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Um1pq Recent Advances in Dermatology Volume 1
Um1pq Recent Advances in Dermatology Volume 1
DERMATOLOGY
Disclaimer
As medicine is an everyday-changing science with newer researches
and refined clinical experiences, and, also in view of the possibility
of human error, neither the editors nor the authors nor the publisher
warrant that the information contained in the book is in every
respect accurate or complete, and they disclaim all responsibility
for any errors or omissions or for the results obtained from use of
the information presented in this work.
Recent Advances in
DERMATOLOGY
Editor-in-Chief
Sanjay Ghosh
Consultant Dermatologist
AMRI-Apollo Hospital
Kolkata
Associate Editors
Dinesh Hawelia
Consultant Dermatologist
Suraksha Hospital
Kolkata
Susmit Haldar
Consultant Dermatologist
Calcutta Skin Institute
Kolkata
JAYPEE BROTHERS
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Recent Advances in Dermatology
2004, Sanjay Ghosh
All rights reserved. No part of this publication should be reproduced, stored in a
retrieval system, or transmitted in any form or by any means: electronic,
mechanical, photocopying, recording, or otherwise, without the prior written
permission of the Editor-in-Chief and the publisher.
This book has been published in good faith that the material provided by
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but the publisher, printer and Editor-in-Chief will not be held responsible for
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settled under Delhi jurisdiction only.
First Edition : 2004
ISBN 81-8061-306-2
Typeset at JPBMP typesetting unit
Printed at Gopsons Papers Ltd., A-14, Sector 60, Noida
To
all the past dermatologists of India,
whose footprints are showing
path in our derma-trek
Contributors
A.K. Bajaj
Formerly Professor and Head
Dept. of Dermatology and STD
MLN Medical College
Allahabad
Anil H. Patki
Consultant Dermatologist
Skin Clinic, Runwal Plaza
41/12, Karve Road
Pune
A. Vilas
Consultant Dermatologist
Hyderabad
Belinda Vaz
Consultant Dermatologist
42A, Luis Apartments
College Street, Dadar
Mumbai
Debabrata Bandyopadhyay
Associate Professor and Head
Dept. of Dermatology
STD and Leprosy
RG Kar Medical College
Kolkata
Deepa Sachdev
Lecturer
Dept. of Dermatology
KEM Hospital and
Seth GS Medical College
Mumbai
Devinder Mohan Thappa
Professor and Head
Dept. of Dermatology and STD
JIPMER
Pondicherry
Dinesh Hawelia
Consultant Dermatologist
Suraksha Hospital
Kolkata
Jayakar Thomas
Senior Consultant Dermatologist
Kanchi Kamakoti
CHILDS Trust Hospitals
Chennai and
Apollo Hospitals, Chennai
Formerly Professor and Head
Dept. of Dermatology
Thanjavur Medical College
Thanjavur
Kaushik Nandy
Consultant Plastic,
Reconstructive and Esthetic
Surgeon
AMRI-Apollo Hospital
Kolkata
K.K. Raja Babu
Consultant Dermatologist
A-62, Road No.12
Film Nagar, Jubilee Hills
Hyderabad
M. Ramam
Additional Professor
Dept. of Dermatology and
Venereology
All India Institute of Medical
Sciences, New Delhi
Nilay Kanti Das
Postgraduate Trainee
(Dermatology), Dept. of
Dermatology,
IPGME & R, Kolkata
viii
Sanjay Ghosh
Consultant Dermatologist
AMRI-Apollo Hospital
27/2C Bakultala Lane
Kasba
Kolkata
Sujit Ranjan Sengupta
Professor
Dept. of Dermatology
IPGME & R
Kolkata
Susmit Haldar
Consultant Dermatologist
Calcutta Skin Institute
169 VI M CIT Scheme
Kolkata
Uday Khopkar
Professor and Head
Dept. of Dermatology
KEM Hospital
and Seth GS Medical College
Mumbai
Foreword
The science of dermatology is rapidly advancing and it is essential for
every practitioner to keep abreast of the latest advances in the subject.
With the advent of Information Technology, medical information is
rapidly dissipated with just the click of a button. However, with volumes
of information that is available, one has to weed out well-researched
information and the practicability of this information in everyday
practice. It is very difficult for a busy practitioner to scan through and
refer to the enormous amount of literature that is available. With this in
mind, the editors have computed advances in various aspects of
dermatology that have been authored by well-known dermatologists in
the field. This update discusses many subjects of current interests.
Narrowband UV-B light is a new modality for treating vitiligo. It is
gaining popularity as this is safe and does not require any systemic
medication. These aspects have made this form of therapy as a treatment
of choice for children in vitiligo.
Computers and digital photography are absolute Must know for
all dermatologists. The Internet is a goldmine of information waiting to
be tapped, and also a means of sharing information as computers connect
you easily and fast to your areas of interest. Digital photography as well
facilitates pictorial record of interesting cases and of the effect of therapy.
The update also includes subjects of contemporary interest as
apoptosis and cell markers in dermatology. Scleroderma and
leukocytoclastic vasculitis have always been enigmatic problems that
have been aptly updated.
Other subjects of interest are emergencies in pediatric dermatology,
recently introduced systemic and topical drugs in dermatology as well
as drug eruptions to new systemic agents.
This book of recent updates in dermatology covers a wide variety of
topics and would be of immense interest and utility to the consultant
dermatologist in practice as well as students of dermatology.
Dr. Rui Fernandez
Preface
Who can utter the last words of one which has no end?
Rabindranath Tagore
I felt somewhat hesitant to accept the proposal given by Jaypee Brothers,
the reputed medical publisher of New Delhi to become the Editor-inChief of such a volume under the title Recent Advances in Dermatology.
The underlying reason was nothing but that it seemed to me a very
difficult task to get writings from the busy dermatologists, who can
perform this only by stealing time from their hectic academic, hospital
or practising schedules. However, later, my fear-complex got completely
erased when I received prompt response from most of them whom we
approached, including some of the senior and eminent dermatologists
of the country. I hereby convey my deepest regards to all the authors
and co-authors for their sincere co-operation with this project.
This book was designed as an academic project with the target readers
as both postgraduate students and practising dermatologists; we,
therefore, desired that the chapters would encompass glimpses of existing
knowledge in the light of recent advances in the field. So, we invited
articles from dermatologists staying at different parts of the country,
both seniors for their retrospective analysis with vast experience and
comparatively younger for their enthusiastic and prospective views on
the subjects. I sincerely apologize to those numerous academic
dermatologists of the country who could be the eligible contributory
authors of this collection but have not been included due to the dearth
of space. However, we firmly believe that we would be able to include
them in rotation in the subsequent editions of this title.
I also acknowledge my heartfelt respect to Dr. R. Fernandez and
Dr. B. Haldar as they kindly agreed to write the Foreword and
Introduction respectively for this volume.
I must thank and pay regards especially to Mr Tarun Duneja, General
Manager (Publishing), Jaypee Brothers for his constant help and cooperation in this project. At the same time, I give my personal thanks
and regards to all the staff of Jaypee Brothers, both New Delhi and
Kolkata Branch. My offer of earnest regards should not have an end
without giving this to Mr. Subhrajyoti Bose, who on behalf of me, has
taken the burden of painstaking job of DTP and all other computer
works of this issue. Last but not the least, no language can express my
gratefulness to my associate editors who have walked beside me
constantly from the beginning to the end of the present journey.
Sanjay Ghosh
Contents
1. Apoptosis : Its Role in Different Dermatoses
Anil H. Patki
24
31
56
88
115
136
147
171
180
204
234
242
255
B Haldar
Introduction
Clinical Dermatology:
Its Past, Present and Future
Diagnosis and treatment for the community are the two watch-words of
every branch of medicine, be it dermatology or any other speciality.
Admittedly, there has been a phenomenal development in medicine
over the past two decades or so. Even though we can now comprehend
many skin disorders at a molecular level and have advanced our
therapeutic realm to include laser technology and immunobiology, the
cornerstone of all dermatological endeavours will always be a careful
clinical observation.1 While for professional safeguard evidence-based
medicine has been a crying need of the day, the importance of clinical
dermatology can neither be underestimated nor ignored. If we look at
the history of growth and development of medicine in totality, along
with the benefits the community had obtained thereby, the role played
by clinical medicine had been of vital importance. It would indeed
constitute a great danger to the wider community if evidence-based
diagnosis outweighs the clinical one where the diagnosis is written
large on the face. One should not forget that the base of diagnosis is
essentially clinical and that it is the clinical findings that dictate the
necessary tests to confirm or reject the diagnosis.
There is also another aspect that cannot be dispensed with outright.
Community is a complex structure, the complexity varying from country
to countryover-rich, rich and utterly poverty-stricken; over-developed,
developed and under-developed. High-skilled investigative facilities are
neither uniformly available everywhere nor every community can afford
to bear the cost thereof. These are naked truths that can hardly be
brushed aside. Cost-benefit analysis is, therefore, equally pertinent.
Some instances may enlighten the matter. For treating scabies, the
demonstration of Sarcoptes scabiei or eggs from the burrows is seldom,
if at all, done in India in spite of the fact that it is considered as a
xvi
Introduction xvii
Recent Advances in
DERMATOLOGY
JAYPEE BROTHERS
MEDICAL PUBLISHERS (P) LTD
EMCA House, 23/23B Ansari Road, Daryaganj
New Delhi 110 002, India
Anil H. Patki
MORPHOLOGY OF APOPTOSIS
As opposed to necrosis, where the cell swells up and lyses, apoptosis
involves reduction in volume, blebbing of the cell membrane and the
margination of chromatin along the nuclear membrane.2 This is followed
by the collapse of the nucleus into apoptotic bodies surrounded by a
membrane. The cytoplasmic organelles are much less affected during
this process. An important difference between necrosis and apoptosis is
that apoptotic cells do not invoke any inflammatory reaction unlike the
necrotic cells which release chemotactic cell contents. The apoptotic bodies
consist of membrane bound fragments of nucleus and cell organelles.
They are phagocytosed by surrounding cells or macrophages. In case of
tubular organs, the apoptotic bodies are released in the lumina. Thus,
apoptosis is a special type of programmed cell death which can occur
in health or disease. The death of keratinocytes in the stratum corneum
is also an example of programmed cell death which is slightly different
from apoptosis and is termed differentiation to death.1
PATHOMECHANISMS OF APOPTOSIS
To die actively, a cell must receive some message to initiate the process.
This message or death signal is received by some transmembrane proteins
of the TNF (Tumor necrosis factor) family of the receptors called the
death receptors. Each death receptor has two or four cysteine-rich
extracellular domains and a cytoplasmic sequence termed death domain.
Six human death receptors have been identified along with their respective ligands which bring the death signal (Table 1.1).7 When a death
ligand combines with a death receptor, a signal is transmitted in the
cytoplasm to a system of enzymes called caspases. Initially, caspase 8
and 10, which are initiator caspases, are activated and later, akin to the
complement cascade, the effector caspases viz., caspases 3,6, and 7 are
activated. The caspases in turn activate a variety of endonucleases and
proteases which cause breakdown of cellular contents and ultimately
apoptosis.
Besides the death receptor pathway, there is another pathway inducing
apoptosis can be: mitochondrial pathway.8 Triggered by factors like
radiation, withdrawal of growth factors and cytotoxic drugs, release of
cytochrome C from the mitochondria activates caspase 9 with further
activation of downstream caspases and finally leads to apoptosis.
Thus, apoptosis is a process by which a cell dies through activating
its own system of serine proteases and endonucleases which breakdown
cellular contents. The nuclear DNA is broken down into various
fragments. This phenomenon is useful in the detection of apoptosis, as
agarose gel electrophoresis reveals a ladder pattern as different DNA
fragments move at different rates.
Death ligands
TRAIL
?
CONCLUSIONS
In conclusion, apoptosis is an important phenomenon both in health and
disease. Excessive and abnormal apoptosis is a feature of disorders like
TEN and LTR while defective apoptosis is a feature of conditions like
malignancies and autoimmune disorders. Since its description more than
30 years ago, apoptosis has, during the last few years, become one of the
hottest topics in biomedical research.
REFERENCES
1. Bowen ID, Bowen SM, Jones AH. Matters of life and death. In: Mitosis and
Apoptosis. London: Chapman and Hall, 1998; 1-16.
2. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon
with wide ranging implications in tissue kinetics. Br J Cancer 1972; 26: 23957.
3. Bowen ID, Bowen SM, Jones AH. The structural and physiological basis of
apoptosis and mitosis. In: Mitosis and Apoptosis. London: Chapman and Hall,
1998; 17-27.
4. Gibson RM. Does apoptosis have a role in neurodegeneration? Br Med J 2001;
322: 1539-40.
5. Barinaga M. Is apoptosis key in Alzheimers disease ? Science 1998; 281: 130912.
6. Patki AH, Lederman MM. HIV-I Tat protein and its inhibitor Ro 24-7429
inhibit lymphocyte proliferation and induce apoptosis in peripheral blood
mononuclear cells from healthy donors. Cell Immunol 1996; 169: 40-6.
7. Wehrli P, Viard I, Bullani R, et al. Death receptors in cutaneous biology and
disease. J Invest Dermatol 2000; 115: 141-8.
8. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309-12.
9. Ko LJ, Prives C. P 53: Puzzle and paradigm. Genes Dev 1996; 10: 1054-1572.
10. Wang HG, Reed JC. Mechanism of Bcl-2 protein function. Histol Histopathol
1998; 13: 521-30.
11. Wolff K, Kiffi AG, Mihm MC. Basic pathological reactions of the skin. In:
Fitzpatrick TB, Eisen AZ, Wolff K, et al (Eds) Dermatology in General Medicine.
4th ed. New York: Mc Graw Hill Inc., 1993: 66-84.
12. Bertolino AP, Klein LM, Freedberg IM: Biology of hair follicles. In: Fitzpatrick
TB, Eisen AZ, Wolff K, et al (Eds) Dermatology in General Medicine. 4th ed.
New York: Mc Graw Hill Inc., 1993: 289-93.
13. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mechanism of keratinocyte
death in toxic epidermal necrolysis. Br J Dermatol 1996; 134: 710-14.
14. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by
blockade of CD 95 with human intravenous immunoglobulin. Science 1998;
282: 490-3.
15. Stella M, Cassano P, Bollero D, et al. Toxic epidermal necrolysis treated with
intravenous high-dose immunoglobulin: Our experience. Dermatol 2001; 203:
45-9.
16. Shiohara T, Moriya N, Nagashima M. The lichenoid tissue reaction. Int J
Dermatol 1998; 27: 365-74.
10
markers for which the antibodies are specific, the antibodies will bind
to the cells. These antibodies bound to the cells are then detected by one
of the following ways:
Immunofluorescence
The tissue section when examined under a fluorescent microscope reveals
the cell-bound antibodies as glowing areas.
Flow Cytometry
In a flow cytometer, the cells in suspended liquid are exposed to a beam
of laser light. If the specific antibodies are bound to their surface, they
will fluoresce and the cytometer will record the signal.
Immunohistochemistry
It is a procedure that enables the identification of cells in a tissue section
by means of antibodies that have attached enzymes. Immunoperoxidase
techniques are widely used, e.g. peroxidase enzyme in peroxidase antiperoxidase, i.e. PAP technique. On exposure of tissue to chromogenic
substrate, the enzyme on the bound antibody will cause the substrate
to change color and precipitate on the cells.
WHAT ARE THE COMMON MARKERS USED IN DERMATOLOGY?
The cell markers are needed in dermatopathology mainly to pinpoint
the diagnosis in an undifferentiated or poorly differentiated neoplasm,
to confirm the diagnosis of an amelanotic melanoma, and for classifying
lymphoproliferative disorders. Some of the commonly used cell markers
in dermatology are listed in Table 2.1.
Antibodies against Cytoskeletal Antigens
The cell cytoskeleton consists of microfilaments, intermediate filaments
and microtubules. Antibodies directed against cytofilaments help to
identify the differentiation of neoplastic cells. It has been found that
primary and secondary malignant tumors retain the intermediate
filament-type characteristic of the cell towards which they differentiate.2
There are five types of intermediate filaments:
i. Cytokeratinscharacteristic for true epithelia
ii. Vimentinfound in mesenchymal cells and melanocytes
iii. Desminfound in muscle cells
11
Normal tissue
Tumors
Cytokeratins*
Epidermal and
appendageal tumors
Sarcomas, lymphomas
and melanomas
Muscle tumors
Neuroectodermal and
neuroendocrine tumors
Rhabdomyosarcomas,
leiomyosarcomas
Rhabdomyomas,
rhabdomyosarcomas
Epithelial tumors,
some mesenchymal
tumors
Melanomas,
liposarcomas,
histiocytosis X
Melanomas, junctional
nevi, dysplastic nevi
Paget cells, tumors of
eccrine and apocrine
glands
Hematopoietic tumors
Vimentin*
Desmin*
NSE
Actin*
Myoglobin
EMA
S-100 protein*
HMB-45
CEA
LCA*
Histiocytes, lymphocytes,
granulocytes
Histiocytes
1-antitrypsin,
1-antichymotrypsin
Factor VIII-related
antigen (FVIII-RA)*
Endothelium
Ulex europaeus
Endothelial cells, keratinocytes
Agglutinin-1 (UEA-1)
Fibrohistiocytic
neoplasms
Endothelial-derived
tumors, e.g.
angiosarcomas
Angiosarcomas,
Kaposis sarcoma
12
13
14
Diagnosis
Lymphoma
Merkel cell carcinoma
Melanoma
Carcinoma
Keratin
LCA
S100
Synaptophysin
+
+/
Keratin
Vimentin
Desmin
S-100
15
S-100
CD-1a
KP 1
MAC 387
LCH
CSHRH
ICH
XD
JXG
VX
+
+
+
+
+
+
+
+
+
* Abbreviations- LCH: Langerhans cell histiocytosis; CSHRH: Congenital selfhealing reticulohistiocytosis; ICH: Indeterminate cell histiocytosis; XD: Xanthoma
disseminatum; JXG: Juvenile xanthogranuloma; VX: Verruciform xanthoma
This modified table is adapted from Levers Histopathology of Skin
16
Langerhans cells stain positive also with CD45, S100 and are negative
for HMB-45.
Classification of Vascular Neoplasms
Classifying vascular tumors is of prognostic significance, as several low
grade variants of angiosarcoma have a distinctly different prognosis as
compared to classical angiosarcoma. The various markers used for
vascular tumors include Factor VIII related antigen (FVIII-RA), Ulex
europaeus agglutinin-1 (UEA-1), CD31 and CD34. Individual vascular
proliferations have specific pattern of positivity.
i. Granuloma pyogenicum shows positive staining of the endothelial
cells for FVIII-RA, UEA-1 and Vimentin.
ii. Reactive angioendotheliomatosis differs from malignant
angioendotheliomatosis by its universal reactivity for endothelial
markers and negativity for LCA, proving that the proliferating
cells are endothelial cells.
iii. Kaposis sarcoma has spindle cells that are of endothelial origin
labeling positive with newer endothelial cell markers CD31 and
CD34.19,20
iv. Angiosarcomas are usually negative for FVIII-RA. UEA-1 is often
positive but has a very low specificity. The newer markers CD31
and CD34 are more sensitive and specific for endothelial cells.
v. Tumors of lymphatic vessels (lymphangiomas) are for the most
part negative for FVIII-RA. This is in contrast to UEA-1, which is
positive in endothelial cells of both hemangiomas and lymphangiomas.
vi. Glomus tumor cells stain positive for smooth muscle actin, musclespecific actin, and myosin. Staining for desmin is only focally
positive.
Diagnosing and Classifying Lymphomas
Leucocyte Common Antigen (LCA, CD45)
LCA, also known as CD45, is expressed on all leucocytes, lymphocytes,
monocytes, macrophages, mast cells, and Langerhans cells. Lymphocytes
and neoplastic cells derived from lymphocytes stain with greatest
intensity. Reactivity of macrophages, granulocytes, and plasma cells is
variable. It helps to differentiate lymphoreticular malignancies from
undifferentiated carcinomas, melanomas and sarcomas.21
17
T Cell Lymphomas
Although T and B lymphocytes are indistinguishable by light microscopy,
T cells can be detected by a series of monoclonal antibodies against
various T cell antigens. The diagnosis of T-cell lymphoma is based on:
Histological features, e.g. epidermotropism.
Pan T cell markers: CD2, CD3, CD5 and CD7 are present on almost
all the T cells.
Gene rearrangement studies: Use of PCR to look for a unique, clonal
rearrangement of T cell receptor gene.
In most of the peripheral T cell lymphomas, it has been observed that
one or more T cell antigens may be aberrantly clonally deleted. CD7 is
often found to be negative. Also some lymphomas can express unnatural
combination of antigens, such as co-expression of CD4 and CD8, or
expression of neither.
T Cell Pseudolymphoma/Lymphocytoma Cutis
This presents clinically as nodules or plaques and histologically as band
like or nodular infiltrates. The cells show convoluted nuclei with
immunophenotypic pattern similar to mycosis fungoides, i.e. CD3, CD4
and CD45RO positivity.22
Pagetoid Reticulosis
It is an indolent form of T cell lymphoma. The localized variant (known
as Woringer-Kolopp disease) is clinically characterized by verrucous
scaly plaques on the acral region. The disseminated form (also known
as Ketron-Goodman variant) clinically resembles with the patch or plaque
stage of mycosis fungoides.23 CD4 positivity is common, while CD7 is
mostly absent or diminished. Besides, there is a lack of expression of
CD45 and CD45RO.
Granulomatous Slack Skin
This rare form of T cell lymphoma, in the early stages, resembles clinically
and histologically with the patch stage of mycosis fungoides. However,
with evolution, the affected skin becomes lax, clinically presenting as
patches resembling anetoderma or plaques with loose hanging skin
involving the axillae or groins. Histopathology shows a granuloma with
numerous giant cells in the dermis. The neoplastic cells are positive for
CD3 and CD4 markers, while they are negative for CD7.24
18
Lymphomatoid Papulosis
This is clinically characterized by papules that evolve into papulovesicular, papulopustular, hemorrhagic or necrotic papules. It is associated
with lymphoma in about 10-20 percent cases. The associated lymphoma
is most commonly mycosis fungoides (40%), a CD30-positive T-cell
lymphoma (30%) or Hodgkins disease (25%). Lymphomatoid papulosis
shows two types of histopathology and the atypical lymphocytes stain
for the activation marker ki-1 or CD30.25
Anaplastic Large Cell Lymphoma (ALCL)
These were once called Ki-1 lymphomas after antibody to CD30. CD30
antigen is a lymphocyte activation marker that can be identified on
either B or T cells. CD30 positivity is seen in LyP, regressing atypical
histiocytosis and ALCL. ALCL clinically presents as cutaneous nodules,
ulcerated or crusted tumors on the extremities. Primary cutaneous ALCLs
are positive for CD30 antigen and other T cell markers. Systemic ALCLs
are often reactive for EMA. Some ALCLs are non-reactive for LCA or Tlineage markers. Cases that lack lymphoid lineage markers are called
null-cell type. CD30 positive ALCL is reported to be the most common
cutaneous lymphoma in HIV patients.26-27 Rarely, ALCLs may be positive
for keratin, which can lead to misdiagnosis of carcinoma.
Angiocentric Lymphomas
These commonly present as subcutaneous or dermal nodules or ulcerated
tumors. The tumor cells can be of T cell or NK-cell lineage. Those of T
cell lineage often show aberrant T cell phenotypes with loss of CD3,
CD5 and CD7 antigens. Those of NK-cell lineage express CD16 and
CD56 antigen.
Mycosis Fungoides
Cell markers are important to diagnose mycosis fungoides in the patch
stage. Immunophenotyping is invaluable in these cases to prove or
support the diagnosis. The cells are positive for CD2, CD3, CD4 and
sometimes CD8.23 When CD4 and CD8 are simultaneously expressed
by the T cells, it indicates a neoplastic infiltrate. Recently gene
rearrangement studies28,29 have shown that all mycosis fungoides lesions
including early macules are produced by single clones of neoplastic
T cells. The immunophenotypic profile of T cell and NK-cell neoplasms
is summarized in Table 2.5.30
19
Positive markers on
neoplastic cells
Expected negative
T markers helping the
diagnosis
1- CD56
2- CD3
CD7
Mycosis fungoides
1-CD3, CD30,
2-CD3
EMA (T cell)
2-CD30, EMA (Null cell)
B Cell Lymphomas
The diagnosis of a lymphoid tumor of B cells is made on the basis of:
1. Presence of surface immunoglobulin specific for B cells. The
demonstration of J-chain establishes the B cell nature of any given
cell population, whether benign or malignant.
2. CD19, which is both sensitive and specific for B cells
3. Rearranged immunoglobulin genes
Most B cell lymphomas express the pan-B cell antigens: CD19, CD20
and CD22. However, as the B cells mature into plasma cells, they tend
to lose their markers. Hence, multiple myeloma cells are negative for
these antigens.
Hodgkins Lymphoma (HL)
Skin involvement by Hodgkins lymphoma clinically presents as papules,
plaques or nodules and signifies a poor prognosis.31 Reed-Sternberg
cells are mostly CD30-positive. CD15 is also positive in Hodgkins disease
except in nodular lymphocyte-predominant variety.32 Gene rearrangement studies are helpful to differentiate HL from CD30+ cutaneous
lymphoproliferative disorders though these conditions can coexist.33
Non-Hodgkins Lymphoma (NHL)
Differentiating reactive lymphoreticular hyperplasia from malignant
lymphoma is a common diagnostic dilemma for pathologists. In such
20
Lymphoma type
Lymphocytic predominance HL
Classical HL
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte depleted
This modified table is adapted from http:/ www.thd.org.tr/ sub/ eng/ lymphoid.php
situations, monoclonal staining for light chain or heavy chain immunoglobulin constitutes a firm indication of the neoplastic nature of the
lesion, while a polyclonal reaction for two or more classes of immunoglobulins indicates a non-neoplastic process. The most practical approach
to the demonstration of monoclonal lymphoid cells is to perform staining
for kappa and lambda light chains. In case of well-differentiated
lymphomas that are associated with monoclonal gammopathy
(Waldenstrms macroglobulinemia), the cytoplasmic immunoglobulin
of plasmacytoid lymphocytes can be readily demonstrated. The detailed
cell marker profile in HL and NHL is discussed in Table 2.6.30
Large cell lymphoma (immunoblastic sarcoma) has been shown to
arise from immunoblastic lymphadenopathy and has predominantly
biclonal staining for kappa and lambda light chains.
Diagnosing and Classifying Leukemias
Leukemia Cutis
The identification of leukemic infiltrate is based on the histochemical
and immunophenotypic studies. No single reagent is sensitive or specific.
Therefore, it has been recommended to use a panel of at least 3 antisera.
CD45, CD45RO, CD3, CD20, CD43, CD68, lysozyme, chloroacetate
esterase are the commonly used markers.34 CD99 is another sensitive
but non-specific marker useful in acute myelogenous leukemia.35Positive
staining for immunoglobulin establishes the lymphoreticular nature of
the neoplasm.
21
Carcinoma vs lymphoma
Melanoma vs carcinoma
Sarcoma vs carcinoma
SUMMARY
The cytologic diagnosis of malignancy is primarily based on the histologic
findings, in conjunction with patients history and clinical examination.
In situations, where the histopathological features are inconclusive, the
use of cell marker studies can help to achieve a definitive diagnosis.
However, it is essential to select the appropriate panel of antibodies.
Selection of an appropriate cell marker as an aid in the diagnosis of a
tumor of uncertain histogenesis depends on various factors, such as the
patients clinical presentation, laboratory and radiographic findings, the
histologic features of the tumor, the skill and experience of the examining
pathologist, the differential diagnosis entertained and the availability of
specific markers. Recently with the availability and application of PCR
technique to the analysis of immunoglobulin and T cell receptor gene
rearrangements, it is possible to arrive at an accurate diagnosis and also
detect minimal residual disease in hematologic malignancies.36
In conclusion, immunocytochemistry is gradually gaining wider
recognition for its role in solving certain diagnostic dilemmas (discussed
in Table 2.7) as well as to decide prognosis and therapy especially for
lymphoreticular malignancies.
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1. Margaret B Listrom, Cecilia M Fenoglio-Preiser. Immunocytochemistry in tumor
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bases. 4th ed. Philadelphia: J.B.lippincott company, 1992:1532-71.
2. Osborn M. Component of the cellular cytoskeleton: A new generation of markers
of histogenetic origin. J Invest Dermatol 1984; 82: 443.
3. Frank WW, Schiller DL, Moll R, et al. Diversity of cytokeratins. Differentiation
specific expression of cytokeratin polypeptides in epithelial cells and tissues.
J Mol Biol 1981; 153:933-59.
4. Sun TT, Eichner R, Nelson WG, et al. Keratin classes:Molecular markers for
different types of epithelial differentiation. J Invest Dermatol 1983; 81 (suppl):
109-15.
22
5. Rosalie E, Patricia Van Belle, David E. Laboratory methods. In: David E, Rosalie
E, Christine J, et al. (Eds). Levers Histopathology of the Skin. 8th ed.
Philadelphia: Lippincott-Raven: 1997: 51-60.
6. Leader M, Collins M, Patel J, et al. Vimentin: An evaluation of its role as a
tumor marker. Histopathology 1987; 11: 63-72.
7. Denk H, Krepler R, Artlieb U, et al. Proteins of intermediate filaments. An
immunochemical and biochemical approach to the classification of soft tissue
tumors. Am J Pathol 1983; 110: 193-208.
8. Heyderman E, Steele K, Ormerod MG. A new antigen on the epithelial
membrane: Its localization in normal and neoplastic tissue. J Clin Pathol 1979;
32: 35-9.
9. Pinkus GS, Kurtin PJ. Epithelial membrane antigena diagnostic discriminant
in surgical pathology: Immunohistochemical profile in epithelial, mesenchymal
and hematopoietic neoplasms using paraffin sections and monoclonal
antibodies. Hum Pathol 1985; 16:929-40.
10. Nadji M, Morales AR, Girtanner RE, et al. Pagets disease of skin. A unifying
concept of histogenesis. Cancer 1982; 50: 2203-6.
11. Lloyd RV, Cano M, Rosa P, et al. Distribution of chromogranin A and
Chromogranin I (chromogranin B) in neuroendocrine cells and tumors. Am J
Pathol 1988; 130: 296.
12. Kahn HJ, Baumal R, Marks A. The value of immunohistochemical studies
using antibody to S-100 protein in dermatopathology.Int J Dermatol 1984; 23:
38-44.
13. Nakajima T, Watanabe S, Sato Y, et al. An immunoperoxidase study of S-100
protein distribution in normal and neoplastic tissues. Am J Surg Pathol 1982;
6: 715-27.
14. Kahn HJ, Marks A, Thom H, et al. Role of antibody to S 100 protein in
diagnostic pathology. Am J Clin Pathol 1983; 79: 341-7.
15. Wick MR, Swanson PE, Rocamora A. Recognition of malignant melanoma by
monoclonal antibody HMB-45. An immunohistochemical study of 200 paraffinembedded cutaneous tumors. J Cut Pathol 1988; 15: 201-7.
16. OReilly FM, Brat DJ, McAlpine BE, et al. Microphthalmia transcription factor
immunohistochemistry: a useful diagnostic marker in the diagnosis and
detection of cutaneous melanoma, sentinel lymph node metastases, and
extracutaneous melanocytic neoplasms. J Am Acad Dermatol 2001; 9: 29-34.
17. King R, Weilbaecher KN, McGill G, et al. Microphthalmia transcription factor:
a sensitive and specific melanocyte marker for melanoma diagnosis. Am J
Pathol 1999;155: 731-8.
18. Burgdorf WHC. The Histiocytoses. In: David E, Rosalie E, Christine J, et al.
(Eds). Levers Histopathology of the Skin. 8th ed. Philadelphia: LippincottRaven: 1997: 591-616.
19. Orchard GE, Wilson Jones E, Russel Jones R. Immunocytochemistry in the
diagnosis of Kaposis sarcoma and angiosarcoma. Br J Biomed Sci 1995;
52: 35.
20. Nickoloff BJ. The human progenitor cell antigen (CD34) is localized on
endothelial cells, dermal dendritic cells, and perifollicular cells in formalinfixed normal skin, and on proliferating endothelial cells and stromal spindleshaped cells in Kaposis sarcoma. Arch Dermatol 1991; 127:523.
21. Battifora H, Trowbridge IS. A monoclonal antibody useful for the differential
diagnosis between malignant lymphoma and nonhematopoietic neoplasm.
Cancer 1983; 51: 816-21.
23
22. Rijlaarsdam JU, Scheffer E, Meijer CJ, et al. Cutaneous pseudo-T-cell lymphomas:
A clinicopathologic study of 20 patients. Cancer 1992; 69: 717.
23. LeBoit PE, McCalmont TH. Cutaneous lymphomas and leukemias. In: David
E, Rosalie E, Christine J, et al. eds. Levers Histopathology of the Skin. 8th ed.
Philadelphia: Lippincott-Raven: 1997: 805-46.
24. LeBoit PE. Granulomatous slack skin. Dermatol Clin.1994; 12: 375.
25. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol1994; 30:
379.
26. LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J
Dermatopathol 1996; 18: 221.
27. Kerschmann RL, Berger TG, Weiss LM, et al. Cutaneous presentation of
lymphoma in human immunodeficiency virus disease: Predominance of T cell
lineage. Arch Dermatol 1995; 131: 1281.
28. Weiss LM, Hu E, Wood GS, et al. Clonal rearrangements of T cell receptor
genes in mycosis fungoides and dermatopathic lymphadenopathy. N Engl J
Med 1985; 313: 539.
29. Wood GS. Using molecular biologic analysis of T cell receptor gene
rearrangements to stage cutaneous T cell lymphoma. Arch Dermatol 1998; 134:
221.
30. Lymphoid markers used for the diagnosis of lymphomas according to the
REAL or WHO classification, 13/3/2001, http:/ www.thd.org.tr/ sub/ eng/
lymphoid.php, 27/8/2003.
31. White RM, Patterson JW. Cutaneous involvement in Hodgkins disease. Cancer
1985; 55: 1136.
32. Moretti S, Pimpinelli N, Di Lollo S, et al. In situ immunologic characterization
of cutaneous involvement in Hodgkins disease. Cancer 1989; 63: 661.
33. Willenbrock K, Ichinohasama R, Kadin ME, et al. T cell variant of classical
Hodgkins lymphoma with nodal and cutaneous manifestations demonstrated
by single-cell polymerase chain reaction. Lab Invest 2002; 82: 1103-9.
34. Ratnam KV, Su WPD, Ziesmer SC, et al. Value of immunohistochemistry in the
diagnosis of leukemia cutis: Study of 54 cases using paraffin-section markers.
J Cutan Pathol 1992; 19: 193-200.
35. Dorfman DM, Kraus M, Perez-Atayde AR, et al. CD99 (p30/32 MIC2)
immunoreactivity in the diagnosis of leukemia cutis. Mod Pathol 1997; 10: 2838.
36. van der Velden VH, Hochhaus A, Cazzaniga G, et al. Detection of minimal
residual disease in hematologic malignancies by realtime quantitative PCR:
principles, approaches, and laboratory aspects. Leukemia 2003; 17: 1013-34.
24
M. Ramam
Cutaneous Tuberculosis:
Recent Perspective
METHODOLOGY
The definition of recent can be flexible; I have chosen a cut-off of 5
years from the time of writing this account. The primary source of
information for this chapter was PubMed, the online retrieval system for
digital biomedical archives maintained by the National Center for
Biotechnology Information at the U.S. National Library of Medicine. A
search was conducted with the term cutaneous tuberculosis NOT
lupus erythematosus. All citations from 1998 onwards were screened
and the abstracts available perused. When further details were required,
the full article was consulted. In addition, we searched IndMed, the
online site of the National Informatics Center, New Delhi which contains
a database of 75 medical journals including the Indian Journal of Dermatology, Venereology and Leprology (IJDVL) and the Indian Journal of
Dermatology. A hand search of all copies of the IJDVL received by the
author in the last 5 years was also conducted to look for relevant articles.
From among all these sources, information judged to be new and/or
relevant was included in this account.
EPIDEMIOLOGY AND CLINICAL FEATURES
Three hospital-based studies of cutaneous tuberculosis were published.
Dr Bhushan Kumars group from Chandigarh reported their experience
with cutaneous tuberculosis at a teaching hospital between 1975 and
1995.1 Lupus vulgaris was the commonest variant seen. An interesting
finding was the association of regional lymphadenopathy at the site of
the cutaneous lesion with disseminated disease in other organ systems.
The Chandigarh group also reported their experience in 75 children
with cutaneous tuberculosis.2 Scrofuloderma was the commonest
presentation, followed by lupus vulgaris and tuberculosis verrucosa
cutis; tubercular gummata and tuberculids were rare. Regional
lymphadenopathy was noted more frequently in patients with disseminated disease. The Mantoux test was positive in 91.8 percent with
25
26
27
28
29
REFERENCES
1. Kumar B, Muralidhar S. Cutaneous tuberculosis: A twenty-year prospective
study. Int J Tuberc Lung Dis 1999;3:494-500.
2. Kumar B, Rai R, Kaur I, et al. Childhood cutaneous tuberculosis: A study over
25 years from northern India. Int J Dermatol 2001;40:26-32.
3. Ramesh V, Misra RS, Beena KR, et al. A study of cutaneous tuberculosis in
children. Pediatr Dermatol 1999;16:264-9.
4. Sardana K, Koranne RV, Langan U, et al. Ocular scrofuloderma with unilateral
proptosis. J Dermatol 2002;29:232-4.
5. Mignogna MD, Muzio LL, Favia G, et al. Oral tuberculosis: A clinical evaluation
of 42 cases.Oral Dis 2000;6:25-30.
6. Kaur C, Sarkar R, Kanwar AJ. How safe is nose-piercing? Inoculation cutaneous
tuberculosis revisited. Int J Dermatol 2003;42:645-6.
7. Ghorpade A. Lupus vulgaris over a tattoo mark - inoculation tuberculosis. J
Eur Acad Dermatol Venereol. 2003;17:569-71.
8. Ozkaya-Bayazit E, Baykal C, Buyukbabani N, et al. Earlobe dermatitis.Arch
Dermatol 2002;138: 1607-12.
9. de Jong JW, van Altena R. Non-respiratory tuberculosis with Mycobacterium
tuberculosis after penetrating lesions of the skin: five case histories. Int J Tuberc
Lung Dis. 2000;4:1184-7.
10. Vidal D, Barnadas M, Perez M, et al. Tuberculous gumma following
venepuncture. Br J Dermatol 2001;144:601-3.
11. Motta A, Feliciani C, Toto P, et al. Lupus vulgaris developing at the site of
misdiagnosed scrofuloderma.J Eur Acad Dermatol Venereol 2003;17:313-5.
12. Khandpur S, Nanda S, Reddy BS. An unusual episode of lupus vulgaris
masquerading as sporotrichosis. Int J Dermatol 2001; 40:336-9.
13. Jagdish N, Sameer R, Omprakash R. Port-site tuberculosis: A rare complication
following laparoscopic cholecystectomy. Scand J Infect Dis 2002;34:928-9.
14. Gangopadhyay AK. Tuberculosis lymphedema cutis. Ind J Dermatol 2001; 46:
50-1.
15. Kivanc-Altunay I, Baysal Z, Ekmekci TR, et al. Incidence of cutaneous
tuberculosis in patients with organ tuberculosis.Int J Dermatol 2003; 42: 197200.
16. Angus BJ, Yates M, Conlon C, et al. Cutaneous tuberculosis of the penis and
sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect
Dis 2001;33:E132-134. Epub 2001 Oct 22.
17. Thami GP, Kaur S, Kanwar AJ, et al. Lichen scrofulosorum: A rare manifestation
of a common disease. Pediatr Dermatol 2002;19:122-6.
18. Cuende E, Almeida V, Portu J, et al. Poncets disease and papulonecrotic
tuberculid in a patient infected with the human immunodeficiency virus.
Arthritis Rheum 1998; 41: 1884-8.
19. Jordaan HF, Schneider JW, Abdulla EA. Nodular tuberculid: A report of four
patients. Pediatr Dermatol 2000; 17:183-8.
20. Kumar B, Parsad D. Is nodular tuberculid a distinct entity? Pediatr Dermatol
2001; 18: 164-7.
21. Mahaisavariya P, Chaiprasert A, Manonukul J, et al. Scrofuloderma and Sweets
syndrome.Int J Dermatol 2002; 41:28-31.
22. Lanjewar DN, Bhosale A, Iyer A. Spectrum of dermatopathologic lesions
associated with HIV/AIDS in India. Indian J Pathol Microbiol 2002;45:293-8.
30
31
Debabrata Bandyopadhyay
32
33
34
1.
2.
3.
4.
5.
6.
Infections
Connective tissue diseases
Malignancies
Drugs
Foods and food additives
Systemic vasculitic syndromes
Henoch-Schnlein purpura, mixed cryoglobulinemia, Wegeners
granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis
7. Other systemic diseases
Alpha1-antitrypsin deficiency, Behcets disease, congenital deficiency of
complement components, chronic active hepatitis, cystic fibrosis,
inflammatory bowel disease, intestinal bypass surgery, primary biliary
cirrhosis, relapsing polychondritis, sarcoidosis, Wiskott-Aldrich syndrome
35
Anticonvulsants
Barbiturates
Diphenylhydantoin
Gabapentin
Diuretics
Thiazides
Antidiabetic
Glyburide
Anti-gout
Allopurinol
Antipsychotic
Phenothiazines
Antiretrovirals
Indinavir
Efavirenz
Anti-thyroid
Propylthiouracil
Methimazole
Anti-ulcer
Cimetidine
Omeprazole
Disease-modifying antirheumatic
Leflunomide
Immunosuppressive
Methotrexate
Gold salts
Leukotriene inhibitor
Zafirlukast
Non-steroidal anti-inflammatory drugs
Aspirin
Ibuprofen
Phenylbutazone
Naproxen
Celecoxib
Vaccines
Hepatitis B
Influenza
Measles
Typhoid
Miscellaneous
Bupropion
Iodides
Radiocontrast media
Streptokinase
36
HIV infection
Brucellosis
Leprosy
Candidiasis
Meningococcosis
Cytomegalovirus infection
Rickettsioses
Ehrlichiosis
Staphylococcal infection
Streptococcal infection
Gonorrhoea
Syphilis
Tuberculosis
Varicella
Herpes simplex
37
LE, 13.7 percent was found to have cutaneous LV. Cutaneous LV, like
some other LE-nonspecific skin lesions, were detected only in patients
with SLE and usually in the active phase of the disease.47 LV with the
clinical feature of a figurate erythema mimicking erythema gyratum
repens has been described in SLE.48 LV in rheumatoid arthritis may
present clinically with palpable purpura, maculopapular erythema,
erythema elevatum diutinum, and hemorrhagic blisters.49 In patients
with RA, development of vasculitis is related to the severity of the
disease.12 Vasculitis is commoner in children than in adults in dermatomyositis. In adult patients, features of LV in lesional skin biopsy have
a predictive value for the presence of underlying malignancy.50
LV occurring in association with various malignant conditions is
termed paraneoplastic vasculitis. Neoplasia is a relatively rare cause of
LV. In a study of 222 cases of vasculitis, only 11 had associated malignancies.51 Paraneoplastic vasculitis is usually described in association
with hematologic malignancies and rarely, solid organ tumors.52,53
Hematologic malignancies described in association with cutaneous LV
include various forms of leukemia, Hodgkins and non-Hodgkins
lymphoma,54 multiple myeloma,55 Waldenstroms macroglobulinemia,56
and myelodysplastic syndrome.57 Among the solid organ malignancies
reported in association with LV are carcinomas of prostate, breast, and
colon,53 ovarian carcinoma,58 squamous cell carcinoma of the lung59 and
renal cancer.60 In most of the cases, manifestations of vasculitis appeared
before or concurrent with the initial recognition or the relapse of the
tumor.53
Besides infections, connective tissue diseases, and malignancies, other
underlying systemic diseases may also be associated with cutaneous LV.
Among the various diseases described in the literature1,61-63 are Behcets
disease, inflammatory bowel disease, autoimmune liver diseases, cystic
fibrosis, relapsing polychondritis, sarcoidosis and Wiskott-Aldrich
syndrome.
CLASSIFICATION
Vasculitides constitute the myriad clinicopathologic entities resulting
from a multitude of etiological factors and range in severity from
inconsequential skin rashes to life-threatening multisystem diseases, the
disorders sharing the common feature of injury to blood vessels with
resultant tissue damage. For accurate diagnosis, rational management
and prognostication, as well as for the purpose of studying uniform
populations of patients for clinical trials, there is a need for an allencompassing classification system with clearly defined diagnostic
38
39
40
41
42
complexes containing IgA and C3 have been found in the skin, kidney,
intestinal mucosa, and synovia, thus explaining the major organ site
involvement seen in HSP. HSP is the commonest form of systemic
vasculitis encountered during childhood. Seventy five percent of cases
occur between two and 11 years of age, with a peak incidence at five
years of age.77 In the Indian population, the age of onset of disease,
however, is higher than that in the west.78,79 HSP can occur in response
to infectious agents such as group A streptococci, mycoplasma, EpsteinBarr virus and varicella virus. Parvovirus B19,41,80 campylobacter,81 and
Bartonella henselae44 infections have been implicated in the causation of
HSP. Cases of HSP following vaccinations for typhoid, measles, cholera
and yellow fever have also been reported82.
The disease often begins after an upper respiratory tract infection.
The dominant clinical features of HSP, in descending order of frequency,
are cutaneous purpura, arthritis, abdominal pain, nephritis and
gastrointestinal bleeding. Pulmonary disease and peripheral neuropathy
occur rarely. Scrotal involvement with severe pain may occur. Scrotal
sonographic findings are sufficiently characteristic to allow distinction
from torsion in most cases.83 The rash occurs in 100 percent of cases. The
lesions occur predominantly on the lower limbs and buttock, but may
involve other areas of the body. The classic lesions consist of palpable
purpura and urticarial wheals. Necrotic and bullous hemorrhagic lesions
may also occur. HSP is generally benign and self-limited in children and
more severe in adults.84 The most serious manifestation of HSP is renal
involvement which occurs in 50 percent of older children but in only 25
percent of children younger than two years. The main long-term
morbidity is from progressive renal disease. End-stage renal disease
develops in approximately 5 percent of patients.14
Diagnosis of HSP depends on clinical findings and history. According
to the diagnostic criteria proposed by Michel et al,85 three or more of the
following six features should be present to diagnose HSP: palpable
purpura, bowel angina, gastrointestinal bleeding, hematuria, age of onset
younger than twenty years, and no medications as a precipitating agent.
Since renal manifestation may follow the development of the rash by up
to three months, monthly urinalysis should be done for a few months
following resolution of the condition.
Cryoglobulinemic Vasculitis
Cryoglobulins are circulating immunoglobulins or complexes containing
immunoglobulins that precipitate in the cold and dissolve on rewarming.
Cryoglobulins are classified according to their constituents. Type I
cryoglobulins are monoclonal immunoglobulins associated with multiple
43
44
45
46
Urticarial Vasculitis
Urticarial vasculitis (UV) is a clinicopathologic entity typified by recurrent
episodes of urticaria that have the histopathologic features of LV. The
condition is idiopathic in many patients but can also occur in the context
of autoimmune disorders, infections, drug reactions, or as a
paraneoplastic syndrome.113 Clinical features include12,113 pruritic, painful,
or burning urticarial lesions, which, in contrast to allergic urticaria,
usually persist longer than 24 hours and may show pronounced central
clearing of lesions often leaving residual hyperpigmentation. However,
because clinical characteristics of urticarial vasculitis may overlap with
those of allergic urticaria, confirmation of diagnosis requires lesional
skin biopsy.113 Systemic features may include fever, malaise, lymphadenopathy, hepatosplenomegaly, arthralgia, renal, gastrointestinal, or
ocular manifestation.12 Urticarial vasculitis typically affects young women
and usually pursues a chronic course. Patients with UV can be divided
into two types, those with normal complement levels and those with
hypocomplementemic UV.114 The latter condition has a strong association
with SLE and is commonly associated with angioedema, ocular
inflammation, obstructive lung disease, and glomerulonephritis.114,115
APPROACH TO DIAGNOSIS AND TREATMENT
Leukocytoclastic vasculitis presents a diagnostic and therapeutic
challenge to the physicians. Appreciation of the fact that, LV is only a
non-specific reaction pattern and its significance ranges from a selflimiting mild rash to life-threatening multisystem diseases, is crucial to
the diagnosis and management principles. Since cutaneous lesions are
very common manifestations of nearly all vasculitic syndromes,
dermatologists are often the first contact-points for patients affected
with such disorders. It is the onus of the physician to evaluate the
patients thoroughly in order to confirm the diagnosis, search for etiological factors, and identify the organs involved. In most cases,
dermatologists will be required to treat the patients and, if serious
systemic involvements are detected, to refer them to appropriate
specialists.
The first step in the diagnosis of LV is to suspect that a rash and its
accompanying symptoms are features of a vasculitic process. While
palpable purpura is the most easily recognizable sign of LV, other lesions
which are suggestive of LV include persistent urticarial wheals,
hemorrhagic pustules, livedo reticularis, subcutaneous nodules, and
cutaneous infarcts. The clinical diagnosis of cutaneous LV is confirmed
by histopathological examination of biopsy specimens. The unequivocal
47
48
Initial screening:
Complete blood count
ESR
C-reactive protein
Urinalysis
Stool guaiac
Focussed tests:
ANA
Rheumatoid factor
ANCA
Hepatitis B, C serology
HIV testing
CH 50, C3, C4
Cryoglobulins
Throat swab
Blood culture
Hence, the next level of laboratory tests is more focussed and directed
at diagnosing specific vasculitic disease entities (Table 4.6). These often
include tests for antinuclear antibodies and rheumatoid factor for
detecting connective tissue disorders; serologic tests for hepatitis B and
C viruses; an ANCA profile for systemic small-vessel vasculitis and
appropriate tests to detect any infective disorders, malignancies, and
other underlying diseases if clinical suspicion so directs. Cryoglobulins
are looked for if hepatitis C virus infection is present.
Once evaluations are completed and systemic affections, if present,
are clearly identified, it is imperative to recognize the specific vasculitic
syndrome from the characteristic combinations of clinical and laboratory
features. This is extremely important from the point of view of treatment
and prognosis. For example, the same combination of palpable purpura,
arthritis, and renal involvement have a much better prognosis when
they occur as components of Henoch-Schnlein purpura than as components of Wegeners granulomatosis. After recognition of the syndrome
as one of the systemic vasculitides with prominent visceral involvement,
referral to appropriate specialities like rheumatology, nephrology,
gastroenterology or neurology is imperative for proper management of
the case.
Treatment of vasculitis depends on the identified causative factors,
the nature of the syndrome, and more importantly, the degree and extent
of systemic involvement. If drug-induced vasculitis is suspected,
withdrawal of the drug results in rapid improvement of symptoms and
49
50
51
23. Pierard FC, Henry F, Pierard GE. Severe pustular and plymorphous vasculitis
caused by losartan. Ann Dermatol Venereol 2001; 128:1040-2.
24. Soy M, Ozer H. Canatarglu A, et al. Vasculitis induced by Zafirlukast therapy.
Clin Rheumatol 2002; 21: 328-9.
25. Davidson KA, Ringpfeil F, Lee JB. Ibuprofen-induced bullous leukocytoclastic
vasculitis. Cutis 2001; 6:303-7.
26. Borman P, Boden H, Gulec AT, et al. Atypical methotrexate dermatitis and
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28. Domingo P, Barcelo M. Efavirenz-induced leukocytoclastic vasculitis. Arch
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29. Tavadia S, Drummond A, Evans CD, et al. Leukocytoclastic vasculitis and
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30. Cueller ML. Drug-induced vasculitis. Curr Rheumatol Rep 2002; 4:55-9.
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35. Watkins KV, Ittman MM. Necrotizing vasculitis in a patient with acquired
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65. Hunder GG, Arend WO, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990;
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68. Savage COS, Harper L, Cockwell P, et al. ABC of arterial and vascular diseases:
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69. Hoffman GS, et al: Wegener granulomatosis: An analysis of 158 patients. Ann
Intern Med 1992; 116: 448-98.
70. Daoud MS, Gibson LE, et al. Cutaneous Wegeners granulomatosis: Clinical,
histopathologic, and immunopathologic features of thirty patients. J Am Acad
Dermatol 1994;31:605-12.
71. Patten SF, Tomecki KJ. Wegeners granulomatosis: cutaneous and oral mucosal
disease. J Am Acad Dermatol 1993, 28:710-8.
72. Mansi IA, Opran A, Rosner F. ANCA associated small-vessel vasculitis. Am
Fam Physician 2002; 65: 1615-20.
73. Mukhopadhyay A, Stanley NN. Churg-Strauss syndrome associated with
montelukast. Postgrad Med J 2001; 77:390-1.
74. Tang MBY, Yosipovitch G. Acute Churg-Strauss syndrome in an asthmatic
patient receiving montelukast therapy. Arch Dermatol 2003; 139: 715-8.
75. Vogel PS, Nemer J, Sau P, et al. Churg-Strauss syndrome. J Am Acad Dermatol
1992; 27: 821-4.
76. Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of ChurgStrauss syndrome: A clinicopathologic correlation. J Am Acad Dermatol.
1997:37:199-203.
77. Amitai Y, Gillis D, Wasserman D, et al. Henoch-Schnlein purpura in infants.
Pediatrics 1993; 92:865-7.
78. Murali NS, George R, John GT, et al. Problems of classification of Henoch
Schnlein purpura: An Indian perspective. Clin Exp Dermatol 2002; 27:260-3.
79. Bagga A, Kabra SK, Srivastava RN, et al. Henoch-Schnlein syndrome in
Northern Indian children. Indian Pediatr 1991; 28:1153-7.
80. Finkel TH, Torok TJ, Ferguson PJ, et al. Chronic parvovirus B19 infection and
systemic necrotizing vasculitis: opportunistic infection or aetiological agent?
Lancet 1994; 343:1255-8.
81. Lind KM, Gaub J, Pedersen RS. Henoch-Schnlein purpura associated with
Campylobacter jejuni enteritis. Scand J Urol Nephrol 1994; 28:179-81.
82. Szer IS. Henoch-Schnlein purpura. Curr Opin Rheumatol 1994; 6:25-31.
83. Ben-Sira L, Laor T. Severe scrotal pain in boys with Henoch-Schnlein purpura:
Incidence and sonology. Pediatr Radiol 2000; 30:125-8.
84. Garcia-Porrua C, Calvino MC, Llorca J, et al. Henoch-Schonlein purpura in
children and adults: Clinical differences in a defined population. Semin Arthritis
Rheum 2002; 32:149-56.
85. Michel BA, Hunder GG, Bloch DA. Hypersensitivity vasculitis and HenochSchnlein purpura: A comparison between the 2 disorders. J Rheumatol 1992;
19:721-8.
86. Cacoup P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic
hepatitis C. Arthritis Rheum 1999; 42:2204-12.
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108. Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral
penicillin drugs. Three case reports. Ann Allergy Asthma Immunol 2001; 86:
330-4.
109. Creamer JD, McGrath JA, Webb-Peploe M, et al. Serum sickness-like illness
following streptokinase therapy. A case report. Clin Exp Dermatol 1995; 20:46870.
110. Sanklecha MU. Cefaclor-induced serum sickness-like reaction. Indian J Paediatr
2002;69:921.
111. Harel L, Amir J, Livni E, et al. Serum sickness-like reaction associated with
minocycline therapy in adolescents. Ann Pharmacother 1996; 30:481-3.
112. McCollom RA, Elbe DH, Ritchie AH. Bupropion-induced serum sickness-like
reaction. Ann Pharmacother 2000; 34:471-3.
113. Venzor J, Lee WL, Huston DP. Urticarial vasculitis. Clin Rev Allergy Immunol
2002; 23:201-16.
114. De Amicis T, Mofid MZ, Cohen B, et al. Hypocomplementemic urticarial
vasculitis: Report of a 12-year-old girl with systemic lupus erythematosus. J
Am Acad Dermatol 2002; 47:273-4.
115. Wisnieski JJ, Baer NN, Christensen J, et al. Hypocomplementemic urticarial
vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine
1995; 74:24-41.
116. Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis: Serial
histopathologic evaluation demonstrates the dynamic nature of the infiltrate.
Arch Dermatol 1990; 126:69-72.
117. Choi SJ, Park SK, Uhm WS, et al. A case of refractory Henoch-Schnlein
purpura treated with thalidomide. Korean J Intern Med 2002; 17:270-3.
118. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of 42 Wegeners
granulomatosis patients treated with methotrexate and prednisolone. Arthritis
Rhem 1995; 38:608-13.
119. Zuckerman E, Keren D, Siobodin G, et al. Treatment of refractory, symptomatic,
hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferonalpha. J Rheumatol 2000; 27:2172-8.
120. Dowlati B, Firooz A, Dowlati Y. Granuloma faciale: successful treatment of
nine cases with a combination of cryotherapy and intralesional corticosteroid
injection. Int J Dermatol 1997; 36:548-51.
56
Jayakar Thomas
Emergencies in
Pediatric Dermatology
INTRODUCTION
The word emergency means sudden happening that needs immediate
and quick attention. It was something that was never thought of earlier
in the speciality of dermatology. But today we know that the reality is
far from this and current dermatological practice has undergone
tremendous change in the direction of crisp, comprehensive, and critical
care being offered to various conditions ranging from urticaria through
gangrenous conditions to vesiculo-bullous disorders. There are several
studies on the subject of emergency dermatology in terms of the nature
of consultations, direct or referrals, in an emergency setting and in terms
of evaluation of the same in tertiary care centres. Some of the common
dermatological emergencies seen in the pediatric age group will be
discussed and brief description of the condition and steps involved in
management of the conditions are provided in this article. Novel concepts
of acute skin failure (ASF) like cardiac, renal or respiratory failures and
intensive skin care unit (ISCU) put forward by Rene Touraine in 19761
will also be described briefly.
PEDIATRIC SIGNIFICANCE
These concepts of ASF and ISCU have to be perceived with more
seriousness from the pediatric point of view. The reasons for such
significance in children include:
Improper development of barrier function in children skin.
Lack of fully formed immunological role.
Both of the above leading to increased susceptibility to infection.
Increased metabolic rates in children leading to increase in energy
expenditure and these in turn demand more of fluid and nutrition
supplement.
Impaired thermoregulatory function of skin in children requiring
better management of ambience.
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may be on the skin but usually is in the eye or nasopharynx. The toxin
enters the circulation and affects the skin systemically, as in scarlet
fever.
In infants, illness often begins during the first few days of life with
a localized crusted infection (often impetigo-like), most often at the
umbilical stump or in the diaper area. Sporadic cases often start with a
superficial crusted lesion, frequently around the nose or ear. Within 24
hours, tender scarlet areas appear around the crusted area and may
become painful and generalized. Large, flaccid blisters arise on the
erythematous skin and quickly break to produce erosions. The epidermis
peels off easily, often in large sheets, when the red areas are rubbed
(Nikolskys sign). Widespread desquamation of the skin occurs within
36 to 72 hours, and patients may become very ill with systemic manifestations (e.g., malaise, chills, fever). Loss of the protective skin barrier can
lead to sepsis and fluid and electrolyte imbalance.
Symptoms and signs are indistinguishable clinically from toxic
epidermal necrolysis; yet SSSS must be distinguished rapidly from TEN
because therapy is different. Cultures should be obtained from the skin
and nasopharynx. Diagnosis is confirmed by skin biopsy and examination
of frozen tissue sections or exfoliative cytology, showing epithelial cells.
Although final biopsy results may be available until well after treatment
has been started, frozen tissue sections and cytology can provide rapid
confirmation.
Differential diagnosis includes drug hypersensitivity (most notably,
TEN), viral exanthems and scarlet fever, but none of these causes a
painful rash. Bullae, erosions, and an easily loosened epidermis occur in
thermal burns, genetic bullous diseases (e.g., some types of epidermolysis
bullosa) and acquired bullous diseases (e.g., pemphigus vulgaris, bullous
pemphigoid).
With prompt diagnosis and therapy, death rarely occurs. Systemic
penicillinase-resistant antistaphylococcal antibiotics (e.g., cloxacillin,
cephalexin) must be started as soon as the clinical diagnosis is made,
without waiting for culture results. In early-stage disease, oral cloxacillin
12.5 mg/kg q 6 h (for infants and children weighing <=20 kg) and 250
to 500 mg q 6 h (for older children) may be given; in severe disease,
gentamicin IV in 4 divided doses should be additionally given until
improvement is noted, followed by oral cloxacillin 25 mg/kg/day up to
100 mg/kg/day for >=10 days. Corticosteroids are contraindicated, and
topical therapy and patient handling must be minimized. If the disease
is widespread and the lesions are weeping, the skin should be treated
as if it were burned. Hydrolyzed polymer gel dressings may be very
useful, and the number of dressing changes should be minimized. Because
the split is high in the epidermis, the stratum corneum is quickly replaced
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the skin and subcutaneous tissues and can be due to drug allergy, insect
stings or bites, desensitization injections, or ingestion of certain foods
(particularly eggs, shellfish, or nuts). Some reactions occur explosively
after ingestion of minute amounts. Others (e.g., reactions to strawberries)
may occur only after overindulgence and possibly result from direct
(toxic) mediator liberation. Urticaria may accompany or even be the first
symptom of several viral infections, including hepatitis, infectious
mononucleosis, and rubella. Some acute reactions are unexplained, even
when recurrent. If acute angioedema is recurrent, progressive, painful
rather than pruritic and not associated with urticaria, a hereditary enzyme
deficiency should be considered (see Hereditary Angioedema, below).
Chronic urticaria and angioedema lasting more than 6 weeks are more
difficult to explain and only in exceptional cases can a specific cause be
found. The reactions are rarely IgE-mediated. Occasionally, chronic
ingestion of an unsuspected drug or chemical is responsible; e.g., from
penicillin in milk; from the use of nonprescription drugs; or from
preservatives or other food additives. Chronic underlying disease (SLE,
polycythemia vera, lymphoma, or infection) should be ruled out. Though
often suspected, controllable psychogenic factors are rarely identified
below. A few patients with intractable urticaria have thyroid disease.
Occasionally, urticaria may be the first or only visible sign of cutaneous
vasculitis.
In urticaria, pruritus (generally the first symptom) is followed shortly
by the appearance of wheals that may remain small (1 to 5 mm) or
enlarge. The larger ones tend to be clear in the center and may be
noticed first as large rings (> 20 cm across) of erythema and edema.
Ordinarily, crops of hives appear and subside; a lesion may remain in
one site for several hours and then disappear, only to reappear elsewhere.
If a lesion persists >=24 h, the possibility of vasculitis should be
considered. Angioedema is characterized by a more diffuse and painful
swelling of loose subcutaneous tissue, dorsum of hands or feet, eyelids,
lips, genitalia and mucous membranes. Edema of the upper airways
may produce respiratory distress and the stridor may be mistaken for
asthma. The cause of acute urticaria or acute angioedema is usually
obvious. Even when it is not, diagnostic tests are seldom required because
of the self-limited, nonrecurring nature of these reactions. In chronic
urticaria, an underlying chronic disease should be ruled out by a detailed
history and physical examination and routine screening tests. Eosinophilia
is uncommon in urticaria. Other tests (e.g., stool examination for ova
and parasites, serum complement, antinuclear antibody, and sinus or
dental X-rays) are not helpful without additional clinical indications.
Since acute urticaria generally subsides in 1 to 7 days, treatment is
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and suppositories. Some eruptions start after the drug has been
stopped (e.g., ampicillin) or continue for weeks or months; minute
amounts of some drug may produce a reaction. However, most drug
reactions resolve when the offending drug is stopped and require no
further therapy. Often, especially in hospitalized patients, all but lifesustaining dugs can be discontinued and each reinstituted at weekly
intervals in order of importance. A physician well versed in the incidence
and types of drug eruptions can often withhold the most likely offender
while continuing all other drugs. When suspected offending drugs are
necessary, chemically unrelated compounds should be substituted when
possible. No laboratory tests are available to aid diagnosis, although
lymphocyte transformation and penicillin skin tests are under study.
Biopsy of affected skin may be helpful. Sensitivity can be definitively
established only by readministration of the drug, but this may be
hazardous or unethical.
A lubricant (e.g., white petrolatum) may provide symptomatic relief
for a dry, itching maculopapular eruption. A fluorinated corticosteroid
ointment may be applied in a small area initially and, if effective, applied
to the entire eruption. Acute urticaria may be a sign of anaphylaxis and
may require aqueous epinephrine (1:1000) 0.2 ml sc or IM or the sloweracting but more persistent soluble hydrocortisone 100 mg IV, which may
be followed by an oral corticosteroid for a short period.
Kawasaki Syndrome9
A syndrome, occurring usually in infants and children less than 5 years,
characterized by prolonged fever, exanthem, conjunctivitis, mucous
membrane inflammation, cervical lymphadenopathy and polyarteritis
of variable severity. Its etiology is unknown, but the epidemiology and
clinical presentation suggest an infection or an abnormal immunologic
response to an infection.
Since the syndrome was first described in Japan in the late 1960s,
thousands of cases have been reported worldwide in diverse racial and
ethnic groups, although children of Japanese descent have a higher
incidence. The male: female ratio is about 1.5 : 1. Eighty percent of
patients are less than 5 years (median, 2 years); true cases in teenagers
or adults are rare. Cases occur year-round, but most often in spring or
winter. Clusters have been reported in communities without clear
evidence of person-to-person spread. Recurrences occur in about
1 percent of patients.
The pathology is nearly identical to infantile periarteritis nodosa,
with vasculitis primarily affecting the coronary arteries, but also other
medium-sized and large arteries. The illness tends to progress in stages,
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beginning with fever, usually remittent and > 39C (> 102.2F), which
is associated with irritability, often extreme, and occasional lethargy or
intermittent colicky abdominal pain. Fever lasts 1 to 2 weeks or more in
untreated patients. Usually within a day or two of fever onset, bilateral
bulbar conjunctival injection without exudate appears. Within 5 days, a
polymorphous, erythematous macular rash appears, primarily over the
trunk, often with accentuation in the perineal region. The rash may be
urticarial, morbilliform, or scarlatiniform and is accompanied by injected
pharynx; reddened, dry, fissured lips; and a red strawberry tongue.
During the first week, pallor of the proximal portion of the fingernails
or toenails (leukonychia partialis) may occur. Erythema or a purple-red
discoloration and variable edema of the palms and soles usually appear
on about the third to fifth day. Although edema may be slight, it is often
tense, hard, and nonpitting. Periungual, palmar, and plantar
desquamation begins on about the 10th day after onset. The superficial
layer of the skin sometimes comes off in large casts, revealing
new normal skin. Tender, nonsuppurative cervical lymphadenopathy
(>=1 node, >= 1.5 cm in size) is present throughout the course in about
50 percent of patients; the other findings each are present in about
90 percent of patients. The illness may last from 2 to 12 weeks or longer.
Other less specific findings indicate involvement of many systems.
Arthritis or arthralgias (mainly involving large joints) occur in about
1/3 of patients. Other clinical features may include urethritis, aseptic
meningitis, diarrhea, hydrops of the gallbladder, and anterior uveitis.
The most important complications are those of cardiac inflammation,
most notably coronary arteritis. Cardiac manifestations usually begin on
about the 10th day, as the rash, fever, and other early acute clinical
symptoms begin to subside; i.e., in a subacute phase of the syndrome.
Inflammation of the coronary arteries with dilation and aneurysm
formation occurs in 5 to 20 percent of all cases, sometimes associated
with acute myocarditis with heart failure, arrhythmias, and pericarditis
and rarely with cardiac tamponade, thrombosis, or infarction.
Leukocytosis, often with a marked increase in immature cells, is
common in the acute phase of the illness. Other hematologic findings
include a mild anemia, thrombocytosis (>= 500,000/uL) in the second or
third week of illness and elevated ESR (often strikingly so).
Other abnormalities, depending on the organ systems involved, may
include pyuria, proteinuria, CSF pleocytosis and ECG changes (arrhythmias, decreased voltage, or left ventricular hypertrophy). Echocardiography should be performed in all patients at diagnosis (for
establishing a baseline and detecting coronary artery aneurysms,
pericarditis, or myocarditis); at 3 to 4 weeks after onset; at 6 to 8 weeks
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after onset; and perhaps at 6 to 12 months after onset. Coronary arteriography is occasionally useful in patients with aneurysms and abnormal
stress testing. ECGs are often repeated along with echocardiograms.
Diagnosis is based on the clinical findings and on exclusion of other
diseases. Results of cultures for bacteria and viruses as well as serologic
tests for evidence of infection are negative, but may be useful for
diagnosing other illnesses with similar presentations. Differential
diagnosis includes bacterial diseases (especially scarlet fever,
staphylococcal exfoliative syndromes, and leptospirosis), viral exanthems
(e.g., measles, viral hemorrhagic fever), toxoplasmosis, acrodynia (caused
by mercury poisoning), Stevens-Johnson syndrome and juvenile RA.
The mortality rate is 0.1 percent with adequate therapy; without
therapy, mortality may approach 1 percent. Deaths most commonly
result from cardiac complications, but can be sudden and unpredictable;
50 percent occur within 1 month of onset, 75 percent within 2 months
and 95 percent within 6 months, but may occur as long as 10 years later.
Effective therapy reduces acute symptoms and, more importantly,
reduces the incidence of coronary artery aneurysms from 20 percent to
< 5 percent. In the absence of coronary artery disease, the prognosis for
complete recovery is excellent. About 2/3 of coronary aneurysms regress
within 1 year, although it is unknown whether residual coronary stenosis
remains or not. Giant coronary aneurysms (> 8 mm internal diameter on
echocardiogram) are less likely to regress and require more intensive
follow-up and therapy.
Children with Kawasaki syndrome should be treated by or in close
consultation with an experienced pediatric cardiologist or pediatric
infectious disease specialist. Therapy is started as soon as possible,
optimally within the first 10 days of illness, with a combination of highdose immune globulin intravenous (IGIV-a single dose of 2 g/kg given
over 10 to 12 h) and oral high-dose aspirin (80 to 100 mg/kg/day in 4
divided doses). The aspirin dose is reduced to 3 to 5 mg/kg/day as a
single dose when the child becomes afebrile. (Some authorities prefer to
continue high-dose aspirin until the 14th day of illness.) Aspirin
metabolism is erratic during acute Kawasaki syndrome, which partially
explains the reason for the high dose requirements. Some authorities
monitor serum aspirin levels during high-dose therapy, especially if
therapy is given for 14 days. Most patients have a brisk response over
the 24 hours after therapy begins; a small fraction continue to be ill with
fever for several days and require repeat dosing with IGIV. An alternative
regimen, which may lead to slightly slower resolution of symptoms but
may benefit those with cardiac dysfunction who could not tolerate the
volume of a 2 g/kg IGIV infusion, is 400 mg/kg/day of IGIV daily over
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suppression.
Meningococcal Disease14
Meningococcal disease is an illness caused by the bacteria Neisseria
meningitides. The two common presentations of meningococcal infection
are meningococcal meningitis and meningococcemia. An infected
individual may suffer one or both of these diseases. Meningococcal
disease is a medical emergency and patients showing signs and symptoms
suspicious of meningococcal infection need to seek medical advice from
their doctor or a hospital immediately. A delay of even hours can be
fatal.
Most patients with meningococcal disease are otherwise healthy
individuals. However, there are some patient groups who are at an
increased risk for developing meningococcal infection.
Children 6 months to 4 yearsuntil about 6 months immunity from
the mother is present. Beyond 4 years many children have developed
immunity to many strains of Neisseria meningitides.
Individuals with complement deficiencies. Complement is a part of
the immune system required for the breakdown of meningococcal
bacteria.
Individuals without spleens (asplenic).
Individuals taking immunosuppressive drugs such as prednisolone
or cyclosporine.
Individuals with a current viral infection.
The most common signs and symptoms of meningococcal disease are
listed in the Table 5.1.
If an individual has both meningococcal meningitis and meningococcemia, they may present with a mixture of symptoms and signs
characterisic to each of the diseases.
Meningococcal meningitis and meningococcemia is often suspected
from the history and physical examination. Blood culture and/or lumbar
puncture are used to confirm diagnosis. A lumbar puncture involves
putting a needle in the lower back to obtain some spinal fluid. An
increased number of white cells are seen under the microscope.
Early recognition of meningococcal infection is critical as meningococcemia spreads so quickly that with hours of symptoms appearing, a
patient may rapidly die. Patients may initially just have a rash and not
be particularly unwell. Meningococcemia can kill more rapidly than any
other infectious disease. Patients with either meningococcemia or
meningococcal meningitis must be hospitalized and treatment with
antibiotics and supportive care instituted immediately. Many patients
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Meningococcal meningitis
Children >1 year and adults
Neck stiffness
Headache
Nausea and vomiting
Neck and/or back pain
Fever and chills
Increased sensitivity to light
Irritability, confusion
Infants
Refusing feeds
Increased irritability
Sleeping all the time
Fever
Bulging fontanelle (soft spot on the
top of the head)
Inconsolable crying
Epileptic fits (seizures)
Meningococcemia
Signs on the skin
Petechie (rash of small red or
purple spots that do not disappear
when pressure is applied to the
skin) occur in 50-75 percent of
cases
Rash may progress to larger red
patches or purple lesions (similar
to bruises)
Most often found on the trunk and
extremities but may progress to
involve any part of the body
In severe cases lesions may burst
and lead to necrosis.
Other signs and symptoms
Acute fever and chills
Headache
Neck stiffness
Low back and thigh pain
Nausea and vomiting
Confusion or unconsciousness
Epileptic fits (seizures)
Unstable vital signs, e.g. very low
blood pressure, reduced blood
flow, low urine output
Collapse from septic shock
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disease may occur at the time of the acute disease or during the recovery
period. Some complications are so severe that they may reduce the
chances of survival.
Massive hemorrhage of the adrenal glands
Disseminated intravascular coagulopathy (DIC), which prevents blood
clotting
Arthritis
Heart problems, e.g. pericarditis
Neurological problems, e.g. deafness or peripheral neuropathy
(damage to the nerves in feet and hands)
Permanent musculoskeletal problems
Amputation
Graft Versus Host Disease15
Graft versus host disease (GVHD) is a condition where, following
transplantation, the donors immune cells in the transplant (graft) make
antibodies against the patients tissues (host) and attack vital organs.
Organs most often affected include the skin, gastrointestinal (GI) tract
and the liver.
Ninety percent of bone marrow transplants lead to GVHD. Solid
organ transplantation, blood transfusions and maternal-fetal transfusions
have also been reported to cause GVHD less frequently.
There are two forms of GVHD:
1. Acute GVHD
Early form of GVHD that occurs within the first 3 months of
transplantation.
First sign is usually a skin rash appearing on the hands, feet
and face.
Gastrointestinal and liver dysfunction symptoms may follow.
2. Chronic GVHD
Late form of GVHD that develops 3 months post-transplantation.
Usually evolves from acute GVHD but occurs de novo in
20-30 percent of patients.
Cutaneous (skin) reactions resemble those of autoimmune
disorders such as lupus, lichen planus and especially systemic
sclerosis.
Acute GVHD and chronic GVHD are distinct diseases. One common
factor is that they both increase the patients susceptibility to infection.
The features of acute and chronic GVHD have been enumerated in
Table 5.2.
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Acute GVHD
Tender, red spots usually appear 10-30 days post-transplantation
Face, hands and feet affected first then spreading to whole body (erythroderma)
Spots may coalesce to form widespread red rash
Rash may develop into raised spots or blisters that resemble toxic epidermal
necrolysis
Fever may be present
Watery or bloody diarrhea with stomach cramps indicates GI involvement
Jaundice (yellowing of the skin and eyes) indicates liver involvement
Abnormal liver function tests
Chronic GVHD
Dry, itchy raised rash develops over whole body
Dry mouth and sensitivity to spicy or acid foods leading to mouth lesions
Dry eyes causing irritation and redness
Skin thickening, scaling, hyper or hypopigmentation (resembling lichen planus)
Hardening of skin (scleroderma) may interfere with joint mobility
Hair loss or premature graying
Decreased sweating
Liver involvement causing jaundice
Lung and GI disorders may occur
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Epidermolysis Bullosa16
Several forms are described of this disease, but only the major lifethreatening forms are discussed here.
Junctional Epidermolysis Bullosa (JEB)
JEB Subtypes
Features
Herlitz (JEB
letalis or
lethal JEB)
JEB mitis or
non-lethal JEB
Generalized
atrophic
benign EB
Recessive DEB
Features
Generalized blistering present at birth
Blistering becomes localized to hands, feet, elbow or
knees as child grows older and in response to friction
Small white spots called milia are often present at
healed but scarred sites
May be mild or severe presentations
Generalized severe blistering is more common and
involves large areas of skin and mucous membranes
Blisters heal but with scarring and deformity causing
limited movement, as fingers and toes may be fused
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together
Complications such as infection, malnutrition and
dehydration may cause death in infancy and those
who survive are at great risk of developing squamous
cell carcinoma
There is no cure for EB. Treatment is symptomatic and the primary
aim is to protect the skin and stop blister formation, promote healing
and prevent complications. Because EB can affect so many different
parts of the body, a team of medical specialists is usually required for
overall care. When necessary, treatment with oral and topical medications
may be prescribed to assist healing or prevent complications.
The following are some general measures used in caring for a patient
with EB.
Maintain a cool environment and avoid overheating
Use foam padding or sheepskins to help reduce friction on furniture
such as beds, chairs and infant car seats
Wear clothing made of soft non-irritating fabrics
Pierce, drain and dress blisters to promote healing (this should be
done only by the people who have received training on wound care)
Try to avoid using nappies in infants with severe EB, instead place
child on a clean pad.
Linear IgA Disease17
Linear IgA disease is a rare blistering disorder. It is nearly identical to
a similar condition that affects children, chronic bullous disease of
childhood.
Chronic bullous disease of childhood usually presents before puberty
with an abrupt onset of blistering in the genital region, later affecting
hands, feet and face. In adults with linear IgA disease, the limbs are
more often the first sites, although any area of the body may be affected
later.
Clear round or oval blisters may arise from normal-looking or red
skin. Red flat or elevated patches may arise, studded with small blisters
(vesicles) or large ones (bullae), often target-shaped. The tendency for
new blisters to arise in a ring around an old one is called the string of
beads sign and groups of small blisters may be described as a cluster of
jewels. Crusts, scratch-marks, sores and ulcers may arise. The lesions
can resemble other uncommon blistering skin diseases especially
erythema multiforme, bullous pemphigoid and dermatitis herpetiformis.
The intensity of itching is variable. Blisters and ulceration on the lips and
inside the mouth affect about 50 percent. Eye involvement may result
in irritation, dryness, light sensitivity and blurred vision. Biopsy shows
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are most reliable and invariably show IgG on the epidermal or epithelial
cell surfaces. Indirect tests of immunofluorescence usually show
pemphigus antibodies in the patients serum, even when the lesions are
localized in the mouth. The antibody titer may correlate with disease
severity. Pemphigus is a serious disease with an inconsistent and
unpredictable response to therapy. The aim of treatment, both immediate
and subsequent, is to stop the eruption of new lesions. Specific therapy
depends on the extent and severity of disease. The mainstay is systemic
corticosteroids. Some patients with few lesions may respond to lowdose oral prednisolone (e.g., 20 to 30 mg/day), but most require much
higher doses. Hospitalization and high-dose corticosteroids are indicated
for children with widespread disease, which may be fatal if inadequately
treated. The initial dose of oral prednisolone, 30 to 40 mg bid (or
equivalent), should be repeatedly doubled if new lesions continue to
appear after 5 to 7 days. Very high doses may be necessary. Corticosteroid
dose should be tapered if no new lesions appear for 7 to 10 days, with
the total daily dose given every morning at first, then every other
morning. The maintenance dose should be as low as possible. Many
patients require maintenance therapy, which can usually be discontinued
after months or years if no new lesions appear during a trial of several
weeks without treatment.
Methotrexate, cyclophosphamide, azathioprine, gold, or cyclosporine
used alone or with corticosteroids reduces the need for corticosteroids
and thus minimizes the undesirable effects of long-term corticosteroid
use, but the aforementioned drugs also carry serious risks. Plasmapheresis
combined with an immunosuppressive drug to reduce antibody titers
has also been effective. Active skin infections are treated with systemic
antibiotics. Reverse isolation procedures may be required. Generous use
of talc on the patient and sheets may prevent oozing skin from adhering;
hydrocolloid dressings may be useful. Silver sulfadiazine cream used on
erosions can prevent secondary infection.
Hemangiomas19
These vascular proliferations or ectasias are grouped as superficial, deep
and mixed. Infants are at a great risk during the first 6 months of age.
However, the danger is governed by factors such as site and size of the
angioma. Vascular malformations have to be distinguished from
hemangiomas. A vascular malformation is almost always present from
birth, remians stable or might progress very slowly. The absence of brisk
proliferative response in vascular malformations is due to the absence
of endothelial cell proliferation. Unlike hemangiomas, they do not resolve
spontaneously. Hemangiomas will need early treatment when alteration
81
to vital functions can occur (like around the eye, nose, ear, throat) or
with Kasabach-Merritt syndrome or congestive heart failure. When
treatment is required, oral prednisolone 1 to 3 mg/kg bid or tid should
be given as soon as possible and for about 2 weeks. If resolution starts,
the prednisolone should be decreased slowly; if not, the drug should be
stopped.
Interferon alfa is an antiangiogenic drug that inhibits epithelial cell
proliferation and motility and is the first line of therapy in KasabachMerritt syndrome.
Histiocytosis X20
Langerhans cell granulomatosis (histiocytosis X) is a group of disorders
(Letterer-Siwe disease, Hand-Schuller-Christian disease, pulmonary
histiocytosis X) in which histiocytes and eosinophils proliferate, especially
in the skin, bone and lung, often causing scarring. The cause of these
disorders is not known. They all start with infiltration of the lung (and
other tissues) by histiocytes, which are cells that scavenge for foreign
materials, and to a lesser extent by eosinophils, which are cells that are
normally involved in allergic reactions. Letterer-Siwe disease starts before
age 3 and is usually fatal without treatment. The histiocytes damage not
only the lungs but also the skin, lymph glands, bones, liver and spleen.
A small portion of the lung may rupture into the pleural space (a condition
called pneumothorax). Hand-Schuller-Christian disease usually begins
in early childhood but can start in late middle age. The lungs and bones
are most frequently affected. Rarely, damage to the pituitary gland causes
diabetes insipidus, a condition in which large quantities of urine are
produced, leading to dehydration. Some people develop bulging eyes
(exophthalmos) because the bones of the eye sockets are affected.
Pulmonary histiocytosis X (eosinophilic granuloma) is a rare, smokingrelated lung disease. The disease occurs more often in men than in
women. Symptoms usually start between the ages of 20 and 40. About
16 percent of people have no symptoms, but the rest develop coughing,
shortness of breath, fever, chest pain and weight loss. Pneumothorax is
a common complication due to rupture of a lung cyst. Scarring makes
the lungs stiff and impairs their ability to transfer oxygen into and out
of the blood. Chest X-rays show nodules, small lung cysts (honeycombing) and other changes that are typical of these diseases. X-rays
may also show that the bones are affected. Pulmonary function tests
show reduced function. Hemoptysis and diabetes insipidus are rare
complications.
People with Hand-Schuller-Christian disease may recover spontaneously. Most people with pulmonary histiocytosis X have persistent or
progressive disease. Death usually results from respiratory failure or cor
82
83
84
85
86
87
4. Whitley RJ, Namiaz AJ, Soong SJ, et al. Therapy of Neonatal Herpes simplex
virus infection. Paediatr 1980; 66: 495-501.
5. Jacobs MI, Magid MS, Jarowski CT. Disseminated Candidiasis. Arch Dermatol
1980; 116: 1277-99.
6. Beltrani VS. Urticaria and Angioedema. Dermatol Clin 1996; 171-98
7. Rosen FS, Charache P, Pensky J, et al. Angioedema-2 genetic variants. Science
1964; 148: 957-8.
8. Kramer MS, Leventhal JM, Hutchinson TA, et al. Adverse drug reactions.
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9. Kawasaki T, Kosaki F. A new infantile acute febrile mucocutaneous lymph
node syndrome (MLNS) in Japan. Paediatr 1974; 54: 271.
10. Ramsay DL, Hurley HJ. Papulosquamous eruptions and exfoliative dermatitis.
In: Moschella SL, Hurley HJ, eds. Dermatology. WB Saunders.
11. Tonnesen MG, Soter NA. Erythema multiforme. J Am Acad Dermatol 1978;
1: 357-64.
12. Heinbeck DM, Hengrave LH, Marvin JA, et al. Toxic epidermal necolysis. A
step forward in the treatment. JAMA 1985; 257: 2171-5.
13. Lentz CL, Altman J. Lamellar ichthyosis. The natural history of collodion
babies. Arch Dermatol 1968; 97: 3-5.
14. Ognibene AJ, Dito WR. Chronic meningococcemia: further comments on the
pathogenesis of associated skin lesions. Arch Intern Med 1964; 114: 29.
15. Grogen TM, Odom RB, Bargeta JH. Graft versus host reaction. Arch Dermatol
1977; 113: 806-12.
16. Briggaman RA. Hereditary epidermolysis bullosa with special emphasis on
newly recognized syndromes and complications. Dermatol Clin 1983; 1: 26380.
17. Chorzelski TP, Jablonska S. IgA linear dermatosis of childhood. Br J Dermatol
1979; 101: 535-42.
18. Ahmed RA, Moy R. Death in pemphigus. J Am Acad Dermatol 1982; 7: 2218.
19. Lang PG. Dubin HV. Hemangioma-thrombocytopenia syndrome: A disseminated intravascular coagulopathy. Arch Dermatol 1975; 111: 105-7.
20. Vogel JM, Vogel P. Idiopathic histiocytosis: A discussion of eosinophilic
granuloma, the Hand-Schuller-Christian disease and Letterer-Siwe syndrome.
Semin Hematol 1972; 9: 3-19.
21. Demis DJ. The mastocytosis syndrome. Ann Intern Med 1963; 59: 194-206.
22. Moynahan EL. Acrodermatitis enteropathica: A lethal inherited human zincdeficiency disorder. Lancet 1974; 2: 399-400.
23. Kellum RE, Ray TL, Brown GR. Sclerema neonatorum. Arch Dermatol 1968;
97: 372-5.
24. Miller ME, Koblenzer PJ. Leiners disease and C5 dysfunction. J Paediatr 1972;
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25. Shuster S. Systemic effects of skin disease. Lancet 1967; 1: 907-12.
26. LeGall JR, Loirat P, Alperovitch A, et al. A simplified acute physiological score
for intensive care unit patients. Critical Care Medicine 1984; 12: 975-7.
88
Cutaneous Adverse
Drug Reactions to
Systemic Drugs: Recent Update
The field of medicine is broadening with the passage of time along with
the list of drugs in the pharmacopeia. Every month a few new drugs
gain its entry in the market and many remain in the pipeline for
introduction. It is quite common to find new dangers of the marketed
drugs, with more than half of the approved drugs having serious side
effects that were not detected before approval.1
Any adverse drug reaction is described as an appreciably harmful
or unpleasant reaction, resulting from an intervention related to the use
of a medicinal product, which predicts hazard from future administration
and warrants prevention or specific treatments or alteration of the dosage
regimen or withdrawal of the product.2
Studies have documented that approximately 14 percent of such
adverse drug reactions in hospital care are cutaneous or allergic in nature,3
amongst which the exanthematous drug reaction is the commonest.4
Pattern of the cutaneous adverse drug reaction (CADR) varies among
various drugs, hence understanding the precise nature of CADR helps
to narrow down the search for the incriminating drugs. This chapter
attempts to highlight the features of CADR though presenting the entire
catalogue of all the drugs used in the past or the present is beyond the
scope of this article. The aim will be to describe the CADR of the recently
introduced non-dermatological drugs, newly described CADR of longknown drugs (many of which are yet to find its place in the textbooks)
with the exclusion of topical medicaments from this review.
SOURCES OF INFORMATION
The sources of information regarding the side effects of the drugs5 are
enlisted in Table 6.1 along with their merits and demerits. The MEDLINE
database was searched for the studies that contain information regarding the various forms of CADR. The bibliographies of the retrieved
articles were also searched to find relevant information.
89
Merits
Demerits
1. Clinical trial
2. Case reports
No comparison group to
allow for a quantitation
estimation of risk.
Invaluable function of
Incidence rate cannot be
raising suspicions that
assessed due to lack of
can be assessed in more
reliable denominator.
formal research.
3. Epidemiological Only practical option in Needs prolonged time and
studies
post-marketing situation
enough funding to conduct
(Case-control
to have the real estimate
the study.
studies or
of relative and absolute
Cohort studies)
risk and incidence rate.
Best source of information
on adverse drug reaction.
90
91
92
93
94
95
96
97
98
99
100
101
102
Other new introductions to this list include gabapentin,163 spironolactone,164 and cephalexin.165 Lichen planus pemphigoides, a condition
which shares the features of both lichen planus and BP, is reported to
be induced by the lipid lowering agent-simvastatin.166 The anti-neoplastic
agent, azathioprine is implicated in the development and exacerbation
of lesions of cicatricial pemphigoid. 167
Drug Induced Pseudo-porphyria
Drug-induced pseudo-porphyria presents with discrete blisters on the
face and dorsal surface of the hands, like that of porphyria cutanea tarda
(PCT), though the other cutaneous manifestations of PCT are absent.
The pathogenesis of drug-induced pseudo-porphyria is largely
unknown and unlike PCT, no abnormality is found in porphyrin metabolism. The skin biopsy shows pauci-inflammatory sub-epidermal blisters
like that of PCT.
Drugs associated with the development of pseudo-porphyria are
NSAIDs (naproxen), chlorthalidone, thiazides, furosemide and
tetracycline.
Many new drugs added to the list include flutamide,168 relafen,169
and nabumetone. 170 Apart from these drugs porphyria cutanea tarda is
related to imatinib and tamoxifen.171,172
Drug Induced Lupus Erythematosus
The subset of patients developing systemic lupus erythematosus
following ingestion of drug are more likely to have systemic involvement
(esp. pulmonary manifestation) than cutaneous and renal features.
The drugs causing lupus erythematosus (LE) inhibit T-cell DNA
methylation, thereby provoking autoreactivity and generating antibodies
against histone-DNA complex (anti-histone antibodies). Drug induced
LE is histologically indistinguishable from spontaneously arising LE.
Among the drugs incriminated in the development of LE are
acebutalol, procainamide, hydralazine, isoniazide, chlorpromazine,
dilantin, diltiazem, hydrochlorthiazide, penicillamine, sulfonylurea, betablocker, griseofulvin, NSAIDs and minocycline.
Reports suggesting the role of other drugs in the development of LE
endorse the names of amiodarone,173 etanercept,174 infliximab,175 antiTNF-alpha,176 propylthiouracil177 and ticlopidine178
Drug-induced subacute lupus erythematosus (SCLE) is a newly
described entity which is associated with the calcium channel blocker,
diltiazem. Such SCLE like lesions are also reported to result from the use
of antifungal agent, terbinafine.179
103
104
Anti-retroviral drugs
Side-effects
Indinavir
Ritonavir
Nelfinavir
Saquinavir
Nevirapine
Zidovudine
Didanosine
Lamivudine
Zalcitabine
Acute porphyria183
Hypersensitivity syndrome24
SJS184
Maculopapular drug eruption185
Gynecomastia186,187
Alopecia188,189
Paronychia and Pyoderma gangrenosum190
Spontaneous bleeding hematoma formation (especially
in hemophiliac)191
Morbilliform eruption192
Urticaria193
Fixed drug eruption194
Gynecomastia195
SJS80,81,196,197
Hypersensitivity syndrome198,199
Nail pigmentation200
Cutaneous pigmentation201
Vasculitis202
Hypertrichosis (including eye-lash hypertrichosis)203,204
Paronychia with nail fold pyoderma gangrenosum205
Hypersensitivity syndrome206
Heightened reaction to mosquito bite207
Vasculitis208
SJS209
Papuloerythroderma of Ofuji210
Paronychia211
Hypersensitivity syndrome212
Morbilliform eruption213
105
106
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hypersensitivity syndrome. Arch Dermatol 1996; 132: 1315-21.
200. Fisher CA, Mc Poland PR. Azidothymidine induced nail pigmentation. Cutis
1988; 43: 552-4.
201. Obuch ML, Baker C, Roth Ri, et al Selective cutaneous hyperpigmentation in
mice following zidovudine administration. Arch Dermatol 1992: 28: 508-13.
114
202. Torres RA, Lin RY, Lee M, et al. Zidovudine induced leucocytoclastic vasculitis.
Arch Intern Med. 1992; 152: 850-1.
203. Sahai J, Conway B, Cameron D, et al. idovudine associated hypertrichosis and
nail pigmentation in a HIV-infected patient. AIDS 1991; 5: 1995.
204. Kintman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with
AIDS being trated with zidovudine. N Eng J Med 1991: 324: 1896.
205. Russo F, Collantes C, Guerren J. Severe paronychia due to zidovudine
neutropenia in neonate. J Am Acad Dermatol 1999. 40: 322-4.
206. Jacobson MA, McGarth MS, Joseph P. et al. Zidovudin induced fever. J. Acquir
Immune Defic Syndr 1984; 100: 495-9.
207. Diven DG, Newton RC, Ramsey KM. Heightened cutaneous reaction to
mosquito bites in patients with acquired immuno-deficiency syndrome
receiving zidovudine. Arch Intern Med. 1988; 148: 2296.
208. Herranz P, Fernandez-Diaz ML, Lucas R, et al. Cutaneous vasculitis associated
with didanosine. Lancet 1994; 344: 680.
209. Parneix Spake A, Bastuji-Garin S, Levy Y. et al Didanosine as a probable cause
of Stevens-Johnson syndrome. Lancet 1992; 340: 857-8.
210. Just M, Carrascosa JM, Ribera M, et al. Dideoxyinosine associated Ofuji
ppuloerythroderma in a HIV infected patient. Dermatology 1997; 1995; 4101.
211. Zerboni R, angins AG, Cusini M, et al. Lamivudine induced paronychia. Lancet
1998; 351 1256.
212. Tancred-Bohin E. Grange F, Bournerios I et al. Hypersensitivity syndrome
associated with zalcitabine. Lancet 1996: 347: 971.
213. Yarchoan R, Thomas RV, Allain JP, et al. Phase I studies of 2,3-dideoxycytidine
in severe human immuno deficiency virus infection as a single agent and
alternating with zidovudine. Lancent 1988; 1: 76-81.
115
Sanjay Ghosh
The Scleroderma
Disorders: An Update
The scleroderma disorders encompass a group of heterogeneous disorders
representing sclerosis of skin as the linking clinical feature.1
The dust of controversies regarding many facts of these disorders are
yet to settle. However, recent researches have thrown some scattered
light in the different misty corners of these disorders, which have led to
better understanding of their pathogenesis and thus more rational
approach in their management.
The detailed description of every aspect of these disorders is beyond
scope of the present article which will mainly highlight certain intriguing
facts as well as some recent informations about the disorders.
CLASSIFICATION
The scleroderma-related disorders have been primarily classified into
two basic types: localized and systemic. These localized and systemic
forms have again been subdivided into different subtypes (Tables 7.1
and 7.2).2,3 The term systemic sclerosis seems to be preferable over
systemic scleroderma, as the former denotes the frequent occurrence of
internal manifestations seen in these disorders.4
Inclusion of lichen sclerosus et atrophicus (LSA) into the localized
scleroderma group has been questioned, but certain rational facts may
firmly support this view: (i) guttate morphea and LSA clinically resemble
each other quite often; (ii) co-existence of LSA and morphea has been
well documented both clinically and histopathologically;5 (iii) in partially
treated morphea with intralesional corticosteroid, LSA types of lesions
appeared5 and (iv) Borrelia burgdorferi has been detected both in morphea
and LSA patients of Europe and Asia by PCR analysis.6
Severe generalized morphea may mimick diffuse systemic sclerosis
but the former always spares the hands and face and does not present
with manifestations of major vascular or visceral involvement.4 Morphea
patch may simulate Hansens patch because both may show diminished
sensation as depicted by quantitative thermal test,7 diminished sweating
response and absence of hairs. Histopathology may ultimately solve this
dilemma.
116
Plaque morphea
Morphea en plaque
Guttate morphea
Atrophoderma of Pasini and Pierini
Keloid morphea (nodular morphea)
[Lichen Sclerosus et atrophicus]
Generalized morphea
Bullous morphea
Linear morphea
Linear morphea (linear scleroderma)
En coup de sabre
Progressive hemifacial atrophy
Deep morphea
Subcutaneous morphea
Eosinophilic fascitis
Morphea profunda
Disabling pansclerotic morphea of children
Systemic
Sclerosis
(SSc)
Related forms
Prescleroderma
Overlap syndrome
Environment-induced scleroderma
Systemic sclerosis sine scleroderma
117
Limited (lcSSc)
Diffuse (dcSSc)
Years
2. Involvement
a. Skin
b. Systemic
c. Vascular
d. Fibrosis
Acral
Late, uncommon
Predominant
Less
Truncal + Acral
Early, common
Less
Predominant
3. Nailfold capillary
No drop out
Drop out
4. Antibodies
Anticentromere
antibodies (ACA)
(40%)
Scl-70 (30%)
5. Prognosis
Less gloomy
Gloomy
by the extent of the skin sclerosis: lcSSc is restricted to the hands, and
to some extent, the face and neck, whereas dcSSc extends proximal to
the wrists and involves proximal limbs and trunk but commonly sparing
the upper back. The salient features of the two subsets have been
enumerated in the Table 7.3.
Drawbacks of Current Classification System
The present two subset classification system is of some definite practical
value as working classification but possesses some inherent flaws:
(1) Clinical outcomes within each major subset are so diverse, (2)
Prognosis remains unpredictable; although overall survival is graver for
dcSSc than for lcSSc, certain patients with lcSSc may also show high
mortality rate, e.g., lcSSc patients showing pulmonary hypertension,
lung fibrosis or acute renal failure, (3) Genetic and serological predictors
of end-organ involvement have not been accounted into the present
classification system: antibodies to topoisomerase-I (Scl-70) are associated
with increased risk of pulmonary fibrosis both in lcSSc and dcSSc,8
anticentromere antibodies (ACA) are almost always sign of lcSSc and
are especially associated with the classical CREST variants of this disorder,
anti-histone antibodies (AHA) are associated with cardiac, pulmonary
and renal involvement, and (4) Racial factors and HLA types have also
not been considered into this system; HLA-DR52a is associated with an
increased risk of lung fibrosis in Caucasians, but not in the other racial
groups.10
118
119
120
121
122
been indentified and carriage of one or two alleles with deletion genotype
has been associated with increased risk of developing scleroderma. A
single nucleotide polymorphism in the gene for endothelial nitric oxide
synthase (eNOS) has similarly got increased risk of developing
scleroderma.40
Infectious Agents
An infectious agent may trigger autoimmune and other events in a
genetically susceptible host, resulting in scleroderma. Infection with a
virus containing a similar amino acid sequence to that of a host protein
may precipitate scleroderma. This phenomenon, although not unique to
scleroderma, is called molecular mimicry. Such a shared epitope between
topoisomerase I and certain retroviruses has been found.37
Latent viral infection may also augment or promote disease expression
in the susceptible host. Cytomegalovirus may thus alter the vascular,
fibrotic and immunologic features of systemic sclerosis. 41 Recent
investigations33 have shown that the autoantibodies in SSc react with the
UL94 human cytomegalovirus protein. These auto-antibodies also induce
endothelial cell apoptosis.
Morphea/LSA: Borrelia Controversy
The hypothesis that morphea is caused by infection with Borrelia
burgdorferi has been challenged repeatedly. The following facts may be
noteworthy: (1) morphea shares many clinico-pathological features of
acrodermatitis chronica atrophicans caused by Borrelia burgdorferi;42
(2) Borrelia burgdorferi DNA was detected in morphea and LSA patients
of Europe and Asia but not of North America,43 (3) geographical
differences exist between different species of Borrelia; Borrelia burgdorferi
has three geno species namely, B. garinii and B. afzelli (in Europe and
Asia) and B. sensu stricta (in North America). Thus, it can be concluded
that a subset of morphea/LSA, not all, especially among patients in
Euope and Asia but not in North America may be caused by special
subspecies of Borrelia burgdorferi.44
Non-infectious Environmental Agents
A number of environmental agents have been incriminated in the etiology
of systemic sclerosis. Exposure to silica has been suspected for long
period, but recent epidemiological studies have uniformly failed to
support a causative relationship.45 Scleroderma-like diseases clearly
appear to occur among individuals exposed to manufacturing process
123
124
125
missed during the first few months of disease as arthralgia and soft
tissue swelling may be the most prominent clinical features in this phase
rather than skin sclerosis.51
Certain organ specific investigations and serological tests are also
required for confirmation of diagnosis and for correct classification. In
a patient of Raynauds phenomenon, for example, abnormal esophageal
motility by scintigraphy or barium swallow may aid in the diagnosis of
scleroderma. Abnormal nailfold capillaroscopy also confirms a diagnosis
of secondary Raynauds in case of diagnostic dilemma.51
The combination of sclerodermatous skin changes plus one or more
of the following features point towards the diagnosis of systemic sclerosis:
1. The abrupt onset of renal insufficiency plus hypertension in the
absence of significant urine pathology
2. Dyspnea due to pulmonary interstitial fibrosis
3. Pulmonary hypertension
4. Diarrhea with malabsorption51
Serological Tests
Scleroderma or an overlap syndrome may be associated with the presence
of characteristic autoimmune antibodies: anticentromere, antitopoisomerase-I (Scl 70), anti-RNA polymerase, or U3-RNP antibodies. A positive
antinuclear staining pattern, seen in most of the SSc patients, has much
less sensitivity and specificity than previously thought.51
Some important observations regarding autoantibodies in systemic
sclerosis are as follows:
1. Anticentromere antibodies favour a diagnosis of lcSSc (especially
CREST)
2. Antitopoisomerase I (Scl 70), although not very sensitive, are highly
specific for dcSSc.
3. Anti-RNA polymerase I and III are only seen in systemic sclerosis;
Anti-RNA polymerase II are found only in systemic sclerosis or SLE.53
4. Antibodies to U3-RNP (fibrillarin) are found in systemic sclerosis,
especially those with pulmonary hypertension.51
In a patient suspected to be suffering from scleroderma should
undergo a baseline antibody profile test including ANA, anti-Scl 70 and
anti-centromere antibodies (ACA). However, a diagnosis of scleroderma
cannot be excluded by a negative serological test due to the low sensitivity
of these antibodies.54
Anti PM-Scl antibodies are associated with myositis and the presence
of high titers of rheumatoid factor, anti U1-RNP antibodies or lupusassociated antibodies suggests overlap syndromes. These syndromes
126
Diffuse cutaneous
(dcSSc)
Vascular therapy
Early
Immunomodulatory
quickly
followed by
antifibrotic
agents
NonPharmacological
pharmacological
Surgical
Late
Antifibrotic
agents
127
128
129
130
131
132
133
134
135
69. Stratlon RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus
mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology
(Oxford) 2001; 40: 83-5.
70. Casciola-Rosen L, Wigley F, Rosen A. Scleroderma autoantigens are uniquely
fragmented by metal-catalyzed oxidation reactions: Implications for
pathogenesis. J Exp Med 1997; 185: 70-3.
71. Clements PJ, Furest DE, Worg WK, et al. High-dose versus low-dose
D-penicillamine in early diffuse systemic sclerosis. Arthritis Rheum 1999;
1193-6.
72. Freundlich B, Jimenez SA, Steen VD, et al. Treatment of systemic sclerosis with
recombinant inteferon-gamma. Arthritis Rheum 1999; 35: 1133-7.
73. Stratton R, Shiwen X, Martini G, et al. Iloprost suppresses connective tissue
growth factor production in fibroblasts and in the skin of scleroderma patients.
J Clin Invest 2001; 108: 240-4.
74. Seibola JR, Kom JH, Simms R, et al. Recombinant human relaxin in the treatment
of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann
Intern Med 2000; 132; 870-4.
75. Le SCH, Morales A, Trentham DE. Minocycline in early diffuse scleroderma.
Lancet 1998; 352; 1753-7.
76. Ghosh S. Glimpses of scleroderma. 31st National Conference of IADVL, Kolkata
Abstracts, 2003; 76.
77. Binks M, Passweg JR, Furst D, et al. Phase I/II trial of autologous stem cell
transplantation in systemic sclerosis: procedure related mortality and impact
on skin disease. Ann Rheum Dis 2001; 60: 576-9.
78. McSweerey PA, Nash RA, Sulbivan KM, et al. High dose immunosuppressive
therapy for severe systemic sclerosis: initial outcomes. Blood 2002; 100: 16013.
79. Farge D, Marolleau JP, Zohar S, et al. Autologous bone marow transplantation
in the treatment of refractory systemic sclerosis: early results from a French
multicenter phase I-II study. Brit J Haematol 2002; 119: 724-8.
80. Denton CP, Abraham DJ. Transforming growth factor-beta and connective
tissue growth factor: Key cytokines in scleroderma pathogenesis. Curr Opin
Rheumatol 2001; 13: 504-7.
81. Cunnigham BB, Landello IDR, Langman G, et al. Topical calcipotriene for
morphea/linear scleroderma. J Am Acad Dermatol 1998; 39: 211-5.
82. Kerscher M, Volkanandt M, Gruss C, et al. Low-dose UVA phototherapy for
treatment of localised scleroderma. J Am Acad Dermtol 1998; 38: 21-6.
83. Seyger MMB, vanden Hoogen FHJ, de Boo T, et al. Low-dose methotrexate in
the treatment of widespread morphea. J Am Acad Dermatol 1998; 39: 220-5.
84. Denton CP. Organ-based therapy in scleroderma. www. UpToDate.com. 2002;
August: 10.3.
85. Palmieri GM, Sabes JI, Aclion JA, et al. Treatment of calcinosis with diltiazem.
Arthritis Rheum 1995; 38: 1645-8.
136
A.K. Bajaj
137
138
have also been introduced. However, even with the correct techniques
small amounts of test material may diffuse slightly beyond the site of
patch test. Occasionally metal salts-like mercury, cobalt and nickel interact
with aluminium but this effect can be eliminated by plastic coated Finn
chamber.
The concept and technique of patch testing has been revolutionized
by the pioneering work of Fischer and Maibach who have introduced
the TRUE (Thin layer rapid use epicutaneous) Test.9,10 It is an innovative
ready to apply test method that uses polyester patches coated with
allergens in hydrophilic vehicle. It meets almost all the pre-requisites of
an ideal test method due to the least possible time consumed in
application of the patches, uniform distribution and release of antigen,
less amount of antigen required, minimum irritant reactions, easy storage
and stability, whereas the significant drawbacks are the limited number
of antigens available and high cost.
Several studies have been conducted comparing Finn chambers and
TRUE Test methodologies. In a European multicenter study of TRUE
Test,11 808 patients were simultaneously tested with 11 different allergens
(Panel 12) by both TRUE Test and Finn Chamber method. Left/right
application of the respective test varied at random. Most tests were
removed after 48 h and evaluated after 72 or 96 h according to generally
accepted recommendations. The concordance of positive reactions was
63 percent between TRUE test and the control method; 17 percent of
positive reactions occurred only with TRUE test and 20 percent only
with Finn Chamber method. Approximately 75 percent of all positive
reactions were explained by the patients present or past history. Irritant/
questionable reactions occurred in the same frequency for the two
methods and were less than 10 percent of all patches applied. No late
reactions were recorded.
In a recent study,12 167 patients were patch tested using both the
NACDG (North American Contact Dermatitis Group) standard screening
tray and TRUE Test. TRUE Test missed 50 percent of relevant reactions
to fragrances that were detected by the fragrance-mix applied with Finn
Chamber. In contrast the Finn Chamber method missed only 1 of 14
relevant reactions to fragrances. Of positive reactions with balsam of
Peru, 88.9 percent were clinically relevant and 55.6 percent of the relevant
reactions detected by Finn Chamber were missed by TRUE Test. Similarly
TRUE Test missed 4 of 7 relevant reactions to thiuram mix. TRUE Test
performed somewhat better than the Finn Chamber methodology in
detecting allergic reactions to nickel, neomycin and kathon CG. Of all
relevant positive reactions to nickel sulphate, Finn Chamber missed 25
percent while TRUE Test 6.25 percent. Similarly in the case of neomycin
139
140
141
142
after 6-8 weeks with positive patches placed widely apart and usage
test may be helpful.
c. Artefact: Sometimes a patient seeking compensation may try to
simulate a positive reaction by scratching or otherwise irritating the
skin.
False Negative Reactions
A false-negative reaction is one in which the patch test is negative despite
the patient being sensitive to the allergen. The various causes of false
negative reaction are:
a. The substance is small, the concentration of the allergen is low or it
is poorly absorbed or insufficiently released.
b. Non-occlusion, loosening of the patch and early removal.
c. Refractory state, which sometimes occurs immediately after a very
severe allergic contact dermatitis. The patient fails to respond to the
dilute allergens but reacts when retested several weeks later. A similar
diminution of reactivity may occur in patients who are on oral
prednisolone in daily doses of more than 20 mg.
d. False false-negative reactions: these reactions are observed when
patients are tested with TRUE Test methodology. Sherertz et al32
evaluated 318 patients by patch testing simultaneously with Hermal
allergens using Finn Chambers and the TRUE Test allergen system.
Finn Chamber tests showed reactions in 84 percent of balsam of
Peru, 67 percent of fragrance, 76 percent of thiuram and 75 percent
of carba mix reactions. TRUE Test was positive in only 29 percent,
50 percent, 46 percent, and 64 percent respectively for the same
allergens in this patient population. These results suggested that
positive reactions to fragrance, thiuram and carba mix allergens may
be missed if only the TRUE Test is used.
PATCH TESTING OF UNKNOWN SUBSTANCES
For patch testing of unknown substances, the following steps should be
taken.
Try to search for safety data on the given substance.
Perform open test with dilutions.
Try to dissolve the substance in water, petrolatum, acetone, methyl
ketone, ethanol etc.
In case of leave on products (body lotions, creams, lipsticks etc.), use
them as such for patch testing.
In case of wash off products (shaving creams, tooth pastes etc.), use
10 and 100 times dilutions.
143
144
145
Usage Tests
When the history suggests contact hypersensitivity and the patch tests
are negative, the patient should be asked to use the preparation again.
As it reproduces all the factors associated with the original dermatitis
(sweating, friction, damaged skin), it is sometimes positive when a
conventional patch test is negative. However, it may not always
differentiate allergic from non-allergic reactions. This test is useful in
suspected cosmetic and clothing dermatitis.
Repeated Open Application Test (ROAT)
The substances are applied twice daily on at least a 5 cm2 area on the
upper arm for 7 days or until positive eczematous reaction develops.33
This test may be used to help determine the relevance of doubtful
positive patch-test reactions to preparations in which the suspected
allergen is present in a low concentration.
Intradermal Tests
It is not commonly used, except for investigative purposes, due to
numerous technical pitfalls, non-availability of sterile solutions, active
sensitization and ethical considerations. It has been proved reliable for
nickel and corticosteroids.
REFERENCES
1. Staedeler J. Uber die eigen Thumlichen Bestandtheile der Anacardium Fruchte.
Ann Chemie Pharmacie 1847;1:87-98.
2. Collins EJ. Atropine irritation. R Lond opthal Hosp Rep 1889;12:164.
3. Jadassohn J. Zur kenntnis der medicamentosen Dermatosen verhandlingen
der Deutschen. Dermatologischen Gesellschaft, V Congress, Wien 1895:103129.
4. Sulzeberger MB, Wise F. The contact or patch test in dermatology. Arch Dermatol
1931;23:519-31.
5. Revised European Standard Series. Contact Dermatitis 1988;19:391.
6. Cronin E, Calnan CD. Allergy to hydroabietic alcohol in adhesive tape. Contact
Dermatitis 1978; 4:57-9.
7. Fregert S. Manual of contact dermatitis. 2nd ed. Copenhagen.
8. Fischer T, Maibach HI. The Finn chamber patch test technique. Contact
Dermatitis 1984;11:137-140.
9. Fischer T, Maibach HI. The thin layer rapid use epicutaneous test (TRUE test)
a new patch test method with high accuracy. Br J Dermatol 1985;112:63-8.
10. Fischer T, Maibach HI. Easier patch testing, TRUE test . J Am Acad Dermatol
1989;20:447-53.
146
11. Wilkinson JD, Bruynzeel DP, Ducombs G et al. European multicenter study of
TRUE Test Panel 2. Contact Dermatitis 1990;22:218-25.
12. Suneja T, Belsito DV. Comparative study of Finn chambers and TRUE test
methodologies in detecting the relevant allergens inducing contact dermatitis.
J Am Acad Dermatol 2001;45:836-9.
13. Ruhnek Forsbeck M, Fischer T, Meding B, et al. Comparative multi-center
study with TRUE test and Finn Chamber Patch Test Methods in eight Swedish
Hospitals. Acta Derm Venereol 1988;68:123-8.
14. Lachapelle JM, Bruynzeel DP, Ducomb G, et al. European multicenter study
of the TRUE Test. Contact Dermatitis, 1988;19:91-7.
15. Goh CL. Comparative study of TRUE Test and Finn chamber patch test
techniques in Singapore. Contact Dermatitis 1992;27:84-9.
16. Vozmediano JMF, Hita JCA. Concordance and discordance between TRUE Test
and Finn chamber. Contact Dermatitis 2000;42:182-3.
17. Cronin E. Contact Dermatitis Edinburgh, London, New York: Churchill
Livingstone 1980;7-8.
18. Fisher AA. Contact Dermatitis, 3rd edn. Philadelphia: Lea and Febiger
1986;10,394,423.
19. Rietschel RL, Adams RM, Maibach HI, et al. The case for patch test readings
beyond D2. J Am Acad Dermatol 1988;18:42-5.
20. Todd DJ, Handley J, Metwali M, et al. Day 4 is better than day 3 for a single
patch test reading. Contact Dermatitis 1996;34:402-04.
21. Uter WCJ, Geier J, Schnuch A. Good clinical practice in patch testing; readings
beyond day 2 are necessary. A confirmatory analysis. Am J Contact Dermatitis
1996;7:231-7.
22. Geier J, Gefeller O, Weichmann K, Fuchs T. Patch test reactions at D4, D5 and
D6. Contact Dermatitis 1999;40:119-26.
23. Jonker MJ, Bruynzeel DP. The outcome of an additinal patch test reading on
days 6 or 7. Contact Dermatitis 2000;42:330-5.
24. Mitchell JC. The angry back syndrome. Eczema creates eczema. Contact
Dermatitis 1975;1:193-4.
25. Maibach HI. The excited skin syndrome. In: Ring J, Burg G, eds. New Trends
in Allergy. New York: NY Springer Verlag, 1981, 208-291.
26. Mitchell JC. Multiple concomitant positive patch test reactions. Contact
Dermatitis 1977;3:315-20.
27. Bruynzeel DP, Maibach HI. Excited skin syndrome (Angry Back). Arch Dermatol
1986;122:323-8.
28. Andersen KE, Maibach HI. Cumulative irritancy in the guinea pig from low
grade irritant vehicles and the angry back syndrome. Contact Dermatitis
1980;6:130-4.
29. Kligman A, Gollhausen R. The angry back; a new concept or old confusion?
Br J Dermatol 1986;115:93-100.
30. Cockayne SE, Gawkrodger DJ. Angry back syndrome is often due to marginal
irritants; a study of 17 cases seen over 4 years. Contact Dermatitis 2000; 43:
280-2.
31. Duarte I, Lazzarini R, Bedrikow R. Excited Skin Syndrome; study of 39 patients.
Am J Contact Dermatitis 2002;13:59-65.
32. Sherertz EF, Fransway AF, Belsito DV et al. Patch testing discordance alert;
False negative findings with rubber additives and fragrances. J Am Acad
Dermatol 2001;45:313-4.
33. Hannuksela M, Salo H. The repeated open application test (ROAT). Contact
Dermatitis 1986;14:221-7.
147
148
S. Clinical entities
No.
1. Primary syphilis
2. Chancroid
3. Donovanosis
4. Lymphogranuloma
venereum
5. Herpes genitalis
6. Gonorrhea
7. Non-gonococcal
urethritis
8. Trichomoniasis
149
Table contd...
S. Clinical entities
No.
9. Genital chlamydial
infection
150
S. Clinical entities
No.
1. Primary syphilis
2. Chancroid
3. Donovanosis
4. Lymphogranuloma
venereum
5. Herpes genitalis
or
or
or
or
or
151
Table contd...
S. Clinical entities
No.
6. Gonorrhea
7. Non-gonococcal
urethritis
8. Trichomoniasis
9. Genital chlamydial
infection
10. Bacterial vaginosis
examination or direct immunofluorescent staining. More recent technological methods, such as solid phase enzyme linked immunosorbent
assay and PCR evaluations, have failed to improve diagnostic detection
rates of T. pallidum that are at approximately 85 to 92 percent.1
Penicillin has remained the mainstay of therapy for syphilis.1,3 CDC
recommended treatment for primary, secondary and early latent syphilis
consists of a single intramuscular injection of 2.4 million units of
benzathine penicillin. Treatment failures with this regimen may reach as
high as 5 to 10 percent. Non-pregnant, penicillin allergic patients may
be given a 2 weeks course of either doxycycline 100 mg twice daily,
tetracycline 500 mg 4 times daily or erythromycin 500 mg 4 times daily.
The management of early syphilis in those who are HIV co-infected
remains controversial. Some authorities recommend weekly 3 injections
of benzathine penicillin in order to prevent possible progression to
152
153
154
diameter while the Donovan bodies are 0.50.7 by 11.5 m and may or
may not be capsulated.12 Specimens from sites just below the surface of
the ulcer are more likely to yield positive results than those from
superficial tissue. Donovan bodies have also been identified from
Papanicolaou smears used in routine cervical cytology screening.
Additional methods used in the past that have only limited relevance
now include antigen detection, complement fixation, and skin tests.
The causative organism, Calymmatobacterium granulomatis, has been
cultured for the first time in many years and a polymerase chain reaction
using a colorimetric detection system has been developed that could be
used by diagnostic laboratories in the future.12
Important new agents introduced in the treatment of donovanosis
include azithromycin, ceftriaxone and fluorinated quinolones.13 WHO
guidelines recommend azithromycin 1 g, immediately then 500 mg daily
but do not state the duration of therapy.14 In Australia, doses of either
1 g of azithromycin weekly for 46 weeks or less, if healing is complete,
or 500 mg once daily for 1 week only were adequate.12,15
Center for Disease Control and Prevention (CDC)8 in 2002 recommends therapy in the form of doxycycline 100 mg orally twice a day for
at least 3 weeks, or trimethoprim-sulfamethoxazole one double-strength
(800 mg/160 mg) tablet orally twice a day for at least 3 weeks. Alternative
regimens includes ciprofloxacin 750 mg orally twice a day for at least
3 weeks, or erythromycin base 500 mg orally four times a day for at least
3 weeks, or azithromycin 1 g orally once per week for at least 3 weeks.
Therapy should be continued for at least 3 weeks or until all lesions
have completely healed. Some specialists recommend addition of an
aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to the
above regimens, if improvement is not evident within the first few days
of therapy. Epidemiological treatment can be considered in the absence
of signs and symptoms in sexual partners of index cases.
Lymphogranuloma Venereum (LGV)
Lymphogranuloma venereum (LGV) is a rare disease caused by serovars
L1, L2 and L3 of the obligate intracellular bacterium Chlamydia trachomatis.16 Whereas serovars AK are largely confined to mucosal columnar
epithelial surfaces of the genital tract and eye, the LGV serovars infect
predominantly monocytes and macrophages, pass through the epithelial
surface to regional lymph nodes and may cause disseminated infection.
The clinical course of LGV can be divided into three stages. The
primary stage involves the site of inoculation; the secondary stage the
regional lymph nodes and sometimes the anorectum; and late sequelae,
affecting the genitals and/or rectum, comprise the tertiary stage.16
155
156
157
158
Center for Disease Control and Prevention (CDC)8 in 2002 recommends following treatment for genital herpes:
First Clinical Episode of Genital Herpes
Acyclovir 400 mg orally three times a day for 710 days, or acyclovir
200 mg orally five times a day for 710 days, or famciclovir 250 mg
orally three times a day for 710 days, or valacyclovir 1 g orally twice
a day for 710 days.
Recurrent Eisodes of HSV Disease
Acyclovir 400 mg orally three times a day for 5 days, or acyclovir 200
mg orally five times a day for 5 days, or acyclovir 800 mg orally twice
a day for 5 days, or famciclovir 125 mg orally twice a day for 5 days,
or valacyclovir 500 mg orally twice a day for 35 days, or valacyclovir
1.0 g orally once a day for 5 days.
For Suppressive Therapy for Recurrent Genital Herpes
Acyclovir 400 mg orally twice a day, or famciclovir 250 mg orally twice
a day, or valacyclovir 500 mg orally once a day, or valacyclovir 1.0 gram
orally once a day. Periodically, once a year discontinuation of suppressive
therapy should be discussed. In HIV infected patients, a higher dose of
antiherpes drugs for longer duration may be required.
Increasing evidence shows that many herpes infections are
asymptomatic.26 The rate of viral shedding from the genital tract of
asymptomatic and seropositive people is similar to that of those with a
history of symptomatic infection (3% and 2.7%, respectively). Consistent
use of condoms may help to reduce the risk by covering exposed or
susceptible mucous membranes and skin. It has also been suggested
that the continuous use of antiherpes drugs may reduce the risk of
transmission by decreasing the quantity of asymptomatic viral shedding.
Considerable interest has been shown in the development of a vaccine
to prevent acquisition of genital herpes, although results from early
trials have been conflicting.26
URETHRITIS, CERVICITIS AND/OR VAGINITIS RELATED STDs
Gonorrhea
Gonorrhea has always taken second place to syphilis.30 In recent years
it has been considered as one of those bacterial sexually transmitted
diseases (STDs) that persists despite modern antibiotics. The continued
159
spread of the disease warns that the safer sex message has not been
brought home to those individuals and their sexual partners. There is
also some evidence to link both ulcerative and purulent genital infections
to HIV acquisition.30
In men, there is urethral discharge and variable dysuria, but in women,
one-third will have no symptoms.30 In heterosexuals, one-third of patients
will also be infected with concurrent C. trachomatis. Rectal gonorrhea has
either no symptoms, or at the most, some minimal discomfort or
discharge. Often, it is a sexual partner who complains of catching an
infection. Likewise, gonorrhea in the throat usually has no symptoms;
diagnosis is commonly made after a throat culture as part of the clinical
examination.30
These days, eye infection is rare in adults.30 Very little of disseminated
gonococcal infection or gonococcal dermatitis syndrome seems to be
reported at present. The possibility always remains of untreated
gonorrhea in men leading to epididymo-orchitis, chronic urinary tract
pathology and infertility. If left untreated in women, it leads to acute,
then chronic, pelvic inflammatory disease and infertility and rarely,
gonococcal perihepatitis. Septic arthritis is more common in women
than men.30
Resistance to antimicrobials is found all over the world.30 Comparative results for resistance to penicillin were 8.1 percent, the resistance
being either plasmid-mediated or chromosomally-mediated whereas
resistance to tetracycline was up to 32.5 percent. Additionally, resistance
to azithromycin was shown in 0.3 percent of cases. The worldwide
resistance trends to the fluoroquinolones are well recognized, first being
noted in Southeast Asia. Resistance to ciprofloxacin has been reported
in several regions of the world, including India.31 In India, ciprofloxacin
is still being used as single-dose treatment for gonorrhea. In the recently
published study from India, 35.3 percent and 52.9 percent of Neisseria
gonorrhoeae isolates were found to be resistant and less sensitive,
respectively, to penicillin; 67.3 percent and 28.2 percent strains were
observed to be resistant and less sensitive, respectively, to ciprofloxacin.31
The diagnosis of gonorrhea is based on microscopic identification of
the organisms and culture.32 No serologic testing for N. gonorrhoeae is
available. A variety of direct methods including DNA hybridization,
direct immunofluorescent examination and ELISA are available, but
they have not yet replaced culture and direct examination. Recently,
nucleic acid amplification tests (NAATs) have been introduced as critical
new tools to diagnose and treat C. trachomatis and N. gonorrhoeae
infections.33 NAATs can detect both C. trachomatis and N. gonorrhoeae
organisms in the same specimen. However, NAATs are usually more
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Patients, who have persistent or recurrent urethritis, should be retreated with the initial regimen, if they did not comply with the treatment
regimen or if they were re-exposed to an untreated sex partner.8
Otherwise, a culture of an intraurethral swab specimen and a first-void
urine specimen for T. vaginalis should be performed. Some cases of
recurrent urethritis following doxycycline treatment may be caused by
tetracycline-resistant U. urealyticum.8
Trichomoniasis
Trichomoniasis remains an extremely common infection despite the fact
that rates of other treatable sexually transmitted diseases are declining.35
Trichomonas vaginalis, a flagellated parasite, is the causative agent of this
infection. Symptoms of trichomoniasis in women include vaginal
discharge, irritation and pruritus; however, about half of all women
infected with T. vaginalis are asymptomatic.36 Signs of infection in women
include vaginal discharge, odor and oedema or erythema. In males, the
prevalence and spectrum of disease is far less well characterized; the
infection appears usually to be asymptomatic. However, it has been
suggested as an increasingly important cause of non-gonococcal urethritis
(NGU).37
Diagnosis of trichomoniasis in the female is usually accomplished
via direct microscopic examination of the vaginal fluid. The sensitivity
of this test is only 60 percent.38 Culture of T. vaginalis is currently the
gold standard for diagnosis of trichomoniasis.39 Polymerase chain reaction
(PCR) techniques thus far have given variable results, especially in
women.35, 40 Diagnosis, in general, is much more difficult for males with
the best culture results yielded by combining urethral swabs and urine
sediment.37
In most cases, trichomoniasis is easily treated with a single dose of
metronidazole and because it is an STD, sexual partners should be
routinely treated.8 Center for Disease Control and Prevention (CDC) in
2002 recommends metronidazole 2 g orally in a single dose or alternative
regimen-metronidazole 500 mg twice a day for 7 days. Resistant cases
of trichomoniasis appear to occur sporadically.41 Tinidazole appears to
be an attractive alternative to metronidazole. It has a longer half-life
than metronidazole and has been effective in some cases of trichomoniasis
that were resistant to metronidazole.41
Chlamydia Infection
Chlamydia trachomatis is the most commonly diagnosed bacterial sexually
transmitted infection in the developed world and a leading cause of
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3. Thappa DM. Current status of HIV modified syphilis in Indian scenario. Indian
J Sex Transm Dis 2002; 23: 5-13.
4. Balchandran C, Pai BS. Chancroid. In: Sharma VK, ed. Sexually Transmitted
Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003: 21620.
5. Lewis DA. Diagnostic tests for chancroid. Sexually Transm Inf 2000; 76:137141.
6. Odom RB, James WD, Berger TG. Andrews Diseases of the Skin-Clinical
Dermatology, 9th edn. Philadelphia: WB Saunders Company 2000:335.
7. Lewis DA. Chancroid: from clinical practice to basic science. AIDS Patient Care
STDs 2000; 14:1936.
8. Center For Disease Control. Sexually transmitted diseases: Treatment guidelines
2002. MMWR Morbidity Mortality Weekly Report 2002; 51 (No. RR-6): 11-50.
9. Ernst AA, Marvez-Valls E, Martin DH. Incision and drainage versus aspiration
of fluctuant buboes in the emergency department during an epidemic of
chancroid. Sex Transm Dis 1995; 22:21720.
10. Ganesh R. Donovanosis. In: Sharma VK, ed. Sexually Transmitted Diseases
and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:221-25.
11. Rao MV, Thappa DM, Jaishankar TJ, et al. Extragenital donovanosis of the
foot. Sex Transm Inf 1998; 74:298-9.
12. OFarrel N. Donovanosis. Sex Transm Inf 2002; 78:452-7.
13. Birley H, Duerden B, Hart CA, et al. Sexually transmitted diseases: microbiology
and management. J Med Microbiol. 2002; 51(10): 793-807.
14. WHO. Guidelines for the management of sexually transmitted infections.
2001;22-35.
15. Bowden FJ, Mein J, Plunkett C, et al. Pilot study of azithromycin in the treatment
of genital donovanosis. Genitourin Med 1994; 72:179.
16. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Inf 2002;
78:90-2.
17. Bajaj AK, Sharma R. Lymphogranuloma venereum. In: Sharma VK, ed. Sexually
Transmitted Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited,
2003: 247-52.
18. Van Dyck E, Meheus AZ, Piot P. Laboratory diagnosis of sexually transmitted
diseases. Geneva: World Health Organization, 1999.
19. Wang SP, Grayston JT. Immunologic relationship between genital TRIC,
lymphogranuloma venereum and related organisms in a new microtiter indirect
immunofluorescence test. Am J Ophthalmol 1970; 70:36774.
20. Clad A, Freidank HM, Kunze M, et al. Detection of seroconversion and
persistence of Chlamydia trachomatis antibodies in five different serological
tests. Eur J Clin Microbiol Infect Dis 2000; 19:9327.
21. Viravan C, Dance DAB, Ariyarit C, et al. A prospective clinical and bacteriologic
study of inguinal buboes in Thai men. Clin Infect Dis 1996; 22:2339.
22. Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis
infections. Clin Micro Rev 1997; 10:16084.
23. Kumar B, Gupta S, Sahoo B. Epidemiology of genital herpes-current concepts.
Indian J Sex Transm Dis 2001; 22:2-4.
24. Thappa DM. History of venereal diseases and venereology in India. Indian J
Sex Transm Dis 2002; 23:67-79.
25. Singh S, Jaisankar TJ, Thappa DM. Risk factors for transmission of HIV among
STD clinic attendees at Pondicherry. Indian J Sex Transm Dis 2001; 22:27-30.
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48. Stanek R, Gain RE, Glover DD, et al. High performance ion exclusion
chromatographic characterization of the vaginal organic acids in women with
bacterial vaginosis. Biomed Chromatog 1992; 6: 2315.
49. Thomason JL, Gelbart SM, James JA, et al. Is analysis of vaginal secretions for
volatile organic acids to detect bacterial vaginosis of any diagnostic value? Am
J Obstet Gynecol 1988; 159: 150911.
50. Cauci S, Monte R, Driussi S, et al. Impairment of the mucosal immune system:
IgA and IgM cleavage detected in vaginal washings of a subgroup of patients
with bacterial vaginosis. J Infect Dis 1998; 178: 16981706.
51. McGregor JA, French JI, Jones W, et al. Association of cervicovaginal infections
with increased vaginal fluid phospholipase A2 activity. Am J Obstet Gynecol
1992; 167: 158894.
52. Schoonmaker JN, Lunt BD, Lawellin DW, et al. A new proline aminopeptidase
assay for diagnosis of bacterial vaginosis. Am J Obstet Gynecol 1991; 165:
73742.
53. Thomason JL, Gelbart SM, Wilcoski LM, et al. Proline aminopeptidase activity
as a rapid diagnostic test to confirm bacterial vaginosis. Obstet Gynecol 1988;
71: 607-11.
54. Spiegel CA, Amsel R, Holmes KK. Diagnosis of bacterial vaginosis by direct
gram stain of vaginal fluid. J Clin Microbiol 1983; 18: 1707.
55. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis
is improved by a standardized method of gram stain interpretation. J Clin
Microbiol 1991; 29: 297301.
56. Thomason JL, Anderson RJ, Gelbart SM, et al. Simplified gram stain
interpretative method for diagnosis of bacterial vaginosis. Am J Obstet Gynecol
1992; 167: 169.
57. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole
therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992; 268:
925.
58. Sweet RL. New approaches for the treatment of bacterial vaginosis. Am J
Obstet Gynecol 1993; 169: 47982.
59. Hillier SL, Lipinski C, Briselden AM, et al. Efficacy of intravaginal 0.75%
metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol
1993; 81: 9637.
60. von Krogh G, Lacey CJN, Gross G, et al. European course on HPV associated
pathology: guidelines for primary care physicians for the diagnosis and
management of anogenital warts. Sex Transm Inf 2000; 76:162-8.
61. Usman N. Anogenital warts. In: Sharma VK, ed. Sexually Transmitted Diseases
and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:273-82.
62. Dogra S, Kumar B. Circumcision in genital wartslet us not forget! (Letter).
Sex Transm Inf 2003; 79:265.
63. von Krogh G, Longstaff E. Podophyllin office therapy against condyloma
should be abandoned. Sex Transm Inf 2001; 77:409-12.
64. Brook MG. Sexually acquired hepatitis. Sex Transm Inf 2002; 78:235-40.
65. Singh S, Thappa DM, Jaisankar TJ, et al. Sexual co-transmission of HIV, hepatitis
B and hepatitis C viruses, Sex Transm Inf 2000; 76:317.
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Narrowband
UV-B Phototherapy:
A Newer Advance in
the Treatment of Vitiligo
Phototherapy using psoralens has been a time-tested treatment for
vitiligo, perhaps since vedic times. A combination of oral psoralens and
UVA (either from an artificial source or from natural sunlight) still remains
the mainstay therapy for vitiligo even in modern times. However, adverse
effects like nausea and other gastrointestinal discomfort, persistent UVA
sensitivity, the potential risk for liver toxicity, cataracts, melanoma and
non-melanoma skin cancer, and therapeutic helplessness in treating
children young of age limit the utility of systemic PUVA in the treatment
of vitiligo.1 Topical PUVA therapy has some advantages over systemic
PUVA therapy but inability to employ on wide areas and an increased
potential for photo-irritant reactions limit its use as well.
A significant advance in the treatment of dermatological disorders in
recent years has been the introduction of fluorescent bulbs (Philips model
TL-01) with a spectrum of 310- 315 nm and a peak emission at 311 nm.
These longer, specific wavelengths of UV-B, labeled as narrowband UVB which are less erythemogenic than the shorter forms of UV-B have
been used successfully for the treatment of a number of dermatological
diseases. In studies on psoriasis,2-5 narrowband UV-B therapy has been
found to be as effective as PUVA without the distinct disadvantages of
the latter and was considerably superior to broadband UV-B (290-320
nm) and bath PUVA. Narrowband UV-B therapy was subsequently found
to be effective for the treatment of atopic dermatitis in both children and
adults,6-8 and in a host of other diseases that include seborrheic dermatitis,9 subcorneal pustular dermatosis,10,11 small plaque parapsoriasis,12
pruritic folliculitis of pregnancy,13 pruritus of polycythemia vera,14
polymorphic light eruption,15,16 erythropoietic protoporphyria,17 and
mycosis fungoides.18 The pioneering work of Westerhof and colleagues
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176
better had their disease for a shorter duration of time. Adverse effects
were minimal and transient.
In a left-right comparative study in a 20-year-old Indian male with
vitiligo, a combination of calcipotriol (50 mcg/g) and narrowband UVB was found to be superior to narrowband UV-B given as monotherapy
in achieving lesional re-pigmentation.30
NEWER DEVELOPMENTS
Narrowband UV-B Micro-phototherapy
One of the disconcerting effects of phototherapy or photochemotherapy
is the uneven re-pigmentation of the treated areas (although this is
minimal with narrowband UV-B therapy). One of the innovations that
is claimed to overcome this erratic effect is narrowband UV-B microphototherapy that delivers narrowband UV-B directly to the lesions,
using different conical hoods, through special phototherapy devices
(Bioskin). Recent studies31,32 have shown that this type of therapy is
particularly applicable for the treatment of limited vitiligo (with less
than 30 percent skin surface involvement) and segmental vitiligo.
308-nm Excimer Laser Therapy
The 308-nm excimer laser is a new and exciting innovation combining
the two major achievements in medical photo-technology, viz., the use
of a fiber-optic light delivery system and having a 308 nm emission line,
and has FDA, U.S.A. approval for treatment of patients with psoriasis.
Several recent studies attest to its usefulness in focal, non-responding
recalcitrant plaques of psoriasis.33,34 Its use in vitiligo is new and relatively
unexplored. Spencer and colleagues from the US.35 undertook a pilot
study to see its effects in focal vitiligo. 29 patches of vitiligo from 18
patients were treated with the laser, 3 times a week for a maximum of
12 treatments. At the end of the study period, partial to near complete
re-pigmentation was seen in those who completed the treatment protocol.
308-nm excimer laser carries the same advantages as microphototherapy,
but because of the small spot size, its use can be limited only to focal
examples of vitiligo. In a recent study, Taneja and colleagues from U.S.A.
using twice-weekly 308-nm UV-B radiation for a maximum of 60
treatments demonstrated that the excimer laser is an effective option for
inducing re-pigmentation in localized, stable, recalcitrant lesions of
vitiligo.36
177
CONCLUSIONS
While PUVA in its various forms has remained and continues to remain
the mainstay therapy for vitiligo for many physicians and most patients
who do not have access to sophisticated phototherapy units, Narrowband
UV-B therapy is indeed a very significant advance to those adults and
children of vitiligo who have such access. Our experience with this new
technology is limited at this point of time and its long-term safety is
unknown. Although the potential for skin carcinogenicity in type V and
VI skin even with PUVA therapy is low, dose-response models suggest
that long-term narrowband UV-B therapy may carry less risk for skin
cancer than PUVA.18 If proved in further trials, narrowband UV-B
microphototherapy and the super narrowband 308-nm excimer laser
therapy may even be greater advances than narrowband UV-B therapy,
as the UV radiation can be directly delivered to the lesions.
REFERENCES
1. Morison WL, Baughman RD, Day RM, et al. Consensus workshop on the toxic
effects of long-term PUVA therapy. Arch Dermatol 1998;134: 595-8.
2. Coven TR, Burack LH, Gilleaudeau R, et al. Narrowband UV-B produces
superior clinical and histopathological resolution of moderate-to-severe psoriasis
in patients compared with broadband UV-B. Arch Dermatol 1997; 133: 151422.
3. Tanew A, Radakovic-Fijan S, Schemper M, et al. Narrowband UV-B
phototherapy vs photochemotherapy in the treatment of chronic plaque-type
psoriasis: a paired comparison study. Arch Dermatol 1999: 135: 519-24.
4. Markham T, Rogers S, Collins P. Narrow-band UV-B (TL-01) phototherapy vs.
oral 8-methoxypsoralen UV-A for the treatment of chronic plaque psoriasis.
Arch Dermatol 2003;139:325-8.
5. Dawe RS, Cameron H, Yule S, et al. A randomized controlled trial of narrowband
ultraviolet B vs. bath-psoralen plus ultraviolet A photochemotherapy for
psoriasis. Br J Dermatol 2003;148:1194-1204.
6. George SA, Bilsland DJ, Johnson BE, et al. Narrowband (TL-01) UVB airconditioned Phototherapy for chronic severe adult atopic dermatitis. Br J
Dermatol 1993; 128: 49-56.
7. Collins P, Ferguson J. Narrowband (TL-01) UVB air-conditioned Phototherapy
for atopic eczema in children. Br J Dermatol 1995; 133:653-5.
8. Der-Petrossian M, Seeber A, Honigsmann H, et al. Half-side comparison study
on the efficacy of 8-methoxypsoralen bath-PUVA versus narrow-band ultraviolet
B phototherapy in patients with severe chronic atopic dermatitis. Br J Dermatol
2000; 142: 39-43.
9. Pirkhammer D, Seeber A, Honigsmann H, et al. Narrow band ultraviolet B
(TL-01) Phototherapy is an effective and safe treatment option for patients
with severe seborrhoeic dermatitis. Br J Dermatol 2000; 143: 964-8.
10. Cameron H, Dawe RS. Subcorneal pustular dermatosis (Sneddon-Wilkinson
disease) treated with narrowband (TL-01) UVB phototherapy. Br J Dermatol
1997; 137: 150-1.
178
11. Orton DI, George SA. Subcorneal pustular dermatosis responsive to narrowband
(TL-01) UVB Phototherapy. Br J Dermatol 1997; 137: 149-50.
12. Hofer A, Cerroni L, Kerl H,et al. Narrowband (311-nm) UV-B therapy for small
plaque parapsoriasis and early stage mycosis fungoides. Arch Dermatol 1999;
135: 1377-80.
13. Reed J, George S. Pruritic follicultits of pregnancy treated with narrowband
(TL-01) ultraviolet B Phototherapy. Br J Dermatol 1999; 141: 177-9.
14. Baldo A, Sammarco E, Plaitano R, et al. Narrowband (TL-01) ultraviolet B
phototherapy for pruritus in polycythemua vera. Br J Dermatol 2002; 47:97881.
15. Bilsland D, George SA, Gibbs NK, et al. A comparison of narrow band
phototherapy (TL-01) and photochemotherapy (PUVA) in the management of
polymorphic light eruption. Br J Dermatol 1993; 129: 708-12.
16. Collins P, Ferguson J. Narrow-band UVB (TL-01) Phototherapy: an effective
preventative treatment for the photodermatoses. B J Dermatol 1995; 132: 95663.
17. Warren LJ, George S. Erythropoietic protoporphyria treated with narrow-band
(TL-01) UVB phototherapy. Australas J Dermatol 1998; 39: 179-82.
18. Clark C, Dawe RS, Evans AT, et al. Narrowband TL-01 phototherapy for patch
stage mycosis fungoides. Arch Dermatol 2000;136: 748-52.
19. Westerhof W, Nieweboer-Krobotova L. Treatment of vitiligo with UV-B radiation
vs topical psoralen plus UV-A. Arch Dermatol 1997; 133: 1525-8.
20. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children
with narrowband (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000;
42: 245-53.
21. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for vitiligo. J Am
Acad Dermatol 1996;35:620-6.
22. Westerhof W. The treatment of vitiligo with UV-B 311 nm: Fine Tuning. CME
lecture on pigmentary disorders. 31st National conference of I.A.D.V and L,
30th January to 2nd February 2003, Kolkata, India.
23. Imokawa G, Miyagishi M, Yada Y. Endothelin-I as a new melanogen: Coordianted expression of its gene and the tyrosinase gene in UVB exposed
human epidermis. J Invest Dermatol 1995; 105: 32-7.
24. Huang CL, Nordlund JJ, Boisy R. Vitiligo: A manifestation of apoptosis? Am
J Clin Dermatol 2002;3:301-8.
25. Moodycliffe AM, Kimber I, Norval M. The effect of ultraviolet B irradiation
and urocanic acid isomers on dendritic cell migration. Immunology 1992;77:3949.
26. el-Ghorr AA, Norval M, Lappin MB, et al. The effect of chronic low-dose UVB
radiation on Langerhans cells, sunburn cells, urocanic acid isomers, contact
hypersensitivity and serum immunoglobulins in mice. Photochem Photobiol
1995: 62: 326-32.
27. Seite S, Zucchi H, Moyal D, et al. Alterations in human epidermal Langerhans
cells by ultraviolet radiation: quantitative and morphological study. Br J
Dermatol 2003;148:291-9
28. Njoo MD, Spuls PI, Boss MD, et al. Nonsurgical pigmentation therapies in
vitiligo: meta-analysis of the literatue. Arch Dermatol 1998;134: 1532-40.
29. Scherschun L, Kim JJ, Lim HW. Narrow-Band ultraviolet B is a useful and
well-tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44: 999-1003.
30. Dogra S, Parsad D. Combination of narrowband UV-B and topical calcipotriol
in vitiligo. Arch Dermatol 2003; 139: 393.
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11
Dinesh Hawelia
Newer Drugs in
Dermatology: Systemic
Within the past few years, a number of new systemic drugs has been
showing quite effective and encouraging therapeutic outcome in different
skin diseases. In fact, a few of them are gradually elbowing out the
existing choices and establishing their indispensability. Interestingly,
certain abandoned drugs have taken rebirth to find new indications.
Keeping these in mind, the following newer agents have been chosen
and discussed.
MYCOPHENOLATE MOFETIL
It is a morpholinoethyl ester prodrug of the active mycophenolic acid
(MPA), a fermentation product of several Penicillium species. It acts as
a potent immunosuppressant.1
Mechanism of Action
It selectively and non-competitively inhibits the type 2 isoform of inosine
monophosphate dehydrogenase (IMPDH) which is an enzyme required
for the conversion of IMP (inosine monophosphate) to XMP (xanthine
monophosphate), a precursor of guanine nucleotides.2 Thus the de novo
synthesis of guanine nucleotides are blocked, which are necessary
substrates for the DNA and RNA synthesis. Lymphocytes depend
primarily on de novo pathway of purine synthesis whereas other cell
types have a salvage pathway of purine synthesis. Type 2 isoform of
IMPDH is present in proliferating lymphocytes3 whereas type 1 isoform
is present in resting lymphocytes. Capacity of mycophenolate mofetil
(MMF) to inhibit IMPDH type 2 isoform is five times greater than that
for type 1 isoform.3 MMF is, therefore, cytotoxic to proliferating T and
B lymphocytes.4 MMF also leads to decreased level of immunoglobulins
and delayed type hypersensitivity responses.5
Pharmacokinetics6,7
MMF is well absorbed orally and is rapidly converted to active metabolite
MPA by plasma esterases. MPA is then further metabolized in the liver
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182
Contraindications
Hypersensitivity to any component of the drug is the chief contraindication. It has category C prescribing status in pregnancy.
Adverse Effects
MMF is usually well tolerated. The most common side effect is
gastrointestinal, which is dose related and includes nausea, vomiting,
diarrhoea, anorexia, soft stools, abdominal cramps and anal tenderness.28,29 The incidence of these side-effects decrease dramatically after
first year of therapy.7 There may be reversible dose-related anemia,
neutropenia and decreased platelet count.30-33
The incidence of infections may increase after MMF therapy,
particularly, Herpes Zoster. There may be an increased risk of lymphoma
or malignancies when MMF is used as a component of immunosuppressive regimen and this risk is probably due to duration and
intensity of immunosuppression rather than to the use of any specific
agent. No incidence of carcinogenesis was reported in a 13-year study
by Epinette 34 for psoriasis. Urgency, frequency, dysuria and sterile pyuria
may be observed and these are common, dose and time dependent sideeffects.7 Clinically significant nephrotoxicity has never been reported.
Its potential teratogenic status is still unknown. There are reports of
headache, tinnitus, insomnia, weakness and fatigue which, however, do
not necessitate discontinuation of therapy.
Drug Interaction
Agents interfering with enterohepatic recycling (e.g. Antibiotics, bile
acid sequestrants) reduce the amount of MPA available for reabsorption.
Drugs eliminated by renal tubular secretion (e.g. Acylovir, ganciclovir)
inhibit the elimination of MPAG by competing for renal tubular secretion.
Concomitant administration of oral MMF with ferrous sulfate tablets
may lead to decrease in MMF absorption.35
IVERMECTIN
Ivermectin is a semi-synthetic derivative of a family of macrocyclic
lactones, the avermectins, which are naturally produced in soil by
Streptomyces avermitilis. It is a macrocyclic lactone structurally similar to
macrolide antibiotics but devoid of antibacterial activity. It was approved
by US-FDA in 1996 for the treatment of strongyloidiasis and onchocerciasis. However, off-label uses of this compound are widespread.
183
Mechanism of Action
Ivermectin binds selectively and with high-affinity to structures of
glutamate-gated chloride ion channels, 36,37 which are present in
invertebrate nerve and muscle cells. Some suggest that it binds with
glycine-gated structures.38 In either case, ivermectin simulates the ligand
and increases the permeability of cell membrane to chloride ions by
opening the gate and thus, allowing an efflux of chloride ions leading
to the release of associated neuro-transmitter, gamma-aminobutyric acid
(GABA) which results in hyperpolarisation of nerve and muscle cells
causing paralysis and death of the parasite. At higher concentration,
ivermectin acts as an antagonist of the GABA neuro-transmitter. In insects,
these GABA neurons and receptors are mainly present in peripheral
nervous system whereas in mammals, they are located in central nervous
system.36,39 Ivermectin does not readily cross blood-brain barrier in
humans and this adds to the safety of ivermectin therapy.
Many authorities believe that ivermectin primarily interferes with
function of gastrointestinal tract of target parasites and thus, these insects
starve to death under the influence of the drug.38,40,41
Pharmacokinetics
Ivermectin is absorbed from gastrointestinal tract after oral intake and
peak plasma level is achieved in 4 hours. It is absorbed well in an empty
stomach. It is 93 percent bound to plasma-proteins and has a plasma
elimination half-life of about 12 to 16 hours.42 Main metabolism takes
place in liver and it is excreted largely as metabolites over a period of
2 weeks, mainly in feces.
Indications and Dosage
Ivermectin was approved by US-FDA in 1996 for use in strongyloidiasis
and onchocerciasis.43-46 Even low doses of ivermectin are quite effective
in strongyloidiasis. When compared with albendazole, it is significantly
more effective.48-50 Nearly 95 percent of thiabendazole-treated subjects
had short-term adverse effects during therapy in contrast to only 18
percent of those treated with ivermectin.51 Ivermectin is also effective
for strongyloidiasis in the setting of HIV infection.52 An oral dose of
ivermectin 200 micrograms/kg effectively treats all types of scabies in
otherwise healthy patients and in many patients with HIV infections.53,54
Most authorities recommend a second dose 5 to 14 days after the first
dose because it is probably not ovicidal.55 Two such doses of ivermectin
given 1 to 2 weeks apart are equivalent to topical permethrin in efficacy56
184
185
186
187
well.98 Thalidomide99 in the dose of 100-300 mg/day controls the symptoms within two weeks and ulcers heal dramatically within 2-4 weeks,99
but relapses commonly occur on discontinuation of therapy. Interestingly,
thalidomide treated group showed increased plasma levels of TNFalpha and HIV-RNA.100 Chronic diarrhea of AIDS patients due to microsporidiosis respond to 100 mg daily dose of thalidomide.101 Thalidomide,
probably due to its antiangiogenic property, is found to be useful in
Kaposis sarcoma in a case study.102 Recurrent aphthous stomatitis and
Behcets disease in immunocompetent patients also respond to thalidomide at a dose of 100-300 mg/day. Ulcers remit within 1-2 weeks but
relapse on cessation of therapy.103 In Behcets syndrome, oral and genital
lesions heal very rapidly, but not the ocular lesions by thalidomide in
a dose of 400 mg/day for five days which is then tapered to 200 mg/
day for up to two months.104 Clearly, patients with HIV-associated oral
and esophageal ulcer benefit more from thalidomide therapy than
immunocompetent patients with aphthous ulcers with or without
Behcets disease.73
Thalidomide is an effective therapeutic alternative for various
cutaneous forms of lupus erythematosus (LE).105-113 Fifty to ninety percent
of patients with chronic cutaneous LE (CCLE)105,107 and subacute
cutaneous LE (SCLE)105,110 achieve complete or near-complete remission.
Both CCLE and SCLE usually respond to 50-200 mg/day of thalidomide
within 2-4 weeks and then a maintenance dose of 25-50 mg/day is
required for most patients.105,107,108,110 Relapse occurs in 70-75 percent of
patients on discontinuing thalidomide, but patients usually respond to
a new course of the drug.105 Systemic features of systemic LE (SLE) do
not show any response to thalidomide but skin lesions show 90 percent
improvement and steroid dosage can be reduced on concomitant
thalidomide therapy. Lupus profundus112 showed favourable response
to thalidomide.
Thalidomide is useful in treating chronic graft vs host disease
(CGVHD)114-116 refractory to conventional immunosuppressive/glucocorticoid therapy, when added to the regime, provided the patients can
tolerate side-effects. This beneficial effect is more pronounced in children
because they tolerate the drug better. However, thalidomide cannot be
used for prophylaxis of CGVHD.117
Actinic prurigo118,119 and prurigo nodularis120,121 respond to thalidomide in initial doses of 300-400 mg/day within three months in most
instances. Dose can be tapered to 50 mg/day subsequently but symptoms
recur if drug is stopped.119 Ninety percent of patients of polymorphous
light eruption (PMLE)122 show good to excellent response in an average
of two weeks on thalidomide therapy. Thalidomide may be considered
188
189
190
191
192
193
194
195
196
32. Gomez EC. Efficacy of mycophenolic acid for the treatment of psoriasis. J Am
Acad Dermatol 1979; 1:531.
33. Marinari R, Fleischmajer R, Schragger AH, et al. Mycophenolic acid in the
treatment of psoriasis: Long-term administration. Arch Dermatol 1977;113:9302.
34. Epinette WW, Parker CM, Jones EL, et al. Mycophenolic acid for psoriasis: A
review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol
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35. Morii M, Ueno K, Ogawa A, et al. Impairment of mycophenolate mofetil
absorption by iron ion. Clin Pharmacol Ther 2000; 68:613-6.
36. Burkhart CN. Ivermectin: An assessment of its pharmacology, microbiology
and safety. Vet Hum Toxicol 2000;42:30-5.
37. Kane NS, Hirschberg B, Qian S, et al. Drug-resistant Drosophilia indicate
glutamate-gated chloride channels are targets for the antiparasites nodulispordic
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38. Shan Q, Haddrill JL, Lynch JW. Ivermectin, an unconventional agonist of the
glycine receptor chloride channel. J Biol Chem 2001;276;12556-64.
39. Bredal WP. Death associated with ivermectin for scabies. Lancet 1997;350:216.
40. Ros-Moreno RM, Moreno-Guzman MJ, Jimenez-Gonzalez A, et al. Interaction
of ivermectin with gamma-aminobutyric acid receptors in Trichinella spiralis
muscle larvae. Parasitol Res 1999;85:320-3.
41. Shoop WL. Structure and activity of ivermectins and milbemycins in animal
health. Vet Parasitol 1995;59:139-56.
42. James ER. Antiparasitic agents. In: Wolverton SE, ed. Comprehensive
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43. Brieger WR, Awedoba AK, Eneanya CI, et al. The effects of ivermectin on
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44. Brown KR, Neu DC. Ivermectin clinical trials and treatment schedules in
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45. Newell ED. Effect of mass treatments with ivermectin, with only partial
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46. Ngoumou P, Essomba RO, Godin C. Ivermectin-based onchocerciasis control
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47. Stromectol (ivermectin). Package insert, Merck and Co.West Point, PA.1996.
48. Datry A, Hilmarsdottir I, Mayorga- Sagastume R, et al. Treatment of
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49. Toma H, Sato Y, Shiroma Y, et al. Comparative studies on the efficacy of three
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50. Marti H, Haji HJ, Savioli L, et al. A comparative trial of a single-dose ivermectin
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51. Gann PH, Neva FA, Gam AA. A randomized trial of single-and two-dose
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52. Celedon JC, Mathur-Wagh U, Fox J, et al. Systemic strongyloidiasis in patients
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53. Alberici F, Pagani L, Ratti G, et al. Ivermectin alone or in combination with
benzyl benzoate in the treatment of human immunodeficiency virus- associated
scabies. Br J Dermatol 2000;142:969-72.
54. Meinking TL, Taplin D, Hermida JL, et al. The treatment of scabies with
ivermectin. N Engl J Med 1995;333:26-30.
55. Elgart GW, Meinking TL. Ivermectin, Dermatol Clin 2003;21:277-82.
56. Usha V, Gopalakrishnan- Nair TV. A comparative study of oral ivermectin and
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57. Madan V, Jaskiran K, Gupta U, et al. Oral ivermectin in scabies patients: A
comparison with 1% topical lindane lotion. J Dermatol 2001;28:481-4.
58. Ivermectin is better than benzyl benzoate for childhood scabies. J Paediatr
Child Health 2002;38:401-4.
59. Burkhart CG, Burkhart CN. Optimal treatment for scabies remains
undetermined. J Am Acad Dermatol 2001;45:637-8.
60. Haas N, Henz BM, Ohlendorf D. Is a single oral dose of ivermectin sufficient
in crusted scabies? Int J Dermatol 2001;40:599-600.
61. Glaziou P, Nyguyen LN, Moulia- Pelat JP, et al. Efficacy of ivermectin for the
treatment of head lice (Pediculosis capitis). Trop Med Parasitol 1994;45:253-4.
62. Das PK, Ramaiah KD, Vanamail P, et al. Placebo-controlled community trial
of four cycles of single-dose diethylcarbamazine or ivermectin against
Wuchereria bancrofti infection and transmission in India. Trans R Soc Trop
Med Hyg 2001;95:336-41.
63. El Haouri M, Erragragui Y, Sbai M, et al. (Cutaneous filariasis Loa Loa: 26
Moroccan cases of importation). Ann Dermatol Venereol 2001;128:899-902.
64. Ismail MM, Jayakody RL, Weil GL, et al. Efficacy of single dose combinations
of albendazole, ivermectin and diethylcarbamazine for the treatment of
Bancroftian filariasis. Trans R Soc Trop Med Hyg 1998;1:94-7.
65. Nguyen NL, Moulia-Pelat JP, Cartel JL. Control of Bancroftian filariasis in an
endemic area of Polynesia by ivermectin 400 micrograms/kg. Trans R Soc Trop
Med Hyg 1996;90:689-91.
66. Bouchaud O, Houze S, Schiemann R, et al. Cutaneous larva migrans in
travellers: A prospective study, with assessment of therapy with ivermectin.
Clin Infect Dis 2000;31:493-8.
67. Caumes E, Datry A, Paris L, et al. Efficacy of ivermectin in the therapy of
cutaneous larva migrans. Arch Dermatol 1992;128:994-5.
68. Caumes E, Carriere J, Datry A, et al. A randomized trial of ivermectin versus
albendazole for the treatment of cutaneous larva migrans. Am J Trop Med Hyg
1993;49:641-4.
69. Caumes E. Treatment of cutaneous larva migrans. Clin Infect Dis 2000;30:8114.
70. Jelenek T, Nothdurft HD, Rieder N, et al. Cutaneous myiasis: Review of 13
cases in travellers returning from tropical countries. Int J Dermatol 1995;34:6246.
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74. Tseng S, Pak G, Washenik K, et al. Rediscovering thalidomide: A review of its
mechanism of action, side-effects and potential uses. J Am Acad Dermatol
1996;35:969-79.
75. Powell RJ, Gardner-Medwin JMM. Guideline for the clinical use and dispensing
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76. Stirling D, Sherman M, Strauss S. ThalidomideA surprising recovery. J Am
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77. Alfred LK Jr. Miscellaneous Systemic Drugs. In Wolverton SE, ed.
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78. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumour
necrosis factor-alpha production by stimulated human monocytes. J Exp Med
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79. Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by
thalidomide. J Immunol 1997; 159:5157-61.
80. McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug
thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1
cytokine production in mitogen-and antigen-stimulated human peripheral blood
mononuclear cell cultures. Clin Exp Immunol 1995;99:160-7.
81. Gad SM,Shannon EJ, Krotoski WA, et al. Thalidomide induces imbalances in
T-lymphocyte sub-populations in the circulating blood of healthy males. Lepr
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82. Hastings RC. Kellersberger Memorial Lecture 1979: Immunosuppressive/antiinflammatory thalidomide analogues. Ethiop Med J 1980;18:65-71.
83. Faure M, Thivolet J, Gaucherand M. Inhibition of PMN leucocytes chemotaxis
by thalidomide. Arch Dermatol Res 1980;269:275-80.
84. Neubert R, Helgel L, Neubert D. Downregulation of adhesion receptors on
cells of primate embryos as a probable mechanism of the teratogenic action of
thalidomide. Life Sci.1995;58:295.
85. McCarty MF. Thalidomide may impede cell migration in primates by downregulating integrin beta-chains: Potential therapeutic utility in solid
malignancies,proliferative retinopathy,inflammatory disorders, neo-intimal
hyperplasia, and osteoporosis. Med Hypotheses 1997;49:123.
86. DAmato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of
angiogenesis. Proc Natl Acad Sci USA 1994;91:4082-5.
87. Chen TL, Vogelsang GB, Petty Busy, et al. Plasma pharmacokinetics and urinary
excretion of thalidomide after oral dosing in healthy male volunteers. Drug
Metab Dispos 1989;17:402-05.
88. Schumacher H, Smith RL, Williams RT. The metabolism of thalidomide: The
fate of thalidomide and some of its various hydrolysis products in various
species. Br J Pharmacol 1965;25:338-51.
89. Robertson J. Thalidomide revisited. Okla St Med Assoc J 1972;65:45.
90. Marwick C. Thalidomide back under strict control. JAMA 1997;278:1135-7.
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113. Warren KJ, Nopper KJ, Crosby DL. Thalidomide for recalcitrant discoid lesions
in a patient with systemic lupus erythematosus. J Am Acad Dermatol
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114. Parker PM, Chao N, Nadermanee A, et al. Thalidomide as salvage therapy for
chronic graft-versus-host disease. Blood 1995;86:3604-9.
115. Cole CH, Rogers PCJ, Pritchard S, et al. Thalidomide in the management of
chronic graft-versus-host disease in children following bone-marrow
transplantation. Bone Marrow Transplant 1994;14:937-42.
116. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of
chronic graft-versus-host disease. N Engl J Med 1992;326:1055-8.
117. Chao NJ. Paradoxical effect of thalidomide prophylaxis in chronic graft-versushost disease. Biol Blood Marrow Transplant 1996;2:86.
118. Grabczyska SA, Hawk JL. Managing PLE and actinic prurigo. Practitioner
1997;241:74-9.
119. Londono F. Thalidomide in the treatment of actinic prurigo. Int J Dermatol
1973;12:326-28.
120. van den Broek H. Treatment of prurigo nodularis with thalidomide. Arch
Dermatol 1980;116:571.
121. Winkelmann RK, Connolly SM, Doyle JA, et al. Thalidomide treatment of
prurigo nodularis. Acta Derm Venereol 1984;64:412.
122. Saul A, Flores O, Novales J, et al. Polymorphous light eruption: Treatment with
thalidomide. Australas J Dermatol 1976;17:17-21.
123. Thomas L, Ducros B, Secchi T, et al. Successful treatment of adults Langerhans
cell histiocytosis with thalidomide: Report of two cases and literature review.
Arch Dermatol 1993;129:1261-4.
124. Dallafior S, Pugin P, Cerny T, et al. Successful treatment of a case of cutaneous
Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide.
Hautarzt 1995;46:553-60.
125. Meunier L, Marck Y, Ribeyre C, et al: Adult cutaneous Langerhans cell
histiocytosis: Remission with thalidomide treatment. Br J Dermatol 1995;132:168.
126. Misery L, Larbre B, Lyonnet S, et al. Remission of Langerhans cell histiocytosis
with thalidomide treatment. Clin Exp Dermatol 1993;15:487.
127. Eravelly J, Waters MF. Thalidomide in Weber-Christian disease. Lancet
1977;1:251.
128. Hamza M. Behcets disease, palmoplantar pustulosis and HLA-B27 treatment
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130. Barnhill RL, McDougall AC. Thalidomide: Use and possible mode of action in
reactional lepromatous leprosy and in various other conditions. J Am Acad
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131. Naafs B, Faber WR. Thalidomide therapy: An open trial. Int J Dermatol
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132. Moisson YF, Janier M, Civatte J. Thalidomide for recurrent erythema
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12
Susmit Haldar
Newer Drugs in
Dermatology: Topical
With the turn of the new millennium, a number of new topical therapeutic
agents has emerged as promising and effective remedies for treating
various skin diseases. Dermatologists are now happy to have a series of
new drugs, both topical and systemic, in their armamentarium. A few
topical agentsTacrolimus and pimecrolimus especially in the treatment
of atopic dermatitis (AD), Imiquimod as an immune response modifier
in warts, Cidofovir in viral skin diseases and Tazarotene as a new topical
retinoid especially for psoriasis and acnedeserve mention. These drugs
are discussed and reviewed below.
TACROLIMUS
Topical corticosteroids are till now the pivot in the management of
inflammatory skin diseases since 1952.1 In spite of arduous attempts to
lessen the side effects of topical corticosteroids without compromising
its efficacy, we could hardly achieve this goal.1 Topical tacrolimus is the
first of a new class of non-steroidal immunosuppressants which does
not cause dermal atrophy, an important advantage over topical
corticosteroid.2
Tacrolimus, previously known as FK506, was first discovered in 19842
and its immunosuppresant properties were first described in 1987.1
Tacrolimus is a macrolide produced by a soil fungus Streptomyces
tsukubaensis present in the soil of Mount Tsukuba, Japan.3 The new
name Tacrolimus is derived from t for Tsukuba, its place of discovery;
acrol for macrolide, its chemical class; and imus for its
immunosuppressive activity.2,3
Mechanism of Action
The mechanism of action of tacrolimus is closely related to that of
cyclosporine.2 Calcineurin, a calcium-activated phosphatase is the
common target which is blocked by both cyclosporine and tacrolimus.4
205
206
207
15 years, both 0.03 percent and 0.1 percent tacrolimus oinment were
more effective than 1 percent hydrocortisone acetate.28 Similar findings
were shown when 0.1 percent tacrolimus was compared with
aclomethasone dipropionate for atopic eczcma of head and neck.27
Other Uses
Topical tacrolimus has been found to be ineffective in chronic plaque
psoriasis probably because of poor penetration through hyperkeratotic
skin.29 However, it is reported to be effective in facial lesions of psoriasis
and initial observations in inverse psoriasis appear encouraging.2
Tacrolimus 0.3 percent in carmellose sodium paste is found to be effective
in parastomal pyoderma gangrenosum where 4 out of 5 patients were
completely cured.30 A few studies have shown the efficacy of topical
tacrolimus in mucosal erosive lichen phanus.31-33 Tacrolimus has been
found to be as equally effective as mometasone furoate in chronic
dyshidrotic eczema of the hands.34 In a series of 18 cases of graft-versushost disease (GVHD), more than 70 percent has rapid alleviation of
erythema and pruritus by 0.1 percent tacrolimus ointment although all
patients required additional systemic therapy.2 In these patients of GVHD,
tacrolimus is not an adequate therapy, but may be a useful agent in
rapid controlling of symptoms while slower therapies are initiated. In
open trial of chronic actinic dermatitis involving face and neck, 0.1
percent tacrolimus appeared to be effective in facial skin.35 Tacrolimus
has been used successfully in ichthyosis linearis circumflexa, recalcitrant
leg ulcers associated with rheumatoid arthritis, allergic contact dermatitis
and rosacea while no effect in alopecia areata.2 There are a host of other
skin diseases like seborrheic dermatitis, dyshidrotic eczema, hand eczema
and vitiligo where trial of topical tacrolimus is going on.2
Side Effects
Skin burning at the site of application, flu-like symptoms, headache,
skin tingling, folliculitis, alcohol intolerance, skin infection, acne,
hyperesthesia and cyst are all reported, but among these, burning at the
site has been the most frequently observed side effects.2 Interestingly,
skin infection incidence is almost similar between vehicle and 0.03 percent
tacrolimus oinment, but 0.1 percent tacrolimus shows significantly lower
incidence than vehicle (4.7% versus 11%).17 So far as safety is concerned
on long-term use of topical tacrolimus, it can be used safely up to
1 year.17-19 Even then, there is a theoretical risk of skin malignancy on
long-term use of topical tacrolimus,3 especially an increased risk of photocarcinogenesis which needs to be monitored.22 Although a formal
208
209
210
211
212
1.
2.
3.
4.
5.
6.
Cytokines
Designation
Putative function
Interferon
Interferon
Interleukin 1
Interleukin 5
Interleukin 6
Interleukin 8
IFN-
IFN-
IL-1
IL-5
IL-6
IL-8
IL-1RA
Antiviral
Antiviral
Lymphocyte stimulation
B-cell growth and activation
NK cell activation
T lymphocyte, neutrophil
attraction
B cell activation
NK cell activation; IFN-
production
IL1 inhibition
GM-CSF
MIP1 ,
Macrophage activation
MCP-1
Macrophage attraction
TNF-
Interferon-like protective
effects
Stimulates cytokine
production
Tumor-killing by macrophages
7. Interleukin 10
8. Interleukin 12
9. Interleukin 1 receptor
antagonist
10. Granulocyte-macrophage
colony-stimulating factor
11. Macrophage inflammatory
protein
12. Macrophage chemotactic
protein
13. Tumor necrosis factor-
IL-10
IL-12
NKNatural Killer.
Quoted and adapted from the article by Mark V. Dahl. J Am Acad Dermatol 2002;
47: S205-8.
213
214
215
216
217
and acts as a competitive inhibitor and alternate substrate for viral DNA
polymerase.83 When it is incorporated in the DNA strand of a growing
virus, it acts as a chain terminator and blocks further viral DNA synthesis.
The unique difference between cidofovir and acyclovir (ACV) in an
otherwise similar mechanism of action lies in the first step of
phosphorylation. While ACV depends on viral thymidine kinase (TK) to
undergo first stage phosphorylation, cidofovir does not.83 This can well
explain how cidofovir remains sensitive to strains of HSV resistant to
acyclovir, ganciclovir or foscarnet.84 In addition, cidofovir inhibits viral
DNA polymerase more selectively than human DNA polymerase.85 The
human DNA polymerase is not capable of excising the incorporated
cidofovir diphosphate from viral DNA strand. This fact, in combination
with reduction of viral DNA synthesis, may explain the prolonged activity
of cidofovir beyond the half-life (17 to 65 hours) of the active metabolite.86
Cidofovir does not demonstrate activity against RNA viruses.
Pharmacology
There has been report only for the intravenous preparation of cidofovir
so far as the pharmacokinetic properties are concerned.87,88 Cidofovir,
when administered systemically, shows pharmacokinetic features (i.e.
volume of distribution, Cmax) in a dose-independent manner.86 Approximately 90 percent of cidofovir is recovered in the urine within 24 hours
after a single intravenous bolus dose.88 Elimination of cidofovir from the
systemic circulation depends not only on filtration, but also on active
tubular secretion. This has been suggested based on observation of
reduced clearance of cidofovir by probenecid.88
Though no human study report is available regarding the
bioavailability of topical or intralesional cidofovir, there are several animal
studies on topical administration. While investigating the
pharmacokinetic properties of cidofovir in African green monkeys
through different routes of administration (IV, oral and subcutaneous),
the subcutaneous bioavailability of cidofovir was noted to be 9.8 percent
to 15.8 percent.87 Investigations on the bioavailability of topical cidofovir
in different vehicles on normal and abraded skin in rabbits show marked
increase in abraded skin (41%) compared to normal skin (0.2% to 2.1%)
in a vehicle containing propylene glycol.89 Systemic exposure to the
drug is found to be negligible on those animals treated with topical
cidofovir on intact skin.
Regarding systemic adverse reaction to topical or intralesional
cidofovir, there has been a report of precardial complaints, presumably
chest pain, in only one patient of severe recurrent laryngeal papillomatosis
treated with intralesional cidofovir (2.5 mg/5 ml).90 But no cardiac
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TAZAROTENE
It is a synthetic retinoid that has a distinct structural difference from the
naturally occurring retinoidsall-transretinoic acid (tretinoin) and alltransretinol.111 It is a prodrug of the more water-soluble tazarotenic acid
(TA), a receptor-selective acetylenic retinoid.112 TA is the active metabolite
of tazarotene.
Mechanism of Action
TA has a selective binding affinity to nuclear retinoid acid receptors
(RAR), but not with nuclear retinoid X receptors (RXR).111 Among the
RARs, relatively strong binding is found with RAR- subtypes, moderate
binding with RAR and minimal with RAR- (RAR- > RAR- > RAR). TA after binding with these RARs, modulates the expression of
retinoid responsive genes that regulates cell proliferation, cell
differentiation and inflammation.113-116
The abnormal expressions of epidermal growth factor receptor,
keratinocyte transglutaminase I (Tgase I) and hyperproliferative keratins
K6 and K16 are also down-regulated by tazarotene.117,118 Tazarotene
blocks the induction of ornithine decarboxylase activity, as a result of
which cell proliferation and hyperplasia are checked.111 It also inhibits
cornified as well as cross-linked envelope formation.111 It has been shown
that migration inhibitory factor-related protein (MRP-8), a marker of
inflammation decreases with tazarotene treatment.116,118
Pharmacology
The majority of topical tazarotene remains in the skin.119 The systemic
absorption of tazarotene is virtually negligible because of rapid
metabolism (less than 20 minutes) to its more hydrophilic metabolite
and for limited percutaneous penetration.111,119 Thus, accumulation of
the drug in lipophilic tissues of the body is prevented. The percentages
of absorption of a dose of topically applied tazarotene within 10 hours
in unoccluded psoriatic skin and occluded normal skin are calculated as
less than 1 percent and 6 percent respectively.119 Other than TA,
tazarotene is metabolized in the skin and plasma to sulfoxides, sulfones
and other polar metabolites. The maximal concentration of TA in the
blood occurs 9 hours after application of tazarotene.
The elimination half-life of tazarotene and its metabolites is found to
be approximately 17 to 18 hours.119 The urinary and fecal elimination
almost become complete within 2 to 3 days and 7 days respectively.120
This short stay in the body and the limited percutaneous penetration
223
result in low plasma levels of tazarotene and TA. It has also been found
that TA does not undergo interconversion to any other retinoids which
can activate other retinoid receptors.112 All these above facts are important
so far as the potential risk for teratogenicity is concerned.
Clinical Uses
Psoriasis
US-FDA has approved tazarotene cream (0.5% and 0.1%) for treatment
of plaque psoriasis in 2000.112 Although tazarotene is effective as
monotherapy,121,122 it is more commonly used in combination either
with phototherapy or topical corticosteroids with view to enhancing
efficacy and tolerability.123-126 Tazarotene 0.1 percent gel plus mometasone
furoate cream (each used once daily) are found to be more effective than
twice daily treatment of either mometasome furoate or calcipotriol
ointment.127,128
Apart from increasing the efficacy, combination of both topical
tazarotene and corticosteroid has a few more advantages. Skin atrophy
from prolonged use of topical corticosteroids can be prevented when
tazarotene is combined.123,129 On the other hand, local site irritation
(retinoid dermatitis) by tazarotene can also be taken care of by topical
corticosteroid. Another additional benefit of combining tazarotene is
that there is less chance of rebound flare up of healed psoriatic plaques
compared to plaques treated with corticosteroid monotherapy.130 Even
combined therapy results in a better maintenance of remission than
vehicle.131 Thus, adjunctive use of tazarotene with corticosteroid promotes
superior efficacy, faster remission, more prolonged therapeutic benefit
after treatment. The duration of remission is also being prolonged.129
The local side effects of both are also symbiotically handled by each
other. The stability of both the compounds remains unaffected in the
physical presence of each other, although they are being used on either
ends of the day in most of the clinical trials.132
Besides the adjunctive use of tazarotene with topical corticosteroids,
the enhanced efficacy have been found with combined use of narrowband
UVB phototherapy and bath PUVA.3, 133
Acne Vulgaris
US-FDA has also approved 0.1 percent tazarotene cream for the treatment
of acne vulgaris in October 2001. The efficacy and tolerability of tazarotene
0.1 percent gel has been compared with those of tretinoin 0.025 percent
gel and adapalene 0.1 percent gel in acne vulgaris.134 The reduction of
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10. Cheer SM, Plosker G. Tacrolimus Oinment. A review of its Therapeutic Potential
as a Topical Therapy in Atopic Dermatitis. Am J Clin Dermatol 2001; 2(6):389
406.
11. Lin AN. Topical Immunotherapy. In: Wolverton SE, ed, Comprehensive
Dermatologic Drug Therapy. Philadelphia, Pennsylvania: W.B.Saunders, 2001:
60729.
12. Smith CM. New approaches to topical therapy. Clin Exp Dermatol 2000; 25:567
74.
13. Cather JC, Abramovits W, Menter A. Cyclosporine and Tacrolimus in
Dermatology. Dermatol Clin 2001;19:119-37.
14. Alaiti S, Kang S, Fiedler VC, et al. Tacrolimus (FK506) ointment for atopic
dermatitis: A phase I study in adults and children. J Am Acad Dermatol 1998;
38:6976.
15. Hanifin JM, Ling MR, Langley R, et al. Tacrolimus ointment for treatment of
atopic dermatitis in adult patients: Part I, Efficacy. J Am Acad Dermatol 2001;
44:S28S38.
16. Paller A, Eichenfield LF, Leung DYM, et al. A 12-week study of tacrolimus
ointment for the treatment of atopic dermatitis in pediatric patients. J Am
Acad Dermatol 2001; 44:S47S57.
17. Soter NA, Fleischer AB Jr, Webster GF, et al. Tacrolimus ointment for the
treatment of atopic dermatitis in adult patients: Part II, Safety. J Am Acad
Dermatol 2001;44:S39S46.
18. Kang S, Lucky AW, Pariser D, et al. Long term safety and efficacy of tacrolimus
ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol
2001;44:S58S64.
19. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of
tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch
Dermatol 2000;136:999-1006.
20. Ruzicka T, Bieber T, Schopf E, et al. A short term trial of tacrolimus ointment
for atopic deramatitis. N Engl J Med 1997;337:81621.
21. Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehiclecontrolled
trial of tacrolimus ointment for treatment of atopic dermatitis in children.
Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998;102:637 44.
22. Reitamo S, Remitz A, Kyllonen H, et al. Topical noncorticosteroid
immunomodulation in the treatment of atopic dermatitis. Am J Clin Dermatol
2002;3(6):3818.
23. Meagher L, Wines NY, Cooper AJ. Atopic dermatitis: Review of immunopathogenesis and advances in immunosuppressive therapy. Australas J
Dermatol 2002;45:24754.
24. Hauk PJ, Leung D. Tacrolimus (FK506): New treatment approach in
superantigenassociated diseases like atopic dermatitis? J Allergy Clin Immunol
2001;107:391-2.
25. Remitz A, Kyllonen H, Granlund H, et al. Tacrolimus ointment reduces
staphylococcal colonization of atopic dermatitis lesions [letter]. J Allergy Clin
Immunol 2001;107:196-7.
26. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment
compared with that of hydrocortisone butyrate ointment in adult patients
with atopic dermatitis. J Allergy Clin Immunol 2002;109:54755.
27. Williams H, Thomas K, Smethurst D, et al. Atopic Eczema. In: Williams H,
Bigby M, Diepgen T, et al, eds. Evidencebased Dermatology. London: BMJ
Publishing Group, 2003:144218.
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28. Reitamo S, Van Leent EJM, Ho V, et al. Efficacy and safety of tacrolimus
ointment compared with hydrocortisone acetate ointment in children with
atopic dermatitis. J Allergy Clin Immunol 2002;109:53946.
29. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective
in chronic plaque psoriasis: A pilot study. Arch Dermatol 1998;134:1101-2.
30. Lyon CC, Smith AJ, Beck MK, et al. Parastomal pyoderma gangrenosum:
Clinical features and management. J Am Acad Dermatol 2000;42:992-1002.
31. Vente C, Reich K, Rupprecht R, et al. Erosive mucosal lichen planus: Response
to topical treatment with tacrolimus. Br J Dermatol 1999;140:338-42.
32. Kaliakatason P, Hodgson TA, Lewsey D, et al. Management of recalcitrant
ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol
2002;46:3541.
33. Rozycki TW, Rogers RS, Pittelkow MR, et al. Topical tacrolimus in the treatment
of symptomatic oral lichen planus: A series of 13 patients. J Am Acad Dermatol
2002; 46:2734.
34. Schnopp C, Remling R, Mohrenschlager M, et al. Topical tacrolimus (FK-506)
and mometasone furoate in the treatment of dyshidrotic plamer eczema: A
randomized observer blinded trial. J Am Acad Dermatol 2002; 46:737.
35. Uetsu N, Okamoto H, Fujii K, et al. Treatment of chronic actinic dermatitis
with tacrolimus ointment. J Am Acad Dermatol 2002; 47:8814.
36. Bhat R, Rammam M. Tacrolimus. In: Hot topics in Dermato-venereology, 30th
National Conference of IADVL, 24th27th January 2002, Cochin, Kerala: 51
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37. Wellington K, Jarvis B. Spot light on topical pimecrolimus in atopic dermatitis.
Am J Clin Dermatol 2002;3(6):4358.
38. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of
pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate
atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:
495-504.
39. Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug,
SDZ ASM 981, for the treatment of skin diseases: In vitro pharmacology. Br
J Dermatol 1999;141:26473.
40. Hultsch T, Muller KD, Meingassner JG, et al. Ascomycin macrolatum derivative
SDZ ASM 981 inhibits the release of granuleassociated mediators and of
newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin
dependent manner. Arch Dermatol Res 1998;290:5017.
41. T Luger. Pemicrolimus: Skinselective, anti-inflammatory profile supports
clinical efficacy and safety. Satellite Symposium (SA0705) in 20th World
Congress of Dermatology 2002 [abstract]. Ann Dermatol Venereol
2002;129:IS81IS141.
42. Meingassner JG, Grassberger M, Fahrngruber H, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin disease:
In vivo pharmacology. Br J Dermatol 1997;137:568-76.
43. Queille Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative
SDZ ASM 981 does not induce skin atrophy when applied to normal skin for
4 weeks: A randomized, doubleblind controlled study. Br J Dermatol
2001;144:507-13.
44. Luger T, VanLeent EJM, Graeber M, et al. SDZ ASM 981: An emerging safe
and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-94.
45. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic dermatitis
in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J
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Pharmacol 1992;41:197202.
86. Zabawski EJ Jr, Cockerell CJ. Topical and intralesional cidofovir: A review of
pharmacology and therapeutic effects. J Am Acad Dermatol 1998;39:7415.
87. Cundy KC, Li ZH, Hitchcock MJ, et al. Pharmacokinetics of cidofovir in
monkeys: Evidence for a prolonged elimination phase representing
phosphorylated drug. Drug Metab Dispos 1996;24:73844.
88. Cundy KC, Petty BG, Flaherty J, et al. Clinical pharmacokinetics of cidofovir
in human immunodeficiency virus-infected patients. Antimicrob Agents
Chemother 1995;39:1247-52.
89. Cundy KC, Lynch G, Lee WA. Bioavailability and metabolism of cidofovir
following topical administration to rabbits. Antiviral Res 1997;35:11322.
90. Soneck R, Wellens W, Deslooovere C, et al. Treatment of severe recurrent
laryngeal papillomatosis by local injections of (S)I(3hydroxy2
phosphonylmethoxy propyl)cytosine (cidofovir). Abstract presented at the
9th International Conference on Antiviral Research, Urbandai, Fuku-shima,
Japan, May 19-24,1996.
91. Snoeck R, Ranst MV, Andrei G, et al. Treatment of anogenital papillomavirus
infections with an acyclic nucleoside phosphonate analogue. N Eng J Med
1995;333:9434.
92. Snoeck R, Bossens M, Parent D, et al. Phase II double blind, placebo-controlled
study of the safety and efficacy of cidofovir topical gel for the treatment of
patients with human papillomavirus infection. Clin Infect Dis 2001;33:597
602.
93. Matteelli A, Beltrame A, Graifemberghi S, et al. Efficacy and tolerability of
topical 1% cidofovir cream for the treatment of external anogenital warts in
HIV-infected persons. Sex Transm Dis 2001;28:3436.
94. Douglas J, Corey L, Tyring S, et al. A phase I/II study of cidofovir topical gel
for refractory condyloma accuminatum in patients with HIV infection [Poster
334]. 4th Conference on Retroviruses and Opportunistic infections, Washington
DC, January 22 to 26,1997.
95. Zabawski EJ, Sands B, Goetz D, et al. Treatment of verruca vulgaris with
topical cidofovir. JAMA 1997; 278:1236.
96. Davis MD, Gostout BS, McGovern RM, et al. Large plantar wart caused by
human papilloma virus66 and resolution by topical cidofovir therapy. J Am
Acad Dermatol 2000;43:340-3.
97. Snoeck R, Van Laethem Y, De Clercq E, et al. Treatment of a bowenoid papulosis
of the penis with local applications of cidofovir in a patient with acquired
immunodeficiency syndrome. Arch Intern Med 2001;161:23824.
98. Koonsaeng S, Verschraegan C, Freedman R, et al. Successful treatment of
recurrent vulvar intraepithelial neoplasia resistant to interferon and isotretinoin
with cidofovir. J Med Virol 2001; 6:1958.
99. Snoeck R, Noel JC, Muller C, et al. Cidofovir, a new approach for the treatment
of cervical intraepithelial neoplasia grade III (CIN III). J Med Virol 2000; 60:205
9.
100. Geodert JJ, Cote TR, Virgo P, et al. Spectrum of AIDSassociated malignant
disorders. Lancet 1998; 4:41528.
101. Calista D. Topical cidofovir for erythroplasia of Queyrat of the glans penis. Br
J Dermatol 2002;147:399-400.
102. Meadows KP, Tyring SK, Pavia AT, et al. Resolution of recalicitrant molluscum
contagiosum virus lesions in human immunodeficiency virus-infected patients
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141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
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13
Kaushik Nandy
Wound Dressings:
Newer Concepts
INTRODUCTION: THE MOIST ENVIRONMENT IN WOUND HEALING
Central to the efforts at introducing newer dressing materials has been
the establishment of the idea that a moist environment enhances wound
healing. This has been demonstrated well as by experimental studies as
in the clinical setting.1-5 Being able to choose the right dressing material
from among the myriad options available is essential for successful and
appropriate management of wounds, in the quickest possible time, with
the minimum possible effort and expense and at maximum comfort and
convenience to the patient.
The right choice of dressing materials is, of course, of real relevance
in the context of wounds that are going to heal by secondary intention
as also of wounds being prepared for surgical intervention. Maintenance
of a moist environment affords many benefits to such wounds.6 It prevents
desiccation of the wound which would otherwise lead to cell death and
eschar formation. It increases breakdown of dead tissue (slough) and
the pericapillary fibrin cuff. It enhances the process of angiogenesis
essential to wound healing and also helps growth factors to interact
with their target cells. It has been experimentally demonstrated that
maintenance of a moist environment shortened the inflammatory and
proliferative phase of dermal repair in wounds7 which would be expected
to shorten the overall period of healing. A moist environment also helps
make the wound more comfortable for the patient. It is worth stating
here that for practical purposes, use of special dressings as a means of
debriding wounds is recommended only when a comparatively small
amount of dead tissue is present. Otherwise a surgical debridement is
indicated.
The idea of the benefits of maintaining a moist environment for
enhancement of wound healing has been taken one step further.
Experiments have shown that maintenance of a wet (liquid) as opposed
to a moist environment produces quite different results.8 The wet wounds
(saline) healed the fastest at least partly because they showed accelerated
235
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237
are suitable for moderate to heavily exuding wounds. They are not
suitable for dry wounds or eschars. Because they are removed easily,
change of dressings is very comfortable for the patient and there is no
damage to the delicate forming granulation tissue. They require a
secondary covering. They have no reported adverse effects except for
one published report of a florid foreign body giant cell reaction to
alginate used in a tooth socket.13 Alginate is used with the purpose of
achieving better hemostasis but this has not been substantiated by a
controlled trial.14
Comparatively shallow wounds such as leg ulcers can be covered
with alginate sheets whereas deeper cavity wounds such as pressure
sores15 and abscess cavities16 can be effectively filled with alginate ropes.
Alginate has been effectively used in footcare.17
Hydrocolloid Dressings
Hydrocolloid dressings contain gel-forming agents such as sodium
carboxy-methylcellulose and gelatin together with elastomers and
adhesives which are applied to a carrier usually a polyurethane foam
or film. The result is an occlusive, conformable, absorbent, self-adhesive,
waterproof wafer. They are non-toxic and non-particulate. On contact
with wound exudates, the hydrocolloid absorbs moisture and forms a
gel. Though initially waterproof, with the progress of the gelling process,
these dressings become progressively permeable. This increases their
ability to deal with exudates.
Because of their comparatively limited fluid handling capacity, they
are suitable for use in mild to moderately exuding wounds only, including
leg ulcers and pressure sores. Hydrocolloid powder and pastes are used
for filling cavities. Hydrocolloid combination dressings with alginate
are available to improve their fluid handling ability. Hydrocolloid
dressings provide superior occlusion and can be used in dry wounds to
soften them by effective moisture retention and have been used for the
prevention of spread of MRSA18 by acting as a physical barrier.
A clinically very useful property of hydrocolloid dressings is their
ability to adhere to wet surfaces. Once applied to a wound, the peripheral
area of the dressings, which needs to overlap onto normal skin, remains
firmly adherent whereas the central area in actual contact with the
exuding wound forms the gel and loses its adhesive property. Thus, at
the time of removal the wound surface is not damaged though the
peripheral adhering area has to be removed with caution from delicate
skin. Change of dressings is usually required every three to five days
which makes them more comfortable and reduces need for nursing
attention.
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14
Belinda Vaz
243
Resolution
When the number of pixels that capture an image is high, it produces
a digital replica of the original subject wherein the human eye cannot
see the dots in the image without looking very closely. This means that
the quality of a digital image depends upon the number of pixels used
to create the image. Greater the resolution of a digital camera, better the
image quality. The size of a digital photograph can be specified in two
ways i.e., by its dimensions in pixels (e.g., 1800 1600 pixels) or by the
total number of pixels it contains (e.g. 2.88 million pixels or mega pixels).
A study of dermatological images has shown that the minimum resolution
needed to recognize the relevant details of a dermatological lesion is 768
512.4 A camera with a higher resolution has a greater memory
requirement for storing the image.
Compression
Compression is one way by which the memory required to store the
image is reduced by eliminating redundant information from an image.
Many cameras store images in a format called JPEG (Joint Photographic
Experts Group) setting. This file format compresses images and specifies
how much they are compressed. With compression one can store more
images which makes it easier to post an image on a Web page or send
it as an e-mail. However, it lowers the quality of the image. For the
highest quality printed images, TIFF or RAW format should be used.
Storage of Images
The number of images that one can store in a camera depends upon the
capacity of the storage device (expressed in Megabytes), the resolution
used for taking pictures and the amount of compression used. Older
cameras have fixed and inbuilt storage capacity. Once the capacity is
full, one cannot take any more pictures until the older pictures are
erased. Most of the newer digital cameras have some form of removable
storage media, usually flash memory cards, floppy disk, CDs or small
hard disks. With removable storage media once the capacity is full, one
can insert another storage device and take more pictures. Memory cards
are very popular these days and come in different capacities from 8 MB
to 1 GB.
Transfer of Images to a Computer
Images can be downloaded from a digital camera to a PC using a cable
connected with the serial, parallel or USB port. A USB cable is fast and
244
efficient. Software that comes with the camera is used to transfer images
from the camera to the computer, to convert images into other file
formats for use in word documents or graphics, to organize, work with,
and share photos by sending as e-mail, or posting to a personal Web site.
Cableless transfer of images is possible if the digital camera stores the
images directly on a floppy disc or CD or if a laptop PC has a built-in
slot for a memory card. If the system does not have a slot for memory
cards, the memory cards are inserted into a card reader, which is
connected to the PC using a cable.
SELECTING A DIGITAL CAMERA
There is a wide range of cameras in the market with features for different
applications from outdoor photography to fashion photography. The
Internet is a useful resource for evaluating the capabilities of different
cameras. Most camera manufacturers have their updated home pages
on the Internet. Table 14.1 lists some of the features of different digital
cameras. Some features that would be useful in selecting a camera for
dermatological practice are:
1. Resolution: Cameras with a resolution of 2 Megapixel are generally
adequate for photographing skin lesions. A resolution of 3 Megapixel
gives better pictures and a much higher resolution is preferred, if
the pictures are to be printed.
2. Type of Camera: Point and shoot cameras are like their name and
easy to use because the focus and exposure are automatically set.
They have fixed lenses, a built-in flash and are cheaper and more
compact. The disadvantage is that the user has limited control over
the camera. Single lens reflex (SLR) cameras have removable lenses
and so high quality lenses can be used for better pictures. The
exposure can be controlled manually when required. Manual mode
lets one select both the shutter speed and the aperture. For close
up photographs of skin lesions where depth of field is important,
an aperture preferred mode lets one select the aperture needed and
automatically sets the shutter speed to give a good picture.
3. Macro Mode: Macro mode is a lens that lets one get very close to
the lesion to be photographed. It is good for photographing small
lesions.
4. Flash: Most digital cameras have a built-in flash. A ring flash is a
special kind of flash that fits around the lens and throws a circle
of light on the subject. It is ideal for shadowless close up
photography of skin lesions.
5. Zoom: It is preferable to have cameras with both optical and digital
zoom. Optical zoom is similar to what is found in a conventional
3.2 Mega
Pixel
Cybershot
DSC-P72
Cybershot
DSC-P92
Mavica
MVC-CD500
Coolpix
SQ
Coolpix
5400
Coolpix
3100
DiMAGE Xt
DiMAGE
F300
Powershot
G5
Powershot
S50
Sony
Sony
Sony
Nikon
Nikon
Nikon
Minolta
Minolta
Canon
Canon
5 Mega
Pixel
5 Mega
Pixel
5 Mega
Pixel
3.2 Mega
Pixel
3.2 Mega
Pixel
5.1 Mega
Pixel
3.1 Mega
Pixel
5 Mega
Pixel
5 Mega
Pixel
Resolution
Manufacturer Model
3X Optical zoom,
4.1X Digital zoom
4X Optical zoom,
4X Digital zoom
4X Digital zoom
4X Digital zoom
3X Optical Zoom
3X Optical,
zoom-Nikkor
lens
3X Optical, Total
12 X Zoom
3X Optical, Total
12 X Zoom
3X Optical, Total
9.6 X Zoom
Zoom
Compact flash
memory card
Compact flash
memory card
Flash memory
card
Memory
card
Memory
Cards
Memory
Cards
Memory
card
Memory
cards, Floppy
discs, CD-R
Memory
Cards
Memory
Cards
Storage
Built-in flash
Built-in flash
Auto flash
Auto flash
Built-in flash
Built-in flash
Built-in flash
Built-in flash
AF illuminator,
Built-in flash
AF illuminator,
Built-in flash
Flash
USB cable
Movie
Automatic and
Manual modes
Macro shooting
up to lem, movie
Macro shooting
up to 4 cm, Swivel
zoom lens
Movie
Movie, multi
point focus
Movie, multi
point focus
Other features
246
6.
7.
8.
9.
10.
11.
247
better to overestimate the need for storage when determining the memory
of the computer.
The system requirements of PC are as follows:
PC with 300 megahertz or higher processor clock speed
recommended; 233 Mhz minimum required (single or dual
processor system); Intel Pentium/Celeron family, or AMD K6/
Athlon/Duron family
128 megabytes (MB) of RAM or higher recommended
9 gigabytes (GB) hard disk
Super VGA (800 x 600) or higher-resolution video adapter and
monitor
CD-ROM or DVD drive
Keyboard and Microsoft Mouse or compatible pointing device
USB port
Another commonly used operating system for professional digital
photography is Macintosh OS 9. The system requirements of the
Macintosh are as follows:
G4 800 MHz processor
256 MB RAM
9 GB hard disk
1920-by-1200-pixel resolution monitor
CD-ROM or DVD drive
Firewire port
USB ports
ADVANTAGES OF DIGITAL PHOTOGRAPHY
1. Digital cameras are very user friendly and even beginners can take
good photographs.
2. One can immediately review ones images on the cameras LCD
preview screen and reshoot any unsatisfactory images.
3. One can shoot as many images as the storage capacity of the camera
permits, and later choose the best.
4. Digital photographs are more economical in the long run as one
saves on print roll and developing and printing charges.
5. Photographs are immediately available. One does not have to finish
the roll before having it processed.
6. One can improve or alter the images with a photo editing program.
One can crop the photograph to emphasize the key aspect.
7. One can post a photograph on the Internet or e-mail the photograph.
8. Photographs can be compactly stored in the computer or on CDROMs.
9. With some cameras one can record sounds and even short videos
with the same camera.
248
249
250
Education
Digital imaging has made it easy for even the technologically challenged
dermatologist to take good pictures. It is possible to add text, lines and
graphics to the digital pictures, remove photographic artefacts and alter
colour brightness and contrast and thus enhance the communication
power of digital images. Photographs can be used for clinical presentations, grand rounds and for teaching medical and postgraduate
students. Many dermatology textbooks and atlases are available as
CD-ROMs containing digital images. Manipulation of digital photographs
used in presentations, journals and scientific meetings is possible with
the purpose of wilfully deceiving the audience. Hence, a code of ethics
is followed by various scientific bodies to cope with such issues.
Communication
In Dermatology, sharing images and text on the Internet has great
potential. The Internet is a link-up of public, private, government and
university computer networks that encompass almost all the countries
in the world. There are many Internet sites devoted to Dermatology and
vast reserves of specialist literature in the form of news, articles,
conference proceedings, patient literature, product catalogues and more.22
Web-sites and home pages are electronic spaces via which one can
disseminate information. There are entire textbooks and dermatological
atlases available online. It is also possible to access journals online for
free or for a fee. E-mail is one way by which digital images can be sent
over the Net. There are also various interactive discussion groups for
dermatologists on the Internet (e.g., rxderm), where one can post ones
difficult cases and have dermatologists from around the world opine,
suggest treatment options and share their own experiences. The ability
to post a patients digital photograph with the history makes this forum
even more interesting. Digital images can also be posted to online journals
and online grand rounds.
Telemedicine
Telemedicine is the application of the advances in telecommunication
technology to health care delivery. It allows physicians to consult on
patients at a distance via an interactive video format. Since dermatology
is a visual speciality and consultation involves a quick recognition of a
disease pattern and a straightforward clinical decision, it lends itself
well to telemedicine and is known as teledermatology. The transmitted
digital images are a substitute for a physical examination. 23,24
251
252
253
16. Del Mar CB, Green AC. Aid to diagnosis of melanoma in primary medical
care. BMJ 1995; 310: 492-5.
17. Elbaum M, Kopf AW, Rabinovitz HS et al. Automatic differentiation of
melanoma from melanocytic nevi with multispectral digital dermoscopy: A
feasibility study. J Am Acad Dermatol 2001; 44: 207-18.
18. Eubanks L, McBurney E. Videomicroscopy of port-wine stains: Correlation of
location and depth of lesion. J Am Acad Dermatol 2001; 44: 948-51.
19. Langley R, Rajadhyaksha M, Dwyer P at al. Confocal scanning laser microscopy
of benign and malignant melanocytic skin lesions in vivo. J Am Acad Dermatol
2001; 45: 365-76.
20. Gibbons RD, Fiedler-Weiss VC, West DO, Lapin G. Quantification of scalp
hair: Computer-aided methodology. J Invest Dermatol 1986; 86: 78-82.
21. Grove GL, Grove MJ, Leyden JJ. Optical profilometry: An objective method of
quantification of facial wrinkles. J Am Acad Dermatol 1989; 21: 631-7.
22. Huntley, AC, Bittorf A, Taragin M. Configuring for the World Wide Web:
Recommendations for dermatologists. J Am Acad Dermatol 1996; 34: 125-136.
23. Kvedar JC, Edwards RA, Menn ER, et al. The substitution of digital images
for dermatologic physical examination. Arch Dermatol 1997; 133: 161-7.
24. Norton SA, Burdick AR, Phillips CM, et al. Teledermatology and underserved
populations. Arch Dermatol 1997; 133: 197-200.
25. Schmid-Grendelmeier P, Masenga EJ, Haeffner A, Burg G. Teledermatology as
a new tool in sub-Saharan Africa: An experience from Tanzania. J Am Acad
Dermatol 2000; 42: 833-5.
26. High WA, Houston MS, Calobrisi SD, et al. Assessment of the accuracy of lowcost store-and forward teledermatology consultation. J Am Acad Dermatol
2000; 42: 776-83.
27. Piccolo D, Smolle J, Wolf IH, et al. Face to face diagnosis of pigmented skin
tumors: A teledermoscopic study. Arch Dermatol 1999; 135: 1467-71.
28. Piccolo D, Soyer HP, Burgdorf W, et al. Concordance between telepathologic
diagnosis and conventional histopathologic diagnosis: A multiobserver storeand-forward study on 20 skin specimens. Arch Dermatol 2002; 138: 53-8.
29. Zelickson BG, Homan L. Teledermatology in the nursing home. Arch Dermatol
1997; 133: 171-4.
30. Gilmour E, Campbell SM, Loane MA, et al. Comparison of teleconsultation
and face to face consultations: Preliminary results of a UK multicentre
teledermatology study. Br J Dermatol 1998; 139: 81-7.
31. Phillips CM, Burke WA, Shechter A, et al. Reliability of dermatology
teleconsultations with the use of teleconferencing technology. J Am Acad
Dermatol 1997; 37: 398-402.
32. Lesher JL, Davis LS, Gourdin FW, et al. Telemedicine evaluation of cutaneous
diseases: A blinded comparative study. J Am Acad Dermatol 1998; 38: 27-31.
33. Lowitt MH, Kessler II, Kauffman L, et al. Teledermatology and in-person
examinations. Arch Dermatol 1998; 134: 471-6.
34. Williams TL, May CR, Esmail A, et al. Patient satisfaction with teledermatology
is related to perceived quality of life. BJD 2001; 145: 911-7.
35. Wootton R, Bloomer SE, Corbett R, et al. Multicentre randomised control trial
comparing real time teledermatology with conventional outpatient
dermatological care: Societal cost-benefit analysis. BMJ 2000; 320: 1252-6.
36. Gibbs S. Losing touch with the healing art: Dermatology and the decline of
pastoral doctoring. J Am Acad Dermatol 2000; 43: 875-8.
Index
A
Acne vulgaris 223
Acrodermatitis enteropathica 82
Actin 12
Acute hemorrhagic edema 43
Acute skin failure 84
Adverse drug reaction 88
sources of information 88, 89
Allergens 136
Anaplastic large cell lymphoma 18
Angiocentric lymphomas 18
Angioedema 62
hereditary 64
Anogenital squamous cell carcinoma 219
Anogenital warts 165, 213
Antibodies 10
Apoptosis 1
apoptosis and skin disorders 3
genes and apoptosis 3
morphology 2
pathomechanisms 2
Atopic dermatitis 206, 209
Autoimmune disorders 6
B
B cell lymphomas 19
Bacterial vaginosis 163
Bexarotene 192
adverse effects 193
indications and dosage 193
mechanism of action 192
pharmacokinetics 192
Bowenoid papulosis 219
C
Candidiasis 62
Carcinoembryonic antigen 13
Cell markers 9
common markers used in dermatology 10
Cellulitis 57
Chancroid 152
Charge couple device 242
Chlamydia infection 161
Chromogranin 13
Churg-Strauss syndrome 40
Cidofovir 216
D
Death domain 2
Dermatitis medicamentosa 65
Desmin 12
256
E
Emergency 56
Epidermolysis bullosa 76
dystrophic 77
junctional 77
Epithelial membrane antigen 13
Erythema elevatum diutinum 44
Erythema multiforme 70
Erythroplasia of Queyrat 219
Henoch-Schonlein pupura 41
Herpes simplex virus infection 61, 220
Histiocytic disorders 15
Histiocytosis X 81
HMB-45 15
Hodgkins lymphoma 19
HPV infections 218
I
Ideal dressing material 235
Imiquimod 211
clinical uses 213
mechanism of action 211
pharmacology 213
safety profile 216
side effects 216
Immunofluorescence 10
Immunohistochemistry 10
Immunophenotyping 9
Infliximab 190
adverse effects 191
contraindications 191
indications and dosage 191
mechanism of action 190
pharmacokinetics 190
Intensive skin care units 86
Involucrin 13
Ivermectin 182
adverse effects 184
contraindications 184
indications and dosage 183
mechanisms of action 183
pharmacokinetics 183
K
Kaposis sarcoma 221
Kawasaki syndrome 66
Flow cytometry 10
L
G
Generalized exfoliative dermatitis 69
Genital herpes simplex virus infection 156
Genital ulcer diseases 147
Gonorrhea 158
Graft versus host disease 6, 75
acute and chronic 76
Granuloma faciale 44
Granulomatous slack skin 17
H
Hemangiomas 80
Index
infections associated with 36
overview of syndromes associated with
40
Lichen planus 5
Lichenoid tissue reaction 5
Linear IgA disease 78
Lymphocytoma cutis 17
Lymphogranuloma venereum 154
Lymphomas 16
Lymphomatoid papulosis 18
257
tacrolimus 204
tazarotene 222
Non-genital warts 215
Non-gonococcal urethritis 160
Non-Hodgkins lymphoma 19
Mastocytosis 82
Melanoma 15
Meningococcal disease 73
clinical features 74
Microscopic polyangitis 41
Moist environment in wound healing 234
Molluscum contagiosum virus infection 220
Mononuclear phagocytic cells 13
Mycophenolate mofetil 180
adverse effects 182
contraindications 182
drug interaction 182
indications and dosage 181
mechanism of action 180
pharmacokinetics 180
Mycosis fungoides 18
Pagetoid reticulosis 17
Patch test units/devices 137
Patch testing 136
complications 143
interpretation of results 140
false-negative reactions 142
false-positive reactions 141
technique 139
testing of unknown substances 142
Pediatric dermatological emergencies 57
Pemphigus 79
Photopatch testing 144
Pimecrolimus 208
clinical uses 209
dosage and administration 210
mechanism of action 208
pharmacology 209
Poorly differentiated neoplasm 14
Prekeratins 11
Psoriasis 223
Pustular vasculitis 44
Resolution 243
Ritter-Lyell syndrome 59
S
S 100 protein 15
Sclerema neonatorum 83
Scleroderma disorders
classification 115
drawbacks 117
diagnosis 124
serological tests 125
etiology 121
drugs 123
genetic factors 121
infectious agents 122
microchimerism 123
non-infectious environmental agents
122
management 126
antifibrotic therapy 129
immuno-modulation therapy 128
other therapeutic agents 130
258
T
T cell lymphomas 17
T cell pseudolymphoma 17
Tacrolimus 204
clincal uses 206
dosage and administration 208
mechanism of action 204
pharmacology 205
side effects 207
Tazarotene 222
clinical uses 223
drug interaction 225
mechanism of action 222
pharmacology 222
safety and side effects 224
Telemedicine 250
Thalidomide 185
adverse effects 188
contraindications 188
indications and dosage 186
mechanism of action 185
pharmacokinetics 186
Toxic epidermal necrolysis 4, 71
Transfer of images to a computer 243
Trichomoniasis 161
Tuberculids 26
U
Urticaria 62
Urticarial vasculitis 46
V
Vascular neoplasms 16
Vasculitis 31
Vimentin 12
Vulvar intraepithelial neoplasia 219
W
Wegeners granulomatosis 40