diagnosis of mucosal (oral) lesions in

B. The differential diagnosis of cutaneous lesions: