Sie sind auf Seite 1von 275

Recent Advances in

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
MEDICAL PUBLISHERS (P) LTD
New Delhi

Published by
Jitendar P Vij
Jaypee Brothers Medical Publishers (P) Ltd
EMCA House, 23/23B Ansari Road, Daryaganj
New Delhi 110 002, India
Phones: 23272143, 23272703, 23282021, 23245672, 23245683
Fax: +91-11-23276490
e-mail: jpmedpub@del2.vsnl.net.in
Visit our website: http://www.jpbros.20m.com
Branches
202 Batavia Chambers, 8 Kumara Krupa Road
Kumara Park East, Bangalore 560 001
Phones: 2285971, 2382956 Tele Fax : 2281761
e-mail: jaypeebc@bgl.vsnl.net.in
282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza
Pantheon Road, Chennai 600 008
Phone: 28262665 Fax: 28262331
e-mail: jpmedpub@md3.vsnl.net.in
4-2-1067/1-3, 1st Floor, Balaji Building
Ramkote Cross Road, Hyderabad 500 095
Phones: 55610020, 24758498 Fax: 24758499
e-mail: hyd2_jpmedpub@sancharnet.in
1A Indian Mirror Street, Wellington Square
Kolkata 700 013, Phone: 22451926 Fax: 22456075
e-mail: jpbcal@cal.vsnl.net.in
106 Amit Industrial Estate, 61 Dr SS Rao Road
Near MGM Hospital, Parel, Mumbai 400 012
Phones: 24124863, 24104532 Fax: 24160828
e-mail: jpmedpub@bom7.vsnl.net.in
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
contributors is original. Every effort is made to ensure accuracy of material,
but the publisher, printer and Editor-in-Chief will not be held responsible for
any inadvertent error(s). In case of any dispute, all legal matters are to be
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

Recent Advances in Dermatology

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

2. Cell Markers in Dermatology


Uday Khopkar, Deepa Sachdev

3. Cutaneous Tuberculosis: Recent Perspective


M. Ramam
4. The Spectrum of Leukocytoclastic Vasculitis:
Etiology, Classification and Approach to Management
Debabrata Bandyopadhyay
5. Emergencies in Pediatric Dermatology
Jayakar Thomas
6. Cutaneous Adverse Drug Reactions to Systemic Drugs:
Recent Update
Sujit Ranjan Sengupta, Nilay Kanti Das

24

31
56

88

7. The Scleroderma Disorders: An Update


Sanjay Ghosh

115

8. Patch Testing: An Overview


A.K. Bajaj

136

9. Laboratory Diagnosis and Treatment of Common


Sexually Transmitted Diseases: An Update
Devinder Mohan Thappa
10. Narrowband UV-B Phototherapy: A Newer Advance
in the Treatment of Vitiligo
K.K. Raja Babu, A. Vilas

147

171

11. Newer Drugs in Dermatology: Systemic


Dinesh Hawelia

180

12. Newer Drugs in Dermatology: Topical


Susmit Haldar

204

13. Wound Dressings: Newer Concepts


Kaushik Nandy

234

14. Computer and Digital Photography:


Newer Tools in Dermatological Practice
Belinda Vaz
Index

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

Recent Advances in Dermatology

pathognomonic sign. Similarly, in pure neuritic leprosy, the finding of


AFB in nerve biopsy is not routinely made. It is also difficult to locate
the offending drug in dermatitis medicamentosa, and challenging the
patient with suspected offending drug runs the risk of flaring up the
eruption severely. In chronic urticaria, often the causative agent cannot
be pinpointed and is termed idiopathic. In clinically obvious tinea
cruris or corporis, rarely the causative fungus is identified. In various
eczemas, the treatment is, more often than not, based on clinical
judgement. In treating a vitiligo patient, empirical treatment is still
followed. In trichotillomania and neurotic excoriation, an in-depth
psychological analysis is mostly not done.
The above narration of the Indian scene and, for the matter, a common
scene of all developing countries only shows that what Haves can
afford, the Have-nots unfortunately cannot. Let the Haves have both
the examinationsclinical and high-tech one, and the rest be satisfied
with the clinical one unless highly imperative. And here lies the
importance of clinical medicine and clinical dermatology.
One is happy to note that the American Journal of Clinical
Dermatology claims to promote rational therapy and effective patient
management within the disciplines of dermatology and appearance
medicine.2 Happily, all recently published books, including textbooks,
provide a good number of excellent coloured clinical photographs to
emphasize on the clinical aspects of the described diseases. This, in fact,
goes a long way to bedside clinical teaching in internal medicine, the
importance of which can hardly be overlooked. The colour and smell of
sputum, stool and urine give us a lot of prima facie information and
provide important clues towards diagnosis. There are records that in
ancient India, a careful examination of pulse could give enough
information regarding the condition of the patient so as to provide even
the prognosis.
Clinical judgement gives the solid data-base which one can ill-afford
to neglect in dermatology, particularly when even histological diagnosis
is not always infallible. Histology depicts only a particular stage of
evolution of the disease. Every disease has a characteristic pattern of
clinical evolution and rarely the same could be followed accurately even
by having a series of temporal histological specimens. Even spongiosis,
the hallmark sign or eczema, may not be found in the very early stage.
But symptoms and signs in dermatology are of great diagnostic value.
The pruritus and its intensity can be judged only by applying the mind
and not by any instrument. The diagnosis of scabies (the itch) mainly
depends on the symptoms and signs which must be allowed to speak
for themselves. Just as a skilful statistician finds from the apparent mess

Introduction xvii

of figures facts of significance, a good clinician may also bag useful


information for diagnostic purpose by applying his eyes (physical and
mental) to see the signs and his ears to hear the symptoms.
Another feature of importance in clinical dermatology is the
psychological aspect and is particularly felt in case of vitiligo. No amount
of evidence that it is just a cosmetic disorder can help remove the
patients mental depression. What is needed most to do good to the
patient is a skilled reassurance by the physician. And here lies the
importance of patient-doctor relationship.
In conclusion, the scientific value of clinical dermatology in diagnosis
of disorders is convincingly clear and it is not possible to dislodge it
from its unique position of importance. The edifice of evidence-based
dermatology can only be built on the sure foundation of clinical
dermatology. Its importance is all the more glaringly established in the
perspective of developing nations. In the final analysis, however, there
is no inherent quarrel between clinical dermatology and evidence-based
dermatology. They are not antagonistic but complementary to each
othera relationship of symbiosis. While we shall not be blind to science
and its development, we shall not also be blinded by it. A torch-light is
focussed only at night in the dark and not in daytime when the sun
steadily shines. We must appear logically sensible. No microscope, simple
or compound, polarising or electron, is of any avail without our physical
eyes. Let not our clinical eyes be allowed to get lost.
REFERENCES
1. Heymann RW. Foreword, Goodhearts Photoguide of common skin disorders,
2nd ed, Lippincott Williams and Wilkins, Philadelphia, 2003; XIII.
2. Cochrane D. Aim and Scope, Am J Clin Dermatol 2001; 2: 389-406.

Recent Advances in
DERMATOLOGY

JAYPEE BROTHERS
MEDICAL PUBLISHERS (P) LTD
EMCA House, 23/23B Ansari Road, Daryaganj
New Delhi 110 002, India

Apoptosis: Its Role in Different Dermatoses 1

Anil H. Patki

Apoptosis: Its Role in


Different Dermatoses
INTRODUCTION
There are two ways in which an eukaryotic cell can die: necrosis and
programmed cell death. Apoptosis represents an important type of
programmed cell death.1 Since necrosis occurs as a result of some external
insult and apoptosis occurs due to an innate cellular programme, they
may as well be described as cell murder and cell suicide respectively.
The term apoptosis, which is pronounced with a short a and a
silent second p, is a Greek word literally meaning falling of leaves from
a tree or of petals from a flower (Apo = away, ptosis = to droop). It was
first used by Kerr et al2 in 1972 to describe the mechanism of controlled
cell deletion little described till that time. The process of apoptosis is
important in both physiological and pathological contexts. During the
embryonic life, various organs and limbs are carved by controlled death
of certain cells. In adult life, apoptosis is necessary to maintain the
homeostasis by a balance with mitosis. The size of organs like liver
remains the same as the number of cells produced by mitosis are balanced
by the number of cells eliminated by apoptosis.3 Also, autoimmune
responses are normally prevented by apoptotic death of auto-reactive
lymphocyte clones. Thus, apoptosis is important in eliminating the
unnecessary or senescent cells without causing any damage to the
surrounding normal cells. Necrosis, by contrast, attracts inflammatory
cells which lead to tissue damage.
Apoptosis, if gone awry, can lead to certain disorders. If auto-reactive
immune cells or cancer cells are not eliminated, an autoimmune or
malignant disorder may be the result. Also, excessive and uncontrolled
apoptosis may lead to disorders like Parkinsonism, Alzheimers disease
and amyotrophic lateral sclerosis.4,5 It has also been found that certain
viral infections like that due to the human immunodeficiency virus [HIV]
induce apoptosis in CD4 lymphocytes.6
Thus, apoptosis is an important phenomenon in both health and
disease. This essay will discuss the mechanisms of apoptosis and the
importance of apoptosis in different dermatoses.

Recent Advances in Dermatology

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.

Apoptosis: Its Role in Different Dermatoses 3


Table 1.1: Death receptors and ligands7
Death receptors

Death ligands

1. Fas (CD 95, Apo 1)

Fas-L (CD 95L)


(Fas ligand)
TNF
Apo 3 L,
TWEAK (TNF-like
weak inducer of apoptosis)
TRAIL

2. TNF-R1 (Tumor necrosis factor receptor 1)


3. TRAMP (Apo 3)
(TNF related apoptosis
mediating protein)
4. TRAIL-R1
(TNFrelated apoptosis
inducing ligand receptor 1)
5. TRAIL-R2
6. DR 6

TRAIL
?

GENES AND APOPTOSIS


Several genes are important in either promoting or inhibiting apoptosis.
Amongst them, the p53 gene and those of Bcl-2 (B cell lymphoma)
family are important. The p53 gene is a tumor suppressor gene whose
product, the p53 phosphoprotein, has a molecular weight of 53000 and
is important in protection against malignancy.9 It acts in two ways.
Whenever there is a mild damage to the cellular DNA, the p53 protein
arrests the cell in G1 phase, allowing the cell to repair the damage before
it proceeds to the S phase. If the damage to the DNA is irrepairable, the
p53 protein eliminates that cell by inducing apoptosis. Thus it is a
guardian of the genome. Absence or abnormalities of the p53 gene are
found in almost 50 percent malignancies found in man. p53 mutations
are associated with aggressive malignancies and poor prognosis.
The Bcl family of genes consists of about 20 members, some of which
are pro-apoptotic and the rest anti-apoptotic. The products of these
genes can form either homodimers or heterodimers in the cytoplasm
and can exert their control on apoptosis at the level of release of
cytochrome C from the mitochondria.10
APOPTOSIS AND SKIN DISORDERS
Excessive or defective apoptosis of epidermal cells or those of the immune
system is an important feature of many dermatological conditions. The
dyskeratotic and eosinophilic keratinocytes, seen in the epidermis after
exposure to ultraviolet radiation (UVB and UVC), are apoptotic cells.11
These, so called sunburn cells, appear in the epidermis within 30 minutes
of the exposure and reach their maximum number in 24 hours. These
cells then move upwards within the epidermis to be shed off. Another

Recent Advances in Dermatology

common physiological example of apoptosis in the skin is that of the


regression of the portion of hair follicle during catagen.12 Besides these
common examples, apoptosis is an important feature of many
hypersensitivity reactions, autoimmune disorders, malignancies and
graft-versus-host disease.
Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN) is a severe drug reaction resulting in
extensive epidermal damage and separation of sheets of epidermis from
the underlying dermis. The common drugs causing TEN are antibiotics
and antibacterials, non-steroidal anti-inflammatory drugs and
anticonvulsants. Some cases of TEN also show lesions suggestive of
erythema multiforme and this group of patients is considered to have
an overlap of TEN and Stevens-Johnson syndrome (SJS). The keratinocyte
death in TEN and TEN-SJS overlap conditions was shown to be due to
apoptosis by Paul et al in 1996.13 They demonstrated the apoptosis of
keratinocytes by electron microscopy which revealed the typical changes
of apoptosis; by DNA-nick end labeling which stained apoptotic cells
and by agarose gel electrophoresis of DNA extracted from the epidermis
which revealed the ladder pattern due to DNA fragmentation. TEN is
a life-threatening condition with a high mortality rate and requires
intensive care. Paul et al conjectured that agents inhibiting apoptosis
may play an important part in management of TEN.13
Subsequently, an important advance in the therapy of TEN was
reported by Viard et al in 1998.14 It was known that keratinocytes normally
express Fas (CD 95) receptor on their surfaces. Viard et al showed that
in TEN, keratinocytes also express Fas ligand which is lytically active
and induces apoptosis in Jurkat cells (a T-lymphocyte line) in vitro.
Intravenous immunoglobulin (IVIG), prepared from multiple donors,
contains naturally occurring anti-Fas antibodies. If keratinocytes are
treated with IVIG (leading to blockade of Fas receptors), futher exposure
to Fas ligand does not lead to apoptosis. Armed with this knowledge,
Viard et al treated 10 patients of TEN with high doses of IVIG (0.2 to
0.75 gm/kg per day) for 4 successive days. The disease process halted
in 1-2 days and epidermal regeneration was complete in 7-12 days with
a favourable outcome in all patients.14 In a subsequent study, Stella
et al treated 9 patients of TEN with high doses of IVIG (0.6 to 0.7gm/
kg per day) for 4 days out of which 8 healed and survived.15 However,
whether systemic problems in TEN (hepatitis, pancreatitis, hematological
abnormalities, lung involvement) also involve apoptosis is not known.
Treatment of TEN with IVIG denotes a very good example of

Apoptosis: Its Role in Different Dermatoses 5

development of a treatment modality on the basis of understanding the


pathomechanisms of apoptosis.
Lichen Planus and Lichenoid Tissue Reaction (LTR)
The lichenoid tissue reaction (LTR) is characterized by damage to basal
cells in the epidermis associated with a massive infiltrate of mononuclear
cells in the upper dermis.16 Many clinically diverse skin disorders ranging
from lichen planus to lupus erythematosus have in common lichenoid
histopathological features. The epidermal cell death, usually found in
the LTR, results from apoptosis. The mode of cell death mediated by
cytotoxic T cells and natural killer cells represents apoptosis. Cytotoxic
T cells mediate apoptosis by atleast 2 ways: i) by perforin and serine
proteases (Granzyme A and B), ii) by interaction of Fas receptors on the
target cells and Fas ligand on the cytotoxic cells.17
The formation of colloid bodies, also referred to as hyaline, cytoid or
Civatte bodies in the lower epidermis and upper dermis is a characteristic
histological feature of LTR and is commonly seen in lichen planus. The
colloid bodies are nothing but apoptotic cells. Bloor et al have shown
that in oral lichen planus, approximately one apoptotic cell is detected
per mm of basal layer and the number of apoptotic cells is proportional
to the density of the lymphocytic infiltrate.18 Bcl-2 expression (which is
anti-apoptotic) is weak or absent in the lesions and Bax expression is
localized to the upper prickle cell layer. Neppelberg et al19 using a different
method have found a higher number of apoptotic cells than Bloor et al.18
The apoptotic cells in oral lichen planus are mostly confined to the basal
layer. Fas and Fas-L are expressed by the basal keratinocytes as well as
by majority of the mononuclear cells in the subepithelial infiltrate.19
In cutaneous lichen planus lesions, granzyme pathway seems to be
at work. Shimuzu et al have shown that granzyme-B-positive CD8 cells
induce keratinocyte apoptosis in cutaneous lichen planus.20 Perforin and
granzymes are the main constituents of the granules of cytotoxic T cells
and natural killer cells. Perforin is a pore forming protein which drills
a hole in the cell membrane of the target cell through which granzyme
B is injected in the cytoplasm of the target cell. Granzyme, a serine
protease, activates or subsitutes for interleukin1-alpha-converting enzyme
(ICE) and promotes apoptosis. Shimuzu et al have shown by
immunoelectron microscopy that granzyme B molecules are secreted
from a lymphocyte to an apoptotic keratinocyte. They also found the
infiltrate to consist of CD4, CD8 cells as well as a few natural killer
cells.20 Apoptosis is thus an important feature of lichen planus and
lichenoid tissue reaction.

Recent Advances in Dermatology

Graft-Versus-Host Disease (GVHD)


GVHD occurs as a result of bone marrow transplantation and an attack
by the donors immunocompetent lymphocytes on the host tissue. The
skin, the intestines and the liver are the tissues mostly involved. In the
acute phase of GVHD and lichenoid type of chronic GVHD, apoptotic
cells are observed in the epidermis.21 These dyskeratotic cells with
eosinophilic cytoplasm and small pyknotic nuclei were termed
mummified cells by earlier workers.22 Various studies have shown that
lymphocyte Fas-L, induced during acute GVHD, is involved in inducing
Fas mediated apoptosis in the target organs viz., skin, liver and gut.
Malignancies
Malignant cells expressing Fas are normally eliminated through apoptosis
by cytotoxic T cells expressing Fas-L. However, absence of Fas receptors
on the malignant cells allows them to escape Fas-Fas-L mediated
apoptosis. This phenomenon is found in basal cell carcinoma and
melanoma.23,24 Thus, defective apoptosis is a feature of these malignant
conditions. Reinduction of Fas expression on tumor cells of basal cell
carcinoma by intralesional injection of interferon-alpha causes regression
of tumour by apoptosis.23
Primary cutaneous T cell lymphoma (CTCL) represents a group of
T cell neoplasm of skin-homing, CD 4-positive T cells. All the successful
therapies in the treatment of CTCL like radiotherapy, electron beam
therapy, topical chemotherapy, psoralen and UVA therapy (PUVA) and
topical steroids, work by inducing apoptosis of neoplastic T cells.25 Loss
of Fas expression on neoplastic cells is found in aggressive types of
CTCL but not in indolent types.26 Thus, loss of Fas expression allows
tumor cells to escape an effective immune response and may contribute
to unfavourable prognosis in some types of CTCL.
Autoimmune Disorders
During the development of T cells, the autoreactive T cells are eliminated
in the thymus by a process involving apoptosis. Any defect in this
process results in persistence of autoreactive immune competent cells
which may be an etiological factor in autoimmune disorders of the
skin.27
Phototherapy: Underlying Mechanism
The narrowband UVB phototherapy of psoriasis has been shown to be
causing apoptosis of T cells in the lesions of psoriasis.28 Even UVA
phototherapy is known to induce apoptosis of T helper lymphocytes.29

Apoptosis: Its Role in Different Dermatoses 7

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.

Recent Advances in Dermatology


17. Kagi D, Vignaux F, Lederman B, et al. Fas and perforin pathways as major
mechanisms of T-cell-mediated cytotoxicity. Science 1994; 265: 528-30.
18. Bloor BK, Malik FK, Odell EW, et al. Quantitative assessment of apoptosis in
oral lichen planus. Oral Surg Oral Med Oral Pathol 1999; 88: 187-95.
19. Neppelberg E, Johannessen AC, Jonssan R. Apoptosis in oral lichen planus.
Eur J Oral Science 2001; 109: 361-4.
20. Shimuzu M, Higaki Y, Higaki M, et al. The role of granzyme-B expressing
CD8 positive cells in apoptosis of keratinocytes in lichen planus. Arch Dermatol
Res 1997; 289: 527-32.
21. Gilliam AC, Whitaker Menezes D, Kamgold R, et al. Apoptosis is the
predominant form of epithelial target cell injury in acute experimental graftversus-host disease. J Invest Dermatol 1996; 107: 377-83.
22. Slavin RE, Santos GW. The graft-versus-host reaction in man after bone marrow
transplantation: pathology, pathogenesis, clinical features and implications.
Clin Immunol Immunopathol 1973; 1: 472-98.
23. Buechner SA, Wernii M, Harr T, et al. Regression of basal cell carcinoma by
intralesional interferon-alpha treatment is mediated by CD 95 (Apo-1/Fas)
CD95 ligand-induced suicide. J Clin Invest 1997; 100: 2691-2726.
24. Hahne M, Rimoldi D, Schroter M, et al. Melanoma cell expression of Fas (Apo1/CD 95) ligand: implications for tumor immune escape. Science 1996; 274:
1363-6.
25. Kacinski BM, Flick M. Apoptosis and cutaneous T cell lymphoma. Ann NY
Acad Sci 2001; 941: 194-9.
26. Zio-Toli O, Vermeer MH, D-Vries E, et al. Expression of Fas and Fas ligand
in primary cutaneous T-cell lymphoma (CTCL): association between lack of
Fas expression and aggressive types of CTCL. Br J Dermatol 2000; 143: 3139.
27. Cohen JJ. Programmed cell death in the immune system. In: Dixon FJ (Ed).
Recent Advances in Immunology. Vol 50. San Diego: Academic Press Inc.
1991: 5585.
28. Kruegaer JG, Wolfe JT, Nabeya RJ, et al. Successful ultraviolet B treatment of
psoriasis is accompanied by a reversal of keratinocyte pathology and by selective
depletion of intraepidermal T cells. J Exp Med 1995; 182: 2057-68.
29. Morita A, Werfel T, Stege H, et al. Evidence that singlet oxygen-induced
human T helper cell apoptosis is the basic mechanism of ultraviolet-A radiation
phototherapy. J Exp Med 1997; 186: 1763-8.

Cell Markers in Dermatology

Uday Khopkar, Deepa Sachdev

Cell Markers in Dermatology


INTRODUCTION
An average dermatologist rarely deals with a report of cell marker
studies in his or her clinical practice. However, access to knowledge
about them is handy at times to understand ones patients condition as
well as to explain him or her prognosis and the course of action to be
followed. For the pathologists and dermatopathologists, the subject is of
interest for pinpointing the differentiation of various neoplasms and at
times, to reach a specific diagnosis.
WHAT ARE CELL MARKERS?
These are functional molecules reflecting the state of cellular
differentiation, expressed on the outer cell surface membrane. Monoclonal
and polyclonal antibodies directed to the surface molecules on B cells,
T cells, macrophages and natural killer cells are now available. When a
cluster of monoclonal antibodies is found to be reactive to the same
surface molecule, it clearly represents a series of reagents defining a
given marker (cell surface molecule). The cell marker is then assigned
a CD number, 1 i.e. cluster designation (also known as cluster
differentiation) number meaning that a known cluster of antibodies
bind to this known antigen/molecule.
HOW ARE CELL MARKER STUDIES DONE?
Immunophenotyping is a technique of identifying surface molecules
that are associated with the tumor cells and that help to characterize
them. The molecules are then identified by using specific antibodies that
bind to them. Use of monoclonal antibodies is preferred to polyclonal
antibodies as the former are more sensitive and do not have risk of
cross-reacting antibodies. The only disadvantage of monoclonal
antibodies is that the majority of them require frozen sections.
PROCEDURE
The serum (containing antibodies) is poured over the tumor cells, which
may be present in the tissue section. If the tumor cells bear the surface

10

Recent Advances in Dermatology

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

Cell Markers in Dermatology

11

Table 2.1: Commonly used cell markers


Antigen/Cell marker

Normal tissue

Tumors

Cytokeratins*

Epidermis and its


appendages
Mesenchymal cells,
melanocytes, lymphocytes
Smooth and skeletal muscle
Neurons, endocrine system

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

Smooth and skeletal muscle,


myofibroblasts
Striated muscle

EMA

Fetal skin, adult sweat glands

S-100 protein*

Melanocytes, Langerhans cells,


eccrine and apocrine glands

HMB-45

Fetal and neonatal melanocytes

CEA

Eccrine and apocrine glands

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

*Standard panel of antibodies

iv. Neurofilamentsfound in neuronal cells


v. Glial filamentsfound in astrocytes
Cytokeratins/Prekeratins
These are a family of heterogenous proteins with molecular weight
varying from 40,000 to 68,000.3 Keratin is present in all epithelial cells.
The high molecular weight keratins are present in the more differentiated
cells of the epidermis, while the low molecular weight keratins are

12

Recent Advances in Dermatology

found in simple epithelia and non-keratinising squamous epithelia.4


Thus antikeratin antibodies help to differentiate epithelial tumors from
non-epithelial (melanocytic, mesenchymal and hematopoietic) tumors.
A mixture of low and intermediate keratins such as AE1 and AE3 is
commonly used.5 CK20 is a keratin marker specific for Merkel cell
carcinoma. However, it has been observed that certain non-epithelial
tumors like leiomyosarcomas, rhabdomyosarcomas and plasmacytomas
can react with cytokeratin antibodies.
Vimentin
It is an intermediate filament expressed by a number of different cell
types such as lymphocytes, melanocytes, macrophages, endothelial cells,
fibroblasts and smooth muscle cells. Because of its nonspecific nature,
it is useful only as a panel approach to support mesenchymal or
melanocytic differentiation. Thus, it is a valuable tool in differentiating
sarcomas from carcinomas, and malignant melanomas from carcinomas.
When used in combination with cytokeratin markers in spindle cell
tumors, it helps to make a definite histopathological diagnosis.6 Moreover,
it has been found to be the only intermediate filament present in certain
soft tissue tumors, e.g. malignant fibrous histiocytomas.
Desmin
It is an intermediate filament expressed by smooth, skeletal and
cardiac muscle cells. Its main diagnostic application is in the differential
diagnosis of soft tissue tumors as its presence establishes the myogenic
nature of any neoplasm.7 Thus, it is positive in leiomyomas, rhabdomyomas, leiomyoblastomas, leiomyosarcomas and rhabdomyosarcomas.
Neurofilaments
Neuron-specific enolase (NSE) is an enzyme found in neurons,
neuroendocrine cells, and tumors derived from them. However, it has
low specificity, as it is detectable in a variety of tumors like Merkel cell
carcinoma and malignant melanoma.
Actin
It is a contractile protein present in smooth and striated muscle,
myoepithelial cells of salivary gland, breast and the sweat gland. Tumor
cells of a number of muscular and nonmuscular neoplasms also stain
positive for actin.

Cell Markers in Dermatology

13

Epithelial Membrane Antigen (EMA)


It is a glycoprotein isolated from human milk fat globule membrane.
EMA is detectable in the majority of carcinomas, mesotheliomas, and
synovial and epitheloid sarcomas.8 However, basal cell carcinomas do
not express EMA.9 Thus EMA is neither sensitive nor specific as an
epithelial cell marker as is keratin.
Carcinoembryonic Antigen (CEA)
Ordinarily present in gastrointestinal malignancies, it has been found in
normal eccrine and apocrine units as well as benign and malignant
sweat gland tumors, and in mammary and extra-mammary Pagets
disease of the skin.10 It may help in distinguishing Pagets disease from
pagetoid melanoma.
Miscellaneous
Involucrin
It is present in the maturing stratified squamous epithelia. It has been
detected in the majority of reactive hyperplasias and condylomata of the
cervix, whereas cervical dysplasias do not express this protein.
Chromogranin and Synaptophysin
These are neuroendocrine antigens found in normal endocrine glands
and neuroendocrine tumors such as Merkel cell carcinoma.11
Antibodies against Lysozyme, -1-antitrypsin and
-I-antichymotrypsin
These are regarded as markers of mononuclear phagocytic cells. They
help in the diagnosis of fibrohistiocytic neoplasms but are not specific
markers as they have also been detected in carcinomas and melanomas.
WHAT ARE THE SITUATIONS WHERE
CELL MARKER STUDY IS REQUESTED?
1.
2.
3.
4.
5.

Diagnosis of a poorly differentiated neoplasm


Classifying spindle cell neoplasms
Suspected malignant melanoma that lacks pigment
Diagnosis of histiocytic disorders
Classifying vascular neoplasms

14

Recent Advances in Dermatology


Table 2.2: Panel for basophilic small cell tumors5

Diagnosis
Lymphoma
Merkel cell carcinoma
Melanoma
Carcinoma

Keratin

LCA

S100

Synaptophysin

+
+/

This table is adapted from Levers Histopathology of Skin

6. Diagnosing and classifying lymphoma


7. Diagnosing and classifying leukemias
8. As a research tool
Diagnosis of a Poorly Differentiated Neoplasm
In the diagnosis of a poorly differentiated neoplasm (including metastases), a standard panel of antibodies is done. This usually includes the
antibodies marked with an asterisk in Table 2.1. They help in deciding
whether the neoplasm is epithelial, mesothelial, melanocytic or
lymphoreticular. Additional antibodies may be included in the panel
depending on clinical and histopathological inputs.
Immunohistochemistry plays a vital role in the diagnosis of poorly
differentiated basophilic small cell neoplasms in the skin. The panel
used and its interpretation is mentioned in Table 2.2.
Classifying Spindle Cell Neoplasms
Cell marker studies are crucial in the diagnosis of poorly differentiated
spindle cell neoplasms in the skin. The panel used and its interpretation
is mentioned in Table 2.3.
Table 2.3: Panel for malignant spindle cell tumors5
Diagnosis
Squamous cell
carcinoma
Melanoma
Angiosarcoma
Leiomyosarcoma

Keratin

Vimentin

Desmin

S-100

This table is modified from Levers Histopathology of Skin

HMB-45 Factor VIIIrelated antigen

Cell Markers in Dermatology

15

Suspected Malignant Melanoma that Lacks Pigment


S 100 Protein
S 100 protein is an acidic protein present in a large variety of cells such
as the melanocytes, Langerhans cells, histiocytes, eccrine and apocrine
gland cells, Schwann cells, myoepithelial cells, nerves, muscles,
chondrocytes and their malignant counterparts.12-14 It has a high
sensitivity but low specificity that restricts its utility to the following
indications:
1. Diagnosis of spindle cell and desmoplastic melanoma
2. Diagnosis of poorly differentiated cutaneous metastases.
HMB-45
HMB-45 is an antigen expressed only by melanocytes. However, its
sensitivity is only about 70 percent. It mainly helps to differentiate
melanoma from carcinoma.15 However, it cannot differentiate between
a benign nevus and a malignant melanoma.
Recently, a new panel consisting of Melan-A, Tyrosinase, and MiTF
(microphthalmia gene) has been recommended for melanocytic
neoplasms.
Studies have shown that monoclonal antibody to MiTF is a sensitive
and specific marker for epitheloid melanomas.16-17 Rarely carcinomas
are S-100 positive and sometimes melanomas, unlike carcinomas, express
an intermediate filament vimentin.
Diagnosis of Histiocytic Disorders
It is important to distinguish Langerhans cell histiocytosis from other
histiocytoses by presence of Birbeck granules and S-100 and CD 1a
positivity. Table 2.418 summarizes the characteristics of all histiocytoses.
Table 2.4: Cell markers in histiocytic disorders18
Disease

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

Recent Advances in Dermatology

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

Cell Markers in Dermatology

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

Recent Advances in Dermatology

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

Cell Markers in Dermatology

19

Table 2.5: Cell markers in T cell and NK-cell neoplasms30


Lymphoma type

Positive markers on
neoplastic cells

Expected negative
T markers helping the
diagnosis

T-PLL (Peripheral T cell


lymphoepitheloid lymphoma)

CD2, CD3, CD4,


CD5, CD7

T-large granular lymphocytic


leukemia(T-LGL)

1-Tcell: CD3, CD57(+/-)


2-NK cell: CD56(+/-),
CD57(+/-)

1- CD56
2- CD3

Adult T cell leukemia/


lymphoma (HTLV-1+)

CD2, CD3, CD4,


CD5, CD25

CD7

Mycosis fungoides

CD2, CD3, CD4,


CD5, CD103

CD7, CD8 (+/-)

Anaplastic large cell lymphoma

1-CD3, CD30,
2-CD3
EMA (T cell)
2-CD30, EMA (Null cell)

This modified table is adapted from http:/ www.thd.org.tr/sub/eng/lymphoid.php

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

Recent Advances in Dermatology


Table 2.6: Differential diagnosis of HL and some of the NHL subtypes30

Lymphoma type

Immunophenotypic profile of malignant cells

Lymphocytic predominance HL

Positive: CD45, CD20, CD79a


Negative: CD30(+/-), CD15

Classical HL

Positive: CD30, CD15, CD20(+/-)

1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte depleted

Can be positive: EMA


Negative: CD45, CD79a

T cell histiocyte rich B cell lymphoma

Positive: CD45, CD20, CD79a


Negative: CD15, CD3

Anaplastic large cell lymphoma

Positive: CD30, CD45(+/-), EMA(+/-)


Negative: CD20, CD15

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.

Cell Markers in Dermatology

21

Table 2.7: Diagnostic dilemmas assisted by immunocytochemistry1


Differential diagnosis

Cell markers used

Carcinoma vs lymphoma

LCA, T and B cell markers, keratin, CEA

Melanoma vs carcinoma

Keratin, CEA(carcinoma), S-100, HMB-45 (melanoma)

Sarcoma vs carcinoma

Keratin, CEA, EMA(carcinoma), vimentin, desmin

Carcinoma vs mesothelioma CEA, CD15 (carcinoma), EMA (mesothelioma)


This modified table is adapted from textbook of Diagnostic cytology and its
histopathologic bases

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.
REFERENCES
1. Margaret B Listrom, Cecilia M Fenoglio-Preiser. Immunocytochemistry in tumor
diagnosis. In: Leopold G Koss, (Ed). Diagnostic cytology and its histopathologic
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

Recent Advances in Dermatology

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.

Cell Markers in Dermatology

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

Recent Advances in Dermatology

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

Cutaneous Tuberculosis: Recent Perspective

25

localized disease and 50 percent with disseminated disease. Skin biopsy


showed characteristic tubercular changes in 80 percent of patients with
lupus vulgaris and in 47.5 percent of patients with scrofuloderma. The
lung, bone and abdomen were the sites of extracutaneous tuberculosis
in 21.3 percent of patients.
A report from New Delhi described 63 children with cutaneous
tuberculosis.3 Culture was positive in only 3 children. Regional
lymphadenopathy with lupus vulgaris was commoner than in adults.
No difference in the clinical presentation was seen between children
who were vaccinated with BCG and those who were not.
Some reports of unusual clinical manifestations have appeared.
Proptosis was described in a child who had facial lesions of scrofuloderma
associated with an intraorbital abscess. Both cutaneous and orbital lesions
subsided with antitubercular therapy.4 Oral ulcers are not generally
recognized by dermatologists as a manifestation of tuberculosis. A study
of 42 cases with orofacial tuberculosis revealed oral ulcers in 70 percent
of cases. Other manifestations included bony lesions and involvement of
the salivary glands and lymph nodes.5 Inoculation tuberculosis has been
described following nose piercing6 and tattooing.7 A report from Turkey
states that the ear lobe is a relatively common site of lupus vulgaris
occurring in about 12 percent of patients.8 Could this also be related to
piercing? Cutaneous tuberculosis has also been described following injury
to the skin and corticosteroid injections.9 Tuberculous gumma developed
at the site of venepuncture in a man who had had pulmonary tuberculosis
in the past. It was postulated that endogenous tuberculosis had localized
to the site of a sterile injury.10 A recent report describes a patient who
developed lupus vulgaris at the site of previously healed scrofuloderma.11
This is not a particularly novel or rare phenomenon in our experience.
The rare presentation of lupus vulgaris in a sporotrichoid pattern was
reported.12 Tuberculosis has been reported at the sites of ports used for
laparoscopic surgery.13 We have also observed draining sinuses at these
sites in a few patients. However, the diagnosis of tuberculosis is difficult
to establish and patients usually receive a trial of antitubercular therapy
which may not always be successful. The possibility of a foreign body
leading to a persistent infection or of another non-tuberculous infection
must be kept in mind in such patients. Tuberculosis is not usually
considered as a cause of lymphedema. A case with nodules on the leg
followed by lymphedema was reported. Biopsy of the nodules revealed
granulomas and a Mantoux test was positive. The nodules subsided
with antitubercular therapy, though the lymphedema was unchanged.14
As dermatologists, we look for evidence of tuberculosis in other
systems in patients who present to us with cutaneous tuberculosis. One
study turned that question around and asked what proportion of patients

26

Recent Advances in Dermatology

with tuberculosis in other organs have cutaneous tuberculosis? Cutaneous


tuberculosis was seen in 7 (2.6%) of patients with tuberculosis in other
organs, viz. lymph node and lung.15
Sexual transmission of tuberculosis was described in an Indian man
who had penile tuberculosis that was confirmed by culture. A year later,
his wife developed endometrial tuberculosis. The organism grown from
the woman was identical on molecular typing to that grown from her
husband providing strong evidence of sexual transmission in this couple.16
TUBERCULIDS
Lichen scrofulosorum was noted to develop in 2 children after initiation
of therapy for tuberculosis. The pathogenesis was ascribed to an
improvement in cell-mediated immunity similar to type I reaction
developing after the initiation of antileprosy treatment. The skin lesions
of lichen scrofulosorum subsided on continuation of therapy.17
Papulonecrotic tuberculids and a sterile, symmetric arthritis (Poncets
arthritis) developed in an HIV-positive patient. Both skin and joint lesions
improved after anti-tubercular therapy.18 Arthritis, like tuberculids, is a
rare hypersensitivity response to tuberculosis that dermatologists should
be aware of.
Nodular tuberculid has been suggested as a designation for
subcutaneous, non-ulcerated nodules that showed granulomatous
inflammation in the deep dermis and adjacent fat. The biopsies also
showed vasculitis in 2 out of 4 cases. The Mantoux test was positive in
all and there was a good response to antituberculous therapy.19 This
entity shows features of erythema induratum though the changes are
not confined to the panniculus. A new term for these lesions does not
appear to be justified.20
Multiple episodes of Sweets syndrome during treatment were
reported in 5 out of 18 patients with scrofuloderma due to atypical
mycobacteria and M. tuberculosis. This association has recently been
highlighted.21 This probably represents a hypersensitivity phenomenon
similar to the tuberculids.
CUTANEOUS TUBERCULOSIS IN
THE IMMUNOSUPPRESSED HOST
Cutaneous tuberculosis was described in immunosuppressed hosts. A
study from Mumbai reported the histopathological analysis of cutaneous
lesions in 195 patients with HIV/AIDS which revealed cutaneous tuberculosis in 13 patients.22 A report from Thailand described 3 patients with
HIV/AIDS who had cutaneous tuberculosis.23 One patient presented

Cutaneous Tuberculosis: Recent Perspective

27

with a nodule on the forearm while 2 had generalized erythematous


papules and vesicopustules. The latter is an unusual presentation and
may represent miliary tuberculosis of the skin in these immunosuppressed
patients. Four patients with HIV/AIDS and cutaneous miliary
tuberculosis were described in another report. All patients also had
miliary lesions in other organs. Skin biopsies revealed no or ill-formed
granulomas, extensive necrosis and many acid-fast bacilli. Three patients
had multidrug resistant organisms and all these patients had a rapid
downhill course.24
PATHOGENESIS
A woman with tuberculosis of the axillary lymph nodes and erythema
induratum was found to have circulating T cells that were stimulated
by purified protein derivative (PPD). These T cells produced interferon
gamma in response to PPD. It is possible that these cells mediated the
development of erythema induratum at skin sites where mycobacterial
antigen was present.25
The tissue levels of collagen, elastin, fibronectin, transforming growth
factor-beta (TGF-beta) was higher in active lesions compared to healed
lesions of cutaneous tuberculosis indicating that effective chemotherapy
reduces the fibrosis that accompanies active infection.26
DIAGNOSIS
A study from Mumbai reported the growth of mycobacteria in 29 (56.9%)
out of 51 cases of cutaneous tuberculosis. Twenty-six of the isolates were
M. tuberculosis.27 This is a much higher isolation rate than is usually
reported from our country.
PCR is yet to find a definite place in the diagnosis of cutaneous
tuberculosis. Different studies provide conflicting evidence of its value.
In a study that did not include controls and did not specify a gold
standard, 18 (56.2%) of 34 cases of granulomatous inflammation were
considered to have tuberculosis or atypical mycobacterial infection based
on the results of PCR analysis.28 A study of 10 patients with cutaneous
tuberculosis and 20 controls from Chandigarh showed a positive PCR
result in 6 (60%) of cases and in none of the controls.29 In another study
using controls, 1 out of 23 cases of cutaneous tuberculosis and 1 out of
22 healthy controls showed amplification of M. tuberculosis DNA.30 This
indicates a poor sensitivity and specificity of the test. In a study from
Taiwan, 12 cases were diagnosed to have erythema induratum based on
the findings of tender subcutaneous nodules on the legs, granulomatous
panniculitis with vasculitis and a therapeutic response to antitubercular

28

Recent Advances in Dermatology

therapy. PCR for M. tuberculosis DNA was positive in 9 cases.31 A study


from Singapore found that PCR was highly sensitive and specific in
immunocompromised patients who had multibacillary disease and
showed acid-fast bacilli on biopsy. The sensitivity was considerably less
in paucibacillary diseae: lupus vulgaris (55%), tuberculosis verrucosa
cutis (60%) and erythema induratum (54%). The authors suggest that the
clinical decisions in paucibacillary cutaneous tuberculosis should not be
based on PCR results alone.32 The same group had reported their findings
earlier using another PCR technique which was less sensitive.33 However,
their conclusions about the value of PCR remained unchanged. A similar
conclusion was reached by another group who performed PCR in facial
lesions.34
Mycobacterial DNA was detected in 16 (80%) out of 20 cases of
cutaneous sarcoidosis indicating that mycobacteria may play a role in
the development of sarcoidosis.35 It also indicates that PCR for mycobacterial DNA is not a reliable way to differentiate cutaneous tuberculosis
from sarcoidosis.
TREATMENT
Standard treatment regimens consisting of isoniazid 300 mg daily and
rifampicin 450 mg daily for 6 months along with pyrazinamide 1500 mg
daily and ethambutol 800 mg daily for the first 2 months are used for
cutaneous tuberculosis. Some workers use only 3 drugs if there is no
evidence of extracutaneous tuberculosis. These schedules are effective.
A recent retrospective analysis found that nearly all patients show a
clinical response within 4 weeks of starting treatment. By extension, it
was suggested that when a therapeutic trial of the diagnosis is undertaken
in cutaneous tuberculosis, a period of 6 weeks is enough to decide
whether the patient has tuberculosis (or not). Longer durations of therapy
do not appear to be justified in those who have not responded within
this period.36
The bad news is that two culture-documented cases of drug resistant
tuberculosis were reported from Delhi.37,38 One patient had tuberculous
gummata while the other had scrofuloderma. The patients were treated
with second-line drugs with improvement. This is a serious development
that bodes ill for patients. So far, reports of drug resistance in cutaneous
tuberculosis were rare. The situation may change for the worse in the
future and require the use of expensive, less effective medication to treat
these patients.

Cutaneous Tuberculosis: Recent Perspective

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

Recent Advances in Dermatology

23. Chiewchanvit S, Mahanupab P, Walker PF. Cutaneous tuberculosis in three


HIV-infected patients. J Med Assoc Thai 2000;83:1550-4.
24. Daikos GL, Uttamchandani RB, Tuda C, et al. Disseminated miliary tuberculosis
of the skin in patients with AIDS: report of four cases.Clin Infect Dis 1998;
27:205-8.
25. Koga T, Kubota Y, Kiryu H, et al. Erythema induratum in a patient with active
tuberculosis of the axillary lymph node: IFN-gamma release of specific T cells.
Eur J Dermatol 2001; 11:48-9.
26. Jayasankar K, Shakila H, Umapathy KC, et al. Biochemical and histochemical
changes pertaining to active and healed cutaneous tuberculosis. Br J Dermatol
2002;146: 977-82.
27. Gopinathan R, Pandit D, Joshi J, et al. Clinical and morphological variants of
cutaneous tuberculosis and its relation to mycobacterium species. Indian Journal
of Medical Microbiology 2001; 19: 193-6.
28. Hsiao PF, Tzen CY, Chen HC, et al. Polymerase chain reaction based detection
of Mycobacterium tuberculosis in tissues showing granulomatous inflammation
without demonstrable acid-fast bacilli. Int J Dermatol 2003;42:281-6.
29. Arora SK, Kumar B, Sehgal S. Development of a polymerase chain reaction
dot-blotting system for detecting cutaneous tuberculosis. Br J Dermatol
2000;142:72-6.
30. Senturk N, Sahin S, Kocagoz T. Polymerase chain reaction in cutaneous
tuberculosis: Is it a reliable diagnostic method in paraffin-embedded tissues?
Int J Dermatol 2002;41:863-6.
31. Chen YH, Yan JJ, Chao SC, et al. Erythema induratum: a clinicopathologic and
polymerase chain reaction study. J Formos Med Assoc 2001;100:244-9.
32. Tan SH, Tan HH, Sun YJ, et al. Clinical utility of polymerase chain reaction
in the detection of Mycobacterium tuberculosis in different types of cutaneous
tuberculosis and tuberculids. Ann Acad Med Singapore 2001; 30: 3-10.
33. Tan SH, Tan BH, Goh CL, et al. Detection of Mycobacterium tuberculosis DNA
using polymerase chain reaction in cutaneous tuberculosis and tuberculids. Int
J Dermatol 1999;38:122-7.
34. Ferrara G, Cannone M, Scalvenzi M, et al. Facial granulomatous diseases: A
study of four cases tested for the presence of Mycobacterium tuberculosis DNA
using nested polymerase chain reaction. Am J Dermatopathol 2001; 23:8-15.
35. Li N, Bajoghli A, Kubba A, et al. Identification of mycobacterial DNA in
cutaneous lesions of sarcoidosis.J Cutan Pathol 1999;26:271-8.
36. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond
to treatment? Implications for a therapeutic trial of diagnosis. Int J Dermatol
In press.
37. Sharma N, Kumar P, Mantoo S, et al. Primary multi-drug resistant tuberculous
gumma. J Commun Dis 2001;33:170-3.
38. Ramesh V, Murlidhar S, Kumar J, et al. Isolation of drug-resistant tubercle
bacilli in cutaneous tuberculosis. Pediatr Dermatol 2001;18:393-5.

The Spectrum of Leukocytoclastic Vasculitis

31

Debabrata Bandyopadhyay

The Spectrum of Leukocytoclastic


Vasculitis: Etiology, Classification
and Approach to Management
BACKGROUND
Vasculitis is a clinicopathological process characterized by inflammation
of and damage to blood vessels.1 Compromise of vascular lumen occurs
and the resultant ischaemia causes damage to the organs in which the
vasculitic process takes place. Since vessels of any calibre in any organ
may be affected, vasculitis can result in a wide variety of clinical entities.
The pathogenic mechanisms largely remaining uncertain, vasculitic
disorders continue to be defined and categorized according to their
clinical and pathological findings.
Leukocytoclastic vasculitis (LV) is a category of vasculitis that includes
clinicopathological entities characterized by inflammation of small blood
vessels (mainly post-capillary venules, also small arterioles and
capillaries) with neutrophilic infiltration in and around vessel walls,
and fragmentation of nuclei of neutrophils (leukocytoclasis). Fibrinoid
changes of vessel walls and extravasation of red blood cells also occur.2
LV is not a disease in itself, but rather a pathologic process associated
with diseases of diverse causes.3 LV has many synonyms, and the term
has been used interchangeably with nomenclatures such as allergic
vasculitis, allergic angiitis, hypersensitivity vasculitis, hypersensitivity
angiitis, necrotizing venulitis, and others.
Palpable purpura is the hallmark lesion of LV. This term appropriately
describes the elevated, firm, hemorrhagic, non-blanchable lesions most
commonly seen on the lower limbs, often appearing in crops. Generally
asymptomatic, the lesions may be pruritic or tender. Other types of
lesions associated with LV include urticarial wheals, papules, plaques,
pustules, nodules, blisters, necrotic ulcerations and livedo reticularis.4
General symptoms of fever, malaise, arthralgia and myalgia are often
present. LV may be associated with systemic involvements. The common
sites of visceral affection include kidney, joints, lung, gastrointestinal
tract, and nervous system. Cutaneous LV may result from, or associated

32

Recent Advances in Dermatology

with a variety of causes like drugs, infections, connective tissue diseases,


malignancies, systemic vasculitic syndromes, and other underlying
systemic diseases. The pathologic links of these causes with the
development of LV remain largely speculative or unknown, but immune
mechanisms are believed to play important roles.5 However, no
aetiological factors can be demonstrated despite thorough clinical and
laboratory investigations in about one-third to half of the patients with
LV.6,7 Although LV usually follows a benign course limited to the skin
in most of the patients,8 the importance of cutaneous LV lies in the fact
that the skin lesions may provide with the dermatologists a window to
the early diagnosis of serious life-threatening systemic vasculitic
disorders. In this context, the recently described antineutrophil
cytoplasmic antibodies may provide important input for the diagnosis
and categorizations of systemic small-vessel vasculitides. Management
of LV requires a rational diagnostic approach that takes into consideration
the possibilities of various etiological factors that may give rise to this
disorder.
ETIOPATHOGENESIS
Leukocytoclastic vasculitis is a heterogenous group of disorders having
the unifying features of histological evidence of inflammation and
necrosis of small blood vessels and a neutrophilic infiltrate in and around
vessel walls. Although the pathomechanisms leading to this vascular
damage are not fully elucidated, various immune-mediated tissue
reactions are generally implicated.5 There is compelling animal and
human experimental evidence that leukocytoclastic vasculitis results
from a hypersensitivity reaction similar in nature to the experimental
Arthus reaction, the essential elements of which include antigen,
complement-fixing antibodies, intact complement pathway and an
adequate number of neutrophils.5 The initiating event at the level of the
vasculature is deposition of circulating immune complexes, formed in
situations of antigen excess. This leads to a sequence of tissue reactions.
Complement is activated and activated complement components (C5a
and C3a) then attract neutrophils to the site. Phagocytosis of immunecomplexes by infiltrating neutrophils is associated with the release of
neutrophil granules containing proteolytic enzymes like collagenase and
elastase and production of oxygen free radicals that damage the vessel
wall and surrounding tissue. The membrane attack complex of the
complement also plays a role in the mechanisms of endothelial cell
damage.9 Expression of adhesion molecules, which are present on cell
surfaces and mediate cell-cell interaction, are upregulated on activated
neutrophils and endothelial cells and play a crucial role in the processes

The Spectrum of Leukocytoclastic Vasculitis

33

of neutrophil margination along vessel wall and their migration outside


the vessel lumen into the extravascular space.10 Cytokines such as
interleukins (like IL-1, IL-6, IL-8), tumor necrosis factor-alpha (TNFalpha) and granulocyte monocyte colony-stimulating factor (GM-CSF)
are synthesized by activated endothelial cells and act as mediators of
inflammation in the vasculitic process.5,11 Apart from neutrophils and
endothelial cells, other cell types also takes part in the inflammatory
reaction. Mast cells, by releasing histamine, chemoattractants and
proteolytic enzymes, participate in the inflammatory process and cause
tissue damage.12 Formation of platelet aggregates and release of secretory
products from platelets also contribute to the inflammatory response
and tissue damage in vasculitis.13
A variety of mechanisms involving antibodies like antineutrophil
cytoplasmic antibodies (ANCA), anti-endothelial antibodies, and
anticardiolipin antibodies are believed to contribute to the pathogenesis
of LV.5 ANCAs are antibodies directed against specific cytoplasmic
proteins of neutrophils and are present mainly in the sera of patients
with systemic vasculitides and certain other systemic disorders like
connective tissue disorders, inflammatory bowel diseases and
autoimmune liver diseases. In the indirect immunofluorescence test,
alcohol-fixed indicator neutrophils are treated with patients sera and
examined for patterns of immunofluorescence. Two main types of
fluorescence patterns are recognized, a diffuse staining pattern of the
cytoplasm (cytoplasmic ANCA, cANCA), and a staining around the
nucleus (perinuclear ANCA, pANCA). The specific protein recognized
by cANCA is nearly always proteinase 3, a serine proteinase present in
the primary granules of neutrophils, while the pANCAs are directed
mainly against myeloperoxidase as well as other proteins present in the
cytoplasm of neutrophils, like elastase, cathepsin and lactoferrin. cANCAs
against proteinase 3 are commonly designated as PR3 ANCA while
pANCAs against myeloperoxidase are called MPO ANCA. Although
their pathogenetic role remains to be fully elucidated, detection of ANCAs
has important diagnostic and prognostic roles in systemic small vessel
vasculitides like Wegeners granulomatosis and microscopic
polyangiitis.14
What brings about or initiate the above-mentioned tissue reactions
may remain undetermined in most patients, but etiological factors (Table
4.1) like infections, drugs, food and food additives,15 connective tissue
disorders, malignant disease processes, and a number of various
underlying systemic diseases may be responsible in a large proportion
of cases.
Drug-induced vasculitis is a common cause of LV. In a retrospective
study of an unselected population of adults with LV, 23.9 percent of 138

34

Recent Advances in Dermatology


Table 4.1: Etiological factors in cutaneous LV

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

patients were diagnosed with drug-induced vasculitis.16 Drugs from


almost every pharmacologic class have been implicated in causing
vasculitis in sporadic cases (Table 4.2). The level of certainty and quality
of evidence for these associations between specific agents and vasculitis
varies greatly.17 Drug-induced vasculitis develops within 7 to 21 days
after treatment begins.14 Drugs that have been commonly implicated
include penicillins, aminopenicillins, sulphonamides, allopurinol,
thiazides, pyrazolones, retinoids, quinolones, hydantoin and nonsteroidal anti-inflammatory drugs.12 Some recent reports of drug-induced
vasculitis have incriminated such varied agents as clarithromycin,18
naproxen,19 omeprazole,20 glyburide,21 celecoxib,22 losartan,23 zafirlukast,24 ibuprofen,25 methotrexate,26 infliximab,27 efavirenz28 and
influenza vaccinations29 among others. The pathologic mechanisms of
drug-induced vasculitis remain to be defined and appear to be
multifactorial with humoral and cell-mediated immune mechanisms
playing important roles.30 Some drugs such as penicillins, cause vasculitis
by conjugating to serum proteins and mediating immune-complex
vasculitis. Other drugs that cause immune-complex formation are foreign
proteins, such as streptokinase, cytokines, and monoclonal antibodies.14
Drugs such as propylthiouracil and hydralazine appear to cause vasculitis
by inducing ANCA.15,31 In a study of 56 patients with Graves disease
receiving treatment with propylthiouracil, 37.5 percent developed MPOANCA positivity.32 There are no significant differences in clinical
presentation, serologic abnormalities, and pathologic findings of druginduced vasculitis with the idiopathic forms of vasculitis.30 However, it
is extremely important to identify the offending drug because the
discontinuation of the agent is often followed by a rapid improvement
of the underlying vasculitic disorder.30

The Spectrum of Leukocytoclastic Vasculitis

35

Table 4.2: List of drugs causing LV


Antibacterials
Ciprofloxacin
Cefaclor
Clarithromycin
Clindamycin
Minocycline
Penicillins
Sulphonamides

Biological response modifiers


Granulocyte colony stimulating factor
(G-CSF)
Infliximab
Interferon-alpha

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

Infections may precipitate LV (Table 4.3). The pathogenic mechanisms


appear to be complex and may include immune complex formation to
microbial antigens, damage to vessels directly mediated by pathogens
and humoral or cellular immune response. The most commonly
recognized infectious agents are group A hemolytic streptococci,
Staphylococcus aureus, Mycobacterium leprae, and hepatitis B virus.12
Leprosy is perhaps the commonest cause of vasculitis in the world.4 An
immune-complex mediated vasculitis in multibacillary leprosy causes

36

Recent Advances in Dermatology


Table 4.3: Infections associated with LV

Bartonella henselae infection

HIV infection

Brucellosis

Leprosy

Candidiasis

Meningococcosis

Chlamydia pneumoniae infection

Parvovirus B19 infection

Cytomegalovirus infection

Rickettsioses

Ehrlichiosis

Staphylococcal infection

Epstein-Barr virus infection

Streptococcal infection

Gonorrhoea

Syphilis

Helicobacter pylori infection

Tuberculosis

Hepatitis A, B and C infection

Varicella

Herpes simplex

the clinical syndrome of erythema nodosum leprosum. Hepatitis C virus


(HCV) infection runs a chronic course in a large majority of the affected
individuals involving many extra-hepatic organ systems including the
skin. HCV-induced mixed cryoglobulinemia is a frequently recognized
cause of cutaneous vasculitis.14,33 Polymerase chain reaction analyses
could detect HCV RNA expression in endothelia and perivascular
inflammatory cells.34 It was postulated that viral infection of endothelia,
cross-reactivity between endogenous and viral antigens leading to
immune reactions, viral tropism to B lymphocytes resulting in B cell
proliferation and resultant autoantibody production, and circulating
immune complexes containing cryoglobulins could all be of pathogenic
significance.34 Other infections reported to be associated with LV include
human immunodeficiency virus (HIV) infection,35,36 hepatitis A virus
infection,37,38 Epstein-Barr virus infection,39 and Chlamydia pneumoniae
infection.40 Parvovirus B 19 infection has been reported to be associated
with LV in a number of reports.41 Infections with cytomegalovirus,42
Mycoplasma pneumoniae,43 and Bartonella henselae44 were also implicated
in a number of cases. Pulmonary tuberculosis,45 brucellosis,46 bacterial
endocarditis, and meningococcemia were also among the infective
diseases reported to have caused LV.
A number of connective tissue diseases are sometimes associated
with cutaneous leukocytoclastic vasculitis. Autoimmunity and formation
of immune complex are believed to be the usual pathomechanism. Systemic lupus erythematosus (SLE), Sjgrens syndrome, and rheumatoid
arthritis (RA) are the commonly implicated disorders among this group
of patients. LV occurs rarely in patients with scleroderma and mixed
connective tissue disease.12 In a retrospective study of 186 patients with

The Spectrum of Leukocytoclastic Vasculitis

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

Recent Advances in Dermatology

criteria. But lack of knowledge about etiopathogenesis of individual


disorders, compounded by confusing terminology, imprecise case
definitions and overlapping clinicopathologic and laboratory features,
has rendered the classification of vasculitis a taxonomists nightmare.
Pending a fuller understanding of the pathogenic mechanisms, classification of vasculitic syndromes will continue to be based on clinical and
histological findings. Depending on the chosen perspectives, vasculitic
disorders can be classified according to the calibre of the blood vessels
involved, nature of the infiltrate, presence or absence of systemic
involvement, serologic markers and the presumed etiology. For example,
the case of a child who presents, after an attack of upper respiratory
streptococcal infection, with abdominal pain, renal manifestations and
palpable purpuras that on histology shows features of small-vessel
vasculitis with neutrophilic infiltrate and is ANCA-negative, may be
variously classified as having infection-associated vasculitis, leukocytoclastic vasculitis, systemic small-vessel vasculitis, or ANCA-negative
vasculitis and so on. The case would usually, however, be classified as
having the distinctive syndrome of Henoch-Schnlein purpura.
Zeek64 developed the first classification system of vasculitis in 1952;
the classification included the terms hypersensitivity vasculitis,
polyarteritis nodosa, granulomatous vasculitis, rheumatic vasculitis, and
large vessel vasculitis. Decades later, the American College of Rheumatology published a classification system65 with criteria that separated
Henoch-Schnlein purpura from hypersensitivity vasculitis and
subdivided granulomatous vasculitis into Wegeners granulomatosis and
Churg-Strauss syndrome. These criteria were meant for homogenous
grouping of patients for clinical trials, and not designed for diagnosis
of individual patients, although they are widely used for this purpose.
The criteria were not adequate for differentiating among the various
clinicopathological expressions of small-vessel vasculitis.14 Moreover,
this system lacked input from dermatological community, explaining
the difficulty for dermatologists in placing a patient into one group or
another66. The Chapel Hill International Consensus Conference in 1994
tried to address this problem and proposed names and definitions for
categories of vasculitis67 without suggesting diagnostic criteria. This
system classified vasculitis into 3 major subtypes, depending on the
calibre of blood vessels involved: (1) Large vessel vasculitis (Giant cell
arteritis and Takayasus arteritis), (2) Medium-sized vessel vasculitis
(polyarteritis nodosa and Kawasakis disease) and (3) Small vessel
vasculitis (Wegeners granulomatosis, Churg-Strauss syndrome,
microscopic polyangiitis, Henoch-Schnlein purpura, cryoglobulinemic

The Spectrum of Leukocytoclastic Vasculitis

39

Table 4.4: Classification of diseases associated with LV


I. Systemic small-vessel vasculitis
A. ANCA-associated:
Wegeners granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
B. Non-ANCA associated:
Henoch-Schnlein purpura
Mixed cryoglobulinemia
II. Predominantly cutaneous vasculitis
A. Idiopathic
B. Drug-induced (Table 4.2)
C. Infection-mediated (Table 4.3)
D. Connective tissue disease-associated
E. Paraneoplastic
F. Associated with other diseases (Table 4.1)
G. Miscellaneous syndromes:
Acute hemorrhagic oedema of infancy
Cutaneous polyarteritis nodosa
Erythema elevatum diutinum
Granuloma faciale
Neutrophilic dermatosis of dorsal hands
Serum sickness
Urticarial vasculitis

vasculitis, and cutaneous vasculitis). This widely accepted classification


system is also fraught with problems from a dermatological viewpoint,
since patients with cutaneous LV with systemic manifestations may be
placed in more than one category. Faucis classification of vasculitic
syndromes, popular among internists, included the term predominantly
cutaneous vasculitis in place of cutaneous LV or hypersensitivity
vasculitis for conditions where skin involvement generally dominate
the clinical picture but skin is not the exclusive organ involved.1 From
a dermatological perspective and using one common denominator - the
presence of leukocytoclastic vasculitis on histologic examination of skin
biopsy specimens, vasculitic disorders can be classified as given in Table
4.4. Disorders like Wegeners granulomatosis and Churg-Strauss
syndrome, which are generally classified on histologic ground as
granulomatous vasculitis, are included in the territory of leukocytoclastic
vasculitis as these disorders frequently produce skin lesions that on
histology shows LV. This will help dermatologists appreciate the fact
that cutaneous lesions of LV, notably palpable purpuras, can actually
have more sinister implications than the innocuous-looking rashes
suggest.

40

Recent Advances in Dermatology

A QUICK OVERVIEW OF SYNDROMES ASSOCIATED


WITH LEUKOCYTOCLASTIC VASCULITIS
Wegeners Granulomatosis
Wegeners granulomatosis (WG) is characterized by granulomatous
inflammation of the respiratory tract, necrotizing vasculitis affecting
small to medium sized arteries and necrotizing glomerulonephritis.67
Upper respiratory tract disease occurs in more than 90 percent of cases
and includes sinusitis, nasal crusting, bleeding, obstruction, otitis media
and conductive deafness and tracheal stenosis.68
Pulmonary involvement manifests with cough, hemoptysis, and
dyspnea. Proteinuria, hematuria, and urinary casts are signs of renal
involvement. Renal failure may develop rapidly. Other systemic involvements include ocular, neurological and coronary heart diseases. Cutaneous manifestations are reported in 14 to 50 percent of cases in different
series and may be the presenting feature in a significant proportion of
cases.69-71 Palpable purpura was found to be the commonest cutaneous
manifestation, and leukocytoclastic vasculitis the commonest pathology.
Papular, plaque-like, ulcerated lesions, vesicles, urticarial lesion,
subcutaneous nodules and panniculitis have all been described.69-71
Although, in its classical form, WG is a multisystem disease with
protean manifestations, there can actually be a spectrum of clinical
manifestations and the disease may present with limited organ
involvement.12 WG can affect patients at any age with a peak incidence
during fourth decade of life and is slightly more common in men.72
Serum antiproteinase3 ANCA (cANCA) is positive in 75 to 90 percent,
although 20 percent may have positive pANCA.72
The classic triad of respiratory tract granulomatous inflammation,
systemic small-vessel vasculitis, and necrotizing glomerulonephritis
readily suggest the diagnosis, but in atypical cases a positive ANCA test
is helpful in substantiating a case of WG.14
Churg-Strauss Syndrome
Churg-Strauss syndrome (CSS) is also known as allergic granulomatosis.
CSS is a systemic disorder characterized by asthma, pulmonary infiltrates,
peripheral blood as well as tissue hypereosinophilia and systemic
vasculitis.
The etiology of CSS is uncertain; however, allergic and autoimmune
processes are suspected. Drug sensitivity to leukotriene inhibitors (used
in the treatment of asthma) has been implicated in the aetiology of CSS
in some recent reports.73,74 A perinuclear antineutrophilic cytoplasmic
antibody (pANCA) directed predominantly against a myeloperoxidase

The Spectrum of Leukocytoclastic Vasculitis

41

is detected in up to 75 percent of patients with CSS. Antineutrophil


cytoplasmic antibody (cANCA) directed against serine proteinase 3 is
positive in about 10 percent of cases of CSS.
Evolution of CSS occurs in 3 distinct phases. The first phase is
characterized by asthma and allergic rhinitis. The second phase is marked
by a peripheral blood eosinophilia and eosinophilic tissue infiltration,
eosinophilic pneumonia, or eosinophilic gastroenteritis. The third phase
is characterized by a systemic vasculitis. The three phases may or may
not be sequential. The organs that may be involved include the heart,
lung, central nervous system, kidney, muscle, and skin. In contrast to
Wegeners granulomatosis and microscopic polyangiitis, CSS causes
much less frequent and less severe renal disease, but more frequent
neuropathy and cardiac disease. Coronary arteritis and myocarditis are
the principal causes of morbidity and mortality accounting for
approximately 50 percent of deaths.14
Skin involvement occurs in more than two-thirds of patients75 and
may be the initial manifestation of this multisystem disease. The lesions
consist of palpable purpura and large ecchymoses often with necrosis.
Cutaneous and subcutaneous nodules may also occur.76 The histology
of purpuric lesions typically shows features of LV,76 but eosinophils may
be conspicuous.2
Microscopic Polyangiitis
Microscopic polyangiitis (MPA) is the most common ANCA-associated
small vessel vasculitis. MPA is characterized by necrotizing vasculitis
with few or no immune deposits affecting small vessels, necrotizing
glomerulonephritis, and pulmonary capillaritis.67 MPA is differentiated
from classic polyarteritis nodosa by the absence of small vessel vasculitis
(venulitis) in the latter. MPA is commoner in men and involves people
in the age group 40 to 60. MPA has the same spectrum of manifestations
of small-vessel vasculitis as Wegeners granulomatosis, but does not
include granulomatous inflammation.14 Approximately 90 percent of
patients have glomerulonephritis, which is accompanied by a variety of
other organ involvement.
Patients present with the variable combinations of renal manifestations, abdominal pain, palpable purpura, cough and hemoptysis.72 Most
patients have MPO ANCA (pANCA) although PR3 ANCA (cANCA)
may also be present in 40 percent of patients.72
Henoch-Schnlein Purpura
Henoch-Schnlein purpura (HSP) is an immunoglobulin A-mediated LV
that predominantly affects children but is also seen in adults. Immune

42

Recent Advances in Dermatology

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

The Spectrum of Leukocytoclastic Vasculitis

43

myeloma or other paraproteinemias. Type II and type III are mixed


cryoglobulins. Type II is the complex of a monoclonal component with
polyclonal immunoglobulins while type III is a heterogenous mixture of
polyclonal immunoglobulins that sometimes contain non-immunoglobulin molecules like complement or lipoproteins. Type III mixed
cryoglobulinemia is the commonest variety encountered in patients.
Mixed cryoglobulinemia is associated with autoimmune diseases,
lymphoproliferative diseases, liver disorders, and various chronic
infections among which hepatitis C has a central role. Mixed cryoglobulins were demonstrated in 40 percent of a series of 1202 patients with
chronic hepatitis C infection.86
Patients with cryoglobulinemia occasionally develop a vasculitic
syndrome which features skin manifestations, arthralgia, nephritis, and
hepatitis. In some patients, the syndrome may progress to life-threatening
renal or pulmonary disease. Palpable purpura that typically shows
histologic features of LV is the hallmark of cryoglobulinemic vasculitis.
This is present in 100 percent of cases. Cryoglobulins were demonstrated
in 25.4 percent of a series of 160 patients of LV in whom it was found
to be a risk factor for the chronicity of skin lesions.87
Acute Hemorrhagic Edema of Childhood
Acute hemorrhagic edema of childhood, also known as acute infantile
hemorrhagic edema, is a cutaneous LV clinically characterized by an
acute illness consisting of a symptom triad of fever, large purpuric skin
lesions and peripheral edema.88 It usually involves children younger
than two years of age. The disease follows a short, benign course with
spontaneous complete recovery usually within one to three weeks
without recurrence or long-term complications. In most cases, the origin
is not clear, but underlying infections are assumed to play a causative
role. Cytomegaloviral infection,89 hepatitis A infection,90 and drugs91
have been implicated in the etiology.
This disease is considered by many to be a variant of HenochSchnlein purpura because of similarities in cause and histopathology.
However, because of the benign nature of the condition and frequent
absence of IgA associated with HSP, it may be sensible to consider as
a distinct variety of cutaneous LV.92
Cutaneous Polyarteritis Nodosa
Cutaneous polyarteritis nodosa is characterized by the appearance of
crops of nodules predominantly affecting the lower limbs and
occasionally elsewhere. Livedo reticularis is also a feature of this benign

44

Recent Advances in Dermatology

disorder.4,93 Apart from local neuromuscular involvement in some cases,


no visceral manifestations are seen. Cutaneous biopsy shows a
segmentary LV in the arteries of the deep dermis and/or hypodermis.93
The relationship of this disorder with systemic polyarteritis is so remote
that some authors prefer the term livedo with nodules.4
Erythema Elevatum Diutinum
Erythema elevatum diutinum (EED) is a rare form of LV characterized
clinically by chronic papules, plaques, and nodules that occur symmetrically over the extensor surface of the body, mainly over the joints. The
lesions are initially soft, red to violaceous in color, later becoming brown
to yellowish and acquire a firm to hard consistency owing to fibrosis.
The disease may persist for years, but spontaneous resolution may occur.
EED is probably not a distinct disease entity, but rather a clinicopathologic
reaction pattern that can be seen in a number of different disease
processes.2 EED may be associated with HIV infection,94,95 rheumatoid
arthritis,96 inflammatory bowel disease,97 IgA paraproteinemias and
myelodysplastic syndrome.98 Histopathology of EED in its early phase
shows features of LV. Older lesions show formation of granulation tissue
and fibrosis, but even in later stages, neutrophil predominates the
infiltrate and capillaries may still show deposits of fibrinoid material.2
Granuloma Faciale
Granuloma faciale is a rare disease of unknown cause that typically
presents with soft, brownish red, slowly growing, asymptomatic papules
or plaques occurring on the face. Extrafacial lesions may rarely occur.99,100
Other than the involvement of upper respiratory tract mucosa,101 no
other systemic affection has been reported. Histology of granuloma faciale
shows a dense polymorphous infiltrate beneath a narrow sub-epidermal
grenz zone. The infiltrate is composed of neutrophils, eosinophils,
mononuclear cells, plasma cells and mast cells. Features of LV may be
detected within the infiltrate.99 Immunofluorescence studies also support
vascular etiology of the disease by showing deposits of immunoglobulins
and complement components around the blood vessels and along the
dermo-epidermal junction.4
Neutrophilic Dermatosis (pustular vasculitis)
of the Dorsal Hands
Neutrophilic dermatosis of the dorsal hands, also known as pustular
vasculitis of the dorsal hands, is a recently described entity, which may

The Spectrum of Leukocytoclastic Vasculitis

45

clinically resemble a localized variant of Sweets syndrome.102 The


disorder was first reported in 1995 in six patients who had an eruption
involving the dorsa of hands.103 The lesions clinically resembled Sweets
syndrome and showed similar histologic feature of a dense dermal
neutrophilic infiltrate. In contrast to Sweets syndrome, however, the
lesions were limited almost exclusively to the dorsal hand and definite
LV was evident on histologic examinations. More similar cases were
subsequently described.104-6
Although originally described as pustular vasculitis of dorsal hands,
due to absence of vasculitis in some of the latter cases, the term
neutrophilic dermatosis of the dorsal hands was proposed by authors
who consider the disorder to be a subset of Sweet syndrome.106 Similarity
in location and histology has led others to suggest that this disorder
may in fact be a variant of erythema elevatum diutinum.107 Thus, the
nosologic position of this clinical entity has remained uncertain. The
condition is characterized by102-6 predominant involvement of middleaged to elderly women with erythematous plaques and nodules with
pustules and occasional ulceration on the surface, limited to the dorsal
hands. Other anatomical sites are minimally involved. Skin biopsy
specimens show dense dermal infiltration with leukocytoclasis and
fibrinoid vascular necrosis. Vasculitis may, however, be absent.106 The
importance of this entity lies in its liability to be misdiagnosed as
cutaneous infective diseases. As relatively few cases have been reported
till date, the possible systemic associations are less clear. Associations of
uncertain significance have included a history of breast cancer,103
metastatic renal adenocarcinoma,104 Raynauds disease with arthritis,106
and concurrent bowel disorders.102 Most cases have responded to dapsone
and systemic corticosteroids therapy.102-6 Subsequent relapse has been
reported.102
Serum Sickness
Serum sickness is an acute hypersensitivity reaction which was originally
defined to occur in association with administration of heterologous
serum. Serum sickness or serum sickness-like reactions (SSLR) usually
occur now in the context of chronic hepatitis B virus infection or drug
administration. The most frequently described drugs in recent reports
include oral penicillins,108 streptokinase,109 cefaclor,110 minocycline,111
and bupropion.112
The syndrome is characterized by the symptom complex of fever,
arthralgia, skin rashes in the form of urticaria, angioedema, palpable
purpura, and lymphadenopathy. The symptoms of SSLR typically begin
six to 21 days after administration of the causative agents and they are
usually self-limiting, lasting 4 to 14 days.

46

Recent Advances in Dermatology

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

The Spectrum of Leukocytoclastic Vasculitis

47

histologic evidence of LV is provided by fibrinoid degeneration of vessel


walls together with a neutrophilic infiltrate and fragmentation of nuclei
of leukocytes (leukocytoclasis). It is important to appreciate the dynamic
nature of the infiltrate in LV, which, in older lesions may show a
lymphocytic predominance.116 Hence, a fresh lesion should be selected
for biopsy. Once the diagnosis of LV is made, emphasis should be on the
search for causative factors and detection of systemic involvements. The
role of detailed history taking and a thorough physical examination for
this purpose cannot be over-emphasized.
Details of medications used during the few weeks preceding the rash
should be enquired about. A check-list of enquiry about indicators of
systemic affection should include features like joint pain, abdominal
pain, gastrointestinal bleeding, upper and lower respiratory symptoms
like nasal stuffiness, discharge or bleeding, cough, hemoptysis, and
breathing difficulties, urinary symptoms, muscular weakness and
paresthesia and ocular complaints. Presence of features of general illness
like fever, malaise, bodyache, anorexia, and weight loss should also be
looked into.
Laboratory workup in a patient with LV has basically two goals.
First, to detect underlying causative factors or disease associations, and
secondly, to identify or exclude systemic involvements. However, in a
developing country setting, the extent and range of laboratory tests
ordered are often subject to financial and infrastructural constraints. The
initial screening tests should include routine hemogram, urinalysis,
examination of stools for occult blood, erythrocyte sedimentation rate,
blood biochemistry panel for hepatic or renal involvement, ASO titre,
and a chest X-ray. The nature of further lab tests advised will depend
on the indications obtained from physical examination and routine tests.
Table 4.5: Steps in the diagnosis and management of LV
I. Suspect diagnosis of LV
II. Confirm diagnosis by histology
III. Detailed clinical evaluation to detect underlying diseases and
systemic involvement
IV. Laboratory workup:
A. Initial screen
B. Focussed tests
V. Syndrome recognition
VI. Appropriate referral if necessary
VII. Treatment:
A. Elimination of underlying cause
B. Treatment of underlying disease
C. Treatment of vasculitis
VIII. Follow-up

48

Recent Advances in Dermatology


Table 4.6: Laboratory workup in patients of LV

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

Blood urea, creatinine


LFT
X-ray chest
ECG
ASO titre
Bone marrow exam
Tissue biopsy
Visceral angiography
Creatine kinase
EMG, MCV
Mantoux test
Serum protein electrophoresis
Sinus X-ray, CT scan
Other appropriate tests for suspected
systemic diseases/infections

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

The Spectrum of Leukocytoclastic Vasculitis

49

Table 4.7: Drugs used in the treatment of LV


For mild/skin-limited disease
Antihistaminics
Non-steroidal anti-inflammatory drugs
Antimalarials
Dapsone
Colchicine
Thalidomide
Potassium iodide
For systemic disease/severe cutaneous disease
Systemic corticosteroids
Cyclophosphamide
Azathioprine
Methotrexate
Cyclosporine

complete recovery without sequelae.16,30 Treatment of infections and


underlying systemic diseases is undertaken in appropriate cases. Mild
affection limited to the skin may not require anything more than rest,
antihistaminics, and non-steroidal antiinflammatory agents. In
moderately severe cutaneous LV and in skin-limited vasculitic syndromes,
dapsone, colchicine, and antimalarials frequently control the disease.
Thalidomide is the drug of choice in erythema nodosum leprosum.
Thalidomide was also used successfully in refractory Henoch-Schnlein
purpura.117 Treatment of ANCA-associated systemic vasculitic syndromes
needs a multidisciplinary approach. Treatment of Wegeners granulomatosis and microscopic polyangiitis are similar and undertaken in
three phases: induction of remission, maintenance of remission, and
treatment of relapse.14 Current induction therapy uses high-dose systemic
steroids in combination with cyclophosphamide. Once remission is
achieved, it is maintained by cyclophosphamide or azathioprine.
Methotrexate may also be used for maintenance of remission in relatively
less severe disease.117 Severe or chronic and disabling cutaneous disease
may also need treatment with systemic steroid and immunosuppressive
agents. Mixed cryoglobulinemia due to hepatitis C infection may be
treated with a combination of interferon-alpha and ribavirin.119 Finally,
there is also a place for physical modalities of treatment like liquid
nitrogen cryotherapy in cutaneous disease like granuloma faciale.120
REFERENCES
1. Fauci AS. The vasculitis syndromes. In: Fauci AS, Braunwald E, Isselbacher K,
et al (Eds). Harrisons Principles of Internal Medicine. 14th ed. New York:
McGraw Hill, 1998: 1910-22.

50

Recent Advances in Dermatology

2. Elder D, Elenitsas E, Jaworsky C, et al (Eds). Levers Histopathology of the


Skin. 8th edn. Philadelphia: Lippincot Raven. 1997.
3. Sanches NP, Van HHM, Su WP. Clinical and histopathologic spectrum of
necrotizing vasculitis: Report of findings in 101 cases. Arch Dermatol 1985;
121:220-4.
4. Ryan TJ. Cutaneous vasculitis. In: Champion RH, Burton JL, Burns DA, et al
(Eds) Textbook of Dermatology. 6th ed. Oxford, Blackwell Science, 1998: 21552225.
5. Claudy A. Pathogenesis of leukocytoclastic vasculitis. European J Dermatol
1998; 8:75-9.
6. Sais G, Vidaller A, Jucgla A, et al. Prognostic factors in leukocytoclastic vasculitis.
A clinicopathologic study of 160 patients. Arch Dermatol 1998; 134:309-315.
7. Gyselbrecht L, De Keyser F, Ongenae K, et al. Aetiological factors and underlying
conditions in patients with leukocytoclastic vasculitis. Clin Exp Rheumatol
1996; 14:665-8.
8. Garcia-Porrua C, Llorca J, Gonzalez-Louzao C, et al. Hypersensitivity vasculitis
in adults: A benign disease usually limited to skin. Clin Exp Rheumatol 2001;
19:85-8.
9. Kawana S. The membrane attack complex of complement alters the membrane
integrity of cultured endothelial cells: A possible pathophysiology for immune
complex vasculitis. Acta Derm Venereol 1996; 76:13-6.
10. Sais G, Vidaller A, Jucgla A, et al. Adhesion molecule expression and endothelial
cell activation in cutaneous leukocytoclastic vasculitis. An immunohistologic
and clinical study in 42 patients. Arch Dermatol 1997; 133:443-50.
11. Besbas N, Saatci U, Ruacan S, et al. The role of cytokines in Henoch-Schnlein
purpura. Scand J Rheumatol 1997; 26:456-60.
12. Soter NA. Cutaneous necrotizing venulitis. In: Fitzpatrick TB, Eisen AZ, Wolff
K, et al (Eds). Dermatology in General Medicine. 4th ed. New York: McGraw
Hill,1993; 1501-10.
13. Meijer-Jorna LB, Mekkes JR, van der Wal AC. Platelet involvement in cutaneous
small vessel vasculitis. J Cutan Pathol 2002; 29:176-80.
14. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997; 337:1512-23.
15. Businco L, Falconieri P, Bellioni-Businco B, et al. Severe food-induced vasculitis
in two children. Pediatr Allergy Immunol 2002; 13:68-71.
16. Garcia-Porrua C, Gonzalez-Gay MC, Lopez-Lazaro L. Drug associated
cutaneous vasculitis in adults in northwestern Spain. J Rheumatol 1999; 26:
1942-4.
17. Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am 2001; 27:
849-62.
18. Gavura SR, Nusinowitz S. Leukocytoclastic vasculitis associated with
clarithromycin. Ann Pharmacother 1998; 32:543-5.
19. Schapira P, Balbir-Gurman A, Nahir AM. Naproxen-induced leukocytoclastic
vasculitis. Clin Rheumatol 2000; 19:242-4.
20. Odeh M, Lurie M, Oliven A. Cutaneous leukocytoclastic vasculitis associated
with omeprazole. Postgrad Med J 2002; 78:114-5.
21. Bukhalo M, Zeitouni NC, Cheney RT. Leukocytoclastic vasculitis induced by
use of glyburide: a case of possible cross-reaction of a sulphonamide and a
sulphonylurea. Cutis 2003; 71:235-8.
22. Gscheidel D, Daspet MK, Le Coz CJ, et al. Allergic vasculitis following ingestion
of celecoxib? Hautarzt 2002; 53:488-91.

The Spectrum of Leukocytoclastic Vasculitis

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
vasculitis in a patient with ankylosing spondylitis. Rheumatol Int 2000; 19:1913.
27. Devos SA, Van ben Bossche N, Vos M, et al. Adverse skin reactions to antiTNF-alpha monoclonal antibody therapy. Dermatology 2003; 44:42-4.
28. Domingo P, Barcelo M. Efavirenz-induced leukocytoclastic vasculitis. Arch
Intern Med 2002; 162:355-6.
29. Tavadia S, Drummond A, Evans CD, et al. Leukocytoclastic vasculitis and
influenza vaccination. Clin Exp Dermatol 2003; 28:154-6.
30. Cueller ML. Drug-induced vasculitis. Curr Rheumatol Rep 2002; 4:55-9.
31. Morita S, Ueda Y, Eguchi K. Anti-thyroid drug-induced ANCA-associated
vasculitis: A case report and review of the literature. Endocr J 2000; 47:467-70.
32. Sera N, Ashizawa K, Ando T, et al. Treatment with propylthiouracil is associated
with appearance of antineutrophil cytoplasmic antibodies in some patients
with Graves disease . Thyroid 2000; 10:595-9.
33. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type
LL cryoglobulinemia. N Engl J Med 1992; 327:1490-5.
34. Crowson AN, Nuovo G, Ferri C, et al. The dermatopathologic manifestations
of hepatitis C infection: A clinical, histological, and molecular assessment of
35 Case. Hum Pathol 2003; 34:573-9.
35. Watkins KV, Ittman MM. Necrotizing vasculitis in a patient with acquired
immunodeficiency syndrome. J Oral Maxillofac Surg, 1992; 50:1003.
36. Fakhiri A, Gupta SM, White SM, et al. Erythema elevatum diutinum in a
patient with human immunodeficiency virus. Cutis 2001; 41:55.
37. Kuroda K, Yabunami H, Hisanaga Y. Henoch-Schnlein purpura associated
with hepatitis A infection. Pediatr Int 2003; 45:114-6.
38. Bozaykut A, Atay E, Atay Z et al. Acute infantile haemorrhagic oedema
associated with hepatitis A. Ann Trop Paediatr 2002; 22:59-61.
39. Leukocytoclastic vasculitis neuropathy associated with chronic Epstein-Barr
virus infection. Muscle Nerve 2003, 27:113-6.
40. Cascina A, Marone Bjanco A, Mangiarotti P, et al. Cutaneous vasculitis and
reactive arthritis following respiratory infection due to chlamydia pneumoniae.
Report of a case. Clin Exp Rheumatol 2002; 20:845-7.
41. Cioc AM, Sedmac DD, Nuovo GJ, et al. Parvovirus B19 associated adult HenochSchnlein purpura. J Cutan Pathol 2002; 29:602-7.
42. Acute haemorrhagic oedema of infancy associated with cytomegalovirus
infection. Br J Dermatol 2002; 147:1254-7.
43. Perez C, montes M. Cutaneous leukocytoclastic vasculitis and encephalitis
associated with mycoplasma pneumoniae infection. Arch Intern Med 2002;
162:352-4.
44. 44.Ayoub EM, McBride J, Schmiederer M, et al. Role of Bartonella henselae in
the etiology of Henoch-Schnlein purpura. Pediatr Infect Dis J 2002; 21:28-31.
45. Minguer P, Pintor E, Buron R, et al. Pulmonary tuberculosis presenting with
leukocytoclastic vasculitis. Infection 2000;28:55-7.

52

Recent Advances in Dermatology

46. Nagore E, Sanchez-Motilla JM, Navarro V, et al. Leukocytoclastic vasculitis as


a cutaneous manifestation of systemic infection caused by Brucella melitensis.
Cutis 1999; 63:25-7.
47. Cardinali C, Caproni M, Brnacchi E, et al. The spectrum of cutaneous
manifestations in lupus erythematosus the Italian experience. Lupus 2000;
9:417-23.
48. Pique E, Palacios S, Santana Z. Leukocytoclastic vasculitis presenting as an
erythema gyratum repens-like eruption on a patient with systemic lupus
erythematosus. J Am Acad Dermatol 2002; 47:S254-6.
49. Chen KR, Toyohara A, Suzuki A, et al. Clinical and histopathological spectrum
of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol 2002;147:905-13.
50. Hunger RE, Durr C, Brand CU. Cutaneous leukocytoclastic vasculitis in
dermatomyositis suggests malignancy. Dermatology 2002; 202:123-6.
51. Sanchez-Guerrero, Gutierrez-Urena S, Vidaller A, et al. Vasculitis as a
paraneoplastic syndrome. Report of 11 cases and review of the literature. J
Rheumatol 1990; 17:1458-62.
52. Paydas S, Zorludemir S: Leukaemia cutis and leukaemic vasculitis. Br J Dermatol
2000; 143:773-9.
53. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in
patients with solid tumors. A case report and review of the literature. Arch
Intern Med 1994; 154:334-40.
54. Wilson D, McCluggage WG, Wright GD. Urticarial vasculitis: A paraneoplastic
presentation of B-cell non-Hodgkins lymphoma. Rheumatology 2002; 41:4767.
55. Bayer-Garnez IB, Smoller BR. The spectrum of cutaneous disease in multiple
myeloma. J Am Acad Dermatol 2003; 48:497-507.
56. Cho S, Chang SE, Kim KR, et al. Waldenstroms macroglobulinaemia presenting
as reticulate purpura and bullae in a patient with hepatitis B virus infection.
Clin Exp Dermatol 2001; 26:513-7.
57. Blanco R, Gonzalez-Gay, Ibanez D, et al. Henoch-Schnlein purpura as clinical
presentation of myelodysplastic syndrome. Clin Rheumatol 1997; 16:626-8.
58. Stashower ME, Rennie TA, Turiansky GW, et al. Ovarian cancer presenting as
leukocytoclastic vasculitis. J An Acad Dermatol 1999; 40:287-9.
59. Odeh M, Misselevich I, Oliven A. Squamous cell carcinoma of the lung
presenting with cutaneous leukocytoclastic vasculitis: A case report. Angiology
2001; 52:641-4.
60. Lacour JP, Castanet J, Perrin C, et al. Cutaneous leukocytoclastic vasculitis and
renal cancer: two cases. Am J Med 1993; 94:104-8.
61. Gyselbrecht L, De Keyser F, Ongenae K, et al. Etiological factors and underlying
conditions in patients with leucocytoclastic vasculitis. Clin Exp Rheumatol
1996; 14:665-8.
62. Aractingi S, Cadranel J, Milleron B, et al. Sarcoidosis associated with
leucocytoclastic vasculitis. A case report and review of the literature.
Dermatology 1993; 187:50-3.
63. Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott-Aldrich
syndrome: risk factors, clinical features, and outcome in a single center cohort
of 55 patients. Pediatrics 2003; 111:622-7.
64. Zeek PM. Periarteritis nodosa: a critical review. Am J Clin Pathol 1952; 22:77792 cited in ref. no. 63.

The Spectrum of Leukocytoclastic Vasculitis

53

65. Hunder GG, Arend WO, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990;
33:1065-1144.
66. Callen JP. Cutaneous vasculitis. What have we learned in the past thirty years?
Arch Dermatol 1998; 134:355-7.
67. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides:
proposal of an international consensus conference. Arthritis Rheum 1994; 37:18792.
68. Savage COS, Harper L, Cockwell P, et al. ABC of arterial and vascular diseases:
Vasculitis. BMJ 2000; 320: 1325-8.
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.

54

Recent Advances in Dermatology

87. Sais G, Vidaller A, Jucgia A, et al. Prognostic factors in leukocytoclastic vasculitis.


A clinicopathologic study of 160 patients. Arch Dermatol 1998; 134: 309-15.
88. Caksen H, Odabas D, Kosem M, et al. Report of eight infants with acute
infantile hemorrhagic oedema and review of the literature. J Dermatol 2002;
29:290-5.
89. Kuroda K, Yabunami H, Hisanaga Y. Acute haemorrhagic oedema of infancy
associated with cytomegalovirus infection. Br J Dermatol 2002;147:1254-7.
90. Bozaykut A, Atay E, Atay Z, et al. Acute infantile haemorrhagic oedema
associated with hepatitis A. Ann Trop Paediatr 2002; 22:59-61.
91. Paradisi M, Annessi G, Corrado A. Infantile acute hemorrhagic oedema of the
skin. Cutis 2001;68:127-9.
92. Millard R, Harris A, Macdonald D. Acute infantile hemorrhagic oedema. J Am
Acad Dermatol 1999; 41:837-9.
93. Bauza A, Espana A, Idoate M. Cutaneous polyarteritis nodosa. Br J Dermatol
2002; 146: 694-9.
94. Muratori S, Carrera C, Gorani A, et al. Erythema elevatum diutinum and HIV
infection: A report of five cases. Br J Dermatol 1999; 141:335-8.
95. Johnson RM, Barbarini G, Barbaro G. Kawasaki-like syndromes and other
vasculitic syndromes in HIV-infected patients. AIDS 2003; (Suppl1): S77-82.
96. Chen KR, Toyohara A, Suzuki A, et al. Clinical and histopathological spectrum
of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol 2002; 147:90513.
97. Buahene K, Hudson M, Mowat A, et al. Erythema elevatum diutinum: An
unusual association with ulcerative colitis. Clin Exp Dermatol 1991; 16: 2046.
98. Yiannias JA, Ez-Azhary RA, Gibson LE. Erythema elevatum diutinum: a clinical
and histopathological study of 13 patients. J Am Acad Dermatol 1992; 26:3844.
99. Castellano-Howard L, Fairbee SI, Hogan DJ, et al. Extrafacial granuloma faciale:
report of a case and response to treatment. Cutis 2001; 67: 413-5.
100. Roustan G, Sanchez Yus E, Salas C, et al. Granuloma faciale with extrafacial
lesions. Dermatology 1999; 198:79-82.
101. Burns BV, Roberts PF, De Carpentier J, et al. Eosinophilic angiocentric fibrosis
affecting the nasal cavity. A mucosal variant of the skin lesion granuloma
faciale. J Laryngol Otol 2001 115(3):223-6.
102. DiCaudo DJ, Connolly SM. Neutrophilic dermatosis (pustular vasculitis) of
the dorsal hands. A report of seven cases and review of the literature. Arch
Dermatol 2002; 138:361-5.
103. Strutton G, Weedon D, Robertson I . Pustular vasculitis of the dorsal hands.
J Am Acad Dermatol 1995; 32:192-8.
104. Curco N, Pagerols X, Tarroch X, et al. Pustular vasculitis of the hands: report
of two men. Dermatology 1996; 196:346-7.
105. Hall AP, Goudge RJ, Ireton HJC, et al. Pustular vasculitis of the hands. Australas
J Dermatol 1999; 40:204-7.
106. Galaria NA, Junkins-Hopkins JM, Kligman D, et al. Neutrophilic dermatosis
of the dorsal hands: Pustular vasculitis revisited. J Am Acad Dermatol 2000,
43: 870-4.
107. Ayoub N, Tomb R. Neutrophilic dermatosis of dorsal hands: a variant of
erythema elevatum diutinum? Arch Dermatol 2003; 139:102.

The Spectrum of Leukocytoclastic Vasculitis

55

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

Recent Advances in Dermatology

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.

Emergencies in Pediatric Dermatology

57

The different proportion of body weight and body surface area of a


childs skin in comparison to the adult (almost three times) making
it difficult to evaluate the dosage of medication to be used.
Easy hemodynamic instability resulting from increased cutaneous
blood flow.
More percutaneous absorption of topically used drugs making the
physician to be more alert about side effects.
All of the above heightening the chances of multi-organ and multisystem failures.
CLASSIFICATION
For the purposes of orderly thinking and for the ease of presentation,
the following classification of pediatric dermatological emergencies might
prove helpful:
Infections: Cellulitis, Staphylococcal scalded skin syndrome, Neonatal
herpes, Neonatal candidiasis
Toxic erythemas: Urticaria and angioedema, Drug eruptions, Kawasaki
syndrome, Exfoliative dermatitis
Drug reactions: Erythema multiforme, Stevens Johnson syndrome, Toxic
epidermal necrolysis
Keratinization disorders: Collodion baby, Harlequin fetus
Purpuric and hemorrhagic disorders: Meningococcal disease, Graft
versus host disease
Vesiculo-bullous disorders: Pemphigus, Epidermolysis bullosa, Linear
IgA disease
Proliferative disorders: Hemangiomas, Histiocytosis, Mastocytosis
Miscellaneous: Acrodermatitis enteropathica, Sclerema, Leiners disease,
etc.
PEDIATRIC DERMATOLOGICAL EMERGENCIES
As a complete description of all the conditions included in this group
of dermatoses is not within the scope of this article, the more important
one will be discussed.
Cellulitis2
Streptococcus pyogenes (group A-hemolytic streptococcus) is the most
common cause of superficial cellulitis; diffuse infection occurs because

58

Recent Advances in Dermatology

streptokinase, DNase, and hyaluronidase enzymes produced by the


organism break down cellular components that otherwise would contain
and localize the inflammation. Group B, C, D, or G-hemolytic streptococci
are less common causes. Staphylococcus aureus occasionally produces a
superficial cellulitis typically less extensive than that of streptococcal
origin and usually only in association with an open wound or cutaneous
abscess. Superficial cellulitis caused by other organisms, primarily aerobic
gram-negative bacilli, occurs rarely (generally in special circumstances).
With granulocytopenia, diabetic foot ulcers, or severe tissue ischemia,
aerobic gram-negative bacilli (e.g., Escherichia coli, Pseudomonas aeruginosa)
may be responsible. Unusual bacteria may cause cellulitis occurring
after animal bites, especially Pasteurella multocida from dogs and cats.
Immersion injuries in fresh water may result in cellulitis caused by
Aeromonas hydrophila; in warm salt water, Vibrio vulnificus may cause
cellulitis. Infection is most common in the lower extremities. A cutaneous
abnormality (e.g., skin trauma, ulceration, tinea pedis, dermatitis) often
precedes the infection; areas of lymphedema or other edema seem to be
especially susceptible. Frequently, however, no predisposing condition
or site of entry is evident. The major findings are local erythema and
tenderness, frequently with lymphangitis and regional lymphadenopathy.
The skin is hot, red and edematous, often with an infiltrated surface
resembling the skin of an orange (peau dorange). The borders are usually
indistinct, except in erysipelas, a type of cellulitis in which the raised
margins are sharply demarcated. Petechiae are common; large areas of
ecchymosis are rare. Vesicles and bullae may develop and rupture,
occasionally with necrosis of the involved skin. Systemic manifestations
(fever, chills, tachycardia, headache, hypotension, delirium) may precede
the cutaneous findings by several hours, but many patients do not appear
ill. Leukocytosis is common, but not constant.
The diagnosis usually depends on the clinical findings. Unless pus
has formed or an open wound is present, the responsible organism often
is difficult to be isolated, even on aspiration or skin biopsy. Blood cultures
are occasionally positive. Serologic tests, especially measurement of rising
titers of anti-DNase B, confirm a streptococcal cause, but are usually
unnecessary.
Although cellulitis and deep vein thrombosis usually are easily
differentiated clinically, many physicians confuse these entities when
edema occurs in the lower extremities. Local abscesses form occasionally,
requiring incision and drainage. Serious but rare complications include
severe necrotizing subcutaneous infection and bacteremia with metastatic
foci of infection. Even without antibiotics, most cases of superficial
cellulitis resolve spontaneously; however, recurrences in the same area
are common, sometimes causing serious damage to the lymphatics,

Emergencies in Pediatric Dermatology

59

chronic lymphatic obstruction, marked edema, and rarely, elephantiasis.


With antibiotics, such complications are uncommon. Symptoms and signs
of superficial cellulitis usually resolve after a few days of antibiotic
therapy.
For streptococcal cellulitis, penicillin is the drug of choice: For mild
outpatient cases, penicillin V in the dose of 15-30 mg/kg/24 hr, divided,
every 6-8 hours is adequate. For severe infections, which require
hospitalization, aqueous penicillin G 25,000-50,000 units/kg/24 hr is
indicated. In penicillin-allergic patients, erythromycin 30-50 mg/kg/
24 hr, divided, every 6 hr is effective for mild infections, and parenteral
gentamicin for severe infections. Although S. aureus rarely causes typical
cellulitis, many clinicians prefer using antibiotics also active against this
organism: cloxacillin 50-100 mg/kg/24 hr, divided, every 6 hr qid for
mild infections, or cefotaxime 100-150 mg/kg/24 hr, divided, every
4-6 hr IV for severe infections. For penicillin-allergic patients or those
with suspected methicillin-resistant S. aureus infection, vancomycin
45-60 mg/kg/24 hr, divided, every 6-8 hr is the drug of choice. When
pus or an open wound is present, results of a Gram stain should dictate
antibiotic choice. Immobilization and elevation of the affected area help
reduce edema, and cool, wet dressings relieve local discomfort.
Cellulitis in a neutropenic patient requires antibiotics effective against
aerobic gram-negative bacilli until culture results are available. Penicillin
is the drug of choice for P. multocida, an aminoglycoside (e.g., gentamicin)
is effective against A. hydrophila, and tetracycline is the preferred antibiotic
for V. vulnificus.
Treating concomitant tinea pedis, which often eliminates the source
of bacteria residing in the inflammed, macerated tissue prevents recurrent leg cellulitis. If such therapy is unsuccessful or not indicated,
recurrent cellulitis sometimes can be prevented by benzathine penicillin
1.2 million U IM monthly, or penicillin V or erythromycin for 1 week
every month.
Staphylococcal Scalded Skin Syndrome3
(Ritter-Lyell Syndrome)
Staphylococcal scalded skin syndrome (SSSS) almost always occurs in
infants and in children below 6 years. Epidemics may occur in nurseries,
presumably transmitted by the hands of personnel in contact with an
infected infant. However, nursery personnel may be nasal carriers of S.
aureus. Sporadic cases also occur.
Group II coagulase-positive staphylococci, usually phage type 71
and often resistant to penicillin, elaborate exfoliatin (also called
epidermolysin), an epidermolytic toxin that splits off the upper part of
the epidermis just beneath the granular cell layer. The inciting infection

60

Recent Advances in Dermatology

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

Emergencies in Pediatric Dermatology

61

and healing is usually within 5 to 7 days after the start of treatment.


Steps to detect carriers and prevent or treat nursery epidemics are to be
taken.
Neonatal Herpes Simplex Virus Infection4
Infection with herpes simplex virus is usually transmitted during
parturition, typically causing vesicular eruption and subsequent
disseminated disease. Neonatal herpes simplex virus (HSV) infection
has high mortality and significant morbidity. Incidence estimates range
from 1/3,000 to 1/20,000 live deliveries. HSV type 2 causes about 80
percent of cases; 20 percent are caused by HSV type 1. HSV type 2 is
usually transmitted to the newborn during delivery by passage through
an infected maternal genital tract. Transplacental transmission of virus
and nosocomial spread from one newborn to another by hospital
personnel or family has also been implicated in about 15 percent of
cases. Mothers of newborns with HSV infection tend to have no history
or symptoms of genital infection at the time of delivery.
Manifestations generally occur between the 1st and 2nd week of life;
however, symptoms may not appear until as late as the 4th week. The
hallmark of infection is skin vesicles, which, if untreated, frequently lead
to progressive or more serious froms of disease within 7 to 10 days.
However, up to 45 percent of infected newborns initially have no skin
vesicles; usually these newborns have localized CNS disease. Other signs
of infection, which can occur singly or in combination, include
temperature instability, lethargy, hypotonia, respiratory difficulty (apnea
or pneumonia), convulsions, hepatitis, and disseminated intravascular
coagulation (DIC).
Newborns with disseminated disease and visceral organ involvement
have hepatitis, pneumonitis, and/or DIC with or without encephalitis or
skin disease.
Newborns with localized disease can be subdivided into two groups.
The first group has encephalitis manifested by neurologic findings, CSF
pleocytosis and elevated protein concentration, with or without
concomitant involvement of the skin, eyes, and mouth. The second group
has only skin, eye, and mouth involvement and no evidence of CNS or
organ disease.
Rapid and specific diagnosis of neonatal HSV infection is essential.
Infection can be confirmed by isolating virus in tissue culture, using
vaious cell lines of human or nonhuman origin. The most common site
of retrieval is a skin vesicle; the mouth, eye, and CSF are also high-yield
sites. In some newborns presenting with encephalitis, virus is found
only in the brain; however, accurate testing (such as HSV polymerase

62

Recent Advances in Dermatology

chain reaction) is available in only a few research and specialized


laboratories. Cytopathologic effects usually can be demonstrated in tissue
culture within 24 to 48 h after inoculation. The diagnosis can also be
confirmed by neutralization with appropriate high-titer antiserum;
immunofluorescence of lesion scrapings, particularly with use of
monoclonal antibodies and electron microscopy. If no diagnostic virology
facilities are available, a Leishman smear of the lesion base may show
characteristic histopathologic evidence (multinucleated giant cells and
intranuclear inclusions), but this is less sensitive than culture and falsepositive results occur.
The mortality rate of newborns with untreated disseminated disease
is 85 percent; of those with untreated local disease and encephalitis,
about 50 percent. At least 95 percent of the survivors have severe
neurologic sequelae. Death is uncommon in those with local (skin, eyes,
mouth) disease having without CNS or organ disease, except as the
result of concomitant medical problems, but about 30 percent develop
neurologic impairment, which may not manifest until 2 to 3 years of age.
Morbidity in each group parallels mortality and is directly proportional
to disease extent. About 90 percent of infants with viscerally disseminated
neonatal HSV infection have subsequent sequelae. Only 5 percent of
those with CNS infection return to normal. Therapy with acyclovir
decreases the mortality rate by 50 percent and increases the percentage
that develops normally from 10 to 50 percent. Acyclovir 30 mg/kg/day
in standard IV fluid is given q 8 h in divided doses for 10 to 14 days.
Vigorous supportive therapy is required, including appropriate IV fluids,
alimentation, respiratory support, correction of clotting abnormalities,
and control of seizure disorders. Herpes keratoconjunctivitis requires
concomitant systemic acyclovir and topical therapy with a drug such as
trifluridine.
Neonatal Candidiasis5
Systemic or cutaneous candidiasis presenting within 12 hours of birth
are classified as congenital candidal infection. It is an intrauterine infection
acquired by ascending or cervical infection. Oral mucosa and diaper
areas are not involved. The presentation is initially as a morbiliform
eruption, erythematous macules, papulo-vesicles, or pustules. The
condition is best treated with ketoconazole in a dosage of 3 mg/kg/day
for 7 to 10 days.
Urticaria and Angioedema6
Acute urticaria and angioedema are essentially anaphylaxis limited to

Emergencies in Pediatric Dermatology

63

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

64

Recent Advances in Dermatology

chiefly palliative. If the cause is not obvious, all non-essential drugs


should be stopped until the reaction has subsided. Symptoms usually
can be relieved with an oral antihistamine, such as diphenhydramine
5 mg/kg/24 hr, divided, every 6-8 hr, hydroxyzine 2 mg/kg/24 hr,
divided, every 6-8 hr, or cyproheptadine 2 mg/dose (children 2-6 yr)
and 4 mg/dose (children > 7 yr) every 8-12 hr. If these cause drowsiness
(which occurs in a majority of patients), one of the nonsedating
antihistamines should be used. A glucocorticoid (e.g., prednisolone
2 mg/kg/24 hr, divided, every 6-8 hr may be needed for more severe
reactions, especially when associated with angioedema. Topical
glucocorticoids are of no value. Epinephrine 1:1000, 0.3 ml sc, should be
the first treatment for acute pharyngeal or laryngeal angioedema.
This may be supplemented with topical treatment; e.g., a nebulized
adrenergic agent and an IV antihistamine (e.g., diphenhydramine). This
usually prevents airways obstruction, but intubating or performing a tracheostomy and administering O2 might be necessary. In chronic
urticaria, spontaneous remissions occur within 2 yr in about half of
cases. Control of stress often helps reduce the frequency and severity of
episodes.
Hereditary Angioedema7
It is a form of angioedema transmitted as an autosomal dominant trait
and associated with a deficiency of serum inhibitor of the activated first
component of complement. In 85 percent of cases, the deficiency is due
to a lack of the CI esterase inhibitor; in 15 percent, to malfunction of CI
esterase inhibitor. A positive family history is the rule with some
exceptions. Edema is typically unifocal, indurated, painful rather than
pruritic and unaccompanied by urticaria. Attacks are often precipitated
by trauma or viral illness and are aggravated by emotional stress. The
GI tract is often inolved, with nausea, vomiting, colic and even signs of
intestinal obstruction. The condition may cause fatal upper airway
obstruction.
Diagnosis may be made by measuring C4, which is low even between
attacks, or more specifically by showing C1 inhibitor deficiency by
immunoassay, and a functional assay if the immunoassay results are
unexpectedly normal. An acquired form of C1-inhibitor deficiency
secondary to neoplastic diseases such as lymphoma is distinguished by
low C1 levels and by depressed C4 levels.
For short-term prophylaxis of the previously untreated patient (as
before a dental procedure, endoscopy, or surgery), 2 U of fresh frozen
plasma can be given. Although theoretically a complement substrate in
the plasma might provoke an attack, this has not been observed in

Emergencies in Pediatric Dermatology

65

symptom-free patients. Recently, a partially purified C1 esterase inhibitor


fraction of pooled plasma has been shown to be safe and effective for
prophylaxis, but it is unavailable for general use. If time permits, the
patient should be treated for 3 to 5 days with an androgen.
For long-term prophylaxis, androgens are effective. One of the
impeded androgens should be used. Treatment is begun with oral
stanozolol 2 mg tid or danazol 200 mg tid. Stanozolol is less expensive.
Once control is achieved, the dosage should be reduced as much as
possible to reduce the cost and, in women, to minimize masculinizing
side effects. These drugs not only are effective but also have been shown
to raise the low C1 esterase inhibitor and C4 toward normal.
The edema progresses until complement components have been
consumed. Acute attacks that threaten to produce airways obstruction,
therefore, should be treated promptly by establishing an airway. The
use of fresh frozen plasma is controversial. Epinephrine, an antihistamine
and a glucocorticoid should be given, but there is no proof that these
drugs are effective.
Drug Eruptions8
(Dermatitis Medicamentosa)
Although the mechanisms of most drug eruptions are unknown, many
are allergic. Specific antibodies or sensitized lymphocytes to the drug
may develop as soon as 4 to 5 days after initial drug exposure. A later
eruption caused by re-exposure to the drug may appear within minutes,
but may be delayed for days or longer. Other reactions may be caused
by accumulation of a drug (e.g., pigmentation from silver), pharmacologic
action of a drug (e.g., striae or acne from systemic corticosteroids, purpura
from excessive anticoagulation), or interaction with genetic factors (e.g.,
porphyria cutanea tarda from estrogens, which induce an enzyme
involved in porphyrin metabolism).
Drug eruptions vary from a mild rash to toxic epidermal necrolysis.
Onset may be sudden (e.g., urticaria or angioedema from penicillin) or
delayed for hours or days (morbilliform or maculopapular eruptions
from penicillin or sulfonamides) or for years (exfoliation or pigmentation
from arsenic). The lesions may be localized (fixed drug eruptions, oral
ulcers, dermatitis in light-exposed areas), but many are generalized.
Reactions may be characteristic of certain drugs or may imitate practically
features of any dermatosis. The drugs added to therapy most recently
are most likely to be the cause, but drugs taken for long periods must
also be suspected.
Identification of the causative agent is essential. A detailed history is
often required, with persistent inquiry about all drugs, including OTC
drugs for sleep, pain, colds, constipation, headache, eyedrops, nose drops

66

Recent Advances in Dermatology

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,

Emergencies in Pediatric Dermatology

67

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

68

Recent Advances in Dermatology

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

Emergencies in Pediatric Dermatology

69

4 days (again in combination with high-dose aspirin). The efficacy of


IGIV/aspirin therapy, when begun more than 10 days after onset of
illness, is unknown, but therapy should still be considered. After the
child has improved, aspirin 3 to 5 mg/kg/day is continued for at least
8 weeks until repeat echocardiographic testing is completed. If there are
no coronary artery aneurysms and signs of inflammation are receding
(demonstrated by normalization of ESR and platelets), aspirin may be
discontinued. Because of its antithrombotic effect, aspirin is continued
indefinitely for children with coronary artery abnormalities. Children
with giant coronary aneurysms may require additional anticoagulant
therapy (e.g., coumarin or dipyridamole).
Children who receive IGIV therapy may have a lower response rate
to live viral vaccines. Thus, measles-mumps-rubella vaccine should
generally be delayed 11 months after IGIV administration and varicella
vaccine should be delayed for at least 5 months. If the risk of measles
exposure is high, vaccination should proceed, but revaccination (or
serologic testing) should be performed 11 months later.
A small risk of Reyes syndrome exists in children receiving longterm aspirin during outbreaks of influenza or varicella. Parents of children
receiving aspirin should be instructed to contact their childs physician
promptly if the child is exposed to or develops symptoms of influenza
or varicella. Temporary interruption of aspirin may be considered (with
substitution of dipyridamole for children with documented aneurysms).
Annual influenza vaccination is indicated for children receiving longterm aspirin therapy.
Generalized Exfoliative Dermatitis10
Usually no cause is found. Some cases are secondary to certain dermatitis
(e.g., atopic, psoriatic, pityriasis rubra pilaris, contact dermatitis); others
may be induced by a systemic drug (e.g., penicillin, sulfonamides,
isoniazid, phenytoin, barbiturates) or a topical agent. Exfoliative
dermatitis may also be associated with mycosis fungoides or lymphoma.
The onset may be insidious or rapid. The entire skin surface becomes
red, scaly, thickened, and occasionally crusted. Pruritus may be severe
or absent. The characteristic appearance of any primary dermatitis is
usually lost. Localized areas of normal skin may be seen when the
exfoliative dermatitis is caused by such conditions as psoriasis, mycosis
fungoides, or pityriasis rubra pilaris. Generalized superficial
lymphadenopathy is frequent, but biopsy usually shows benign
lymphadenitis,
The child may feel cold and have an elevated temperature caused by
excessive heat loss from increased blood flow to the skin. Generalized

70

Recent Advances in Dermatology

exfoliative dermatitis may also cause weight loss, hypoproteinemia,


hypocalcemia, iron deficiency or (in patients with borderline cardiac
compensation) high-output heart failure.
Every attempt must be made to determine the cause. A history or
signs of a primary dermatitis may be helpful. Biopsy is usually not
helpful, but pemphigus foliaceus or mycosis fungoides may be diagnosed
by skin biopsy, or lymphoma by a lymph node biopsy. Sezary syndrome
may be diagnosed by a blood smear.
The disease may be life-threatening and hospitalization is often
necessary. Because drug eruptions and contact dermatitis cannot be
ruled out by history alone, all drugs should be stoped, if possible, or
essential systemic drugs should be changed to chemically dissimilar
ones. Petrolatum applied after tap-water baths gives temporary relief.
Oral corticosteroids should be used only when other measures fail.
Prednisolone 40 to 60 mg/day is given; after about 10 days, the drug is
given on alternate days. Usually the dose can be further decreased, but
if an underlying cause is not eliminated, long-term prednisolone will be
required.
Erythema Multiforme11
An inflammatory eruption characterized by symmetric erythematous,
edematous, or bullous lesions of the skin or mucous membranes.
No cause of erythema multiforme can be found in over 50 percent
of cases. Most other cases are due to infectious diseases (e.g., herpes
simplex [probably most common], coxsackie viruses and echoviruses,
Mycoplasma pneumoniae, psittacosis, histoplasmosis) or drug therapy.
Almost any drug can cause erythema multiforme; penicillin, sulfonamides
and barbiturates are the most likely. Vaccinia, Bacille Calmette-Guerin
(BCG) and poliomyelitis vaccines have also induced erythema multiforme.
The mechanism by which infectious agents, drugs or vaccines cause
erythema multiforme is unknown, but it is generally considered a
hypersensitivity reaction. Onset is usually sudden, with erythematous
macules, papules, wheals, vesicles and sometimes bullae appearing
mainly on the distal portion of the extremities (palms, soles) and on the
face. Hemorrhagic lesions of the lips and oral mucosa can also occur.
The skin lesions (target or iris lesions) are symmetric in distribution and
often annular, with concentric rings, central purpura and grayish
discoloration of the epidermis or vesicle. Itching is variable. Systemic
symptoms vary; malaise, arthralgia and fever are frequent. Attacks
sometimes last 2 to 4 weeks and recur in the fall and spring for several
years. Stevens-Johnson syndrome is a severe form of erythema multiforme
(erythema multiforme major) characterized by bullae on the oral mucosa,

Emergencies in Pediatric Dermatology

71

pharynx, anogenital region and conjunctiva, target-like lesions and fever.


The patient may be unable to eat or properly close the mouth. The eyes
may become very painful; purulent conjunctivitis may make it impossible
for the patient to open them. Symblepharon production, keratitis with
corneal ulceration, iritis, and uveitis may occur. The conjunctival lesions
may leave resistant corneal opacity and synechia. The condition is
occasionally fatal.
The skin lesions of erythema multiforme must be distinguished from
bullous permphigoid, urticaria and dermatitis herpetiformis; the oral
lesions from aphthous stomatitis, pemphigus and herpetic stomatitis.
Hand, foot and mouth disease produced by coxsackieviruses A5, A10
and A16 must also be considered. Pneumonia should be treated with
tetracycline. Local treatment depends on the type of lesion. Vesicles and
bullous or erosive lesions can be treated with intermittent Burrows
solution, saline, or tap-water compresses. Cheilitis and stomatitis of
erythema multiforme require special care. Use of systemic corticosteroids
is controversial; some patients, especially those with severe mouth and
throat lesions, seem to succumb more readily to fatal respiratory
complications. The cause, if found, should be treated, eliminated, or
avoided. Simple erythema multiforme often needs no treatment. Systemic
antibiotics (as indicated by culture and sensitivity) and fluid and
electrolyte replacement may be lifesaving in childen with extensive
mucous membrane lesions. If frequent or severe erythema multiforme
is preceded by herpes simples, acyclovir 200 mg orally five time daily
may prevent attacks.
Toxic Epidermal Necrolysis12
Toxic epidermal necrolysis (TEN) more often occurs in adults. Sulfonamides, barbiturates, NSAIDs, phenytoin, allopurinol and penicillin
are most frequently associated, but numerous other drugs have been
less commonly implicated. Intake of drugs is denied by about 1/5 of
patients. In about 1/3 of cases, the cause is unclear because of concomitant
serious disease and drug treatment. TEN is one of the few true
dermatologic emergencies; the mortality rate is 61 percent.
TEN typically begins with painful localized erythema that
disseminates rapidly. At the sites of erythema, flaccid blisters occur or
the epidermis peels off in large sheets with gentle touching or pulling
(Nikolskys sign). Malaise, chills, myalgias and fever accompany the
denudation. Widespread areas of erosion, including all mucous membranes (eyes, mouth, genitalia), occur within 24 to 72 h and the patient
may become gravely ill. Affected areas of skin often resemble seconddegree burns. Death is caused by fluid and electrolyte imbalance and

72

Recent Advances in Dermatology

multiorgan sequelae (e.g. pneumonia, GI bleeding, glomerulonephritis,


hepatitis, infection). Rapid diagnosis is important so that a possibly
offending drug can be stopped. Before widespread erythema and
epidermal denudation occur, it may be difficult to distinguish TEN from
morbilliform drug eruptions or erythema multiforme minor and the
Stevens-Johnson syndrome (erythema multiforme major). TEN is often
thought to be a continuum of the latter two diseases. Although TEN
closely resembles staphylococcal scalded skin syndrome, these disorders
can be differentiated by the patients age, the clinical setting, and the
level of the epidermal split seen on biopsy.
Patient should be hospitalized; excellent nursing care and close
observation are essential. Suspected drugs should be stopped
immediately. Patients should be isolated to minimize exogenous infection
and treated as are those with severe burns by protecting the skin and
denuded areas from trauma and infection and by replacing fluid and
electrolyte losses.
Although controversial, systemic corticosteroid use has been successful
when initiated early in the course of disease. The idea is to stop further
immunologic injury to the skin, but systemic corticosteroids will not
breathe life into dead keratinocytes or reverse programmed death of
skin. Some severe cases require high-dose parenteral corticosteroids for
several days; most authorities recommend prednisolone 80 to 200 mg/
day IV (or equivalent), although some recommend 500 to 1000 mg/day
IV. This type of corticosteroid therapy has been associated with many
adverse effects and should be given under well-controlled conditions.
Corticosteroids often seem to enhance the propensity to gram-negative
or other sepsis and increase the mortality rate; thus, if these drugs are
used, a short course is safer. Septicemia, the most common cause of
death, often occurs with pulmonary infections and must be recognized
and treated promptly. Ophthalmologic consultation is often required
because there may be considerable crusting of the conjunctiva. To prevent
phimosis, urologic consultation may be necessary.
Collodion Baby13
Autosomal recessive lamellar ichthyosis manifest as collodion babies.
These babies are born with a thick armour-like collodion membrane
around them that is replaced much later by essentially normal skin.
Such babies are at a high risk of dehydration, sepsis, and temperature
lability. Emollients such as liquid paraffin are the best topical agents
helpful along with control of infection. Topical salicylic acid should
never be used because of the danger of salicylism and likewise topical
steroids are to be avoided to prevent rapidly developing adrenal

Emergencies in Pediatric Dermatology

73

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

74

Recent Advances in Dermatology


Table 5.1: Clinical features for meningococcal diseases

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

are admitted to an intensive care unit.


Penicillin is the drug of choice. Some strains of Neisseria meningitides
resistant to penicillin have been isolated; in these cases, third-generation
cephalosporins are a suitable alternative. Very sick patients are often
treated with both penicillin and cephalosporins prior to obtaining the
laboratory results.
Other treatments may include:
intravenous fluids to treat shock and prevent organ damage
medications such as noradrenaline for patients with very low
blood pressure
blood products such as platelets and fresh frozen plasma
oxygen and ventilation to assist with breathing
Patients who survive very severe cases of meningococcemia may
have suffered severe necrosis of skin and underlying tissue. Skin grafts
and amputation may be necessary. Complications from meningococcal

Emergencies in Pediatric Dermatology

75

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.

76

Recent Advances in Dermatology


Table 5.2: Features of acute and chronic GVHD

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

Patients recovering from bone marrow transplantation are usually


hospitalized for several weeks following transplant and are monitored
closely for signs of developing GVHD or infection. The best treatment
for GVHD is prevention. This consists of a cocktail of immunosuppressive
drugs such as cyclosporine, methotrexate, cyclophosphamide,
mycophenolate, tacrolimus and sirolimus with or without prednisolone.
The combination of cyclosporine and methotrexate has been found to
significantly decrease the severity of GVHD. These drugs weaken the
ability of the donors immune cells to launch an attack on the patients
organs.
Treatment for patients who do develop GVHD depends on the severity
of the disease. Mild cases with only skin involvement of acute GVHD
may settle without treatment. More severe acute or chronic GVHD
predisposes the patient to infection and overwhelming sepsis is the
main cause of death in patients with GVHD. The aim is to treat GVHD
before life-threatening sepsis occurs. High dose corticosteroids are usually
added to the immunosuppressive regime. New monoclonal antibodies
appear very effective, but are very costly. Photochemotherapy (PUVA)
and high dose long wave ultraviolet radiation (UVA1) may reduce the
severity of the skin problems.

Emergencies in Pediatric Dermatology

77

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)

Generalized and most severe form of JEB where blisters


appear all over the body and often involve mucous
membranes and internal organs
May only present at birth with small single blister but
becoming more widespread soon after
Hoarse cry or cough is indicative of internal organ
involvement
Complications such as infection, malnutrition and
dehydration usually lead to early death in infancy

JEB mitis or
non-lethal JEB

Generalized blistering and mucosal involvement


present at birth or soon after
Scalp, nails and tooth more involved
Complications such as infection, malnutrition and
dehydration may cause death in infancy, but those
who survive clinically improve with increasing age

Generalized
atrophic
benign EB

Mild generalized blistering present at birth, usually


with scalp, nail and teeth involvement
Blisters heal with a distinctive atrophic appearance
Blisters worsen in warmer climates

Dystrophic Epidermolysis Bullosa (DEB)


DEB Subtypes
Dominant DEB

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

78

Recent Advances in Dermatology

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

Emergencies in Pediatric Dermatology

79

a subepidermal blister. Direct immunofluorescence reveals the


immunoglobulin IgA along the basement membrane of the epidermis in
a linear pattern. Sometimes these IgA antibodies can be detected in the
blood (indirect immunofluorescence). Research indicates that the
antibodies are directed against various basement membrane components
(target antigens).
Most children with Linear IgA disease improve or clear with Dapsone
50-100 mg daily. Other helpful medications include corticosteroids
(prednisolone) and erythromycin. Although the condition may eventually
be cured, many patients require long-term treatment as a reduction in
dose of medication results in further blistering.
Pemphigus18
An uncommon, potentially fatal autoimmune skin disease characterized
by intraepidermal bullae and extensive erosions on apparently healthy
skin and mucosa, pemphigus usually occurs in middle-aged or elderly
persons and is rare in childen. In active pemphigus, the serum and skin
show readily demonstrable IgG antibodies that bind at the site of
epidermal damage. The primary lesions are flaccid bullae of various
sizes, but often the skin or mucosae just shear off, leaving painful erosions.
Lesions typically occur first in the mouth where they rupture and remain
as chronic, often painful, erosions for variable periods before the skin is
affected. The bullae typically arise from healthy-appearing skin, rupture
and leave a raw area and crusting. Any area of stratified squamous
epithelium may be affected, but the extent of skin and mucosal
involvement varies (e.g., lesions may occur in the oropharynx and upper
esophagus).
Pemphigus should be suspected in any bullous disorder or chronic
mucosal ulceration. It must be differentiated from other chronic oral
ulcers and from other bullous dermatoses (e.g., bullous pemphigoid,
benign mucosal [cicatricial] pemphigoid, drug eruptions, toxic epidermal
necrolysis, erythema multiforme, dermatitis herpetiformis, bullous contact
dermatitis). In pemphigus vulgaris, the epidermis is easily detached
from the underlying skin (Nikolskys sign) and biopsy usually shows
typical suprabasal epidermal cell separation. In pemphigus foliaceus,
the separation does not occur in the suprabasal region but rather in the
upper layers of the stratum spinosum or stratum granulosum. A Tzanck
test is frequently diagnostic when Wrights or Giemsa stain is used on
a smear of cells obtained by scraping the base of a lesion. The acantholytic
cells typical of pemphigus are unattached and basal cell-like, with large
centrally placed nuclei and peripherally condensed cytoplasm. Direct
immunofluorescence tests of perilesional skin or mucous membranes

80

Recent Advances in Dermatology

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

Emergencies in Pediatric Dermatology

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

Recent Advances in Dermatology

pulmonale, although when people with pulmonary histiocytosis X stop


smoking, improvement occurs in about one-third of cases. All three
disorders may be treated with corticosteroids and immunosuppressant
drugs such as cyclophosphamide, although no therapy is clearly
beneficial. The treatment for affected bones is similar to that for bone
tumors.
Mastocytosis21
A condition of unknown etiology is characterized by excessive
accumulation of mast cells in various body organs and tissues. Tissue
mast cells may contribute to host defense by releasing potent preformed
mediators (e.g., histamine) from their granules and by generating newly
formed mediators (e.g., leukotrienes) from membrane lipids. Normal
tissue mast cells also mediate the symptoms of common allergic reactions
by means of IgE antibodies attached to specific surface receptors.
Mastocytosis can occur in three forms: mastocytoma (a benign cutaneous
tumor); urticaria pigmentosa (multiple small cutaneous collections of
mast cells that develop as salmon-colored or brown macules and papules
which urticate when stroked and may become vesicular or even bullous)
and systemic mastocytosis (mast cell infiltrates in the skin, lymph nodes,
liver, spleen, GI tract and bones).
Patients with systemic mastocytosis have arthralgias, bone pain and
anaphylactoid symptoms. Other symptoms (increased gastric acid and
mucus secretion) are caused by stimulation of H2 receptors. Thus, peptic
ulcer disease and chronic diarrhea are common problems. The histamine
content of tissue biopsies can be extremely high, commensurate with the
elevated mast cell concentration. The urinary excretion of histamine and
its metabolites is high in systemic mastocytosis and plasma histamine
may be elevated. Increased plasma levels of tryptase, heparin and
prostaglandin D2 have also been reported.
Cutaneous disease involutes spontaneously; urticaria pigmentosa
either clears completely or is substantially improved before adolescence.
These conditions rarely progress to systemic mastocytosis. Usually, only
treatment of pruritus with H1 blocker is needed. The symptoms of
systemic mastocytosis should be treated with H1 and H2 blocker. Because
prostaglandins, especially prostaglandin D2, may contribute to mast
cell-related symptoms, aspirin therapy may be tried cautiously. While
inhibiting prostaglandin synthesis, aspirin and similar drugs may enhance
leukotriene production. If GI symptoms are not controlled, oral cromolym
100 mg qid for children 2 to 12 yr old (not to exceed 40 mg/kg/day)
should be given. No effective treatment is available to reduce the number

Emergencies in Pediatric Dermatology

83

of tissue mast cells. The solitary mastocytoma should be surgically


excised.
Acrodermatitis Enteropathica22
Acrodermatitis enteropathica is a rare congenital disorder characterized
by diarrhea, an inflammatory rash around the mouth and/or anus and
hair loss. The inheritance is autosomal recessive. Symptoms usually
occur within the first few months after birth. Both males and females are
equally affected. In some cases, discontinuation of breastfeeding appears
to trigger the disease. This has led researchers to believe that human
milk may affect zinc bioavailability. However, the disease is also found
in healthy breast-fed infants, thus the exact mechanism of the metabolic
defect remains unclear.
An acquired form, although extremely rare, is also possible in children
who are on total parenteral nutrition (TPN). For the last few years since
the disease has been recognized, TPN has included zinc supplementation.
Clinical features include:
Red and inflammed patches of dry and scaly skin, particularly around
body openings such as the mouth, anus and eyes, and the skin on
elbows, knees, hands and feet. It may look like atopic dematitis.
Patches evolve into crusted, blistered, pus-filled and eroded lesions.
There is usually a sharp demarcation between the affected area and
normal skin.
Skin around nails becomes inflamed and there may be abnormal nail
growth.
Hair loss on the scalp, eyebrows and eyelashes.
Conjunctivitis.
Sensitivity to light.
Loss of appetite.
Diarrhea, mild or severe.
Irritability and withdrawal.
Blood zinc level is abnormally low.
Acrodermatitis enteropathica is easily and effectively treated with
zinc supplementation. Daily oral zinc supplementation will need to be
continued for life. Secondary bacterial and/or fungal infection of lesions
require appropriate antibiotic therapy. If acrodermatitis enteropathica is
left untreated, symptoms of zinc deficiency progress further and may
even result in death.
Sclerema Neonatorum23

84

Recent Advances in Dermatology

It is seen in a preterm, ill neonate. Almost always associated with


metabolic acidosis, hypothermia and infection; the mortality rate of this
condition is around 60 percent. The disease presents as woody induration
of the skin and subcutis over the buttocks, cheeks, thighs, and lowe legs.
Histopathology helps to differentiate it from subcutaneous fat necrosis
that has a good prognosis. Sclerema does not show necrosis, but shows
cleft-filled fat cells that contain triglyceride crystals. The presence of
erythema, bluish discoloration of the skin, focal distribution and the
histologic presence of inflammatory cells, giant cells and calcium crystals
may differentiate subcutaneous fat necrosis. Children with sclerema may
respond to corticosteroids with packed cells transfusion.
Leiners Disease24
Leiners disease occurs in infants and is characterized by severe
generalized seborrheic dermatitis, recurrent diarrhea, recurrent skin and
internal infections and failure to thrive. It may be present at birth, but
more commonly develops within the first few months of life. It appears
to be more common in females than males and in breast-fed infants.
The precise cause of Leiners disease remains unknown, but it is
known that a defect in the bodys complement system has a major role
to play in its development. The complement system is a vital part of the
bodys immune system and in Leiners disease, an inherited dysfunction
or deficiency in the C5 component of complement alongside other factors
have been implicated. Other immune deficiencies may present in an
identical fashion in infancy. The condition usually starts off as a scaly
rash on the scalp, face or napkin area. Very rapidly it spreads to other
parts of the body. The affected area is bright red and may look swollen.
Infants appear uncomfortable but do not itch. Other symptoms include
recurrent diarrhea, infant not thriving or gaining weight and local skin
infections. There is also a risk of developing more severe infections that
may lead to pneumonia, meningitis and septicemia. Initially affected
babies may need to be hospitalized to manage fluid and heat loss. Bland
emollients may be used to treat the rash. Providing adequate nutrition
is also an essential part of treatment. Biotin, a water-soluble vitamin that
is found naturally in foods such as liver, kidney, meat, milk, egg yolks
and vegetables, appears to be useful in treating Leiners disease.
ACUTE SKIN FAILURE25
What are the Consequences of ASF?

Emergencies in Pediatric Dermatology

85

These include the following:


Loss of barrier function
Loss of immunological function
Loss of fluids
Increased cutaneous blood flow
Increase in energy expenditure
Impaired thermoregulation
Increased susceptibility to infections
Increased percutaneous absorption
Development of multi-organ failure
Management of ASF
The principles of managment are as follows:
Fluid and electrolytes balance
Hemodynamic balance
Prevention of sepsis
Treatment of infection
Nutritional supplementation
Maintenance of environmental temperature
Anticoagulant therapy in cases of DIC
Skin grafting in conditions such as TEN
Criteria for Poor Prognosis of ASF

Younger children, particularly the neonate


Extension of skin involvement
Altered states of consciousness
Increased respiratory rate
Increased cardiac rate
Drop in systolic blood pressure
Reduced neutrophil counts
Decreased urinary output

Monitoring of Children with ASF26


Centers specialized in management of ASF have created what is known
as Simplified Acute Physiological Scores (SAPS), a scoring system builtup in order to predict the outcome of severe skin disorders. This system
takes into consideration a combination of several clinical and biological
parameters following admission of the patient into the ward.
The parameters include
Hourly recording of respiratory rate, pulse rate, blood pressure, and

86

Recent Advances in Dermatology

urine output volume


Four hourly observation of body temperature, consciousness and
gastric emptying
Daily monitoring of body weight, extension of skin involvement,
fluid losses, blood chemistry and blood gas analysis. The urine is
examined for glycosuria
Bacteriology of skin lesions at least once every other day
INTENSIVE SKIN CARE UNITS (ISCU)
From the brief description of the disease entities mentioned above and
the concept of ASF, it is needless to say that there is a definite need for
specialized ISCUs in every teaching hospital and tertiary health care
centers. However, in countries such as India, the economics of such
ISCUs do not work out to be a feasible project. This should not deter our
enthusiasm. But the emphasis should be on building the perception of
teamwork that is the key to the successful outcome of pediatric
dermatological emergencies. There is always scope for innovation,
indigenization and improvisation. They are the determinants that drive
us through our search for excellence.
CONCLUSION
Unsurprisingly intensive care is absolutely necessary in a wide range of
dermatoses. Acute skin failure often leads to several changes such as
fluid loss, electrolyte imbalance, infections, etc. Cardiac or renal failure
may be the terminal eventuality of acute skin failure. Diseases such as
toxic epidermal necrolysis have to be managed just as a case of extensive
burns. Precise watching of hemodynamic and cutaneous bacteriological
data help in the assessment of prognosis. The guidelines of treatment
include careful attention to electrolyte equilibrium, nutrition, aseptic
precautions, energy expenditure and environmental temperature. All
these therapeutic measures should best be given in specialized wards
that will get to be known as intensive skin units in future.
REFERENCES
1. Roujeau JC, Revuz J. Intensive care in dermatology. In: Champion RH, Pye RJ,
eds. Recent advances in dermatology. No. 8. London: Churchill Livingstone,
1990:85-99.
2. Feingold DS. Gangrenous and crepitant cellulitis. J Am Acad Dermatol 1982;
6: 289-99.
3. Snyder RA, Eliaz PM. Toxic epidermal necrolysis and staphylococcal scalded
skin syndrome. Dermatol Clin 1988; 235-48.

Emergencies in Pediatric Dermatology

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.
JAMA 1979; 242: 623-68.
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;
80: 879-81.
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

Recent Advances in Dermatology

Sujit Ranjan Sengupta, Nilay Kanti Das

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.

Cutaneous Adverse Drug Reactions to Systemic Drugs

89

Table 6.1: Sources of information on adverse drug reaction


Source

Merits

Demerits

1. Clinical trial

Study group designed


Sample size too small to
to show efficacy of some
detect uncommon serious
drug may also document
reaction.
common side effects
during the course of
Short duration of trial not
trial.
sufficient to document the
late-onset side effects.

2. Case reports

First line of defense in


the detection of unanticipated drug reaction.

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.

NATURE OF THE CUTANEOUS ADVERSE DRUG REACTION


Adverse reaction to drugs involves different systems of the body, of
which cutaneous reactions are the most frequent. They manifest with
varied and diverse morphological pattern starting from trivial urticaria
to severe form of vasculitis or toxic epidermal necrolysis and cutaneous
necrosis or gangrene. The wide array of its clinical presentation mimics
innumerable dermatological disorders and often poses a serious
diagnostic problem. It is an utmost necessity for an internist or a
dermatologist to have a comprehensive understanding of the cutaneous
and histological spectra of the drug reactions as well as the knowledge
of the drugs incriminated for such adverse reactions. It helps to lower
or minimize the incidence of iatrogenic morbidity or mortality.
Untoward reaction to drugs can arise as a result of immunologic as
well as non-immunologic mechanism. The immunologic mechanisms
primarily thought to be responsible in cutaneous drug reaction include,
immediate hypersensitivity reaction (type I), cellular cytotoxic reaction
(type II) immune-complex reaction (type III), or delayed type of T-cell

90

Recent Advances in Dermatology

mediated immune response (type IV). Non-immunologic cutaneous


reactions occur due to several unrelated mechanisms like immunologic
activation of effector pathway, synergistic or cumulative toxicity,
overdose, drug interaction, metabolic alteration, inherited enzyme and
protein deficiency.
It is not often possible to specify the offending drugs or the exact
underlying pathogenetic mechanism as some common reaction patterns
are elicited by a variety of stimuli. To attribute a drug as a causal factor
in a specific cutaneous drug reaction, one has to establish a temporal
relationship with ingestion of the incriminating drug and appearance of
the lesion as well as reappearance of the lesion on rechallenge.6 Patch
test is generally satisfactory and well-tolerated method7 in establishing
a diagnosis, but oral rechallenge is not without risk and often not
performed. Radio-allergosorbent testing (RAST), lymphocyte
transformation assays, assay of drug specific antibodies7 are of limited
value to the clinician because of low sensitivity.
Exanthematous/Morbillform/Maculopapular Drug Eruption
It is the most common form of CADR constituting 90 percent4 of all skin
eruptions. The patient usually presents with an acute onset of
symmetrically distributed erythematous maculo-papular lesions, starting
most commonly on the trunk, which may then involve the extremities
but usually spares the face. The lesions are extremely pruritic and often
mimic viral exanthem; withdrawal of the drug is helpful in differentiating
the two conditions. The lesions usually resolve within 7-12 days but may
lead to erythroderma if offending drug is not withdrawn.
It is proposed that the lesional skin shows up-regulation of intercellular
adhesion molecule 1 (ICAM-1) or CD54 along with the up-regulated
corresponding lymphocyte function antigens, which play a role in the
pathogenesis of the disease.8
Histopathology of the lesional skin shows vascular interface dermatitis
with dyskeratotic cells and lymphocytes along dermo-epidermal junction.
Sparse superficial perivascular infiltrate may also be found along with
papillary dermal edema. Tissue eosinophilia, which is present in some
cases helps to differentiate it from viral exanthems.
The drugs commonly involved for causing exanthematous drug
eruption include aminopenicillins (penicillin), sulfonamides, antiepileptics and the non-nucleoside reverse transcriptase inhibitors
(nevirapine).
Lamotrigine, a newer antiepileptic, is also implicated9,10 along with
the anti-cancer drug, docataxel11 in causing such reaction. Thalidomide
is shown to cause exanthematous reaction and it is reported that such

Cutaneous Adverse Drug Reactions to Systemic Drugs

91

reaction can be suppressed if methylprednisolone is concomitantly used.12


Celecoxib, a COX II inhibitor13 and the contrast agent sodium ioxaglic
acid meglumine14 are also known to cause maculo-papular exanthem.
Hypersensitivity Syndrome Reaction
It is one of the severe forms of CADR, which begins as a widespread
morbilliform eruption that may become indurated and infiltrated, and
may progress to exfoliative dermatitis later. Mucus membrane is seldom
involved and necrolysis of skin is never present. It is associated with
fever, lymphadenopathy and visceral involvements, which differentiate
it from exanthematous reaction. Eosinophilia (in about 90%) or
mononucleosis-like atypical lymphocytes (in about 40%) are the
hematological hallmark of this syndrome. Hence the acronym DRESS15
(Drug Rash with Eosinophilia and Systemic Symptoms) has been
proposed for this clinical variant.
This syndrome is thought to be the result of immunologic mechanism.
Histopathology reveals dense lymphocytic with occasional eosinophilic
infiltrate of the papillary dermis along with epidermotropism.
Aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine),
sulfonamide, dapsone, minocycline and allopurinol are the drugs
responsible for this disorder.
Exfoliative Dermatitis/Erythroderma
It is one of the severe forms of CADR, which may follow exanthematous
drug reaction. Patient presents with an abrupt onset of erythema, edema,
tenderness of skin with scaling involving more than 90 percent of body
surface area (BSA), often associated with intense pruritus. It may start
even several weeks after the drug exposure.
Drug induced erythroderma represents the extension of the same
pathogenetic mechanism as of exanthematous drug reaction and is
histopathologically characterized by psoriasiform hyperplasia of
epidermis with adherent parakeratotic scales and loss of granular cell
layer. It is distinguished histologically from other causes of erythroderma
by the presence of architectural disarray, dysmaturation, scattered
necrotic keratinocytes and tissue eosinophilia. Absence of
epidermotropism, supra-papillary thinning with dilated capillaries in
dermal papillae and neutrophil-imbued parakeratosis help to differentiate
drug induced erythroderma from erythroderma due to mycosis
fungoides, psoriasis and seborrheic dermatitis respectively.
The drugs that are known to cause erythroderma include
acetylsalicylic acid, allopurinol, captopril, cefoxitine, clofazimine,

92

Recent Advances in Dermatology

cotrimoxazole, diltiazem, etretinate, fenbufen, gentamicin, GM-CSF,


ketoconazole, lithium, minoxidil, methotrexate, nystatin, oxytetracycline,
phenobarbital, quinidine, sulfonamide, thalidomide and timolol.
Recently it has been reported that continuous therapy with
epoprostenol (PGI2), which is used for preventing platelet aggregation
and damage during hemodialysis and cardiopulmonary bypass, may
also lead to exfoliative dermatitis.16 Bupropion,17 an antidepressant and
the proton pump inhibitors18,19 like omeprazole and lansoprazole are
also being reported along with calcitonin20 as a cause of erythroderma.
Other drugs implicated in causing exfoliative dermatitis include
erythropoietin,21 lipid lowering agent-pentostatin, 22 cyanamide,23
indinavir24 and ticlopidine.25
Urticaria, Angioedema and Serum Sickness
Urticaria is the second most common type of CADR, next to exanthematous drug reaction, accounting for about 6 percent of drug reaction.26
It appears within 36 hours of drug administration but on rechallenge the
lesions may develop within minutes. Angioedema however, is rarely
seen as a CADR and accounts for less than 1 percent of the patients
receiving a particular drug. Serum sickness has a distinctive clinical
findings with erythema first appearing on the sides of the fingers, toes
and hands later turning into extensive morbilliform rash (in two-third
of the patient) sometimes with urticaria.27
Immediate (type I) hypersensitivity reaction leading to degranulation
of mast cells with the release of histamine plays the key role in urticaria
and angioedema. Cross linking of cell bound IgE or high affinity Ig
receptors either by immunologic or non-immunologic mechanism is the
basis for mast cell degranulation. Serum sickness is a type III
hypersensitivity reaction that is mediated by the deposition of immune
complexes in the small vessels, activating the complement system and
recruiting the granulocytes.
Histology of urticaria shows dermal edema and sparse perivascular
infiltrate consisting of lymphocytes and eosinophils whereas in
angioedema, the edema and infiltrate extend into the sub-cutaneous
tissue. Serum sickness shows leucocytoclastic vasculitis (LCV) with no
other remarkable features on histology.
Urticaria/angioedema is commonly caused by ACE inhibitors, antifungals (ketoconazole, fluconazole), antibiotics (penicillins, cephalosporins), aspirin, codeine, food additives, hydantoin, hydralazine,
NSAIDs, quinidine and radiologic contrast media.
The additions to this list include interferon-beta la,28 interferon beta
lb,29 the heparin substitute-danaparoid, steroid analogue-deflazacort,30

Cutaneous Adverse Drug Reactions to Systemic Drugs

93

muscle relaxant-carisoprodol.31 The antihistaminic cetirizine is also


documented in causing urticaria32,33 as also intra-articular injection of
mehyl-prednisolone.34 Though NSAIDs are responsible in causing
urticaria, the newer COX II inhibitors, such as rofecoxib, are relatively
safe in NSAID-sensitive patients with urticaria or angioedema.35
The drugs implicated in causing serum sickness include bupropion,
cefaclor, cephalexin, cefprozil, minocycline, propranolol and streptokinase.
Eczematous Drug Eruption
The persons who are previously sensitized to a drug may develop
eczematous lesion on ingestion, inhalation or topical application of that
particular compound. Following ingestion, the lesions typically develop
within 2 to 24 hours and over the site which previously showed contact
dermatitis.
The pathology is similar to that of allergic contact dermatitis and the
skin biopsy shows spongiosis with exocytosis of lymphocytes and
eosinophils, edema of the papillary dermis and perivascular lymphohistiocytic and eosinophilic infiltrate.
The drugs commonly implicated in causing eczematous drug reaction
are antibiotics, aminophylline, antihistaminics containing ethylene
diamine and oral hypoglycemic agents.
Other agents that are recently documented in causing eczematous
reaction include heparin alternative-danaparoid,36 phenobarbitone,37
synergistins,38 hepatitis B vaccine39 and anthrax vaccine.40
Photosensitive Drug Eruption
Photosensitivity causes cutaneous eruptions on the sun-exposed areas
with sparing of retro-auricular folds, upper eyelids and submental region.
It accounts for about 8 percent of all CADRs. 41 Drug induced
photosensitivity may be either photoallergic or phototoxic drug eruption
(it may sometimes coexist).
Photoallergic reactions are a form of delayed hypersensitivity reaction
where the hapten or the avidity with which the hapten binds with the
carrier is altered by light, leading to the formation of photoantigen.
Phototoxic reaction, on the other hand, is due to reactive oxygen species
resulting from the dissipation of the absorbed solar energy by the drug.
Photoallergic dermatitis presents within 24 hours of sun exposure
and is clinically manifested by acute, subacute or chronic dermatitis and
occasionally with lichenoid papules. In a few cases, the photoallergic
lesions may become generalized due to autosensitization phenomenon
and can involve covered area of the body.

94

Recent Advances in Dermatology

On the other hand, the phototoxic reaction is sunburn reaction usually


appearing within hours of sun exposure on the exposed parts of the
body. It is clinically characterized by erythema, edema, vesiculation,
peeling or desquamation. Chronic exposure for a long time produces
scaling and lichenification; the severity of clinical manifestation depends
on the combined effects of concentration of the drugs and duration of
sun exposure.
Histopathology of photoallergic dermatitis is that of allergic contact
dermatitis which shows spongiosis of the epidermis, angiocentric
lymphocytic and eosinophilic iniltrate, exocytosis, microvesiculation and
papillary dermal edema. In phototoxic dermatitis, necrotic keratinocytes
in all layer of epidermis with architectural disarray and dismaturity is
found in acute stage. Both vacuolated keratinocytes (sunburn cells) or
dyskeratotic keratinocytes may be found. Over time, photo adaptive
changes occur and hyperkeratosis, hypergranulosis, melanocytic
hyperplasia, epidermal architectural disarray and dysmaturity are found
on histopathology.
Drugs frequently associated with photosensitivity are amiodarone,
NSAIDs, nalidixic acid, phenothiazine, psoralens, sulfonamide,
tetracyclines, thiazides. Other systemic drugs associated with photosensitivity include ampicillin, antidepressants, antifungals (griseofulvin,
ketoconazole), beta-blocker, carbamazepine, cimetidine, cytotoxic agents,
diazepam, fluoroquinolones, furosemide, oral contraceptives, quinine,
quinidine, sulphonylurea.
Recently, this list is further lengthened by inclusion of new drugs.
Triflusal, a fluorinated aspirin derivative with antiplatelet properties, is
reported to be associated with photosensitivity.42-44 Anti-HIV drugs
ribavirin,45 efavirenz46 and the anti-neoplastic agent capecitabine47 are
also reported to cause photosensitivity. Other agents include antiandrogen flutamide,48 newer quinolone lomefloxacine,49 itraconazole,50
paroxitine.51 Photosensitivity is also noted with lipid lowering agent
simvastatin,52 anti-thrombotic agent clopidogrel.53 Hydroxychloroquine,
which is a systemic photo-protective agent, is reported to cause photosensitivity in 4 cases.54
Erythema Multiforme, Stevens-Johnson
Syndrome and Toxic Epidermal Necrolysis
Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) are often considered to be the part of the
same disease spectrum. Some authors believe that EM represents a
separate clinical entity from that of SJS/TEN.55 A consensus agreement

Cutaneous Adverse Drug Reactions to Systemic Drugs

95

was made on the three-grade classification of SJS/TEN spectrum of


disorder.55
EM represents a self-limiting acute onset dermatosis where target
lesions with peripheral rim of erythema, a central zone of pallor and
sometimes dusky or violaceous macular blister arise, preferentially on
the distal extremities. SJS includes the cases that are manifested clinically
as small blisters or dusky purpuric macules or a typical target rarely.
The areas of confluence/detachment do not exceed 10 percent of BSA
and there are usually more than two areas of mucosal erosion.56 TEN
represents those cases where individual lesions resemble SJS but in
addition have large sheets of necrotic epidermis which peel off easily
with pressure, and the total detachment exceeds 30 percent of BSA.56 In
cases where the detachment is between 10 to 30 percent of BSA, SJS and
TEN are thought to overlap and represent Transitional SJS-TEN.55
It has been hypothesized that EM is mediated by type III
hypersensitivity phenomenon where impaired histamine metabolism is
thought to play a role.57 Further immuno-pathologic studies have found
that epidermis of the lesional skin are infiltrated by activated lymphocytes,
mainly CD8+ cells and macrophages,58 which suggests cell-mediated
cytotoxic reaction against the epidermal cells playing the vital role in
this disease spectrum. The cytotoxic T-cells, apart from causing direct
damage, also release cytokines, tumor necrosis factor a (TNF ) and
interleukin 6 (IL 6), all of which also play a damaging role in SJS/TEN.59
Recently, the role of FAS (CD 95)FAS ligand (CD 95 L) interaction in
cell necrosis in TEN has been described and it has been found that
epidermal keratinocytes in TEN express a large amount of FAS ligand
(CD 95 L) on their surface.60
EM, SJS and TEN display the vacuolar form of interface dermatitis
with orthokeratotic stratum corneum, mild spongiosis with exocytosis,
tagging of lymphocytes along the dermo-epidermal junction. Early lesions
show sparse lymphocytic infiltrates and scattered or grouped dyskeratotic
(apoptotic) keratinocytes, whereas in advanced lesion the whole of the
epidermis shows necrosis with detachment from a seemingly normal
dermis.61 Satellite cell necrosis, characterized by intra-epidermal
lymphocytes surrounding necrotic keratinocytes are often found in this
group of disorders.
Drugs commonly incriminated in causing EM, SJS/TEN include anticonvulsants (including lamotrigine), allopurinol, NSAIDs, sulfonamides
and dapsone. Other drugs including penicillin, barbiturates, dilantin,
sulfonamides, phenothiazines, griseofulvin, phenolphthalein, nitrogen
mustard, codeine, tetracycline, minocycline, cotrimoxazole, glutethimide,
cimetidine, methotrexate, prazosin, ethinyl estradiol, ketoconazole,

96

Recent Advances in Dermatology

sulfasalazine, cefaclor, methazualone, furosemide, aminopenicillins,


streptomycin are also implicated in this group of disorder.
The additions to this long list include aceclofenac (Beofenac),62
ofloxacin,63 Fenoterol, 64 bupropion,65,66 sestamibi,67 vancomycin, 68
granulocyte colony-stimulating factor, 69 Bufexamac,70 roxatidine,71
pyrazolon derivatives,72 celecoxib,73 and 5-fluorouracil.74
Apart from the above drugs, there are reports of SJS caused by
cefotazime,75 azithromycin,76 ranitidine,77 celocoxib,78 methotrexate,79
nevirapine,80,81 imatinib (or ST 1571),82,83 bromhexine,84 hydroxychloroquine,85 leflunomide,86 rituximab,87 bezafibrate.88 SJS/TEN are also
reported with amifostine, a phosphorylated aminothiol prodrug, that
can selectively protect normal tissues against the toxic effects of
chemotherapy and radiotherapy, 89,90 and also with cytosine arabinoside.91
Fixed Drug Eruption
Fixed drug eruption (FDE) is clinically manifested as sharply marginated
pruritic dusky erythema or violaceous macules which usually start within
minutes to hours of drug intake, may evolve into a vesicle and heal with
hyperpigmentation. The lesions more commonly involve acral skin or
genitalia and perianal skin and characteristically show recurrence in the
same area(s) with or without appearance of new lesion on rechallenge.
Up-regulation of the expression of ICAM 1 (or CD 54) of the keratinocytes as well as endothelial expression of E-selectin and vascular adhesion
molecule are thought to represent the pathogenetic mechanism of
FDE.92,93
Histologically, it is characterized by interface dermatitis with vasculopathy, dyskeratotic keratinocytes (civatte bodies) in the epidermis,
pigmentary incontinence, tissue eosinophilia and neutrophilia and
presence of intra-epithelial granulocytic abscess. Histologically it mimics
erythema multiforme except for the presence of acanthosis, hypergranulosis, hyperkeratosis and which help to differentiate the two.
The common offending drugs causing FDE are oral contraceptives,
opiates, barbiturates, benzodiazepine, anticonvulsants, phenolphthalein,
phenacetin, salicylates, sulindac, naproxen, ibuprofen, paracetamol,
indomethacin, tolmetin, nystatin, tetracycline, minocycline, sulfonamides,
metronidazole, antifungals, dapsone, clindamycin, antimalarials.
Newer drugs, also reported to cause FDE, include nimesulide,94
rofecoxib,95 ticlopidine,96,97 lamotrigine,98 ciprofloxacin,99 paclitaxel,100
phenylpropanolamine hydrochloride,101 tosufloxacin tosilate,102 atenolol,103 metamizole,104 interleukin-2105 and cetirizine.106
Apart from the usual clinical type, other variants of FDE are also
known. Non-pigmenting FDE is reported to result from eperisone

Cutaneous Adverse Drug Reactions to Systemic Drugs

97

hydrochloride107 and after skin testing and intra-articular injection of


triamcinolone acetonide.108 Rifampicin109 and influenza vaccination110
are reported to result in bullous FDE. Acetaminophen111 is reported to
give rise to papular fixed drug eruption which resembles folliculitis.
There are reports of fixed plaque of erythrodysesthesia resulting from
docetaxel112 and daunorubicin.113
Lichenoid Drug Eruption
Lichenoid drug eruptions clinically manifest as extensive papular skin
eruptions which resemble classic lichen planus. In contrast to classic
lichen planus, it is more psoriasiform and rarely involve oral mucosa.
It usually develops weeks to months following initiation of therapy and
initially may present as eczematous lesion.
The lag period between the commencement of therapy and onset of
the lesions along with the slow resolution following withdrawal of
the drug points towards the role of delayed type hypersensitivity in its
pathogenesis.
Histologically, it is manifested by a band shaped infiltrate in upper
dermis with vacuolar degeneration of basal cell, dyskeratosis, effete
keratinocyte in papillary dermis (manifested as colloid-body accumulation) and perivascular infiltrate comprising of lymphocyte with scattered
eosinophils, plasma cells and histiocytes.
The drugs incriminated in the causation of lichenoid drug eruption
are beta-blockers, ACE inhibitors, thiazides, furosemide, methyldopa,
antimalarials, oral hypoglycemic agents, penicillamine, phenytoin,
carbamazepine, phenothiazine, lithium, antihistaminics.
Among the newer agents, lichenoid drug eruption is reported to
result from the leflunomide,114 clopidogrel,115 imatinib,116 sildenafil,117
ursodeoxycholic acid,118 granulocyte colony stimulating factor.119 Apart
from these newer agents, sparfloxacin120 and amlodipine121 are also
reported to cause lichenoid drug eruption.
Psoriasiform Drug Reaction
This variant of drug reaction manifests clinically as classic papulosquamous lesions of psoriasis. The only clue to the diagnosis being the
temporal association of the drug with the lesion.
Histopathology reveals psoriasiform epidermal hyperplasia,
hypogranulosis, foci of neutrophil-imbued parakeratosis sometimes
associated with interface dermatitis and eczematous epithelial changes.
Absence of tortuous capillary in the dermal papillae in apposition to the
supra-papillary thinned epidermis helps to differentiate the drug reaction
from psoriasis.

98

Recent Advances in Dermatology

Drugs that are implicated in precipitating or aggravating psoriasiform


lesion include aspirin, morphine, NSAIDs, ampicillin, antimalarials, ACE
inhibitors, quinidine, terbinafine, beta-blockers, lithium, cyclosporine,
penicillamine, interleukins, interferon and methoxypsoralen.
Recently, there has been three case reports of psoriasiform skin lesion
in patients on dialysis receiving icodextrin.122
Drug Induced Pustular Eruption
Drug induced pustular eruption may manifest itself as a mild form of
acneiform eruption to the severe CADR, acute generalized exanthematous
pustulosis.
Acute generalized exanthematous pustulosis (AGEP) is a form of
pustular eruption where widespread non-follicular pustules develop
over diffuse total body erythema usually within hours of administration
of the implicated drug and is associated with constitutional symptoms
and leucocytosis. AGEP can be differentiated from pustular psoriasis
based upon more acute onset, temporal relationship with the drug and
rapid resolution (within 10-15 days) following drug withdrawal.
The precise nature of AGEP is not known, but the patch test with the
offending drugs is more frequently positive in this disorder than in any
other CADR,123 suggesting immunologic background.
Histopathology shows spongiform subcorneal pustulation, which may
manifest follicular and/or acrosyringeal accentuation. It can be
differentiated from pustular psoriasis by the presence of papillary edema,
angiocentric neutrophillic and some eosinophilic infiltrate, LCV or
sometimes by focal necrosis of keratinocytes.
The common incriminating agents causing AGEP include calcium
channel blockers, NSAIDs, anticonvulsants, antibiotics (especially betalactum and macrolide), antifungals (itraconazole, terbinafine).
In recent years numerous other drugs are implicated in causing AGEP
which includes sertraline,124 hydrochlorothiazide,125 imatinib (ST 1571),126
mexiletine,127 methylprednisolone,128 teicoplanin,129 dextropropoxyphene,130 clindamycin,131 sulfamethoxazol,132 famotidine,133 bamifylline,134 cytarabine,135 allopurinol,136 meladinine,137 icodextrin138 and
furosemide.139
Vasculitis
Drug-induced vasculitis (DIV) clinically manifests itself as palpable
purpuric papule,56 which is its hallmark, or sometimes as purpuric
maculo-papular rash classically involving the lower extremities within
7-21 days of starting the drug. Hemorrhagic blisters, urticaria, ulcers,

Cutaneous Adverse Drug Reactions to Systemic Drugs

99

nodules, Raynauds phenomenon and digital necrosis may be less


frequent accompaniments of DIV.56
The persons developing vasculitis following drug ingestion have an
underlying immune-dysregulatory state. Reports of cases where antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis
developed following intake of certain drugs,140 support the fact that DIV
is manifested in predisposed individuals.
DIV is a sub-type of hypersensitivity vasculitis involving the small
vessels.141-143 It is thought that antibodies against drug-related hapten
result in DIV but substantial proof is lacking.144 Alternative mechanisms
of DIV which are also being proposed include direct drug toxicity against
vessel walls, autoantibodies reacting with endothelial cells and cell
mediated cytotoxic reactions against blood vessels.145,146
Mild leukocytoclastic vasculitis (LCV) is the prototype of DIV where
sparse, superficial perivascular and interstitial leukocytoclasis is found
along with fibrin deposit and hemorrhage. It can be differentiated from
systemic vasculitis by the absence of pandermal severe LCV. Druginduced lymphocytic vasculitis is also observed in some instances where
lymphocytic vascular reaction with hemorrhage and tissue eosinophilia
is present in the absence of luminal thrombosis, a feature of lymphocytic
vasculitides of collagen vascular disease. Eosinophilia is a common feature
of systemic DIV (79%) though it is only present in 29 percent of cutaneous
DIV. The pustular variant of drug-induced hypersensitivity vasculitis
shows vascular deposition of IgA.147
The drugs associated with LCV include phenylbutazone, indomethacin, allopurinol, penicillins, erythromycin, sulfonamides, thiazide
and hydantoin. The pustular vasculitis can result from the use of
naproxen, penicillins, furosemide, diltiazem and carbamazepine.
Recent, ibuprofen-induced bullous vasculitis148 and vasculitis resulting
from the use of COX II inhibitor, celecoxib149 are described.
Churg-Strauss syndrome, which is a form of necrotizing eosinophilic
vasculitis inolving predominantly the small and medium sized vessels,
is reported to result from the use of zafirlucast150 in asthma patients.
Drug Induced Pseudolymphoma Syndrome
The cutaneous manifestations in pseudolymphoma may range from a
few erythematous plaques or nodules to generalized maculo-papular
eruption and rarely exfoliative dermatitis. Generalized lymphadenopathy,
hepatosplenomegaly, fever, arthralgia and eosinophilia are characteristically present in this disorder. All the cases improve completely
following the withdrawal of the incriminating drug.
Histopathology is indistinguishable from mycosis fungoides (hence
also termed as pseudomycosis fungoides) with pautriers micro-abscess

100

Recent Advances in Dermatology

in the epidermis and cerebriform nuclei in the dermal infiltrate. Large


masses of atypical lymphocytes may also be found in the dermis.
The offending drugs causing pseudolymphoma include phenytoin,
phenothiazine, barbiturates, beta-blockers, ACE inhibitors, calcium
channel blockers, H1 and H2 blockers, benzodiazepine and antidepressants.
Drug Induced Erythema Nodosum
It usually presents as tender erythematous nodules of acute onset with
size varying from 1-5 cm on the anterior surface of the lower limb,
though calves, thighs, forearms may also be involved. The lesions involute
spontaneously with desquamation and pigmentary change.
Paucity of immune complex suggests type IV hypersensitivity reaction.
Histopathology shows changes predominantly in the subcutaneous tissue
where there is septal inflammation together with inflammation of septal
blood vessels. The infiltrate mainly consists of lymphocytes and
histiocytes with a few neutrophils and eosinophils. Extravasations of
RBCs are found mostly near the septa.
Drugs implicated in causing erythema nodosum include sulfonamides, analgesics, antipyretics, oral contraceptive pills as well as granulocyte colony stimulating factor. Recently, panniculitis mimicking erythema
nodosum is described in a patient of asthma who received leukotriene
modifying agents.151
Blistering Drug Eruption
Blistering drug eruption may be of varied etiologies and clinical
manifestations as described below:
Linear IgA Bullous Dermatosis
The clinical manifestations of drug induced linear IgA bullous dermatosis
(LAD) may vary from tense vesicles on erythematous base resembling
bullous pemphigoid (BP), grouped papulovesicular lesions like dermatitis
herpetiformis (DH) to urticaria or EM like lesion. Mucosal involvement
is absent in case of drug-induced LAD which differentiate it from the
idiopathic LAD.
The antibodies are either produced against lamina lucida (laminin 5)
or against anchoring fibrils (collagen IV), determining the localization of
the bullae. The histopathology shows interface dermatitis with the
formation of micro-abscess in dermal papillae and subsequent subepidermal blister. The infiltrate consists of neutrophils around the

Cutaneous Adverse Drug Reactions to Systemic Drugs

101

superficial vascular plexus. The direct immunofluorescence (DIF) shows


deposition of IgA along the dermo-epidermal junction.152
The main offending drugs are amiodarone, ampicillin, cephalosporins,
captopril, diclofenac, interferon-gamma, interleukin-2, lithium, phenytoin
and vancomycin.
Recently, atorvastatin, a lipid lowering agent, has also been documented to cause LAD.153
Drug Induced Pemphigus
The drug-induced pemphigus usually starts with some prodromal
features which may be either morbilliform rash or urticarial lesion,
following which the blisters develop. These features help to differentiate
the drug-induced variety from the idiopathic pemphigus state.
It is postulated that the offending drugs bind to the disulfide bond
on the inter-cellular junction and render them antigenic. Some drugs,
however, may cause direct toxic effect on inter-cellular junction leading
to blister formation. The antibodies are either against desmoglein I or
desmoglein III except the cases of direct toxicity where no antibodies are
found.
The skin biopsy shows features similar to pemphigus foliaceous or
vulgaris. The early lesion may show parakeratosis, eosinophilic spongiosis and variable dermal infiltrate. DIF shows pericellular deposition
of IgG in about 90 percent of cases. Indirect immunofluorescence may
show circulating antibodies in about 70 percent of cases.
Drugs implicated include thiol group containing drug captopril,
penicillamine, and non-thiol drugs penicillins, cephalosporins, phenylbutazone etc.
Drug-induced pemphigus is also reported to result from carbamazepine,154 indapamide,155 Quinolones,156 fosinopril157 interferon alpha2a,158 fludarabine,159 bucillamine,160 quinapril161 and also following
tetanus and diphtheria vaccination.162
Drug Induced Pemphigoid
The clinical manifestation of drug-induced pemphigoid varies widely. It
may resemble BP and sometimes may present with EM or pemphigus
like picture. The antibodies found in this group of disorder are of IgG
class and are directed against 230-Kda and 180-Kda antigens of hemidesmosomes. Histopathology mimics BP with eosinophil-rich subepidermal blister.
Among the drugs related to the development of drug-induced
pemphigoid are diuretics (furosemide), neuroleptic agents, phenacetin,
penicillamine, penicillin and sulfasalazine.

102

Recent Advances in Dermatology

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

Cutaneous Adverse Drug Reactions to Systemic Drugs

103

Scleromatoid Tissue Reaction


Drug may provoke scleromatous tissue reaction, which may be either
confined to skin or associated with systemic involvements. Typically
the plaques affect the thighs bilaterally and are found to have an
erythematous rim.
The pathogenesis of such reaction is not yet clearly known. Abnormality of the vascular supply is an accompaniment in this disorder.
Drugs causing scleromatoid tissue reaction with systemic involvement include serotonin, methysergide, hydralazine and practolol; while
bromocriptine, lithium, valproate, hydantoin and L-tryptophan leads to
tissue reaction confined to the skin.
Recently, paclitaxel, the anti-tumor drug, is also documented to cause
scleroderma-like skin condition.180-182
CADR TO ANTI-RETROVIRAL THERAPY
The review is incomplete without a comprehensive outline of the CADR
to anti-retroviral therapy in this era of AIDS. The drugs used are classified
in three broad categories, namely: protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitor (NNRTIs) and nucleoside
reverse transcriptase inhibitor (NRTIs).
The PIs include indinavir, ritonavir, saquinavir and nelfinavir which
increase the CD4 count and reduce the viral load rapidly. In general the
CADR to PIs are lipodystrophy, hypersensitivity and AGEP. The NNRTIs,
which acts by inhibiting the enzyme reverse transcriptase by binding with the enzyme and altering its structure, include nevirapine,
delavir-dine and loviride. The major toxicity of NNRTIs are rash, SJS
and hypersensitivity syndorme. The NRTIs are nucleoside analogue,
which get incorporated in the DNA of virus impending the process of
replication. Important NRTIs are zidovudine, didanosine, lamivudine,
zalcitabine and stavudine.
The anti-retroviral drugs can be used alone, but in highly active antiretroviral therapy (HAART) they are used in combination (PIs in
combination with nucleoside analogue). The CADR to individual drugs
are enlisted in Table 6.2.
CONCLUSION
The article makes an attempt to bring forth the CADR which the
dermatologists might encounter in their clinical practice. With the
advancement of medical science, many new diseases are likely to be
identified and many new drugs are going to be introduced in the market.

104

Recent Advances in Dermatology


Table 6.2: CADR associated with anti-retroviral agents

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

It is not unexpected to recognize many newer forms of CADR to


previously as well as newly introduced drugs. Any atypical presentation
of seemingly unknown etiology in the clinical practice should cast a
shadow of doubt regarding the causal-relationship of drugs in its origin.
The present article is a brief update of the CADR known till date and
the pursuit for the search and research of CADR needs to be continued.
REFERENCES
1. Moorre TJ, Psaty BM, Furberg CD. Time to act on drug safety. JAMA 1998;
279: 1571-3.
2. Edward IR, Aronson JK. Adverse drug reaction: definition, diagnosis and
management. Lancet 2000; 356: 1255-9.
3. Leape LL, Brennan TA, Laird N, et al. Results of the Harvard Medical Practice
study II. N Eng J Med 1991; 324: 377.
4. Bigby M, Jick S, Jick H, et al. Drug induced cutaneous reaction. A report from
the Boston collaborative drug surveillance programme on 15,438 consecutive
inpatient 1975 to 1981. JAMA 1986; 256: 3358-63.

Cutaneous Adverse Drug Reactions to Systemic Drugs

105

5. Kaufman DW, Shapiro S. Epidemiological assessment of drug induced disease.


Lancet 2000; 356; 1339-43.
6. Shear NH. Diagnosing cutaneous adverse reaction to drugs. Arch Dermatol
1990; 126: 94-7.
7. Rieder MJ. In vivo and in vitro resting for adverse drug reactions. Pediatr Clin
North Am 1997; 44: 93-111.
8. Barbaud AM, Bene MC, Schmutz JL. Role of delayed type hypersensitivity and
adhesion molecules in amoxycillin induced morbilliform rashes. Archg
Dermatol 1997; 133: 481-6.
9. Labiner DM. Lanotrigine and rash: scratching beneath the surface. J Clin
Psychiatry 2002; 63(11): 1010-1.
10. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of
lamotrigine in mood disorders: clinical relevance and management. J Clin
Psychiatry 2002; 63(11): 1012-9.
11. Hirai K, Ishiko O, Nakajima S, et al. Local erythematous dermatitis after
intravenous docetaxel. Gynecol Obstet Invest 2002; 53(2): 118-20.
12. Nijsten T, Meuleman L, Schroyens W. et al. Thalidomide-induced morbilliform
rash: diagnosis and continuation of therapy, premedicated with
methylprednisolone. Dermatology 2002; 204(4): 365-7.
13. Murr D, Bocquet H, Lelouet H, et al. Adverse cutaneous reaction to celecoxib:
6 cases. Ann Dermatol Venereol 2003; 130(5): 519-21.
14. Kanny G, Marie B, Hoen B, et al. Delayed adverse reaction to sodium ioxaglic
acid meglumine. Eur J Dermatol 2001; 11: 134-7.
15. Bocquet H, Bagot M, Roujeau JC, Drug induced pseudolymphoma and drug
hypersensitivity syndrome (Drug rash with eosinophilia and systemic
symptoms-DRESS). Semin Cutan Med Surg 1996; 15: 250-7.
16. Ahearn GS, Selim MA, Tapson VF. Severe erythroderma as a complication of
continuous epoprostenol therapy. Chest 2002; 122(1): 378-80.
17. Generalized pustular and erythrodermic psoriasis associated with bupropion
treatment. Br J Dermatol 2002; 146(6): 1061-3.
18. Borras-Blasco J, Navarro-Ruiz A, Navarro-Blasco F, et al. Erythrodermia induced
by omeprazole. Int J Clin Pharmacol Ther 2001; 39(5): 219-23.
19. Cockayne SE, Glet RJ, Gawkrodger DJ, et al. Severe erythrodermic reactions
to the proton pump inhibitors omeprazole and lansoprazole. Br J Dermatol
1999; 141: 173-5.
20. Scrivener Y, Jeandidier N, Asch PH, et al. Erythroderma induced by
hypercalcitoninemia: two cases. Ann Dermatol Venereol 2002; 129(2): 221-4.
21. Cuxart M, Just M, Sans R, et al. Generalized exfoliative dermatitis caused by
erythropoietin. Med Clin (Barc) 2000; 115(4): 158.
22. Ghura HS, Carmichael AJ, Bairstow D, et al. Fatal erythroderma associated
with pentostatin. BMJ 1999; 319(7209): 549.
23. Abajo P, Feal C, Sanz-Sanchez T, et al. Eczematous erythroderma induced by
cyanamide. Contact Dermatitis 1999; 40(3): 160-1.
24. Rietsema WJ. Fever, erythroderma, abdominal pain, and renal failure following
initiation of indinavir therapy. Clin Infect Dis 1997; 25(5): 1268-9.
25. Rai R. Mukhi SV, Srinivas CR. Exfoliative dermatitis due to ticlopidine. Indian
J Derm 2002; 47(3): 195.
26. Hunziker T, Kunzi UP, Braunschweig S, et al. Comprehensive hospital drug
monitoring: adverse skin reaction, a 20 year survey. Allergy 1997; 52: 388-93.

106

Recent Advances in Dermatology

27. Bielary L, Yancey KB, Young NS, et al. Cutaneous manifestations of serum
sickness in patients receiving anti-thrombocyte globulin. J Am Acad Dermatol
1985; 13: 411-7.
28. Mazzeo L, Ricciardi L, Fazio MC, et al. Severe urticaria due to recombinant
inteferon beta-la. Br J Dermatol, 2003; 148(1): 172.
29. Broun DL, Login IS, Barish L, et al. An urticarial IgE-mediated reaction to
interferonb-ib, Neurology 2001; 56: 1416-7.
30. Gomez CM, Higuero NC, Moral de Gregorio A, et al. Urticaria-angioedema
by deflazacort. Allergy 2002; 57(4): 370-1.
31. Dernandez-Rivas M, Gonzalez Mancebo E. Urticaria to carisoprodol. Allergy
2002; 57(1): 55.
32. Schroter S, Damveld B, Marsch WC. Urticarial intolerance reaction to cetirizine.
Clin Exp Dermatol 2002; 27(3): 185-7.
33. Calista D, Scianchi S, Morri M, Urticaria induced by cetirizine. Br J Dermatol
2001; 144: 196.
34. Pollock B, Wilkinson SM, MacDonald H. Chronic urticaria associated with
intra-articular methylprednisolone. Br J Dermatol 2001; 144: 1228-30.
35. Sanchez Borges M, Capriles-Hulett A, Caballero-Fonseca F, et al. Tolerability
to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions.
Ann Allergy Asthma Immunol 2001; 87(3): 201-4.
36. Szolar-Platzer C, Aberer W, Kranke B. Delayed type skin reaction to the heparin
alternative danaparoid. J Am Acad Dermatol 2000; 43(5): 920-2.
37. Fernandez de Corres L, Leanizbarrutia I, Munoz D. Eczematous drug reaction
from phenobarbitone. Contact Dermatitis 1984; 11(5): 319.
38. Michel M, Dompmartin A, Szczurko C, et al. Eczematous-like drug eruption
induced by synergistins. Contact Dermatitis 1996; 34(2): 86-7.
39. McKenna KE. Eczematous reaction to hepatitis B vaccine. Contact Dermatitis
1999; 40(3): 158-9.
40. Carlton DW, Hagan LL. Anthax vaccine as a cause of vhronic eczematous
dermatitis. Ann Allergy Asthmsa Immunol 2001; 86: 79.
41. Selvaag E. Clinical drug photosensitivity: retrospective analysis of reports to
the Norwegian adverse reaction committee from years 1970-1994.
Photodermatol Photoimmunol Photomed 1997; 13: 21-3.
42. Nagire E, Perez-Ferriols A, Sanchez-Motilla JM, et al. Photosensitivity associated
with treatment with triflusal. J Eur Acad Dermatol Venereol 2000; 14(3): 21921.
43. Bosca F, Cuquerella MC, Marin ML, et al. Photochemistry of 2-hydroxy-4trifluoromethylbenzoic acid, major metabolite of the photosensitizing platelet
antiaggregant drug triflusal. Photochem Photobiol 2001; 73(5): 463-8.
44. Lee AY, Joo HJ, Chey WY, Kim YG. Photopatch testing in seven cases of
photosensitive drug eruptions. Ann Pharmacother 2001; 35(12): 1584-7.
45. Stryjek-Kaminska D, Ochsendorf F, Roder C, et al. Photoallergic skin reaction
to ribavirin. Am J Gastroenterol 1999; 94(6): 1686-8.
46. Treudler R, Husak R, Raiova M, et al. Efavirenz induced photoallergic dermatitis
in HIV. AIDS 2001; 15: 1085-6.
47. Willey A, Glusac EJ, Bolognia JL. Photoeruption in a patient treated with
capecitabine (Xeloda) for metastatic breast cancer. J Am Acad Dermatol 2002;
47(3): 453.
48. Kaur C, Thami GP. Flutamide-induced photosensitivity: is it a forme fruste of
lupus? Br J Dermatol 2003; 148(3): 603-4.

Cutaneous Adverse Drug Reactions to Systemic Drugs

107

49. Oliveira HS, Goncalo M, Figueiredo AC. Photosensitivity to lomefloxacin. A


clinical and photobiological study. Photodermatol Photoimmunol Photomed
2000; 16(3): 116-20.
50. Alvarez-Fernandez JG, Castano-Suarez E, Cornejo-Navarro P, et al.
Photosensitivity induced by oral itraconazole. J Eur Acad Dermatol Venereol
2000; 14(6): 501-3.
51. Vilaplana J, Botey E, Lecha M, et al. Photosensitivity induced by paroxetine.
Contact Dermatitis 2002; 47(2): 118-9.
52. Holme SA, Pearse AD, Anstey AV. Chronic actinic dermatitis secondary to
simvastatin. Photodermatol Photoimmunol Photomed 2002; 18(6): 313-4.
53. Dogra S, Kanwar AJ, Clopidogrel bisulphate-induced photosensitive lichenoid
eruption: first report. Br J Dermatol 2003; 148(3): 609-10.
54. Metayer I, Balguerie X, Courville P, et al. Photodermatosis induced by
hydroxychloroquine: 4 cases. Ann Dermatol Venereol. 2001; 128(6-7): 729-31.
55. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic
epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.
Arch Dermatol 1993; 129: 92-6.
56. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Eng J
Med 1994; 331: 1272-85.
57. Imamura S, Horio T, Yanase K, et al. Erythema multiforme. Pathomechanism
of papular erythema and target lesion. J Dermatol 1992; 19: 524.
58. Correia O, delgado L, Ramus JP, et al. Cutaneous T-cell recruitment in toxic
epidermal necolysis: further evidence of CD8 + lymphocyte inolvement. Arch
Dermatol 1993; 129: 466-8.
59. Paquet P, Pierard GE. Soluble fractions of tumour necrosis factor-a, interleukin6 and their receptors in toxic epidermal necrolysis. Arch Dermatol 1998; 130:
605-8.
60. Vivard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by
blockage of CD95 with human intravenous immunoglobulin. Science 1998;
282: 490-3.
61. Revuz JE, Roujeau JC. Advances in toxic epidermal necrolysis. Sem Cut Med
Surg 1996; 15: 258-66.
62. Ludwig C, Brinkmeier T, Frosch PJ. Exudative erythema multiforme with
transition to a toxic epidermal necolysis after taking aceclofenac (Beofenac).
Dtsch Med Wochenschr 2003; 128(10): 487-90.
63. Nettis E, Giordano D, Pierluigi T, et al. Erythema multiforme-like rash in a
patient sensitive to ofloxacin. Acta Derm Venereol 2002; 82(5): 395-6.
64. Sachs B, Renn C, al Masaoudi T, et al. Fenoterol-induced erythema exudativum
multiforme-like exanthem: demonstration of drug-specific lymphocyte reactivity
in vivo and in vitro. Acta Derm Venereol 2001; 81(5): 368-9.
65. Carrillo-Jimenez R, Zogby M, Treadwell TL. Erythema multiforme associated
with bupropion use. Arch Intern Med 2001; 161(12): 1556.
66. Lineberry TW, Peters GE Jr, Bostwick JM. Bupropion-induced erythema
multiforme. Mayo Clin Proc 2001; 76(6): 664-6.
67. Thomson LE, Allman KC. Erythema multiforme reaction to sestamibi. J Nucl
Med 2001; 42(3): 534.
68. Padial MA, Barranco P, Lopez-Serrano C. Erythema multiforme to vancomycin.
Allergy 2000; 55(12): 1201.
69. Mori T, Sato N, Watanabe R, et al. Erythema esudativum multiforme induced
by granyulocyte colony-stimulating factor in an allogeneic peripheral blood
stem cell donor. Bone Marrow Transplant 2000; 26(2): 239-40.

108

Recent Advances in Dermatology

70. Koch P, Bahmer FA. Erythema-multiforme-like, urticarial papular and plaque


eruptions from bufexamac: report of 4 cases. Contact Dermatitis 1994; 31(2):
97-101.
71. Horiuchi Y. Erythema multiforme caused by the H2-blocker, roxatidine. J
Dermatol 2000; 27(5): 352-3.
72. Chen W, Hsieh FS. Dimorphic exanthema manifested as reticular
maculopapular exanthema and erythema multiforme major associated with
pyrazolon derivatives. Eur J Dermatol 2002 12(5): 488-90.
73. Ernst EJ, Egge JA, Celecoxib-induced erythema multiforme with glyburde
cross-reactivity, Pharmacotherapy 2002. 22(5): 637-40.
74. Lo SK, Yip D, Leslie M, Harper P. 5-fluorouracil-induced erythema multiforme.
Int J Clin Pract 1999; 53(3): 219-21.
75. Liberopoulos EN, Liamis GL, Elisaf MS. Possible cefotaxime-induced StevensJohnson Syndrome. Ann Pharmacother 2003; 37(6):812-4.
76. Brett AS, Phillip D, Lynn AW. Intravenous immunoglobulin therapy for StevensJohnson Syndrome. South Med J 2001; 94: 342-3.
77. Lin CC, Wu JC, Huang DF, Et al, Ranitidine related stevens-Johnson Syndrome
in a patient with severe liver disease: a report of 2 cases. J Gastroenterol
Hepatol 2001; 16: 481-3.
78. Grill S, Hermolin R-H. Case report of a Stevens-Johnson type reaction to
celocoxib. Can J hosp Pharm 2001; 54: 146.
79. Hani N, Casper C, Groth W, et al. Stevens-Johnson Syndrome to methotrexate
histologically simulating acute graft vs host disease. Eu J Dermatol 2000; 10:
548-50.
80. Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, et al. Euro SCAR Study Group.
Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal
necrolysis. AIDS 2001; 15(14): 1843-8.
81. Dodi F, Alessandrini A, Camera M. et al. Stevens-Hohnson syndrome in HIV
patients treated with nevirapine: two case reports. AIDS 2002; 16(8): 1197-8.
82. Vidal D, Puig L, Sureda A, et al. STI 571-induced Stevens-Johnson Syndrome.
Br J Haematol 2002; 119(1): 274-5.
83. Hsiao LT, Chung HM, Lin JT, et al. Stevens-Hohnson syndrome after treatment
with ST1571: a case report. BrJ Haematol 2002; 117(3): 620-2.
84. Cafacco A, Rao F, Mucciarone L. Stevens-Johnson syndrome presumably
induced by bromhexine. A case report. Minerva Stomatol 2002; 51(4): 151-6.
85. Leckie MJ, Rees RG. Stevgens-Johnson syndrome in association with
hydroxychloroquine treatment for rheumatoid arthritis. Rheumatology (Oxford)
2002; 41(4): 473-4.
86. Krathen RA, Iyengar V, Page RN, et al. Stevens-Hohnson syndrome associated
witgh leflunomide. J Am Acad Dermatol 2002; 46:e9 (Published online March
4, 2002).
87. Lowndes S, Darby A, Mead G, et al Stevens-Honshon syndrome after treatment
with rituximab Ann Oncol 2002; 13(12): 1948-50.
88. Sawamura D, Umeki K. Stevens-Johnson syndrome associated with bezafibrate.
Acta Derm Venereol 2000; 80(6): 457.
89. Lale Atahan I, Ozyar E, Sahin S. et al. Two cases of Stevens-Johnson syndrome:
toxic epidermal necrolysis possibly induced by amifostine during radiotherapy.
Br. J Dermatol. 2000; 143(5): 1072-3.
90. Demiral AN, Yerebakan O, Simsir V Amifostine-induced toxic epidermal
necrolysis during radiotherapy: a case report. Jpn J Clin Oncol 2002: 32(11):
477-9.

Cutaneous Adverse Drug Reactions to Systemic Drugs

109

91. Ozkan A, Apak H, Celkan T, et al, Toxic Eipdermal Necrolysis after the use
of high-dose cytosine arabinoside. Pediatr Dermatol 2001; 18: 38-40.
92. Teraki Y, Moriya N, Shiohara T. drug induced expression of intracellular
adhesion molecule 1 on lesional keratinocytes in fixed drug eruption. Am J
Pathol 1994; 145: 550-60.
93. Alanko K, Kanerva L, Mohella=Toloahti B. Nonpigmented fixed drug eruption
from pseudoephidrine. J Am Acad Dermatol 1996; 35:647-8.
94. Srkar R, Kaur C, Kanwar AJ. Extensive fixed drug eruptin to nimesulide with
cross-sensitivity to sulfonamides in a child Pediatr Dermatol 2002; 19(6): 5534.
95. Kaur C, Sarkar R, Kanwar AJ. Fixed drug eruption to rofecoxib with crossrectivity to sulfonamides. Dermatology 2001; 203(4): 351.
96. Borras-Blasco J, Navarro-Ruiz A, Gutierrez-Casbas A, et al. Multiple fixeddrug eruption and diarrhea with ticlopidine. Ann Pharmacother 2002; 36(2):3445.
97. Martin Garcia C, Carmena R, Garcia R, et al. Fixed drug eruption from
ticlopidine with positive lesional patch test. Contact Dermatitis 2001 44: 40-1.
98. Hsiao CJ, Lee JY, Wrong TW, et al. Extensive fixed drug eruption due to
lamotrigine. Br J. Dermatol 2001; 144(6): 1289-91.
99. Rodriguez-Morales A, Llamazares AA, Benito RP, et al. Fixed drug eruption
from quinolones with a positive lesional patch test to ciprofloxacin. Contact
Dermatitis 2001; 44(4):255.
100. Baykal C, Erkek E, Tutar E, et al. Cutaneous fixed drug eruption to patlitaxel;
a case report. Eur J Gynaecol Oncol 2000; 21(2):190-1.
101. Heikkila H, Kariniemi AL, Stubb S. Fixed drug eruption due to
phenylpropanolamine ydrochloride. Br. J Dermatol 2000; 142(4): 845-7.
102. Sangen Y, Kawada A, Asai M, et al. Fixed drug eruption induced by tosufloxacin
tosilate. Contact Dermatitis. 2000; 42)5): 285.
103. Palungwachira P. Fixed drug eruption due to atenolol: a casse report. J. Med
Assoc Thai 1999; 82(11): 1158-61.
104. Sempere Verdu E, Sorando Serra R, Bayon Rueda A, The fixed drug eruption
due to metamizole. Aten Primaria 1999; 24(5): 304-5.
105. Bernand S, Scheidagger EP, Dummer R, et al. Mutifocal fixed drug eruption
to paracetamol, tropisetron and ondansetron induced by interleukin 2.
Dermatology 2000; 201:194-50.
106. Kranke B, Kern T. Multilocalized fixed drug eruption to the antihistaminic
cetirizine. J. Allergy Clin Immunol 2000; 106: 988.
107. Choonhakarn C. Non-pigmenting fixed drug eruptin: a new case due to
eperisone hydrochloride. Br J Dermatol 2001; 144(6) 1288-9.
108. Sener O, Caliskaner Z, Yazicioglu K, et al. Nonpigmenting solitary fixed drug
eruption after skin testing and intra-articular injection of triamcinolone
acetonide. Ann Allergy Asthma Immunol 2001; 86(3) 335-6.
109. Goel A, Balachandran C. Bullous necrotizing fixed drug eruption with hepatitis
due to rifampicin. Indian J. Lepr. 2001; 73 (2): 159-62.
110. Grcia-Doval I, Roson E, Feral C., et al. Generalized bullous fixed drug eruption
after influenza vaccination, simulating bullous permphigoid. Acta Derm
Venereol 2001; 81(6): 450-1.
111. Ko R, Tanaka M, Murata T. et al. Papular fixed drug eruption mimicking
folliculitis due to acetominophen. Clin Exp Dermatol 2000; 25(1): 96-7.
112. Chu CY, Yang CH, Yang CY, et al. Fixed erythrodysaesthesia plaque due to
intravenous injection of docetaxel. Br. J. Dermatol 2000; 142(4) 808-11.

110

Recent Advances in Dermatology

113. Hui YF, Cortes JE. Palmar-plantar erythrody sensthesia syndrome associated
with liposomal daunorubicin. Pharmacotherapy 2000; 20:1221-3.
114. Canonne Courivaud D, Carpentier O, Dejobert Y, et al. Lichenoid drug reaction
to leflunomide. Ann Dermatol Venereol 2003; 130(4): 435-7.
115. Guijarro B, Lopez A. Lichenoid reaction caused by Clopidogrel, a new antiplatelet drug. Med Oral 2003; 8(1): 33-7.
116. Lim DS, Muir J. Oral lichenoid reaction to imatinib (STI 571, Gleevec).
Dermatology 2002; 205(2): 169-71.
117. Goldman BD. Lichenoid drug reaction due to sildenafil, Cutis 2000; 65(5):2823.
118. Buyukgebiz B, Arslan N, Ozturk Y, et al. Drug reaction to ursodeoxycholic
acid: lichenoid drug eruption in an infant using ursodeoxycholic acid for
neonatal hepatitis. Pediatr Gastroenterol Nutr 2002; 35(3): 384-6.
119. Viallard AM, Lavenue A, Balme B, et al. Lichenoid cutaneous drug reaction
in injection sites of granulocyte colony-stimulating factor (Filgrastim).
Dermatology. 1999; 198(3): 301-3.
120. Hamanaka H, Mizutani H, Shimizu M. Sparfloxacin-induced photosensitivity
and the occurrence of a lichenoid tissue reaction after prolonged exposure. J.
Am Acad Dermatol 1998: 38 (6 Pt 1): 945-9.
121. Swale VJ, McGregor JM. Amlodipine associated Lichen Planus. Br. J. Dermatol
2001; 144: 920-1.
122. Valance A, Lebrum-Vignes B, Descamps V, Icodextrin cutaneous
hypersensitivity: report of 3 psoriasiform cases. Arch Dermatol 2001; 137(3):
309-10.
123. Woikenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous
adverse drug reactions including Stevens-Johnson syndrome and toxic
epidermal necrolysis. Contact Dermatitis 1996; 35: 234-6.
124. Thedenat B, Loche F, Albes B, et al. Acute generalized exanthematous pustulosis
with photodistribution pattern induced by sertraline. Dermatology 2001; 203(1):
87-8.
125. Petavy-Catala C, Martin L, Fontes V, et al. Hydrochlorothiazide-induced acute
generalized exanthematous pustulosis. Acta Derm Venereol 2001; 81(3): 209.
126. Brouard MC, Prins C, Mach-Pascual S et al. Acute generalized exanthematous
pustulosis associated with ST1571 in a patient with chronic myeloid leukemia.
Dermatology 2001; 203(1):57-9.
127. Sasaki K, Yamamoto T, Kishi M, et al. Acute exanthematous pustular drug
eruption induced by mexiletine. Eur J Dermatol 2001; 11(5):469-71.
128. Mussot-Chia C, Flechet ML, Napolitano M. et al. Methylprednisolone induced
acute generalized exanthematous pustulosis Ann Dermatol Venereol 2001; 128
(3 Pt 1): 241-3.
129. Chu CY, Wu J, Jean SS, et al. Acute generalized exanthematous pustulosis due
to teicoplanin. Dermatology 2001; 202(2): 141-5.
130. Machet L, Martin L, Machet MC et al. Acute generalized exanthematous
pustulosis induced by dextropropoxyphene and confirmed by patch testing.
Acta Derm Venereol 2000; 80(3):224-5.
131. Schwab RA, Vogel PS, Warschaw KE. Clindamycin-induced acute generalized
exanthematous pustulosis. Cutis 2000; 65(6): 391-3.
132. Anliker MD, Wuthrich B. Acute generalized exanthematous pustulosis due to
sulfamethoxazol with positive lymphocyte transformation test (LTT) J Investig
Allergol Clin Immunol 2003; 13(1): 66-8.

Cutaneous Adverse Drug Reactions to Systemic Drugs

111

133. Scheinfeld N, Wesson K, Perry P. Acute generalized exanthematous pustulosis


resembling toxic epidermal necrolysis caused by famotidine. Acta Derm
Venereol 2003; 83(1):76-7.
134. Galvao C, Criado RF, Criado PR, Acute generalized exanthematous pustulosis
induced by ingestion of bamifylline J Eur Acad Dermatol Venereol 2002; 16(6):
634-7.
135. Chiu A, Kohler S, McGuire J, et al. Cytarabine-induced acute generalized
exanthematous pustulosis. J Am Acad Dermatol 2002; 47(4): 633-5.
136. Lun K, Harley W. Allopurinol-induced pustular eruption: an unusually mild
case. Australas J Dermatol 2002; 43(2): 140-3.
137. Moorant C, Devis T, Alcaraz I, et al. Acutre generalized exanthematous
pustulosis due to meladinine with positive patch tests. Ann Dermatol venereal
2002; 129(2):234-5.
138. Al-Hoqail Ia, Crawford RI. Acute generalized exanthematous pustulosis
induced by icodextrin. Br J Dermatol 2001; 145(6): 1026-7.
139. Noce R, Paredes BE, Pichler WJ, et al. Acute generalized exanthematous
pustulosis (AGEP in a patient with furosemide. Am J Med Sci 2000; 320: 3313.
140. Merkel PA. Drug induced vasculitis. Rheum Dis Clin North Am 2001; 27:84962.
141. Calabrese LH, Michel Ba, Bloch DA, et al, the American college of rheumatology
1990 criteria for the classification of hypersensitivity vasculitis. Arhritis Rheum
1990; 33:1108-13.
142. Callen JP. Cutaneous vasculitis: relationship to systemic disease and therapy.
Curr Probl Dermatol 1993 5: 45.
143. Jennette JC. Vasculitis affecting the skin. Arch Dermatol 1944; 130: 899.
144. Wintroub BU, Stern R. Cutaneous drug reaction: pathogenesis and clinical
classification. J Am Acad Dermatol 1985 13: 167-79.
145. Dubost JJ, Souteyraud P, Sauvezie B. Drug induced vasculitis. Baillieres Clin
Rheumatol 1991; 119-38.
146. Brasil L, Kremer JM, Clarke JL, et al. Identification of an autoantibody to
vascular endothelial cell specific antigen in patients with systemic vasculitis.
Am J Med 1989; 87: 74-80.
147. Kaneko K, Igarashi J, Suzuki Y, et al. Carbamazepine induced thrombocytopenia
and leucopenia complicated by Henoch-Schonlein purpura symptoms. Eur J
Pediatr 1993; 52:769-70.
148. Davidson KA, Ringpfeil F, Lee JB. Ibuprofen-induced bullous leukocytoclastic
vasculitis. Cutis 2001; 67(4): 303-7.
149. Schneider F, Meziani F, Chartier C, et al. Fetal allergic vasculitis associated
with celecoxib. Lancet 2002; 359(9309): 852-3.
150. Green RL, Vayonis AG. Churg-Stauss syndrome after zafirlucast in two patients
not receiving systemic steroid treatment. Lancet 1999; 353:725-6.
151. Dellaripa PF, Wechsler ME, Roth ME. Recurrent panniculitis in a man with
asthma receiving treatment with leukotriene-modifying agents. Mayo Clin
proc 2000; 75(6): 643-5.
152. Kuechle MK, Stegemeir E, Maynard B, et al. Drug induced linear IgA bullous
dermatosis. Report of 6 cases and review of the literature. J Am Acad Dermatol
1994; 30: 187-92.
153. Konig C, Eickert A, Scharfelter-Kochanek K, et al. Linear IgA bullous dermatosis
induced by Atarvastatin J Am Acad Dermatol 2001; 44: 689-92.

112

Recent Advances in Dermatology

154. Patterson CR, Divies MG. Carbamazepine-induced pemphigus. Clin Exp


Dermatol 2003; 28(1):98-9.
155. Bayramgurler D, Ercin C, Apaydin R, et al. Indapamide-induced pemphigus
foliaceus. J. Dermatolog Treat 2001; 12(3): 175-7.
156. Anadolu RY, Birol A, Bostanci S, et al. A case of pemphigus vulgaris possibly
triggered by quinolones. J Eur Acad Dermatol Venereol 2002; 16(2): 152-3.
157. Parodi A, Cozzani E, Milesi G. et al. Fosinopril as a possible pemphigusinducing drug. Dermatology 2002; 204(2):139-41.
158. Marinho RT, Johnson NW, Fetela NM, et al. Oropharyngeal pemphigus in a
patient with chronic hepatitis C during interferon alpha-2a therapy. Eur J
Gastroenterol Hepatol 2001; 13(7): 869-72.
159. Gooptu C, Littlewood TJ, Frith P, et al. Para-neoplastic pemphigus: An
association with fludarabine? Br J Dermatol 2001; 144: 1255-61.
160. Ogata K, Nakajima H, Ikeda M, et al. Drug induced pemphigus foliaceus with
features of pemphigus vulgaris Br. J Dermatol 2001; 144: 421-2.
161. Ong CS, Cook N, Lee S. Drug related pemphigus and angiotensin converting
enzyme inhibitors. Australas J Dermatol 2000; 41: 242-6.
162. Cozzani E, Cacciapuoti M, Parodi A, et al. Pemphigus following tetanus and
diphtheria vaccination. Br. J. Dermatol. 2002; 147(1): 188-9.
163. Zachariae CO. Gabapentin-induced bullous pemphigoid. Acta Derm Venereol
2002; 82(5): 396-7.
164. Modeste AB, Cordel N, Courville P. et al. Bullous pemphigoid induced by
spironolactone. Ann Dermatol Venereol 2002; 129 (1 Pt 1): 56-8.
165. Czechowicz RT, Reid CM, Warren LJ et al. Bullous pemphigoid induced by
cephalexin. Australas J. Dermatol 2001; 42(2): 132-5.
166. Stoebner PE, Michot C, Ligeron C, et al. Simvastatin-induced lichen planus
pemphigoides. Ann. Dermatol Venereol 2003; 130(2 Pt 1): 187-90.
167. Burgess MJA, Fivenson DP. Generalisation of cicatricial pemphigoid during
azathioprine therapy, Arch Dermatol 2000; 136: 1274.
168. Mantoux F, Bahadoran P, Perrin C, et al. Flutamide-induced late cutaneous
pseudoporphyria. Ann Dermatol Venereol 1999; 126(2): 150-2.
169. Magro CM, Crowson AN. Pseudoporphyria associated with Relafen therapy.
J Cutan pathol 1999; 26(1): 42-7.
170. Krischer J, Scolari F, Kondo-Oestreicher M. et al. Pseudoporphyria induced
byt nabumetone. J. Am Acad Dermatol 1999; 40(3): 492-3.
171. Ho AY, Deacon A, Osborne G, et al. Precipitation of porphyria cutanea tarda
by imatinib mesylate? Br J Haematol 2003; 121(2):375.
172. Agarwal R, Peters TJ, Coombes RC et al. Tamoxifen-related porphyria cutanea
tarda. Med Oncol 2002; 19(2) 121-3.
173. Kundu AK. Amiodarone-induced systemic lupus erythematosis. J Assoc
Physician India. 2003; 51: 216-7.
174. Carlson E, Rothfield N. Etanercept-induced lupus-like syndrome in a patient
with rheumatoid arthritis. Arthritis Rheum 2003; 48(4): 1165-6.
175. Favalli EG, Sinigaglia L, Varenna M. Drug-induced et al. lupus following
treatment with infliximab in rheumatoid arthritis. Lupus 2002; 11(11):753-5.
176. Debandt M, Vittecoq O, Descamps V, et al. Anti-TNF-alpha-induced systemic
lupus syndrome. Clin Rheumatol 2003; 22(1): 56-61.
177. Yamada A, Sato K, Hara M, et al. Propylthiouracil-induced lupus-like syndrome
developing in a Graves patient with a sibling with systemic lupus
erythematosus. Intern Med 2002; 41 (12): 1204-8.

Cutaneous Adverse Drug Reactions to Systemic Drugs

113

178. Spiera RF, Berman RS, Werner AJ, et al. Ticlopidine-induced lupus: a report
of 4 cases. Arch Intern Med. 2002, 162 (19): 2240-3.
179. Bonsmann G, Schuller M, Luger Ta, et al. Terbinafin induced sub-acute lupus
erythematosus. J Am Acad Dermatol 2001; 44: 925-31.
180. Kupfer I, Balguerie X, Courville P, et al. Scleroderma-like cutaneous lesions
induced by paclitaxel: a case study. J Am Acad Dermatol 2003; 48(2): 279-81.
181. De Angelis R, Bugatti L, Cerioni A, et al. Diffuse Scleroderma occurring after
the use of paclitaxel for ovarian cancer. Clin Rheumatol 2003; 22(1): 49-52.
182. Lauchli S, Trueb RM, Fehr M. et al. Scleroderma-like drug reaction to paclitaxel
(Taxol). Br. J Dermatol 2002; 147(3): 619-21.
183. Fox PA, Boang FC, Hawkins DA, et al. Acute porphyria following
commoncement of indinavir. AIDS 1999; 13: 622-3.
184. Teira R, Zubero Z, Munoz J, et al. Stevens-Johnson syndrome caused by
indinavir. Scand J Infect Cis 1998: 30: 634-5.
185. Fung HB, Pecini RA, Brown ST, et al Indinavir associated maculopapular
eruption. J Clin Immunol 1991; 11: 52-64.
186. Toma E, Therrien R. Gynecomastia during antiretroviral therapy in HIV
infection. AIDS 1998. 12:681-2.
187. Herry I. Hypertrophy of breast in a patient treated with indinavir. Clin Infect
Dis 1997; 25: 937-8.
188. Bouscarat F, Prevot MH, Matheron S, Alopecia associated with indinavir
therapy. N. Eng J Med 1999; 8: 618.
189. Monforte A, Testa L, Gianotto M, et al. Indinavir related alopecia. AIDS 1998;
338: 1776-7.
190. Bouscant F, Bouchard C. Paronychia and pyogenic granuloma of the great toe
in patients treated with indinavir. N Eng J Med 1998; 338: 1776-7.
191. Hagerty SL, Asher DP. Spontaneous bleeding associated with the use of the
protease inhibitor ritonavir in a hemophiliac patient with HIV infection. Pediatr
Infect Dis 1998: 17: 929-30.
192. Vicant MA, Medina MM, Gonzalez-Ensenat A. Rash as a side effect of nelfinavir
in children. AIDS 2000; 114: 335-6.
193. Demoly P, Messad D, Trylesinski A, et al. Nelfinavir induced urticaria and
successful desensitization. J Allergy Clin Immunol 1998; 102: 875-6.
194. Smith KJ, Yeager J, Skelton H. Fixed drug eruption to HIV-I protease inhibitor.
Cutis 2000; 66: 29-32.
195. Chopra K, Tyring SK. Current antiretroviral therapy in the treatment of HIV
infection Semin Cutan Med Surg 1997; 16: 224-34.
196. Barner A, Myers M. Nevirapine and rashes. Lancent 1998; 351:1133.
197. Warren KJ, Boxwell DE, Kim NY et al Nevirapine associated Stevens-Johnson
syndrome. Lancet 1998; 351: 567.
198. Bourezane Y, Salard D, Hoen B, et al. DRESS (drug rash with eosinophilia and
systemic symptom) syndrme associated with nevirapine therapy. Clin Infect
Dis 1998; 27: 1321-2.
199. Callot V, Roujeau JC, Bagot M, et al. Drug induced pseudo lymphoma and
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

Recent Advances in Dermatology

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.

The Scleroderma Disorders: An Update

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

Recent Advances in Dermatology


Table 7.1: Classification of localized
scleroderma (morphea) (proposed)2

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

Table 7.2: Classification of systemic sclerosis3

Systemic
Sclerosis
(SSc)

Limited cutaneous (lcSSc)

Diffuse cutaneous (dcSSc)

Related forms
Prescleroderma
Overlap syndrome
Environment-induced scleroderma
Systemic sclerosis sine scleroderma

Systemic sclerosis sine scleroderma, a rare form of disorder, shows


features of typical vascular and visceral involvement without having
any skin sclerosis. Overlap syndromes represent the disease where
systemic sclerosis coexists with features of other rheumatic disorders.
Prescleroderma denotes the subjects with definite Raynauds phenomenon (RP) who also shows positivity to one of the hallmark autoantibodies of SSc, like anticentromere, antitopoisomerese I or anti-RNA
polymerase I or II antibodies.
Systemic sclerosis is usually subdivided into limited (lcSSc) and diffuse
cutaneous (dcSSc) subsets. These two subsets are basically differentiated

The Scleroderma Disorders: An Update

117

Table 7.3: Two subsets of SSc: Salient features


Type

Limited (lcSSc)

Diffuse (dcSSc)

Years

Less than 1 year

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

1. Interval between Raynauds


phenomenon and appearance
of skin changes

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

Recent Advances in Dermatology

Thus, it is expected that in future the classification system would be


increasingly supported by genetic and immunological markers, which
may give vital clue to identify the risk of serious complications like
pulmonary hypertension, lung fibrosis, and renal failure, ultimately
predicting the prognosis of the disorders.11
PATHOGENESIS
The complex and yet incompletely understood pathogenesis of systemic
sclerosis depends on three basic underlying factors: (a) vascular damage,
(b) immune activation, and (c) increased synthesis of extracellular matrix
with deposition of excessive amounts of structurally normal collagen.
These patho-mechanisms result from cell-cell, cell-cytokine and cellmatrix interactions. The heterogeneous nature of the clinical presentations
of the disorder probably represents the variable contributions from each
of these pathogenic factors.12
Current hypotheses regarding the pathogenesis of scleroderma
mainly pay attention to the interplay between early immunological
events and vascular changes, yielding the generation of a population of
activated fibrogenic fibroblasts, considered to be the effector cell in the
disease.13,14 Recent investigations have solved a much hotly debated
egg before? hen before? mystery regarding systemic sclerosis
(which one is earlier? vascular changes or fibrosis?) that vascular changes
precede fibrosis in its pathogenesis. The observations which have proved
this fact include: (1) markers of vascular damage like endothelin-1,15
von Willebrand-factor antigen etc. appear early in the disease process,
(2) Raynauds phenomenon frequently starts early, (3) photoplethysmographic (PPG) studies in systemic sclerosis16 have shown early
vascular changes, and (4) digital arteriography17 has shown narrowing
of digital arteries in systemic sclerosis.
Vascular Changes
Vascular and endothelial changes, predominantly affecting vascular tone,
as discussed above, appear to precede other features of scleroderma.
Endothelins, nitric oxide and superoxide anions are the most significant
inflammatory mediators whose derangements are currently thought to
be associated with altered vascular tone in scleroderma.18 Endothelin
(ET), the most potent vasoconstrictor known, contributes to both vascular
dysfunction and the development of the fibrotic lesion in systemic
sclerosis.19 The basal secretion of ET-1 from the endothelial cells may
provide an important early link between endothelial cell damage and
fibroblast activation.12 Levels of circulating ET-1 have been found to be

The Scleroderma Disorders: An Update

119

significantly raised in both lcSSc having primarily vascular involvement


as well as in dcSSc having widespread fibrosis as the predominant
feature.20 Nitric oxide (NO) counteracts the vasoconstrictive action of
ET-1 in normal blood vessels whereas an alteration in the relative amount
of these two mediators has been postulated to play a pathogenic role in
scleroderma.12 Superoxide anions liberated from the endothelium may
damage the endothelium by neutralizing NO and oxidizing circulating
low-density lipoproteins (LDL). Oxidized LDL may be cytotoxic for
endothelial cells.21 Studies have documented that LDLs in patients with
scleroderma are much more susceptible to oxidations (perhaps via free
radical attack) than those from patients with primary Raynauds
phenomenon or other rheumatic diseases.22
The scleroderma patients sera possess certain factors which are
cytotoxic to endothelial cells. Twenty to thirty percent of scleroderma
patients have circulating anti-endothelial cell antibodies which, however,
may be found in the sera of patients suffering from other rheumatic
diseases. These antibodies can upregulate the expression of adhesion
molecules on endothelial cells and induce apoptosis of these cells.23 The
vascular cytotoxicity in some scleroderma patients has been documented
to be attributed by tumor necrosis factor-alpha and -beta, proteases or
complement membrane attack complex (C 5b-C9).24,25
Scleroderma patients have increased endothelial cell surface expression
of adhesion molecules like ICAM-1 and E-selectin.26 Elevated levels of
soluble VCAM-1, E-selectin and ICAM-1 have been shown in certain
group of scleroderma patients,27 especially in scleroderma renal-crisis
but not in scleroderma-associated pulmonary disease.12 One study has
depicted a correlation between changes in soluble VCAM-1 and soluble
E-selectin and clinical deterioration or improvement of systemic
sclerosis.28
Immunologic Activity
The continuing activation of endothelial cells, leading to upregulation of
adhesion molecules, leukocyte adhesion and leukocyte leaking out of
the vasculature plays an underlying factor in the pathogenesis of systemic
sclerosis.12 The expression of ELAM-1 on endothelial cells correlates
with the degree of mononuclear cell infiltration in the early inflammatory
lesion of scleroderma.28 In scleroderma patients, subpopulations of
lymphocytes, namely activated/cytotoxic/inducer T-cells, natural killer
cells and some helper T-cells acquire a significantly increased ability to
adhere to endothelium.29 The mononuclear cells in systemic sclerosis
patients which migrate into the extracellular matrix express differentiation
markers of activated T-cells including CD3, CD4, CD45, HLA-DR and

120

Recent Advances in Dermatology

LFA-1 (lymphocyte function associated antigen-1).30 The surface of these


cells also possesses subsets of integrin molecules including those of beta
1 and beta 2 class, which facilitate binding to other cells including
fibroblasts and tissue components like types I and IV collagens,
fibronectin, and laminin.31
Circulating autoantibodies directed against a variety of antigens are
found in about 75 percent of systemic sclerosis patients which include
topoisomerase I (formerly called Scl-70) (15 to 20%), centromere antigens
(25 to 30 percent), fibrillin-1, and RNA I, II and III (20 percent).12 The
provocative stimulus for the production of these antibodies is yet
unknown. One hypothesis is that these autoantibodies are targeted against
those autoantigens who have been fragmented via reactive oxygen species
and specific metals such as copper or iron.32 Another theory has explained
that these antibodies are produced as a result of infection (e.g.,
cytomegalovirus) and via molecular mimicry, crossreact with a native
antigen.33 Autoantibodies interacting with fibroblasts may have some
potential pathogenic role in systemic sclerosis. One study has shown
significantly elevated levels of anti-fibroblast antibodies of IgG and IgMclass in systemic sclerosis, both limited and diffuse types.34
Interplay between a number of cytokines and growth factors seems
to contribute significantly to the pathogenesis of systemic sclerosis.
Increased levels of circulating IL-1, IL-2, IL-2R, IL-4, IL-8, IL-17, TNFalpha and interferon, and antibodies to IL-6 and IL-8 have been found
in patients with systemic sclerosis.35 The marked matrix stimulatory
properties of the transforming growth factors, particularly TGF-beta,
have implicated these proteins as potentially important mediators in
systemic sclerosis. Increased expression of endoglin, a non-activated
TGF beta receptor occurs in sclerodermatous skin and these levels increase
with the duration of the disease. Although high level of a particular
cytokine does not necessarily imply a causative role, the increased levels
of various cytokines support a cellular immune mechanism in systemic
sclerosis and an on-going expression of T-cells and their secreted
products.12
Increased Fibroblast Activity and Collagen Synthesis
The development of the fibroblast capable of excess matrix production
and deposition is the hallmark of systemic sclerosis. The scleroderma
fibroblasts have been clearly shown to be the effector cells which, as
activated fibroblasts, mediate the fibrogenic pathway. The theory put
forward to unify several of the different pathogenic events seen in
systemic sclerosis tells that the development of the activated fibroblast
places the initiating event in the vascular bed, leading to growth factor

The Scleroderma Disorders: An Update

121

and cytokine production with resulting fibroblast activation and


subsequent fibrosis. However, this cannot explain adequately the
abnormal phenotype of scleroderma fibroblast.12
The missing link between the systemic autoimmunity and fibrosis in
the pathogenesis of systemic scleroderma has been attempted to be
searched in a recent study.36 The net accumulation of extracellular matrix
depends on the balance between the synthesis and degradation of
extracellular matrix components, the latter process being regulated by
matrix metalloproteinases. Matrix metalloproteinase-1 (interstitial
collagenase-1) can initiate degradation of collagen types I-III, that are
major extracellular matrix constituents of affected skin of systemic
sclerosis. The hypothesis that systemic autoimmunity in systemic sclerosis
induces anti-matrix metalloproteinase-1 autoantibodies which inhibit
matrix metallo-proteinase-1 activity, resulting in collagen accumulation
has been proved by the following observations: (1) IgG anti-matrix
metalloproteinase-1 auto-antibody levels were significantly elevated in
sera of the patients with SSc but not with SLE or dermatomyositis, (2)
the same autoantibody levels were significantly high in dcSSc as
compared with those in lcSSc, (3) these autoantibody levels significantly
correlate with the extent of fibrosis in the skin, lung and renal blood
vessels in SSc. Thus the presence of anti-matrix metalloproteinase-1
autoantibody in SSc confirms the link between systemic autoimmunity
and fibrosis.36
ETIOLOGY
Although we had already deposited a lot of informations in our
knowledgebank regarding the pathogenesis of scleroderma, it is not
fully clear to us, till date, how these pathogenic pathways are initially
switched on. However, certain possible etiological and risk factors37
have been enumerated below. No single gene or environmental factor
is likely to be the sole contributory factor for this disorder.
Genetic Factors
Genetic factors clearly affect both disease susceptibility and patterns of
disease expression. The presence of antitopoisomerase antibodies have
been strongly linked with HLA haplotype DQ7, DR2 (DRB1 1602).38
Recently, the fibrillin 15 gene located on human chromosome 15q has
been found to be strongly linked to scleroderma.39 The beneficial effects
of angiotensin converting enzyme (ACE) inhibitors in scleroderma renal
disease have led to search the role of ACE in the pathogenesis of
scleroderma. An insertion/deletion polymorphism of the ACE gene has

122

Recent Advances in Dermatology

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

The Scleroderma Disorders: An Update

123

of vinyl chloride polymer but not in connection with any finished


product.37 Other contributing agents include epoxy resins, pesticides
and a number of organic solvents used in paints. Ingestion of contaminated rapeseed oil may lead to an epidemic of toxic oil syndrome, which
was characterized by acute myalgia, fever, neuropathy, sclerodermalike skin disease and pulmonary hypertension.46 Another clinically similar
syndrome called eosinophilia-myalgia syndrome with fascitis and dermal
induration has been found in individuals consuming the nutritional
supplement L-trytophan.47
Drugs
Some drugs, particularly bleomycin, have been implicated in the genesis
of scleroderma-like syndrome. Bleomycin may induce chromosomal break
which may lead to formation and release of unique autoantigens
responsible for development of scleroderma. The other drugs incriminated in causing scleroderma-like syndromes are pentazocine and
cocaine.37
Microchimerism
Normal women harbor viable immunologic stem cells of fetal origin for
long years following pregnancy. Women with scleroderma, who have
been pregnant, possess much greater number of fetal cells as compared
to those without scleroderma. Such persistent fetal cell may mount an
immune response against the mother or the maternal response to the
fetal cells may subsequently be directed against self leading to
autoimmunity. A graft-versus-host disease type of mechanism may
originate from the persistent fetal cells to induce sclerodermatous disease
process, since both disorders share many clinical features. In men with
scleroderma and women who have never been pregnant, their maternal
cells crossing the placenta and then carried by the fetus may play the
immunomodulatory role.48 A recent study has shown that in SSc patients,
cellular microchimerism is accounted for by a lage number of cells that
have the characteristics of T lymphocytes specific for maternal allogenic
antigens.49
Why Scleroderma Common in Female?
There exist two possible explanations for female predominance of
scleroderma: (1) IL-1, TNF, and IFN gamma have been shown to modulate
the expression of ICAM-1 by scleroderma fibroblasts, an effect enhanced
by the female sex hormone beta-estradiol,50 and (2) microchimerism as
discussed above.

124

Recent Advances in Dermatology

MANIFESTATIONS AND DIAGNOSIS


Skin involvement in the scleroderma-related disorders includes: sclerosis
or thickening of the skin, pruritus, calcinosis, edema, telangiectasia,
sclerodactyly, and digital ulcers and infection. Ultrasonography can
definitely determine skin thickness and durometer can assess skin
hardness.51
Among vascular manifestations of scleroderma, Raynauds
phenomenon has been classically viewed as reversible vasospasm; many
patients, however, develop structural changes in the vessels with
permanently impaired flow. Episodes of Raynauds phenomenon may
be prolonged and lead to digital ulcers or infarcts.51
Photoplethysmographic (PPG) studies16 in systemic sclerosis (lcSSc)
has demonstrated diminished digital flow in all the extremities
irrespective of clinical findings. Some digits even showed critical flow
(almost zero) without having any external sign of digital gangrene. This
is in contrast to PPG studies in SLE patients,52 where not all the extremitis
showed such diminshed digital flow and not a single digit had depicted
critical flow.
Organ involvement in scleroderma frequently affects the kidneys,
gastrointestinal tract and lungs. Severe and life-threatening renal disease
termed scleroderma renal-crisis which develops in approximately 10 to
15 percent of patients is manifested by: (1) the acute onset of renal
failure, (2) the sudden onset of moderate to marked hypertension (some
subject may remain normotensive), and (3) a urine sediment that usually
reveals only mild proteinuria with few cells or casts. Esophageal
hypomotility and incompetence of the lower esophageal sphincter
represent the earliest visceral manifestation described and remains the
most common source of gastrointestinal symptoms in scleroderma.
Symptoms usually arise from gastroesophageal reflux, stricture formation,
and abnormal motility. The two chief clinical presentations of lung
involvement are interstitial lung disease (also termed fibrosing alveolitis
or pulmonary fibrosis) and pulmonary vascular disease leading to
pulmonary hypertension.51
Diagnosis
The diagnosis of the scleroderma group of disorders depends mainly on
the presence of characteristic clinical features. As an example, localised
scleroderma and lcSSc can usually be diagnosed clinically. However,
there underly certain fallacies in the diagnosis: (a) morphea may
sometimes mimic tuberculoid leprosy lesions,7 (b) generalised morphea
may simulate dcSSc,4 or (c) early diagnosis of dcSSc can sometimes be

The Scleroderma Disorders: An Update

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

Recent Advances in Dermatology

present with more prominent arthritis than seen in systemic sclerosis


alone and may be associated with features of systemic lupus
erythematous.51 Antineutrophil cytoplasmic antibodies (ANCA) are found
to be not associated with systemic sclerosis.55
PROGNOSIS
The prognosis for patients with scleroderma depends on the extent of
skin involvement. Patients having diffuse skin disease have poorer
survival rate than those with limited scleroderma.56 Four other adverse
prognostic factors were identified:
1. Visceral involvement (cardiac, pulmonary, renal)
2. Presence of antibodies to topoisomerase I (anti-Scl 70)
3. Elevated ESR (> 25 mm/hr)
4. Anemia.56
MANAGEMENT
Optimal management of scleroderma varies with the subset and stage
of the disease (see Table 7.4). In lcSSc, effective therapies are primarily
targeted at the vasculature, including Raynauds phenomenon and later
in the course of the disease, pulmonary hypertension. In early diffuse
cutaneous scleroderma, immune-mediated therapy followed quickly by
antifibrotic agents should be the rational choice, whereas in late stage,
Table 7.4: Systemic sclerosis: management approach
Systemic sclerosis
Limited cutaneous
(lcSSc)

Diffuse cutaneous
(dcSSc)

Vascular therapy
Early
Immunomodulatory
quickly
followed by
antifibrotic
agents
NonPharmacological
pharmacological

Surgical

Late
Antifibrotic
agents

The Scleroderma Disorders: An Update

127

where inflammatory phase has already subsided, therapy with only


antifibrotic agents would be more effective.57
Vascular Therapy
The vasospasm associated with SSc may be controllable, but the
proliferative structural vascular changes, playing more significant role
in its pathogenesis, have not been yet successfully prevented or cured.
Therapeutic options in treating vascular changes in SSc depends on
three modalities: nonpharmacological, pharmacological and surgical.57,58
Nonpharmacological ways predominantly include prevention of
vasospasm induced by cold and other precipitating factors. Patients
should have warm-water bath and avoid cold contact and exposure
especially in winter. They should wear woollen gloves and socks
particularly during winter morning and evening. Smoking and drugs
inducing vasospasms (like beta-blockers) should be strictly restricted.
Whirling of arms and other biofeedback measures may help in the acute
episodes. 57,58
Pharmacological therapies are indicated in patients with frequent
episodes, prolonged functional impairment, severe pain or digital
ischemia. Calcium channel blockers like long-acting nifedipine at doses
of 30 to 90 mg/day may be beneficial. Some patients intolerant or nonresponding to nifedipine have been managed successfully by nicardipine
(30 to 60 mg BID). Selective alpha-blockers such as prazosin have been
effective only in primary Raynauds phenomenon (RP) but not in
scleroderma. The fact that platelet serotonin (5HT) may be a contributory
factor for triggering RP has prompted the use of agents affecting platelet
serotonin either by blocking serotonin receptors (ketanserin 40 mg TID)59
or inhibiting serotonin reuptake (SSRIs: fluoxetin 20 mg/day).60
Combination of pentoxiphylline (400 mg BID) which improves digital
perfusion by increasing the deformability of RBC plasma membranes
and antiplatelet agent like low dose aspirin (75 mg daily) have also been
quite effective in preventing and amelioration of digital gangrenous
changes (personal observation). The nonselective endothelin antagonist,
bosentan, which has been approved for treatment of pulmonary
hypertension in patients with scleroderma, may be beneficial upon digital
ischemia and may decrease the incidence of digital ulceration. The role
of bosentan (62.5 mg BID with dose escalation to 125 mg BID as tolerated),
which although prevents new ulcer formation, in healing of establisted
digital ulceration is not certainly known. Iloprost, the synthetic analogue
of prostacyclin, given parenterally at doses of 0.5 to 2 ng/kg per min,
is a potent vasodilator which inhibits platelet aggregation and adhesion,
increases RBCs deformability, alters neutrophilic functions including

128

Recent Advances in Dermatology

free radical formation and probably helps in repairing of damaged


endothelium. It also reduces the production and release of the profibrotic
cytokine, connective tissue growth factor from fibroblasts, and thus
lessening its concentration in sclerodermatous skin.62 Considerable side
effects, however, have limited its use only in short-term palliation of
severe RP in SSc, especially in helping to avoid amputation of the distal
tip of a digit.63 Oral prostaglandin analogue, beraprost, which is comparatively safer, has been evaluated recently in some trials for patients with
SSc and digital necrosis.64
Surgical manoeuvre includes different forms of sympathectomy in
severe RP in SSc. While cervical sympathectomy provides only shorttime benefit, lumbar sympathectomy leads to long-term beneficial effects
for severe RP of feet. The reason of this discrepancy between the upper
and lower limbs has yet not been explained. In some of our SSc patients
with impending toe gangrene lumbar sympathectomy has been able
to reverse the digital ischemic process and prevent severe RP in followup for long period.58 Recently radical microarteriolysis (digital sympathectomy) or vein by-pass have been effectively performed to minimize
severe pain, augment feeling of digital ulcer and prevent severe, acute
episode of RP.65
Immuno-Modulation Therapy
Activation of immune system may be major provocating factor for both
the vascular and fibrotic lesion in SSc, whose maximum damaging effect
occurs in the early stage of the disease. This initial immune activation,
by producing cytokines and growth factors, could create autocrine loops
which, however, do not require further stimulus to perpetuate the
vascular and fibrotic lesions. Due to these autocrine loops formation,
immuno-suppressive therapy, showing good response in the early phase
of SSc, is not that effective in the late phase.57
The role of cyclophosphamide as a single agent in scleroderma remains
uncertain. It is mainly useful in patients with fibrosing alveolitis in
combination with corticosteroids but not in the cases of advanced
fibrosis.57
Corticosteroids in high-dose for long period have potential toxicity
and may precipitate normotensive renal crisis.66 Steroids should therefore
be better restricted only in patients having myositis, active fibrosing
alveolitis, symptomatic serositis and tenosynovitis. Moreover, the lowest
possible effective dose should only be used in these conditions, preferably
below 20 mg/day.57
Cyclosporine, which acts as both suppressor of cell mediated
immunity and reducer of collagen synthesis has the limitation of using

The Scleroderma Disorders: An Update

129

in scleroderma by its significant nephrotoxicity.67 Other cyclophilins,


such as rapamycin, may provide more targeted immunosuppression,
improved efficacy, and reduced toxicity.57
Other immunosuppressive drugs have been employed in scleroderma
with varying degree of success. The role of azathioprine, however, is
anecdotal. Methotrexate, that although corrects the skin induration, has
shown conflicting results in randomised double-blind trials.68
An uncontrolled study has shown promising result in early stage
diffuse cutaneous disease by anti-thymocyte globulin followed by
mycophenolate mofetil.69
Antifibrotic Therapy
The management of established fibrosis still remains a therapeutic
challenge due to paucity of safe and effective agents which can remove
excess insoluble cross-linked collagen fibers without destroying structural
framework of the body and individual organs.57
The major drawbacks of the antifibrotic drugs are that they are slow
to act and not powerful enough to prevent rampant fibrosis. Such agents
are unnecessary for cutaneous manifestations in patients with lcSSc.
However, they are indicated in cases of lcSSc when associated with
visceral fibrosis.57
D-penicillamine can reduce collagen biosynthesis as well as suppress
immune disorders. Autoantibodies in scleroderma are produced against
autoantigens that have been fragmented via reactive oxygen species and
specific metals such as copper or iron.70 Penicillamine, as a chelator of
metals, may thus reduce the formation of these autoantigens in systemic
scleroderma. The precise role of penicillamine, however, in the treatment
of scleroderma has yet not been defined.57 High dose of penicillamine
(750-1000 mg/day) seems to possess no advantage over low dose
(125 mg every other day).71 Even with penicillamine therapy skin sclerosis
worsens during the first four to six months of therapy which indicates
the need of quickly effective antifibrotic agents. Penicillamine has been
recommended for use in comparatively stable patients with established
diffuse scleroderma or as a follow-up to more aggressive agents
(e.g., anti-thymocyte globulin) in more active scleroderma.57
Interferon gamma (IFN-gamma), a more potent inhibitor of collagen
synthesis in vitro as compared to IFN-alpha, may be effective in the
treatment of scleroderma. IFN-gamma may, however, cause aberrant
cellular activation in SSc and considerable vascular side effects, including
renal hypertensive crisis.72
Iloprost, mentioned earlier in the vascular therapy of scleroderma,
has also some antifibrotic properties. Five days of iloprost infusion among

130

Recent Advances in Dermatology

six patents of dcSSc reduced concentration of the profibrotic cytokine,


connective tissue growth factor (CTGF) in the dermal interstitial fluid.73
However, clinically significant efficacy of iloprost as antifibrotic agent
could not be ascertained.
Relaxin, a natural antifibrotic protein, produced by the uterus and
corpus luteum during pregnancy, enhances the degradation of collagen
and suppresses the formation of new collagen by fibroblasts. A placebocontrolled trial74 showed reduction in mean skin thickness in SSc by
human recombinant relaxin (25 microg/kg per day by continuous
subcutaneous infusion). A subsequent larger multicenter study, however,
could not confirm the said benefit.57
Other Therapeutic Agents
Due to paucity of specific medication in systemic sclerosis and difficulties
in conducting double-blind trials in these disorder, anecdotal evidences
of effectivity of some agents have been claimed. Minocycine, in an open
trial of eleven patients in the early diffuse scleroderma, but without
having any affection of internal organ system, has shown some benefit.75
The drug may act as a disease-modifying agent.76
Stem cell transplantation, showing some benefit in other auto-immune
diseases, has been attempted in some patients of SSc. In majority of the
patients skin diseases responded but the mortality rate during the first
year of post-transplantation period was as high as 27 percent.77 High
dose immunosuppression (total body irradiation, cyclophosphamide, and
anti-thymocyte globulin) followed by autologous stem cell support have
been tried in diffuse disease with visceral involvement. Such attempt
has shown slightly lower mortality in the follow-up period.78 Another
multicenter study 79 used cyclophosphamide or melphalan for
immunosuppression and peripheral stem cell support or bone marrow
transplantation for hematopoietic reconstitution. Most patients
demonstrated some initial benefit in skin scores and disability along
with the cardiac and renal function of survivors remained at or near
baseline. Long-term follow-up, however, showed relapse in some
survivors. Thus, high dose immunosuppression with autologous stem
cell rescue till date remains as an experimental therapeutic option. In
Europe a trial has begun to compare this mode of therapy with
cyclophosphamide alone.57
Better understanding of pathogenesis has revealed that the key
mediators like cytokines play a definite role in the evolution of systemic
sclerosis. Combinations of anticytokine therapies like agents directed
against both TGFbeta and CTGF (connective tissue growth factors) are
being investigated recently for their potentiality as clinically effective

The Scleroderma Disorders: An Update

131

regimens.80 Parenteral prostacycline-like iloprost, already mentioned,


represents significant example of anticytokine therapy as it suppresses
CTGF.57
Therapy for Cutaneous Involvement
Localised scleroderma seems to soften with topical intralesional corticosteroids, topical calcipotriene,81 and UVA-182 therapy. Widespread
morphea was treated with oral methotrexate 15 mg/week for a 24-week
period which showed some benefit.83
Telangiectasia, which may induce more cosmetic problem especially
when on face, may be covered with camouflage make-up or treated with
laser therapy.84
Calcinosis, that may cause considerable distress, may be surgically
removed if present in a suitable location, occasionally with the help of
a dental drill which creates less tissue damage than the conventional
ways.57 While pharmacological attempts with probenecid, colchicine or
warfarin have failed to reduce calcinosis, diltiazem, in an anecdotal
study, has shown some promise.85
REFERENCES
1. Black CM. Sclerodermaclinical aspects. J Intern Med 1993; 234: 114-6.
2. Peterson LS, Nelson AM, Su WP. Classification of morphea (localised
scleroderma). May Clin Proc 1995; 70: 1068-76.
3. LeRoy EC, Black CM, Fleischmajer R, et al. Scleroderma (systemic sclerosis):
Classification, subsets and pathogenesis. J Rheumatol 1988; 15: 201-4.
4. Black CM, Denton CP. Classification of scleroderma. www. Up To Date.com.
2000, Dec: 9.1.
5. Ghosh S, Haldar B. Coexistence of lichen sclerosus et atrophicus and morphoea.
Ind J Dermatol Ven Leprol 1987; 53: 369-70.
6. Ozkan S, Atabey N, Fetil E, et al. Evidence of B. burgdorferi in morpha and
lichen sclerosus. Int J Dermatol 2000; 39: 278-83.
7. Ghosh S, Haldar B. Quantitative evaluation of cutaneous thermal sensation in
psoriasis, morphea and vitiligo. Ind J Dermatol Ven Leprol 1989; 55: 30-2.
8. Kuwana M, Medsger Jr TA, Wright TM. T cell proliferative response induced
by DNA topoisomerase1 in patients with systemic sclerosis and healthy donors.
J Clin Invest 1995; 96: 586-8.
9. Hesselstrand R, Scheja A, Shen GQ, et al. The association of antinuclear
antibodies with organ involvement and survival in systemic sclerosis.
Rheumatology 2003; 42: 534-40.
10. Altmann RD, Medsger JA Jr, Bloch DA, et al. Predictors of survival in systemic
sclerosis (scleroderma). Arthritis Rheum 1990; 34: 401-3.
11. Denton CP, Black CM, Korn JH, et al. Systemic sclerosis: Current pathogenetic
concepts and future prospects for targeted therapy. Lancet 1996; 347: 1452-4.
12. Block CM, Denton CP. Pathogenesis of scleroderma-I and II. www. Up To
Date. com, 2003, April: 11.2

132

Recent Advances in Dermatology

13. Piela-Smith TH, Korn JH. Lymphocyte modulation of fibroblast function in


systemic sclerosis. Clin Dermatol 1994; 12: 368-9.
14. Sollberg S, Mauch C, Eches B, et al. The fibroblast in systemic sclerosis. Clin
Dermatol 1994; 12: 378-9.
15. Vancheeswarah R, Azam A, Black C, et al. Localisation of endothelin-1 and
its binding sites in scleroderma skin. J Rheumatol 1994; 21: 1267-9.
16. Ghosh S, Biswas A. Digital blood flow in systemic sclerosis. Ind J Dermatol
Venereol Leprol 1992; 58: 169-72.
17. Dobich L, Bookstein JJ, Zweiffer A, et al. Digital arteries in patients with
scleroderma. Arch Intern Med 1972; 130: 708-14.
18. Flavahan NA, Flavahan S, Liu Q, et al. Increased alpha 2-adrenargic constriction
of isolated arterioles in diffuse scleroderma. Arthritis Rheum 2000; 43:
1884-6.
19. Kahaleh MB. Endothelin: An endothelial-dependent vasoconstrictor in
scleroderma. Arthritis Rheum 1991; 34: 97-8.
20. Vancheswaron R. Magoulas T, Etrat G, et al. Circulating endothelin-1 levels
in systemic (SSc) subsetsA marker of fibrosis or vascular dysfunction? J
Rheumatol 1994; 21: 1837-9.
21. Blake DR, Winyard P, Scott D GL, et al. Endothelial cell cytoxicity in
inflammatory vascular diseasesthe possible role of oxidised lipoproteins.
Ann Rheum Dis 1985; 44: 176-7.
22. Bruckdorfer KR, Hilary JB, Bunce T, et al. Increased susceptibility to oxidation
of low-density lipoproteins isolated from patients with systemic sclerosis.
Arthritis Rheum 1995; 38: 1060-1.
23. Sgonc R, Gruschwitz MS, Boeck G, et al. Endothelial cell apoptosis in systemic
sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95.
Arthritis Rheum 2000; 43: 2550-2.
24. Kahaleh MB, Fan PS. Mechanism of serum-mediated endothelial injury in
scleroderma: identification of a granular enzyme in scleroderma skin and sera.
Clin Immunol Immunopathol 1997; 83: 32-4.
25. Sprott H, Muller-Ladner U, Distler O, et al. Detection of activated complement
complex C5b-9 and complement receptor C5a in skin biopsies of patients with
systemic sclerosis (scleroderma). J Rheumatol 2000; 27: 401-3.
26. Gruschwitz M, Driesch P, Kellner I, et al. Expression of adhesion proteins
involved in cell-cell and cell-matrix interactions in the skin of patients with
progressive systemic sclerosis. J Am Acad Dermatol 1992; 27: 168-70.
27. Sfikakis PP, Tesar J, Baraf H, et al. Circulating intercellular adhesion molecule1 in patents with systemic sclerosis. Clin Immunol Immunopathol 1993;
68: 87-9.
28. Denton CP, Bickerstaff MCM, Shoiwen X, et al. Serial circulating adhesion
molecule levels reflect disease severity in systemic sclerosis. Brit J Rheumatol
1995; 34: 1047-9.
29. Rudnicka L, Majewski S, Blaszcyk M, et al. Adhesion of peripheral blood
mononuclear cells to vascular endothelium in patients with systemic sclerosis
(scleroderma). Arthritis Rheum 1992; 35: 770-3.
30. Prescott RJ, Freemont AJ, Jones CJP, et al. Sequential dermal microvasculature
and perivascular changes in the development of scleroderma. J Pathol 1992;
166: 254-6.
31. Hynes RO. Interins: Versatility, modulation, and signaling in cell adhesion.
Cell 1992; 69: 11-3.

The Scleroderma Disorders: An Update

133

32. Cascolo-Rosen L, Wighlay F, Rosen A. Scleroderma autoantigens are uniquely


fragmented by metal-catalyzed oxidation reactions: Implications. J Exp Med
1997; 185: 71-3.
33. Lunard C, Beson C, Navone R, et al. Systemic sclerosis immunoglobulin G
autoantibodies bind the human cytomegalovirus late protein UL94 and induce
apoptosis in human endothelial cells. Nat Exed 2000; 6: 1182-4.
34. Chizzolini C, Raschi E, Rezzonico R, et al. Autoantibodies to fibroblasts induce
a proadhesive and proinflammatory fibroblast phenotype in patients with
systemic sclerosis. Arthritis Rheum 2002; 46: 1601-3.
35. Kwcasawa K, Hirose K, Sani H, et al. Increased interleukin-17 production in
patients with systemic sclerosis. Arthritis Rheum 2000, 43: 2454-6.
36. Sato S, Hayakawa I, Hasegawa M, et al. Function blocking autoantibodies
against matrix metaloproteinase-1 in systemic sclerosis. J Invest Dermatol 2003;
120: 542-7.
37. Korn J. Risk factors for and possible causes of scleroderma. www. UpTo Date.
com. 2002; August: 10.3.
38. Tan FK, Stivers DN, Arnett FC, et al. HLA haplotypes and micosatellite
polymorphisms in and around the major histocompatibility complex region in
Native American population with a high prevalence of scleroderma (systemic
sclerosis). Tissue Antigens 1999; 53: 73-5.
39. Tan FK, Stivers DN, Foster MW, et al. Association of microsatellite markers
near the fibrillin 1 gene on human chromosomes 15q will scleroderma in a
Native American population. Arthritis Rheum 1998; 41: 1728-31.
40. Fatini C, Gensini F, Sticchi E, et al. High prevalence of polymorphisms of
angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase
(Glu 298 Asp) in patients with systemic sclerosis. Am J Med 2002;112: 539-42.
41. Pandey JP, Leroy EC. Human cytomegalovirus and the vasculopathies of
autoimmune disease (especially scleroderma), allograft rejection and coronary
restenosis. Arthritis Rheum. 1998; 41: 9-11.
42. Aberer E, Neumann R, Stanek G. Is localised scleroderma a Borrelia infection?
(letter) Lancet 1985; ii: 278.
43. Weide B, Walz T, Garbe C. Is morphea caused by B. burgdorferi? A review.
Br. J Dermatol 2000; 142: 636-44.
44. Bajaj AK. Morphea and Borrelia burgdorferi: Causal or casual relationship?
Whats New? In Dermatology, Sexually transmitted diseases and Leprosy.
2001; 28: 11-3.
45. Janowsky EC, Kupper LL, Hulka BS. Meta-analysis of the relation between
silicone breast implants and the risk of connective tissue diseases. N Eng J
Med 2000, 342; 780-3.
46. Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil
denatured with antiline. Lancet 1981; 2: 565-8.
47. Silver RM, Heyes MP, Maize JC, et al. Scleroderma, fascitis and eosinophilia
associated with the ingestion of tryptophan. N Eng J Med 1990; 322; 873-6.
48. Johnson KL, Nelson JL, Furst DE, et al. Fetal cell microchimerism in tissue
from multiple sites in women with systemic sclerosis. Arthritis Rheum 2001;
44: 1846-9.
49. Burasteno SE, Galbiati S, Vassollo A, et al. Cellular microchimerism as a
lifelong physiological status in parous women: an immunologic basis for its
amplification in patients with systemic sclerosis. Arthritis Rheum 2003; 48:
1109-16.

134

Recent Advances in Dermatology

50. Shi-Wen X, Panesar M, Vancheeswaran R, et al. Expression and shedding


intercellular adhesion molecule 1 and lymphocyte function associated antigen
3 by normal and scleroderma fibroblasts. Effects of interferon. gamma, tumor
necrosis factor alpha, and estrogen. Arthritis Rheum 1994; 37: 1688-91.
51. Korn JH. Overview of the manifestations and diagnosis of scleroderma. www.
UpToDate.com 2003 April; 11.2
52. Ghosh S, Biswas A. Digital blood flow in systemic lupus erythematosus by
photoplethysmography. Ind J Dermatol 2002; 47: 152-5.
53. Satol M, Kuwana M, Ogasawara T, et al. Association of autoantibodies to
topoisomerase I and the phosphorylated (IIO) form of RNA polymerase II in
Japanese scleroderma patients. J Rheumatol 1996; 23: 637-40.
54. Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis.
Anti-centromere and anti-Scl. 70 antibodies. Am J Med 1997; 103: 241-3.
55. Merkel PA, Polisson RP, Chang Y, et al. Prevalence of antineutrophil cytoplasmic
antibodies in a large inception cohort of patients with connective tissue disease.
Ann Intern Med 1997; 126: 864-7.
56. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: Demographic, clinical
and serologic features and survival in 1,012 Italian patients. Medicine
(Baltimore) 2002; 81: 137-41.
57. Denton CP. General approach to the treatment of sclerodorma - I and II, www.
UpTo Date.com, 2003 May, 11.2
58. Ghosh S. Digital vasculopathy in systemic scleroderma: Management strategy.
AMRI Apollo Journal 2002; 2: 15.
59. Seibold JR, Janeneau AH. Treatment of Raynauds phenomenon with ketanserin,
a selective antagonist of the serotonin 2 (5-HT2) receptor. Arthritis Rheum
1984; 27: 139-40.
60. Bolte MA, Avery D. Case of fluoxetin-induced remission of Raynauds phenomenon: a case report. Angiology 1993; 44: 161-2.
61. Black C, Kom J, Mayes M, et al. Prevention of ischemic digital ulcers in
systemic sclerosis by endothelin receptor antagonism (abstract) Arthritis Rheum
2002; 46: 341-4.
62. Stratton R, Shiwen X, Martine G, et al. Iloprost suppresses connective tissue
growth factor production in fibroblasts and in the skin of scleroderma patients.
J Clin Invest 2001; 108: 240-3.
63. Wigley FM, Wise RA, Scibold RJ, et al. Intravenous iloprost infusion in patient
with Raynauds phenomenon secondary to systemic sclerosis. A multicenter,
placebo controlled, double-blind study. Ann Interm Med 1994; 120: 197-9.
64. Vayssaairat M. Preventive effect of an oral prostacyclin analog, beraprost
sodium, on digital necrosis in systemic sclerosis. J Rheumatol 1999; 26:
217-9.
65. OBrion BM, Kumar PA, Mellow CG, et al. Radical microarteriolysis in the
treatment of vasospastic disorders of the hand, especially scleoderma. J Hand
Surg 1992; 7: 447-9.
66. Steen VD, Conte C, Medsger TA Jr. Case-control study of corticosteroid use
prior to scleroderma renal crisis (abstract). Arthritis Rheum 1994; 37: 5360.
67. Denton CP, Abdullah A, Sweny P, et al. Acute renal failure occurring in
scleroderma treated with cyclosporine A: A report of three cases. Brit J
Rheumatol 1994; 3: 90-2.
68. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of
methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum
2001; 44: 1350-3.

The Scleroderma Disorders: An Update

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

Recent Advances in Dermatology

A.K. Bajaj

Patch Testing: An Overview


The earliest account of patch testing is by Staedler who, in 1847, described
the blotting paper method to test idiosyncracy.1 In 1889, Collins,2 an
ophthalmologist applied patches of atropine to his patients who were
getting reactions to instillation of atropine. It was Jadassohn3 (The father
of patch testing) who unequivocally established the role of patch testing
in dermatitis medicamentosa. By applying chemicals (on pieces of blotting
paper) to the skin he was able to reproduce the clinical picture of contact
dermatitis from iodoform mercury salts in patients suffering from skin
intolerance to those substances. Bloch, Bonnevie and Sulzberger further
contributed towards establishment of patch testing as a useful diagnostic
tool in dermatology.4 The standardization and importance of patch testing
has rightly been highlighted by Sulzberger as one of the most important
advances in clinical dermatology during the twentieth century.
Patch testing at present is the only scientific method to detect the
cause of contact dermatitis. The present standard test methods involve
a device and patch test material. The patch test material consists of
allergens incorporated in a suitable base in proper concentrations which
are known for most of the substances.
ALLERGENS
There are more than 6 million chemicals in the worlds environment
today and approximately 4000 have been reported to have contact
sensitizing properties. Selection of chemicals for patch testing is always
difficult and demanding but fortunately a small number of substances
account for the majority of contact allergies. National and international
groups of patch test specialists recommend that allergen series (standard
battery) including mixes of allergens be used for routine testing. Such
series comprise 20-25 test substance mixes containing 50-60 different
allergens. Testing with these detects about 70-80 percent of allergic contact
sensitivity.5 Test series for special purposes include those for footwear,
cosmetics, fragrances, sunscreens, preservatives, rubber chemicals,
plastics, textile dyes etc and also include occupations such as engineering,
hair-dressing, bakery work, dentistry etc. The allergens must be stored
properly so that they are protected from environmental influences.

Patch Testing: An Overview

137

Polypylene syringes kept in a cool dark place (refrigerator) protect the


allergens from heat, light, uv-rays, air, humidity and microbial contaminants. Paraphenylenediamine (PPD) should be kept in amber coloured
syringe.
VEHICLES
The antigens/allergens are incorporated in appropriate vehicles and in
proper concentration. At present the standard vehicle is petrolatum due
to its refined nature and almost negligible sensitizing potential.
Paradoxically petrolatum is highly lipophilic and most allergens are
hydrophilic. Aqueous solutions and solvents such as ethanol, acetone,
methyl ethyl ketone and ethyl ether have been tried and are
recommended for some special allergens only because stability of
solutions is low and they are difficult to handle, preserve and quantify.
TAPES
Most modern tapes have adequate tack and keep the patches in close
approximation to the skin. They are made from non-woven textile and
acrylate adhesive. Allergy is rare but may occur due to uncured acrylate
or to formaldehyde and even to additives. Scanpore, Norgesplaster and
Micropore are the common non-occlusive tapes used for occluding the
patch test material. Old fashioned tapes used to produce frequent allergic
reactions and they were commonly due to colophony.6
PATCH TEST UNITS/DEVICES
The earlier patches used were pieces of cotton fabric soaked with allergen
solutions. Later filter paper discs were used in a similar way and taped
to the skin under a water impermeable cover. The Al-test is a development
of this method.7 It is an effective and usually non-irritant test unit that
consists of aluminium foil covered with polythene with a 10 mm central
disc of filter paper adhered by heat. Reactions to the polythene covering
on the aluminium foil, spread of strong positive reactions to surrounding
areas, use of occlusive tape with resultant reactions and large areas
required for patches are some of the disadvantages leading to the disuse
of this patch test device.
At present the commonly used device is Finn8 chamber which consists
of stiff aluminium and has a diameter of 8 mm and depth of 0.5 mm.
The particular advantage of this chamber is its tight apposition to the
skin thus localizing reaction to the test site and a small area is required
for patch testing. Chambers made of plastic with diameters of 10-15 mm

138

Recent Advances in Dermatology

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

Patch Testing: An Overview

139

Finn Chamber missed 3 of 16 and TRUE Test 1 of 14 relevant reactions.


TRUE Test did not miss any relevant reaction to kathon CG while Finn
Chambers methodology missed 2 out of 7. Neither the TRUE Test nor
the Finn Chamber performed optimally in detecting relevant reactions
to formaldehyde or carbamates.
A number of other studies13-16 have also shown similar results with
some variations. In general the concordance has been 63-75 percent and
better detection of kathon CG, nickel and neomycin positivity with
TRUE Test while Finn Chamber technique was found to be superior for
detection of fragrances, thiuram mix and chromates. More false positive
reactions with Finn Chambers and more false negative with TRUE Test
were observed. Both the methods seem to have their advantages and
disadvantages and the search and research are ongoing for improvement
and perfection of the patch test technology.
TECHNIQUE OF PATCH TESTING
A detailed history should be taken to decide the supplemental antigens
required over and above the standard battery of allergens. In case of
occupational dermatitis the special kits if available and the substances
the patient comes into contact should also be added. Patch testing should
not be carried out if the patient has active disease and is on large dose
of steroids (>20 mg prednisolone) or is applying topical steroids on the
back. Routinely the patches are applied on the upper back after cleaning
the area with water, spirit or acetone. Avoid the vertebral column and
angle of the scapulae. The patient is instructed to avoid exercise, sweating,
wetting the area, rubbing and scratching. The patient should not expose
the area to sunlight or sunlamps. The patches are normally removed
after about 48 h and reading taken after 30-60 min. The test area should
be marked with colored or fluorescent ink.
The ICDRG (International Contact Dermatitis Research Group)
recommendations of evaluating the patch test reactions are as follows
+ or ?
Doubtful reaction (faint erythema only)
+
Weak (Nonvesicular ) positive reaction
++
Strong (vesicular) positive reaction
+++
Extreme (bullous) positive reaction
Negative -, IR Irritant reaction, NT Not tested
Reading a diagnostic patch test should not cease at day 2 (D2) after
application of allergens as numerous allergic reactions need more time
to evolve. Consequently a further reading is regarded as mandatory, but
it is not universally agreed upon when it should be taken though
recommendations vary from D3 to D7.17-19 Todd et al20 performed

140

Recent Advances in Dermatology

readings on D2, D3 and D4 after application of patch tests in 88 patients.


Ninety patch test reactions in 49 patients were interpreted as allergic. A
single D2 reading detected 58 allergic reactions with 32 false negatives
and 23 false positives. A single D3 reading detected 77 allergic reactions
with 13 false negatives and 17 false positives. A single D4 reading detected
85 allergic reactions with 5 false negatives and 9 false positives. The
authors concluded that if only a single reading is feasible it is better
performed on D4. Analysis of the data of the Information Network of
Departments of Dermatology (INDK) also pointed to possible superiority
of D4 reading.21
Geier et al22 carried out retrospective analysis of patch test reactions
in 3 groups of patients in order to obtain informations on the best day
for the second patch test reading after D2 and also on the usefulness of
additional readings after D3. In the years 1990 to 1995, patch tests were
routinely read at D3 and D4 in 1096 patients, at D3 and D5 in 1243
patients and at D3 and D6 in 1136 patients. In all the 3 groups,
significantly more positive reactions diminished than appeared de novo
from D3 to the later reading. Reactions to individual allergens showed
wide differences in this connection. Neomycin sulphate, cobalt salts and
paraphenylenediamine were slow allergens with reactions increasing
than diminishing from D3 to the later readings. With fragrance mix and
balsam of Peru the opposite pattern occurred. The authors concluded
that D3 reading is better than D4, but if a third reading is performed it
should be done at D5 to get the maximum information out of patch
testing. In a recent retrospective study,23 the usefulness of an additional
patch test reading on D6 or D7 was investigated. In 62 out of 760
patients (8.2%), 77 late positive reactions (after D3) were seen. Allergens
most involved in producing late positive reactions were nickel sulphate
(20 reactions), neomycin sulphate (7), tixocortol - 21 pivalate (5), paratertiary butylphenol formaldehyde resin (5) and kathon CG (5). The
authors concluded that it was preferable to have a reading on D2 and
D3 but an extra reading on D6 or D7 was very useful as it gave additional
information in 8.2 percent of patch tested patients.
INTERPRETATION OF PATCH TEST RESULTS
Though apparently a simple procedure, patch testing is fraught with
various technical pitfalls depending upon the patch test device, the tape
used for occlusion, the vehicle employed for incorporation of the antigen
and the antigen itself. Clinical experience is the best guide to the
interpretation of patch tests. Difficulty arises when allergic and irritant
reactions cannot be differentiated on morphological grounds. The two
great errors in patch testing are false positive and false negative results.

Patch Testing: An Overview

141

False Positive Reactions


A false positive reaction is irritant in nature. Its various causes are:
a. Use of wrong test substance; i.e. when a substance is irritant in
nature or is used in a higher concentration. Contamination of the test
substance may also produce false positive reaction.
b. Hyperreactive skin; (Excited skin syndrome; angry back; crazy back;
status eczematicus); Mitchell24 in 1975 described a phenomenon, which
he termed as angry back, characterized by the presence of multiple
patch tests associated with one or more strongly positive reactions
(+++) in patients submitted to a battery of epicutaneous tests which
were not completely reproducible when the patients were tested
later. In 1981 Maibach25 changed the name to excited skin syndrome
(ESS) because the phenomenon could occur in any part of the body
to which patch tests were applied. Initially active eczematous
dermatitis or several strong positive reactions inducing positive
responses to neighbouring tests were implicated for ESS.26,27 Some
investigators attributed ESS to factors such as long-term eczematous
dermatitis28,29 or to the chemical property of some substances. In a
recent study30 17 patients with angry back syndrome were identified
over a 4-year period (1994-97). Ten patients were classified as multiple
reactors and 7 as exacerbations of atopic eczema. A final diagnosis
of relevant allergic contact dermatitis was made in 8 of the 10 patients
with multiple reactions. Relevant contact allergens were rubber
chemicals, plants, metals and preservatives, all of which can be
marginal irritants. None of the reactions in the patients with
exacerbation of dermatitis were thought to be relevant. In multiple
reactors, marginal irritants were also the most common allergens
finally identified.
In another very recent study31 ESS developed in 39 of the 630
patients tested, corresponding to a frequency of 6.2 percent. Analysis
of data found a longer duration of the primary dermatitis in patients
in whom ESS developed compared to those who did not. Parabens,
fragrance mix and thimerosal had more positive patch test reactions
using standard application technique relative to the retest procedure
which placed the substances at a greater distance from one another.
This observation suggests that, in addition to the factors previously
reported to influence the reduction of ESS, the position of the allergens
in the testing procedure also should be considered. ESS is a major
cause of false positive non-relevant patch test reactions. The incidence
of non-reproducibility of positive patch test reactions can be over 40
percent. In cases of ESS, a detailed retake of clinical history, retesting

142

Recent Advances in Dermatology

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.

Patch Testing: An Overview

143

In case of industrial products, 100 to 1000 dilutions should be used.


In case of positive reactions to unknown substances, do at least 1020 controls to rule out false positive reactions.
The ideal control subjects are trauma patients who are confined to
bed (in slings/plaster/traction). They can not run away, do not exercise,
do not bathe and are not on immunosuppressive drugs. They are also
available in large numbers in any hospital.
COMPLICATIONS OF PATCH TESTING
Patch testing is a fairly safe investigation, but it may occasionally cause
some adverse reactions.
1. Severe reaction: Occasionally, very severe reactions to the allergen
occur and may lead to exacerbation of the patients eczema.
2. Plaster reactions: A mild plaster reaction due to irritation by an
occlusive zinc oxide strapping is not uncommon but in a few cases
severe eczematous reactions occur and are usually associated with a
reaction to colophony.
3. Persistent positive reaction: A patch test reaction normally takes 1 to
2 weeks to disappear. A test reaction may remain for longer than 1
month and persistence up to 8 months has been reported.
4. Anaphylaxis: Though rare, formaldehyde has been suspected as the
cause in a few cases of anaphylaxis during patch testing.
5. Active sensitization: This is a well known complication though its
exact incidence is not known. When a patch test site becomes positive
10-14 days later, active sensitization may have occurred. Such reactions
are common with dinitrochlorobenzene (DNCB), natural primin,
cobalt, p-phenylenediamine and Kathon CG.
6. Focal flare: It means activation at the patch site. It could be due to
active sensitization or due to activation of the patients eczema leading
to flare up of a positive patch test reaction, which had completely
subsided.
7. Depigmentation, scars and keloids are other rare risks of patch testing.
SENSITIVITY, SPECIFICITY, ACCURACY, AND
RELEVANCE OF PATCH TEST REACTION
Sensitivity is defined as the ability of a test to detect contact allergy
whereas specificity means the capability of the test to discriminate
between true allergic and non-allergic test reactions. Thus, low sensitivity
indicates a risk of false negative test reactions and low specificity the
risk of false positivity. Taken together, sensitivity and specificity describe
the accuracy of a test.

144

Recent Advances in Dermatology

The determination of relevance of positive patch test is highly


dependent on the clinical judgement of the physician which is acquired
by knowledge and experience. A positive reaction may be having past
relavance or relevant to the present episode of dermatitis (primary cause
or aggravating factor). Unknown relevance usually means an ignorant
physician.
The accuracy of a doubtful () reaction is low; that of weak (+)
positive reactions depends some what on the allergen and the patch test
methodology and varies from 20-50 percent. The accuracy of strong
positive (++) reaction is 80-90 percent and of extreme (+++) positive
reactions is 95-100 percent. In cases of questionable but important
reactions, retesting with another test technique or intracutaneous testing
may help in confirming the results. A complementary history after the
test is extremely useful in establishing relevance.
PHOTOPATCH TESTING
Antigens are applied in duplicate parallel to each other and covered
with opaque material. The patches are removed on day 2 and read as
usual. One set is then irradiated with UVA (50% of the minimum
erythema dose). When an allergic reaction occurs only on the irradiated
side and not on the control side, it is recorded as a positive photoallergic
patch test. Phototest series have been developed in various countries. It
is important to distinguish phototoxic from photoallergic reactions.
OTHER TESTS FOR ALLERGIC CONTACT DERMATITIS
Patch testing is the common procedure employed for detecting contact
hypersensitivity, but it is an artificial procedure and under certain
circumstances other tests may be required to reconfirm or detect the role
of some allergens.
Open Tests
The liquid test substance is dropped on an area of the skin measuring
about 1 cm in diameter and the solution is allowed to dry. The time for
reading and the characteristics of the reaction are the same as with
closed patch testing. The reaction is often weaker and may consist of
isolated papules only. Open tests are used as a preliminary screening
procedure with less familiar substances to reduce the risk of severe
reactions.

Patch Testing: An Overview

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

Recent Advances in Dermatology

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.

Laboratory Diagnosis and Treatment of Common STDs: An Update

147

Devinder Mohan Thappa

Laboratory Diagnosis and


Treatment of Common Sexually
Transmitted Diseases: An Update
GENITAL ULCER DISEASES
Genital ulcer disease is a common presentation of sexually transmitted
diseases. In developing countries, chancroid and granuloma inguinale
may be more common, but in developed nations, majority of the cases
are due either to herpes genitalis, syphilis or chancroid.1 Regardless of
locality, more than one venereal diseases may be detectable in 3 to 10
percent of patients with genital ulceration of infectious etiology, in case
they are evaluated by traditional tests. The concomitant occurrence of
two or more organisms causing genital ulcers may be even more common.
This has been demonstrated when such lesions are evaluated by more
sensitive means such as polymerase chain reaction (PCR). Therefore,
diagnosis of genital ulceration based solely upon morphologic
examination is fraught with difficulty and subject to a high degree of
inaccuracy.1 Physical examination findings have a low sensitivity and
specificity for diagnosing primary syphilis, chancroid and genital herpes,
even in areas where these diseases are common and where attending
physicians are experienced in the management of genital ulcer disease.2
All patients with genital ulcers should receive appropriate health
education and safer sex practices should be discussed. Serological
screening for both syphilis and HIV infection should be offered at the
time of genital ulcer presentation and again after 3 months at the end
of the window period for both diseases. In clinics where diagnostic
facilities are available, patients should be appropriately screened for all
pathogens causing genital ulceration as well as for other STDs. Laboratory
diagnostic tests and treatment options for common STDs have been
summarized in Tables 9.1 and 9.2.
Primary Syphilis
Syphilis is a sexually transmitted disease due to the fastidious spirochete,
Treponema pallidum.1 The primary chancre begins at the site of inoculation

148

Recent Advances in Dermatology


Table 9.1: Laboratory tests in the diagnosis of STDs

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

Laboratory tests required


Darkfield examination or direct immunofluorescent
staining on serous ulcer exudates, serologic tests for
syphilis, solid phase enzyme linked immunosorbent
assay and PCR evaluations
Grams stained smear from genital ulcer, culture for
H. ducreyi, multiplex polymerase chain reaction.
Histological examination may be useful to exclude
malignancy in non-healing or atypical ulcers.
Identification of intracellular Donovan bodies is the
gold standard for the diagnosis of donovanosis.
Culture and PCR are rarely used diagnostic tests.
Frei skin test not used now a days. The confirmation
of diagnosis of LGV now demands serological tests
(complement fixation test, microimmunofluorescence
test) or the identification/isolation of C. trachomatis
(tissue culture, using HeLa-229 or McCoy cell lines) in
appropriate clinical samples (bubo fluid or ulcer
material).
Virus isolation in cell culture has been the mainstay
of HSV diagnosis in Western countries. In our set
up, Tzanck smear is still the main tool.
Immunofluorescence staining of a Tzanck smear
increases the sensitivity and specificity of the
Tzanck test. Application of polymerase chain
reaction (PCR) offers rapid, sensitive and specific
identification of HSV. Serological tests may be used
to detect antibodies to HSV in blood, however, they
are generally indicative of past infection.
The diagnosis of gonorrhea is based on microscopic
identification of the organisms and culture. A
variety of direct methods including DNA
hybridization, direct immunofluorescent
examination and ELISA are available. Recently,
nucleic acid amplification tests (NAATs) have been
introduced.
Grams stained urethral discharge shows more than
5 pus cells per oil emersion field, but no gramnegative intracellular diplococci are seen. Urethral
swabs are sent for N. gonorrhoeae, mycoplasma,
and anaerobes culture. Chlamydial antigen
detection may be done on swab.
Usually accomplished via direct microscopic
examination of the vaginal or urethral discharge.
Culture of Trichomonas vaginalis is currently the
gold standard for diagnosis of trichomoniasis. PCR
has given variable results.
contd....

Laboratory Diagnosis and Treatment of Common STDs: An Update

149

Table contd...
S. Clinical entities
No.
9. Genital chlamydial
infection

10. Bacterial vaginosis

11. Anogenital warts

Laboratory tests required


Although there is no absolute gold standard for
chlamydia diagnostic tests, amplification assays
have a sensitivity of at least 90 percent compared
with 60-70 percent for culture and 60 percent for a
antigen assays. Nucleic acid amplification tests
(NAAT) for chlamydia, including polymerase chain
reaction, ligase chain reaction and transcription
mediated amplification assays, are more sensitive
and highly specific.
The diagnosis is usually made clinically based upon
the composite (Amsel) criteria and is based on
detecting at least three of four following composite
criteria:
Excessive homogeneous uniformly adherent
vaginal discharge
Elevated vaginal pH >4.5
Positive amine test (Whiff test)
Clue cells (20%)
Diagnosis of warts in the anogenital region is based
on the history of the exposure, clinical appearance,
epidemiological proof of the warts in the sexual
contact and the histological appearance. The most
sensitive method for detection of HPV DNA is PCR.

after an incubation period of 9-90 days (average 3 weeks). Within one


week, non-tender, rubbery, often bilateral, regional lymphadenopathy
develops. Without treatment, the chancre will resolve in 3-8 weeks. The
presence of a rash in conjunction with a genital ulcer does not rule out
syphilis, as 18 to 32 percent of patients may develop signs and symptoms
of secondary syphilis before chancre resolution.
Although the clinical presentation is commonly the same in the HIV
infected host, as it is in the otherwise healthy host, unusual features may
be seen.3 The primary stage of syphilis may consist of painful primary
chancre due to secondary infection, multiple or more extensive chancres
in the HIV patient. Instead of healing within 3 to 6 weeks, persistent
ulceration may occur.
The diagnosis of syphilis is based upon clinical suspicion and detection
of the causative organism within the genital ulcer.1 This should be noted
that serologic tests for syphilis might not become reactive for up to two
weeks after the onset of chancre. A positive serology may reflect a
temporarily distant syphilitic infection and therefore may be misleading.
Treponema pallidum can be detected in serous ulcer exudates by darkfield

150

Recent Advances in Dermatology


Table 9.2: Current treatment options in the STDs

S. Clinical entities
No.
1. Primary syphilis

2. Chancroid

3. Donovanosis

4. Lymphogranuloma
venereum
5. Herpes genitalis

Treatment options with or without associated HIV infection


Single intramuscular injection of 2.4 million units of
benzathine penicillin. 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. Some
authorities recommend weekly 3 injections of benzathine
penicillin in cases having HIV coinfection.
Azithromycin 1 g orally in a single dose or ceftriaxone
250 mg intramuscularly (IM) in a single dose or
ciprofloxacin 500 mg orally twice a day for 3 days
(contraindicated for pregnant and lactating women) or
erythromycin base 500 mg orally three times a day for
7 days.
Doxycycline 100 mg orally twice a day for at least 3
weeks or trimethoprim-sulfamethoxazole one doublestrength (800 mg/160 mg) tablet orally twice a day for at
least 3 weeks. Alternative regimens include 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.
Doxycycline 100 mg orally twice a day for 21 days.
Alternative treatment is erythromycin base 500 mg orally
four times a day for 21 days.
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 episodes of HSV disease
Acyclovir 400 mg orally three times a day for 5 days
acyclovir 200 mg orally five times a day for 5 days
acyclovir 800 mg orally twice a day for 5 days
famciclovir 125 mg orally twice a day for 5 days
valacyclovir 500 mg orally twice a day for 35 days
valacyclovir 1.0 g orally once a day for 5 days.

or
or
or
or
or

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.
contd....

Laboratory Diagnosis and Treatment of Common STDs: An Update

151

Table contd...
S. Clinical entities
No.
6. Gonorrhea

7. Non-gonococcal
urethritis

8. Trichomoniasis
9. Genital chlamydial
infection
10. Bacterial vaginosis

11. Anogenital warts

Treatment options with or without associated HIV infection


Cefixime 400 mg orally in a single dose or ceftriaxone 125
mg IM in a single dose or ciprofloxacin 500 mg orally in
a single dose or ofloxacin 400 mg orally in a single dose
or levofloxacin 250 mg orally in a single dose plus, if
chlamydial infection is not ruled out, azithromycin 1 g
orally in a single dose or doxycycline 100 mg orally twice
a day for 7 days.
Azithromycin 1 gm PO once or doxycycline 100 mg PO
BD for 7 days. Alternative regimen includes erythromycin
base 500 mg PO QID for 7 days or ofloxacin 300 mg PO
BD for 7 days or levofloxacin 500 mg once daily orally for
7 days.
Metronidazole 2 gm orally in a single dose or metronidazole 500 mg twice a day for 7 days.
A single dose of azithromycin 1 g or doxycycline 100 mg
PO BD for 7 days.
The precise dosage and duration varies, but metronidazole
400 mg twice a day for 5 days is adequate. Topical treatments with intravaginal clindamycin 2 percent cream or
metronidazole 0.75 percent gels are other treatment
options.
Therapies which can be employed by the patient at home
are: podophyllotoxin (0.15% cream or 0.5% solution) and
imiquimod (5% cream). Hospital based/office based
treatments include podophyllin, electrosurgery, laser,
curettage, scissors excision, cryotherapy and trichloroacetic
acid cautery.

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

Recent Advances in Dermatology

neurosyphilis.1,3 In HIV infected patients with syphilis, 2 rules of clinical


management apply: (1) disseminated infection, particularly with central
nervous system involvement should be assumed as neurosyphilis and
appropriate therapy for neurosyphilis should be prescribed for any
patient coinfected with syphilis and HIV who has the evidence of
compromised immune function, regardless of the apparent clinical stage
of syphilis observed; (2) close follow-up with repeated clinical, serological
and cerebrospinal fluid examinations are necessary, as even the best
regimens will sometimes fail in HIV infected patients with significant
immunocompromise.3
Chancroid
Chancroid is a sexually transmitted infection caused by the Gramnegative bacterium Haemophilus ducreyi.2 The disease manifests as painful
genital ulceration that may be accompanied by regional lymphadenitis
and bubo formation. The lymphadenopathy is usually unilateral and
tends to be more prevalent in men.
The diagnosis of chancroid is basically made on clinical grounds,
which has an accuracy of 30 to 50 percent.4 On Grams stained smear
from genital ulcer, various morphological forms of H. ducreyi have been
described such as schools of fish, railroad tracks and fingerprints
appearance.2 This pattern is due to an unusual tendency of H. ducreyi to
agglutinate. The organisms are visualised extracellularly more often than
intracellularly and tend to occur in close proximity to polymorphonuclear
leucocytes.5 Smears are only diagnostic in 50 percent of cases in the best
hands.6
In vitro culture for H. ducreyi currently remains the main tool for the
diagnosis of chancroid in the clinical setting and for many years was the
gold standard for evaluating newer methods of diagnosis.5 The
sensitivity of H. ducreyi culture relative to the multiplex polymerase
chain reaction (M-PCR) has been shown to be approximately 75 percent
in studies that have used genital ulcer-derived swabs. The technique of
M-PCR involves the addition of multiple primer pairs to the reaction
mixture in order to simultaneously amplify distinct DNA sequences
from different targets in the processed lesion material. The research
based M-PCR offers a highly sensitive and specific way to detect the
three most common etiological agents of genital ulcer diseasenamely,
HSV, T. pallidum and H. ducreyi.2 Thus, monoclonal antibody based
technology has the potential to provide a simple, inexpensive, rapid and
sensitive means of detecting H. ducreyi in genital ulcer specimens. So far,
serology has limited usefulness in the routine diagnosis of chancroid

Laboratory Diagnosis and Treatment of Common STDs: An Update

153

infection, but may be useful in population based epidemiological research


as a screening method for past infection.5
Histological examination is not a recommended diagnostic method
for chancroid, but may be useful as a means to exclude malignancy in
non-healing or atypical ulcers.5
Plasmid mediated antimicrobial resistance of H. ducreyi has been
documented for a number of agents, including penicillins, tetracyclines,
chloramphenicol, sulfonamides and aminoglycosides.7 Much less is
known about chromosomally mediated resistance to antimicrobials in
H. ducreyi, but decreased susceptibility has been described for penicillin,
ciprofloxacin, ofloxacin, and trimethoprim.2
Center for Disease Control and Prevention (CDC)8 in 2002 recommends therapy in the form of azithromycin 1 g orally in a single dose,
or ceftriaxone 250 mg intramuscularly (IM) in a single dose, or
ciprofloxacin 500 mg orally twice a day for 3 days (contraindicated for
pregnant and lactating women), or erythromycin base 500 mg orally
three times a day for 7 days. Patients should be re-examined 37 days
after initiation of therapy. If treatment is successful, ulcers usually
improve symptomatically within 3 days and objectively within 7 days
after therapy.
Fluctuant buboes should be aspirated in order to provide symptomatic
relief for the patient and to avoid the further complication of spontaneous
rupture. Incision and drainage of fluctuant buboes, with subsequent
packing of the wound, has also been recommended as an effective
management strategy for chancroid and avoids the need for frequent
bubo re-aspirations.2,9
Donovanosis
Donovanosis is a chronic destructive and slowly progressive, mildly
contagious disease caused by Calymmatobacterium granulomatis and is
characterized by granulomatous ulceration affecting primarily the
genitalia.10,11 Overall, the incidence of donovanosis seems to be decreasing.12 The disease tends to affect the poorest and most disadvantaged
communities and it is much more difficult to envisage an efficient casefinding and treatment approach that could work in the crowded slums
of Indian cities.13
Identification of intracellular Donovan bodies is the gold standard
for the diagnosis of donovanosis. 10 The identification of typical
intracellular Donovan bodies within large mononuclear cells is done on
Giemsa or Leishmans or Wrights stained smears obtained directly from
tissue or biopsy samples. These characteristic cells are 2590 m in

154

Recent Advances in Dermatology

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

Laboratory Diagnosis and Treatment of Common STDs: An Update

155

The diagnosis is established after taking careful history and proper


clinical examination, looking especially for painful lymphadenopathy
(Groove sign of Greenblat).17 In the past, LGV diagnosis was supported
by the Frei skin test (The Frei test antigen is no longer available), a test
of delayed type hypersensitivity to chlamydial antigens, similar to the
tuberculin test.16 When available, histopathological examination of biopsy
specimens can support the diagnosis. The confirmation of diagnosis of
LGV now demands serological tests or the identification/isolation of C.
trachomatis in appropriate clinical samples.
Among the serological tests, complement fixation (CF) test used for
diagnosis of chlamydial infections is genus specific.16 This test, therefore,
does not distinguish between infections with C. trachomatis, C. psittaci,
and C. pneumoniae. Since LGV is more invasive, it leads to higher titers
of serum antibody than uncomplicated genital infections with C.
trachomatis serovars DK. A titer of >1:256 strongly supports the diagnosis, while a titer of < 1:32 rules it out except in the very early stages
of the disease.18 The microimmunofluorescence (MIF) test can distinguish
between infections with different chlamydial species, but has not been
much used in routine clinical practice, since it requires a fluorescent
microscope and a skilled technologist trained in the technique.19 A number
of enzyme immunoassays (EIAs) are available, but they do not distinguish
between infections with different chlamydial species.20
C. trachomatis can be identified in bubo fluid following aspiration
or in ulcer material. In contrast with chancroid, buboes of which contain
large amounts of pus, the buboes of LGV may contain only small amounts
of thin milky fluid and it may be necessary to inject 25 ml of sterile
saline to obtain any fluid by aspiration.21 C. trachomatis can be isolated
in tissue culture, using HeLa-229 or McCoy cell lines, but this technique
is not widely available. Alternatively, C trachomatis can be identified by
direct fluorescent microscopy using a commercially available conjugated
monoclonal antibody on a smear of bubo or ulcer material. This method
is less demanding, but still requires a fluorescent microscope and a
skilled technologist.21
Commercially available EIAs, which detect chlamydial antigens
(usually lipopolysaccharide, LPS), are widely used to diagnose urethral
and cervical infection with C. trachomatis serovars DK, but have not
been evaluated for the diagnosis of LGV. DNA amplification assaysfor
example, polymerase chain reaction (PCR) or ligase chain reaction (LCR),
which detect Chlamydia specific genomic or plasmid DNA, are the most
sensitive tests available for the diagnosis of genital C. trachomatis
infection but have not been well evaluated for the diagnosis of LGV. 22

156

Recent Advances in Dermatology

Recommended treatment for both bubonic and anogenital LGV is


doxycycline 100 mg orally twice a day for 21 days. Alternative treatment
is erythromycin base 500 mg orally four times a day for 21 days.8 Erythromycin should be given to pregnant women, in whom tetracyclines
are contraindicated.
Large collections of pus in buboes should be aspirated, using a lateral
approach through normal skin.16 Late complications such as rectal
stricture may be improved by antibiotic treatment, which reduces the
inflammatory component, but does not correct damage due to fibrosis.
Rectovaginal fistula, bowel obstruction and esthiomene require surgical
correction under antibiotic cover.
Genital Herpes Simplex Virus (HSV) Infection
In India, genital herpes is the commonest infectious cause of genital
ulceration in some centers.23-25 Genital herpes can be caused by either
herpes simplex virus (HSV) type 1 or herpes simplex virus type 2.26 Most
cases of recurrent genital herpes are caused by HSV-2.
Infection is predominantly subclinical and individuals with unrecognized infection account for the majority of new transmission episodes to
susceptible partners.27 There is a need for better diagnostic methods to
identify individuals with minimally symptomatic disease.
The diagnosis of herpes genitalis is usually made clinically in typical
cases. It is important to realize that the sensitivity of clinical diagnosis
is low.28 In view of the fact that herpes may masquerade as a number
of genital ulcer diseases, laboratory tests are frequently called upon to
resolve the issue. Laboratory tests available for the diagnosis of herpes
virus infection include Tzanck smear, histopathology, viral culture and
serology. Tzanck smear test is not a sensitive test. Immunofluorescence
staining of a Tzanck smear increases the sensitivity and specificity of the
Tzanck test, but is not available in most laboratories.
Virus isolation in cell culture has been the mainstay of HSV diagnosis
in Western countries.29 Although HSV can be isolated from over 90
percent of vesicular or pustular lesions, the isolation rate from ulcerative
lesions is only 70 percent and falls to 27 percent at the crusting stage.
The characteristic cytopathic effect of HSV generally appears within 24
to 72 hours, but may take up to five days. Virus isolation is therefore,
slow and labour intensive, but has the advantage of demonstrating active
infection within a clinical lesion and also allows virus typing and antiviral
sensitivity testing.
Application of polymerase chain reaction (PCR) offers rapid, sensitive
and specific identification of HSV, but has hitherto been difficult to

Laboratory Diagnosis and Treatment of Common STDs: An Update

157

apply to routine clinical practice because of its technical requirements.27


However, introduction of the LightCycler (Biogene) has rendered PCR
feasible on a larger scale and potentially applicable to routine clinical
healthcare practice. Real time PCR protocols employ the incorporation
of dyes or the binding of probes during each cycle of the PCR so that
accumulation of product can be measured while the reaction is proceeding. In direct comparison of PCR with virus culture in patients presenting
to a large GUM clinic with clinical features suggestive of genital herpes,
PCR increased the overall detection rate of HSV by 24 percent.27
Serological tests may be used to detect antibodies to HSV in blood,
however, they are generally indicative of past infection.29 Although the
utility of type specific serology for herpes simplex virus in epidemiological studies is undisputed, the use of these tests for diagnostic purposes
remains more contentious.26 Possible uses include assessment of
asymptomatic sexual partners of patients with genital herpes, diagnosis
of genital ulcers where viral culture repeatedly gives negative results,
exclusion of herpes in pregnancy and routine testing as part of a screen
for sexually transmitted diseases. There are several limitations: the test
usually does not give positive results until about six weeks after exposure;
a positive test result indicates previous exposure but does not prove that
particular clinical signs or symptoms are due to herpes; and the sensitivity
and specificity of the tests range from 95 to 99 percent (in populations
with a low prevalence, most positive test results will be false positives).26
Both type-specific and nonspecific antibodies to HSV develop during
the first several weeks following infection and persist indefinitely.8 Type
specific serological tests are better than the tests based one nonspecific
antibodies and they are evaluated by either western blot (which tests for
a range of type specific antigens) or glycoprotein G (gG) assays.29 Western
blot tests are expensive, take 25 days to complete the screening and
confirmatory steps, and require expert interpretation. Glycoprotein G
assays detect antibodies to the type specific proteins gG-1 and gG-2.
Very little sequence homology exists between gG-1 and gG-2, allowing
differentiation between established infection with HSV-1 and HSV-2
respectively. A number of gG-based tests have been commercially
marketed, using a variety of test formats, most often using enzyme
immunoassay (EIA) methods.29
Knowledge of the HSV type has important implications for
patient management.29 Firstly, the natural history of first episode genital
HSV-1 infection is more favourable than that of HSV-2. Secondly, the
frequency of subclinical viral shedding following initial genital infection
with HSV-1 is consistently lower than for HSV-2; this is likely to be
associated with a reduced risk of future sexual transmission.29

158

Recent Advances in Dermatology

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

Laboratory Diagnosis and Treatment of Common STDs: An Update

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

160

Recent Advances in Dermatology

expensive than previous tests, making test performance from an economic


perspective a key consideration.33
For uncomplicated gonococcal infections of the cervix, urethra, and
rectum, Center for Disease Control and Prevention (CDC)8 in 2002
recommends cefixime 400 mg orally in a single dose, or ceftriaxone
125 mg IM in a single dose, or ciprofloxacin 500 mg orally in a single
dose, or ofloxacin 400 mg orally in a single dose, or levofloxacin 250 mg
orally in a single dose, plus, if chlamydial infection is not ruled out,
azithromycin 1 g orally in a single dose or doxycycline 100 mg orally
twice a day for 7 days.
In Europe, the following antibiotics are all recommended as first-line
treatment for uncomplicated gonorrhea in adults: ceftriaxone 250 mg IM
single dose, ciprofloxacin 500 mg or ofloxacin 400 mg or cefixime 400 mg
orally single dose; or spectinomycin 2 g IM single dose.30 Generally
penicillin analogs are not recommended as first-line treatment. In Britain,
as one-third of the patients have concomitant chlamydial infection,
treatment is given with doxycycline 100 mg twice daily for 7 days or
azithromycin 1 g orally to be taken after treatment for gonorrhea. There
is always the possibility of chlamydial genital infection, syphilis or viral
STDs such as human papilloma virus, herpes genitalis and HIV being
acquired at the same time.30
Non-gonococcal Urethritis (NGU)
NGU is diagnosed if gram-negative intracellular organisms cannot be
identified in the discharge on Grams stain in a patient with urethral
discharge and burning micturition.34 Chlamydia trachomatis is responsible
for 30 to 50 percent, Ureaplasma urealyticum for 10 to 40 percent and the
rest are due to Trichomonas vaginalis, yeasts, Herpes simplex virus,
Adenovirus, Hemophilus sp., Bacteroides etc. In males, urethritis begins
with dysuria and mucoid urethral discharge. In contrast to gonococcal
urethritis, symptoms are usually mild. Most cases in females are
asymptomatic.34
Grams stained urethral discharge shows more than 5 pus cells per
oil immersion field but no gram-negative intracellular diplococci are
seen.34 Urethral swabs are sent for N. gonorrhoeae, mycoplasma, and
anaerobes culture. Chlamydial antigen detection may be done on swab.
Center for Disease Control and Prevention (CDC) 8 in 2002
recommends therapy in the form of azithromycin 1 gm PO once or
doxycycline 100 mg PO BD for 7 days. Alternative regimen includes
erythromycin base 500 mg PO QID for 7 days or ofloxacin 300 mg PO
BD for 7 days or levofloxacin 500 mg once daily orally for 7 days.

Laboratory Diagnosis and Treatment of Common STDs: An Update

161

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

162

Recent Advances in Dermatology

pelvic inflammatory disease.26 Genital chlamydial infection is responsible


for about half of non-gonococcal urethritis (NGU) cases or even more,
if highly sensitive methods are used for diagnosis.42 Chlamydial cervicitis
may lead to pelvic inflammatory disease, cervical neoplasia and adverse
pregnancy outcome. Given the potential for morbidity from ectopic
pregnancy and tubal infertility, the case for screening for chlamydia
among those most at risk is strong.26
Many diagnostic tests for C. trachomatis have been available over the
past decade, ranging from antigen detection by monoclonal or polyclonal
antibodies to molecular biologic methods. The clinical bedside diagnostic
test Two glass test of urine, however, still remains an effective tool for
NGU.43 The presence of NGU is also demonstrated by the absence of
gram-negative intracellular diplococci, a negative gonococcal culture
and the detection of inflammatory cells (at least five polymorphonuclear
leukocytes) in the urethral smear or in the urine sediment.44 In case of
females, a simple objective criterion for the clinical diagnosis of cervicitis
has been developed.42 The cervical infection with the principal recognized
infectious causes (C. trachomatis, N. gonorrhoeae and herpes simplex virus)
correlates best with the presence of mucopurulent endocervical discharge
and the presence of > 10 polymorphonuclear (PMN) leukocytes per 1000
x microscopic field (oil immersion) in Grams stained smears. At times,
this mucopus is best confirmed by visualization of yellow
or green endocervical mucopus on a white swab (positive swab test).
Two other common signs of mucopurulent cervicitis are edema and
erythema in an area of ectopy and easily induced mucosal bleeding.
Other investigators suggest, the use of > 30 PMN leukocytes per 400x
microscopic field in Grams stained specimens of endocervical mucus as
criterion to diagnose cervicitis.42
Although, there is no absolute gold standard for chlamydia diagnostic tests, amplification assays have a sensitivity of at least 90 percent
compared with 60-70 percent for culture and 60 percent for antigen
assays.26 Nucleic acid amplification tests (NAAT) for chlamydia, including
polymerase chain reaction, ligase chain reaction and transcription
mediated amplification assays are more sensitive and highly specific.
The sensitivity of nucleic acid amplification tests on urine samples from
males is high and may even be higher than a urethral swab, perhaps
because of the limitations on taking an adequate urethral swab sample.
In women the sensitivity of urine testing is lower and a vaginal swab
is a better alternative.26
Recent restructuring of an older enzyme immunoassay (EIA) to have
an amplified signal, using recycling enzymes, has produced a more
promising EIA called IDEIA PCE.45 This assay now deserves further
critical evaluation of its use. Also during the antigen detection era of

Laboratory Diagnosis and Treatment of Common STDs: An Update

163

the 1980s, the commercialization of nucleic acid hybridization (NAH)


testing, the PACE 2 assay from GenProbe became available. This test
also contributed substantially towards our understanding of the natural
history of C. trachomatis infections, but it too, is being threatened with
replacement by NAATs.45
A single dose of azithromycin 1 gm has been shown to be effective
in treating chlamydia and other causes of non-gonococcal urethritis, but
at a much greater cost than a 7 day course of doxycycline.8,26 Single dose
treatment may be cost effective because of improved compliance,
however, even with poor compliance the cure rate with doxycycline
is still high, typically 95 percent. This is consistent with evidence that
the effective dose and possibly the duration of doxycycline treatment is
less than that recommended.26
Bacterial Vaginosis
Bacterial vaginosis (BV) is a clinical syndrome of unknown etiology
characterized by an overgrowth of vaginal anerobes and variable degrees
of depletion of the normal Lactobacillus spp. population.46 The organisms
most commonly associated with BV are Gardnerella vaginalis, Prevotella
(often described generically as Bacteroides) spp., Mobiluncus spp. and
Mycoplasma hominis.13 Symptomatic women report an offensive, fishy
smelling discharge, which is most marked after unprotected intercourse
or at the time of menstruation. Approximately 50 percent of women with
BV appear to be asymptomatic.13
BV is the commonest cause of vaginal discharge occurring in women
attending the gynecological clinics in our country.46 The diagnosis is
usually made clinically based upon the composite (Amsel) criteria and
is based on detecting at least three of four following composite criteria:
Excessive homogeneous uniformly adherent vaginal discharge
Elevated vaginal pH > 4.5
Positive amine test (Whiff test)
Clue cells (20%)
These criteria arose from the original description of Hemophilus
vaginitis by Gardner and Dukes in 1955.47 They recognized the typical
thin homogeneous discharge, elevated vaginal pH and the fishy smell.
Moreover, they described the appearance, on wet mount examination of
vaginal fluid, of epithelial cells covered with so many small bacteria that
the border was fuzzy. They called them clue cells, as their presence was
a clue to the diagnosis. These criteria remain the mainstay of diagnosis
for clinical practice. They are simple to perform in an office setting and,
apart from the outlay for the microscope, require minimal materials.13

164

Recent Advances in Dermatology

BV produces many biochemical changes in vaginal fluid. Anerobic


bacteria produce trimethylamine and polyamines such as putrescine or
cadaverine, which are associated with the fishy smell. There is an increase
in the ratio of succinate to lactate.48,49 Many bacterial enzymes are
detectable including sialidase50,51 and proline aminopeptidase.52 These
can be measured by techniques such as gas chromatography, HPLC or
by biochemical assays. Simple assays have been developed for these and
some are now becoming commercially available. A proline aminopeptidase test was found to have a sensitivity of 79 percent and specificity
of 95 percent.53
The Gram-stained vaginal smear has been compared with the
composite criteria in several studies.13 Typical lactobacilli are large grampositive rods, with blunt ends. In contrast, G. vaginalis is usually a
gram-negative coccus, although described as a gram-variable coccobacillus. Mobiluncus spp. are also easily recognised as curved rods with
pointed ends. Mob. mulieris bacilli are longer than Mob. curtissi. On wet
mount, they are highly motile by means of their central flagella. Systems
for interpreting gram-stained smears have been used by Spiegel et al,54
Nugent et al55 and Thomason et al.56 Most of these scoring systems show
a high sensitivity, >90 percent, but low specificity, 7090 percent, when
compared with Amsel criteria.13
Because BV follows a relapsing remitting course in many women, the
value of treating asymptomatic BV has not been established.13 Antibiotics
with good anti-anerobic activity should be effective treatment for BV.
The standard treatment for BV is a course of oral metronidazole. The
precise dosage and duration varies, but 400 mg twice a day for 5 days
is adequate. The cure rate immediately after treatment with metronidazole is up to 95 percent, but after 4 weeks this falls to 80 percent in
open label studies and to < 70 percent in blinded studies. A meta-analysis
concluded that a single 2 g dose of metronidazole is as effective as 5or 7-day regimens.57 Up to 30 percent of women treated for BV will
relapse within 1 month of treatment. 13 Topical treatments with
intravaginal clindamycin 2 percent cream, or metronidazole 0.75 percent
gels are licensed for the treatment of BV. Efficacy is similar to oral
metronida-zole.58, 59
BV is associated with second trimester miscarriage and preterm
birth.13,46 Several studies have evaluated the value of screening and
treating BV to prevent adverse pregnancy outcome. Unfortunately, the
results have been variable. Use of intravaginal preparations is attractive to reduce the incidence of side effects and the potential for
teratogenicity. Once infection is established in the uterus, intravaginal
treatment is unlikely to be sufficient to prevent progression to preterm
birth. Thus, topical treatment might work best in the first trimester of

Laboratory Diagnosis and Treatment of Common STDs: An Update

165

pregnancy. On current data from trials, women with a history of second


trimester loss or idiopathic preterm birth should be screened and treated
with metronidazole, if BV is found, early in the second trimester of
pregnancy.13,46
OTHER SEXUALLY TRANSMITTED DISEASES
Anogenital Warts
Condylomata acuminata are benign anogenital warts caused by human
papillomavirus (HPV), genotypes 6 and 11 being found in >90 percent
of cases.60 Patients with visible warts may be infected simultaneously
with oncogenic high risk HPVs, such as types 16 and 18, which mostly
give rise to subclinical lesions associated with intraepithelial neoplasia
(IN) and anogenital cancer.
Anogenital warts are disfiguring and can impact sexual lifestyle.60
They cause feelings of anxiety, guilt, anger and loss of self-esteem and
create concerns about future fertility and of cancer risk. Physical
symptoms may include inflammation, fissuring, itching, bleeding or
dyspareunia.
Diagnosis of warts in the anogenital region is based on the history
of the exposure, clinical appearance, epidemiological proof of the warts
in the sexual contact and the histological appearance.61 A fuller inspection
of the fossa navicularis in men is performed by meatoscopy using a
small speculum (spreader) or an otoscope.60 All women with anogenital
warts should have a speculum examination to identify the presence of
coexisting vaginal and/or cervical warts. Concurrent perineal and
perianal warts exist in one-third of patients, so anoscopy is indicated.
Following application of 5 percent acetic acid (Acetic acid test), HPV
lesions may turn grayish white for a few minutes. As the test has poor
specificity, it is only recommended for use in specialist settings where
colposcopy is available. Biopsy is unnecessary for newly occurring,
multiple, acuminate lesions, but is recommended in atypical cases for
differential diagnostic purposes or in any case where the benign nature
of a papular or macular lesion is unclear such as conspicuous Bowenoid
papulosis, Bowens disease and giant condylomas.60
The most sensitive method for detection of HPV DNA is PCR.61 This
technique is able to detect latent infection, but has little benefit in routine
diagnosis and management of condyloma and is primarily used as a
research tool. Gel electrophoresis and restriction endonuclease cleavage
are other methods employed in the detection of viral warts.
The principal shortcoming of available therapies is that no method
necessarily eradicates warts, maintains clearance and eliminates the virus;

166

Recent Advances in Dermatology

recurrence rates, including new lesions at previously treated or new,


remote sites, are often 2030 percent.60 All therapies are associated with
local skin reactions including itching, burning, erosions and pain.
Various treatments tried in the management of genital warts are
topical podophyllin, podophyllotoxin, cryotherapy, electrosurgery,
chemical cautery, carbon dioxide laser, 5-fluorouracil cream, topical
imiquimod cream, and intralesional interferon.62
Podophyllin, a crude plant extract with low efficacy, high toxicity,
and a serious mutagenicity profile does not comply with the WHO
guidelines for plant-derived treatments.63 It has been suggested that this
product should be removed from clinical treatment protocols.
Therapies which can be employed by the patient at home are:
podophyllotoxin (0.15% cream or 0.5% solution) and imiquimod (5%
cream). Each course of podophyllotoxin treatment comprises self
application twice daily for 3 days, followed by 47 rest days.60 Use of
0.5 percent podophyllotoxin solution is convenient for penile warts.
However, vulvar and anal warts are more feasibly and efficiently treated
with 0.15 percent podophyllotoxin cream when digital self-examination
and tactile sensations facilitate the application procedure. Up to 5065
percent of patients using podophyllotoxin experience transient and
acceptable burning, tenderness, erythema, and/or erosions for a few
days when the warts necrotise. Imiquimod (a new immune response
modifier) cream, supplied in single use sachets, is applied to the warts
three times a week at bedtime and the area washed with mild soap and
water the next morning. Treatment continues until wart clearance or for
a maximum of 16 weeks. Local reactions at the treatment site may occur
and a rest period of several days may be taken if required. The most
common adverse reaction seen with imiquimod use is erythema, which
occurred in 67 percent of patients. Podophyllotoxin is contraindicated
during pregnancy and women of childbearing age must use contraception
or abstain from penetrative sexual activity during therapy. No studies
have been conducted with imiquimod in pregnant women, but the drug
has not been found to be teratogenic in animal studies.60
Hospital based/office based treatments include electrosurgery, laser,
curettage, scissors excision, cryotherapy and trichloroacetic acid cautery.60
Extensive genital warts with evidence of keratinisation are often refractory to podophyllin, podophyllotoxin and cryotherapy, etc, and are best
dealt with surgically or by topical 5-fluorouracil cream. Scissor excision
has been mentioned in the treatment of sessile lesions over the shaft of
penis, labia majora, and perianal warts.62 However, circumcision for
extensive prepucial warts finds no place in the list of treatments for
genital warts in men, which was tried successfully in a case in India.62

Laboratory Diagnosis and Treatment of Common STDs: An Update

167

Because of several shortcomings including low efficacy and toxicity


problems, routine use of interferons, 5-fluorouracil, or podophyllin is
not recommended for use in the primary care setting.60 In the specialist
setting, 5-fluorouracil is sometimes used against urethral warts and
interferons alfa and beta as adjuvant to surgery in problem cases.
Immunosuppression, as consequence of HIV infection, and iatrogenically, as a result of transplant grafting, is linked to a significant increase
in multicentric and refractory condylomas and of intraepithelial neoplasia, hence, annual cytological screening of HIV positive women is
recommended.60
Sexually Acquired Hepatitis
There are now numerous reports of hepatitis A virus (HAV) outbreaks
among men who have sex with men (MSM).64 Infection correlates with
visits to saunas and darkrooms, sex with anonymous partners, group
sex, oro-anal and digital-rectal intercourse and number of partners.
Hepatitis B virus (HBV) is very efficiently transmitted sexually during
heterosexual65 and male homosexual contact.64 Heterosexual transmission
occurs in many situations, which includes sex with female sex workers
in many resource-poor countries. Transmission of HBV in homosexual
men correlates with duration of sexual activity, number of partners, oroanal and genito-anal sexual contact. Several studies have shown sexual
transmission of hepatitis D (delta virus) in both heterosexual couples
and homosexual men and this route is significant both in endemic areas
and in relation to injecting drug users in low prevalence countries.
Hepatitis C virus (HCV) can be sexually transmitted (unprotected vaginal
sex),65 but at a relatively low rate, probably 0.52 percent per year of a
relationship or 5 percent of all heterosexual relationships.64 Transmission
rates are markedly higher, if the source patient is also HIV positive.
There is also evidence for homosexual spread.64
To conclude, in heterosexual relationships, hepatitis B is readily
transmitted sexually and hepatitis C and D less so, with little evidence
for sexual transmission of hepatitis A. Hepatitis types AD are all
transmissible sexually in male homosexual relationships under certain
conditions. In resource-poor countries, sexual transmission is generally
only a significant route of transmission for hepatitis B.64
REFERENCES
1. Rosen T, Brown TJ. Genital ulcersevaluation and treatment. Dermatol Clin
1998; 16:673-85.
2. Lewis DA. Chancroid: clinical manifestations, diagnosis, and management.
Sex Transm Inf 2003; 79:68-71.

168

Recent Advances in Dermatology

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.

Laboratory Diagnosis and Treatment of Common STDs: An Update

169

26. Gilson RJC, Mindel A. Recent advancesSexually transmitted infections. BMJ


2001; 322:1160-4.
27. Scoular A, Gillespie G, Carman WF. Polymerase chain reaction for diagnosis
of genital herpes in a genitourinary medicine clinic. Sex Transm Inf 2002;
78:21-5.
28. Sundharam JA. Herpes genitalis. In: Sharma VK, ed. Sexually Transmitted
Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:25972.
29. Scoular A. Using the evidence base on genital herpes: optimising the use of
diagnostic tests and information provision. Sex Transm Inf 2002; 78:160-5.
30. Waugh M. Update on Gonorrhea. SKINmed 2003; 2(3): 188-9.
31. Bala M, Ray K, Kumari S. Alarming Increase in Ciprofloxacin- and PenicillinResistant Neisseria gonorrhoeae Isolates in New Delhi, India. Sex Transm Dis
2003; 30:523-5.
32. Braun-Falco O, Plewig G, Wolff HH, et al. Dermatology 2nd edn. Berlin:
Springer, 2000:251.
33. Johnson RE, Newhall WJ, Papp JR, et al. Screening tests to detect Chlamydia
trachomatis and Neisseria gonorrhoeae infections2002. MMWR Recomm
Rep. 2002; 51(RR-15): 1-38.
34. Thappa DM. Essential in Dermatology with MCQs. 1st edn, New Delhi: Ahuja
Publishing House, 2003:213.
35. Schwebke J R. Update of trichomoniasis. Sex Transm Inf 2002; 78:378-9.
36. Fouts AC, Kraus SJ. Trichomonas vaginalis: re-evaluation of its clinical
presentation and laboratory diagnosis. J Infect Dis 1980; 141:13743.
37. Krieger JN, Verdon M, Siegel N, et al. Natural history of urogenital
trichomoniasis in men. Urology 1993; 149:1455-8.
38. Krieger JN, Tam MR, Stevens CE, et al. Diagnosis of trichomoniasis. JAMA
1988; 259:12237.
39. Draper D, Parker R, Patterson E, et al. Detection of Trichomonas vaginalis in
pregnant women with the In Pouch TV system. J Clin Microbiol 1993; 31:
10168.
40. Lawing L, Hedges S, Schwebke J. Detection of trichomonas in vaginal and
urine specimens from women by culture and PCR. J Clin Microbiol 2000;
38:35858.
41. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management.
Am J Obstet Gynecol 1991; 165:121722.
42. Sweet RL. The enigmatic cervix. Dermatol Clin 1998; 16:739-45.
43. Majumdar S, Saha GC. Chlamydia infections and Non-gonococcal urethritis.
In: Sharma VK, ed. Sexually Transmitted Diseases and AIDS, 1st edn, New
Delhi: Viva Books Private Limited, 2003:232-46.
44. Stary A. Urethritis-Diagnosis of non-gonococcal urethritis. Dermatol Clin 1998;
16:723-6.
45. Chernesky MA. Chlamydia trachomatis diagnostics. Sex Transm Inf 2002;
78:232-4.
46. Thappa DM. Bacterial vaginosis. In: Sharma VK, ed. Sexually Transmitted
Diseases and AIDS, 1st edn, New Delhi: Viva Books Private Limited, 2003:
253-8.
47. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis. A newly defined
specific infection previously classified nonspecific vaginitis. Am J Obstet
Gynecol 1955; 69: 96276.

170

Recent Advances in Dermatology

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.

Narrowband UV-B Phototherapy

10

171

K.K. Raja Babu, A. Vilas

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

172

Recent Advances in Dermatology

from Netherlands extended its use to the treatment of vitiligo both in


adults and children.19,20
WHAT IS NARROWBAND UV-B THERAPY?
Narrowband UV-B therapy involves delivery of specific wavelengths of
light (311 nm), in gradually increasing doses two or three times a week,
to the entire body or to a part of it using specially designed lamps
(TL-01, Philips). The letters TL stand for Tube light! in phototherapy
chambers. The nominal wattage of each lamp is 100 watts at 1000 milliAmperes.
Now many manufacturers have whole body units that have only
narrowband UV-B lamps, (e.g. Spectra 311, Daavlin, USA) or a combination of both narrowband UV-B and UV-A lamps, generally 24 of each
(e.g. Spectra 311/350, Daavlin, USA). Hand and foot units that are
especially suitable to treat these areas are also available but without the
gadgetry or the sophistication of the whole body units (Spectra Mini
series, Daavlin, USA). Less expensive Indian-made machines are also
currently available.
METHOD OF USE
Narrowband UV-B therapy is most ideally suited for treatment of patients
with generalized vitiligo, although localized disease affecting hands or
feet can be treated in the Hand and Foot units. The distinct advantage
of narrowband UV-B is the ability to treat children below 12 years of age
in whom systemic PUVA therapy is generally contraindicated.21 Children
of vitiligo old enough to understand and follow instructions can be
considered for narrowband UV-B therapy.
It is important to have a general treatment protocol before recruiting
patients for narrowband UV-B phototherapy. This should include the
patients name, age, sex, address and occupation, the duration and extent
of the disease and previous treatment if any. A checklist should
categorically exclude patients with known history of photosensitivity
or photosensitive disorders or a history of skin malignancy. Patients
who are inadequately motivated or unwilling to commit themselves to
complete the course of treatment should also be excluded. So are also
patients, like the elderly and the infirm and those who cannot withstand
the rigours of therapy. Patients with more than 50 percent of body
involvement are also not ideal candidates for narrowband UV-B therapy.
To be extra cautious a prior ophthalmic examination may be performed
and aphakic patients excluded from therapy if they do not have intraocular lenses implanted. Pregnancy and lactation are not contra-

Narrowband UV-B Phototherapy

173

indications. Explanatory counseling of the therapy and its potential


benefits, or the absence of them, is necessary and an informed consent
from each patient should be taken.
A phototherapy treatment chart should be prepared and should
include the name of the patient, a PIN code, the name of the treating
doctor, the center, the date of treatment, the type of treatment (whole
body or hands/feet), the dose in mJ/cm2 and any concurrent medication
(both topical and systemic), the treatment effects, response to treatment
and special instructions, if any. The patient should be questioned about
post-treatment erythema and the length of its persistence. Generally
patients should be free of lesional erythema before the next treatment.
Narrowband UV-B therapy is given twice or thrice a week and not
on two consecutive days. As vitiligo lesions are totally devoid of pigment,
all patients are to be categorized as Fitzpatrick skin type I and no MED
determinations are generally needed. Initial dose is normally between
250 to 300 mJ/cm2 and the dose is increased by 10-20 percent at each
session of treatment (20% initially and 10% later). A 50-100 mJ increase
at every subsequent visit is satisfactory. In the authors experience, the
optimal dose is one when minimal post-treatment erythema develops in
the lesions, and disappears in a few hours (unpublished observations).
Patients should be free from post-treatment lesional erythema before
they are ready for the next increase in dose. If erythema persists, a
dosage adjustment should be made. No guidelines are available with
regard to dosage adjustments in vitiligo, and we may have to extrapolate
data from our experience of using narrowband UV-B in psoriasis. If
mild, barely perceptible, erythema is present, the previous dose is
repeated and the next increments are in the order of 10 percent. In the
presence of moderate, well-defined and asymptomatic erythema, it will
be prudent to postpone one treatment, and to repeat the earlier dose at
next visit, and only 10 percent increments are given further on.
With severe erythema (painful and persisting for more than 24 hours),
treatment should be postponed and a re-evaluation is made.
The eyes must be protected with UV blocking goggles during the
treatment sessions, but if the patient has lesions on the eyelids, goggles
are not worn but the eyes are kept shut. Unlike with PUVA there is no
need to protect the eyes post-treatment. All patients should wear thick
cotton underwear to protect the genitalia. The patients should be asked
to stay in the center of the chamber to get even exposure to all the
affected areas. Parts of the body that are lesion-free can be protected
with appropriate clothing. A broad-spectrum sunscreen may be
prescribed to prevent post-treatment excess tan of the uninvolved sunexposed skin.

174

Recent Advances in Dermatology

As narrowband UV-B therapy is fairly a new innovation, experience


with its use, especially in vitiligo, is limited. The maximum tolerable
dose of narrowband UV-B in patients of vitiligo is unknown. However,
patients have been treated up to a maximum dose of 5000 mJ/cm2
(Henry W.Lim, personal communication). Cumulative doses exceeding
100 J/cm2 have been used.20 It is also not clear, how long a patient can
be treated without a break. Westerhof recommends that a 3-month break
should be given after one year of continuous therapy.22 Once substantial
response (75% and more) occurs, the frequency of treatments can be
reduced until complete clearance of lesions. The need for maintenance
treatments has not been studied.
RESPONSE TO TREATMENT
With appropriate methodology and dose, re-pigmentation generally
begins after about 6 weeks of therapy. Some patients may take longer
to respond. If there is no response even after 6 months of continuous
therapy, it is not prudent to continue with the exercise any more. Newly
formed pigment appears perifollicularly and also at the margin of the
lesion and is initially darker than the patients skin color. Like PUVA,
certain anatomical areas respond better and faster than others. Face,
neck, arms, legs and trunk respond in that order. Lips, bony points,
fingers and toes respond poorly. Localized and generalized vitiligo
respond favourably compared to segmental and acrofacial vitiligo.19,20
Lesions of shorter duration respond better than the long-standing ones.
SIDE EFFECTS
Narrowband UV-B therapy is generally safe. No phototoxic or
photoallergic reactions have been reported. The sun exposed skin may
show an excessive tan if it is not protected adequately. Itching is rare.
Some patients may develop mild dryness of the treated skin and this
quickly clears with emollient application. As narrowband UV-B units
emanate certain heat, patients are likely to face some discomfort,
especially after longer treatment exposures (Unpublished observations).
The fewer the TL-01 lamps in a unit, the longer the exposure time
required to receive the same amount of fluence. In such a contingency,
patients may be advised to take a break in between a treatment session.
Air-conditioning phototherapy room also lessens patient discomfort.
MECHANISM OF ACTION OF NARROWBAND UV-B
The mechanism of usefulness of narrowband UV-B phototherapy in
vitiligo is unknown. Expression of endothelin I, IL-1 and tyrosinase in

Narrowband UV-B Phototherapy

175

human keratinocytes has been shown to increase both in vitro and in


vivo after UV-B radiation suggesting their possible role in UV-B induced
pigmentation.23 UV light has also been shown to stimulate the production
of nerve growth factor by keratinocytes.24 Whether nerve growth factor
has the ability to protect melanocytes in the follicular reservoir from
immunological destruction or play some role in their proliferation is not
known. What role cis-urocanic acid or the morphological and functional
alterations in Langerhans cells that follow UV-B radiation play in the
development of new pigment formation is also not clear.25-27
CLINICAL STUDIES
Westerhof and Nieweboer-Krobotova19 were the first to study the effect
of narrowband UV-B on vitiligo in 1997. In a two-arm treatment trial,
the investigators compared twice-weekly topical PUVA with twice-weekly
narrowband UV-B therapy. They showed that after 4 months of therapy,
67 percent of vitiligo patients undergoing narrowband UV-B therapy
showed re-pigmentation compared to 46 percent of vitiligo patients on
topical PUVA. Importantly, 8 percent of patients showed more than 75
percent repigmentation only after 3 months of narrowband UV-B therapy.
The researchers concluded that narrowband UV-B phototherapy was an
effective treatment option for patients with active, extensive and
generalized vitiligo and was associated with fewer side effects. In a
further study in 2000, Njoo, Bos and Westerhof reported the effects of
narrowband UV-B therapy in children (including one Indian girl
child) with generalized vitiligo.20 In an open study, 51 children (20 boys,
31 girls, age range 4 to 16 years) with generalized vitiligo were treated
with twice-weekly narrowband UV-B radiation for a maximum of 1
year. The treatment resulted in more than 75 percent overall re-pigmentation in 53 percent of patients and in stabilization of the disease in
80 percent. There were very few adverse effects. One meta-analysis
study28 comparing different forms of non-surgical therapies for vitiligo
had revealed the following success rates for different types of
phototherapy in generalized vitiligo: Oral PUVA51 percent, UV-B
57 percent and Narrowband UV-B63 percent.
Scherschun and colleagues from the U.S. reported in 2001 their
experience with seven patients of vitiligo (4 males and 3 females, age
range 19 to 59 years) who received narrowband UV-B, three times a
week, over a 12-month period.29 Three patients were of skin types IV
and V, four with types II and III. Five of the 7 patients achieved more
than 75 percent pigmentation after a mean of 19 treatments. The
remaining 2 patients had 50 percent and 40 percent re-pigmentation
after 46 and 48 treatments respectively. Those who responded faster and

176

Recent Advances in Dermatology

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

Narrowband UV-B Phototherapy

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

Recent Advances in Dermatology

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.

Narrowband UV-B Phototherapy

179

31. Lotti TM, Menchini G, Andreassi L. UV-B radiation microphototherapy: An


elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999;
113: 102-8
32. Menchini G, Tsoureli-Nikita E, Hercogova J. Narrow-band UV-B microphototherapy: a new treatment for vitiligo. J Eur Acad Dermatol Venereol
2003; 17:171-7.
33. Trehan M, Taylor CR. High dose 308-nm excimer laser for the treatment of
psorisis. J Am Acad Dermatol 2002; 46: 732-7.
34. Feldman SR, Mellen BG,Housman TS, et al. Efficacy of the 308-nm excimer
laser for treatment of psoriasis: Results of a multicenter study. J Am Acad
Dermatol 2002;46:900-6.
35. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer
laser: A pilot study. J Am Acad Dermatol 2002; 46: 727-31.
36. Taneja A, Trehan M, Taylor CR. 308-nm excimer laser for the treatment of
localized vitiligo. Int J Dermatol 2003; 42: 658-62.

180

Recent Advances in Dermatology

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

Newer Drugs in Dermatology: Systemic

181

to MPA glucuronide (MPAG) which is inactive. MPAG cannot penetrate


the cell membrane of most tissue types and more than 90 percent of the
drug is excreted in the urine as MPAG and 6 percent is eliminated in
feces. Bioavailability of MPA is 94 percent after oral intake. Peak MPA
level occurs approximately 1 hour post-dose with a secondary peak
occurring 6 to 8 hours later due to enterohepatic recirculation of MPAG
and its hydrolysis back to MPA in gastrointestinal tract.
Indications and Dosage
MMF is primarily used, as approved by FDA, for the prophylaxis of
organ rejection in patients receiving allogenic renal, hepatic or cardiac
transplant in conjunction with cyclosporine and corticosteroids.8,9 MMF
2 gm daily seems to be an effective therapeutic tool for psoriasis and
psoriatic arthritis patients,10 particularly those who are intolerant of or
unresponsive to other treatment modalities or who are at risk of
developing renal toxicity due to cyclosporine.11-16
MMF may be used as monotherapy for pemphigus vulgaris or bullous
pemphigoid17,18 and this offers the advantage of lesser side-effects in
comparison to combination with steroids or other immunosuppressants.
However, it may be used in combination with steroids19 in refractory
cases. It is going to be the drug of choice as adjuvant therapy along with
corticosteroids in the treatment of pemphigus vulgaris by replacing
other immunosuppressants like azathioprine, cyclophosphamide, etc.
MMF is found to be quite safe, effective and well tolerated in moderate
to severe atopic dermatitis.20,21
MMF seems to be an attractive treatment option for cases of subacute
cutaneous lupus erythematosus (SCLE), not responsive to steroids,
immunosuppressants or antimalarials.22 There are reports of successful
treatment of resistant cases of DLE of palms and soles with MMF.23
Severe recalcitrant pyoderma gangrenosum may be treated with MMF
in combination with cyclosporine or autologous keratinocyte transplantation.24,25 Skin and oral lesions of paraneoplastic pemphigus were found
to become inactive with oral MMF.26
MMF alone or in combination with IVIG can avoid side-effects of
high doses and prolonged duration of steroid therapy in dermatomyositis
and can induce long-lasting remission of this disorder.27
MMF should be administered on an empty stomach because food
diminishes its absorption. The dose of the drug is as follows:
For renal transplant patients1 gram twice a day; other diseases
1 to 2 grams per day in divided doses.

182

Recent Advances in Dermatology

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.

Newer Drugs in Dermatology: Systemic

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

Recent Advances in Dermatology

and a single dose of ivermectin appears to be of equal or better efficacy


in comparison to topical lindane.57 Ivermectin is better than benzyl
benzoate for childhood scabies.58 Optimum dosing for scabies, however,
remains somewhat uncertain.59,60 A dose of 200 mcg /kg should be most
widely employed; but whether one, two or three such doses should be
routinely given is a subject of conjecture.
Therapeutic dose for pediculosis capitis is 400 mcg/kg and should
be repeated in 7 to 10 days.61
Ivermectin shows excellent efficacy in several types of filariasis62-65
and dose to be given should be 400 mcg/kg repeated twice yearly.
Ivermectin is effective against nematodes, especially ascariasis,
threadworm, whipworm and pinworm, but has an insignificant effect
on hookworms. Trematodes and cestodes have a natural resistance against
ivermectin, since they do not use GABA as a peripheral nervous system
neuro-transmitter. It does not cross blood-brain barrier and hence, is not
effective in neurocysticercosis.
A single dose of ivermectin 200 mcg/kg is potentially quite effective
in cutaneous larva migrans caused by cat and dog hookworms.66-69
Ivermectin can be considered in a sufficiently extensive case of myiasis,
as suggested by its usage in a single case report.70
Contraindications
Ivermectin has the following contra-indications:
Known hypersensitivity to the ivermectin group of drugs.
Pregnancysafety not established (category C prescribing status).
Should be avoided in patients with CNS disorders.
Children less than 15 kg body weight and those below 5 years of
agesafety not established yet.
Adverse Effects
No major side effects attributable to ivermectin have been seen in
onchocerciasis control programmes wherein more than 19.5 million doses
have been distributed all over the world. Mild and transient side effects
may be tachycardia, flushing, nausea, headache, pruritus, rash, arthralgia,
dizziness and lymphadenopathy.
The Mazottis reaction is a unique reaction seen in onchocerciasis
patients undergoing treatment. It is characterized by major features like
fever, orthostatic hypotension, bronchospasm and neurologic
deterioration and by minor features like itching, rash, headache and
joint pain. This serious side effect has been linked to a hypersensitivity
reaction to dead and dying systemic parasites.

Newer Drugs in Dermatology: Systemic

185

Interestingly, multi-drug resistance (MDR) gene product functions as


a cellular pump which moves some drugs (including ivermectin) outside
the cell. Ivermectin is an excellent substrate for MDR gene product.
Perhaps MDR, in association with blood-brain barrier, functions as a
potent protector of human central nervous system. Thus, nearly all
humans seem to be protected from potential toxic effects of the drug.
MDR gene product is entirely absent or dysfunctional in susceptible
animals.50,71 Young children weighing less than 15 kg or less than two
years of age should be given ivermectin cautiously because of a
diminished blood-brain barrier and perhaps defective MDR gene product.
THALIDOMIDE
Thalidomide is a non-polar glutamic acid derivative, alpha-Nphthalimidoglutarimide and acts as an immunomodulatory agent.72 It
was introduced in 1950 in Europe, Australia and various African and
Asian countries but was not approved by US-FDA for marketing. It was
found to be useful as a barbiturate-free sedative with potent antiemetic
action,73 and therefore, was being used as an antiemetic and sedative in
pregnancy as well. Soon the reports of infantile limb defects (phocomelia)74,75 and internal deformities came into focus and in 1961, this
drug was rapidly withdrawn from the world market in view of its high
teratogenic potential. In 1965, it was reported to dramatically improve
the symptoms of erythema nodosum leprosum (ENL).76 In 1997, it was
granted approvable status for the treatment of ENL by US-FDA.77 Since
then, it is being used in various conditions as an off-label drug.
Mechanism of Action
Thalidomide possesses multiple biologic activities probably attributed
to its various cleavage products.77 It has hypno-sedative effect comparable
to that of barbiturates, though it acts in a different way not determined
as yet. By virtue of this sedative property, it is probably useful in actinic
prurigo and prurigo nodularis.77
It has potent anti-inflammatory activity, presumably by specific
inhibition of tumour necrosis factor-alpha (TNF-alpha).78 It also inhibits
IL-12 production.79 IL-12 inhibition leads to inhibition of interferongamma production80 which suppresses immunity mediated by T-helper
(Th) cells.81 There is a selective increased production of IL-4 and IL-5
which are B-cell activators.80
Thalidomide decreases neutrophil chemotaxis and phagocytosis82,83
as well as antagonizes actions of inflammatory mediators82 which explains
its role in inflammatory diseases.

186

Recent Advances in Dermatology

Thalidomide also down-modulates selected cell surface adhesion


molecules involved in migration of leucocytes.84,85 It down-regulates
beta-2 integrin mainly and also beta-1 integrin and alpha-4 integrin on
circulating human leucocytes.
Thalidomide inhibits angiogenesis86 especially that stimulated by
the protein FGF-2 (fibroblast growth factor-2) and IGF-1(insulin-like
growth factor type 1). Anti-angiogenesis explains its teratogenic potential
as well as its usefulness as an antineoplastic agent.
Thalidomide inhibits TNF-alpha production and NFkB, a cytoplasmic
protein that enhances HIV transcription. Inhibition of TNF-alpha and
NFkB thus leads to inhibition of HIV replication in vivo.73
Pharmacokinetics
It is poorly soluble in water72 and is available as an oral formulation
only.77 Food does not interfere with its absorption. It is slowly absorbed
from gastro-intestinal tract and peak plasma level is attained within 26 hours.87 Due to its lipid solubility, it readily crosses the placental
membrane.76 Absolute bio-availability of thalidomide is not yet
characterized in humans because of poor water solubility.72 It undergoes
non-enzymatic hydrolysis88 in plasma to most of its twelve theoretically
possible metabolites89 and does not appear to be metabolized in liver to
a large extent.72
Half-life of thalidomide is approximately 5-9 hours following a single
dose and is not altered on multiple dosing.72 Its excretion is primarily
non-renal, with less than 1 percent of a dose found unchanged in the
urine after 24 hours.
Indications and Dosage
Thalidomide is the drug of choice for ENL82,90 and is FDA-approved for
this purpose. Ninety-nine percent of patients of ENL were found to
respond to thalidomide in a review of more than 4500 cases.91 Lesions
resolve within 24-48 hours91 and other symptoms also respond in a few
days. Motor nerve conduction velocity returns to almost normal within
2 weeks.73 The initial regimen is 100 mg four times daily92-94 and after
control of the reaction, the dosage is tapered over two weeks to a
maintenance level, usually 100 mg daily.95,96 Thalidomide has no action
on M.leprae and anti-leprosy chemotherapy should continue throughout the treatment of reactional state of leprosy.97 The drug is not effective
in type 1 lepra reaction.97
Thalidomide is quite effective in HIV-associated mucosal ulceration.
AIDS wasting associated with tuberculosis and aphthous ulcer respond

Newer Drugs in Dermatology: Systemic

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

Recent Advances in Dermatology

as a treatment of choice for Langerhans cell histiocytosis123-25 because


induction of proliferation of Langerhans cells can be reversed by thalidomides inhibition of TNF-alpha production.126
Anecdotal evidence exists to support a trial of thalidomide in the
following conditions: Weber-Christian disease, 127 palmo-plantar
pustulosis,128 uremic pruritus,129 post-herpetic neuralgia,130 bullous
pemphigoid,131 cicatricial pemphigoid,131 erythema multiforme,132-134
sarcoidosis,135 pyoderma gangrenosum136,137 and Jessner-Kanof disease.138
Contraindications77
Thalidomide is absolutely contraindicated in:
Known sensitivity to thalidomide
Pregnancy
Women of childbearing potential without strict contraception
Men actively engaging in sexual intercourse with women who may
become pregnant
Pre-existing peripheral neuropathy.
Relative contraindications are:
Significant liver or kidney impairment
Neuritis or other neurological disorder
Congestive cardiac failure
Hypertension
Significant constipation
Hypothyroidism
Adverse Effects
If thalidomide is taken during pregnancy, it can cause severe birthdefects or death to an unborn baby. The most common defects are
phocomelia (deformity with under-development of arms, legs or both)
or amelia (absence of limbs). Other defects are aplasia of thumbs, anotia,
facial palsy, microphthalmia and ophthalmoplegia.73 Abnormalities of
renal, gastrointestinal and urogenital systems also may occur.74,76 Even
a single dose of 50 mg, if taken during pregnancy can cause severe birth
defects.74,76 Because of this toxicity and in an effort to make the chance
of fetal exposure to thalidomide as negligible as possible, thalidomide
is approved for marketing only under a special restricted distribution
programme approved by FDA. This programme is called the System
for thalidomide education and prescribing safety (S.T.E.P.S). Under this
programme, only prescribers and pharmacists registered with the
programme are allowed to prescribe and dispense the product.

Newer Drugs in Dermatology: Systemic

189

Effective contraception must be used for at least four weeks before


initiating thalidomide therapy, during thalidomide therapy, and for four
weeks following discontinuation of thalidomide therapy. Two reliable
forms of contraception must be used simultaneously. Pregnancy test
with a sensitivity of at least 50 miu/ml should be performed within 24
hours prior to beginning therapy in women of child-bearing potential.
Once treatment is begun, pregnancy testing should be done weekly
during first month, then monthly thereafter. If menstrual cycles are
irregular, pregnancy testing should occur every two weeks. Males
receiving thalidomide must always use a latex condom during any
sexual contact with women of child-bearing potential. Male patients
should not be permitted to donate sperms while on thalidomide therapy.
Patients should be instructed not to share medication with anyone else.
Peripheral neuropathy is a common, potentially severe, side effect of
thalidomide that may be irreversible. It usually occurs following chronic
use over a period of months, but short-term use may also cause peripheral
neuropathy. Patients most commonly present with mild proximal muscle
weakness with pain, tingling and numbness in the hands and feet and
sensory loss in lower limbs.139 Patients should be regularly counseled
and evaluated for signs and symptoms of peripheral neuropathy, monthly
for first three months and thereafter every one to six months as indicated.
To detect asymptomatic neuropathy, electrophysiologic testing consisting
of measurement of sensory nerve action potential (SNAP) amplitudes
from at least three nerves as baseline and every six months thereafter,
should be considered. A fall of 40 percent or more from baseline should
be considered significant.77 Thalidomide should be immediately stopped
if signs and symptoms of neuropathy develop. Motor weakness usually
improves rapidly after stopping the drug but sensory dysfunction
improves slowly, if at all.74
Thalidomide frequently causes drowsiness and sedation. Patients
should be asked to avoid situations where drowsiness may be a problem
and concomitant medication that may cause sedation should be avoided.
Thalidomide may potentiate somnolence caused by alcohol. Orthostatic
hypotension and dizziness may occur after thalidomide intake. Therefore,
patients should sit upright for a few minutes before standing up from
recumbent position.
Other less common side effects with potentially severe complications
include neutropenia140 and erythroderma.141,142 If absolute neutrophil
count is below 750 per cubic mm, thalidomide should not be started.
Total and differential count of WBC and platelet count should be
measured on initiating thalidomide therapy and monthly thereafter until
the dose is stable.

190

Recent Advances in Dermatology

HIV seropositive patients may show increase in plasma HIV RNA


levels after thalidomide therapy, clinical significance of which is not
known.
Other adverse effects of less consequence include constipation, nausea,
increased appetite, xerosis, pruritus, hyperglycemia, bradycardia,
decreased libido, brittle finger-nails.74,143 SJS/TEN and seizures have
also been reported.72
INFLIXIMAB
Infliximab is a chimeric immunoglobulin (IgG1k) monoclonal antibody144
that binds specifically to and inactivates human tumour necrosis factoralpha (TNF-alfa).145 It is composed of human constant and murine variable regions146 and is produced by a recombinant cell line cultured by
continuous perfusion.146
Mechanism of Action
Infliximab binds to both monomer and trimer forms of soluble TNF-alfa
as well as cell-surface transmembrane forms of TNF-alfa.147 It forms
stable complexes with them and inhibits binding of TNF-alfa with its
receptors.146
TNF-alfa is a key cytokine in innate immune response and in inflamed
skin, keratinocytes and inflammatory cells both produce large amounts
of TNF-alfa.148 TNF-alfa increases production of pro-inflammatory
cytokines such as IL-1, IL-6, IL-8, NF-kappaB.149 It also enhances migration of leucocytes by increasing the permeability of endothelial cells146
and expession of adhesion molecules (e.g. Intercellular adhesion
molecule-1, E-selectine, P-selectine) by endothelial cells and leucocytes.149
TNF-alfa promotes apoptosis by binding to TNF-receptor 1.149 Psoriatic
lesions are hyperproliferative despite an increase in TNF-alfa. Perhaps
NF-kappaB activation seems to inhibit TNF-alfa-induced apoptosis in
psoriasis.149
Blockade of this proinflammatory cytokine, TNF-alfa by infliximab
may thus be effectively used in treatment of inflammatory conditions
e.g. psoriasis, rheumatoid arthritis, Crohns disease, etc.148
Pharmacokinetics
There is a predictable and linear relationship between the dose given
and the peak serum concentration and area under the concentrationtime curve, after a single IV infusion.146 Terminal half-life of infliximab
is 8-9.5 days.146

Newer Drugs in Dermatology: Systemic

191

Indications and Dosage


It is FDA-approved for use in combination with methotrexate in
moderately to severely active rheumatoid arthritis showing inadequate
response to methotrexate.146 It is also approved by FDA for moderate to
severely active Crohns disease refractory to conventional therapy146,150,151
and also for reduction in number of draining enterocutaneous fistulae
in patients with fistulising Crohns disease.146
Infliximab IV infusion as a monotherapy152-155 gives rapid, effective
and prolonged remission156 in moderate to severe plaque psoriasis
without adverse events.144 A single infusion of infliximab at 5-10 mg/
kg was found to clear recalcitrant plaque of psoriasis and erythroderma
rapidly and completely for a period of 3-4 months.145 It may be combined
with low-dose methotrexate for severe recalcitrant pustular psoriasis157
and psoriatic arthritis.148,158,159 It is speculated that infliximab may
actually alter the natural history of skin manifestation of psoriasis.156
TNF-alfa blockade is being studied in treatment of uveitis, graft vs
host disease and myelodysplastic syndrome150 to circumvent serious
side-effects with cytotoxic agents and immunosuppressants.
Other potential indications160,161 seem to be Behcets disease, bullous
dermatoses, neutrophilic dermatitis, TEN, systemic vasculitis.
Contraindications
The principal contraindication is known hypersensitivity to any murine
proteins or other components of the product.
Adverse Effects
Acute infusion reaction may occur during the infusion or within 1-2
hours after the infusion and is manifested by fever or chills, pruritus,
urticaria or cardio-pulmonary symptoms. Patients who become positive
for antibody to infliximab are more likely to develop infusion reaction.
After a drug-free interval of 2 years, reactions may occur on readministration, particularly on those who did not have reaction on initial
infliximab therapy.146
Dyspnea, urticaria, and headache are most common adverse effects
requiring discontinuation of therapy.
Serious infections including sepsis have been reported in patients on
infliximab. It should not be given to patients with a clinically important
active infection and patients should be monitored for signs and symptoms
of infection while on infliximab therapy. Cases of histoplasmosis,
listeriosis, pneumocystosis and tuberculosis162 have been reported.

192

Recent Advances in Dermatology

There may be formation of auto-antibodies against infliximab and


rarely lupus-like syndrome may develop which requires discontinuation
of therapy.146
In patients with pre-existing or recent onset of CNS demyelinating
disorder, one should exercise caution in prescribing infliximab.146
It is recommended that live vaccines should not be given concurrently.146 There are insufficient data to determine whether infliximab
contributes to development of malignancies.
Infliximab has a pregnancy prescribing category B status. Infliximab
may increase triglyceride level and decrease HDL-cholesterol level
without affecting total cholesterol level.163 Lipid levels should be checked
and monitored in patients receiving infliximab therapy, particularly in
patients with vascular disease.163
Conclusion
Infliximab forms a member of new generation of biologic therapy
targeting the activity of T-lymphocytes and cytokines responsible for
inflammatory nature of the disease. Other biologic agents of importance
include etanercept, efalizumab and alefacept.164 Further studies of optimal
dosing, combination with other therapies and long-term benefits and
side effects will emerge from future trials.150
BEXAROTENE
It is a novel synthetic retinoid analogue (rexinoid) that binds selectively
to retinoid x receptors (RXR)165 and is approved by FDA for all stages
of cutaneous T-cell lymphoma (CTCL).166
Mechanism of Action
Bexarotene is a selective retinoid x receptor (RXR) agonist. It binds and
transactivates nuclear RXR which acts as ligand-activated transcription
factors.167 Retinoid receptors bind their ligands in form of dimers.
Heterodimers can be formed between RXR and triiodothyronin receptors
or vitamin D receptors.168 Gene expression is controlled by these ligandactivated transcription factors which lead to modulation of cell growth,
differentiation and apoptosis.167 It may exert its antineoplastic effect by
regulating tumour suppressor gene such as RAR-B2.169
Pharmacokinetics
Bexarotene is well absorbed orally and its bioavailability is increased if
taken with fatty meal.170,171 Peak level of the drug is reached after two

Newer Drugs in Dermatology: Systemic

193

hours of oral intake172 and it is 99 percent bound to plasma proteins.170


However, within 1 month after stopping the drug, it is not detected in
serum.
It is mainly metabolized in liver by oxidation and chain-shortening.
Terminal elimination half-life of bexarotene is 7 to 9 hours.172 It is mainly
excreted through hepatobiliary route.172
Indications and Dosage
It is FDA approved for selected cases of mycosis fungoides173-176 which
is resistant to at least one systemic therapy. Patch and early plaque stage
respond the most.170 It can be used as monotherapy or in combination
with interferon, PUVA, etc. Bexarotene shows a dose response antitumour
activity in CTCL.173 It is recommended that bexarotene should be taken
as a single daily oral dose with a meal and initial dose should be
300 mg/sq.m/day which can be increased later according to the response
and may be continued indefinitely. It is not necessary to take precautions
for short-term exposure with bexarotene treatment.177
Mycosis fungoides pursues an aggressive course when associated
with follicular mucinosis. It may undergo large-cell transformation which
is associated with poor prognosis and resistance to therapy.178 Bexarotene
in combination with local radiation therapy, total-skin electron beam
therapy achieved a durable complete remission of CTCL.178 It is found
to be quite effective in palliative therapy of lymphomatoid papulosis.179
It is used in all stages of CTCL at a dosage of 300 mg/sq.m/day180
both as a monotherapy and in combination with other agents.181
Bexarotene is effective both for early stage patients with extensive plaques
of long duration and for late stage patients with Szarys syndrome or
large-cell transformation.182,183 Lesional size, duration and scaling of
earlier lesions show marked improvement.184
Use of statins with bexarotene permit higher dose usage of the
latter with high response rate.181
Adverse Effects
The common side effects associated with bexarotene therapy include
hypertriglyceridemia, hypercholesterolemia, central hypothyroidism,
headache and asthenia.167 Bexarotene increases triglyceride and
cholesterol levels even in modest doses.167,170 To circumvent the risk of
increased TG and pancreatitis, it is recommended that atorvastatin should
be co-administered with bexarotene. Gemfibrozil increases bexarotene
level which limits their concurrent use.173,185 Instead, fenofibrate may be
used.

194

Recent Advances in Dermatology

Teratogenicity is the most important adverse effect of bexarotene.


Adequate contraception should be employed by females at least 1 month
before therapy, during therapy and for 1 month after stopping the drug.
At least two methods of contraception should be used. Serum or urine
pregnancy test should be obtained within one week of expected menstrual
cycle and monthly thereafter. Bexarotene should be started on the second
or third day of a normal menstrual cycle. Male patients must use condoms
during therapy and for one month after stopping the drug.186
High incidence of reversible acute pancreatitis167 (1-3%) has been
seen in patients getting bexarotene 300 mg/day. Patients having riskfactors for pancreatitis should avoid bexarotene.
Bexarotene has the potential of inducing reversible central hypothyroidism.167 Baseline TFT should be performed before initiating therapy
and then regularly monitored.
It may cause reversible leucopenia within 4 to 8 weeks after therapy
which becomes normal after stopping the drug or reducing the dose.
REFERENCES
1. Mitsui A, Suzuki S. Immunosuppressive effect of mycophenolic acid. J Antibiot
(Tokyo) 1969; 22:358-63.
2. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of
mycophenolate mofetil (MMF). Clin Transplant 1996; 10:7784.
3. Carr SF, Papp E, Wu JC, et al. Characterization of human type 1 and type 2
IMP dehydrogenases. J Biol Chem 1996;268:2728690.
4. Eugui EM, Mirkovitch A, Allison AC. Lymphocyte-selective anti proliferative
and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol
1991;33:175.
5. Schiff MH, Goldblum R , Rees MMC. New DMARD. Mycophenolate mofetil
(Myco M) effectively treats rheumatoid arthritis (RA) patients for one year.
Arthritis Rheum 1991;34:S89.
6. Hoffman La Roche Inc. Cellcept (Mycophenolate mofetil) Product Information,
1995.
7. Nousari HC, Grant JA. Immunosuppressive and immunomodulatory drugs.
In: Freedberg IM, Eisen AZ, Wolff K eds. Fitzpatricks Dermatology in general
medicine. 5th ed. Philadelphia: McGraw Hill,International ed. 1999:2860.
8. European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled
study of mycophenolate mofetil combined with cyclosporine and corticosteroids
for prevention of acute rejection. Lancet 1995;345:1321-5.
9. Solinger HW, US Renal transplant Mycophenolate Mofetil Study Group:
Mycophenolate mofetil for the prevention of acute rejection in cadaveric renal
allograft recipients. Transplantation 1995;60:225-232.
10. Grundmann-Kollmann M, Mooser G, Schraeder P, et al. Treatment of chronic
plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J
Am Acad Dermatol 2000; 42: 835-7.
11. Ameen M, Smith HR, Barker JN. Combined mycophenolate mofetil and
cyclosporine therapy for severe recalcitrant psoriasis. Clin Exp Dermatol 2001;
26: 480-3.

Newer Drugs in Dermatology: Systemic

195

12. Feldman S. Advances in psoriasis treatment. Dermatol Online J 2000; 6:4.


13. Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: Positive experience in 11 patients. Br J Dermatol 2001; 144:
583-6.
14. Davison SC, Morris-Jones R, Powles AV, et al. Change of treatment from
cyclosporine to mycophenolate mofetil in severe psoriasis. Br J Dermatol
2000;143:405.
15. Tong DW, Walder BK. Widespread plaque psoriasis responsive to mycophenolate mofetil. Australas J Dermatol 1999; 40:135-7.
16. Haufs MG, Beissert S, Grabbe S, et al. Psoriasis vulgaris treated successfully
with mycophenolate mofetil. Br J Dermatol 1998; 138:179-81.
17. Grundmann-Kollmann M, Korting HC, Behrens S, et al. Mycophenolate mofetil:
New therapeutic option in the treatment of blistering autoimmune diseases.
J Am Acad Dermatol 1999; 40: 957-60.
18. Nousari HC, Sragovich A, Kimyai-Asadi A, et al. Mycophenolate mofetil in
autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999; 40:
265-8.
19. Enk AH, Knop J. Mycophenolate is effective in the treatment of pemphigus
vulgaris. Arch Dermatol 1999; 135:54-6.
20. Grundmann-Kolmann M, Podda M, Ochsendorf F, et al. Mycophenolate mofetil
is effective in the treatment of atopic dermatis. Arch Dermatol 2001;137:
870-3.
21. Neuber K, Schwartz I, Itschert G, et al.Treatment of atopic eczema with oral
mycophenolate mofetil. Br J Dermatol 2000; 143:385-91.
22. Schanz S, Ulmer A, Rassner G, et al. Successful treatment of subacute cutaneous
lupus erythematosus with mycophenolate mofetil. Br J Dermatol 2002;147:
174-8.
23. Goyal S, Nousari HC. Treatment of resistant discoid lupus erythematosus of
the palms and soles with mycophenolate mofetil. J Am Acad Dermatol
2001;45:142-4.
24. Gilmour E, Stewart DG. Severe recalcitrant pyoderma gangrenosum responding
to a combination of mycophenolate mofetil with cyclosporine and complicated
by a mononeuritis. Br J Dermatol 2001;144:397-400.
25. Wollina U, Karamfilov T. Treatment of recalcitrant ulcers in pyoderma
gangrenosum with mycophenolate mofetil and autologous keratinocyte
transplantation on a hyaluronic acid matrix. J Eur Acad Dermatol Venereol
2000; 14:187-90.
26. Williams JV, Marks JG Jr., Billingsley EM. Use of mycophenolate mofetil in the
treatment of paraneoplastic pemphigus. Br J Dermatol 2000; 142:506-8.
27. Anne-Kathrin T, Michael M. Mycophenolate mofetil for dermatomyositis.
Dermatology 2001; 202:341-43.
28. Kitchin JE, Pomeranz MK, Pak G, et al. Rediscovering mycophenolic acid: A
review of its mechanism, side effect, and potential uses. J Am Acad Dermatol
1997;37:445-9.
29. Platz KP, Sollinger HW, Hullett DA, et al. RS-61443: A new, potent
immunosuppressive agent. Transplantation 1991;51:27-31.
30. Lynch WS, Roenigk HH Jr. Mycophenolate acid for psoriasis. Arch Dermatol
1977;113:1203.
31. Spatz S, Rudnicka A, McDonald CJ. Mycophenolic acid in psoriasis. Br J
Dermatol 1978;98:429-35.

196

Recent Advances in Dermatology

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
1987;17:962-971.
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
acid and ivermectin. Proc Natl Acad Sci USA 2000; 97:13949-54.
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
Dermatologic Drug Therapy, Philadelphia: WB Saunders Company, 2001:
537-546.
43. Brieger WR, Awedoba AK, Eneanya CI, et al. The effects of ivermectin on
onchocercal skin disease and severe itching: Results of a multicentre trial. Trop
Med Int Health 1998;3:951-61.
44. Brown KR, Neu DC. Ivermectin clinical trials and treatment schedules in
onchocerciasis. Acta Leiden 1990;59:169-75.
45. Newell ED. Effect of mass treatments with ivermectin, with only partial
compliance, on the prevalence and intensity of O.volvulus infection in adults
and in untreated 4 and 5 year old children in Burundi. Trop Med Int Health
1997;2:912-6.
46. Ngoumou P, Essomba RO, Godin C. Ivermectin-based onchocerciasis control
in Cameroon, World Health Forum 1996;17:25-8.
47. Stromectol (ivermectin). Package insert, Merck and Co.West Point, PA.1996.
48. Datry A, Hilmarsdottir I, Mayorga- Sagastume R, et al. Treatment of
Strongyloides stercoralis infection with ivermectin compared with Albendazole:
Results of an open study of 60 cases. Trans R Soc Trop Med Hyg 1994;88:
344-5.
49. Toma H, Sato Y, Shiroma Y, et al. Comparative studies on the efficacy of three
antihelminthics on treatment of human strongyloidiasis in Okinawa, Japan.
Southeast Asian J Trop Med Public Health 2000;31:147-51.
50. Marti H, Haji HJ, Savioli L, et al. A comparative trial of a single-dose ivermectin
versus three days of albendazole for the treatment of strongyloides stercoralis
and other soil-transmitted helminth infections in children. Am J Trop Med
Hyg 1996;55:477-81.

Newer Drugs in Dermatology: Systemic

197

51. Gann PH, Neva FA, Gam AA. A randomized trial of single-and two-dose
ivermectin versus thiabendazole for treatment of strongyloidiasis. J Infect Dis
1994;169:1076-9.
52. Celedon JC, Mathur-Wagh U, Fox J, et al. Systemic strongyloidiasis in patients
infected with the human immunodeficiency virus. A report of 3 cases and
review of the literature. Medicine (Baltimore) 1994;73:256-63.
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
topical permethrin cream in the treatment of scabies. J Am Acad Dermatol
2000;42:236-40.
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.

198

Recent Advances in Dermatology

71. Schinkel AH, Wagenaar E, Mol CA, et al. P-glycoprotein in the blood-brain
barrier of mice influences the brain penetration and pharmacological activity
of many drugs. J Clin Invest 1996;97:2517-24.
72. Thalidomide (003413) Mosbys Drug Consult Copyright 2003 Mosby, Inc.
73. Tappeiner G, Wolff K. Thalidomide. In: Freedberg IM, Eisen AZ, Wolff K, eds.
Fitzpatricks Dermatology in General Medicine, 5th ed.International edition,
Philadelphia: McGraw-Hill,1999:2864-70.
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
of thalidomide. Postgrad Med J 1994;70:901-904.
76. Stirling D, Sherman M, Strauss S. ThalidomideA surprising recovery. J Am
Pharm Assoc 1997; NS37:306-13.
77. Alfred LK Jr. Miscellaneous Systemic Drugs. In Wolverton SE, ed.
Comprehensive Dermatologic Drug Therapy. Philadelphia, WB Saunders
Company, 2001:445-70.
78. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumour
necrosis factor-alpha production by stimulated human monocytes. J Exp Med
1991;173:699-703.
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
Rev 1985;56:35-39.
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.

Newer Drugs in Dermatology: Systemic

199

91. Sheskin J. The treatment of lepra reaction in lepromatous leprosy:15 years


experience with thalidomide. Int J Dermatol 1980;19:318-22.
92. Sheskin J, Convit J. Results of a double-blind study of the influence of
thalidomide on the lepra reaction. Int J Lepr 1969;37:135-46.
93. Iyers CGS, Languillon J, Ramanujam K, et al. WHO coordinated short-term
double-blind trial with thalidomide in the treatment of acute lepra reactions
in male lepromatous patients. Bull World Health Org 1971;45:719-32.
94. Jew LJ. Thalidomide in erythema nodosum leprosum. DICP. Ann Pharmacother
1990;24:482-3.
95. Reynolds JEF. editor: Martindale: The Extra Pharmacopoeia (electronic version),
Denver, Co, 1993, Micromedix, Inc.
96. Levis WR. Treatment of leprosy in the United States. Bull NY Acad Med
1984;60:696-711.
97. AMA Department of Drugs: Drug evaluation subscription, Chicago, 1991, Am
Med Association.
98. Haslett P, Hempstead M, Seidman C, et al. The metabolic and immunologic
effects of short-term thalidomide treatment of patients infected with the human
immunodeficiency virus. AIDS Res Hum Retroviruses 1997;13:1047-54.
99. Ghigliotti G, Repetto T, Farris A, et al. Thalidomide: Treatment of choice for
aphthous ulcers in patients seropositive for human immunodeficiency virus.
J Am Acad Dermatol 1993;28:271-2.
100. Moreira AL, Corral LG, Ye W, et al. Thalidomide and thalidomide analogues
reduce HIV type 1 replication in human macrophages in vitro. AIDS Res Hum
Retroviruses 1997;13:857-63.
101. Sharpstone D. Thalidomide: A novel therapy for microsporidiosis.
Gastroenterology 1997;112:1823.
102. Soler RA, Howard M, Brink NS, et al. Regression of AIDS-related Kaposis
sarcoma during therapy with thalidomide. CID 1996;23:501-3.
103. Grinspan D. Significant response of oral aphthosis in thalidomide treatment.
J Am Acad Dermatol 1985;12:85.
104. Saylan T, Saltik I. Thalidomide in the treatment of Behcets syndrome. Arch
Dermatol 1982;118:536.
105. Stevens RJ, Andujar C, Edwards CJ, et al. Thalidomide in the treatment of the
cutaneous manifestations of lupus erythematosus: Experience in sixteen
consecutive patients. Br J Rheum 1997;36:353-9.
106. Holm AL, Bowers KE, McMeekin TO, et al. Chronic cutaneous lupus
erythematosus treated with thalidomide. Arch Dermatol 1993;129:1548-50.
107. Grosshans E, Illy G. Thalidomide therapy for inflammatory dermatoses. Int J
Dermatol 1984;23:598-602.
108. Lo JS, Berg RE, Tomecki KJ. Treatment of discoid lupus erythematosus. Int J
Dermatol 1989;28:497-507.
109. Knop J, Bonsmann G, Happle R, et al. Thalidomide in the treatment of sixty
cases of chronic discoid lupus erythomatosus. Br J Dermatol 1983;108:461-6.
110. Naafs B, Bakkers EJM, Flinterman J, et al. Thalidomide treatment of subacute
cutaneous lupus erythematosus. Br J Dermatol 1982;107:83-86.
111. Atra E, Sato EI. Treatment of the cutaneous lesions of systemic lupus
erythematosus with thalidomide. Clin Exp Rheum 1993;11:487-93.
112. Burrows NP, Walport MJ, Hammond AH, et al. Lupus erythematosus profundus
with partial C4 deficiency responding to thalidomide. Br J Dermatol 1991;
125:62-7.

200

Recent Advances in Dermatology

113. Warren KJ, Nopper KJ, Crosby DL. Thalidomide for recalcitrant discoid lesions
in a patient with systemic lupus erythematosus. J Am Acad Dermatol
1998;39:293-5.
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
with thalidomide. Clin Exp Rheumatol 1990;8:427.
129. Silva S, Viana PC, Lugon NV, et al. Thalidomide for the treatment of uraemic
pruritus: A crossover randomized double-blind trial. Nephron 1994;67:270-3.
130. Barnhill RL, McDougall AC. Thalidomide: Use and possible mode of action in
reactional lepromatous leprosy and in various other conditions. J Am Acad
Dermatol 1982;7:317-23.
131. Naafs B, Faber WR. Thalidomide therapy: An open trial. Int J Dermatol
1985;24:131.
132. Moisson YF, Janier M, Civatte J. Thalidomide for recurrent erythema
multiforme(letter). Br J Dermatol 1992;126:92-3.
133. Pinto JS, Sobrinho L, da Silva MB, et al. Erythema multiforme associated with
autoreactivity to 17 alpha-hydroxyprogesterone. Dermatologica 1990;180:14650.
134. Bahmer FA, Zaun H, Luszpinski P, et al. Thalidomide treatment of recurrent
erythema multiforme. Acta Derm Venereol 1982;62:449-50.

Newer Drugs in Dermatology: Systemic

201

135. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary


sarcoidosis with thalidomide. J Am Acad Dermatol 1995;32:866-69.
136. Rustin MHA, Gilkes JJH, Robinson TWE, et al. Pyoderma gangrenosum
associated with Behcets disease: Treatment with thalidomide. J Am Acad
Dermatol 1990;23:941-4.
137. Venencie PY, Saurat JH. Pyoderma-gangrenosum in a child: Treatment with
thalidomide. Ann Pediatr Paris 1982;29:67.
138. Guillaume JC, Moulin G, Dieng MT, et al. Crossover study of thalidomide vs
placebo in Jessners lymphocytic infiltration of the skin. Arch Dermatol
1995;131:1032-5.
139. De longh RU. A quantitative ultra-structural study of motor and sensory
lumbosacral nerve roots in the thalidomide-treated rabbit foetus. J Neuropathol
Exp Neurol 1990;49:564-81.
140. Anonymous. Thalidomide: Important patient information. Health and
Human Services, Public Health Service,http://www.fda.gov/cder/news/
thalidomide.htn.
141. Salafia A, Kharkar RD. Thalidomide and exfoliative dermatitis. Ann Dermatol
Venereol 1990;117:313-21.
142. Bielsa I, Teixido J, Ribera M, et al. Erythroderma due to thalidomide: Report
of two cases. Dermatology 1994;189:179-81.
143. Clemmensen OJ, Olsen PZ, Andersen KE. Thalidomide neurotoxicity. Arch
Dermatol 1984;120:338-41.
144. Chan JJ, Gebaver K. Treatment of severe recalcitrant plaque psoriasis with
single-dose intravenous tumour necrosis factor-alpha antibody (infliximab).
Australas J Dermatol 2003;44:116-20.
145. OQuinn RP, Miller JL. The effectiveness of tumour necrosis factor-alpha
antibody (infliximab) in treating recalcitrant psoriasis: A report of two cases.
Arch Dermatol 2002;138:644-8.
146. Infliximab: Mosbys Drug Consult; Copyright 2003 Mosby Inc.
147. Scallon B, Cai A, Solowski N, et al. Binding and functional comparison of
two types of tumour necrosis factor-antagonists. J Pharmacol Exp Ther 2002;
301:418-26.
148. Ogilvie AL, Antoni C, Dechant C, et al. Treatment of psoriatic arthritis with
antitumour necrosis factor-alpha antibody clears skin lesions of psoriasis
resistant to treatment with methotrexate. Br J Dermatol 2001;144:587-9.
149. Victor FC, Gottlieb AB. TNF-alpha and apoptosis: Implications for the
pathogenesis and treatment of psoriasis. J Drugs Dermatol 2002;1:264-75.
150. Reimold AM. New indications for treatment of chronic inflammation by TNFalpha blockade. Am J Med Sci 2003;325:75-92.
151. Braun J, de Keyser F, Brandi J, et al. New treatment options in spondyloarthropathies: Increasing evidence for significant efficacy of anti-tumour necrosis
factor therapy. Curr Opin Rheumatol 2001;13:245-9.
152. Al-Salem IH. Striking and rapid improvement of plaque psoriasis with
infliximab. A report of two cases. Dermatology 2003;207:54-6.
153. Gottlieb AB, Chaudhari U, Mulcahy LD, et al. Infliximab monotherapy provides
rapid and sustained benefit for plaque-type psoriasis. J Am Acad Dermatol
2003;48:829-35.
154. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab
monotherapy for plaque-type psoriasis: A randomized trial. Lancet 2001;
357:1842-7.

202

Recent Advances in Dermatology

155. Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumour necrosis factor-alpha
(TNF-alpha) monoclonal antibody dramatically decreases the clinical activity
of psoriasis lesions. J Am Acad Dermatol 2000;42:829-30.
156. Gottlieb AB. Clinical research helps elucidate the role of tumour necrosis factoralpha in the pathogenesis of T1-mediated immune disorders: Use of targeted
immunotherapeutics as pathogenic probes. Lupus 2003;12:190-4.
157. Barland C, Kerdel FA. Addition of low-dose methotrexate to infliximab in the
treatment of a patient with severe, recalcitrant pustular psoriasis. Arch Dermatol
2003;139:949-50.
158. Wollina U, Konrad H. Treatment of recalcitrant psoriatic arthritis with antitumour necrosis factor-alpha antibody. J Eur Acad Dermatol Venereol
2002;16:127-9.
159. Mease PJ. Cytokine blockers in psoriatic arthritis. Ann Rheum Dis 2001; 60:
37-40.
160. Mahe E, Descamps V. Anti-TNF alpha in dermatology. Ann Dermatol Venereol
2002;129:1374-9.
161. Laduca JR, Gaspari AA. Targeting tumour necrosis factor alpha. New days
used to modulate inflammatory diseases. Dermatol Clin 2001;19:617-35.
162. Cauza E, Cauza K, Hanusch-Enserer U, et al. Intravenous anti TNF-alpha
antibody therapy leads to elevated triglyceride and reduced HDL-cholesterol
levels in patients with rheumatoid and psoriatic arthritis. Wien Klin Wochenschr
2002;114:1004-7.
163. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasisthe first
wave: infliximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol
2002;1:303-10.
164. Maksymowych WP. Novel therapies in the treatment of spondyloarthritis.
Expert Investig Drugs 2002;11:937-46.
165. Prints HM, McCormack C, Ryan G, et al. Bexarotene capsules and gel for
previously treated patients with cutaneous T-cell lymphoma: Results of the
Australian patients treated on phase 2 trials. Australas J Dermatol 2001;42:
91-7.
166. Hurst RE. Bexarotene ligand pharmaceuticals. Curr Opin Investig Drugs
2000;1:514-23.
167. Lowe MN, Plosker GL. Bexarotene. Am J Clin Dermatol 2000;1:245 50.
168. Zouboulis CC. Retinoidswhich dermatological indications will benefit in the
near future? Skin Pharmacol Appl Skin Physiol 2001;14:303-15.
169. Camacho LH. Clinical applications of retinoids in Cancer medicine. J Biol
Regul Homeost Agents 2003;17:98-114.
170. Bexarotene (Targretin) package insert and product monograph. San Diego,
CA.Ligand Pharmaceuticals, 2000.
171. Wiegand UW, Chou RC. Pharmacokinetics of acitretin and etretinate. J Am
Acad Dermatol 1998;39;S2533.
172. Nguyen EH, Wolverton SE. Systemic retinoids. In: Wolverton SE, ed
Comprehensive Dermatologic Drug Therapy, Philadelphia, WB Saunders,
2001:269 310.
173. Rook AH, Junkins-Hopkins JM, McGinnis KS, et al. Cytokines and other
biologic agents as immunotherapeutics for cutaneous T-cell lymphoma. Adv
Dermatol 2002;18:29-43.
174. Mielke V, Staib G, Sterry W. Systemic treatment for cutaneous lymphomas.
Results Cancer Res Recent1995;139:403-8.

Newer Drugs in Dermatology: Systemic

203

175. Dreno B, Celerier P, Litoux P. RoferonA in combination with Tigason in


cutaneous T-cell lymphomas. Acta Haematol 1993;89:S2832.
176. French LE, Ramelet AA, Saurat JH. Remission of cutaneous T-cell lymphoma
with combined calcitriol and acitretin (letter). Lancet 1994;344:6867.
177. Smit JV De Jong EM , Van De Kerkhof PC. Effects of oral Bexarotene (Targretin
(R) on the minimal erythema dose for broad spectrum UVB light. Skin
Pharmacol Appl Skin Physiol. 2003;16:237-41.
178. Apisarnthanarax N, Ha CS, Duvic M. Mycosis fungoides with follicular
mucinosis displaying aggressive tumourstage transformation: Successful
treatment using radiation therapy plus oral bexarotene combination therapy.
Am J Clin Dermatol 2003;4:429-33.
179. Krathen RA, Ward S, Duvic M. Bexarotene is a new treatment option for
lymphomatoid papulosis. Dermatology 2003;206:142-7.
180. Apisarnthanarax N, Talpur R, Duvic M. Treatment of cutaneous T-cell
lymphoma: Current status and future directions. Am J Clin Dermatol 2002;3:
193 215.
181. Talpur R, Ward S, Apisarnthanarax N, et al. Optimizing bexarotene therapy
for cutaneous T-cell lymphoma. J Am Acad Dermatol 2002; 47:672-84.
182. Duvic M, Martin AG, Kim Y, et al: Phase 2 and 3 clinical trial of oral bexarotene
(Targretin capsules) for the treatment of refractory or persistent early stage
cutaneous T-cell lymphoma. Arch Dermatol. 2001;137:581- 93.
183. Duvic M. Bexarotene and DAB (389) IL2 (denileukin diftitox, ONTAK) in
treatment of cutaneous T-cell lymphomas: Algorithms. Clin Lymphoma.
2000;1Suppl.1:S515.
184. Heald P. The treatment of cutaneous T-cell lymphoma with a novel retinoid.
Clin Lymphoma 2000;1Suppl.1:S459.
185. Vahlquist C, Olsson AG, Lindholm A, et al. Effects of gemfibrozil (Lopid) on
hyperlipidaemia in acitretin-treated patients. Results of a doubleblind cross
over study. Acta DermVenereol 1995;75:377380.
186. Chaspoux C, LehucherCeyrac D, Morel P, et al. Acne in the male resistant to
isotretinoin and responsibility of androgens: 9 cases, therapeutic implications.
Ann Dermatol Venereol 1999;126:179.

204

Recent Advances in Dermatology

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

Newer Drugs in Dermatology: Topical

205

Tacrolimus exerts its biologic effects after binding to macrophilins, a


cytosolic protein formerly called FK506-binding proteins (FKBP).5 This
complex of tacrolimus and macrophilin gains the ability to bind to
calcineurin and blocks its ability to dephosphorylate cytoplasmic subunit
of the nuclear factor of activated T cells (NFATc).2 As the phosphate is
not cleaved off the NFATc, its translocation to the nucleus does not take
place. Thus, the nuclear subunit of the nuclear factor of activated T cells
(NFATn) cannot bind to NFATc in nucleus. Failure of the formation of
an essential complex by these two nuclear factors inhibits transcription
of numerous cytokines including tumor necrosis factor (TNF ) and
interleukins 2, 3 and 4 (IL-2, IL-3, IL-4) and thus Tcell response.6,7 In
a nutshell, tacrolimus inhibits T-cell response by inhibiting calcineurindependent inflammatory cytokine gene transcription.
Other than T-lymphocyte, Langerhans cells and other inflammatory
dendritic cells are also the targets of tacrolimus. The lesional skin of AD,
after being treated with tacrolimus, shows downregulation of high-affinity
IgE receptor (FcRI) present on the Langerhans cells and inflammatory
dendritic epidermal cells.5 The number of inflammatory dendritic
epidermal cells also falls below detection level.8 Tacrolimus blocks the
function of Langerhans cells 100 times more potently than betamethasone
valerate when used topically.9 It has also been shown that tacrolimus
and cyclosporine suppress the degranulation of mast cells and expression
of genes responsible for leukotriene synthesis and multiple cytokines
required to activate cellular immunity.2
Tacrolimus may also exert immunomodulatory action by enhancing
expression of the gene coding for transforming growth factor B1 (TGFB1),
a multifunctional cytokine with potent immunosuppressive activity.10
TGFB1 inhibits IL2 dependent T and Bcell proliferation and production
of TNF, and .
Pharmacology
Tacrolimus can penetrate intact human skin better than cyclosporine
presumably because of its lower molecular weight (822.05 versus
1202.635).11 It does not accumulate in the skin or any system following
repeated applications.12,13 Systemic absorption of tacrolimus appears to
be more during active stage of the disease (of AD) and higher in facial
lesion than trunk and limbs in an adult.14 Based on blood concentrations,
there is no evidence that tacrolimus accumulates systemically on
intermittent topical application for up to 1 year.10 Mean or median blood
concentrations of tacrolimus were below the limit of quantification in
two 12-week randomized vehicle-controlled clinical trials in adults and
children respectively.10 One percent of patient using 0.1 percent ointment

206

Recent Advances in Dermatology

had tacrolimus blood concentration 5 g/L while it is 0.5 percent in


case of patient using 0.03 percent ointment. No patient in pediatric age
has achieved this blood concentration ( 5 g/L).
Topical tacrolimus neither shows any alteration of collagen synthesis
(even under occlusion) nor produces any skin atrophy in AD as well as
normal human volunteers.11 This is a definite advantage over topical
corticosteroids in treating inflammatory dermatoses for a long-term basis.
Thus, topical tacrolimus has a special role in treating dermatitis of face,
neck which are readily vulnerable for atrophy.11 It also takes an upper
hand over topical corticosteroid so far as eyelid dermatitis is concerned.
Unlike steroids, with their potential of producing glaucoma, tacrolimus appears to be safe with no evidence of increased intraocular
tension.2
Topical tacrolimus is almost exclusively metabolized in the liver by
the cytochrome P-450 3A4 isoenzyme in contrast to oral tacrolimus which
is metabolized in liver and gut.5
Clinical Uses
Atopic Dermatitis (AD)
Topical tacrolimus has shown significantly greater efficacy in comparison
with vehicle in patients with moderate to severe AD both in adult and
pediatric age-group.15-21 The severity of AD is contributed by the
colonization of superantigen producing Staphylococcus aureus on the
lesional skin.22 In fact, persistence of S.aureus on the skin may be
responsible for continued T-cell activation, release of pro-inflammatory
mediators, corticosteroid resistance and chronic inflammation.23 It has
been shown that tacrolimus specifically blocks S.aureus superantigeninduced T-cell proliferation in patients with AD and healthy volunteers
compared with dexamethasone.24 Tacrolimus has no direct inhibitory
effect on bacteria including S.aureus, thus, decrease in colonization
probably reflects improved skin barrier function.22,25
Although topical tacrolimus shows definite superiority in efficacy
compared to vehicle, currently there are a few data comparing its efficacy
with topical steroids in AD. There are studies where topical tacrolimus
is compared with either mid-potent or very weak topical corticosteroids.
While comparing with hydrocortisone butyrate (midpotent ), 0.1 percent
tacrolimus ointment showed similar efficacy in adults, but not with 0.03
percent.26 Even both hydrocortisone butyrate and 0.1 percent tacrolimus
show statistically and clinically better result than 0.03 percent tacrolimus
ointment. Similar equivalent efficacy was found between 0.1 percent
tacrolimus and betamethasone valerate.27 In children between 2 to

Newer Drugs in Dermatology: Topical

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

Recent Advances in Dermatology

guideline for monitoring patients on topical tacrolimus is lacking, blood


sugar assay, renal and hepatic function tests and regular blood pressure
recordings are recommended.36
Dosage and Administration10
In US, tacrolimus ointment is indicated for the short-term or intermittent
long-term treatment of moderate to severe AD in adults and children
aged 2 to 15 years who are unable to use standard therapies because of
potential risks, or who are intolerant to or not adequately treated by
standard therapies. It is to be applied twice a day to the affected skin
area and clearing of clinical infection at treatment site must be undertaken
prior to the treatment with topical tacrolimus. Both 0.03 percent and 0.1
percent ointments are approved for use in adults, but only 0.03 percent
for children. The ointment should neither be used in pediatric patients
younger than 2 years nor in patients with Nethertons syndrome and
nursing mother. The ointment used with occlusive dressing is also not
recommended. Discontinuation of tacrolimus oinment is being suggested
in acute infectious mononucleosis or in presence of lymphadenopathy
of unknown etiology. Advice is also given to curtail exposure to natural
sunlight or UV light during treatment. In Japan, 0.1 percent ointment
once or twice a day application for adults with AD is recommended
with the amount not more than 5 gm per dose and a gap of 12 hours
should be kept between doses. Contraindications in Japan include
application on eroded/ulcerated skin, in pregnant and nursing women,
in patients with severe renal damage or severe hyperkalemia and also
in patients undergoing UV radiation treatment. Treated skin with
tacrolimus should be restricted from prolonged sun exposure.
PIMECROLIMUS
Pimecrolimus, also known as SDZ ASM 981, is one of the semisynthetic
derivatives of a parent compound called Ascomycin.3 Ascomycin was
originally isolated in early 1960s from the fermentation product of
Streptomyces hygroscopicus var. ascomyceticus. 5 Like tacrolimus,
pimecrolimus is also a macrolide immunomodulator that produces its
clinical effect by inhibition of calcineurin.
Mechanism of Action
Pimecrolimus, after binding with macrophilin, inhibits calcineurin. As a
consequence, the synthesis of inflammatory cytokines is blocked at the
level of gene transcription.37 Although this mechanism of action is very
much similar to tacrolimus and cyclosporine, pimecrolimus exerts a

Newer Drugs in Dermatology: Topical

209

more selective immunomodulatory effect than either of these two drugs.38


It has been shown that pimecrolimus does not inhibit antigen induction
in sensitization phase in experimentally induced allergic contact
dermatitis in mice, but does inhibit the elicitation phase of immune
response on antigenic re-exposure.38
Pimecrolimus selectively suppresses the activation of both type 1 and
type 2 helper T cells (Th1 and Th2) and thereby production of cytokines
(like IL2, IFN- by Th1 and IL-4, IL-10 by Th2) are downregulated.5,38
This downregulation is of particular importance so far as treatment of
AD is concerned. Several of these cytokines have been implicated at the
initiation and persistence of AD.38
Apart from the T-lymphocyte as a target, pimecrolimus also inhibits
liberation of inflammatory mediators like hexosaminidase, tryptase and
histamine from mast cells and also transcription of the late phase cytokine
tumor necrosis factor (TNF-).5,11,39,40 Furthermore, it inhibits, in a dose
dependent manner, the upregulation of co-receptors CD134 and CD137
which are being implicated in the activation and expansion of effector
T cells.37
Pharmacology
Compared to tacrolimus, pimecrolimus has a higher affinity to the skin
and permeates it to a lesser degree.41 Due to this percutaneous resorption,
there is a lower risk of systemic exposure. While investigating the
magnitude of systemic absorption of topical pimecrolimus 1 percent
ointment in patients with moderate to severe AD in both adults and
children, a consistently low level of blood concentration of pimecrolimus
has been detected regardless of duration of therapy and extent of lesions
treated.37 Systemic accumulation is not also observed during the treatment
period.
Like tacrolimus, pimecrolimus does not produce any skin atrophy or
dermal thinning.38,42,43 Immunosuppressive potency, however, appears
to be less than cyclosporine and tacrolimus and it does not prevent graft
rejection.38
When taken up into circulation, pimecrolimus is metabolized by the
liver by the same isoenzyme (cytochrome P-450 3A4) as in case of
tacrolimus.37
Clinical Uses
Atopic Dermatitis (AD)
Although the clinical effects of pimecrolimus closely resemble those of
tacrolimus, it differs in therapeutic effectiveness as well as structure-

210

Recent Advances in Dermatology

related limitations of formulation.5 This explains why the US-approved


indication for pimecrolimus is mild to moderate AD than moderate to
severe disease.27
While comparing the safety and efficacy of topical pimecrolimus in
different concentrations (0.05%, 0.2%, 0.6% and 1%) with vehicle and
also with 0.1 percent betamethasone valerate (BMV) cream, pimecrolimus
in all concentrations were more effective than vehicle and BMV cream
was more effective than pimecrolimus cream.44 One percent cream was
found to be the most effective among all pimecrolimus cream. In a shortterm (6 weeks) study among children and adolescents with mild to
moderate AD, 1 percent pimecrolimus was significantly more effective
than vehicle.38 An interesting finding in the above study is that the
application site burning is lower with pimecrolimus than vehicle (10.4%
versus 12.5%). This shows a remarkable difference in skin burning
between pimecrolimus and tacrolimus which could be an important
therapeutic difference.2
Twice daily application of pimecrolimus cream (1%) was significantly
more effective than once daily application in adults with mild to moderate
AD.37 Pimecrolimus demonstrated a significant therapeutic effect by
second day compared to vehicle.
Whether the early treatment of AD can prevent disease flare and
influence long-term outcome, pimecrolimus has been compared with
conventional therapy as a control.45,46 The more effective reduction of
the incidence of eczema flare in both infants and children in early stage
of these year-long studies is shown by pimecrolimus. No clinically
relevant adverse events are detected and pimecrolimus is found to be
safe and well tolerated.
Other Uses
Apart from AD, pimecrolimus under occlusive condition is found to be
effective in chronic psoriatic plaques.5 There is a great potential of these
nonsteroidal immunomodulators to be effective in different inflammatory
skin diseases.
Dosage and Administration
Pimecrolimus (1%) cream has got approval in the US for short-term and
intermittent long-term treatment of mild to moderate AD in nonimmunocompromised patients aged > 2 years who do not respond well
to, or may have adverse effects with, conventional treatments.37 This is
to be applied twice daily to all affected skin areas as a thin layer and

Newer Drugs in Dermatology: Topical

211

rubbed in gently and completely. 37 For short-term treatment,


pimecrolimus cream 1 percent has been recommended to apply twice
daily to all affected areas until complete disappearance of signs and
symptoms take place. A short course of topical corticosteroids may be
used to treat flares not adequately controlled by pimecrolimus.47 Dose
adjustment is not required in patients with renal or hepatic insufficiency.37
The use of pimecrolimus is not recommended to apply in areas affected
by active cutaneous viral infections.47 As a general precaution, patients
should curtail UV exposure during treatment with pimecrolimus.47
IMIQUIMOD
This novel molecule is the first of a class of compounds designated as
an immune response modifier. The majority of the immunomodulatory
agents which are now available or in the process of development exert
their activity by inhibiting pathways involved in immune activation.
Imiquimod differs from them as it activates immune function.48 It is a
synthetic, non-nucleoside, heterocyclic (imidazoquinoline) amine.49
Imiquimod enhances both the innate and acquired (adaptive) immune
systems.48
Mechanism of Action
The exact mechanism of action in humans is unknown. However, it
shows indirect antiviral and antitumor effects in animal models through
induction of various cytokines, most notably interferon-alpha (IFN-)
and tumor necrosis factor-alpha (TNF-).49 The various cytokines induced
by imiquimod and their putative actions are given in Table 12.1.50
As stated earlier, imiquimod enhances innate immunity by induction
of TNF-, IFN-, and acquired immune system by stimulation of NK
cells, proliferation of B cells and activation and migration of Langerhans
cells.3
In response to viral infection, IFN- induces keratinocytes to produce
enzymes and other factors to block viral replication. It itself also gets
secreted into intercellular spaces where it helps protecting nearby cells
from virally infected cells and waits for a specific cell-mediated immune
(CMI) response to take over for more efficient viral killing.51 In warts,
this specific CMI is difficult to initiate because virus-infected keratinocytes
are sitting merrily on the top of a wall of epidermis and no way in touch
with the cells of the immune systems patrolling in the dermis below.
Imiquimod helps in this context also. It helps to build up a cytotoxic
specific immune response by inducing lymphocytes to produce the potent
antiviral agent, IFN-.51 Furthermore, IL-12 induced by imiquimod keeps
on nurturing generation of cytotoxic T cells.

212

Recent Advances in Dermatology


Table 12.1: Cytokines induced by Imiquimod50

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

Mimics actions of IFN-

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.

On oral administration of imiquimod to human and other animals,


the serum concentration of an interferon-inducible enzyme (2-5)oligoadenylate synthetase is increased.48 This enzyme confers an antiviral
state and up-regulates NK cell activity in both vivo and vitro.3,49,51
In a recent study on hairless mice, IFN- level increases about 50
times the baseline in 4 hours when imiquimod 1 percent cream is applied
on the skin.52 It results from local transcription as evidenced by increased
mRNA level on treated sites. This quick induction of INF- probably
contributes to the protective effect of imiquimod in herpes simplex
infection as shown in guinea pigs when it is used within 48 hour of
contracting infection.49
Besides stimulation of macrophages and dendritic cells to produce
IFN-, IL-12 and TNF- by imiquimod, peripheral blood monocytes are
also stimulated. It has been shown that the increased production of
cytokines by imiquimod is ceased when monocytes are eliminated by
cell depletion methods.49
Imiquimod appears to potentiate T helper cell type 1 (Th-1) immune

Newer Drugs in Dermatology: Topical

213

response (cell mediated) while simultaneously suppresses T helper cell


type 2 (Th-2) immune response (humoral or antibody-mediated
immunity).49,51 This knowledge may be employed in treating diseases
where imbalances of Th1/Th2 ratio or their cytokine release are having
important pathogenic role. AD, as for an example, can have the benefit
possible as imiquimod could theoretically help restoring normal immune
balance by shifting the immune system back to Th1 side.
Finally, it has been shown that imiquimod activates immune cells
through toll-like receptors (TLR), especially TLR 7.53 TLRs are a family
of receptors for early recognition of different microbial antigens. Ten
human TLRs have been identified till now and they respond to lipopolysaccharide of gram-negative bacteria, lipopeptides of gram-positive
cell walls as well as bacterial DNA and flagellar antigens.49
Pharmacology
Slade et al have reviewed the pharmacokinetics and metabolism of
imiquimod.54 The major systemic metabolite is S-26704, a hydroxylation
product of imiquimod.48 The highest plasma concentration of S-26704 is
approximately 25 times greater than that of imiquimod. The half-life of
imiquimod is 14 hours following use through intravenous route. Recovery
of less than 1 percent of imiquimod in the urine is noted after a single
topical application. These data are from combined animal and human
exposure studies.48
Systemic exposure following daily application of imiquimod cream
to genital or perianal skin may occur, but is minimal. This is indicated
by sporadically present, quantifiably low level in urine.55 Serum does
not show quantifiable level of imiquimod or its metabolite.
Clinical Uses
Anogenital Warts
This is the only approved indication for imiquimod by FDA.49 Imiquimod
5 percent cream is approved currently as a patient-applied treatment
option for external genital/perianal warts. It is to be applied three times
per week for up to 16 weeks.3
The apparent low recurrence rate of warts is perhaps the greatest
advantage of imiquimod compared to other therapies.56 This can be well
explained by the fact that imiquimod helps to develop a specific immunity
against warts even when the application of imiquimod is stopped.51
Clinical experience also supports this. Fifty-six percent of patients who
applied 5 percent cream had clearance of genital warts compared to 11

214

Recent Advances in Dermatology

percent in placebo group.57 Only 6 patients (13%) of imiquimod group


had recurrence of at least 1 wart over a 12-week follow up. In another
study, the result of complete clearance of warts by 5 percent imiquimod
cream is 52 percent compared to 4 percent by vehicle.58 Beutner et al59
also showed that 40 percent of imiquimod treated patients (by 5% cream)
had
complete
clearance
compared
to
0 percent of the placebo group. The recurrence rate was 19 percent for
imiquimod treated patients.
Women have shown a better response than men, an interesting finding
observed in a few studies.57,60 Clearance rate for men was 40 percent
compared to 77 percent in women when 5 percent imiquimod was used
three times a week for 16 weeks.57 A similar higher clearance rate in
female was also observed in an open-label study in 20 countries across
the world.60
Apart from the advantage of lower recurrence rate, other benefits of
imiquimod include: 1) superior efficacy than other chemodestructive
therapies like podophyllin, trichloroacetic acid and bichloroacetic acid,
2) less tissue damage than other destructive therapies, 3) the ability to
self-treat in the privacy of the home, 4) the saving of time, expense and
possible embarrassment of multiple visits to the attending doctor and 5)
the advantage of immediate attention to the newer warts by the patients
themselves rather than having to wait for an office visit.56 In a costeffectiveness study, imiquimod is found to be more effective and less
costlier than provider-administered ablative therapies so far as sustained
clearance of warts is concerned.61 Imiquimod was successful to clear off
all the warts in difficult cases like flat warts on the penile shaft, extensive
penile warts, extensive warts on the glans penis, penile and perianal
warts where cryotherapy, trichloroacetic acid and podophyllin had
failed.62 It has also been reported to be successful in patients in whom
conventional therapy failed.63 In a case report extensive condyloma of
the inguinal area and thigh (1,770 mm2) which was resistant to
cryotherapy, podophyllin, podofilox and CO2 laser cleared with 5 percent
imiquimod topically.64
There are disadvantages also. Lack of visualization, particularly in
perianal lesions, renders self-treatment by imiquimod difficult, thereby
also increasing the risk of local irritation.56 Another disadvantage is the
relatively long duration of therapy. A small number of warts may be
more efficiently removed by other methods rather than by imiquimod
in a relatively shorter time.
Although FDA has approved imiquimod use only for patients aged
12 years and older and effective results have been observed in adults,
yet successful results are being reported in children and infants suffering

Newer Drugs in Dermatology: Topical

215

from external genital warts.65-67


Non-genital Warts
Although not approved, imiquimod has been tried in patients with
common warts and plantar warts. The important obstacle is heavily
keratinized nature of these warts where imiquimod probably cannot
penetrate sufficient enough to induce an immune response. Studies have
shown that better efficacy and success are obtained when imiquimod
application is combined with some other procedure like cryosurgery,
occlusion using 40 percent urea gel, or CO2 laser. A case of periungual
warts has been treated successfully by using 5 percent imiquimod under
occlusion at night following a single session of cryotherapy.68 Complete
clearance at 6 weeks has been noted in a patient of plantar wart treated
with nightly application of 5 percent imiquimod under occlusion. The
combination of imiquimod and CO2 laser was reported to be effective in
treatment of verrucae vulgaris in immunocompromised patients.69
Multiple flat warts on face as well as on fingers and dorsum of the hands
have also been cleared completely by thrice weekly application of
imiquimod.70,71
Other Uses
There are reports of efficacy of imiquimod in various other skin disorders
like molluscum contagiosum, superficial basal cell carcinoma (BCC),
Bowens disease, solar keratoses, cervical intraepithelial neoplasia (CIN)
and acyclovir unresponsive herpes simplex virus 2 (HSV-2) infection.3
Preliminary studies show 87 to 88 percent success rate in superficial
BCC and 76 percent of treatment response in nodular BCC using oncedaily regimen for 6 weeks and 12 weeks respectively.72 A long-term
study (3-5 years) is required to endorse these results with excision surgery
as comparator. Other conditions where imiquimod has been reported to
be successful are alopecia areata, keloid, stucco keratosis.73 Recurrence
rate of excised keloids following application of 5 percent imiquimod in
post-operative period is found to be lower.74,75 There are also various
case reports of patients being treated effectively with imiquimod in
porokeratosis of Mibelli, erythroplasia of Queyrat, infantile hemangioma.3
There are also interesting reports where imiquimod alone or in
combination with interlesional IL2 may emerge as a promising topical
adjuvant in treating multiple cutaneous metastases of malignant
melanoma.76,77 Preliminary report on cutaneous leishmaniasis shows
encouraging result (90% cured at a 6-month follow-up) when imiquimod
is used along with conventional antimonial therapy.78 This may be a

216

Recent Advances in Dermatology

significant advance in the treatment of such a vexing disorder. There


may be a possibility of reduction of total antimonial doses, duration of
therapy and decrease in protozoal resistance to antimonials. Further
studies, of course, are required to substantiate these speculations.
Side Effects
Local skin reactions like erythema, itching, scaling and burning are the
most commonly reported adverse effects.3 These are mainly mild to
moderate in nature occurring in < 67 percent of patients who have used
5 percent imiquimod cream thrice a week. The incidence of adverse
effects increases with increase in frequency of dosing e.g. daily
application. Side effects from overdosage, reported rarely, include fever,
diarrhoea, fatigue, abdominal pain and muscle pain. 3 A severe
application-site reaction like ulceration with accompanying pain and
pruritus is observed in one of the patients of BCCs.79 This has happened
because the instruction for taking rest periods during increase in
application site reaction is not followed. This reinforces the need for
proper pretreatment counselling and its strict adherence. The tolerability
profile of imiquimod is found to be favourable compared to
podophyllotoxin.80
Safety Profile
The topical use of imiquimod appears to be safe both in infants and in
older children.3 Imiquimod may be used in pregnancy and has been
designated as pregnancy category B.56 Imiquimod 5 percent cream neither
produces any detectable photosensitizing potential in humans, nor
enhances UVR-induced damage to epidermal cells or DNA.81
CIDOFOVIR
The antiviral properties of cidofovir is first described by De Clercq
et al82 in 1987. Cidofovir, also known as HPMPC (hydroxyphosphonylmethoxy-propyl cytosine), is emerging as a promising new drug that
has pharmacologic activity against a wide range of DNA viruses. It is
a nucleotide analog of deoxcytidine monophosphate.83 Recent studies
have shown the efficacy of cidofovir in the treatment of recalcitrant and
unmanageable cutaneous infections caused by herpes simplex viruses
(HSV), pox viruses and human papilloma viruses (HPV).83
Mechanism of Action
After being incorporated into the host cell, cidofovir is changed to its
active metabolite, cidofovir diphosphate, by two stages of phosphorylation. The diphosphate has the structural similarity to nucleotides

Newer Drugs in Dermatology: Topical

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

218

Recent Advances in Dermatology

abnormalities were detected in that patient. In a recent report, acute


renal failure with features of tubular acidosis was precipitated by topical
cidofovir in a patient of bone marrow transplant with chronic renal
failure and treatment-resistant condyloma.83 Spontaneous recovery was
observed on withdrawal of cidofovir.
Cidofovir is embryotoxic both in rats and rabbits at doses that were
also toxic to the mother.83,86 Fetal soft tissue and skeletal anomalies have
been reported in rabbits treated intravenously at 1.0 mg/kg daily.86 No
studies on pregnant women regarding use of cidofovir in any route are
available. Thus, the use of cidofovir, even in topical from, should be
avoided in infants and pregnant women.83,86
Clinical Uses
Cidofovir is approved by FDA for the treatment of cytomegalovirus
(CMV) retinitis in patients with AIDS by intravenous administration.83
Topical formulation has been compounded extemporaneously. 86
However, the topical formulation is prohibitively expensive (approximately $50 to $75 per gram of 3% cream).83 The trial reports of topical
cidofovir in different clinical conditions have been discussed below.
HPV Infections
Condyloma accuminata Snoeck et al91 first reported successful treatment
with 1 percent cidofovir cream in 3 patients of relapsing anogenital
condylomas with AIDS. In one of the patients, no recurrence was observed
1 year later after discontinuation of therapy. The first double-blind,
placebo-controlled study on genital HPV infections in immunocompetent
patients showed complete response in 47 percent patients in cidofovir
group compared to none in placebo.92 Forty-five percent of the patients
of placebo group experienced disease progression compared to none in
cidofovir group. Similar effective result was also found in HIV-infected
patients in a placebo-controlled single blind cross-over study.93 In another
trial using cidofovir gel in different strengths in HIV-positive patients
with biopsy-proven condyloma, complete and partial responses were
observed in 65 percent of patients. Dose-related application-site reaction
were seen in 39 percent of patients and no systemic toxicity was noted.94
Verruca vulgaris A report of 2 cases of verruca vulgaris refractory to
conventional therapy showed response to treatment with topical cidofovir
3 percent cream.95 The patients were free of lesions for more than 40
weeks and 12 months respectively following treatment. Topical cidofovir
has also been reported to be effective in the treatment of verruca in HIV-

Newer Drugs in Dermatology: Topical

219

infected individuals. Successful treatment was seen in a case having a


large verrucous plaque on right foot where HPV-66 was identified in the
lesional skin biopsy sample.96 There was also report of successful
treatment of multiple warts in gingival mucosa in a 45-year-old man
with AIDS by cidofovir 1 percent cream.83
Bowenoid papulosis Complete resolution has been observed in a
histopathologically proved bowenoid papulosis in a homosexual man
with AIDS with 3 cycles of 5 days treatment at 15 days interval with 1
percent topical cidofovir. No recurrence was noted for 4 years after
treatment.97
Vulvar intraepithelial neoplasia (VIN) Topical cidofovir 1 percent in
Beeler base (cetylic alcohol-15 g, white wax-1 g, propylene glycol-10 g,
sodium lauryl sulfate-2 g and water-72 g)83 completely eradicated
extensive VIN III in a woman with 20 years history of genital warts who
refused surgical resection.98
Cidofovir has also shown specific effect on dysplastic epithelium in
a study of cervical intraepithelial neoplasia.99 This has been confirmed
by histology and PCR for HPV DNA from the post-treatment surgical
excision of cervix.
Anogenital squamous cell carcinoma in situ HIV-infected individuals
are at increased risk for HPV-associated anogenital intrasquamous
epithelial neoplasms including squamous cell carcinoma (SCC).83
Anogenital SCC is emerging as a major problem in HIV-infected
individuals.100 Topical cidofovir (3%) was reported to be effective in
patients of AIDS with anogenital Bowens disease (SCC in situ) refractory
to cryotherapy and electrotherapy.83 Painful erosions and irritation were
common side effects and lesions healed with post-inflammatory hypoor hyperpigmentation. No systemic side effects were noted. Active
antiretroviral therapy (HAART) was unlikely to influence this favorable
outcome because the patients were already on HAART. The authors
conclude that effective treatment with topical cidofovir might represent
a definite therapeutic advance in context of multifocal nature of the
anogenital SCC in situ where complete surgical excision is difficult.
Laryngeal papillomatosis Successful treatment of this condition has
been reported by intralesional injection of cidofovir.86
Erythroplasia of queyrat There is a case report of complete clearance
of lesion in a patient of this condition caused by HPV16/18 by 1 percent
cidofovir applied for consecutive 5 days a week for 2 weeks.101 No
recurrence was observed in 22 months of follow-up.

220

Recent Advances in Dermatology

Molluscum Contagiosum Virus (MCV) Infection


MCV infection in immunocompromised patients (e.g. AIDS) produces
usually extensive, recalcitrant lesions. The patients suffer from increased
morbidity and disfigurement. Thus, recalcitrant MCV represents a
therapeutic challenge.
Report of 3 cases of HIV-positive adults showed complete clearing
of extensive MCV lesions, 2 among them have been treated with
intravenous cidofovir for concomitant CMV retinitis.102 The third
individual was treated with 3 percent cidofovir in Dermovan83 (a vehicle
that contains propylene glycol). Topical cidofovir has also been found
effective in clearing MCV lesions in a boy with Wiskott-Aldrich
syndrome.103 Recently, Toro et al104 reported efficacy of 3 percent cidofovir
in Dermovan in 2 children with AIDS with recalcitrant facial and
disseminated MCV lesions. The patients were socially isolated for their
facial disfigurement. Their MCV lesions were unresponsive to liquid
nitrogen, cantharidin and 0.05 percent tretinoin gel. They had also low
CD4 T-cell count, elevated viral loads despite HAART treatment. The
major advantage of topical cidofovir, according to the authors, is its nonsurgical method which helps avoiding systemic side effects86 like
nephrotoxicity, neutropenia and metabolic acidosis associated with
intravenous use.
Herpes Simplex Virus (HSV) Infection
There are various case reports where cidofovir intravenously and topically
are found to be effective in multi-drug resistant HSV infection in
immunocompromised patients. Saint-Leger et al105 reported such a patient
of AIDS who responded to IV cidofovir for his HSV-II-induced recurrent
scrotal ulcerations. The strain of HSV was found to be resistant to
acyclovir (ACV-R), valacyclovir and foscarnet. Topical cidofovir 1 percent
helped in healing of an ACV-R HSV facial ulcer in a 4-year old boy with
AIDS who did not also respond to flurothymidine and foscarnet.106
Snoeck et al107 reported 2 interesting cases of mucocutaneous HSV
infection. In the first patient of AIDS with chronic perineal HSV-II
ulceration, there were 2 recurrences which responded every time to 3
percent topical cidofovir gel. In the second patient, who was a bone
marrow transplant recipient having ACV-R severe oral HSV-1 infection,
two courses of topical cidofovir resulted in emergence of an acyclovir
susceptible strain that responded to ACV subsequently. In a doubleblind, placebo-controlled study on AIDS having ACV-R HSV infection,
cidofovir topically shows effective result.108 Fifty percent of the patients
of cidofovir group demonstrated complete healing or greater than

Newer Drugs in Dermatology: Topical

221

50 percent improvement of the infection compared to 0 percent in placebo


group. Application site reactions occurred in 25 percent case of cidofovir
group.
Kaposis Sarcoma
Cidofovir has been shown to have marked activity against Kaposis
sarcoma (KS) associated herpes virus (KSHV; HHV-8) in vitro.83 While
evaluating the anti-KSHV activity of various antiviral agents in vitro,
cidofovir was found to be a potent inhibitor of KSHV than acyclovir,
foscarnet and ganciclovir. There is no trial report of use of topical cidofovir
in Kaposis sarcoma.
Smallpox
Although officially eradicated from the world in December 1979, smallpox
has been identified as a potential weapon in bioterrorism.83 In this regard,
the identification of drugs with antiviral activity against the variola
virus becomes important. Cidofovir is the most effective antiOrthopoxvirus agent among all the drugs approved by the FDA.83
Future Research
An oral form of cidofovir-related drug, hexadecyloxypropyl-cidofovir
(HDP-cidofovir), shows promising result in the process of development.109
HDP-cidofovir is 93 percent orally available in mice compared to
cidofovir. It is 100 to 1000-fold more active than cidofovir against herpes
virus, CMV in vitro and 100 to 200 times more active than cidofovir
against pox viruses including smallpox.
Conclusion
Topical cidofovir 13 percent gel or cream has been found to be effective
against many DNA viruses. It also shows potential as an antitumor
agent by inhibiting angiogenesis, including tumor cell differentiation
and apoptosis.101 In HPV infection, its ability to induce apoptosis has
been identified in association with accumulation of oncosuppressor
protein p53 and pRb and the cyclin-dependent kinase inhibitor p21/
WAF1.110 Till date, most of the trials of its use are case reports. So,
controlled investigations with randomized trials with long-term followup are necessary to verify its usefulness in different already attempted
clinical conditions. As stated earlier, the cost of topical cidofovir is very
high. We hope that the cost will decrease in future so that we can use
more widespread, especially in a country like India.

222

Recent Advances in Dermatology

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

Newer Drugs in Dermatology: Topical

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

224

Recent Advances in Dermatology

number of papules, open comedones and pustules are more effectively


controlled by tazarotene than tretinoin, but both are equally effective in
case of closed comedones. Tazarotene takes only half of the frequency
of application compared to adapalene (every other day versus every
day) to reduce inflammatory and non-inflammatory lesions effectively.
The tolerability of tazarotene gel is comparable clinically with tretinoin
and adapalene. There are several other studies where tazarotene 0.1 gel
shows better therapeutic efficacy than tretinoin 0.025 percent, tretinoin
microsponge 0.1 percent and adapalene.135-137 Combined tazarotene and
clindamycin topically have shown significantly greater global
improvement than either of these two used as monotherapy.138
Tazarotene plus erythromycin/benzoyl peroxide are found to be more
effective than all other regimens in controlling inflammatory acne
lesion.138
Keeping the inherent local irritation potential of topical retinoids
(also tazarotene) in mind, short contact therapy (30 seconds to 5 minutes)
with tazarotene in acne vulgaris has been designed and claimed to be
a safe, effective new method of treatment for acne.139
Other Uses
Corticosteroid-induced epidermal atrophy can be significantly minimized
by tazarotene.140 Reduction of epidermal thickness was found to be only
28 percent in combined use of tazarotene and diflorasone diacetate as
compared to 43 percent by steroid alone.123 Tazarotene has also been
found to be effective in photo aging.112 The photo damaged facial skin
shows positive changes with the treatment of tazarotene cream
formulation.141 There are several reports claiming usefulness of topical
tazarotene in different dermatological conditions like warty dyskeratoma,142 fingernail psoriasis,143 elastosis perforans serpiginosa,144 Dariers
disease,145,146 confluent and reticulated papillomatosis,147 basal cell
carcinoma,148 keratoderma blenorrhagicum149 and juvenile acanthosis
nigricans of familial obesity-induced type.150
Safety and Side Effects
The FDA has categorized tazarotene as a category X drug which means
it may or can cause fetal harm when administered to a pregnant woman
and is contraindicated in women who are or may become pregnant.119
Contraceptive counseling should be given to a woman of childbearing
potential if topical tazarotene is planned for treatment.112 Although
absorption is minimal and plasma level of tazarotene and TA are found
to be 100 fold less than that of oral isotretinoin,119 it should not be used
by pregnant woman.112

Newer Drugs in Dermatology: Topical

225

The side effects of topical tazarotene are mainly localized to skin.


Erythema, burning or stinging, pruritus in psoriatic patients and dryness,
desquamation, erythema and burning in acne patients are reported.119
These are usually mild to moderate in nature and dose related. Clinically
significant changes in hematology, blood chemistry, bone radiography
and urinalysis have not been found.119 Contact sensitization, phototoxic
and photoallergic reactions, mutagenicity have not also been found with
topical use of tazarotene. Koebnerization, however, has been seen in
cases of psoriasis.111 It is better to avoid simultaneous use of irritating
topical products such as abrasive or medicated soaps, products containing
high concentration of alcohol, astringents, lime or spices.111 To minimize
local irritation, treatment can be started with lower strength, e.g. 0.05
percent cream and then escalated according to tolerance.112 To protect
the surrounding skin with vaseline and to apply tazarotene to the affected
skin only at night has also been advocated.151
Drug Interaction
Additional dryness can occur if tazarotene topically is used with other
cutaneous medications or cosmetics having strong drying effect.112
REFERENCES
1. Allen BR. Tacrolimus ointment: Its place in the therapy of atopic dermatitis.
J Allergy Clin Immunol 2002;109(3):401-3.
2. Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus: From clever
prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am
Acad Dermatol 2002;46:22841.
3. Thappa DM. Recent advances in topical therapy in dermatology. Indian J
Dermatol 2003;48:1-11.
4. Lui J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of
cyclophilincyclosporine A and FKBPFK506 complexes. Cell 1991;66:807-15.
5. Bornhvd E, Burgdorf WHC, Wollenberg A. Macrolactam immunomodulators
for topical treatment of inflammatory skin diseases. J Am Acad Dermatol
2001;45:736-43.
6. Rao A. NFATp: A transcription factor required for the co-ordinate induction
of several cytokine genes. Immunol Today 1994;15:27481.
7. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporine A and
FK506. Immunol Today 1992;13:13642.
8. Wollenberg A, Sharma S, Von Bubnoff D, et al. Topical Tacrolimus (FK506)
leads to profound phenotypic and functional alterations of epidermal antigen
presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001;107:
519-25.
9. PanhansGross A, Novak N, Kraft S, et al. Human epidermal Langerhans
cells are targets for the immunosuppressive macrolide tacrolimus (FK-506). J
Allergy Clin Immunol 2001;107:34552.

226

Recent Advances in Dermatology

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.

Newer Drugs in Dermatology: Topical

227

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
65.
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

228

Recent Advances in Dermatology

Allergy Clin Immunol 2002;110:277 84.


46. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus
cream in the long term management of atopic dermatitis in children. Pediatrics
2002;110(1). URL:http://www.pediatrics.org/cgi/content/ full/110 /1/e2.
47. Eichenfield LF.Pimecrolimus in clinical practice: guidelines for use. Satellite
Symposium (SA0706) in 20th World Congress of Dermatology 2002 [abstract].
Ann Dermatol Venereol 2002;129: IS81IS141.
48. Sauder DN. Immunomodulatory and pharmacologic properties of Imiquimod.
J Am Acad Dermatol 2000;43:S6-S11.
49. Skinner RB Jr. Imiquimod. Dermatol Clin 2003; 21:291-300.
50. Dahl MV. Imiquimod: A cytokine inducer. J Am Acad Dermatol 2002;47:S205
8.
51. Dahl MV. Imiquimod: An immune response modifier. J Am Acad Dermatol
2000;43:S1S5.
52. Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless
mouse and rat skin after topical application of the immune response modifiers
imiquimod and S28463. J Invest Dermatol 1998;110:734-9.
53. Eedy DJ. Imiquimod: A potential role in dermatology? Br J Dermatol
2002;147(1):1-6.
54. Slade HB, Owens ML, Tomai MA, et al. Imiquimod 5% cream (Aldara). Exp
Opin Invest Drugs 1998;7:43749.
55. Owens ML, Bridson WE, Smith SL, et al. Percutaneous penetration of Aldara
cream 5%, during the topical treatment of genital and perianal warts. Prim
Care Update Obs Gyn 1998;5(4):151.
56. Edwards L. Imiquimod in clinical practice. J Am Acad Dermatol 2000; 43:S12S17.
57. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod
cream for external anogenital warts. Arch Dermatol 1998;134:2530.
58. Beutner KR, Tyring SK, Trofatter KF, et al. Imiquimod, a patientapplied
immuneresponse modifier for treatment of external genital warts. Antimicrob
Agents Chemother 1998;42:789-94.
59. Beutner KR, Spruance SL, Hougham AJ, et al. Treatment of genital warts with
an immuneresponse modifier (imiquimod). J Am Acad Dermatol 1998;38:230
9.
60. Garland S, Sellors J, Wikstrom A, et al. Imiquimod 5% cream is safe and
effective self applied treatment for anogenital warts; results of an open label,
multicenter phase III B trial. Int J STD AIDS 2001;12:722-9.
61. Langley PC, Tyring SK, Smith MH. The cost effectiveness of patient-applied
versus provideradministered intervention strategies for the treatment of
extragenital warts. Am J Manag Care 1999;5:6977.
62. OMahony C. Difficult wart casesuses of imiquimod cream 5%. Int J STD
AIDS 2001;12:4003.
63. Eggleton S, Tang A. Management of difficult anogenital warts. Sex Trans
Infect 1999;75:44950.
64. Weinberg JM, Stewart A, Stern JO. Successful treatment of extensive condyloma
accuminata of the inguinal area and thigh with topical imiquimod cream. Acta
Derm Venerol 2001;81:76 7.
65. Moresi JM, Herbert CR, Cohen BA. Treatment of anogenital warts in children
with topical 0.05% Podofilox gel and 5% Imiquimod cream. Pediatr Dermatol
2001;18:44850.
66. Schaen L, Mecurio MG. Treatment of human papilloma virus in a 6month

Newer Drugs in Dermatology: Topical

229

old infant with imiquimod 5% cream. Pediatr Dermatol 2001;18:450-2.


67. Wagman FA, Estape RE, Angiolo R, et al. Self-administered topical 5%
imiquimod cream for external anogenital warts in adolescent girls. Obstet
Gynecol 2001;97(4 Suppl 1):S14.
68. Sparling JD, Checketts SR, Chapman MS. Imiquimod for plantar and periungual
warts. Cutis 2001; 68:397-9.
69. Weisshar E, Gollnick H. Potentiating effect of imiquimod in the treatment of
verrucae vulgares in immunocompromised patients. Acta Derm Venerol
2000;80:305-7.
70. Schwab RA, Elston DM. Topical imiquimod for recalcitrant flat warts. Cutis
2000;65:160-2.
71. OsterSchmidt C. Imiquimod: A new possibility for treatment of resistant
verrucae planae. Arch Dermatol 2001;137:666-7.
72. Bath F, Perkins W. Basal cell carcinoma. In: Williams H, Bigby M, Diepgen T,
et al, eds. Evidencebased Dermatology. London: BMJ Publishing Group, 2003:
32443.
73. Marini M. Imiquimod 5% cream: A topical immune response modifier. Int J
Dermatol 2002;41(Suppl 1):12.
74. Berman B, Kauffman J. Pilot study of the effect of post operative imiquimod
5% cream on the recurrence rate of excised keloids. J Am Acad Dermatol
2002;47:S209-11.
75. Berman B. Imiquimod: A new immune response modifier for the treatment of
external genital warts and other diseases in dermatology. Int J Dermatol
2002;41(Suppl 1):7-11.
76. Bong AB, Bonnekoh B, Franke I, et al. Imiquimod, a topical immuno response
modifier, in the treatment of cutaneous metastases of malignant melanoma.
Dermatology 2002;205(2):135-8.
77. Ugurel S, Wagner A, Pfohler C, et al. Topical imiquimod eradicates skin
metastases of malignant melanoma but fails to prevent rapid lymphogenous
metastatic spread. Br J Dermatol 2002;147(3):6213.
78. Arevalo I, Ward B, Miller R, et al. Successful treatment of drugresistant
cutaneous leishmaniasis by use of imiquimod, an immunomodulator. Clin Inf
Dis 2001;33:184751.
79. Cowen E, Mercurio MG, Gaspari AA. An open case series of patients with
basal cell carcinoma treated with topical 5% imiquimod cream. J Am Acad
Dermatol 2002;47:S2408.
80. Perry CM, Lamb HM. Topical Imiquimod A review of its use in genital warts.
Drugs 1999;58:37589.
81. Kaidbey K, Owens M, Liberda M, et al. Safety studies of topical imiquimod
5% cream on normal skin exposed to ultraviolet radiation. Toxicology
2002;178(2):17582.
82. DeClercq E, Sakuma T, Baba M, et al. Antiviral activity of phosphomethoxyalkyl
derivatives of purines and pyrimidines. Antiviral Res 1987;8:26172.
83. Toro JR, Sanchez S, Turiansky G, et al. Topical cidofovir for the treatment of
dermatologic conditions: Verruca, condyloma, intraepithelial neoplasia, herpes
simplex and its potential use in small pox. Dermatol Clin 2003;21:3019.
84. Mendel DB, Barkhimer DB, Chen MS. Biochemical basis for increased
susceptibility to cidofovir of herpes simplex viruses with altered or deficient
thymidine kinase activity. Antimicrob Agents Chemother 1995;39:21202.
85. Ho HT, Woods KL, Bronson JJ, et al. Intracellular metabolism of the antiherpes
agent (S)1(3hydroxy2phosphonylmethoxypropyl)-cytosine. Mol

230

Recent Advances in Dermatology

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

Newer Drugs in Dermatology: Topical

231

treated with cidofovir. Arch Dermatol 1997;133:98790.


103. Davies EG, Thrasher A, Lacey K, et al. Topical cidofovir for severe molluscum
contagiosum. Lancet 1999;12;353:2042.
104. Toro JR, Wood LV, Turner ML. Topical cidofovir: A novel treatment of recalcitrant molluscum contagiosum in HIV infected children. Arch Dermatol
2000;136:983-5.
105. SaintLeger E, Fillet AM, Malvy D, et al. Efficacy of cidofovir in a HIV infected
patients with acyclovir and foscarnet resistant herpes simplex virus infection.
Ann Dermatol Venereol 2001;128:7479.
106. Lateef F, Donn PC, Kaufmann M, et al. Treatment of acyclovir-resistant foscarnet
unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch
Dermatol 1998;134:116970.
107. Snoeck R, Andrei G, Gerard M, et al. Successful treatment of progressive
mucocutaneous infection due to acyclovirand foscarnetresistant herpes
simplex virus with (S)I(3hydroxy2phosphonylmethoxypropyl) cytosine
(HPMPC). Clin Infect Dis1994;8:5708.
108. Lalezari J, Schacker T, Feinberg J, et al. A randomized double-blind, placebo
controlled trial of cidofovir gel for the treatment of acyclovirunresponsive
mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect
Dis 1997;176:8928.
109. Bradbary J. Orally available cidofovir derivative active against smallpox. Lancet
2002;359:1041.
110. Andrei G, Snoeck R, Schols D, et al. Induction of apoptosis by cidofovir in
human papillomavirus (HPV)positive cells. Oncology Research, 2001;12:397
408.
111. Prystowsky JH. Topical Retinoids. In: Wolverton SE, ed, Comprehensive
Dermatologic Drug Therapy. Philadelphia, Pennsylvania: W.B. Saunders,
2001;578594.
112. Guenther LC. Topical tazarotene therapy for psoriasis, acne vulgaris and
photoaging. Skin Therapy Lett 2002;7:1-4.
113. Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998;55:705711.
114. Duvic M, Nagpal S, Asano AT, et al. Molecular mechanisms of tazarotene
action in psoriasis. J Am Acad Dermatol 1997;37:S18S24.
115. Chandraratna RAS. Tazarotene: The first receptorselective topical retinoid for
the treatment of psoriasis. J Am Acad Dermatol 1997;37:S12S17.
116. Chandraratna RAS. Tazarotene-first of a new generation of receptor-selective
retinoids. Br J Dermatol 1996;135(S49):1825.
117. EsgleyesRibot T, Chandraratna RA, Lew-Kaya DA, et al. Response of psoriasis
to a new topical retinoid, AGN 190168. J Am Acad Dermatol 1994;30:581590.
118. Duvic M, Asano AT, Hager C, et al. The pathogenesis of psoriasis and the
mechanism of action of Tazarotene. J Am Acad Dermatol 1998;39:S129-S133.
119. Menter A. Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol
2000;43:S31S35.
120. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad
Dermatol 1998;39(Suppl):S134S138.
121. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid for
topical therapy of psoriasis: Vehiclecontrolled study of safety, efficacy and
duration of therapeutic effect. J Am Acad Dermatol 1997; 37(1):8592.
122. Weinstein GD, Koo JYM, Krueger GG, et al. Tazarotene cream in the treatment
of psoriasis: two multicenter, doubleblind, randomized, vehiclecontrolled
studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied

232

Recent Advances in Dermatology

once daily for 12 weeks. J Am Acad Dermatol 2003; 48:7607.


123. Guenther L. Tazarotene combination treatments in psoriasis. J Am Acad
Dermatol 2000; 43:S36S42.
124. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus
corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol
1998;39:5906.
125. Lebwohl M, Poulin Y. Tazarotene in combination with topical corticosteroid.
J Am Acad Dermatol 1998;39:S139-S143.
126. Koo JY. Tazarotene in combination with phototherapy. J Am Acad Dermatol
1998; 39:S144S148.
127. Koo J, Martin D. Double-blind comparison of tazarotene gel q.d. plus
mometasone furoate cream q.d. versus mometasone furoate cream b.i.d. Poster
presented at the Academy 99 meeting of the American Academy of
Dermatology. July 28- August 1, 1999, New York, NY.
128. Guenther LC, Poulin YP, Pariser DM. A comparison of tazarotene 0.1% gel
once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene
0.005% ointment twice daily in the treatment of plaque psoriasis. Clin Ther
2000;22(10): 1225-38.
129. Lebwohl M. Strategies to optimize efficacy, duration of remission and safety
in the treatment of plaque psoriasis by using tazarotene in combination with
a corticosteroid. J Am Acad Dermatol 2000;43:S43S46.
130. Weinstein GD. Tazarotene gel: Efficacy and safety in plaque psoriasis. J Am
Acad Dermatol 1997;37:S33S38.
131. Lebwohl M, Lombardi K, Tam MH. Duration of improvement in psoriasis
after treatment with tazarotene 0.1% gel plus clobetasol propionate 0.05%
ointment: Comparison of maintenance treatment. Int J Dermatol 2001;40(1):64
6.
132. Hecker D, Worsley J, Yuch G, et al. In vitro compatibility of tazarotene with
other topical treatments of psoriasis. J Am Acad Dermatol 2000;42:100811.
133. Behrens S, GrundmannKollmann M, Schiener R, et al. Combination
phototherapy of psoriasis with narrowband UVB irradiation and topical
tazarotene gel. J Am Acad Dermatol 2000;42:4935.
134. Kakita L. Tazarotene versus tretinoin or adapalene in the treatment of acne
vulgaris. J Am Acad Dermatol 2000;43:S51S54.
135. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability of oncedaily
tazarotene 0.1% gel versus oncedaily tretinoin 0.025% gel in the treatment of
facial acne vulgaris: A randomized trial. Cutis 2001; 67(6 Suppl):49.
136. Leyden JJ, Tanghetti EA, Miller B, et al. Oncedaily tazarotene 0.1% gel versus
once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne
vulgaris: A double blind randomized trial. Cutis 2002;69 (Suppl 2):129.
137. Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind,
randomized comparison study of the efficacy and tolerability of oncedaily
tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne
vulgaris. Cutis 2002;69(Suppl 2):411.
138. Draelos ZD, Tanghetti EA. Optimizing the use of tazarotene for the treatment
of facial acne vulgaris through combination therapy. Cutis 2002;69(Suppl 2):20
9.
139. Bershad S, Singer GK, Parente JE, et al. Successful treatment of acne vulgaris
using a new method: Results of a randomized vehiclecontrolled trail of short
contact therapy with 0.1% tazarotene gel. Arch Dermatol 2002;138:4819.
140. Kaidbey K, Kopper SC, Sefton J, et al. A pilot study to determine the effect of

Newer Drugs in Dermatology: Topical

141.

142.
143.
144.
145.
146.
147.
148.
149.
150.
151.

233

tazarotene gel 0.1% on steroid induced epidermal atrophy. Int J Dermatol


2001;40:46871.
Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial
photodamage: A multicenter, investigator-masked, randomized, vehiclecontrolled, parallel comparison of 0.01%, 0.025%, 0.05% and 0.1% tazarotene
creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks.
Arch Dermatol 2001;137(12):1597-1604.
Abramovits W, Abdelmalek N. Treatment of warty dyskeratoma with
tazarotenic acid. J Am Acad Dermatol 2002;46(2):S4.
Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernail
psoriasis: A double-blind, randomized, vehiclecontrolled study. Cutis
2001;68(5):3558.
Outland JD, Brown TS, Callen JP. Tazarotene is an effective therapy for elastosis
perforans serpiginosa. Arch Dermatol 2002;138(2):16971.
Micali G, Nasca MR. Tazarotene gel in childhood Dariers disease. Pediatr
Dermatol 1999;16:2434.
Oster Schmidt C. The treatment of Dariers disease with topical tazarotene.
Br J Dermatol 1999;141:6034.
Bowman PH, Davis LS. Confluent and reticulated papillomatosis: Response to
tazarotene. J Am Acad Dermatol 2003;48:S80S81.
Peris K, Fargnoli MC, Chimenti S. Preliminary observations on the use of
topical tazarotene to treat basalcell carcinoma. N Eng J Med 1999;341:1767
8.
Lewis A, Nigro M, Rosen T. Treatment of keratoderma blennorrhagicam with
tazarotene gel 0.1%. J Am Acad Dermatol 2000;43:400-2.
Weisshaar E, Bonnekoh B, Franke I, et al. Successful symptomatic tazarotene
treatment of juvenile acanthosis nigricans of the familial obesity-associated
type in insulin resistance. Hautarzt 2001;52(6):499-503.
Arndt KA, Bowers KE. Manual of Dermatologic Therapeutics; 6th edn.
Philadelphia: Lippincott Williams and Wilkins 2002:176.

234

Recent Advances in Dermatology

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

Wound Dressings: Newer Concepts

235

wound contraction. However, granulation tissue formation was fastest


in the moist wounds. Though wet wounds healed the fastest, moist
wounds healed faster than dry wounds. This incidentally illustrates
that, at present, though it can be safely stated that a moist environment
enhances wound healing, there are limited guidelines as to the exact
level of moisture that is appropriate.
Steps have been taken towards addressing this issue of how much
moisture is appropriate for optimum wound healing.9 There is no clear
answer at present. However, it has been shown that a low dressing
water vapour transmission rate (WVTR) is a dependable measure of a
particular dressings ability to retain moisture and provide an environment that supports healing. There are considerable variations between
different available dressings of the same broad category in their WVTR.
In general probably it is safe to say that the greater the amount of
moisture a dressing is able to retain, the more will be its ability to
support early wound healing. There is also reason to believe that the
greater the extent of moisture retention, lesser the incidence of clinical
infection, greater the patient comfort and greater the reduction in scarring.
Maceration, which is likely to occur more commonly with the more
moisture retaining dressings is not always associated with adverse events.
In general it can be stated that occlusive dressings of various types,
which help retain moisture and help maintain a moist environment
suitable for wound healing, are currently recommended for use.3
PROPERTIES OF AN IDEAL DRESSING MATERIAL
It is always worth enumerating the ideal situation in any context in so
far as it helps focus attention towards a (unattainable?) goal which one
tries to achieve and in the process hopefully produces the best possible
outcome at that point of time. Thus, an ideal dressing material10 keeps
the wound:
moist without maceration
free of excessive slough, particles or fibres
free of clinical infection
at an optimum temperature and pH value for proper healing
undisturbed by the need for frequent dressing changes
It also must be itself non-toxic, comfortable to the patient and
reasonable in terms of cost.
WHAT TO LOOK FOR WHEN MAKING A CHOICE?
Wounds go through various stages during the process of healing. The
stage, in which the wound exists, is important in deciding the type of
dressing material to use. For clinical purposes these are as follows:

236

Recent Advances in Dermatology

removal of dead tissue


vascularisation and granulation
epithelialisation
The type of wound will also determine the type of dressings that is
most appropriate. In a wound with dry necrotic tissue, which very often
is black, rehydration is a high priority. In a more moist wound with
necrotic tissue, which tend to be gray or yellow, depending on the
amount of exudates, moisture retention and rehydration or fluid
absorption is a priority. Dealing with foul odour can also be important.
For a wound which has started granulating, generally fluid absorption,
protection of the wound during dressing change, i.e. low adherence,
possibly odour removal, etc. are priorities. When the wound is epithelialising, again moisture retention and specially low adherence are of
importance.
BROAD VARIETIES OF DRESSING MATERIALS
There is a vast (and one dare say confusing) array of dressing materials
available nowadays. It is of help to classify them under broad types so
that their properties can be enumerated thus helping to define a clearer
role for the various types in wound healing.10 However, even within
broad categories there is sometimes a considerable variation in the exact
properties of different brands of dressing materials that has to be
accounted for.11,12 Nevertheless, discussing them under different classes
helps clarify their usefulness.
Before discussing the varieties of dressing materials available, it is
worth emphasising that irritant chemicals, that are suitable for cleansing skin, are best avoided on raw areas. Physiological saline is quite
adequate for the purpose. (One should never put anything in the wound
that cannot be comfortably tolerated in the conjunctival sac.2)
Alginate
Alginate dressings are manufactured from seaweed. They are
biodegradable which gives them the advantage that any alginate fibres
which may be trapped in the wound can be removed by the body
(biodegraded).
It is also highly absorbent because it forms a very strongly hydrophilic
gel on contact with fluids. The exact gelling properties vary between
manufacturers, some partially gel and form a sheet which can be lifted
of, others form an amorphous gel which can be washed off with
physiological saline. Because of their highly absorbent property, they

Wound Dressings: Newer Concepts

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.

238

Recent Advances in Dermatology

Limitations of hydrocolloid dressings include, as already mentioned,


a comparatively limited moisture handling capacity and thus they are
unsuitable for use in heavily exuding wounds. Because of their occlusive
nature, they should not be used on clinically infected wounds. Wounds
can sometimes hypergranulate under hydrocolloid dressings. As earlier
mentioned they need to be removed with caution from fragile skin.
Though rarely, they have been associated with allergic contact
dermatitis.19
Hydrocolloid dressings have been used as an effective dressing in
maggot therapy.20 The role of hydrocolloid dressings in diabetic foot
ulcers is less clear and they are best used with caution21,22 in this setting.
Bacteriological studies have shown that after prolonged dressings
also, the bacterial flora tends to remain unchanged under hydrocolloid
dressings and there is no correlation with clinical infection.23,24
Hydrogel Dressings
These consist predominantly of a polymer or copolymer and up to 95
percent water. Thus, they are very suitable for donating water to
dehydrated tissues. They are able to absorb only limited quantities of
moisture and are unsuitable for use on exuding wounds where they will
cause maceration. They are non-particulate, non-toxic and non-adherent.
They are available in two forms, an amorphous cohesive gel which
requires a secondary dressing and hydrogel sheets which have a fixed
structure.
The amorphous form is very suitable for rehydrating dry sloughy
wounds and help in autolytic debridement. They can stay on up to three
days and can be easily washed off by irrigation with physiological
saline. Sheet hydrogels can be used in minor wounds with minimum
exudates where they have a marked cooling and soothing effect. They
are also suitable for pressure sore prevention because they can absorb
significant amounts of friction and shear. They are unsuitable for infected
wounds because they have an occlusive effect.
Many amorphous hydrogels contain propylene glycol which can cause
allergic reactions.
Foam Dressings
They are made of polyurethane foam. The properties of these products
vary from product to product. Some of them are suitable for use in
lightly exuding wounds whereas others are suitable for use in heavily
exuding wounds. They may be used as secondary dressings. In a situation
where there is hypergranulation, it may be beneficial to change from an

Wound Dressings: Newer Concepts

239

occlusive (say hydrocolloid) dressing to a more permeable dressing such


as foam.
Vapour Permeable Films and Membranes
They permit passage of oxygen and water vapour but not bacteria or
water. They may be of use in very lightly exuding wounds to provide
a moist environment but very often their effectiveness is lost because the
rate of evaporation cannot keep up with the rate of exudation. Thus,
they are unsuitable for leg ulcers. Their best use is probably as secondary
dressings over alginates and hydrocolloid gels. They are sometimes
used for protection of delicate skin from minor damage.
Low Adherence Dressings and Wound Contact Materials
These are used as contact material for the wound and used under an
absorbent layer. Most commonly used are tulle dressings. These are
made up of cotton or viscose material impregnated with white or yellow
soft paraffin to make them nonadherent, which in reality is partly
successful. The paraffin also reduces absorbency of the dressing. In spite
of these drawbacks, these are commonly available and are comparatively
inexpensive and when properly used do have a clear role in the Indian
context.
Medicated tulle dressings have come in for criticism. Framycetin
gauze dressing is associated with a high incidence of hypersensitivity
and absorption leading to toxicity is possible when large amounts are
used. The antibacterial efficacy of chlorhexidine gauze dressings has not
been established.
Odour Absorbent Dressings
Dressings are available which incorporate activated charcoal and are
useful in reducing foul odour from wounds.
Surgical Absorbents
They are useful as secondary absorbent material. Direct contact with the
wounds must be avoided as they dehydrate the wound, shed fibres into
it and tend to adhere, making it painful to remove them and causing
injury to the healing surface.
It bears mentioning at this point that in many situations other
measures are very important towards achieving appropriate wound
management. For instance, in venous leg ulcers graduated compression

240

Recent Advances in Dermatology

dressings are an important part of the managenent. In pressure ulcers,


however, good the quality of dressings, they will be of no use if other
measures such as relieving of pressure, maintenance of nutrition etc. are
not meticulously attended to. As always, the patient must be treated as
a whole.
CONCLUSION
It bears repeating again and again that it can now be regarded as accepted
that maintenance of a moist environment provides many advantages in
wound healing. Of course, the other requirements of a good dressing
material are also of importance. To this end many dressing materials
have been made available in the market. It is noteworthy that sometimes
use of a comparatively expensive material that expedites wound healing
and requires infrequent change may in the end be a better option. Thus,
choosing wisely can go a very long way towards appropriate wound
management within the financial constraints we work in India.
REFERENCES
1. Bishop SM, Walker M, Rogers AA, et al. Importance of moisture balance at
wound-dressing interface. J Wound Care; 2003; 12:125-8.
2. Atiyeh BS, Ioannovich J, Al-Amm Caet, et al. Management of Acute and Chronic
open wounds: The importance of moist environment in optimal wound healing.
Curr Pharm Biotechnol 2002; 3:17995.
3. Kannon GA, Garrett AB. Moist wound healing with occlusive dressings: A
clinical review. Dermatol Surg. 1995; 21:58390.
4. Capillas PR, Cabre AV, Gil Colome AM, et al. Comparison of the effectiveness
and cost of treatment with humid environment as compared to traditional
cure. Clinical trial on primary care patients with venous leg ulcers and pressure
ulcers. Rev Enferm 2000; 23:1724.
5. Vogt PM, Andree C, Breuing K, et al. Dry, moist and wet skin wound repair.
Ann Plast Surg 1995; 34:4939.
6. Field FK, Kerateim MD. Overview of wound healing in a moist environment.
Am J Surg 1994; 167:S2-6.
7. Dyson M, Young S, Pendle CL, et al. Comparison of the effects of moist and
dry conditions on dermal repair. J Invest Dermatol 1988; 91:4349.
8. Svensjo T, Pomahac B, Yao F, et al. Accelerated wound healing of full-thickness
skin wounds in a wet environment. Plast Reconstr Surg; 2000 106:60212.
9. Bolton LL, Monte K, Pirone LA. Moisture and healing: Beyond the jargon.
Ostomy Wound Manage 2000; 46:S51-62.
10. British National Formulary 2003; 46:733.
11. Agren MS. Alginate dressings in the treatment of partial thickness wounds: A
comparative experimental study. J Plast Surg 1996; 49:129134.
12. Thomas S, Loveless P. A comparative study of the properties of twelve
hydrocolloid dressings. World Wide Web 1997.

Wound Dressings: Newer Concepts

241

13. Odell EQ, Oades P, Lombardi T. Symptomatic foreign body reaction to


haemostatic alginate. Br J Oral Maxillofac Surg 1994; 32:1789.
14. Henderson NJ, Craqford PJ, Reeves BC. A randomised trial of calcium alginate
swabs to control blood loss in 3-5-year-old chidren. Br Dent J 1998; 184:
187190.
15. Sayag J, Meaume S, Bohbor S. Healing properties of calcium alginate dressings.
J Wound Care 1996; 5:357362.
16. Dawson C, Armstrong MW, Fulford SC, et al. Use of calcium alginate to pack
abscess cavities: A controlled clinical trial. R Coll Surg Edinb 1992; 37:1779.
17. Fraser R, Gilchrist T. Sorbsan calcium alginate dressings in footcare. Biomaterials
1983; 4:2224.
18. Thomas S. Hydrocolloids. Journal of wound care 1992; 1:2730.
19. Sasseville D, Tennstedt D, Lasgapelle JM. Allergic contact dermatitis from
hydrocolloid dressings. Am J Contact Dermat 1997; 8:2368.
20. Sherman RA. A new dressing design for use with maggot therapy. Plast Reconstr
Surg 1997; 100:4516.
21. Apelqvist J, Larsson J, Stenstrom A. Topical treatment of necrotic foot ulcers
in diabetic patients: A comparative trial of DuoDerm and MeZinc. Br J Dermatol
1990; 123:78792.
22. Laing P. Diabetic foot ulcers. Am J Surg 1994; 167:S31-6.
23. Annoni F, Rosina M, Chiurazzi D, The effects of hydrocolloid dressings on
bacterial growth and the healing process of leg ulcers. Int Angiol 1989; 8:224
8.
24. Gilchrist B, Reed C. The bacteriology of chronic venous ulcers treated with
occlusive hydrocolloid dressings. Br J Dermatol 1989; 121:33744.

242

Recent Advances in Dermatology

14

Belinda Vaz

Computer and Digital


Photography: Newer Tools
in Dermatological Practice
Dermatology is the most visual specialty in medicine and photography
has always been an important tool in illustrating and documenting the
different manifestations of dermatological diseases. With the advances
in technology and the ability to encode photographic images into
computer memory instead of onto film, conventional photography is
being replaced by digital photography. Over the last decade, digital
equipment has become easier to use, more sophisticated, more affordable
and hence easier to incorporate into a dermatological practice. The use
of digital imaging in dermatology and the advances in communication
technology like the Internet, have opened up various avenues like
videoconferencing, multimedia mail, teledermatology and image
databases that could not have been envisaged even a decade ago. Digital
photography can help the dermatologist communicate more effectively
with patients, public and peer groups. It is important for the
dermatologist to understand the basics of digital photography and its
myriad uses in practice and beyond.
BASICS OF DIGITAL PHOTOGRAPHY1-3
Charge Couple Device (CCD)
The digital camera has a charge couple device (CCD) that makes it
different from a conventional camera. This CCD is a silicon chip
composed of photosensitive diodes called photosites or pixels that convert
light into voltage. A pixel (picture element) is a little square that makes
up the image on the computer screen. The CCD captures many of the
pixels that are then stored in its memory and later transferred to a
computer. The density of light sensitive elements or pixels that a CCD
can reproduce determines its resolution.

Computer and Digital Photography

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

Recent Advances in Dermatology

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

4X Optical, zoomNikkor lens

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

Table 14.1: Features of commonly available digital cameras

USB cable

Macro made Movie

Movie

Automatic and
Manual modes

Ultra thin camera


120 gm

Movie, Date imprint,


14 scene mode

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

Computer and Digital Photography


245

246

6.

7.
8.

9.

10.

11.

Recent Advances in Dermatology

camera. When the zoom button is pushed, physical lens elements


move inside the camera to achieve the desired zoom effect. Digital
zoom consists of an electronic brain within the camera that takes
a look at the object being photographed and digitally zooms in,
usually 2 or 3 times closer. The problem with digital zoom is that
when this is done, quality is lost, as the images tend to be more
pixelated, than the same image taken with an optical zoom camera.
Auto-focus illuminator: Cameras with auto-focus illuminator cast
a bright focussed beam of light onto the subject being photographed
so that the camera can focus better. This feature is useful for indoor
photography especially where the lighting is not very strong.
Photomicrography: Digital cameras can be used to take
photographs of histopathological sections. For this there are special
lens adaptors.
Movie mode: Many digital cameras can provide for a few seconds
to a few minutes of video imaging. Thus, one can use the camera
as a video recorder albeit for a short time only. This feature is
useful to dermatosurgeons for documenting some key steps of a
surgical procedure. Most cameras have an audio capability as well.
So a short commentary can also be added to the movie clip.
Quality settings: The number of photographs that can be taken at
a time, for a particular storage capacity, depends upon the quality
settings on the camera chosen. The quality settings range, includes
economy, standard, fine and superfine. When superfine or the best
quality image is chosen, fewer photographs can be taken compared
with the lowest quality settings.
Printing options: Print-outs of digital photographs can be taken on
a regular color inkjet or laser or dye sublimation printer.
Photoprinters are also available that use a special paper. They are
not very good at printing out just text. Some photoprinters can be
attached directly to the camera to produce an instant print like a
Polaroid camera. Some photoprinters have slots for memory cards
and hence one does not need a PC for printing these photographs.
Computer compatibility: Different cameras have different
specifications with regards to computer compatibity that should be
checked before buying the camera.

COMPUTER REQUIREMENTS FOR DIGITAL PHOTOGRAPHY


A key advantage of digital photography is, the ability to transmit ones
photographs to a computer. The computer used may be PC or a
Macintosh. In a busy dermatological practice, the number of digital
photographs that are stored is likely to be considerable and hence it is

Computer and Digital Photography

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

Recent Advances in Dermatology

APPLICATIONS OF DIGITAL PHOTOGRAPHY


Clinical Practice
A computer is an invaluable help in a busy dermatological practice and
is used to maintain patients records (demographic data, clinical notes,
diagnoses, treatment given), generate legible prescriptions, keep a track
of patients visits and help with billing. A laptop computer has been
found to be a useful tool that allows the dermatologist to deal with a
number of problems that arise in a hospital setting, e.g., illegible hand
writing, lack of complete information about hospitalised patients in the
outpatient chart, lack of effective library resources on the hospital floor
and lack of readily available patient education material.5 When using
computers for the first time, it is important for the dermatologist to
overcome the fear of computers that some adults have, develop typing
skills and have the support of user-friendly software and a computer
literate colleague to deal with initial teething problems.
Digital photographs of patients can become a very important part of
the patients records. They can also be used to provide documentation
of a procedure, to generate notes with pre- and post-treatment photodocumentation to the referring doctor or to generate histopathological
photodocumentation. A photographic record makes it easy for a
dermatologist to be more objective in monitoring certain diseases like
vitiligo, Hansens disease, hair loss, etc. It is important to take a patients
consent before taking a clinical photograph.6,7 A computer adds immense
value to a practice but it is also important to use a computer without
disturbing the doctor-patient interaction.
Dermatosurgeons can use the system for documentation of a surgical
procedure and pre- and postoperative results. There are systems also
available that allow a prospective cosmetic surgical patient to view their
image on a computer screen and modify the image so as to give them
an idea of the post-surgical outcome.8
Digital Epiluminescence Microscopy
A digital camera can also be combined with dermatoscopy or skin surface
microscopy. Digital Epiluminescence Microscopy (DELM) is the term
used for use of digital images of dermatoscopy, skin surface microscopy
and videomicroscopy techniques.9,10 DELM is a non-invasive clinical
technique that uses the optical phenomenon of oil immersion to render
the epidermis translucent. Digital videomicroscopes use polarizing light
instead of a drop of oil or a glass slide.11 DELM opens a new dimension
of skin morphology by including the dermoepidermal junction into the

Computer and Digital Photography

249

macroscopic evaluation of a lesion. It provides for a more detailed


inspection of the surface of pigmented skin lesions and morphological
criteria that are not readily apparent to the naked eye are easily detected
by epiluminescence microscopy. Features like colors, specific patterns,
intensity of pigmentation, regularity, configuration and other characteristics of the margin and the surface, aid in differentiating between
benign and malignant growth patterns.9 The accurate evaluation of a
pigmented skin lesion by DELM depends on the dermatologists
experience and has been shown to be increased by formal training.12,13
The use of DELM in the follow-up study of patients with melanocytic
lesions has indicated that DELM could identify patterns of morphologic
changes typical for early melanoma and could, therefore, serve as a
useful tool to improve the surveillance of patients with multiple atypical
nevi.14 Using sophisticated computer-based systems it is possible to
quantitatively analyse the DELM pictures of pigmented skin lesions.15
A digital imaging program has been developed for identifying
melanomas rapidly and reproducibly by just scanning in an image of
the lesion or through multispectral digital dermoscopy. This technology
is useful in those with a high risk of melanoma to avoid unnecessary
biopsies.16,17
A videomicroscope consists of a combination of videocamera, microscope and lighting, which allow greater magnification than epiluminescence microscopy. Compact videomicroscopes have been developed
that permit clinical inspection of the subsurface structure. Videomicroscopy has been used in the evaluation of port wine stains, to determine
the depth of the ectatic vessels.18 Confocal scanning laser microscopy is
another system that provides high resolution instantaneous images of
nuclear, cellular and architectural detail in human skin in vivo. It is
capable of identifying distinct patterns and cytologic features of benign
and malignant pigmented skin lesions in vivo.19
Research
Digital photography can be used to objectively assess the effect of various
medications on parameters like hair growth, size and depth of wrinkles,
size of ulcers, etc.20,21 They are used with a special camera system (e.g.
Canfield Scientific Camera System) that has a chin rest and a forehead
rest with a fibreoptic guide light to ensure proper positioning of the
head in before and after pictures. This ensures that the pre- and posttreatment photographs are as similar as possible. The digital images are
quantitatively analysed to assess the progress of the variable or clinical
parameter that is being assessed.

250

Recent Advances in Dermatology

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

Computer and Digital Photography

251

Teledermatology can provide specialized dermatological services to


remote areas where there are no or few dermatologists. Teledermatology
has even been used in sub-Saharan Africa with Swiss dermatologists
providing the teleconsultations.25
A teledermatological set up consists of a digital camera and a
computer workstation, which is handled by a primary care physician or
health care provider in the remote clinical setting. As in a regular faceto-face consultation, a detailed history is taken, the examination
performed and digital images are taken. These are then sent via the
computer to the appropriate server or computer network and then to
the teledermatologist who assesses the case, makes a diagnosis, suggests
further investigation, formulates a treatment plan and communicates
this back to the health care provider.26 Digital images of histopathological
sections and dermatoscopic examination have also been sent to the
teledermatologist to enhance diagnostic accuracy.27,28
The teledermatology consultation can be of 2 types:
Liveusing real time video-conferencing between participating
parties
Store and Forward Systems (SAF)Digital images of patients
and clinical data are stored electronically and accessed later by
the teledermatologist. This system is more economical.29
Various studies have found that the diagnostic accuracy and
management efficacy of teledermatological consultations are comparable
with conventional hospital consultations.30-33 A patients acceptance and
satisfaction with telemedicine services has been found to be dependent
on the patients subjective health status.34 Patients with poor quality of
life prefer a face-to-face interaction with expert clinicians.
The cost of teledermatology consultations, especially where the
services are underutilized, appeared to be higher per patient compared
with the cost of conventional care.35 However, the teleconsultations were
of greater convenience to the patient as they saved on travel time, they
did have a long wait to see the specialist, there was quicker resolution
of the problem and fewer interim visits. The general practitioners
involved with the teledermatology consultations also experienced
enhanced job satisfaction. It is likely that if telemedicine equipment
were less expensive and travelling distances greater, teledermatology
would be a cost-effective alternative to conventional care.
The limitations of teledermatology are the technical drawbacks that
the teledermatologist may face when making a diagnosis because of
poor quality of digital image and the inability to palpate, change the
lighting, perform a total skin examination or view the skin from different
angles. The teledermatologist also misses the subtle nuances in history,

252

Recent Advances in Dermatology

patients body language and demeanour that are an important part of


a face-to-face consultation that can affect the diagnosis and further
management. When questioned specifically, many patients reveal that
they would prefer a face-to-face consultation.36
Technical breakthroughs have brought about a great deal of
improvement and convenience in patient care but at the cost of
depersonalisation of the practice of medicine. It is too early to predict
whether dermatology patients need just a simple answer to their
questions and problems or they need a little more of the human touch.
REFERENCES
1. Ratner D, Thomas CO, Bickers D. The uses of digital photography in
dermatology. J Am Acad Dermatol 1999; 41: 749-56.
2. Perednia DA. What dermatologists should know about digital imaging. J Am
Acad Dermatol 1991; 25: 89-108.
3. Stone JL, Peterson RL, Wolf JE. Digital imaging techniques in dermatology. J
Am Acad Dermatol 1990; 5: 913-7.
4. Bittorf A, Fortasch M, Schuler G, Diepgen TL. Resolution requirements for
digital images in dermatology. J Am Acad Dermatol 1997; 37: 195-8.
5. Marchese S, Nadenichek TJ, Brodell RT. The laptop computer in dermatology.
J Am Acad Dermatol 1997; 37: 284-6.
6. Hood CA, Hope T, Dove P. Videos, photographs and patient consent. BMJ
1998; 316: 1009-11.
7. Nicholl D, Winters G, Davies D. Publishing information about patients. BMJ
1996; 312: 578-79
8. Koch RJ, Chavez A, Dagum P, Newman JP. Advantages and disadvantages of
computer imaging in cosmetic surgery. Dermatol Surg 1998; 24: 195-8.
9. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of
pigmented skin lesions. I. Pattern analyses of pigmented skin lesions. J Am
Acad Dermatol 1987; 17: 571-83.
10. Steiner A, Pehamberger H, Wolff K. In vivo epiluminescence microscopy of
pigmented skin lesions. II. Diagnoses of small pigmented skin lesions and
early detection of malignant melanoma. J Am Acad Dermatol 1987; 17: 58491.
11. Seldenari S, Pallacom G, Pepe P. Digital videomicroscopy improves diagnostic
accuracy for melanoma. J Am Acad Dermatol 1998; 39: 175-81.
12. Binder M, Schwarz M, Steiner A et al. Epiluminescence microscopy of small
pigmented skin lesions: Short-term formal training improves the diagnostic
performance of dermatologists. J Am Acad Dermatol 1997; 36: 197-202.
13. Binder M, Schwarz M, Winkler A et al. Epiluminescence microscopy: A useful
tool for the diagnosis of pigmented skin lesions for formally trained
dermatologists. Arch Dermatol 1995; 131: 286-91.
14. Kettler H, Pehamberger H, Wolff K et al. Follow up of melanocytic skin lesions
with Digital epiluminescence microscopy; Patterns of modifications observed
in early melanoma, atypical nevi, and common nevi. J Am Acad Dermatol
2000; 43: 467-76.
15. Voigt H, Classen R. Computer vision and digital imaging technology in
melanoma detection. Semin Oncol 2002; 29: 308-27.

Computer and Digital Photography

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

clinical uses 218


mechanism of action 216
pharmacology 217
Collodion baby 72
Compression 243
Condyloma accuminata 218
Cryoglobulinemic vasculitis 42
Cutaneous adverse drug reaction 89
anti-retroviral therapy 103
blistering drug eruption
linear IgA bullous dermatosis 100
pemphigoid 101
pemphigus 101
pseudo-porphyria 102
drug induced erythema nodosum 100
drug induced lupus erythematosus 102
drug induced pseudolymphoma
syndrome 99
drug induced pustular eruption 98
eczematous drug eruption 93
erythema multiforme 94
examthematous/morbillform/maculopapular drug eruption 90
exfoliative dermatitis/erythroderma 91
fixed drug eruption 96
hypersensitivity syndrome reaction 91
lichenoid drug eruption 97
photosensitive drug eruption 93
psoriasiform drug reaction 97
scleromatoid tissue reaction 103
Stevens-Johnson syndrome 94
toxic epiderma necrolysis 94
urticaria, angioedema and serum
sickness 92
vasculitis 98
Cutaneous polyarteritis nodosa 43
Cutaneous tuberculosis
clinical features 24
diagnosis 27
in immunosuppressed host 26
pathogenesis 27
treatment 28
Cytokeratins 11

D
Death domain 2
Dermatitis medicamentosa 65
Desmin 12

256

Recent Advances in Dermatology

Digital epiluminescence microscopy 248


Digital photography 242
advantages 247
applications 248
clinical practice 248
communication 250
digital epilumiescence microscopy 248
education 250
research 249
telemedicine 250
computer requirements 246
criteria of selecting a digital camera 244
Donovanosis 153
Dressing materials
alginate 236
foam 238
hydrocolloid 237
hydrogel 238
low adherence 239
odour absorbent 239
surgical absorbents 239
vapour permeable films and membranes
239
wound contact materials 239
Drug eruptions 65

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

Laryngeal papillomatosis 219


Leiners disease 84
Leucocyte common antigen 16
Leukemia cutis 20
Leukocytoclastic vasculitis 31
classification 37
diagnosis and treatment 46, 47
drugs used 49
laboratory workup 48
disease associated with 39
drugs causing 35
etiological factors 34
etiopathogenesis 32

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

Narrowband UV-B therapy 172


clinical studies 175
mechanism of action 174
method of use 172
newer developments
308-nm excimer laser therapy 176
narrowband UV-B micro-phototherapy
176
response to treatment 174
side effects 174
Neurofilaments 12
Neutrophilic dermatosis 44
New drugs in dermatology 180, 204
systemic 180
bexarotene 192
infliximab 190
ivermectin 182
mycophenolate mofetil 180
thalidomide 185
topical 204
cidofovir 216
imiquimod 211
pimecrolimus 208

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

Recent Advances in Dermatology

therapy for cutaneous involvement


131
vascular therapy 127
manifestations 124
pathogenesis 118
immunologic activity 119
increased fibroblast activity and
collagen synthesis 120
vascular changes 118
Sensitivity 143
Serum sickness 45
Sexually acquired hepatitis 167
Sexually transmitted disease 147, 165
current treatment options 150
laboratory tests in the diagnosis 148
Smallpox 221
Specificity 143
Spindle cell neoplasms 14
Staphylococcal scalded skin syndrome 59
Storage of images 243
Sunburn cells 3
Synaptophysin 13
Syphilis 147

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