May / June, 2011 - SKINmed Journal

Transcription

May/June 2011 • Volume 9 • Issue 3
EDITORIAL
Impending Changes in Diagnostic Nomenclature:
Will ICD-10 Be Obsolete by Implementation Time?
REVIEWS
Primary Anetoderma:
A Cutaneous Marker of Antiphospholipid Antibodies
COMMENTARIES
What Is Kindler Syndrome?
Fabry Disease
Abramovits and Baugh
Lai-Cheong and McGrath
Primary Anetoderma
Husain and Lambert
Dengue Fever
Franco-Arcia and Goihman-Yahr
ORIGINAL CONTRIBUTIONS
Doxepin Cream vs Betamethasone Cream for Treatment
of Chronic Skin Lesions Due to Sulfur Mustard
Panahi, Davoudi, Beiraghdar, and Amiri
Follicular Variant of Seborrheic Dermatitis:
Is It Identical to Malassezia Folliculitis?
Valentine
Staiger, Saposnik, Spiner, Schroh, Corbella, and Hassan
Tarabuso
DEPARTMENTS
New to the Clinic
Calcipotriene 0.005% and Betamethasone Dipropionate
0.064% Combination Topical Suspension (Taclonex Scalp)
Scheinfeld
Cosmetic Science
The Next Frontier of Sunscreen Protection
Epstein
Perils of Dermatopathology
Epinephrine: Friend or Foe?
Patel and Lambert
CASE STUDIES
Tufted Hair Folliculitis in a Patient
Affected by Pachydermoperiostosis:
Case Report and Videodermoscopic Features
Baroni and Romano
Familial Juvenile Generalized Pustular Psoriasis:
Response to Methotrexate
Garg, Chander, and Mittal
Vitiligo and Alopecia Areata
Associated With Subclinical/Clinical Hypothyroidism
Sehgal
An Unusual Cutaneous Manifestation of Crohn’s Disease
Weiser, Markowitz, Husain, and Grossman
Cutaneous Manifestations of Strongyloides stercoralis
Hyperinfection in an HIV-Seropositive Patient
Martin, Cohen, MacFarlane, and Grossman
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*
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Important Safety Information
Differin® Lotion, 0.1% is indicated for the topical treatment of acne vulgaris in patients 12 years and older. A thin film of
Differin® Lotion, 0.1% should be applied once per day to the face and other areas of the skin affected by acne. In clinical
trials, the most common adverse event (>1%) reported with use of Differin® Lotion, 0.1% was mild to moderate skin dryness.
Erythema, scaling, stinging and burning may also occur. Excessive exposure to sunlight and sunlamps should be avoided
during treatment, and use of sunscreen products and protective clothing is recommended. Concomitant use of drying or
irritating topical products (like products containing resorcinol, salicylic acid or sulfur) should be used with caution. Instruct
patients to avoid the eyes, lips and mucous membranes when applying Differin® Lotion, 0.1%, and not to apply to areas
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INDICATIONS AND USAGE
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CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight
and sunlamps. Wear sunscreen when sun exposure cannot be avoided.
Erythema, scaling, dryness, and stinging/burning may occur with use of
DIFFERIN Lotion.
ADVERSE REACTIONS
Dry skin of mild to moderate severity was the most frequently reported
(≥ 1%) treatment related adverse event. Erythema, scaling, dryness,
burning/stinging were also seen during treatment.
DRUG INTERACTIONS
Concomitant use of topical products with a strong drying effect can increase
skin irritation. Use with caution, especially in using preparations containing
sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Lotion. Wax
depilation should not be performed on treated skin.
Pregnancy
Pregnancy Category C. There are no well-controlled trials in pregnant women
treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus. Animal reproduction studies have not been conducted with
DIFFERIN Lotion. Furthermore, such studies are not always predictive of
human response.
Human Data
In clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne
vulgaris, women of childbearing potential initiated treatment only after a
negative pregnancy test. Two women became pregnant while using DIFFERIN
Lotion, 0.1%. One patient delivered a healthy full term baby and the other
patient electively terminated her pregnancy.
Animal Data
No teratogenic effects were observed in rats treated with oral doses of 0.15
to 5.0 mg adapalene/kg/day, up to 25 times (mg/m2/day) the maximum
recommended human dose (MRHD) of 2 grams of DIFFERIN Lotion.
However, teratogenic changes were observed in rats and rabbits when treated
with oral doses of ≥ 25 mg adapalene/kg/day representing 123 and 246 times
MRHD, respectively. Findings included cleft palate, microphthalmia,
encephalocele and skeletal abnormalities in rats; and umbilical hernia,
exophthalmos and kidney and skeletal abnormalities in rabbits.
Dermal teratology studies conducted in rats and rabbits at doses of 0.66.0 mg adapalene/kg/day [25-59 times (mg/m2) the MRHD] exhibited no
fetotoxicity and only minimal increases in supernumerary ribs in both species
and delayed ossification in rabbits.
Systemic exposure (AUC 0-24h) to adapalene at topical doses
(6.0 mg/kg/day) in rats represented 101 times the exposure to adapalene in
patients with acne treated with DIFFERIN Lotion applied to the face, chest
and back (2 grams applied to 1000 cm² of acne-involved skin).
Nursing Mothers
It is not known whether adapalene is excreted in human milk following
use of DIFFERIN Lotion. Because many drugs are excreted in human milk,
caution should be exercised when DIFFERIN Lotion is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the
age of 12 have not been established.
Geriatric Use
Clinical studies of DIFFERIN Lotion did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently
from younger subjects.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity, mutagenicity and impairment of fertility studies were
conducted with DIFFERIN Lotion.
Carcinogenicity studies with adapalene have been conducted in mice at
topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m²/day),
and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3.0, and
9.0 mg/m2/day). In terms of body surface area, the highest dose levels are
9.8 (mice) and 7.4 times (rats) the MRHD of 2 grams of DIFFERIN Lotion.
In the rat study, an increased incidence of benign and malignant
pheochromocytomas in the adrenal medulla of male rats was observed.
No photocarcinogenicity studies were conducted with adapalene. However,
animal studies have shown an increased tumorigenic risk with the use
of pharmacologically similar drugs (e.g. retinoids) when exposed to UV
irradiation in the laboratory or sunlight. Although the significance of these
findings to humans is not clear, patients should be advised to avoid or
minimize exposure to either sunlight or artificial irradiation sources.
Adapalene did not exhibit mutagenic or genotoxic effects in vitro (Ames test,
Chinese hamster ovary cell assay, mouse lymphoma TK assay) or in vivo
(mouse micronucleus test).
In rat oral studies, 20 mg adapalene/kg/day (120 mg/m2/day; 98 times the
MRHD based on mg/m2/day comparison) did not affect the reproductive
performance and fertility of F0 males and females, or growth, development
and reproductive function of F1 offspring.
PATIENT COUNSELING INFORMATION
• Apply a thin film of DIFFERIN Lotion to the affected areas of the skin once
daily, after washing gently with a mild soapless cleanser. Dispense a nickel
size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the
entire face. Avoid application to the areas of skin around eyes, lips and
mucous membranes. DIFFERIN Lotion may cause irritation such as
erythema, scaling, dryness, stinging or burning.
• Advise patients to cleanse the area to be treated with a mild or soapless
cleanser; pat dry. Apply DIFFERIN Lotion to the entire face or other
acne affected areas as a thin layer, avoiding the eyes, lips and mucous
membranes.
• Exposure of the eye to this medication may result in reactions such as
swelling, conjunctivitis and eye irritation.
• Patients should be advised not to use more than the recommended amount
and not to apply more than once daily as this will not produce faster
results, but may increase irritation.
• Advise patients to minimize exposure to sunlight including sunlamps.
Recommend the use of sunscreen products and protective apparel
(e.g., hat) when exposure cannot be avoided.
• Moisturizers may be used if necessary; however, products containing alpha
hydroxy or glycolic acids should be avoided.
• This medication should not be applied to cuts, abrasions, eczematous, or
sunburned skin.
• Wax depilation should not be performed on treated skin due to the
potential for skin erosions.
• This product is for external use only.
Marketed by:
GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA
Manufactured by:
Galderma Production Canada Inc., Baie d’Urfé, QC, H9X 3S4 Canada
Made in Canada.
GALDERMA is a registered trademark.
P51503-0
Revised: March 2010
Reference: 1. Data on file. Galderma Laboratories, L.P.
Galderma is a registered trademark.
©2010 Galderma Laboratories, L.P.
Galderma Laboratories, L.P.
14501 N. Freeway
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DIFF-113 Printed in USA 09/10
www.differin.com/HCP
TABLE OF CONTENTS
EDITORIAL
Impending Changes in Diagnostic Nomenclature: Will ICD-10 Be Obsolete by Implementation Time?.............. 143
William Abramovits, MD; Jimmy Baugh, MD
COMMENTARIES
What Is Kindler Syndrome?........................................................................................................................... 145
Joey E. Lai-Cheong, MBBS, PhD, MRCP; John A. McGrath, MD, PhD, FRCP
Primary Anetoderma.................................................................................................................................... 149
Zain Husain, BS; W. Clark Lambert, MD, PhD
Dengue Fever.............................................................................................................................................. 150
Francisco Franco-Arcia, MD; Mauricio Goihman-Yahr, MD, PhD
ORIGINAL CONTRIBUTIONs
Doxepin Cream vs Betamethasone Cream for Treatment of Chronic Skin Lesions Due to Sulfur Mustard......... 152
Yunes Panahi, PhD; Seyyed Masoud Davoudi, MD; Fatemeh Beiraghdar, MD; Mojtaba Amiri, MD
Follicular Variant of Seborrheic Dermatitis: Is It Identical to Malassezia Folliculitis?........................................ 161
Mark C. Valentine, MD
REVIEWS
Primary Anetoderma: A Cutaneous Marker of Antiphospholipid Antibodies..................................................... 168
Hernán Staiger, MD; Miriam Saposnik, MD; Rubén E. Spiner, MD; Roberto G. Schroh, MD, PhD; María C. Corbella, MD;
Mercedes L. Hassan, MD, PhD
Self-Test Review Questions (p. 171)
Fabry Disease.............................................................................................................................................. 173
Ana Lía Tarabuso, MD
Departments
New to the Clinic
Noah S. Scheinfeld, MD, JD, Section Editor
Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Combination Topical Suspension
(Taclonex Scalp).......................................................................................................................................... 179
Noah S. Scheinfeld, MD, JD
Cosmetic Science
Howard A. Epstein, PhD, Section Editor
The Next Frontier of Sunscreen Protection.................................................................................................... 181
Howard A. Epstein, PhD
W. Clark Lambert, MD, PhD, Section Editor
Epinephrine: Friend or Foe?.......................................................................................................................... 184
Laju M. Patel, MD; W. Clark Lambert, MD, PhD
138
TABLE OF CONTENTS
CASE STUDIES
Vesna Petronic-Rosic, MD, MSc, Section Editor
Tufted Hair Folliculitis in a Patient Affected by Pachydermoperiostosis:
Case Report and Videodermoscopic Features............................................................................................... 186
Adone Baroni, MD, PhD; Francesca Romano, MD
Familial Juvenile Generalized Pustular Psoriasis: Response to Methotrexate.................................................. 190
Taru Garg, MD; Ram Chander, MD; Saurabh Mittal, MD
Vitiligo and Alopecia Areata Associated With Subclinical/Clinical Hypothyroidism........................................... 192
Virendra N. Sehgal, MD
An Unusual Cutaneous Manifestation of Crohn’s Disease................................................................................ 196
Jessica A. Weiser, MD; David M. Markowitz, MD; Sameera Husain, MD; Marc E. Grossman, MD
Cutaneous Manifestations of Strongyloides stercoralis Hyperinfection in an HIV-Seropositive Patient.............. 199
Stephanie J. Martin, BA; Philip R. Cohen, MD; Deborah F. MacFarlane, MD, MPH; Marc E. Grossman, MD
Editorial
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SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online
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May/June 2011
EDITORIAL BOARD
EDITOR IN CHIEF
Lawrence Charles Parish, MD, MD (Hon)
Philadelphia, PA
DEPUTY EDITORS
William Abramovits, MD
Dallas, TX
W. Clark Lambert, MD, PhD
Newark, NJ
Larry E. Millikan, MD
Meridian, MS
Jennifer L. Parish, MD
Philadelphia, PA
Marcia Ramos-e-Silva, MD, PhD
Rio de Janeiro, Brazil
EDITORIAL BOARD
Mohamed Amer, MD
Cairo, Egypt
Gibbstown, NJ
Eve J. Lowenstein, MD, PhD
New York, NY
New York, NY
Robert L. Baran, MD
Cannes, France
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George M. Martin, MD
Kihei, HI
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Anthony V. Benedetto, DO
Philadelphia, PA
Anthony A. Gaspari, MD
Baltimore, MD
David I. McLean, MD
Vancouver, British Columbia
Charles Steffen, MD
Oceanside, CA
Brian Berman, MD, PhD
Miami, FL
Michael Geiges, MD
Zurich, Switzerland
Marc S. Micozzi, MD, PhD
Bethesda, MD
Alexander J. Stratigos, MD
Athens, Greece
Jack M. Bernstein, MD
Dayton, OH
Michael H. Gold, MD
Nashville, TN
George F. Murphy, MD
Boston, MA
James S. Studdiford III, MD
Philadelphia, PA
Sarah Brenner, MD
Tel Aviv, Israel
Lowell A. Goldsmith, MD, MPH
Chapel Hill, NC
Oumeish Youssef Oumeish, MD, FRCP
Amman, Jordan
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Los Alamos, NM
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Cadiz, Spain
Aditya K. Gupta, MD, PhD, FRCP(C)
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Joseph L. Pace, MD, FRCP
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Julian Trevino, MD
Dayton, OH
Henry H.L. Chan, MB, MD, PhD, FRCP
Hong Kong, China
Seung-Kyung Hann, MD, PhD
Seoul, Korea
Art Papier, MD
Rochester, NY
Snejina Vassileva, MD, PhD
Sofia, Bulgaria
Noah Craft, MD, PhD, DTMH
Torrance, CA
Roderick J. Hay, BCh, DM, FRCP, FRCPath
London, UK
Vesna Petronic-Rosic, MD, MSc
Chicago, IL
Daniel Wallach, MD
Paris, France
Ncoza C. Dlova, MBChB, FCDerm
Durban, South Africa
Tanya R. Humphreys, MD
Philadelphia, PA
Johannes Ring, MD, DPhil
Munich, Germany
Michael A. Waugh, MB, FRCP
Leeds, UK
Richard L. Dobson, MD
Mt Pleasant, SC
Camila K. Janniger, MD
Englewood, NJ
Roy S. Rogers III, MD
Rochester, MN
Wm. Philip Werschler, MD
Spokane, WA
William H. Eaglstein, MD
Palo Alto, CA
Abdul-Ghani Kibbi, MD
Beirut, Lebanon
Donald Rudikoff, MD
New York, NY
Joseph A. Witkowski, MD
Philadelphia, PA
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Birmingham, AL
Andrew P. Lazar, MD
Highland Park, IL
Robert I. Rudolph, MD
Wyomissing, PA
Ronni Wolf, MD
Rechovot, Israel
Charles N. Ellis, MD
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Zagreb, Croatia
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140
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Printed in USA
May/June 2011
Volume 9 • Issue 3
EDITORIAL
Impending Changes in Diagnostic Nomenclature:
Will ICD-10 Be Obsolete by Implementation Time?
William Abramovits, MD;1,3 Jimmy Baugh, MD2
W
ith the influx of new diagnoses, even a disease with
a long dossier may create problems for the International Classification of Diseases (ICD). Let’s visit with
fictitious patient encounters:
Mr Doe, you have interleukin (IL)-12/23 psoriasiform disease. This is the new way insurance companies want us to
call your condition so that it will be properly coded. A few
years ago, you and I would have called it psoriasis, but now
we know that there are several dermatoses that look like
psoriasis but, at a molecular level, differ enough to make it
of practical value to give them more specific names.
Other patients with skin lesions that look like yours suffer from IL-17–driven psoriasiform disease, which we also
used to call psoriasis. There are a few other types of psoriasiform diseases whose names depend on the molecule that
drives the development of psoriasis-looking lesions. The
one you have will not get well enough with etanercept,
adalimumab, or infliximab, which work great on another
type of psoriasiform disease, driven by a different protein
called tumor necrosis factor alpha (TNF-α), made by
some cells of the immune system. For you, ustekinumab
and briakinumab are the right choice. I can assure you of
this because the test we performed showed that you have
a mutation of the gene modulating IL-12/23 production.
A cardiologist across the hall might be saying: “You don’t
have garden-variety coronary artery disease (CAD), you
have TMEM43 CAD, which is associated with sudden
cardiac death at a young age, and because you also have a
mutant CYP2C19 gene, your disease is resistant to therapy with clopidogrel, so we may have to use low-dose warfarin to prevent your premature demise.”
A rheumatologist at the office above may be telling his patient: “This joint swelling is due to an excess of IL-1. I’m
placing you not just on indomethacin, but also on anakinra,
a biologic drug that blocks the action of such proinflammatory molecule. Even if I’m wrong, and what you have is
gout, you should notice improvement in a few days.”
Comment
The above scenarios are likely to happen before the 10th revision
of ICD (ICD-10) is implemented. Even though about 138,000
diseases are expected to be added to the nearly 17,000 in the
ICD-9, the speed at which we are learning about genetic and
other pathogenic mechanisms will lead to the outpacing of any
fixed catalog based on clinical grounds. ICD-10 is mandated for
implementation on October 1, 2013, after many years of delay.
Estimations for the cost of doing this are as high as $8 billion,
which translates to an expenditure of $84,000 for each small
physician practice.
Coding systems should be flexible enough to incorporate new
diseases as they become accepted by the medical community,
and exact enough to identify a diagnosis. ICD-10 is neither. So,
from the realization of this, ICD-11 is already in advanced stages
of development. The incompetence of the currently used ICD-9
is, by the way, one of the many reasons making it practically impossible to properly implement electronic health records at this
time. But we digress.
Case in point, the auto-inflammatory syndromes, such as the
periodic fevers, which include Muckle-Wells syndrome and the
Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne
(PAPA) syndrome, are now known to be due to cytokine activation of inflammatory pathways. These conditions are increasingly being recognized. They arise from single gene mutations
and are not to be confused with autoimmune diseases mediated
through the adaptive immune system and antibody aberrant recognition of self. With the skin being involved in many of these
conditions, it is inevitable that the scope of dermatology alone
will expand. The last time we checked, there were some 25 ILs,
a couple of tumor necrosis factors, and 3 interferons that you
From the Departments of Dermatology1 and Family Medicine,2 University of Texas Southwestern Medical School, and Baylor University
Medical Center,3 Dallas, TX
Address for Correspondence: William Abramovits, MD, Dermatology Treatment and Research Center, 5310 Harvest Hill Road, Suite 160,
Dallas, TX 75230 • E-mail: dra@dermcenter.us
SKINmed. 2011;9:143–144
143
© 2011 Pulse Marketing & Communications, LLC
May/June 2011
EDITORIAL
may need to memorize. And we can’t forget the receptors (such
as toll-like [at least 9]), which are likely to be targeted for therapeutic reasons in the near future. We may also be giving targeted therapies for spider bites, staphylococcal infections, viral
rashes, melanomas, and epithelial cancers, each with a unique set
of cytokines to inactivate. Our ability to identify what cytokine
must be blocked by what antibody or other biologic product for
successful therapy will be required beyond a board test and will
further separate those who went through medical school from
some usurpers of dermatology, those who think that by learning
through repetition they can become as qualified to deliver skin
care as dermatologists. But we digress.
Conclusions
The above exemplifies how any insufficiently flexible and open disease coding system will, in real-time, become obsolete, as we predict
will happen with ICD-10. We may as well consider skipping it. Otherwise, you may be left with a year or two to relax, retire, or put your
physician assistant or nurse practitioner to good use making them
learn a barrage of new, yet transient, ICD-10 codes, or to prepare.
HISTORICAL DIAGNOSIS & Treatment
Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of steroptic cards published
in 1910 by The Stereoscopic Skin Clinic, by Dr. S. I. Rainforth.
ROSACEA
SYNONYMS: Acne rosacea; Gutta rosea; Telangiectasis
faciei.
DIAGNOSIS: Erythematous eczema burns and itches, causes
early infiltration of the skin and scaling but no vascular dilatation, and does not remain confined to the rosacea region.
The eczema, however, may complicate rosacea. Lupus
erythematosus occurs in the same location but the lesions are
sharply circumscribed and scaling and cause cicatrization.
The distribution of tubercular syphilids is never so symmetrical; their grouping is usually serpiginous and they ulcerate.
Telangiectases are absent.
TREATMENT: The disease is obstinate but mild cases can be
cured and the others favorably influenced. Attention must first
be directed toward the regulation or removal of all the conditions which tend to aggravate the disease. The acne should
receive appropriate treatment. The lotion containing three
per cent each of zinc sulphate and potassium sulphid, used
in acne is beneficial also in rosacea. Or the more powerful
liquor calcis sulphuratae may be used. It should be diluted at
first with five parts of water and applied twice a day. The dilution is to be lessened by degrees. The object is to produce
a mild desquamation. When this is accomplished the treatment should be suspended until the irritation has subsided.
The larger venules are best destroyed by electrolysis. The
needle attached to the negative pole should be inserted into
the lumen of the vessel and a current of two milliamperes
employed. Hypertrophic protuberances can be removed only
by ablation with the scalpel.
SKINmed. 2011;9:143–144
144
Impending Changes in Diagnostic Nomenclature
May/June 2011
COMMENTARY
Joey E. Lai-Cheong, MBBS, PhD, MRCP; John A. McGrath, MD, PhD, FRCP
I
n 1954, Dr Theresa Kindler, a pediatrician working in London,
England, published a case report in the British Journal of Dermatology of a 14-year-old white girl with trauma-induced blistering,
poikiloderma, and skin atrophy.1 The girl had features of both dystrophic epidermolysis bullosa (EB) and a congenital poikiloderma
syndrome. In 2003, the molecular basis of Kindler syndrome (KS;
OMIM 173650), named after the original author, was elucidated
with the discovery of pathogenic mutations in the KIND1 (also
known as FERMT1) gene, which encodes kindlin-1 (or fermitin family homolog 1).2,3 KS is an autosomal recessive genodermatosis, with
approximately 100 cases reported to date. In 2008, KS was added to
the classification of EB,4 but unlike the other forms of EB, which are
caused by defects in the hemidesmosome-anchoring filament complex, KS results from a primary defect in an actin cytoskeleton-related
protein that also impacts the underlying extracellular matrix.5
Clinical Features of KS
The cutaneous features of KS consist of acral trauma-induced blistering and skin atrophy, progressive poikiloderma, and varying
degrees of photosensitivity (Figure).6 Both the blistering and the
photosensitivity tend to diminish with age. Pseudosyndactyly, nail
dystrophy, and finger webbing have also been reported. The noncutaneous features comprise desquamative gingivitis, severe periodontitis with loss of teeth,7 gastrointestinal involvement due to colonic
inflammation resembling ulcerative colitis,8 ectropion, and stenosis
of the esophagus, anus, vagina, and urethra.9 In addition, there is
also an increased risk of mucocutaneous squamous cell carcinoma.
Pathophysiology of KS
KS results from pathogenic mutations in the KIND1/FERMT1 gene
located on chromosome 20.2,3 The gene encodes kindlin-1/fermitin
family homolog 1, an actin cytoskeleton-related protein that localizes
at integrin-rich sites, termed focal adhesions, where it participates in
integrin activation,10 an important process that mediates cell adhesion,
cell migration, and cell-extracellular matrix interactions. Deficiency of
the protein in KS, which is normally mainly expressed in basal keratinocytes, leads to reduced keratinocyte adhesion, loss of cell polarity, abnormal deposition of extracellular matrix such as laminin-332,
and reduced proliferation of keratinocytes.10,11 In KS skin, kindlin-1/
fermitin family homolog 1 is typically undetectable, and there is a major disorganization of the cutaneous basement membrane, with focal
interruptions and reduplication at the dermal-epidermal junction.10
Investigation and Diagnosis of KS
The diagnosis of KS can be difficult due to its clinical overlap with
other mechanobullous and poikiloderma syndromes. The differential diagnoses include dystrophic EB (due to COL7A1 gene mutations)12 with which it is often confused, particularly in infancy; EB
simplex with mottled pigmentation (resulting from KRT5 gene mutations)13; and Rothmund-Thomson syndrome (due to mutations
in the RECQL4 gene).14 A clinical diagnosis of KS can be made on
the basis of features such as acral blistering, poikiloderma, and skin
atrophy, although skin biopsy and gene sequencing are helpful.
Transmission electron microscopy of KS skin often shows extensive
reduplication of the lamina densa, focal widening of the lamina lucida, and multiple planes of cleavage (intra-epidermal, within the
lamina lucida and sublamina densa).15 Immunofluorescence microscopy labeling of KS skin can reveal abnormal labeling patterns
for several basement membrane proteins, including a6b4 integrin,
type XVII collagen, laminin-332, and types IV and VII collagens,
reflecting the basement membrane disruption.10 A marked reduction or complete absence of immunostaining with antibodies to
kindlin-1/fermitin family homolog 1 can also be useful diagnostically, although the availability of robust and reliable antibodies to
the protein is currently limited.
To confirm the diagnosis of KS, KIND1/FERMT1 gene sequencing
is helpful, but this test currently is restricted to a few diagnostic centers. To date, 44 different pathogenic FERMT1 mutations (including nonsense, frameshift, splice site, and large internal deletions)
have been reported in individuals with KS.16
Management of KS
Neonates with KS should be handled with care because of the fragile skin resembling dystrophic EB. During childhood, however, the
blistering tendency diminishes in most cases of KS and may cease
From the St John’s Institute of Dermatology, King’s College London, London, United Kingdom
Address for Correspondence: John A. McGrath, MD, PhD, FRCP, Dermatology Research Laboratories, Floor 9 Tower Wing, Guy’s Hospital,
Great Maze Pond, London SE1 9RT, United Kingdom • E-mail: john.mcgrath@kcl.ac.uk
SKINmed. 2011;9:145–146
145
May/June 2011
COMMENTARY
ogy of this interesting genodermatosis. This may also generate new
data about mechanisms underlying more common acquired skin
pathologies, including skin aging and nonmelanoma skin cancer.
References
1 Kindler T. Congenital poikiloderma with traumatic bulla formation and
progressive cutaneous atrophy. Br J Dermatol. 1954;66:104–111.
2 Jobard F, Bouadjar B, Caux F, et al. Identification of mutations in a
new gene encoding a FERM family protein with a pleckstrin homology
domain in Kindler syndrome. Hum Mol Genet. 2003;12:925–935.
3 Siegel DH, Ashton GH, Penagos HG, et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellularmatrix linker protein UNC-112, causes Kindler syndrome. Am J
Hum Genet. 2003;73:174–187.
4 Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): Report of the Third International
Consensus Meeting on Diagnosis and Classification of EB. J Am
Acad Dermatol. 2008;58:931–950.
5 Lai-Cheong JE, Tanaka A, Hawche G, et al. Kindler syndrome: a focal
adhesion genodermatosis. Br J Dermatol. 2009;160:233–242.
6 Lai-Cheong JE, Liu L, Sethuraman G, et al. Five new homozygous mutations in the KIND1 gene in Kindler syndrome. J Invest
Dermatol. 2007;127:2268–2270.
7 Wiebe CB, Petricca G, Hakkinen L, et al. Kindler syndrome and
periodontal disease: review of the literature and a 12-year follow-up case. J Periodontol. 2008;79:961–966.
Figure. (A) Marked skin atrophy present on the dorsal aspects
of the hands of a 29-year-old man with Kindler syndrome. (B)
Keratoderma on the palms with hyperkeratosis in the skin
creases. (C) The gingiva is very inflamed and there is moderate
dental caries. (D) The toenails are dystrophic. (E) Focal hyperkeratosis on the soles with some maceration and fissuring. (F)
Poikiloderma involving sun-exposed areas such as the neck.
8 Kern JS, Herz C, Haan E, et al. Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms. J Pathol. 2007;213:462–470.
9 Ashton GH. Kindler syndrome. Clin Exp Dermatol. 2004;29:116–121.
completely. The skin can be xerotic, and regular use of an emollient
is advocated. Sun protection is recommended due to photosensitivity and the increased risk of early-onset squamous cell carcinoma.5 In
some individuals, dysphagia can be a presenting symptom of esophageal stenosis. Radiographic imaging should be performed to determine the location and extent of the stricture. Esophageal dilatation
may be required to relieve the stenosis. In men with KS, difficulty
in micturition and urine retention can indicate urethral stenosis. In
pregnant women, elective cesarian sections should be considered, because vaginal stenosis is not an uncommon feature of KS.17 Dental
care, such as scaling and root planing and careful regular hygienist attention, are important due to aggressive periodontitis and gingivitis.18
Conclusions
KS is the first inherited disease resulting from pathogenic mutations
in a gene that encodes an actin cytoskeleton-related and focal adhesion protein. Recent studies in the field of integrin biology and the
clinical features of KS have highlighted the importance of kindlin-1/
fermitin family homolog 1 in skin homeostasis; nevertheless, more
work is required to further our understanding of the pathophysiolSKINmed. 2011;9:145–146
146
10 Lai-Cheong JE, Parsons M, Tanaka A, et al. Loss-of-function
FERMT1 mutations in kindler syndrome implicate a role for
fermitin family homolog-1 in integrin activation. Am J Pathol.
2009;175:1431–1441.
11 Herz C, Aumailley M, Schulte C, et al. Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of
epidermal keratinocytes. J Biol Chem. 2006;281:36082–36090.
12 Hilal L, Rochat A, Duquesnoy P, et al. A homozygous insertion-deletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens
dystrophic epidermolysis bullosa. Nat Genet. 1993;5:287–293.
13 Uttam J, Hutton E, Coulombe PA, et al. The genetic basis of
epidermolysis bullosa simplex with mottled pigmentation. Proc
Natl Acad Sci U S A. 1996;93:9079–9084.
14 Kitao S, Lindor NM, Shiratori M, et al. Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. Genomics. 1999;61:268–276.
15 Hovnanian A, Blanchet-Bardon C, de Prost Y. Poikiloderma of
Theresa Kindler: report of a case with ultrastructural study, and
review of the literature. Pediatr Dermatol. 1989;6:82–90.
16 Lai-Cheong JE, Parsons M, McGrath JA. The role of kindlins in
cell biology and relevance to human disease. Int J Biochem Cell
Biol. 2010;42:595–603.
17 Hayashi S, Shimoya K, Itami S, et al. Pregnancy and delivery
with Kindler syndrome. Gynecol Obstet Invest. 2007;64:72–74.
18 Thomson MA, Ashton GH, McGrath JA, et al. Retrospective diagnosis of Kindler syndrome in a 37-year-old man. Clin Exp Dermatol. 2006;31:45–47.
VELTIN Gel—A Topical Treatment for Patients 12 Years or Older With Acne Vulgaris
Once-daily application in the evening
VELTIN Gel
Combines the acne-fighting properties of tretinoin and clindamycin
Contains tretinoin, solubilized in an aqueous-based gel
Combats inflammatory and noninflammatory acne
Important Safety Information for VELTIN Gel
VELTIN Gel is contraindicated in patients with regional enteritis,
ulcerative colitis, or history of antibiotic-associated colitis
Systemic absorption of clindamycin has been demonstrated
following topical use. Diarrhea, bloody diarrhea, and colitis (including
pseudomembranous colitis) have been reported with the use of
topical clindamycin. VELTIN Gel should be discontinued if significant
diarrhea occurs. Severe colitis has occurred following oral or
parenteral clindamycin administration. Severe colitis may result
in death
Avoid exposure to sunlight and sunlamps when using VELTIN Gel.
Patients with sunburn should be advised not to use VELTIN Gel until
fully recovered. Daily use of sunscreen products and protective
apparel are recommended. Weather extremes (eg, wind and cold)
also may be irritating to patients using VELTIN Gel
Observed local treatment-related adverse reactions (≥1%) in clinical
studies with VELTIN Gel were application site reactions, including
dryness, irritation, exfoliation, erythema, pruritus, and dermatitis.
Sunburn was also reported. Incidence of actively assessed local skin
reactions peaked at week 2 and then gradually decreased
VELTIN Gel should not be used in combination with erythromycincontaining products due to possible antagonism to the clindamycin
component
Please see brief summary of Prescribing Information on the next page.
Clindamycin has been shown to have neuromuscular blocking
properties that may enhance the action of other neuromuscular
blocking agents. VELTIN Gel should be used with caution in
patients receiving such agents
VELTIN Gel should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus
It is not known whether either clindamycin or tretinoin is excreted
in human milk following use of VELTIN Gel. However, orally and
parenterally administered clindamycin has been reported to appear
in breast milk. Due to possible serious adverse reactions in nursing
infants, a decision should be made whether to discontinue
nursing or the drug. Exercise caution if administering VELTIN Gel
to a nursing woman
The efficacy and safety have not been established
in pediatric patients below the age of 12 years
VELTIN Gel is not for oral, ophthalmic,
or intravaginal use
BRIEF SUMMARY
VELTIN™ (clindamycin phosphate and tretinoin) Gel 1.2%/0.025%
The following is a brief summary only; see full prescribing information for complete
product information.
VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients
12 years or older.
CONTRAINDICATIONS
VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis,
or history of antibiotic-associated colitis.
Colitis
Systemic absorption of clindamycin has been demonstrated following topical use.
Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have
been reported with the use of topical clindamycin. If significant diarrhea occurs,
VELTIN Gel should be discontinued.
Severe colitis has occurred following oral or parenteral administration of clindamycin
with an onset of up to several weeks following cessation of therapy. Antiperistaltic
agents such as opiates and diphenoxylate with atropine may prolong and/or worsen
severe colitis. Severe colitis may result in death.
Studies indicate a toxin(s) produced by clostridia is one primary cause of antibioticassociated colitis.
Ultraviolet Light and Environmental Exposure
Exposure to sunlight, including sunlamps, should be avoided during the use of
VELTIN Gel, and patients with sunburn should be advised not to use the product
until fully recovered because of heightened susceptibility to sunlight as a result
of the use of tretinoin. Patients who may be required to have considerable sun
exposure due to occupation and those with inherent sensitivity to the sun should
exercise particular caution. Daily use of sunscreen products and protective apparel
(e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may
be irritating to patients under treatment with VELTIN Gel.
ADVERSE REACTIONS
Adverse Reactions in Clinical Studies
The safety data reflect exposure to VELTIN Gel in 1,104 patients with acne vulgaris.
Patients were 12 years or older and were treated once daily in the evening for
12 weeks. Observed local treatment-related adverse reactions (≥1%) in clinical
studies with VELTIN Gel were application site reactions, including dryness (6%),
irritation (5%), exfoliation (5%), erythema (4%), pruritus (2%), and dermatitis (1%).
Sunburn (1%) was also reported. Incidence of skin reactions peaked at week 2
and then gradually decreased.
Local skin reactions were actively assessed at baseline and at the end of 12 weeks
of treatment in patients exposed to VELTIN Gel. At baseline (N=476), local skin
reactions included erythema (24%), scaling (8%), dryness (11%), burning (8%),
and itching (17%). At 12 weeks of treatment (N=409), local skin reactions included
erythema (21%), scaling (19%), dryness (22%), burning (13%), and itching (15%).
During the 12 weeks of treatment, each local skin reaction peaked at week 2 and
gradually reduced thereafter.
DRUG INTERACTIONS
Erythromycin
VELTIN Gel should not be used in combination with erythromycin-containing products
due to possible antagonism to the clindamycin component. In vitro studies have
shown antagonism between these 2 antimicrobials. The clinical significance of this
in vitro antagonism is not known.
Neuromuscular Blocking Agents
Clindamycin has been shown to have neuromuscular blocking properties that may
enhance the action of other neuromuscular blocking agents. Therefore, VELTIN Gel
should be used with caution in patients receiving such agents.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. There are no well-controlled studies in pregnant women
treated with VELTIN Gel. VELTIN Gel should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. A limit teratology study
performed in Sprague Dawley rats treated topically with VELTIN Gel or 0.025%
tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15 did not result
in teratogenic effects. Although no systemic levels of tretinoin were detected,
craniofacial and heart abnormalities were described in drug-treated groups.
These abnormalities are consistent with retinoid effects and occurred at 16 times
the recommended clinical dose assuming 100% absorption and based on body
surface area comparison. For purposes of comparison of the animal exposure to
human exposure, the recommended clinical dose is defined as 1 g of VELTIN Gel
applied daily to a 50 kg person.
Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters,
rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given
orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose
based on body surface area comparison). However, variations in teratogenic doses
among various strains of rats have been reported. In the cynomologous monkey,
a species in which tretinoin metabolism is closer to humans than in other species
examined, fetal malformations were reported at oral doses of 10 mg/kg/day or
greater, but none were observed at 5 mg/kg/day (324 times the recommended
clinical dose based on body surface area comparison), although increased skeletal
variations were observed at all doses. Dose-related teratogenic effects and
increased abortion rates were reported in pigtail macaques.
With widespread use of any drug, a small number of birth defect reports associated
temporally with the administration of the drug would be expected by chance
alone. Thirty cases of temporally associated congenital malformations have been
reported during two decades of clinical use of another formulation of topical
tretinoin. Although no definite pattern of teratogenicity and no causal association
have been established from these cases, 5 of the reports describe the rare birth
defect category, holoprosencephaly (defects associated with incomplete midline
development of the forebrain). The significance of these spontaneous reports in
terms of risk to fetus is not known.
Nursing Mothers
It is not known whether clindamycin is excreted in human milk following use of
VELTIN Gel. However, orally and parenterally administered clindamycin has been
reported to appear in breast milk. Because of the potential for serious adverse
reactions in nursing infants, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug
to the mother. It is not known whether tretinoin is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when VELTIN
Gel is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of VELTIN Gel in pediatric patients below the age of
12 years have not been established. Clinical trials of VELTIN Gel included 2,086
patients 12-17 years of age with acne vulgaris. [See Clinical Studies (14) of full
prescribing information.]
NONCLINICAL TOXICOLOGY
Long-term animal studies have not been performed to evaluate the carcinogenic
potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was
negative for mutagenic potential when evaluated in an in vitro Ames Salmonella
reversion assay. VELTIN Gel was equivocal for clastogenic potential in the absence
of metabolic activation when tested in an in vitro chromosomal aberration assay.
Clindamycin: Once daily dermal administration of 1% clindamycin as clindamycin
phosphate in the VELTIN Gel vehicle (32 mg/kg/day, 13 times the recommended
clinical dose based on body surface area comparison) to mice for up to 2 years did
not produce evidence of tumorigenicity.
Tretinoin: In two independent mouse studies where tretinoin was administered
topically (0.025% or 0.1%) three times per week for up to two years no
carcinogenicity was observed, with maximum effects of dermal amyloidosis.
However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose
of 5.1 μg (1.4 times the recommended clinical dose based on body surface area
comparison) three times per week for 20 weeks acted as a weak promoter of skin
tumor formation following a single application of dimethylbenz[]anthracene (DMBA).
In a study in female SENCAR mice, papillomas were induced by topical exposure
to DMBA followed by promotion with 12-O-tetradecanoyl-phorbol 13-acetate or
mezerein for up to 20 weeks. Topical application of tretinoin prior to each application
of promoting agent resulted in a reduction in the number of papillomas per mouse.
However, papillomas resistant to topical tretinoin suppression were at higher risk for
pre-malignant progression.
Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed
specific studies, employing concurrent or intercurrent exposure to tretinoin and
UV radiation. The photoco-carcinogenic potential of the clindamycin tretinoin
combination is unknown. Although the significance of these studies to humans is not
clear, patients should avoid exposure to sun.
[See FDA-approved Patient Labeling in full prescribing information.]
Instructions for Use
•
At bedtime, the face should be gently washed with a mild soap and water.
After patting the skin dry, apply VELTIN Gel as a thin layer over the entire affected
area (excluding the eyes and lips).
•
Patients should be advised not to use more than a pea sized amount to cover
the face and not to apply more often than once daily (at bedtime) as this will not
make for faster results and may increase irritation.
•
A sunscreen should be applied every morning and reapplied over the course
of the day as needed. Patients should be advised to avoid exposure to sunlight,
sunlamp, ultraviolet light, and other medicines that may increase sensitivity to
sunlight.
•
Other topical products with a strong drying effect, such as abrasive soaps or
cleansers, may cause an increase in skin irritation with VELTIN Gel.
Skin Irritation
VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
Colitis
In the event a patient treated with VELTIN Gel experiences severe diarrhea or
gastrointestinal discomfort, VELTIN Gel should be discontinued and a physician
should be contacted.
VELTIN is a trademark of Astellas Pharma Europe B.V.
©2010 Stiefel Laboratories, Inc. VEL:2BRS July 2010
©2011 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. VEL049R0 April 2011
May/June 2011
COMMENTARY
Primary Anetoderma
Zain Husain, BS; W. Clark Lambert, MD, PhD
A
netoderma is a dermatologic condition marked by localized laxity of the skin resulting from elastolysis, first
described by Jadassohn in 1892.1 Clinically, lesions
manifest on the upper trunk, arms, and thighs as round, wellcircumscribed patches or papules of slack skin. They may appear
atrophied or flaccid and demonstrate inward herniation. Histopathology often demonstrates deep or perivascular lymphocytic
infiltrates.1 Elastic fiber stains generally show decreased or absent
elastic fibers in the upper and middle dermis.1
Classification
Anetoderma can be classified as primary or secondary based on etiology. Secondary anetoderma arises from an abnormal repairative
mechanism of skin lesions, whereas the pathologic mechanism underlying primary anetoderma (PA) has not been elucidated. Several
theories have been proposed. PA may be caused by immunologic targeting of elastic fibers due to cross-reaction between related epitopes
of elastic fibers and phospholipids.2 It may be due to disequilibrium
of metalloproteinases and their inhibitors as a result of tissue ischemia.
There may be increased release or activation of elastase by inflammatory cells.2 Loss of elastic fibers due to phagocytosis by macrophages
and reduced production of elastic fibers have also been proposed.
pathologic mechanism giving rise to PA, or in contrast, the cutaneous findings are a result of antibody action.
Antiphospholipid Antibodies
The accompanying paper6 suggests that PA may be an early cutaneous manifestation of antiphospholipid antibodies. The authors have
shown evidence from various serologic studies that strongly support
this. The antibodies likely trigger the pathologic mechanism underlying PA. As a result, the diagnosis of PA can be helpful in the identification of other undiagnosed immunologic diseases. Physicians
should be encouraged to test patients with PA for antiphospholipid
antibodies and other autoimmune disorders such as SLE. If the diagnosis of APS is established early, measures can be taken to prevent
thrombotic events induced by antiphospholipid antibodies. These
patients can be given aspirin and preventive anticoagulant therapy
to decrease their risk; furthermore, physicians can recommend lifestyle changes to minimize risk such as increasing exercise, quitting
smoking, and avoiding oral contraceptives.
References
PA may signify the presence of other disease processes. A relationship between PA and immunologic diseases has been well documented, especially with systemic lupus erythematosus (SLE).3 Other systemic associations include discoid lupus erythematosus, lupus
profundus, systemic sclerosis, vitiligo, alopecia areata, thyroiditis,
multiple sclerosis, and Addison’s disease.1 The association between
PA and antiphospholipid syndrome was first described in 1991.4,5
Subsequent studies have shown antiphospholipid antibodies to be
commonly associated with PA. Antiphospholipid syndrome (APS)
is a disorder of hypercoagulation caused by specific autoantibodies
against membrane phospholipids.2 Antibodies against B2GP1 (apolipoprotein H) cause a disturbance in the coagulation cascade, giving rise to hypercoagulation and thrombosis. The close relationship
between PA and APS should be investigated further to determine
whether the antiphospholipid antibodies develop in response to the
1 Weinstein S, Piette W. Cutaneous manifestations of antiphospholipid antibody syndrome. Hematol Oncol Clin North Am.
2008;22:67–77 [vi.].
2 Romaní J, Pérez F, Llobet M, et al. Anetoderma associated with
antiphospholipid antibodies: case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15:175–178.
3 Montilla C, Alarcón-Segovia D. Anetoderma in systemic lupus
erythematosus: relationship to antiphospholipid antibodies. Lupus. 2000;9:545–547.
4 Hodak E, Shamai-Lubovitz O, David M, Hazaz B, Lahav M, Sandbank
M. Primary anetoderma associated with a wide spectrum of autoimmune abnormalities. J Am Acad Dermatol. 1999;25:415–418.
5 Stephansson EA, Niemi KM, Jouhikainen T, et al. Lupus anticoagulant and the skin. A long-term follow-up study of SLE patients
with special reference to histopathological findings. Acta Derm
Venereol (Stockh). 1991;71:416–422.
6 Staiger H, Saposnik M, Spiner RE, et al. Primary anetoderma:
a cutaneous marker of antiphospholipid antibodies. Skinmed.
2011;9:168–171.
See also page 168
From the MS Class of 2011 and Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101
• E-mail: lamberwc@umdnj.edu
SKINmed. 2011;9:149
149
May/June 2011
COMMENTARY
Dengue Fever
Francisco Franco-Arcia, MD;1 Mauricio Goihman-Yahr, MD, PhD2
D
engue fever (dengue hereafter) has shown a significant re-emergence in the world and particularly in the western hemisphere.1
Current statistics indicate that Venezuela alone had 100,000
cases in 2010; however, because dengue is not compulsorily reported, the
true number likely exceeds this estimate. The disease is characterized by
high fever (up to 40°C), profound malaise, headache, and pain within
the orbits and in the bones and joints.2 The term dengue is taught to
mean “breakbone fever.” The etymology is complex and has recently
been well summarized by researchers.3 Yet, breakbone fever is a true and
graphic description of the disease, wherein patients require rest but find
difficulty in being comfortable while lying down. After a week or so,
there may be a respite in discomfort and then another bout of fever and
malaise returns (this is called the “saddle seat febrile curve”). A morbilliform eruption often appears4 and is associated with extreme itchiness and
burning. The cheeks and trunk appear red, but the dorsa of the hands are
usually not affected. There is no gross visible desquamation (Figure 1).
Fever is reduced by lysis, but there is a period of several weeks in which
patients experience extreme weakness, depression, and fatigue. Patients
often complain of feeling dull and uninterested in their usual tasks. Intellectual performance has been shown to decline during this period,
but eventual recovery is complete.
In about 5% of cases, patients show petechiae and ecchymoses (“hemorrhagic dengue”), after temporary defervescence as described above.
There may be bleeding in the gums, nose, or elsewhere in the body
(Figure 2). Symptoms and signs depend on the sites affected by bleeding, which may include the kidneys and brain. In untreated and treated
patients, shock and even death may occur as a result of increased permeability of capillaries.5 Survivors have an evolution similar to what is
described above, but the period of weakness is longer and sequelae may
occur,6 particularly in the nervous system.
Etiology
Dengue is caused by a flavivirus transmitted by the bite of arthropods. It
is argued that the current re-emergence of the disease is the result of the
predominance of aggressive vectors, namely Aedes aegypti, which also
transmits yellow fever.7 Historically, there have been other vectors and
the disease was found in rural areas, but this noiseless slow-flying, white-
banded Aedes is a city-dweller. It deposits its eggs in small amounts of
clear water. They can be found in houses or near them, flower pots,
bonsai, or puddles. The mosquito is very mobile and insecticides have
proven to be ineffective, except for residual compounds that are now
inexistent since the banning of DDT.
There are four known serotypes of the virus. While infection elicits
immunity, this is seemingly effective only against the causing genotype and leaves the host susceptible to infection by other vectors. It
is unclear whether even isologous immunity is all encompassing or
only temporary.
Pathogenesis
Damage caused by viremia is not completely understood in any viral
disease. It is clear, however, that most effects are caused not by the microorganism itself but by immune or inflammatory mechanisms set in
motion by the virus.8 Whether pathways of individuals who have no
or very mild clinical disease and those who have severe conditions are
qualitatively or merely quantitatively different, is something that has to
be determined. Hemorrhagic dengue causes a fall in platelet number
below a critical level. It is taught that this clinical form occurs when successive infections are caused by different serotypes, as if partial immunity is conducive to immune damage. This is congruent with known data,
but it is not satisfying from a conceptual point of view. We do not fully
believe this notion, although we have no valid alternative explanation.
Diagnosis, Follow-Up, and Treatment
Suspicion of dengue is based on clinical features and presence of
the disease in the community. Standard blood tests show leucopenia
with neutropenia and a progressive lowering of platelet numbers.
In typical cases, this does not reach critical levels (ie, <30,000/μL).
There are serologic tests to confirm the diagnosis, usually enzymelinked immunosorbent assay,9 which show positive results after the
first week, but earlier testing may serve to rule out preexisting antibodies. The typical patient needs only rest, an abundance of fluids
with electrolytes, and acetaminophen. Aspirin is formally contraindicated. Dermatitis and pruritus may be difficult to manage. Antihistamines may prove ineffective (although desloratadine seems to work
From the Department of Dermatology, Military Hospital, “Carlos Arvelo,” Caracas, Venezuela;1 and the Departments of Dermatology and
Immunology, Vargas School of Medicine, Central University of Venezuela, Caracas, Venezuela2
Address for Correspondence: Mauricio Goihman-Yahr, MD, PhD, C/O Jet Internacional, PO Box 2200, Greer, SC 26952 •
E-mail: mgoihmanyahr@yahoo.com
SKINmed. 2011;9:150–151
150
May/June 2011
COMMENTARY
better). The same can be said of the usual antipruritic lotions, suspensions, and emulsions. In fact, some patients complain that hydroalcoholic shake lotions produce increased burning. Some patients benefit
markedly from gabapentin 400 mg at bedtime or twice daily. Signs of
concern include the following: age younger than 5 years or older than
65 years, presence of preexisting chronic diseases (diabetes, asthma,
chronic renal ailments, and systemic autoimmune diseases), spontaneous bleeding in skin or other organs (Figure 2), and the presence of
a positive Rumpel-Leede test. In these patients, there should be special
attention to diuresis, hematocrit to detect hemoconcentration, and
levels of transaminases, since the liver may be affected.
Patients with severe cases should be hospitalized to provide adequate
anti-shock treatment10 and, in some instances, platelet transfusions.
Figure 1. Pressure of fingers temporarily blanches exanthema.
Prevention
There is no current vaccine against dengue nor specific antiviral
treatment that prevents transmission. Mosquito nets, including
those treated with insecticides, are of theoretical use and not widely
available or easy to employ. Fumigations with available insecticides
are often performed, mainly for political reasons, but they are ineffective. DDT was useful but is not currently employed except in
some areas of Africa. We know of no modern nontoxic residual
insecticide on the market. Mosquito-fighting measures and public
education to avoid stagnant water in homes and to cover containers
look good on posters, brochures, and television ads, but they are
ludicrous. Anyone who has lived in a country where dengue is endemic, with torrential rain, pot holes, and obstructed drains in the
streets, knows that such posters and educational measures are futile.
Studies on the pathogenesis of the disease and of its immunology,
including vaccines, are urgently needed. It is true that only a fraction
of individuals exposed to Aedes under epidemic conditions develop
the disease, but the mechanism of transmission of dengue parallels
that of yellow fever. The latter is much more lethal but provides
clear postinfection immunity and effective vaccines against it. Neither dengue nor yellow fever are exclusive diseases of the tropics.
Outbreaks of dengue, including hemorrhagic forms, in temperate
areas have been reported.1 Yellow fever has been historically present
as far north as Philadelphia.
Disclosure: This contribution does not necessarily represent the opinion
of the Vargas School of Medicine, Central University of Venezuela.
References
1 Kuno G. Emergence of the severe syndrome and mortality associated with dengue and dengue-like illness: historical records (1890
to 1950 and their compatibility with current hypotheses on the shift
of disease manifestation. Clin Microbiol Rev. 2009;22:186–201.
2 Pinheiro FP, Corber SJ. Global situation of dengue and dengue
haemorrhagic fever and its emergence in the Americas. World
SKINmed. 2011;9:150–151
151
Figure 2. Lachrymal bleeding in hemorrhagic dengue.
Health Stat Q. 1997;50:161–168.
3 Merino F. Historia Natural de las Infecciones y Epidemias en Venezuela (Natural History of Infections and Epidemics in Venezuela. Chapter
XII. Caracas, Venezuela: Editorial Ateproca; 2010:401–423.
4 Gurugama P, Garg P, Perera J, Wijewickrama A, Seneviratne SL.
Dengue viral infections. Indian J Dermatol. 2010;55:68–78.
5 Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev. 2009;22:564–581.
6 Guzmán MG, Kourí G, Valdés L, et al. Enhanced severity of secondary dengue-2 infections, death rate in 1987 and 1981 Cuba.
Rev Panam Salud Publica. 2002;11:223–227.
7 Cologna RP, Armstrong PM, Rico-Hesse R. Selection for virulent dengue viruses occurs in humans and mosquitoes. J Virol.
2005;79:853–859.
8 Littaua R, Kurane I, Ennis FA. Human IgG receptor II mediates
antibody-dependant enhancement of dengue virus infection. J
Immunol. 1990;144:3183–3186.
9 Acosta-Bas C. Biología y métodos diagnósticos del dengue
(biology and diagnostic methods of dengue). Rev Biomed.
2005;16:113–137.
10 Willis BA, Nguyen MD, Ha TL, et al. Comparison of three fluid
solutions for resuscitation in dengue shock syndrome. N Engl J
Med. 2005;353:877–889.
Dengue Fever
May/June 2011
ORIGINAL CONTRIBUTION
Doxepin Cream vs Betamethasone Cream for
Treatment of Chronic Skin Lesions
Due to Sulfur Mustard
Yunes Panahi, PhD;1 Seyyed Masoud Davoudi, MD;1 Fatemeh Beiraghdar, MD;2 Mojtaba Amiri, MD1
Abstract
Oral doxepin was shown to reduce chronic pruritus due to sulfur mustard. The present study compared the effects of topical doxepin 5% with
betamethasone 1% for the treatment of pruritus in veterans exposed to sulfur mustard. This investigator-blinded, randomized, clinical trial was
conducted in an outpatient dermatology clinic. Seventy-five men who were exposed to sulfur mustard 23 to 28 years ago during the Iran-Iraq
war who complained of pruritus were randomized to receive doxepin cream 5% (n=40) or betamethasone cream 0.1% (n=35) twice a day for
6 weeks. Pruritus severity and Dermatology Life Quality Index (DLQI) were evaluated before and after each treatment. Both groups showed
significant improvement regarding pruritus (P<.05), burning sensation, skin dryness (P<.001), and skin scaling (P<0.05). The lesions of all
regions significantly reduced after treatments (P<.05), except those on the head, face, and genitalia. Pruritus, visual analog scores, and DLQI
significantly decreased (P<.01, P<.01, and P<.001, respectively) in doxepin- and betamethasone-treated groups, and there was no difference
between groups. All DLQI subscores decreased after both type of treatments (P<.01). Equal efficacy of doxepin cream and betamethasone
suggest that doxepin is a potential alternative to control pruritus caused by sulfur mustard in exposed veterans. (SKINmed. 2011;9:152–158)
S
ulfur mustard (mustard gas) is an alkylating agent with mutagenic effects1 that was used extensively as a chemical warfare
against Iranian civilians and veterans in the Iran-Iraq conflict
(1983–1988).2 Sulfur mustard produces severe chemical injuries in
primarily 3 major organs: skin, eyes, and lungs.3 Skin, due to its high
surface area, plays an important role as a port of entry for liquid or
vapor sulfur mustard. Sulfur mustard penetrates human skin at a rate
of 1 mg/cm2/min to 4 mg/cm2/min.4 Skin involvement by mustard
gas can be divided into acute and chronic effects. Chronic skin complications of sulfur mustard have been previously reported.4–7
Pruritus, the most common cutaneous complication in the
chronic phase, occurs in 70% to 90% of patients exposed to sulfur mustard. Other late complications of sulfur mustard include
blistering, necrotic wounds, and hyperpigmentation or hypopigmentation.8 Treatment in this phase is mainly symptomatic and
includes topical corticosteroids, systemic antihistamines, and local emollients to reduce itching and improve skin dryness. The
chronic nature of the lesions and their resistance to treatment require long-term application of these drugs.9,10 Long-term application of topical corticosteroids, however, can produce adverse
effects such as skin atrophy, striae, rosacea, and acne.11,12
Doxepin is a tricyclic compound with potent antihistaminic, antimuscarinic (by inhibition of H1 and H2 receptors), and antiserotonergic actions and is commonly used in pruritic conditions such as
atopic eczema and chronic idiopathic urticaria.13–15 Topical doxepin
acts by increasing norepinephrine and serotonin concentrations in
central nervous system synapses and preventing their removal. Although the efficacy and safety of topical doxepin has been reported
in atopic dermatitis associated with severe pruritus,16 its efficacy to
control chronic skin lesions caused by sulfur mustard has not been
evaluated. In the present study, the effect of topical doxepin 5%
cream compared with topical betamethasone for the treatment of
pruritus was investigated. Knowing that pruritus may affect patient’s
quality of life (QOL) and daily activities,17–19 the Dermatology Life
Quality Index (DLQI) was evaluated before and after treatment.20,21
Methods
This investigator-blinded randomized clinical trial was conducted
from December 2009 to August 2010 in an outpatient dermatology clinic of Baqiyatallah Hospital, Tehran, Iran. The sample population consisted of men exposed to sulfur mustard (aged between
30 to 65 years) who were experiencing pruritus. Exclusion criteria
From the Chemical Injuries Research Center, Baqiyatallah Medical Sciences University,1 and the Nephrology and Urology Research Center,
Baqiyatallah Medical Sciences University,2 Tehran, Iran
Address for Correspondence: Yunes Panahi, PhD, Associate Professor of Pharmacotherapy, Chemical Injuries Research Center, Baqiyatallah
Medical Sciences University, Molla-Sadra Avenue, Vanak Square, PO Box 19945/581, Tehran, Iran • E-mail: yunespanahi@yahoo.com
SKINmed. 2011;9:152–158
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May/June 2011
Table I. Calculation of Total Pruritus Score From Detailed-Related Variables
Score
Severity
Distribution
Frequency
Description
Total Score
1
Slight itching sensation without necessity of scratching
2
Slight itching sensation with necessity to scratch, but without excoriations
4
Scratching accompanied by excoriation
5
Pruritus causing total restlessness
1
For each region (arms, trunk, or legs)
5
Generalized itching
0.5
Two periods of less than 10 minutes
1
For each period more than 10 minutes
5
Maximally
5
5
The score of severity, distribution, and frequency of pruritus was recorded separately for the morning and the afternoon, so that
a maximum of 30 points could be achieved.a
Sleep disturbance
1
Each scratching episode leading to excoriation during the night. Maximum=5.
2
Each episode of waking up due to itching. Maximum=10.
For each time, morning, evening, and night with itching, 1 point was added to the score. Maximum=1+1+1=3.b
Total score
5
15+15=30
5
10
3
48
a
For example, in patients who showed maximal frequency both in the morning and the afternoon, their score for frequency calculated as the
following: 5+5=10. bFor example, if a patient had experienced itching through the morning and evening that affected sleep, 2 points were
added to the total score.
included itching caused by systemic or cutaneous nonchemical
diseases and history of topical treatments within 1 month before
the study. The present study was approved by the ethics committee of Baqiyatallah Medical Sciences University, and all patients
signed written informed consent before enrollment.
A total of 75 patients were randomly entered into two groups
(A and B) based on a randomization protocol made by computer-generated random numbers, sequenced blocks AB and BA.
Group A (n=40) received doxepin cream 5% (Zonalon, DPT
Laboratories, Ltd, San Antonio, TX) and group B (n=35) received betamethasone cream 0.1% (Aburaihan Pharmaceutical
Co, Tehran, Iran) twice daily for 6 weeks. To determine effective drug quantity, we applied the fingertip unit (FTU), which
was equal to 0.47 g in men, so that 1 FTU was enough to cover
both sides of a hand from rest to finger tips. The first session
of treatment was held in the outpatient clinic to determine any
hypersensitivity reactions.
Patients could not be blinded to treatment, because there were
obvious differences in the color, smell, and consistency of the two
studied medications. To ensure that the dermatologist remained
blinded to treatment allocation throughout the study, however,
he/she was not permitted to see the medications. Patients were
SKINmed. 2011;9:152–158
visited twice (before and after the treatment), at which times
physical examination and assessment of pruritus severity were
performed by the dermatologist.
Pruritus severity was assessed by both pruritic score questionnaire22,23 and visual analog scale (VAS). The VAS is designed as
a 100-mm horizontal line without scaling (0 = no pruritus to
100 = unbearable pruritus). Patients were then instructed to
place a vertical mark reflecting their feeling of pruritus severity.
A pruritic score was also calculated before and after the treatment course for each patient. The severity, distribution, and frequency of pruritus and pruritus-related sleep disturbance were
monitored (Table I). Pruritus score has ranged from 0 to 48,
where the higher score indicated severe pruritus. The severity of
pruritus was graded to three categories as mild (1–16 points),
moderate (17–32 points), and severe (33–48 points).
The DLQI, which includes 10 items and covers 6 domains, was
used for evaluation of health-related QOL (HRQOL). The 6 domains of DLQI are symptoms and feelings, daily activities, leisure,
work and school, personal relationships, and treatment. The severity of itching during the previous week is assessed by the first
question of the DLQI questionnaire. Patients were asked to score
0, 1, 2, and 3 categories of “not at all,” “a little,” “a lot,” and “very
153
Treatment of Chronic Skin Lesions With Topical Doxepin
May/June 2011
Table II. Distribution of Skin Complications in Both Groups Before and After Treatment
Skin Complication
Treatment Status
Doxepin
Before
Pruritus
Burning sensation
Skin dryness
Scaling
100
Betamethasone
100
P Value
–
After
45.2
37.5
Before
61.3
68.8
.5
After
25.8b
28.1b
.8
Before
58.1
71.9
.2
After
16.1
25.0
.3
Before
71.0
65.6
.6
After
35.5
31.3
.7
a
b
a
a
b
a
.3
All data are expressed as percentage. P<.05 and P<.01 show the significance between before and after treatment values of the same group. P
values for comparison between groups are in the right column of this table.
a
b
much” responses as how much their skin problem has affected
their life during the past week; moreover, “not relevant” and unanswered responses were scored “0.” The total score equals the sum
of the scores of all the items, with a range between a maximum
score of 30 and a minimum score of 0. In this type of evaluation,
the higher scores indicate a lower QOL for patients.
Statistical Analysis
Difference of pruritus severity according to VAS and pruritic
score was tested by the independent sample t test. Comparison
of changes in these two measures before and after the treatment
period was tested by paired sample t test. Chi-square test was
used to compare presentation of other skin lesions between the
two studied groups. Comparison of changes in DLQI and subscores before and after the treatment period was tested by Wilcoxon signed-rank test. Mann–Whitney nonparametric test was
used to compare DLQI or subscores between the two groups.
Data are presented as frequency, percentage, mean (standard
deviation [SD]), and median, and P<.05 was selected as the significance level. All analyses were performed using SPSS software
version 14.0 (SPSS Inc, Chicago, IL).
was observed, however, between the two groups regarding each
of these complications at baseline or after treatment.
Table III presents itching and eczema locations before and after treatment. Doxepin and betamethasone effectively reduced
lesions on the thorax (P<.01 and P<.001, respectively), back
(P<.01 and P<.001, respectively), upper and lower extremities
(P<.001 and P<.01, respectively), and the armpit region (P<.01).
Doxepin, not betamethasone, reduced the itching area in the
groin region (P<.01). Between-group comparisons showed that
the effects of doxepin on the groin region was significantly more
than that seen with betamethasone (P<.05), while the differences
were not significant with other regions.
According to pruritus score, severe pruritus was more frequent
in both groups. A total of 23 patients (57.5%) in the doxepin
group and 21 patients (60%) in the betamethasone group had
severe pruritus. After treatment, 67.5% in the doxepin group
and the majority of patients (30 cases, 94.2%) in the betamethasone group had moderate pruritus (P<.05). The levels of severity
of pruritus (mild, moderate, and severe) in both groups before
and after treatment are shown in Table IV.
All patients were men who had been exposed to sulfur mustard
about 20 to 25 years ago. The mean (SD) age of patients in the
doxepin and betamethasone groups was 44.3 (5.2) and 46.16
years, respectively (P=0.2, data not shown). All patients completed the study.
Pruritus mean score was significantly decreased (P<.01) from
32.4±11.3 and 33.6±7.2 to 21.7±8.4 and 20.8±4.0 in the doxepinand betamethasone-treated groups, respectively (Table V). Similarly,
VAS mean score was decreased from 40.5±20.7 and 49.9±15.3 to
28.4±12.8 and 34.6±11.4 in the doxepin- and betamethasone-treated groups, respectively (Table V). There was no significant difference between the two groups in pruritic score or VAS.
Distribution of skin complications before and after treatment in
each group is presented in Table II. Both groups showed a significant change in pruritus (P<.05), burning sensation, and skin
dryness (P<.001) and scaling (P<.05). No significant difference
The first question of the DLQI questionnaire (Q1) is about the
patient’s skin itchiness during the past week. Analysis of first
question results showed that at baseline, 24 patients (57.5%)
in the doxepin group and 28 patients (80%) in the betametha-
Results
SKINmed. 2011;9:152–158
154
May/June 2011
sone group had very itchy skin during the previous week, which
significantly decreased (P<.01) to 7 (17.5%) and 13 (37.5%)
after treatment, respectively (Table VI). The same results were
obtained for total DLQI (P<.001) and DLQI-Q1 (P<.001) in
the doxepin- or betamethasone-treated patients (Table VII).
Between-group comparisons showed no significant difference
before treatment (Q1, P=.29; DLQI, P=.12; DLQI-Q1, P=.09)
or after treatment (Q1, P=.12; DLQI, P=.09; DLQI-Q1, P=.08).
All evaluated subscores, including symptoms and feelings, daily
activities, leisure, work and school, personal relationships, and
treatment significantly decreased with doxepin or betamethasone (P<.01), and there was no significant difference between
the two types of treatment in DLQI subscores (Table VIII).
Discussion
Treatment of chronic skin complications caused by sulfur mustard
exposure is limited to oral antihistamines and topical corticosteroids.
After exposure to sulfur mustard, 10% of the agent is absorbed and
fixed to the skin for years,24,25 which requires long-term application
of topical medications to relieve pruritus and control other symptoms. The mean DLQI in the present study was 18.6 and 25 for the
doxepin and betamethasone groups, respectively, at the beginning
of the study. Comparison of these results with other skin diseases
such vitiligo, psoriasis, and atopic dermatitis (DLQI=7, 14, and 18,
respectively)26,27 shows that HRQOL of chemically injured veterans
is greatly affected by dermal complications.28
Some clinical trials have been designed to evaluate the efficacy and
safety of treatments that can be administered over a long period
instead of short-term treatment with corticosteroids.28,29 In a recent study in our center, it was revealed that pimecrolimus cream
1% was well tolerated and as effective as topical betamethasone
0.1% in the treatment of chronic skin lesions and pruritus caused
by sulfur mustard.29 In another study, we showed that a combination of phenol 1% and menthol 1% had significant therapeutic
effects on pruritus and other chronic skin lesions compared with
placebo and decreased the prevalence of pruritus from 100% to
85%.30 In the present study, topical treatment with doxepin potently reduced pruritus (from 100% to 45.2%) that was similar
Table III. Distribution of the Involved Region Before and After Treatment in Both Groups
Characteristic
Treatment Status
Doxepin
Betamethasone
Before
19.4
15.6
After
19.4
12.5
Before
29.0
18.8
After
19.7
13.1
Before
48.4
56.3
After
23.3
18.8b
Before
41.9
46.9
After
25.8
9.4b
Before
58.1
53.1
After
16.1b
10.0b
Before
77.4
53.1
After
41.9
25.0a
Before
67.7
62.5
After
21.6
50.0
Before
29.0
25
After
6.5a
4.3a
Before
19.4
25.0
After
16.1
19.4
Head
Face
Thorax
Back
Upper extremities
Lower extremities
Groin
Armpit
Genitals and perinea
a
a
a
a
P Value
.4
.2
.2
.08
.1
.1
.05
.1
.4
All data are expressed as percentage. P<0.01 and P<.001 show the significance between before and after treatment values of the same group.
P values for comparison between groups are in the right column of this table.
a
SKINmed. 2011;9:152–158
b
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May/June 2011
Table IV. Comparison of Pruritus Severity Based on Pruritic Score Before and After Treatment
Treatment Status
Mild
Before
After
Doxepin
Betamethasone
P Value
5 (12.5)
0
–
Moderate
12 (30)
14 (40)
0.3
Severe
23 (57.5)
21 (60)
0.9
Mild
9 (22.5)
1 (2.9)
27 (67.5)
33 (94.2)
0.2
1 (2.9)
0.5
Moderate
Severe
4 (10)
P value
0.05
0.08
0.02
All data are expressed as frequency (percentage).
Table V. Effect of Doxepin or Betamethasone on Pruritus Severity
Assessment Time
Doxepin
Betamethasone
P Value
Baseline
32.4±11.3
33.6±7.2
.6
After
21.7±8.4
20.8±4.0
.5
P value
0.01
0.01
–
Baseline
40.5±20.7
49.9±15.3
.4
After
28.4±12.8
34.6±11.4
.4
P value
0.01
0.01
–
Pruritic score
VAS score
Abbreviation: VAS, visual analog scale. Data are expressed as mean ± standard deviation.
Table VI. Results of Q1 of DLQI Before and After Treatment in Both Groups
Doxepin
Before
A little
After
3 (7.5)
A lot
14 (35)
Very much
23 (57.5)
P value
Betamethasone
Before
8 (20)
After
0
0
25 (62.5)
7 (20)
22 (62.85)
7 (17.5)
28 (80)
13 (37.15)
0.01
0.01
Abbreviations: DLQI, Dermatology Life Quality Index; Q1, question 1. Data are shown as number (percentage) of patients for each group.
to the effect of betamethasone (from 100% to 37.5%). In addition, a significant decrease after treatment was observed regarding
burning sensation, scaling, and skin dryness in both doxepin- and
betamethasone-treated groups (Table II). These findings confirm
the results of a 2007 study that compared the safety and efficacy of
doxepin (oral consumption, 10 mg/d) for the treatment of chronic
pruritus and showed that it decreased the severity of pruritus in
75% of patients.31 Another study also confirmed the role of oral
doxepin in decreasing chronic pruritus as a result of sulfur mustard.32 It seems, however, that the effects of local treatment with
doxepin are comparable with oral consumption, while patients
SKINmed. 2011;9:152–158
can tolerate the topical treatment better than the oral treatment.33
Doxepin can affect different types of receptors13–15; therefore, oral
doxepin can produce systemic side effects that are absent when
doxepin is applied topically.
Doxepin cream 5% showed equal efficacy compared with betamethasone cream 0.1% in decreasing pruritus, scaling, burning
sensation, and skin dryness caused by sulfur mustard. One of the
advantages of topical doxepin compared with systemic doxepin
is a lack of severe side effects, which can make it intolerable for
patients. Although no significant improvement was observed in
156
May/June 2011
Table VII. Results of DLQI Before and After Treatment With Doxepin or Betamethasone
Before
After
Doxepin
Betamethasone
P Value
Q1
2.5±0.3
2.8±0.16
0.29
DLQI
18.6±2.1
25.42±2.48
0.12
DLQI-Q1
16.1±2.06
22.62±2.48
0.09
Q1
0.975±0.19a
1.37±0.21a
0.12
DLQI
7.7±0.95b
11.48±2.17b
0.09
DLQI-Q1
6.72±0.89
10.11±2.07
0.08
b
b
Abbreviations: DLQI, Dermatology Life Quality Index; Q1, question 1. Data are shown as mean ± standard deviation for each group. aP<.01
and bP<.001 show the significance between before and after treatment values of the same group (Wilcoxon signed rank test). P values for
comparison between groups are in the right column of this table (Mann-Whitney test).
lesions of the head and face, both medications reduced lesions on
the thorax, back, upper and lower extremities, and axillae. One
of the reasons for failure of treatment to improve lesions on the
head can be attributed to the presence of hair, which decreases
its absorption. The effect of doxepin treatment in reducing groin
lesions was more significant than with betamethasone; however,
the effect on the genitals and perinea was similar. In a 2007 survey, 68% of chemically injured veterans experienced pruritus on
their inguinal area; itching in this area within the company of
others is an extremely uncomfortable experience.28 In the present
study, the effects of both treatments on DLQI subscores of work
and school activities and personal relationships were significant.
of the DLQI questionnaire (Table VI). Due to long-term application of topical corticosteroids in patients exposed to sulfur mustard, the skin becomes sensitive as a result of scratching behavior
caused by the pruritus, which is believed to play an important role
in initiating cutaneous infections and inflammatory responses;
therefore, reducing the pruritus severity is considered more valuable.28,29 Other DLQI subscores were also significantly affected by
doxepin and showed decreased DLQI scores.
Conclusions
Doxepin cream 5% reduced pruritus, VAS, and DLQI scores
effectively, and these results suggest that it can be applied in the
clinic without producing betamethasone-related adverse effects.
Further studies to evaluate the effects of topical and oral doxepin may highlight the beneficial effects of topical doxepin in
the treatment of chronic skin lesions caused by sulfur mustard.
Pruritus was the most common symptom in the current study (reported in 100% of patients), and its severity according to VAS
and pruritic score decreased significantly in doxepin- or betamethasone-treated patients. In our opinion, this is the most valuable
finding to date, because decreased pruritic and VAS scores accompanied by reduction in itchy skin was revealed in the first question
Disclosure: All financial aid for this study was funded by Baqiyatallah Medical Sciences University, Tehran, Iran.
Table VIII. Results of Subscores of DLQI Before and After Treatment With Doxepin or Betamethasone
Doxepin
Betamethasone
Subscore
Before
After
Symptoms and feelings
5 (4 – 6)
2 (2 – 2.5)
Daily activities
4 (3 – 5)
2 (2 – 3)
Leisure
4 (2 – 5)
2 (2 – 2.75)
Work and school
3 (1 – 3)
0
Personal relationships
2 (2 – 3)
Treatment
2 (2 – 3)
P Value
Before
After
5 (5 – 6)
2 (2 – 4)
a
5 (3 – 5.5)
2 (2 – 4)
a
5 (4 – 6)
2.5 (2 – 5)
3 (1 – 3)
0
1 (0 – 2)a
5 (3 – 5)
2 (1 – 3)a
.14
0a
3 (2 – 3)
1 (1 – 2)a
.26
a
a
a
a
a
.55
.32
a
.08
.92
Abbreviation: DLQI, Dermatology Life Quality Index. Data are shown as median (first quartile – third quartile) for each group. aP<.01 shows
the significance between before and after values of same group (Wilcoxon signed rank test). P values for comparison data between two groups
are in the right column of this table (Mann-Whitney test).
SKINmed. 2011;9:152–158
157
May/June 2011
References
1 Ludlum DB, Austin-Ritchie P, Hagopian M, et al. Detection of
sulfur mustard-induced DNA modifications. Chem Biol Interact.
1994;91:39–49.
2 United Nations Security Council. Report of the Specialists Appointed by the Secretary General to Investigate Allegations by
the Islamic Republic of Iran Concerning the Use of Chemical
Weapons. New York, NY: United Nations; 1984. S/16433.
3 Balali-Mood M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol
Toxicol. 2006;99:273–282.
4 Renshaw B. Mechanisms in production of cutaneous injuries by
sulfur and nitrogen mustards. In: Division 9, National Defense
Research Committee, Comp. Chemical Warfare Agents and Related Chemical Problems. Washington, DC: Office of Scientific
Research and Development; 1946.
5 Hefazi M, Maleki M, Mahmoudi M, Tabatabaee A, Balali-Mood M.
Delayed complications of sulfur mustard poisoning in the skin
and the immune system of Iranian veterans 16–20 years after
exposure. Int J Dermatol. 2006;45:1025–1031.
6 Khateri S, Ghanei M, Keshavarz S, et al. Incidence of lung,
eye, and skin lesions as late complications in 34,000 Iranians
with wartime exposure to mustard gas. J Occup Environ Med.
2003;45:1136–1143.
7 Momeni AZ, Enshaeih S, Meghdadi M, et al. Skin manifestations
of mustard gas. A clinical study of 535 patients exposed to
mustard gas. Arch Dermatol. 1992;128:775–780.
8 Balali-Mood M, Hefazi M. The clinical toxicology of sulfur mustard. Arch Iran Med. 2005;8:162–179.
9 Momeni AZ, Enshaeih S, Meghdadi M, et al. Skin manifestations
of mustard gas. A clinical study of 535 patients exposed to
mustard gas. Arch Dermatol. 1992;128:775–780.
10 Balali-Mood M, Hefazi M, Mahmoudi M, et al. Long-term complications of sulfur mustard poisoning in severely intoxicated
Iranian veterans. Fundam Clin Pharmacol. 2005;19:713–721.
11 Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol.
2006;54:1–15.
12 Schoepe S, Schacke H, May E, et al. Glucocorticoid therapyinduced skin atrophy. Exp Dermatol. 2006;15:406–420.
13 Gupta MA, Gupta AK, Ellis CN. Antidepressant drugs in dermatology. An update. Arch Dermatol. 1987;123:647–652.
14 Groene D, Martus P, Heyer G. Doxepin affects acetylcholine
induced cutaneous reactions in atopic eczema. Exp Dermatol.
2001;10:110–117.
15 Greene SL, Reed CE, Schroeter AL. Double-blind crossover study
comparing doxepin with diphenhydramine for the treatment of
chronic urticaria. J Am Acad Dermatol. 1985;12:669–675.
16 Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with
atopic dermatitis after treatment with topical doxepin cream. The
Doxepin Study Group. J Am Acad Dermatol. 1994;31:613–616.
17 Weisshaar E, Diepgen TL. Pruritus and quality of life. J Invest
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158
Dermatol. 2005;125:855.
18 Weisshaar E, Apfelbracher C, Jager G, et al. Pruritus as a leading symptom: clinical characteristics and quality of life in German and Ugandan patients. Br J Dermatol. 2006;155:957–964.
19 Yosipovitch G, Ansari N, Goon A, et al. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147:32–36.
20 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a
simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210–216.
21 Hongbo Y, Thomas CL, Harrison MA, et al. Translating the science
of quality of life into practice: what do dermatology life quality
index scores mean? J Invest Dermatol. 2005;125:659–664.
22 Balaskas EV, Bamihas GI, Karamouzis M, et al. Histamine and
serotonin in uremic pruritus: effect of ondansetron in CAPD-pruritic patients. Nephron. 1998;78:395–402.
23 Mettang T, Fritz P, Weber J, et al. Uremic pruritus in patients
on hemodialysis or continuous ambulatory peritoneal dialysis
(CAPD). The role of plasma histamine and skin mast cells. Clin
Nephrol. 1990;34:136–141.
24 Smith WJ, Dunn MA. Medical defense against blistering chemical
warfare agents. Arch Dermatol. 1991;127:1207–1213.
25 Somani SM, Babu SR. Toxicodynamics of sulfur mustard. Int J
Clin Pharmacol Ther Toxicol. 1989;27:419–435.
26 Ongenae K, Dierckxsens L, Brochez L, et al. Quality of life and
stigmatization profile in a cohort of vitiligo patients and effect of
the use of camouflage. Dermatology. 2005;210:279–285.
27 Ayyalaraju RS, Finlay AY, Dykes PJ, et al. Hospitalization for severe skin disease improves quality of life in the United Kingdom
and the United States: a comparative study. J Am Acad Dermatol. 2003;49:249–254.
28 Panahi Y, Davoudi SM, Sadr SB, et al. Impact of pruritus on
quality of life in sulfur mustard-exposed Iranian veterans. Int J
Dermatol. 2008;47:557–561.
29 Panahi Y, Moharamzad Y, Beiraghdar F, et al. Comparison of
clinical efficacy of topical pimecrolimus with betamethasone
in chronic skin lesions due to sulfur mustard exposure: a randomized, investigator-blind study. Basic Clin Pharmacol Toxicol.
2009;104:171–175.
30 Panahi Y, Davoodi SM, Khalili H, et al. Phenol and menthol in the
treatment of chronic skin lesions following mustard gas exposure. Singapore Med J. 2007;48:392–395.
31 Shohrati M, Tajik A, Harandi AA, et al. Comparison of hydroxyzine and doxepin in treatment of pruritus due to sulfur mustard.
Skinmed. 2007;6:70–72.
32 Shohrati M, Davoudi SM, Keshavarz S, et al. Cetirizine, doxepin, and hydroxyzine in the treatment of pruritus due to sulfur mustard: a randomized clinical trial. Cutan Ocul Toxicol.
2007;26:249–255.
33 Epstein JB, Truelove EL, Oien H, et al. Oral topical doxepin
rinse: anesthetic effect in normal subjects. Pain Res Manag.
2003;8:195–197.
cy…
Delivers on effica
Handles Patients
With Care
the topical
l is indicated for
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vehicle when use
DUAC Topical Gel is the once-daily
clindamycin/benzoyl peroxide
combination with a patented formula
containing both glycerin and dimethicone
The contribution to efficacy by individual
components of the vehicle has not been established.
• No therapeutically equivalent generic substitute1
• More than 6 million prescriptions of DUAC Topical Gel
dispensed since launch2
PLEASE NOTE:
The soap-free cleanser is
no longer included in the
package. Please prescribe
DUAC Topical Gel 45 g.
DUAC
45 g
Apply once daily
Dispense as written
Important Safety Information for DUAC Topical Gel
• DUAC Topical Gel is contraindicated in patients who have shown hypersensitivity to any of its components or lincomycin
• DUAC Topical Gel is contraindicated in patients with a history of regional enteritis, ulcerative colitis, pseudomembranous colitis,
or antibiotic-associated colitis
• Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death. Diarrhea,
bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.
The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage
of blood and mucus
• For dermatologic use only; not for ophthalmic use
• Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially
with the use of peeling, desquamating, or abrasive agents
• The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms, including fungi. If this occurs,
discontinue use of this medication and take appropriate measures
• Clindamycin- and erythromycin-containing products should not be used in combination. In vitro studies have shown antagonism
between these two antimicrobials. The clinical significance of this in vitro antagonism is not known
• DUAC Topical Gel may bleach hair and colored fabrics
• Excessive or prolonged exposure to sunlight should be limited. To minimize exposure to sunlight, a hat or other clothing should be worn
• DUAC Topical Gel should be given to a pregnant woman only if clearly needed
• It is not known whether DUAC Topical Gel is secreted into human milk after topical application. However, orally and parenterally
administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing
infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother
• Safety and effectiveness of this product in pediatric patients below the age of 12 have not been established
• Adverse reactions may include erythema, peeling, burning, and dryness
• Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with DUAC Topical Gel.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure
Please see brief summary of Prescribing Information on following page.
References: 1. Electronic Orange Book. US Food and Drug Administration Web site. http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm. Accessed February 25, 2011.
2. SDI. VectorOne: National (VONA). October 2009.
BRIEF SUMMARY
DUAC ® Topical Gel
(clindamycin, 1% - benzoyl peroxide, 5%)
The following is a brief summary only; see full prescribing information for
complete product information.
For Dermatological Use Only.
Not for Ophthalmic Use.
Rx Only
DUAC Topical Gel is indicated for the topical treatment of inflammatory acne
vulgaris. DUAC Topical Gel has not been demonstrated to have any additional
benefit when compared to benzoyl peroxide alone in the same vehicle when
used for the treatment of non-inflammatory acne.
CONTRAINDICATIONS
DUAC Topical Gel is contraindicated in those individuals who have shown
hypersensitivity to any of its components or to lincomycin. It is also
contraindicated in those having a history of regional enteritis, ulcerative
colitis, pseudomembranous colitis, or antibiotic-associated colitis.
WARNINGS
ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEEN
ASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENT
DEATH. USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTS
IN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE. DIARRHEA,
BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUS
COLITIS) HAVE BEEN REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC
CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRODUCED BY CLOSTRIDIA
IS ONE PRIMARY CAUSE OF ANTIBIOTIC-ASSOCIATED COLITIS. THE
COLITIS IS USUALLY CHARACTERIZED BY SEVERE PERSISTENT DIARRHEA
AND SEVERE ABDOMINAL CRAMPS AND MAY BE ASSOCIATED WITH
THE PASSAGE OF BLOOD AND MUCUS. ENDOSCOPIC EXAMINATION MAY
REVEAL PSEUDOMEMBRANOUS COLITIS. STOOL CULTURE FOR Clostridium
difficile AND STOOL ASSAY FOR Clostridium difficile TOXIN MAY BE
HELPFUL DIAGNOSTICALLY. WHEN SIGNIFICANT DIARRHEA OCCURS, THE
DRUG SHOULD BE DISCONTINUED. LARGE BOWEL ENDOSCOPY SHOULD
BE CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS IN CASES OF
SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS SUCH AS OPIATES AND
DIPHENOXYLATE WITH ATROPINE MAY PROLONG AND/OR WORSEN THE
CONDITION. DIARRHEA, COLITIS AND PSEUDOMEMBRANOUS COLITIS
HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL WEEKS FOLLOWING
CESSATION OF ORAL AND PARENTERAL THERAPY WITH CLINDAMYCIN.
Mild cases of pseudomembranous colitis usually respond to drug discontinuation
alone. In moderate to severe cases, consideration should be given to management
with fluids and electrolytes, protein supplementation and treatment with an
antibacterial drug clinically effective against Clostridium difficile colitis.
PRECAUTIONS
General: For dermatological use only; not for ophthalmic use. Concomitant topical
acne therapy should be used with caution because a possible cumulative irritancy
effect may occur, especially with the use of peeling, desquamating, or abrasive
agents. The use of antibiotic agents may be associated with the overgrowth of
nonsusceptible organisms, including fungi. If this occurs, discontinue use of this
medication and take appropriate measures. Avoid contact with eyes and mucous
membranes. Clindamycin and erythromycin containing products should not be
used in combination. In vitro studies have shown antagonism between these two
antimicrobials. The clinical significance of this in vitro antagonism is not known.
Information for Patients: Patients using DUAC Topical Gel should receive the
following information and instructions:
1.
DUAC Topical Gel is to be used as directed by the physician. It is for
external use only. Avoid contact with eyes, and inside the nose, mouth,
and all mucous membranes, as this product may be irritating.
2.
This medication should not be used for any disorder other than that for
which it was prescribed.
3.
Patients should not use any other topical acne preparation unless
otherwise directed by their physician.
4.
Patients should report any signs of local adverse reactions to their
physician. Patients who develop allergic symptoms such as severe
swelling or shortness of breath should discontinue use and contact
their physician immediately.
5.
DUAC Topical Gel may bleach hair or colored fabric.
6.
DUAC Topical Gel can be stored at room temperature up to 25°C (77°F)
for up to 2 months. Do not freeze. Keep tube tightly closed. Keep out of
the reach of small children. Discard any unused product after 2 months.
7.
Before applying DUAC Topical Gel to affected areas, wash the skin
gently, rinse with warm water, and pat dry.
8.
Excessive or prolonged exposure to sunlight should be limited. To minimize
exposure to sunlight, a hat or other clothing should be worn.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Benzoyl peroxide has
been shown to be a tumor promoter and progression agent in a number of animal
studies. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice
per week induced squamous cell skin tumors in transgenic TgAC mice in a study
using 20 weeks of topical treatment. The clinical significance of this is unknown.
In a 2-year dermal carcinogenicity study in mice, treatment with DUAC Topical Gel
at doses up to 8000 mg/kg/day (16 times the highest recommended adult human
dose of 2.5 g DUAC Topical Gel, based on mg/m2) did not cause an increase in
skin tumors. However, topical treatment with another formulation containing 1%
clindamycin and 5% benzoyl peroxide at doses of 100, 500, or 2000 mg/kg/day
caused a dose-dependent increase in the incidence of keratoacanthoma at the
treated skin site of male rats in a 2-year dermal carcinogenicity study in rats.
In a 52-week photocarcinogenicity study in hairless mice (40 weeks of treatment
followed by 12 weeks of observation), the median time to onset of skin tumor
formation decreased and the number of tumors per mouse increased relative to
controls following chronic concurrent topical treatment with DUAC Topical Gel and
exposure to ultraviolet radiation.
Genotoxicity studies were not conducted with DUAC Topical Gel. Clindamycin
phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus
test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of
mammalian cell types, to be mutagenic in Salmonella typhimurium tests by some
but not all investigators, and to cause sister chromatid exchanges in Chinese
hamster ovary cells.
Studies have not been performed with DUAC Topical Gel or benzoyl peroxide to
evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300
mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in
the highest recommended adult human dose of 2.5 g DUAC Topical Gel, based on
mg/m2) revealed no effects on fertility or mating ability.
Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction
studies have not been conducted with DUAC Topical Gel or benzoyl peroxide.
It is also not known whether DUAC Topical Gel can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
DUAC Topical Gel should be given to a pregnant woman only if clearly needed.
Developmental toxicity studies performed in rats and mice using oral doses of
clindamycin up to 600 mg/kg/day (240 and 120 times the amount of clindamycin
in the highest recommended adult human dose based on mg/m2, respectively)
or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times
the amount of clindamycin in the highest recommended adult human dose based
on mg/m2, respectively) revealed no evidence of teratogenicity.
Nursing Women: It is not known whether DUAC Topical Gel is secreted
into human milk after topical application. However, orally and parenterally
administered clindamycin has been reported to appear in breast milk. Because
of the potential for serious adverse reactions in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of this product in pediatric patients
below the age of 12 have not been established.
ADVERSE REACTIONS
During clinical trials, all patients were graded for facial erythema, peeling,
burning, and dryness on the following scale: 0 = absent, 1 = mild, 2 =
moderate, and 3 = severe. The percentage of patients that had symptoms
present before treatment (at baseline) and during treatment were as follows:
Local reactions with use of DUAC Topical Gel
% of patients using DUAC Topical Gel with symptom present
Combined results from 5 studies (n = 397)
Before Treatment (Baseline)
During Treatment
Mild
Moderate Severe
Mild
Moderate Severe
Erythema
28%
3%
0
26%
5%
0
Peeling
6%
<1%
0
17%
2%
0
Burning
3%
<1%
0
5%
<1%
0
Dryness
6%
<1%
0
15%
1%
0
(Percentages derived by # subjects with symptom score/# enrolled DUAC Topical
Gel subjects, n = 397).
Anaphylaxis, as well as allergic reactions leading to hospitalization, has been
reported in post-marketing use with DUAC Topical Gel. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship
to drug exposure.
©2010 Stiefel Laboratories, Inc. DUA:2BRS January 2011
©2011 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. DUA063R0 March 2011
May/June 2011
Follicular Variant of Seborrheic Dermatitis:
Is It Identical to Malassezia Folliculitis?
Mark C. Valentine, MD
Abstract
Follicular accentuation in some patients with seborrheic dermatitis of the back and chest has been recognized for more than a century.
The recognition of Malassezia folliculitis in recent decades has led to some confusion regarding categorization of these cases. The author
proposes that there is sufficient clinical variation between the typical case of Malassezia folliculitis and patients with follicular seborrheic
dermatitis to justify continued separation of these entities until further study provides more clarification. (SKINmed. 2011;9:161–166)
A
pattern of seborrheic dermatitis characterized by follicular prominence in truncal lesions has been recognized
by textbook authors for more than a century. Because it
is somewhat uncommon, and shares a number of features with
Malassezia folliculitis it is not consistently diagnosed by all physicians. I will describe a typical case, summarize other cases seen
in my practice, and review the history and differential diagnosis
of this disorder.
Case Report
A 62-year-old man was seen on referral from his primary care
physician because of persistent dermatitis involving his scalp,
neck, and torso. He stated that the problem had been present for
more than 10 years but had only been present on the neck for
about 5 years. He reported that the condition had been partially
controlled with fluocinolone cream applied every 2 to 3 days. He
washed his hair daily with a zinc pyrithione shampoo. He also
previously had used oral ketoconazole and ketoconazole shampoo with some success. He noted that the areas of involvement
seemed to be enlarging gradually.
Skin examination revealed elongated oval patches of erythematous skin parallel to the skin folds on the anterolateral neck, with
trace scaling and without follicular accentuation. There were
large, poorly circumscribed areas of faint erythema on the back
(Figure 1), more prominent on the left side, studded with 1- to
2-mm pink-to-red follicular papules with no visible scale. Similar patches of clustered small papules were prominent on the
lower chest and upper abdominal skin (Figure 2).
The diagnosis of seborrheic dermatitis, follicular variant, was
made, and the patient was treated with ketoconazole foam for
the torso and ketoconazole shampoo for the scalp. Five weeks
later, his neck and back lesions had resolved and the chest lesions
had been reduced to very subtle faint pink papules.
Discussion of Cases
Seven patients were men, and one was a woman (Table I). Only
one patient was younger than 25 years, and he had concomitant
acne. All patients had involvement of the skin of the back, with
some patients having chest and neck involvement as well, and one
patient had similar follicular lesions on his legs. In all cases, the involved areas occupied a geographic pattern (Figure 3) of somewhat
circumscribed areas of follicular macules, small papules, and variable
erythema and fine scaling. These areas were usually asymmetric in
distribution and were not limited to the presternal or interscapular
areas as is seen in classic petaloid seborrheic dermatitis of the torso.
No patients were noted to have associated keratosis pilaris, none had
Down syndrome, and none complained of pruritus.
Only two patients underwent biopsy. One biopsy showed follicular
enlargement and perifollicular lymphocytic inflammation, with a
negative fungal stain. The other patient had a follicular pustule, but
unfortunately the fungal stain, which showed scant surface yeast
forms, did not include any follicular structures to examine.
Some patients had experienced temporary improvement after
the use of ketoconazole or topical steroids, but case 2 showed no
clinical response after 4 weeks of weekly ketoconazole orally at a
dose of 400 mg per week.
From the Department of Medicine, Division of Dermatology, University of Washington School of Medicine, Everett, WA
Address for Correspondence: Mark C. Valentine, MD, Clinical Professor of Medicine (Dermatology), University of Washington School of
Medicine, 3327 Colby Avenue, Everett, WA 98201 • E-mail: mark1105@aol.com
SKINmed. 2011;9:161–166
161
May/June 2011
the name of “seborrhea corporis.”3 He pointed out that the chest
and back may be simultaneously involved, but “owing to the
difference in the anatomical structure of the skin, the lesions are
somewhat unlike.” He describes the chest lesions as smaller and
better circumscribed. The back lesions are said to be “as large as
a silver dollar. They may exist separately, but they more often
coalesce, forming one continuous, irregularly-shaped patch.”
“They are pinkish or reddish in color, but being partially covered
with yellowish or grayish scales often have a pale look. The scales
are rarely in any quantity; they are usually loose, and are in many
cases altogether wanting, having been detached and rubbed away
by the friction of the clothing. The mouths of the follicles are
observed to be open and sluggishly discharging their secretion.”
He further alludes to the follicular prominence by pointing out
that “acne papules and pustules are occasionally seen here and
there about the borders of the disease.” Subsequent Philadelphia
textbooks by John Shoemaker4 and Henry Stelwagon5 reiterate
these descriptions.
The English dermatologist Henry Radcliffe Crocker described
the typical midchest and interscapular eruption of seborrheic
dermatitis familiar to most dermatologists, labeling it “seborrhœa papulosa seu lichenoides” and equating it with Duhring’s
seborrhea corporis. He mentions the presence of pinhead-sized
papules, but only occurring as individual early lesions, or located
at the margins of enlarging patches.6 This localization of papules
at the margins of enlarging patches continues to be mentioned in
textbooks up until the present day, but was not uniformly seen
in the patients described in this article.
Figure 1. Follicular papules and macules in asymmetrical
geographic distribution on back (case 1).
Four of the patients were treated with oral isotretinoin. In two of
these patients, total clearing was achieved by the end of 3 months
of therapy. The dermatitis returned within 2 months of completing treatment in one of these men; the other was lost to follow-up.
One patient failed to improve after 4 weeks and was then lost
to follow-up. The fourth patient discontinued isotretinoin after
2 weeks because of intolerance of the resulting retinoid cheilitis.
Historical Review
While Paul Gerson Unna is often given credit for the best early description of seborrheic dermatitis in 1887,1 the disorder is recognizable in
the writings of earlier authors, under such names as “eczema squamosum,” and Ferdinand von Hebra devoted several pages to the manifestations of seborrhea on the scalp, face, and external genitalia2 in 1860.
Before Unna’s classic paper, Philadelphia dermatologist Louis A.
Duhring had clearly described involvement of the torso under
SKINmed. 2011;9:161–166
Richard Sutton’s dermatology text of 19167 discusses the common
presternal and interscapular presentations of seborrheic dermatitis,
but makes no reference to follicular involvement. Andrews refers
to the follicular variant briefly in his standard textbook.8 Writing
in 1939, he states “the affection has a predilection for the sternal and interscapular areas, the axillae, groins, navel, and gluteal
crease. In these areas symmetrical macular yellowish patches with
more or less greasy scaling are characteristic, but less frequently the
lesions are circinate patches or follicular papules.”
Early editions of Arthur Rook’s textbook also mention follicular
lesions in truncal seborrheic dermatitis. Emphasizing the presence of follicular lesions in the development of petaloid forms of
the disease, it is stated,9 “The initial lesion is a small, red-brown
follicular papule covered by a greasy scale; some patients have a
widespread eruption of lesions which do not progress beyond
this stage. More often, extension and confluence of the follicular papules have given rise to a figured eruption consisting of
multiple circinate patches with fine, branny scaling in their centres and with dark red papules with larger greasy scales at their
162
Follicular Variant of Seborrheic Dermatitis
May/June 2011
advancing margins.” In a subsequent edition, while retaining the
same clinical description, the morphologic variants of seborrheic
dermatitis are enumerated, including a follicular (“acneiform”)
pattern, which is said to be seen predominantly on the back, but
also occasionally elsewhere on the body.10
The authors discuss Pityrosporum folliculitis a few pages later,
and list it as synonymous with “seborrheic folliculitis.” The same
categorization is used in the 2004 edition of Rook’s textbook.11
In reading the clinical description of Pityrosporum folliculitis in
this section, one begins to wonder whether the authors are including follicular seborrheic dermatitis under this label, without providing conclusive evidence that the two conditions are
identical. They write on page 17.15, “The condition most commonly affects adult males, and is associated with a tendency to
seborrhoeic dermatitis or severe dandruff. It has been reported
in 12 of 42 patients with Down’s syndrome. The dermatitis is
dimorphic, with erythematous follicular papules and follicular
pustules. Lesions occur mainly on the upper trunk and shoulders, and are usually pruritic.”
Further potential for confusion can be found elsewhere in the
same textbook,11 where on page 31.14, Hay and Moore describe
Malassezia folliculitis in the Mycology section as comprising
“itchy papules and pustules, which are often diffusely scattered on
the shoulders and back,” consistent with my concept of this disorder. In contrast, on pages 43.33, Simpson and Cunliffe11 discuss
Pityrosporum folliculitis in the differential diagnosis of acne and
characterize it as presenting “on the upper trunk as moderately
ill-defined superficial plaques, among which are scattered many
papules or pustules” and illustrate the disorder with a photograph
of a patient with a large patch of apparently eczematous skin, wellmarginated and studded with papules, that appears to me to be a
typical example of follicular seborrheic dermatitis.
An excellent example of the type of patient I am describing is illustrated with a photograph in Fitzpatrick’s Dermatology in General Medicine, 7th edition, labeled as “seborrheic dermatitis of
the upper back.”12
Two articles describe lesions similar to my cases in individuals
with Down syndrome. In the earliest of these,13 the eruption
was seen in 42% of 110 men, predominantly in those aged 20 to
40 years, and was rare in women. Two cases underwent biopsy,
showing parafollicular inflammation, but without mention of
yeast forms. The authors concluded that the condition was likely
a follicular variety of seborrheic dermatitis.
The second article by Kavanaugh and colleagues14 (mentioned
above in the Rook citation) described a nonpruritic folliculitis in
45% of 22 men with Down syndrome and 10% of 20 women.
A biopsy was not performed, but cultures were attempted in 12
SKINmed. 2011;9:161–166
Figure 2. Clustered follicular papules on lower part of the
chest (case 1).
cases, with 4 growing Malassezia furfur. A good clinical response
to oral itraconazole led the authors to conclude that their patients had Malassezia folliculitis. I believe the clinical description
of the patients in both of these papers is more consistent with
follicular seborrheic dermatitis than with Malassezia folliculitis,
but the authors of the Rook section on Malassezia folliculitis
apparently accept the conclusion of the Kavanaugh presentation
that these are examples of Malassezia folliculitis.
Differential Diagnosis
Several entities can be considered here. Keratosis pilaris shares
some features, but it is most often found on the posterior aspect
of the arms, which is almost never the case with seborrheic dermatitis. The follicular lesions of keratosis pilaris can at times consist solely of discrete dark red circular macules, which are similar
in appearance to some cases of follicular seborrheic dermatitis.
Lichen spinulosus shares the presence of multiple red follicular papules grouped in geographic patterns but is not associated
with superficial scaling of the interfollicular skin and is not predisposed to be limited to the sebaceous areas of the trunk.
Tinea versicolor manifests as patterned areas of scaly erythema
on the sebaceous areas of the torso, but it lacks follicular papules
163
May/June 2011
Table I. Additional Cases
Case
Sex/Age, y
Distribution
Associated Disorders
Biopsy/KOH
Treatment
2
Female/38
Neck, upper part
of back
None
Superficial follicular pustule
with perifollicular lymphocytic infiltrates. Inconclusive
periodic acid-Schiff results
Topical steroids, oral ketoconazole, sulfur/sulfacetamide lotion,
isotretinoin
3
Male/15
Chest and back
Acne vulgaris, bacterial
folliculitis on legs
None
Desoximetasone cream
4
Male/27
Back
Contact dermatitis of
axillae
None
Ketoconazole shampoo scrubs,
isotretinoin
5
Male/52
Lower midback
Psoriasis, rosacea
None
Desoximetasone cream
6
Male/40
Chest, back
None
Slightly widened follicular infundibulum with hyperkeratosis, perifollicular spongiosis,
and lymphocytic exocytosis,
negative fungal stains
Cephalexin, isotretinoin
7
Male/42
Back, chest, abdomen, thighs
None
Negative KOH scraping
Isotretinoin
8
Male/36
Chest, back
Atopic dermatitis and
rhinitis, steroid rosacea
Negative KOH scraping
Tacrolimus ointment, doxycycline
Abbreviation: KOH, potassium hydroxide.
and has a characteristic preponderance of filamentous forms of
Malassezia on potassium hydroxide preparations from the scales.
Petaloid seborrheic dermatitis can overlap or coexist with this
pattern, but it is usually symmetrically centered about the midline of the chest and/or back and often lacks the follicular accentuation seen in these patients.
Malassezia folliculitis is the most important alternate diagnosis
to consider, and if the Rook textbook is to be believed, there may
be no difference. This is not an unreasonable position, considering the fact that the disorders under discussion are both follicu-
Figure 3. Geographic clusters of follicular macules and
papules sparing the midline of the back (case 2).
SKINmed. 2011;9:161–166
lar, both are predominantly seen on areas of abundant sebaceous
glands, and both involve the Malassezia species of yeast in their
pathogenesis. There are stereotypical differences in the clinical
presentations, however, that are troublesome if they are to be
considered synonymous.
Malasezzia (Pityrosporum) Folliculitis
Malassezia folliculitis was first described as a complication of antibiotic administration by Weary in 196915 and in 7 additional
cases by Potter in 1973.16 The lesions may be acute or chronic,
erythematous, pruritic follicular papules and pustules, usually
encountered on the back and chest, and occasionally on the neck,
shoulders, arms, and face. The causative organism is part of the
normal endogenous cutaneous microflora, with a recent study
from Japan demonstrating Malassezia globosa and Malassezia
sympodialis in lesion cultures.17 It is said to have a 1.5:1 female to
male ratio.18 A recent case series from France, however, included
22 men and only 4 women, with 70% of patients complaining
of itching.19 Affected patients are often in the 13- to 45-year age
range and are often treated unsuccessfully for acne.18 A series
from Sweden20 stated that “the typical patient is a young woman
complaining of itching….” In contrast, the Rook description of
Pityrosporum folliculitis11 states that most patients are men, and
many have seborrheic dermatitis. Is it possible that these authors
are discussing two distinct but overlapping disorders?
164
May/June 2011
It is likely that some patients may experience a combination of
Pityrosporum folliculitis and seborrheic dermatitis, but this highlights the question of whether all patients with follicular papules
on the back that respond to antifungal therapy have Malassezia
folliculitis, or do some of them actually have a distinct disorder,
namely follicular seborrheic dermatitis?
Skin biopsy in Malassezia folliculitis shows follicular dilation, keratin plugging, and an inflammatory infiltrate including lymphocytes,
histiocytes, and neutrophils. Malassezia yeasts are abundant in the
ostium, as well as in the central and deep portions of the follicle.18
While most patients with Malassezia folliculitis are treated successfully with antifungal therapy, both successes and failures have
previously been reported with the use of isotretinoin. One case
of unsuccessful treatment occurred in a man with an eruption
similar to the cases reported here but with a biopsy demonstrating yeast elements in a follicle.21
In contrast to the 8 cases reported in this contribution, patients
that I have recognized in my practice as having Malassezia folliculitis have had lesions that are more acute and edematous in
appearance, resembling acne, that are more symmetrically located across the upper torso (Figure 4), and that lack grouping into
geographic patterns. Patients are more likely to have pruritus
and more often are women than men.
Figure 4. Malassezia folliculitis of the upper back in a young
man, with acneiform succulent papules and pustules.
To Lump or to Split?
Are patients fitting the description of follicular seborrheic dermatitis best categorized as Malassezia folliculitis, as portions of
the Rook text and the Kavanaugh articles suggest, or should they
continue to merit a separate designation in the absence of biopsy
proof of intrafollicular Malassezia? Faergemann and associates22
extensively studied the inflammatory mediators and inflammatory cells present in 15 cases of seborrheic dermatitis and 8 cases
of Pityrosporum folliculitis, but the issue of clinical overlap was
not addressed in those patients. The fact that little has been writ-
ten regarding this issue suggests that the distinction is probably
not a very important one. It is a question worth asking, however,
because seborrheic dermatitis, including the follicular variant, is
by definition a chronic and relapsing disorder not amenable to
permanent cure, whereas some cases of yeast folliculitis, especially those provoked by external factors such as antibiotic administration, may clear completely and permanently.
Table II. Distinctions Between Follicular Seborrheic Dermatitis and Malassezia Folliculitis
Follicular Seborrheic Dermatitis
Malassezia Folliculitis
Sex predominance
Male
Female?
Lesion morphology
Monomorphous papules and macules with some scaling
Acneiform, succulent papules, and pustules
Interfollicular skin
Variable redness and scale
Normal
Grouping
Geographic clustering with sharp margination, sometimes asymmetrical
Diffuse and symmetrical
Location
Back and chest
Back, chest, and neck
Pruritus
Usually absent
Usually prominent
Biopsy
Yeast sparse or absent in follicle
Abundant intrafollicular yeast
SKINmed. 2011;9:161–166
165
May/June 2011
It is possible that patients, resembling those described here, do indeed have Malassezia folliculitis superimposed on seborrheic dermatitis, but, to verify this, more cases will need to be examined
with skin biopsy to demonstrate abundant follicular yeast forms.
Since both seborrheic dermatitis and Malassezia folliculitis typically
respond to antifungal agents such as ketoconazole or itraconazole,
response to such therapy cannot be regarded as a distinguishing feature. In the few previous case series of patients resembling mine,
few if any skin biopsies have been performed. If future cases prove
on skin biopsy to be devoid of yeast, such as my case 6, that would
argue for a continued separation of these two diagnoses.
Pending further reports with biopsies, I propose the two disorders be considered separate, with distinguishing features as summarized in Table II.
Disclosure: There are no conflicts of interest.
References
1 Shelley WB, Crissey JT. Classics in Clinical Dermatology. 2nd
ed. New York, NY: Informa Healthcare; 2003:212.
port of seven cases and review of the Pityrosporum organism relative to cutaneous disease. Arch Dermatol. 1973;107:388–391.
17 Akaza N, Akamatsu H, Sasaki Y, et al. Malassezia folliculitis is caused by resident Malassezia species. Med Mycol.
2009;47:618–624.
18 Bower S. Malassezia (Pityrosporum) Folliculitis. Emedicine
from WebMD Web site. http://emedicine.medscape.com/article/1091037. Accessed June 30, 2010.
19 Lévy A, Feuilhade de Chauvin M, Dubertret L, Morel P, Flageul B. Malassezia folliculitis: characteristics and therapeutic
response in 26 patients [in French]. Ann Dermatol Venereol.
2007;134:823–828.
20 Bäck O, Faergemann J, Hörnqvist R. Pityrosporum folliculitis:
a common disease of the young and middle-aged. J Am Acad
Dermatol. 1985;12:56–61.
21 Goodfield M, Sathan E. Failure of isotretinoin therapy in Pityrosporum folliculitis. J Am Acad Dermatol. 1988;18:143–144.
22 Faergemann J, Bergbrant IM, Dohsé M, Scott A, Westgate G.
Seborrheic dermatitis and Pityrosporum (Malassezia) folliculitis:
characterization of inflammatory cells and mediators in the skin
by immunohistochemistry. Br J Derm. 2001;144:549–556.
2 Virchow RLK. Handbuch der Speciellen Pathologie und Therapie.
Vol 3. Erlangen, Germany: von Ferdinand Enke; 1860:57–63.
3 Duhring LA. A Practical Treatise on Diseases of the Skin. 2nd
ed. New York, NY: Lippincott Williams & Wilkins; 1881.
VINTAGE LABEL
4 Shoemaker JV. A Practical Treatise on Diseases of the Skin.
New York, NY: Appleton & Co; 1891:94.
5 Stelwagon H. Treatise on Diseases of the Skin. Philadelphia, PA:
WB Saunders & Co; 1902:316.
6 Crocker HR. Diseases of the Skin. 2nd ed. London, England:
H.K. Lewis & Co; 1893:699.
7 Sutton RL. Diseases of the Skin. St Louis, MO: CV Mosby Company; 1916:188.
8 Andrews GC. Diseases of the Skin. 1st ed. Philadelphia, PA: WB
Saunders Company; 1930:417.
9 Rook A, Wilkinson DS. Textbook of Dermatology. 2nd ed. Hoboken, NJ: Blackwell Scientific Publications; 1972:265.
10 Burton JS, Rook A, Wilkinson DS. Textbook of Dermatology.
4th ed. London, England: Blackwell Scientific Publications;
1986:377.
11 Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook
of Dermatology. 7th ed. Hoboken, NJ: John Wiley & Sons; 2004.
12 Jansen T, Plewig G. Dermatology in General Medicine. 7th ed.
New York, NY: McGraw-Hill; 2007: chap 22, figures 22–24.
13 Finn OA, Grant PW, McCallum DI, Raffle EJ. A singular dermatosis of mongols. Arch Dermatol. 1974;114:1493–1494.
14 Kavanagh GM, Leeming JP, Marshman GM, Reynolds NJ,
Burton JL. Folliculitis in Down’s syndrome, Br J Dermatol.
1993;129:696–699.
15 Weary PE, Russell CM, Butler HK, Hsu YT. Acneiform eruption resulting from antibiotic administration. Arch Dermatol.
1969;100:179–183.
16 Potter BS, Burgoon CF Jr, Johnson WC. Pityrosporum folliculitis. Re-
SKINmed. 2011;9:161–166
166
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May/June 2011
REVIEW
Primary Anetoderma:
A Cutaneous Marker of Antiphospholipid Antibodies
Hernán Staiger, MD;1 Miriam Saposnik, MD;2 Rubén E. Spiner, MD;2 Roberto G. Schroh, MD, PhD;3
María C. Corbella, MD;3 Mercedes L. Hassan, MD, PhD2
Abstract
Primary anetoderma is a rare idiopathic disease of the skin characterized by circumscribed areas of slack skin and loss of elastic fibers found on histopathologic examination. It has been related to systemic lupus erythematosus and other immune diseases. In recent years, however, its association with
antiphospholipid antibodies has been highlighted, and it should be considered a clinical manifestation of these antibodies. (SKINmed. 2011;9:168–171)
A
netoderma is an elastolytic skin process clinically characterized by circumscribed, rounded areas of slack skin. Two forms
are usually recognized: primary and secondary anetoderma.
Secondary anetoderma is due to an abnormal repairing mechanism of
previous skin lesions. Acne and varicella are the most frequent causes.
In the primary form, the lesions appear de novo on previously
healthy skin. Primary anetoderma (PA) has been related to a variety
of pathologies, mainly autoimmune diseases1; however, a strong link
between PA and the presence of antiphospholipid antibodies was
recently established.
Clinical and Histological Findings
Clinically, PA lesions are characterized by circumscribed, round or
oval areas of atrophic skin with reduced consistency on palpation
that occasionally adopt a protruding saccular appearance (Figure 1
and Figure 2). Most frequently, the lesions are localized on the trunk,
neck, and arms, but other sites can be affected. No previous dermatosis precedes them on the location where they develop. Patients with
PA may be totally asymptomatic or may develop pruritus, redness, or
other signs of inflammation at any time.1,2
Histologically, a superficial, and usually deep, perivascular lymphocyte infiltrate is identified with hematoxylin and eosin (Figure 3).
Although lymphocytes dominate, other inflammatory cells may be
found. No epidermal or subcutaneous cell tissue alterations are observed.3 Occasionally, giant cells may be found in the dermis, including granuloma formation.3,4 In a minority of patients, microthrombi
in the dermal vessels has been described.5 This phenomenon is likely
related to the exact period when the biopsy was performed.
Diagnosis of anetoderma is made by finding elastolysis and elastorrhexis via elastic fiber stains. These changes affect mainly the papillar
dermis, but the reticular dermis is also frequently involved. In addition, some fibers may adopt a characteristic tortuous and thinned aspect3 (Figure 4 and Figure 5).
The role of direct immunofluorescence in the study of PA is not clear.
Case series and isolated reports show variable results, and immune deposits may or may not be found.6,7 Morphology of the deposits may be
granular or linear. Several combinations of immunoglobulins (Ig) (mainly IgM and IgG, and occasionally IgA) and complement fractions (especially C3 and C1q) are possible. They may be found in the dermoepidermal junction area, in the vascular walls, or along dermal elastic fibers.7–14
Associations
PA has been related to multiple diseases. Its association with autoimmune
pathologies, mainly lupus erythematosus (LES) and antiphospholipid
syndrome (APS), has been highlighted.15,16 PA has also been related to
other diseases such as cutaneous LES,2,17 thyroiditis,11,15 Addison disease,2
scleroderma,7 hemolytic anemia,7,9 and autoimmune thrombocytopenia.1
Likewise, PA has been associated with antinuclear antibodies, rheumatoid factor, antithyroid antibodies, and other serologic markers. Recently, some cases of PA have been found in patients with the human
immunodeficiency virus (HIV).18
In recent years, many publications have shown, nevertheless, that the
strongest and most constant associated finding of PA is the presence
of antiphospholipid antibodies. Although these antibodies may arise as
an isolated phenomenon, they usually appear related to autoimmune
diseases or infections, and this may, in fact, justify the heterogeneity of
From the Department of Dermatology and School of Medicine, Hospital Italiano of Buenos Aires;1 and the Departments of Dermatology,2 and
Pathology,3 Ramos Mejía School of Medicine, University of Buenos Aires, Buenos Aires City, Argentine
Address for Correspondence: Hernán Staiger, MD, Venancio Flores 93, Autonomous City of Buenos Aires, Argentine • E-mail: hernanstaiger@yahoo.com.ar.
SKINmed. 2011;9:168–171
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REVIEW
conditions linked to PA in the past. As an example, among LES patients, PA is only found in those with antiphospholipid antibodies.5,19,20
Link Between PA and
Antiphospholipid Antibodies
In reviewing the literature, it is noteworthy that several old publications
report cases of PA associated with positive serologic tests for syphilis,
but without cutaneous manifestations of syphilis.2 In one of the largest
series of PA, it was determined that in 14 patients, the Venereal Disease Research Laboratory test (VDRL) (which has low sensitivity and
specificity as an antiphospholipid antibody detection method) found
only one false-positive case.2 Researchers performed VDRL and lupus
anticoagulant on 6 patients, but only one was positive for the latter and
no one was reactive for VDRL.7
Figure 1. Circumscribed, round lesions, slightly more clear than the
surrounding skin, with reduced consistency on palpation (continuous
arrows). Two lesions with saccular aspect (discontinued arrows).
By introducing anticardiolipin (aCL) IgG and IgM antibodies in the
screening of PA patients, however, the sensitivity of antiphospholipid
antibody detection has increased. In one study, 4 of 5 patients with
anetoderma and LES were positive for lupus anticoagulant and 3 for
aCL antibody isotype IgG, IgM, and/or IgA. In spite of that, in a later
survey, the same author studied retrospectively the presence of lupus
anticoagulant and aCL antibody isotypes IgG and IgM in 14 patients
with PA (one of them with LES), but found only one case with antiphospholipid antibodies.21
As the search of antibodies is performed with higher sensitivity and
specificity methods, the association of cases of PA-antiphospholipid
antibodies increases. In this regard, the strongest data are shown by
publications that supplement the analysis with the anti-β2-glycoprotein
I antibodies (anti-β2-GPI) search.22 In one report, antiphospholipid antibodies were found in all patients studied with anetoderma.16 A later
investigation described the same findings in 8 of 9 cases.23 Recently, we
have reported two cases of PA, finding anti-β2-GPI and aCL antibodies in both patients. None of them fulfilled criteria for systemic lupus
erythematosus or APS; however, one patient had glomerulonephritis
(possibly of lupus etiology) and the other had tumid lupus lesions.8
Figure 2. Subtle, rounded lesions with fine superficial wrinkles.
Reduced consistency on palpation.
Where in addition to IgG and IgM isotypes, IgA isotypes of aCL and
anti-β2-GPI antibodies are investigated, the results are even more conclusive. Thus, yet another study detected presence of antiphospholipid antibodies in each of 9 patients with PA analyzed. None of them
had a diagnosis of LES.15
PA is currently recognized as a possible manifestation of the presence of
antiphospholipid antibodies.15,24,25 These antibodies may arise as an isolated laboratory disturbance, they can be found related to autoimmune
diseases and infections, or they can specifically be part of an APS.25–27
Noteworthy, almost half of patients studied in the most recent case series may be included in the cases with APS, since in addition to the
presence of the antiphospholipid antibodies, these patients also showed
thrombotic events or obstetric complications.15,16,23 In some of them,
SKINmed. 2011;9:168–171
169
Figure 3. Slight mononuclear inflammatory dominantly superficial and deep perivascular infiltrate (hematoxylin-eosin stain,
original magnification ×10).
Primary Anetoderma
May/June 2011
REVIEW
the phenomenon.5,21 On the other hand, perivascular immune deposits
would support inflammation as a main cause.7,12,13
Conclusions
PA should be considered a cutaneous lesion highly suggestive of antiphospholipid antibodies presence, with or without APS. In every
patient with PA, therefore, those antibodies should be investigated
thoroughly, in addition to ruling out autoimmune diseases (especially
LES) and HIV infection. In patients with moderate-high titers of antiphospholipid antibodies and without a history of thrombotic events,
treatment with low doses of aspirin is recommended and primary preventive anticoagulant therapy is justified in surgeries requiring immobilization.30 It is also important to prevent other prothrombotic factors
such as obesity, smoking, and use of oral contraceptives. Because PA
may be an early sign of diverse autoimmune diseases, especially APS,
long-term follow-up of this group of patients is mandatory.
Figure 4. Absence of elastic fibers in the papillar dermis
(Resorcin-Fuchsin ×10).
References
1 Burgdorf W, Goltz R. Anetodermia y otras enfermedades atróficas de
la piel. In: Fitzpatrick TB, Katz S et al. Dermatología en Medicina General. Buenos Aires: Edit Médica Panamericana; 2001:1266–1269.
2 Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical
findings, associations, and long-term follow-up evaluations. Arch
Dermatol. 1984;120:1032–1039.
3 Venencie PY, Wimkelmann R. Histophathologic findings in anetoderma. Arch Dermatol. 1984;120:1040–1044.
4 Ishida Y, Naitoh M, Yoneyama K, et al. Coexistence of disseminated primary anetoderma and generalized granuloma annularelike papules. J Dermatol. 2007;34:278–279.
5 Stephansson EA, Niemi K, Jouhikainen T, et al. Lupus anticoagulant and the skin. A long-term follow-up study of SLE patients
with special reference to histopathological findings. Acta Derm
Venereol (Stockh). 1991;71:416–422.
Figure 5. Fragmentation and thinning of elastic fibers in
reticular dermis (Resorcin-Fuchsin ×40).
6 Disdier P, Harlé JR, Andrac L, et al. Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol.
1994;30:133–134.
these alterations took place years after the development of anetodermic
lesions, which had constituted the first clinical sign of the syndrome.15
7 Hodak E, Shamai-Lubovitz O, David M, et al. Immunologic abnormalities associated with primary anetoderma. Arch Dermatol.
1992;128:799–803.
Possible Pathogenic Mechanisms
8 Staiger H, Saposnik M, Spiner RE, et al. Dermatol Argent.
2008;14:372–378.
Pathogenesis of PA is unknown. Many theories try to explain the elastolytic phenomenon. A possible mechanism may be the immunologic
attack of elastic fibers, as a consequence of cross-reaction between β2glycoprotein I and epitopes of those fibers. This would be supported by
the presence of immune deposits surrounding elastic fibers, as is found
in some patients.7,12 The current tendency considers the problem as a
metalloproteinases and their inhibitors disequilibrium. The antiphospholipid antibodies may trigger tissue ischemia and/or an inflammatory response, thus increasing the expression of gelatinase and reducing
the expression of their inhibitors, causing elastolysis.28,29 The presence of
dermal vessel microthrombosis would suggest that ischemia may trigger
SKINmed. 2011;9:168–171
170
9 Walshe MM. Anetoderma. Br J Dermatol. 1980;103(suppl):56–57.
10 Bergman R, Friedman-Birnhaum R, Hazaz B, et al. An immunofluorescence study of primary anetoderma. Clin Exp Dermatol.
1990;15:124–130.
11 Hodak E, Shamai-Lubovitz O, David M, et al. Primary anetoderma associated with a wide spectrum of autoimmune abnormalities. J Am Acad Dermatol. 1991;25:415–418.
12 Roberts NM, Farrell A, Woodrow D, et al. Anetoderma of Jadassohn-Pellizzari. J R Soc Med. 1995;88:599–600.
13 Fernández-Galar M, España A, Lloret P. Systemic lupus erythematosus-associated anetoderma and anti-phospholipid antibodies. Clin Exp Dermatol. 2003;28:39–42.
Primary Anetoderma
May/June 2011
REVIEW
14 Macedo de Souza E, Christofoletti Dalton PE, Cintra ML. Anetoderma associated with primary antiphospholipid syndrome. J
Am Acad Dermatol. 2007;56:881–882.
antiphospholipid antibodies: case report and review of the literature. J Eur Acad Dermatol Veneorol. 2001;15:175–178.
23 Sparza A, Piette JC, Wechsler Bertrand, et al. Anetoderma and its prothrombotic abnormalities. J Am Acad Dermatol. 2003;49:1008–1012.
15 Hodak E, Feuerman H, Molad Y, et al. Primary anetoderma: a cutaneous sign of antiphospholipid antibodies. Lupus. 2003;12:564–568.
24 Gibson GE, Su D, Pittelkow M. Antiphospholipid syndrome and
the skin. J Am Acad Dermatol. 1997;36:970–982.
16 Disdier P, Christides C, Andrac-Meyer L, et al. Anetoderma during antiphospholipid syndrome: 3 cases. Ann Dermatol Venereol. 1996;123:800–803.
25 Hodak E, David M. Primary anetoderma and the antiphospholipid antibodies—review of the literature. Clinic Rev Allerg Immunol. 2007;32:162–166.
17 Hassan ML, Konopka H, Schroh R. Anetodermia y lupus eritematoso. Med Cut ILA. 1987;15:341–349.
26 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.
18 Lindstrom J, Smith KJ, Skelton HG, et al. Increased anticardiolipin antibodies associated with the development of anetoderma
in HIV-1 disease. Int J Dermatol. 1995;34:408–415.
27 Weinstein S, Piette W. Cutaneous manifestations of antiphospholipid antibody syndrome. Hematol Oncol Clin N Am. 2008;22:67–77.
19 Montilla C, Alarcón-Segovia D. Anetoderma in systemic lupus erythematosus: relationship to antiphospholipid antibodies. Lupus.
2000;9:545–547.
28 Venencie PY, Bonnefoy A, Gogly B, et al. Increased expression
of gelatinases A and B by skin explants from patients with anetoderma. Br J Dermatol. 1997;137:517–525.
20 Sabio JM, Tercedor J, Massare E, et al. Anetoderma associated
with systemic lupus erythematosus and antiphospholipid antibodies. Lupus. 2004;13:826–827.
29 Ghomrasseni S, Dridi M, Bruno G, et al. Anetoderma. An altered
balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol. 2002;24:118–129.
21 Stephansson E, Niemi K. Antiphospholipid antibodies and anetoderma: are they associated? Dermatology. 1995;191:204–209.
30 Samaritano LR. Antiphospholipid syndrome: review. South Med
J. 2005;98:617–625.
22 Romaní J, Pérez F, Llobet M, et al. Anetoderma associated with
See also page 149
SELF-TEST REVIEW QUESTIONS
W. Clark Lambert, MD, PhD, Section Editor
Instructions: For each of the following numbered questions, choose the appropriate lettered response(s). Unless directed to choose only one
lettered response, all, some, or none of the responses may be correct.
4) Which of the following infections should be ruled out in patients with PA? (Choose the single best response.)
a.Helicobacter infections
b.Erythrasma
c.Human immunodeficiency virus infection
d.Herpes simplex type 1 infection
e.Herpes simplex type 2 infection
f. Herpes zoster infection
1) Primary anetoderma (PA) has been reported to occur in individuals with: (Answer as many as apply.)
a.systemic lupus erythematosus.
b.cutaneous lupus erythematosus.
c.thyroiditis.
d.Addison’s disease.
e.scleroderma.
2) PA has been reported to occur in individuals with: (Answer as
many as apply.)
a. hemolytic anemia.
b.autoimmune thrombocytopenia.
c.thrombotic events.
d.obstetric complications.
e.associated aberrations that took place years after the PA
appeared.
ANSWERS TO SELF-TEST REVIEW QUESTIONS:
1) a, b, c, d, e; 2) a, b, c, d, e; 3) b; 4) c; 5) a, b, c, d, e, f
3) The strongest and most closely associated finding in PA is the
presence of: (Choose the single best response.)
a.antinuclear antibodies.
b.antiphospholipid antibodies.
c.anti–smooth muscle antibodies.
d.antithyroid antibodies.
e.rheumatoid factor.
5) In patients with moderate to high titers of antiphospholipid
antibodies and without a history of thrombotic events, which
of the following is (are) justified, recommended, or required?
(Answer as many as apply.)
a.Low doses of aspirin
b.Smoking cessation
c.Prevention/correction of obesity
d.Avoidance of oral contraceptives
e.Long-term follow-up
f. Primary preventive anticoagulant therapy in surgeries requiring immobilization
From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101 •
E-mail: lamberwc@umdnj.edu
SKINmed. 2011;9:168–171
171
Primary Anetoderma
May/June 2011
REVIEW
Fabry Disease
Ana Lía Tarabuso, MD
Abstract
Fabry disease (FD) is an X-linked lysosomal disorder caused by the deficient activity of the enzyme a-galactosidase A, which leads to multisystemic storage of globotriaosylceramide in visceral tissues and vascular endothelium. FD manifests primarily in affected hemizygous men,
with a wide range of clinical signs in heterozygous women. Acroparesthesias, angiokeratomas, pain crisis, and cornea verticillata are early
manifestations of FD. With age, severe complications involving the kidneys, heart, and brain cause considerable morbidity and premature
death. Although the clinical onset of FD occurs in childhood, diagnosis is often delayed or missed. In men, the diagnosis must be confirmed biochemically by demonstration of decreased levels of a-galactosidase A activity. In women, the disease is diagnosed by identification of a mutation in the a-galactosidase A gene. Until a few years ago, the existing treatment for FD was based on clinical manifestations,
but the advent of enzyme replacement therapy should stimulate the identification of the signs and symptoms suggestive of this disorder to
allow earlier diagnosis and treatment. (SKINmed. 2011;9:173–177)
A
nderson Fabry disease (FD), is a rare hereditary lysosomal storage disorder caused by partial or absolute deficiency of the a-galactosidase A enzyme, with the resulting accumulation of glycosphingolipids in visceral tissues and
vascular endothelium of the whole body.1
In 1898, FD was first described by two dermatologists working
independently, William Anderson in England and Johannes Fabry
in Germany. They reported on two patients with an unusually extensive angiokeratoma (AK: AK corporis diffusum).2,3 In 1947, researchers reported abnormal vacuoles in blood vessels and the lipid
nature of the storage material was established.4,5 In 1965, experts
demonstrated the X-chromosomal recessive heredity through pedigree analyses.6 In 1970, the defective enzyme was characterized
as a-galactosylhydrolasa.7 Researchers eventually made it possible
to identify biochemically the defective enzyme, and, at the same
time, these findings were used for effective enzyme replacement
treatment.8–10 The isolation of the genomic DNA sequence improves the identification of genetic carriers and results in attempts
to treat the disease by means of recombinant DNA.11
Epidemiology and Pathophysiology
but may also be variably affected by random inactivation of the X
chromosome. Parents with the disease do not transmit the defective
gene to their sons, but they do transmit it to their daughters.1
The gene for a-galactosidase A is located on the X chromosome at
q22.1, and more than 370 mutations have been identified, where
the missense mutations account for more than half. The mutations
are usually “private,” restricted to a single or few families.13
A deficient activity of a-galactosidase A results in impaired biodegradation of glycosphingolipids and progressive accumulation
of globotriaosylceramide (Gb3) in epithelial cells of the kidney,
myocardial cells, valvular fibrocytes, neuronal cells, and endothelial, perithelial, and smooth muscle cells of blood vassels.1
Clinical Manifestations
FD is a slowly progressive disease. Clinical manifestations begin in childhood or adolescence and change as the patient ages
(Table). The main causes of death are renal failure, heart disease,
or stroke around the age of 50 years for hemizygous men14 and
70 years for obligate carrier women.15
FD, after Gaucher disease, is the second most prevalent lipid
storage disease, with an incidence estimated to be 1:117,000 of
live births and 1:40,000 of men.12
Although clinical onset occurs in childhood, the appearance of
the disease may be subtle or attributed to other disorders; therefore, there is often a long delay between the onset of the symptoms and the correct diagnosis of FD.12–16
FD is an X-linked recessive inherited disease; therefore, sons who
inherit the gene are affected by the disease and daughters are carriers
Cutaneous lesions appear in childhood, and their number increases with the age. The simplest recognizable clinical
From the Department of Dermatology, CEAL Medical Center, Trelew, Chubut, Argentina; and the Association for the Study and Diffusion of
Fabry Disease and Lysosomal Diseases in Argentina (AADELFA)
Address for Correspondence: Ana Lía Tarabuso, MD, Condarco 1733, Trelew, Provincia de Chubut, Argentina • E-mail: tarabusoana@hotmail.com
SKINmed. 2011;9:173–177
173
May/June 2011
REVIEW
Table. Anderson Fabry Disease: Clinical Manifestations
Childhood and Adolescence
Adulthood
Acroparesthesias
Fabry disease crisis
Fever
Angiokeratomas
Hypohidrosis and heat intolerance
Abdominal pain, diarrhea
Cornea verticillata
Proteinuria, lipiduria, hematuria
More extensive angiokeratomas
Heart disease
Impaired renal function
Nervous system manifestations: transient ischemic attack, stroke,
headaches
Ocular abnormalities: cornea verticillata, tortuous vascular lesions,
and cataract
characteristics are AKs and telangiectasias. Although not pathognomonic of this disease, they are part of the cutaneous manifestations of “Fabry disease rash” according to some authors.14–17
AKs are red-to-violaceous papular lesions that do not disappear
on pressure, generally in the buttock, umbilical, thigh, and genital areas (typical bathing suit distribution), and may extend to
the lips, fingers, chest, and arms (Figure 1, Figure 2, Figure 3).
In men, AKs tend to join by regions, and in women are usually smaller, more disseminated and more frequent on the chest,
periumbilical area, and fingers.18,19 Histopathology of AK consists of dilated blood filler vessels in the upper dermis lying beneath a thinned epidermis. Hyperkeratosis is especially severe
in AK on the hands, feet, legs, or older lesions, but it may be
absent in scroti or early lesions (Figure 4). Ultrastructural tests
reveal lipid-containing intracytoplasmic vacuoles in endothelial
cells, fibroblasts, and pericytes (“zebra bodies”). Such inclusions,
however, are not pathognomonic for FD, because they are also
found with other lysosomal storage diseases.20
the hands and feet. Recurrent painful episodes are most frequently
triggered by cold, heat, fever, exercise, stress, or fatigue. A burning
sensation in the palms and soles often radiating to the proximal
extremities and occasionally to the abdomen is common.22
Central nervous system symptoms include tinnitus, disturbance
of concentration, dizziness, headaches, and learning difficulties,
and personality changes, cognitive deficits, and dementia have
also been reported. Transient ischemic attacks or stroke affect
15% to 20% of FD patients.23 More frequent misdiagnosis of
pain and neurological symptoms comprise rheumatoid arthritis,
rheumatic fever, arthritis, Raynaud’s syndrome, “growing pains,”
multiple sclerosis, or simulation, among others.16–21
The eyes are affected in most patients, and cornea verticillata is a distinctive sign found in more than 80% of men and 60% of women.
Posterior cataracts, vascular lesions (blood vessels showing varying degrees of tortuosity) in the retina, and conjunctiva are seen in both men
and women.21 High-frequency sensorial hearing loss is common.24
AKs have to be differentiated from hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), solitary AK, AK of Mibelli, AK of Fordyce, eruptive angioma, pyogenic granuloma, petechiae of meningococcal meningitis, fucosidosis, and sialidosis.17–21
Most FD patients develop proteinuria in late adolescence, which
progresses to isosthenuria and produces tubule function alterations. Renal complications announce the terminal stage of the
disease and progression to renal failure is the primary cause of
death in homozygous patients.14–25
Telangiectasias are present mostly in men on the face, lips, oral mucosa, and conjunctivas. Hypohidrosis and, more rarely, anhydrosis,
are reported frequently in men. Impairment of sweating ability in
these patients produces xeroderma with intolerance to heat and exercise, nausea, dyspnea, headache, or loss of consciousness.18,19
Cardiac involvement is variable and includes left ventricular
hypertrophy, an enlarged left atrium, heart valve abnormalities,
atrial arrhythmia, and conduction disturbance.26 Cardiac involvement may be the only symptom in some hemizygous men,
with hypertrophic cardiomyopathy (“cardiac variant of FD”).27
Leg edema and lymphedema, in the absence of cardiac or renal
disease, appear more commonly in patients with FD than in the
general population.19 Fifty percent of patients may also have reduced production of tears and saliva.17
Gastrointestinal manifestations may occur as abdominal pain,
diarrhea, nausea, vomiting, postprandial feeling of fullness, early
satiation, and weight loss.25–28
Neuropathic pain typically occurs during childhood in 80% of
patients and declines as patients age. It may be chronic on the
soles and palms or episodic “crisis” acroparesthesia may occur on
SKINmed. 2011;9:173–177
Obstructive airway disease is common in FD, and is more pronounced in older patients. Smokers with FD exacerbate pulmonary impairment and may produce recurrent respiratory tract
infections than would be expected from smoking alone.29
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Fabry Disease
May/June 2011
REVIEW
Diagnosis
The diagnosis of FD in hemizygous men begins with a comprehensive history taking of the chronologic development of pain,
AKs, hypohidrosis, palpitations, and gastrointestinal symptoms
and with a complete clinical examination. A family history may
reveal relatives of patients who have died from kidney or heart
disease at an early age.
In a series of reported cases, there are positive correlations between the presence of AK and other early signs and symptoms
of FD, such as acroparesthesias, cornea verticillata, and proteinuria,18,19–22 which emphasizes that early recognition of cutaneous
manifestations increases the chances of a timely diagnosis.
In men, the diagnosis must be confirmed biochemically by demonstration of a-galactosidase A activity in plasma or peripheral
leukocytes, tears, tissue biopsies, or culture skin fibroblasts. In
contrast, women can have normal to very low a-galactosidase A
activity; therefore, demonstration of a genetic alteration is necessary to confirm the diagnosis. Prenatal diagnosis is possible by
measurement of a-galactosidase A activity in fetal cells obtained
by amniocentesis of chorionic villus sampling.16
Figure 1. Periumbilical distribution of angiokeratomas.
Treatment
Until a few years ago, treatment was nonspecific, symptomatic,
and supportive.
Standard doses of nonsteroidal antiinflammatory drugs, phenytoin, carbamazepine, or gabapentin often at a low dose, and
minimization of activities that trigger painful episodes (emotional stress, exercise, temperature changes) may treat or prevent
painful crises and acroparaesthesias.16
AKs have been treated with excision surgery, electrocoagulation, freezing with liquid nitrogen or carbon dioxide ice, and laser systems.17
Prophylactic anticoagulants and antiplatelet agents are recommended for patients who are susceptible to stroke, while coronary artery and bypass grafting and heart transplant have been
successfully conducted in a few patients.
Antihypertensive drugs are crucial for management of renal impairment. Angiotensin-converting-enzyme inhibitors are recommended for proteinuria. Dialysis or renal transplant could extend life, but, although the transplanted kidneys remained free
from the disease, damage to other systems continue to progress,
especially in the brain and the cardiovascular system.16
In mid-2001, two groups of investigators published randomized
placebo-controlled studies evidencing that in FD, enzymatic replacement may revert to the main pathological consequences:
agalsidase α, manufactured using a new genetic engineering
SKINmed. 2011;9:173–177
Figure 2. Angiokeratomas on the scrotum and penis.
procedure from a human fibroblast cell line; and agalsidase b,
from genetically modified ovarian cells from Chinese hamsters.
Agalsidase α is infused at a dose of 0.2 mg/kg intravenously every
2 weeks for 40 minutes, and agalsidase b at a dose of 1 mg/kg
intravenously every 2 weeks for 3 or 4 hours.30,31
Patients treated with agalsidase α exhibit a significant reduction
in pain and increase in quality of life, compared with patients
treated with placebo. There is a normalization of the structure of
renal glomeruli, a normalization of cerebral perfusion, and improvement in cardiac function. In addition, agalsidase α therapy
leads to improvements in auditory function, cardiomyopathy,
sweat secretion, gastrointestinal problems, and neuropathy. The
studies that led to the approval of agalsidase b show statistically
significant reduction in urine and plasma Gb3 content and improvement in renal histopathology, and lysosomal inclusions in
liver, heart, and skin decreased. Agalsidase b has shown a benefit
175
Fabry Disease
May/June 2011
REVIEW
directed toward the development of treatment protocols based
on the combination of different therapies to improve the clinical
outcome of FD patients.
Gene therapy offers hope that, one day, there will be a cure for
FD and other lysosomal storage diseases. A possible approach
would involve gene transfer to hematopoietic cells.35
Conclusions
FD is a rare X-linked inherited multisystemic disorder, often underdiagnosed, with early onset, progressive organ damage, and
premature mortality. With the advent of enzyme replacement
therapy, it is important that physicians recognize the signs and
symptoms of this disease so that effective treatment can be given. The early presence of dermatologic manifestations stand out;
therefore, just like the initial description by dermatologists, the
analysis of cutaneous signs emphasize the role that dermatology
plays in the early diagnosis of this disease.
Figure 3. Angiokeratomas around the vermilion border of the lips.
References
1 Desnik RJ, Ioannou YA, Eng CM. a-galactosidase A deficiency:
Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill; 2001:3733–3774.
2 Anderson W. A case of angeio-keratoma. Br J Dermatol.
1898;10:113–117.
3 Fabry J. Ein Beitrag zur kenntnis der Purpura haemorrhagica
nodularis (Purpura papulosa haemorrhagica Hebrae). Arch DermatolSyphilol (Berlin). 1898;43:187–201.
Figure 4. Angiokeratoma: histopathologic findings (hematoxylin-eosin stain, original magnification ×40).
4 Pompen AW, Ruiter M, Wyers HJ. Angiokeratoma corporis diffusum (universale) Fabry, as a sign of an unknown internal disease:
two autopsy reports. Acta Med Scand. 1947;128:234–255.
relative to placebo in delaying progression to a renal, cardiac or
cerebrovascular event, or death in patients with mild to moderate kidney disease.32
The safety of enzyme replacement therapy in children has been
demonstrated recently. Treatment is generally well tolerated, and
the most common adverse events reported are infusion reactions
in the form of rigor and fever. Immunoglobulin G antibody
formation has been reported with both preparations in 50% of
patients, but there is no clear evidence of any impact on clinical
efficacy of treatment.32
Another approach to the treatment of FD is substrate deprivation, based on the inhibition of an earlier step in the synthesis of
the accumulating glycosphingolipid.33
An emerging strategy for the treatment of lysosomal storage diseases is pharmacologic chaperone therapy, based on the use of
chaperone molecules that assist the folding of mutated enzymes
and improve their stability and lysosomal trafficking, increasing
the level of residual enzyme activity.34 Future research should be
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5 Scriba K. Zur Pathogenese des angiokeratoma corporis diffusum Fabry mit cardio-vasorenalem symptomenkomplex. Verh
Dtsch Ges Pathol. 1950;34:221.
6 Opitz JM, Stiles FC, Wise D, et al. The genetics of angiokeratoma corporis diffusum (Fabry´s disease) and its linkage relations
with the Xg locus. Am J Hum Genet. 1965;17:325–342.
7 Kint JA. Fabry´s disease: a-galactosidase deficiency. Science.
1970;167:1268–1269.
8 Desnick RJ, Allen KY, Desnick SJ, et al. Fabry´s disease: enzymatic diagnosis of hemizygotes and heterozygotes. J Lab Clin
Med. 1973;81:157–171.
9 Brady RO, Tallman JF, Johnson WG, et al. Replacement therapy
for inherited enzyme deficiency. Use of purified cemidetrihexosidase in Fabry disease. N Engl J Med. 1973;289:9–14.
10 Desnick RJ, Dean KJ, Grabowxki GA, et al. Enzyme therapy in
Fabry disease: differential in vivo plasma clearence and metabolic effectiveness of plasma and splenic a-galactosidase A isoenzymes. Proc Natl Acad Sci U S A. 1979;76:5326–5330.
11 Bishop DF, Calhoun DH, Berstein HS, et al. Human a-galactosidase A: nucleotide sequence of a cDNA clone encoding the nature enzyme. Proc Natl Acad Sci U S A. 1986;83:4859–4863.
12 Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome
Fabry Disease
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Survey. Eur J Clin Invest. 2004;34:236–242.
Fabry disease. N Engl J Med. 2001;345:9–16.
13 Rozenfeld PA, Tarabuso AL, Ebner R, et al. A successful approach for the detection of Fabry patients in Argentina. Clin
Genet. 2006;69:334–348.
32 Schaefer RM, Tylki-Szymanska A, Hilz MJ. Enzyme replacement
therapy for Fabry disease. A systematic review of available evidence. Drugs. 2009;69:2179–2205.
14 MacDermott KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort
of 98 hemizygous males. J Med Genet. 2001;38:750–760.
33 Abe A, Arend LJ, Lee L, et al. Glycosphingolipid depletion in
Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase. Kydney Int. 2000;57:446–454.
15 MacDermott KD, Holmes A, Miners AH. Anderson-Fabry disease:
clinical manifestations and impact of disease in a cohort of 60
obligate carrier females. J Med Genet. 2001;38:769–775.
34 Germain DP, Fan JQ. Pharmacological chaperone therapy by
active-site-specific chaperones in Fabry disease: in vitro and preclinical studies. Int J Clin Pharmacol Ther. 2009;47:S111–S117.
16 Desnick RJ, Brady R, Barrager J, et al. Fabry disease, an underrecognized multisystemic disorder: expert recommendations
for diagnosis, management and enzyme replacement therapy.
Ann Intern Med. 2003;138:338–346.
35 Siatskas C, Medin JA. Gene therapy for Fabry disease. J Inherit
Metab Dis. 2001;24:25–41.
17 Möhrenschlager M, Braun Falco M, Ring J, et al. Fabry disease.
Recognition and management of cutaneus manifestations. Am J
Clin Dermatol. 2003;4:189–196.
18 Tarabuso AL, Peralta I. Prevalencia de manifestaciones dermatológicas en pacientes con enfermedad de Fabry en Argentina.
Dermatol Argent. 2008;14:362–366.
19 Orteu CH, Jansen T, Lidove O, et al. Fabry disease and the
skin: data from FOS, the Fabry Outcome Survey. Br J Dermatol.
2007;157:331–337.
VINTAGE LABEL
20 O’Brien JS, Bernett J, Beath ML, et al. Lysosomal storage disorders: diagnosis by ultrastructural examination of skin biopsy
specimens. Arch Neurol. 1975;32:592–599.
21 Marchesoni CL, Roa N, Pardal AM, et al. Misdiagnosis in Fabry
disease. J Pediatr. 2010;156:828–831.
22 AADELFA. Asociación Argentina de estudio de enfermedad de
Fabry y otras enfermedades lisosomales. Evaluación de pacientes con enfermedad de Fabry en la Argentina. Medicina (B
Aires). 2010;70:37–43.
23 Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s
disease. Ann Neurol. 1996;40:8–17.
24 Hegeman S, Hajiof D, Conti G, et al. Hearing loss in Fabry disease: data from the Fabry Outcome Survey. Eur J Clin Invest.
2006;36:654–662.
25 Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline
medical characteristics of a cohort of 1765 males and females
in the Fabry Registry. J Inherit Metab Dis. 2007;30:184–192.
26 Linhart A, Kampmann C, Zamoratno JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international
Fabry Outcome Survey. Eur Heart J. 2007;28:1228–1235.
27 Nakao S, Takenaka T, Maeda M, et al. An atypical variant of
Fabry’s disease in men with left ventricular hypertrophy. N Engl
J Med. 1995;333:288–293.
28 Hoffman B, Schwarz M, Metha A, et al. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and responce to enzyme replacement therapy. Clin Gastrointest Hepatol. 2007;5:1447–1453.
29 Rosenberg DM, Ferrans VJ, Fulmer JD, et al. Chronic airflow
obstruction in Fabry’s disease. Am J Med. 1980;68:898–905.
30 Schiffmann R, Koop JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial.
JAMA. 2001;285:2743–2749.
31 Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human a-galactosidase A replacement therapy in
SKINmed. 2011;9:173–177
177
Fabry Disease
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References: 1. SapadinAN,Fleischmajer R.Tetracyclines:nonantibiotic properties and their clinical implications. JAmAcad Dermatol. 2006;54(2):258-265. 2. Leyden JJ,McGinley KJ,KligmanAM.Tetracycline and minocycline
treatment. Arch Dermatol. 1982;118(1):19-22. 3. Hubbell CG,Hobbs ER,RistT,White JW Jr.Efficacy of minocycline compared with tetracycline in treatment of acne vulgaris. Arch Dermatol.1982;118(12):989-992.
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MN-0810-280
May/June 2011
New to the Clinic
Noah S. Scheinfeld, MD, JD, Section Editor
Calcipotriene 0.005% and
Betamethasone Dipropionate 0.064% Combination
Topical Suspension (Taclonex Scalp)
A
novel two-compound scalp formulation (topical suspension) containing calcipotriol (50 mg/g) and betamethasone (0.5 mg/g, as dipropionate) (Xamiol, Taclonex
Scalp, LEO Pharma Inc, Parsippany, NJ) (aka calcipotriene
0.005% and betamethasone dipropionate 0.064% combination
topical suspension) has been shown to be an effective and safe
treatment for scalp psoriasis.1 Betamethasone is a class 2 topical corticosteroid and must be distinguished from augmented
betamethasone, which is a class 1 topical corticosteroid. Studies
have shown that Taclonex Scalp (1) has superior efficacy when
compared with either of its components alone at 8 weeks; (2)
has a rapid onset of action with significant clinical affect in 1
week; (3) improves patient quality of life; and (4) has few side effects. Taclonex Scalp topical suspension joins the combination of
calcipotriol (50 mg/g) and betamethasone ointment in being approved for treatment of limited stable plaque psoriasis. In some
markets, this combination in a gel preparation is also available.
Taclonex Ointment (calcipotriene 0.005% and betamethasone
dipropionate 0.064%) is approved for use on the skin to treat
psoriasis vulgaris (plaque psoriasis) in adults aged 18 years and
older and should be applied to affected areas once daily for up
to 4 weeks. Taclonex Scalp Topical Suspension (calcipotriene
0.005% and betamethasone dipropionate 0.064%) is approved
for treating moderate to severe psoriasis vulgaris of the scalp in
adults aged 18 years and older and should be applied to affected
areas on the scalp once a day for 2 weeks or until cleared. If the
affected area is not cleared, Taclonex Scalp may be continued for
up to 8 weeks. Do not exceed the recommended weekly dosage
of 100 g. Neither product is recommended for use in children.
A new $0 copay program for both Taclonex Ointment and Taclonex Scalp has been put in place in the first quarter of 2011.
The program is offered through health care providers and on-
line at www.taclonex.com. Patients who have been prescribed
Taclonex Ointment or Taclonex Scalp can obtain a patient savings card from their health care providers or visit the Web site
to download the card. The site generates a personalized card that
can be presented at the pharmacy along with a prescription. The
card entitles the patient copay assistance for up to 6 prescriptions, with a maximum benefit of $200 off per prescription.
There is no activation required, and the card is valid until December 31, 2012. This card, as is true with all cards, is not valid
with Medicare or Medicaid patients.
Phase III Data
The approval of Taclonex Scalp Topical Suspension rests on several phase III studies. One 8-week, multicenter, double-blind,
parallel-group study randomized adult patients with scalp
psoriasis involving >10% of the scalp to the two-compound
scalp formulation (n=568), betamethasone dipropionate 0.5
mg/g (n=563) or calcipotriol 50 mg/g (n=286). The primary
efficacy measure was the proportion of patients with “absence
of disease” or “very mild disease” according to investigators’
assessments at week 8. The proportion of patients with “absence of disease” or “very mild disease” at week 8 was significantly higher in the two-compound group (68.4%) than the
betamethasone dipropionate (61.0%) or calcipotriol (43.4%)
groups. The proportion of patients rating their scalp psoriasis
as “clear” or “almost clear” was significantly higher for the twocompound scalp formulation (69.6%) than for betamethasone
dipropionate (59.9%) or calcipotriol (44.7%). The incidence
of lesional/perilesional adverse events was lower in the twocompound and betamethasone dipropionate groups than the
calcipotriol group.
Another phase III study found similar efficacy for the twocompound scalp formulation and betamethasone dipropionate,
From the Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY
Address for Correspondence: Noah S. Scheinfeld, MD, JD, Department of Dermatology, Columbia University, College of Physicians and
Surgeons, 150 West 55th Street, New York, NY 10019 • E-mail: scheinfeld@earthlink.net
SKINmed. 2011;9:179–180
179
May/June 2011
NEW TO THE CLINIC
slightly lower efficacy for calcipotriol, and a noninsubstantial
positive placebo effect.2 In this second 8-week, multicenter, randomized, double-blind study, patients with scalp psoriasis were
randomized to treatment with the two-compound scalp formulation (calcipotriene 50 mg/g plus betamethasone 0.5 mg/g,
as dipropionate) (n=541), betamethasone 0.5 mg/g (as dipropionate) in the same vehicle (n=556), calcipotriene 50 mg/g in
the same vehicle (n=272), or vehicle alone (n=136). More patients achieved “absent” or “very mild” disease at week 8 with
the two-compound scalp formulation (71.2%) compared with
betamethasone dipropionate in the same vehicle (64.0%), calcipotriene in the same vehicle (36.8%), or the vehicle (22.8%).
One-Week Efficacy Data
Calcipotriene 0.005% and betamethasone dipropionate 0.064%
combination topical suspension works quickly. Analysis of pooled
data from two large pivotal phase III trials with 2920 patients receiving once-daily treatment for up to 8 weeks with either the
two-compound scalp formulation (n=1108), betamethasone dipropionate (n=1118), calcipotriol (n=558), or the vehicle (n=136)
assessed the progress that patients had after 1 week of medication use.3 The percentage of patients who had “absent” or “very
mild” disease according to Investigator’s Global Assessment after
1 week of treatment was significantly higher with the two-compound scalp formulation (30.6%) compared with betamethasone
(24.1%), calcipotriol (10.0%), or vehicle (6.9%).
in favor of the two-compound scalp formulation. Change was
significant on both total score and individual scales.
Conclusions
Calcipotriol (50 mg/g) and betamethasone (0.5mg/g, as dipropionate) combination scalp solution (Taclonex Scalp) is a useful
preparation that treats scalp psoriasis. A Scottish study found a
two-compound formulation calcipotriol and betamethasone dipropionate gel for the treatment of scalp psoriasis cost-effective.5,6
No cases of atrophy, striae, or steroid purpura were noted in two
52-week studies of combinations of these agents in a gel form.7
How this combination product compares in effectiveness and side
effects with augmented betamethasone dipropionate scalp solution or clobetasol propionate gel, solution, or foam or class 1 steroids has yet to be determined. The patient assistance cards should
make this preparation widely available to appropriate patients.
References
Positive Effects on Quality of Life
Taclonex Scalp has positive effects on patients’ quality of life.
This 8-week, randomized, investigator-blind study, compared
the once-daily, two-compound scalp formulation (calcipotriol
50 mg/g plus betamethasone 0.5 mg/g) with twice-daily calcipotriol scalp solution (50 mg/mL) in patients with scalp psoriasis of at least moderate severity covering ≥10% of the scalp.4
Quality of life was assessed (weeks 0, 2, 4, and 8) using the 36item Short-Form Health Survey (version 2; SF-36v2) and Skindex-16. Treatment with the two-compound scalp formulation
(n=207) resulted in significant improvements from baseline on
the SF-36v2 (Physical Component Summary week 8; Mental
Component Summary, weeks 2, 4, and 8). A significant change
from baseline in the calcipotriol scalp solution group (n=105)
was seen only on the Mental Component Summary (P=.04,
week 8). Change from baseline in Skindex-16 was significantly
SKINmed. 2011;9:179–180
180
1 van de Kerkhof PC, Hoffmann V, Anstey A, et al. A new scalp
formulation of calcipotriol plus betamethasone dipropionate
compared with each of its active ingredients in the same vehicle
for the treatment of scalp psoriasis: a randomized, double-blind,
controlled trial. Br J Dermatol. 2009;160:170–176.
2 Jemec GB, Ganslandt C, Ortonne JP, et al. A new scalp formulation of calcipotriene plus betamethasone compared with its
active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. J Am Acad
Dermatol. 2008;59:455–463.
3 Jemec GB, van de Kerkhof PC, Enevold A, Ganslandt C. Significant one week efficacy of a calcipotriol plus betamethasone
dipropionate scalp formulation. J Eur Acad Dermatol Venereol.
2011;25:27–32.
4 Ortonne JP, Ganslandt C, Tan J, et al. Quality of life in patients
with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: a randomized controlled trial. J
Eur Acad Dermatol Venereol. 2009;23:919–926.
5 Affleck AG, Bottomley JM, Auland M, et al. Cost effectiveness of
the two-compound formulation calcipotriol and betamethasone
dipropionate gel in the treatment of scalp psoriasis in Scotland.
Curr Med Res Opin. 2011;27:269–284.
6 Luger TA, Cambazard F, Larsen FG, et al. A study of the safety
and efficacy of calcipotriol and betamethasone dipropionate
scalp formulation in the long-term management of scalp psoriasis. Dermatology. 2008;217:321–328.
7 Radtke MA, Herberger K, Kornek T, et al. Calcipotriol plus betamethasone dipropionate gel in the treatment of scalp psoriasis.
A review. Hautarzt. 2010;61:770–775.
Taclonex Scalp
May/June 2011
Cosmetic Science
Howard A. Epstein, PhD, Section Editor
T
he Food and Drug Administration (FDA) has proposed
new rules for sunscreen products. The proposed final
monograph includes a new UV-A rating system for
products with sun protection factor (SPF) claims. It sets standards for formulating, testing, and labeling over-the-counter
sunscreen drug products with UV-A and UV-B protection. In
the United States, very few sunscreens are currently available
that provide adequate UV-A protection. Under the new monograph, only sunscreens that demonstrate both UV-A and UV-B
protection may claim “broad-spectrum” coverage. What remains
unclear is the nature of UV-A–induced mechanisms of skin injury and how adequate UV-A filters provide protection from
UV-A exposure. Under the existing sunscreen monograph, few
approved UV-A sunscreens are available for use. In the absence
of such filters, what additional approaches are available to minimize UV-A damage to skin? What does adequate UV-A protection really mean in the context of our ability to measure it?
SPF values have been used to indicate the level of UV-B protection for more than 30 years. The deleterious effect of UV-A
(320–400 nm) for human skin was not well appreciated at that
time. The proposed final sunscreen monograph will provide ratings derived from two tests that the FDA proposes for assessing
the effectiveness of sunscreens in providing protection against
UV-A light. The first test measures a product’s ability to reduce
the amount of UV-A radiation that passes through it, and the
second test measures a product’s ability to prevent tanning. This
test is nearly identical to the SPF test used to determine the effectiveness of UV-B sunscreen products.
The proposed regulation creates a consumer-friendly rating system
for UV-A products designed to help consumers identify the level
of UV-A protection offered by a product. The FDA proposal provides a rating system for UV-A sunscreen products on a scale of 1
to 4 stars. One star would represent low UV-A protection, 2 stars
would represent medium protection, 3 stars would represent high
protection, and 4 stars would represent the highest UV-A protection available in an over-the-counter sunscreen product.
If a sunscreen product does not provide at least a low level (1
star) of protection, the FDA is proposing to require that the
product bear a “no UVA protection” marking on the front label
near the SPF value.1
Cutaneous Pigmentation
The synthesis of melanin by melanocytes and the transfer of melanosomes containing melanin to the surrounding keratinocytes
results in cutaneous pigmentation. Once in the keratinocytes,
melanin granules accumulate above the nuclei and absorb harmful UV radiation, minimizing DNA damage.2 UV-A (320–400
nm) passes through most glass (auto, office, and windows) and
penetrates deep into the dermal layer of skin. It is estimated that
about 19% to 50% of solar UV-A light can reach the depth of
melanocytes, while only about 9% to 14% of solar UV-B light
reaches the same cells.3 UV-A stimulates tanning that is transient
and less protective against UV-induced injury compared with tans
generated after UV-B exposure.4 It is hypothesized that UV-A reacts with endogogenous photosensitizers, flavins, porphorins, and
melanins, generating reactive oxygen species, which, in turn, generate DNA single-strand breaks or photoadducts.5
Other studies have shown that use of narrow-band UV-B, about
311 nm) is more preferable for phototherapy than psoralen and
UV-A therapy, which can cause undesirable side effects, including cutaneous cancers.6 UV-A causes immediate tanning after
exposure, which begins to fade within 3 hours and may be
based on photooxidation of preexisting melanin, melanin precursors, and possibly other epidermal constituents.1 It is known
that UV-A produces harmful oxygen species including singlet
oxygen, hydroxyl radicals, and superoxide and melanin interacts
with them to protect from further skin damage.7,8
Antioxidants and Solar Exposure
Biopsies from patients with histologically confirmed solar elastosis and biopsies taken from non–UV-exposed sites of agematched controls and young volunteers were analyzed. Levels of
antioxidant enzymes catalase, copper-zinc superoxide dismutase,
From EMD Chemicals Inc, Gibbstown, NJ
Address for Correspondence: Howard A. Epstein, PhD, EMD Chemicals Inc, 480 South Democrat Road, Gibbstown, NJ 08027 •
E-mail: howard.epstein@emdchemicals.com
SKINmed. 2011;9:181–182
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May/June 2011
Cosmetic Science
and manganese superoxide dismutase were investigated using
immunohistochemistry. In photoaged skin, a significant depletion of antioxidant enzyme expression was observed in the
stratum corneum and epidermis. An accumulation of modified
proteins was found within the upper part of the dermis of photoaged skin. Acute UV exposure of healthy persons was associated
with depleted catalase expression and increased protein oxidation. Exposure of keratinocytes and fibroblasts to UV-B and
UV-A and hydrogen peroxide led to dose-dependent protein
oxidation. The investigators concluded that the observed protein
oxidation alterations may be linked with photodamaged skin.
These observations, in the opinion of the investigators, provide
a rationale for antioxidant strategies to prevent photoaging and
acute photodamage in skin.9
Conclusions
Protection against erythema and sunburn is provided primarily
by UV-B filters. UV-B filters do not provide equal immune protection when the immunologic end point is used.11 In addition
to UV-B sunscreens, there is a need for sunscreens and other
topical agents to provide UV-A protection as well.
References
UV-A–Induced Photocarcinogenesis
Both UV-B and UV-A exposure are involved in photocarcinogenesis. UV-A exposure generates dipyrimidine photoproducts, which
are poorly repaired and isomerizes into Dewar products that are
highly mutagenic compared with UV-B produced photoproducts.10 UV-A induction of singlet oxygen production is involved
in signal transcription factor–mediated gene expression and observed in UV-A–damaged skin. Formation of thymine-thymine–
type cyclobutane pyrimidine dimers in UV-A–induced damage is
associated with a greater tendency of UV-A radiation to induce
DNA genotoxicity, promoting malignancy.10 UV-A exposure has
been shown to mediate transcription factor–induced expression of
cell adhesion molecules. The upregulation of matrix metalloproteinases promotes invasiveness of the tumor and expression of cell
adhesion molecules (ICAM-1), permitting tumor anchorage and
vascular invasion, which are involved in tumor metastases.10
UV-Induced Oxidative Stress
and Photoimmunosuppression
Wavelengths in the UV-A region may be equally effective as
UV-B in activating immune suppression.11 Solar-simulated UV
radiation was found to suppress delayed-type hypersensitivity to
recall antigens. UV radiation also suppressed contact allergy in
individuals presensitized to nickel, indicating that solar UV-A
radiation plays a role in activating immune responses.11
SKINmed. 2011;9:181–182
182
1 U.S. Food and Drug Administration, U.S. Department of Health
and Human Services. FDA News Release. http://www.fda.gov/
OHRMS/DOCKETS/98fr/07-4131.pdf. August 23, 2007, FDA
online. Accessed December 2, 2010.
2 Kobayashi N, Nakagawa A, Muramatsu T, et al. Supranuclear
melanin caps reduce ultraviolet induced DNA photoproducts in
human epidermis. J Invest Dermatol. 1998;110:806–810.
3 Costin G-E, Hearing VJ. Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J.
2007;21:976–994.
4 Wang SQ, Setlow R, Berwick M, et al. Ultraviolet A and melanoma: a review. J Am Acad Dermatol. 2001;44:767–774.
5 Garland CF, Garland FC, Gorham ED. Rising trends in melanoma:
an hypothesis concerning sunscreen effectiveness. Ann Epidemiol. 1993;3:103–110.
6 Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J
Med. 1997;336:1041–1045.
7 Pathak MA, Fitzpatrick TB. Preventative treatment of sunburn,
dermatohekiosis and skin cancer with sun protective. In: Fitzpatrick TB, Eisen AZ, Wolff K, Feedberg IM, Austin KF, eds.
Dermatology in General Medicine. New York, NY: McGraw Hill;
1993:1689–1717.
8 Pathak MA, Stratton K. Free radicals in human skin before and after exposure to light. Arch Biochem Biophys.
1968;123:468–476.
9 Sander SC, Chang H, Salzmann S, Mueller CSL, et al. Photoaging is associated with protein oxidation in human skin in vivo. J
Invest Dermatol. 2002;118,4:618–625.
10 Heng CYM. Curcumin targeted signaling pathyways: basis for
anti-photoaging and anti-carcinogenic therapy. Int J Dermatol.
2010;49:608–622.
11 Ullrich SE, Kriple ML, Ananthaswamy HN. Mechanisms underlying UV-induced immune suppression: implications for sunscreen
design. Exp Dermatol. 2002;11:1–4.
May/June 2011
W. Clark Lambert, MD, PhD, Editor
Laju M. Patel, MD; W. Clark Lambert, MD, PhD
T
he use of epinephrine in areas of terminal circulation in
the body has generally been contraindicated. It is standard practice in dermatologic surgery to use anesthetics
without epinephrine, when working with the fingers, toes, nose,
ears, or penis. This is a principle commonly accepted among
practitioners, as we are instilled with the notion that epinephrine
used in these regions can lead to ischemia and necrosis. Medical
textbooks and postgraduate training courses continue to forewarn us about the dangers of epinephrine; yet, it seems the validity of this longstanding dogma is questionable. The belief that
epinephrine should never be used in areas of end circulation has
recently been challenged and may, in fact, be inaccurate.
Background
Epinephrine is an a- and b-receptor agonist. It is considered a potent vasoconstrictor, because it activates the a receptors of blood
vessels.1 Epinephrine is used in conjunction with anesthetic agents
to prolong the duration of analgesia and to minimize complications of bleeding. Historically, it has long been established that
epinephrine injected into the digits, tip of nose, outer ear, or genitals leads to hypoxia or necrosis, and thus should not be used in
these areas. A review was conducted of Index Medicus from 1880–
1966 and a National Library of Medicine search from 1966–2000
for reported cases of digital gangrene and necrosis caused by local
anesthetics with epinephrine. After thorough analysis of the resulting 48 cases, it was established that the data were not sound
or complete enough to conclude with certainty that epinephrine
use resulted in necrosis of the fingers.2 Many of the historic reports had confounding factors such as the use of older anesthetics, postoperative hot soaks, inappropriate tourniquets, excess
anesthetic agent, nonstandardized epinephrine concentrations, or
the presence of concurrent site infections.2,3 These findings were
corroborated by a review which determined, after careful investigation, that epinephrine was not the sole cause of necrosis in
the previously reported cases.4 Also, only 4 of 21 cases that used
epinephrine for digital anesthesia actually reported the concentration, making it difficult to support a generalized warning against
its use. Furthermore, an in-depth literary analysis reinforced the
notion that the established doctrine, regarding the dangers of epinephrine used specifically in the fingers, is invalid.5
Discussion
Historical reports of the consequences of epinephrine use in areas of terminal circulation are unfounded in the claims made. It
is fair to say that after retrospective analysis, the standard practice of not using this agent in the fingers, toes, nose, ears, or penis
is based on unsubstantiated reasoning. Many investigators have
conducted prospective studies to determine the effects of epinephrine use, with appropriate concentrations and technique,
on the development of ischemia and necrosis. Investigators performed 121 digital blocks using 1% lidocaine with 1:200,000
epinephrine in a 30-gauge needle, and none had complications
of finger gangrene6; furthermore, the use of buffered 0.5% lidocaine with 1:200,000 epinephrine was determined to be
safe after local tumor infiltration of the hands and feet in 63
patients undergoing Mohs surgery.1 A multicenter prospective
study of 3110 cases demonstrated no incidence of digital tissue
damage in the hand after elective injection of concentrations of
≤1:100,000 epinephrine.7 In 59 described cases, necrosis of the
fingers did not occur even after injection of high-dose 1:1,000
epinephrine, and only 27 of these cases received any form of
treatment.8 Examination of Doppler flow imaging after digital
block anesthesia revealed a return to normal blood flow after 60
to 90 minutes and deemed the use of a vasoconstrictive agent
safe in patients undergoing surgical procedures of the hands or
feet.9 Many investigations have focused on the use of epinephrine in the fingers or toes. A clinical study in Germany of 10,201
procedures involving the outer ear or nose also resulted in no
problems due to the use of 1:1,000,000 epinephrine.10 On this
basis, recent high-quality investigations into the safety of epinephrine usage in areas with end-arterioles have failed to support
the longstanding principle.
There is concern that using epinephrine in regions of the body with
terminal blood vessels in patients with comorbid conditions may
From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101 •
E-mail: lamberwc@umdnj.edu
SKINmed. 2011;9:184–185
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May/June 2011
be dangerous; however, patients with pheochromocytomas, hyperthyroidism, hypertension, heart disease, or peripheral vascular disease were included in the study of epinephrine effects on cutaneous
ear and nose surgeries.10 No complications of ischemia or necrosis
were noted to occur in this subset of patients. When considering the
conditions of hypertension, diabetes, and circulatory or thrombotic
disorders and patients taking anticoagulation therapy, there was no
change in the findings of the safety of epinephrine use in the hands
or feet.1 Despite these comorbidities, injections of epinephrine did
not cause tissue damage in areas with end circulation.
9 Altinyazar HC, Ozdemir H, Koca R, et al. Epinephrine in
digital block: color Doppler flow imaging. Dermatol Surg.
2004;30:508–511.
10 Hafner HM, Rocken M, Breuninger H. Epinephrine-supplemented
local anesthetics for ear and nose surgery: clinical use without complications in more than 10,000 surgical procedures. J
Dtsch Dermatol Ges. 2005;3:195–199.
11 Andrades PR, Olguin FA, Calderon W. Digital blocks with or without epinephrine. Plast Reconstr Surg. 2003;111:1769–1770.
12 Bruce AM, Spencer JM. Surgical myths in dermatology. Dermatol Surg. 2010;36:512–517.
Conclusions
The longstanding practice of avoiding the use of vasoconstrictive
agents in the fingers, toes, nose, outer ear, or penis is anecdotal and
unsubstantiated. Contrary to this established clinical principle, there
is substantial evidence to support the use of local anesthetics with
epinephrine in these areas of the body. As long as proper technique
is used, with a small-caliber needle, appropriate anesthetic volume,
and correct epinephrine concentration, there is minimal to no risk of
ischemia or necrosis.3,6 In fact, when compared with lidocaine alone,
lidocaine plus epinephrine 1:100,000 was found to decrease patientexperienced pain significantly 1 hour after injection and increased the
total time of analgesia by 2.2 hours.11 Not only is epinephrine use not
dangerous, but it also can be beneficial as a result of enhanced pain
control, reduced bleeding, and the need for less total anesthesia.12
Wax Moulage
References
1 Firoz B, Davis N, Goldberg LH. Local anesthesia using buffered
0.5% lidocaine with 1:200,000 epinephrine for tumors of the
digits treated with Mohs micrographic surgery. J Am Acad Dermatol. 2009;61:639–643.
2 Denkler K. A comprehensive review of epinephrine in the finger:
to do or not to do. Plast Reconstr Surg. 2001;108:114–124.
3 Waterbrook AL, Germann CA, Southall JC. Is epinephrine harmful when used with anesthetics for digital nerve blocks? Ann
Emerg Med. 2007;50:472–475.
4 Krunic AL, Wang LC, Soltani K, et al. Digital anesthesia with
epinephrine: an old myth revisited. J Am Acad Dermatol.
2004;51:755–759.
5 Thomson CJ, Lalonde DH, Denkler KA, et al. A critical look at the
evidence for and against elective epinephrine use in the finger.
Plast Reconstr Surg. 2007;119:260–266.
6 Wilhelmi BJ, Blackwell SJ, Miller JH, et al. Do not use epinephrine in digital blocks: myth or truth? Plast Reconstr Surg.
2001;107:393–397.
7 Lalonde D, Bell M, Benoit P, et al. A multicenter prospective
study of 3,110 consecutive cases of elective epinephrine use
in the fingers and hand: the Dalhousie Project clinical phase. J
Hand Surg [Am]. 2005;30:1061–1067.
8 Fitzcharles-Bowe C, Denkler K, Lalonde D. Finger injection with
high-dose (1:1,000) epinephrine: Does it cause finger necrosis
and should it be treated? Hand. 2007;2:5–11.
SKINmed. 2011;9:184–185
185
Smallpox, 1921, last epidemic in the town Zurich. Moulage
No 297, made by Lotte Volger in the Dermatology Clinic
in Zurich, 1921. Museum of Wax Moulages Zurich, www.
moulagen.ch
Courtesy of Michael Geiges, MD
May/June 2011
CASE STUDY
Vesna Petronic-Rosic, MD, MSc, Section Editor
Tufted Hair Folliculitis in a Patient
Affected by Pachydermoperiostosis:
Case Report and Videodermoscopic Features
Adone Baroni, MD, PhD; Francesca Romano, MD
A 25-year-old man presented with Touraine-Solente-Golé syndrome (primary pachydermoperiostosis), with an area of inflammatory
dermatosis (12-month evolution) of the scalp at the cranial vertex. The patient presented with arthropathy, clubbing of the digits, diffuse
periostosis, pachydermia of the hands and feet, and periosteal hyperostosis of the knee. Facial seborrhea and sebaceous gland hyperplasia
were evident (Figure 1A and 1B and Figure 2A and 2B). Examination of the scalp revealed an erythematous pruritic plaque with erosions, crusts, and pustules, on which multiple tufts of 10 to 20 normal-looking hairs emerged from single follicular openings (Figure 3A).
Slight pressure on the perifollicular areas resulted in the discharge of purulent material through the dilated follicular openings. Cervical
and occipital lymph nodes were not enlarged, and the patient was in generally good health. Routine laboratory findings were normal.
Immunologic studies, including a screening for antinuclear antibody, complement, and immunoglobulins, were normal. Both potassium
hydroxide staining and fungal culture were negative. Bacteriologic culture of purulent material taken from the affected area was positive
for Staphylococcus aureus. Videodermoscopy of the lesion showed rarefied interfollicular twisted red loops centered around actively affected
follicles and white dots with absence of normal vascular pattern (Figure 3B). These dermoscopy patterns are markers for folliculitis decalvans,
of which tufted hair folliculitis (THF) is a clinical variant.1 Histologic examination showed hair plugging, a dense perifollicular infiltrate of
plasma cells, lymphocytes, neutrophils, and large areas of scarring and fibrosis, which would confirm suspected THF. THF was diagnosed
on the grounds of clinical, microbiologic, histologic, and videodermoscopy data. The patient was treated with amoxicillin 875 mg plus
clavulanic acid 125 mg twice daily and topical nadifloxacin 1% twice daily for 20 days, achieving substantial clinical improvement. One
month after antimicrobial therapy, a single area of cicatricial alopecia with a few hair tufts emerging from single orifices was observed, and
no new lesions or symptoms had appeared.
P
achydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy (PHO), is a rare, genetic disease that affects
both the skin and bones.2 In 1868, Friedreich observed
PHO in two brothers and defined it as “hyperostosis of the entire skeleton.”3 In 1935, PDP was identified by Touraine, Solente,
and Gole as the primary form of hypertrophic osteoarthropathy,
distinct from the more common form, secondary hypertrophic
osteoarthropathy (SHO), which always has an underlying cause
(eg, pulmonary or cardiac disease, occasionally neoplastic).4
PDP predominantly occurs in men (with a male to female ratio of
7:1), who usually show a more severe phenotype.2 Disease onset is
often at puberty, with progressive thickening and furrowing of the
skin on the face and the scalp (pachydermia), enlargement of the
fingertips (digital clubbing), swelling of periarticular tissue, and
shaggy, periosteal, new-bone formation in the long bones (periostosis). The major complication is in the joints, in the form of arthralgia, arthritis, and hydrarthrosis/hemarthrosis. Other cutaneous features include seborrhea, blepharoptosis, acne, hyperhidrosis
of palms and soles, cutis verticis gyrata, erythematous lesions over
the joints, pole-like lower legs, and warmth or burning sensation
in the hands and feet.2 Radiologically, acro-osteolysis, periosteal
changes of the short and flat bones, and ossification of ligaments
and interosseous membranes have also been reported. Additional
features include myelofibrosis and gastrointestinal abnormalities
(ie, peptic ulcer, chronic gastritis, gastric carcinoma, Menetrier’s
disease, and Crohn’s disease). Other findings such as compressive neuropathy, corneal leukoma, hypoplastic internal genitalia,
gynecomastia, and periodontal and alveolar bone abnormalities
have been reported in single patients.2
From the Department of Dermatology, Second University of Naples, Naples, Italy
Address for Correspondence: Adone Baroni, MD, PhD, c/o II Policlinico, Edificio 3, Quarto piano, Via Pansini 5 - 80131 Napoli, Italy •
E-mail: adone.baroni@gmail.com
SKINmed. 2011;9:186–188
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May/June 2011
CASE STUDY
Figure 1. Seborrhea and sebaceous gland hyperplasia of the face (A). Pachydermia of the hands with digital clubbing (B).
Both PHO and SHO share the same poorly understood pathogenesis. A neurologic basis is posited.5 More recently, abnormalities in fibroblast functionality have been implicated, along with
an increase in collagen fiber synthesis.6 The involvement of platelets, with their potent growth factors, has also been suspected.6
In certain cases, alcohol intake aggravates the process. PDP is
diagnosed on the basis of 3 major criteria: pachydermia, periostosis, and digital clubbing. Other minor criteria that assist in the
diagnosis include seborrhea with sebaceous gland hyperplasia,
acne, hyperhidrosis, and cutis verticis gyrata.7
THF is a recurrent and progressive folliculitis of the scalp, developing irregular areas of scarring alopecia with numerous hair
tufts emerging from dilated follicular openings. It is considered
a peculiar form of folliculitis decalvans and is characterized by
multiple hair tufts scattered within the patches of scarring alopecia that give the scalp its typical “dolly hair” appearance.8
THF occurs in adults of both sexes. The etiology remains unclear. Staphylococcus aureus may often breed within the pustules.
The chronic/relapsing course of THF could be the result of an
inadequate immune response to the pathogen “noxa.” In fact, hair
tufting can occur in several inflammatory disorders of the scalp,
such as folliculitis decalvans, acne keloidalis nuchae, dissecting
cellulitis of the scalp, kerion celsi, and follicular lichen planus.9,10
Conclusions
The association of PDP with certain dermatologic disorders, such
as papular mucinosis, atopic dermatitis, acanthosis nigricans,
Figure 2. Pachydermia of the feet with clubbed toes and periosteal hyperostosis of the ankles (A). Periosteal hyperostosis of the knees (B).
SKINmed. 2011;9:186–188
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Tufted Hair Folliculitis
May/June 2011
CASE STUDY
Figure 3. Tufted hair folliculitis. Erythematous plaque with erosions, crusts, and pustules, on which multiple tufts of normal-looking
hairs emerge from single follicular openings (A). Videodermoscopy pattern of folliculitis decalvans: interfollicular twisted red loops
and white dots (B).
vitiligo, pyoderma gangrenosum, squamous cell carcinoma, palmoplantar keratoderma, and cutis verticis gyrata, has already
been reported. PDP associated with folliculitis decalvans, such as
THF in our patient’s case, has never previously been described.
Disclosures: Drs Adone Baroni and Francesca Romano had full access
to all of the data in the study and take responsibility for the reliability of
data and the accuracy of data analysis. Study concept and design: Baroni
and Romano. Acquisition of data: Baroni and Romano. Analysis and
interpretation of data: Baroni and Romano. Drafting of the manuscript:
Baroni and Romano. Critical revision of the manuscript for important
intellectual content: Baroni and Romano. Statistical analysis: None.
Obtained funding: Baroni and Romano. Administrative, technical, and
material support: Baroni and Romano. Study supervision: None
drome). Case report. Actas Dermosifiliogr. 2007;98:116–120.
8 Annessi G. Tufted folliculitis of the scalp: a distinctive clinicohistological variant of folliculitis decalvans. Br J Dermatol.
1998;138:799–805.
9 Pujol RM, Garcia-Patos V, Ravella-Mateu A, et al. Tufted hair folliculitis: a specific disease? Br J Dermatol. 1994;130:259–260.
10 Petronic-Rosic V, Krunic A, Mijuskovic M, et al. Tufted hair folliculitis: a pattern of scarring alopecia? J Am Acad Dermatol.
1999;41:112–114.
VINTAGE LABEL
References
1 Ross EK, Vincenzi C, Tosti A. Videodermoscopy in the evaluation of
hair and scalp disorders. J Am Acad Dermatol. 2006;5:799–806.
2 Castori M, Sinibaldi L, Mingarelli R, et al. Pachydermoperiostosis: an update. Clin Genet. 2005;68:477–486.
3 Friedreich N. Hyperostose des Gesammten Skeletties. Virchow’s
Arch Path Arch Path Anat. 1868;43:83.
4 Touraine A, Solente G, Gole L. Un syndrome ostéodermopathique: la pachydermie plicaturée avec pachypériostose
des extrémités. Presse Med. 1935;43:1820–1824.
5 Sohn SH, Ryu SH, Kwon HC, et al. A case of hypertrophic osteoarthropathy associated with nasopharyngeal carcinoma in a
child. J Korean Med Sci. 2003;18:761–763.
6 Fietta P, Manganelli P. Pachydermoperiostosis and psoriatic
onychopathy: an unusual association. J Eur Acad Dermatol Venereol. 2003;17:73–76.
7 Santos-Durán JC, Yuste-Chaves M, Martínez-González O, SánchezEstella J. Pachydermoperiostosis (Touraine-Solente-Golé syn-
SKINmed. 2011;9:186–188
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Courtesy of BuyEnlarge, Philadelphia, PA
Tufted Hair Folliculitis
2011
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May/June 2011
CASE STUDY
Familial Juvenile Generalized Pustular Psoriasis:
Response to Methotrexate
Taru Garg, MD; Ram Chander, MD; Saurabh Mittal, MD
Two siblings with generalized pustular psoriasis were admitted to the hospital. Case 1: A 7-year-old girl presented with recurrent episodes of
multiple pinhead-sized pustules all over her body since the age of 3. The current episode began a week prior to the onset of the lesions. On
cutaneous examination, she had generalized erythema topped with tiny pustules, scales, and crusting (Figure 1A). A Gram stain performed
from the pustule and cultures taken from the pus and blood were sterile. Histopathology of the pustule was suggestive of pustular psoriasis
(Figure 2). Hemoglobin was 8.8 g%. Other hematologic, microbiologic, and radiologic investigations were normal. Treatment was started
with methotrexate, to which she responded dramatically with reduction in appearance of new lesions, erythema, and scaling. After 4 weeks of
treatment, there was almost 90% clearance of skin lesions. Case 2: A 3-year-old boy, brother of the patient in case 1, presented with similar
complaints for the past week. The episode was preceded by high-grade fever. He had generalized erythema, scaling, and edema and multiple
pinhead-sized pustules, some of which were arranged in an annular configuration (Figure 1B). All investigations, as in case 1, were normal
except for hypocalcemia (Ca2+=8.8 g%) and generalized rarefaction on x-rays of both the ankle joints. Treatment was started with prednisolone
(because of poor general condition) and methotrexate. Following therapy, significant improvement was evident with reduction in erythema
and cessation of appearance of new pustules. The dose of prednisolone was gradually tapered after 3 weeks and then stopped.
P
ustular psoriasis is an uncommon form of psoriasis in
children. Annular pustular psoriasis is the most common
form of pustular psoriasis in children. It has a chronic recurrent course and usually a good prognosis.1 Familial juvenile
generalized pustular psoriasis is extremely rare.2
ably idiopathic or due to sudden withdrawal of potent topical steroids. In the brother, it seems to have been precipitated by hypocalcemia. These children were born as a result of consanguineous
marriage. Apart from these two siblings, family history of chronic
plaque psoriasis was also present in their paternal grandmother.
Our patients had skin lesions characteristic of generalized pustular
psoriasis. The onset of the current episode in the sister was prob-
The options available for the treatment of generalized pustular psoriasis in children are mainly systemic retinoids and methotrexate.
Usually, high doses of retinoids are required to achieve control of the
disease. It may be associated with significant side effects, especially
in children. For this reason, we decided to treat these siblings with
methotrexate, which has been used successfully in the past for the
treatment of juvenile generalized pustular psoriasis.3 Juvenile generalized pustular psoriasis has a better prognosis than generalized pustular psoriasis in adults. The cases highlight one of the rarest entities of
psoriasis, ie, familial juvenile pustular psoriasis (generalized form).4,5
Management of such a condition remains a challenge in children.
The response of our patients to methotrexate further strengthens the
role and safety of methotrexate in childhood psoriasis.
Conclusions
Figure 1. Pustules over an erythematous base in case 1 (A).
Generalized scaling, erythema, and pustulation in case 2 (B).
Retinoids, although the drug of choice for pustular psoriasis, are associated with significant side effects, especially in
From the Department of Dermatology, Lady Hardinge Medical College and Associated Hospitals, Shahid Bhagat, Singh Marg, New Delhi, India
Address for Correspondence: Taru Garg, MD, Lady Hardinge Medical College and Associated Hospitals, Department of Dermatology, Shahid
Bhagat Singh Marg, New Delhi, 110001, India • E-mail: drtarugarg@rediffmail.com
SKINmed. 2011;9:190–191
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CASE STUDY
children, thus limiting their use in children. On the other
hand, methotrexate is a relatively safer option with a more convenient dosing schedule.
Methotrexate can serve as a more cost-effective drug for juvenile
generalized pustular psoriasis vis-à-vis retinoids.
References
1 Liao PB, Rubinson R, Howard R, et al. Annular pustular psoriasis—
most common form of pustular psoriasis in children: report of three
cases and review of the literature. Pediatr Dermatol. 2002;19:19–25.
2 Khan SA, Peterkin GAG, Mitchell PC. Juvenile generalized pustular psoriasis: a report of five cases and a review of the literature.
Arch Dermatol. 1972;105:67–72.
3 Kumar B, Dhar S, Handa S, et al. Methotrexate in childhood
psoriasis. Pediatr Dermatol. 1994;11:271–273.
4 Hubler WR. Familial juvenile generalized pustular psoriasis. Arch
Dermatol. 1984;120:1174–1178.
5 Griffiths CEM, Camp RDR, Barker JNWN. Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology. 7th
ed. Oxford, England: Blackwell Publishing; 2004;35.1–35.69.
Figure 2. Histopathology of the pustular lesion (hematoxylineosin stain, original magnification ×100).
VINTAGE LABEL
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Familial Juvenile Generalized Pustular Psoriasis
May/June 2011
CASE STUDY
Vitiligo and Alopecia Areata Associated With
Subclinical/Clinical Hypothyroidism
The parents of an 18-year-old woman had noticed white hair while combing their daughter’s hair 12 years ago. They found tiny white
spots on her scalp, but she was asymptomatic. The spots have since progressed. Examination of the affected skin on the scalp was marked
by the presence of a chalky/ivory white macule, 8 to 10 cm in diameter, conforming to that of segmental (zosteriformis) vitiligo (Figure
1). The lesions were located on the temporoparietal region of the scalp. The hair over the macules was white (leukotrichia) and dry, coarse,
and brittle. The patient’s nails were thin and dull. Her thyroid profile revealed the following: triiodothyronine, 1.12 nmol/L (0.95–2.5
nmol/L); thyroxine, 69.21 nmol/L (60.0–120.0 nmol/L); and thyroid-stimulating hormone, 6.26 mIU/mL (0.25–5.00 mIU/mL), indicative of primary hypothyroidism. Liver and renal function tests were within normal limits. A lipid profile revealed the following: total
lipids, 503.8 mg% (400–700 mg%); triglycerides, 123.0 mg% (160 mg%); cholesterol, 212.0 mg% (150–250 mg%); high-density
lipoprotein, 43.1 mg% (30–63 mg%); and low-density lipoprotein, 144.3 mg% (50 mg%). Electrocardiographic findings were normal.
History of tiredness, constipation, depression, sensitivity to cold, weight gain, muscle weakness, cramps, and increased menstrual flow
supported the diagnosis. The patient was administered 100 mg of thyroxine once a day along with methoxsalen, the dose of which was
calculated at 0.6 mg/kg to 0.7 mg/kg body weight per day given on alternate days, followed 2 hours later by exposure to UV-A (1 J/cm2)
irradiation (psoralen–UV-A [PUVA]), supplemented by 1 mg of b-methasone, 150 mg of levamisole on 2 consecutive days per week, and
an antioxidant. During the course of 7 weeks, the macules (13 exposures) had become erythematous, with an appearance of perifollicular/
marginal pigmentation. Repeat examination showed a thyroid profile of total triiodothyronine (T3), 127.3 mg/dL (86–186); total thyroxine (T4), 6.54 mg/dL (4.5–12.5 mg/dL); and thyroid-stimulating hormone (TSH), 0.32 mIU/mL (0.3–5.6 mIU/mL), supplemented by
antithyroid microsomal peroxidase antibodies (thyroid microsomal antibody and thyroid peroxidase), 21.9 IU/mL (1–40 IU/mL), and
antithyroglobulin antibodies, 78.1 U/mL (1–100 U/mL). During the patient’s treatment period, 4 other patients with clinical symptoms
and signs of long-standing hypothyroidism developed vitiligo, the duration of which was variable in each patient (Table I). All of the
patients were taking thyroxin. Thyroid and lipid profiles were performed periodically to evaluate the progress (Table I). These patients
were also treated with PUVA therapy and thyroxin. During the course of treatment, 2 of the patients noticed asymptomatic, progressive,
localized, and well-circumscribed hair loss at the temporal region of the scalp that extended to involve the vertex, conforming to findings
of alopecia areata (Figure 2A and Figure 2B).
V
itiligo, an idiopathic depigmentation of the skin, is a wellknown entity that is characterized by chalky/ivory white
macule(s).1 It is of autoimmune origin.2 Its association with
various autoimmune disorders, including alopecia areata and subclinical/clinical hypothyroidism, has been well documented.3–11
Vitiligo is an acquired, idiopathic depigmentation of the skin. The
presentation of vitiligo is often exclusive.1 It may coexist occasionally with other cutaneous and/or systemic disorders2,10 (Table II).
Vitiligo and hypothyroidism may coexist and, therefore, should
be considered in patients with either condition. The current case,
along with the other 4 case reports of vitiligo and hypothyroidism, should focus attention on vitiligo as a skin marker of hypo-
thyroidism. This may also be true in other coexisting disorders.
It is, therefore, useful to measure T3 and T4 values, since they
control metabolism of almost all cells in the body. TSH, on the
other hand, is secreted from the pituitary gland and augments
thyroid gland hormone production. Primary hypothyroidism
is frequently accompanied by depressed T3 and T4 values and
an elevated serum TSH level. Hashimoto’s thyroiditis, a result
of the autoimmune process, may destroy the thyroid gland and
bring about systemic or cutaneous changes. These are imperative to define, along with a history of fatigue, constipation, depression, sensitivity to cold, weight gain, muscle weakness and
cramps, increased menstrual flow (menorrhagia), and increased
risk of miscarriage, as has been illustrated presently.
From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Azadpur, Delhi
Address for Correspondence: Virendra N. Sehgal, MD, Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi
110 033 India • E-mail: drsehgal@ndf.vsnl.net.in
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CASE STUDY
Significant symptoms of vitiligo and hypothyroidism include
dry, coarse, cold, and pale skin; puffy, boggy/edematous discoloration; carotenemia ichthyosis; palmoplantar hyperkeratosis; and capillary fragility. In addition, thin, brittle, striated, and slow-growing onycholysis of the nails are common
findings. Other salient features include dull, coarse, brittle,
and slow-growing hair, with an increase in telogen/resting
hair and madarosis.12
In addition to T3, T4, and TSH values, thyroid microsomal
peroxidase antibodies (thyroid microsomal antibody and thyroid peroxidase) and antithyroglobulin antibodies are important to investigate, despite their speculative significance in the
diagnosis of vitiligo. It may prove useful to unfold hypothyroidism of autoimmune origin, in children and adolescents
in particular.11 Vitiligo and the associated systemic disorder
should be treated simultaneously to ensure positive results.13
Figure 1. Vitiligo subclinical/clinical hypothyroidism: ivory/
chalky white macules and white hair (leukotrichia) located on
the temporoparietal region of the head.
Table I. Vitiligo: A Skin Marker of Clinical/Subclinical Hypothyroidism—Clinical Features
Case No.
Age/Sex
Clinical Variants
Thyroid Profilea
Duration of
Hypothyroidism
Duration of Vitiligo
1
64 y/female
Nonsegmental vitiligo
(acrofacialis)
T3=1.68 (0.6–3.0) ng/mL
T4=14.6 (4.0–12) ng/dL
TSH=0.36 (0.3–6.0) mIU/mL
21 y (since 1984)
1.5 mo after diagnosis of
hypothyroidism
2
37 y/male
(acrofacialis)
T3=2.44 (2.30–4.20) pg/mL
T4=0.73 (0.89–1.80) ng/dL
TSH=39.66 (0.35–5.50) mIU/mL
5 y (since 2000)
3 mo
3
52 y/female
(acrofacialis)
T3=102.0 (86–186) ng/mL
T4=7.9 (4.5–12.5) ng/dL
TSH=5.0 (0.2–5.0) mIU/mL
9 y (since 1996)
38 y (1967)
4
11 y/female
Segmental (zosteriformis)
T3=0.2 (0.2–1.8) ng/mL
T4=1.8 (2–11) ng/dL
TSH=9.3 (0.2–6.30) mIU/mL
5 y (since 2005)
5 y (2005)
Abbreviations: T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. aVariation in values was a result of different techniques used.
Table II. Vitiligo, Alopecia Areata, and Hypothyroidism: Association and Coexisting Disorders
Authors
Year
Cutaneous and/or Systemic Disorders
Chojnacki et al
1973
Vitiligo
Diabetes
Hypothyroidism
Midel et al3
1983
Chronic urticaria
Vitiligo
Thyroiditis
Jaggarao et al5
1989
Vogt-Koyanagi-Harada syndrome
Hypothyroidism
Diabetes mellitus
Madden et al6
1989
IgA nephropathy
Vitiligo
Primary hypothyroidism
Curti et al
1992
Vitiligo
Acropachy
1991
Vitiligo
Autoimmune hypothyroidism
Alopecia universalis
2004
Vitiligo
Morphea
Hashimoto’s thyroiditis
2004
Vitiligo
Hypothyroidism
Diabetes mellitus
4
7
Saban et al
8
Dervis et al
9
Aghaei et al
10
Abbreviation: IgA, immunoglobulin A.
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CASE STUDY
adrenocortical insufficiency. Ir J Med Sci. 1989;158:153–154.
7 Curti LG, Siccardi M, Santianello EB, et al. Full-blown hypothyroidism associated with vitiligo and acropachy. Report of one
case. Thyroidology. 1992;4:111–114.
8 Saban J, Rodriguez-Garcia JL, Gil J, et al. Porphyria cutanea
tarda associated with autoimmune hypothyroidism, vitiligo and
alopecia universalis. Neth J Med. 1991;39:350–352.
9 Dervis E, Acbay O, Barut G, et al. Association of vitiligo, morphea,
and Hashimoto’s thyroiditis. Int J Dermatol. 2004;43:236–237.
10 Aghaei S, Salmanpour R, Handjani F, et al. Ulcerated disseminated cutaneous leishmaniasis associated with vitiligo, hypothyroidism, and diabetes mellitus in a patient with Down syndrome.
Dermatol Online J. 2004;10:21.
11 Kurtev A, Dourmishev AL. Thyroid function and autoimmunity
in children and adolescents with vitiligo. J Eur Acad Dermatol
Venereol. 2004;18:109–111.
12 Heymann WR. Cutaneous manifestations of thyroid disease. J
Am Acad Dermatol. 1992;26:885–902.
13 Sehgal VN, Srivastava G. Vitiligo treatment options: an evolving
scenario. J Dermatolog Treat. 2006;17:262–275.
14 Sehgal VN, Jain S. Alopecia areata: clinical perspective and an
insight into pathogenesis. J Dermatol. 2003;30:271–289.
VINTAGE LABEL
Figure 2. Vitiligo, alopecia areata, and subclinical/clinical
hypothyroidism, depicting segmental vitiligo (zosteriformis) of
the neck (A), and alopecia areata affecting the temporoparietal
region of the scalp (B).
Conclusions
Occurrence of alopecia areata is an additional association, a few
reports of which are found in the literature.2,8,14
References
1 Sehgal VN, Srivastava G. Vitiligo: compendium of clinicoepidemiological features. Indian J Dermatol Venereol Leprol.
2007;73:149–156.
2 Sehgal VN, Srivastava G. Vitiligo: auto-immunity and immune responses. Int J Dermatol. 2006;45:583–590.
3 Midel Art K, Moseng D, Kavli G, et al. A case of chronic urticaria
and vitiligo associated with thyroiditis treated with PUVA. Dermtologica. 1983;167:39–41.
4 Chojnacki J, Zydowicz L, Adamiak T. Addison-Biermer disease
associated with vitiligo, diabetes and hypothyroidism. Pol Tyg
Lek. 1973;28:1817–1818.
5 Jaggarao N, Voth D, Jacobsen J. The Vogt-Koyanagi-Harada syndrome: association with hypothyroidism and diabetes mellitus.
Postgrad Med J. 1989;65:587–588.
6 Madden BP, Walker F, Gaffney E, et al. A case of IgA nephropathy associated with vitiligo, primary hypothyroidism and primary
SKINmed. 2011;9:192–194
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May/June 2011
CASE STUDY
An Unusual Cutaneous Manifestation of
Crohn’s Disease
Jessica A. Weiser, MD;1 David M. Markowitz, MD;2 Sameera Husain, MD;1,3 Marc E. Grossman, MD1,4
A 61-year-old man with a 12-year history of quiescent Crohn’s disease on mesalamine presented to his gastroenterologist in April 2009, complaining of abdominal cramping, diarrhea, and a 25-lb weight loss over 6 weeks. He did not respond to prednisone 50 mg and 6-mercaptopurine 100
mg daily. Abdominal computed tomography findings revealed diffuse submucosal edema consistent with extensive colitis. Colonoscopy demonstrated diffuse inflammation with erythema, friability, and shallow ulcerations in the rectum and colon. Biopsies were consistent with Crohn’s
colitis. He was admitted for infliximab infusion for his unremitting diarrhea. Five days before admission, the patient noted mild swelling and
redness of the left lower eyelid, which progressed to involve the right lower eyelid with frank pus draining from both eyes. He had no visual impairment or eye pain. Two days before admission, an ophthalmologist prescribed a steroid eyedrop with no relief. He also complained of seropurulent
painful skin lesions on his face and scalp, which spread to involve his upper trunk and proximal arms. On admission to the hospital, dermatology,
ophthalmology, and infectious disease consultations were obtained to rule out disseminated infection before initiation of infliximab therapy. The
patient was afebrile and hemodynamically stable. His oral mucosa was normal. He had prominent bilateral lower eyelid edema, erythema, and
superficial erosions with hemorrhagic crusting and frank green purulent drainage from both eyes, with crusting along the lower lash line and bilateral sclera injection (Figure 1). On his scalp, face, trunk, and proximal extremities, he had 25 to 30 erythematous, 4- to 8-mm papulopustules
with narrow red halos, some with central necrosis and crusting (Figure 2). Cultures from the purulent ocular drainage and pustules on the trunk
and arms were all negative for bacteria, virus, and fungi. Gram stain from the eye drainage showed polymorphonuclear leukocytes without organisms. Tissue cultures were negative for bacterial, fungal, and mycobacterial infection. Skin biopsy taken from the central upper back demonstrated
subcorneal pustules with areas of eroded epidermis and collections of neutrophils in the superficial dermis (Figure 3). Special stains were negative
for organisms. He received infliximab infusion 5 mg/kg for a total dose of 420 mg over 2 hours. Within 48 hours of infusion, there was notable
decrease in size of lesions, in addition to reduction of purulent drainage from both eyes. The patient was discharged home following infliximab
infusion. His skin lesions resolved during a period of 2 weeks, leaving small pink atrophic scars. He received his second infusion of infliximab 2
weeks after discharge with continued improvement in his gastrointestinal symptoms.
S
Figure 1. Ocular examination demonstrating prominent bilateral lower eyelid edema, erythema, and superficial erosions
with frank green purulent drainage from both eyes and crusting along the lower lash line.
terile pustular eruptions have been reported with ulcerative colitis (UC) but rarely with Crohn’s disease.1–4 In 1978, investigators described a diffuse pustular eruption with UC as “an unusual variant of pyoderma gangrenosum” (PG).5 This impression has
persisted, perhaps incorrectly. The term pustular PG has been used to
describe one of the 4 classic clinical variants of PG, the other 3 include
ulcerative, bullous, and vegetative.6 Pustular PG is at best a forme
fruste or an abortive form of PG.7 The confusion may occur because
of the pustules that develop in the evolution of the classic Brunsting
type of PG.7 Classic or ulcerative PG starts as a tender red nodule that
becomes pustular, then dusky and necrotic, and finally produces an
enlarging ulceration with violaceous undermined borders.8 The pustular subtype does not ulcerate, undermine, or rapidly expand.
The pustular eruption associated with our patient’s Crohn’s
disease flare was characterized by a sudden onset of pustules
From the Departments of Dermatology1 and Gastroenterology,2 Division of Dermatopathology,3 and Dermatology Consultation Service,4
Columbia Presbyterian Medical Center, New York, NY
Address for Correspondence: Jessica A. Weiser, MD, 161 Fort Washington Avenue, New York, NY 10032 • E-mail: jw2690@columbia.edu
SKINmed. 2011;9:196–198
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May/June 2011
CASE STUDY
in association with acute colitis, which were sterile and larger
than the usual pinhead-sized pustules of bacterial folliculitis.
The lesions occurred predominantly on the face, eyelid margins,
and scalp, and did not break down or ulcerate like pyoderma
gangrenosum. Although our patient complained of associated
pain, there was no pathergy, and the lesions resolved rapidly
with treatment of his Crohn’s disease. The differential diagnosis
considered was broad; however, all other entities were carefully
excluded through examination and systemic evaluation.
Drug eruption was readily excluded as our patient was not taking
any systemic medications at the time of onset except for prednisone. The distribution of his lesions was not consistent with pustular bacterid of Andrews, which is primarily palmoplantar, nor
did he have a primary bacterial infection that could account for a
bacterid. All wound and blood cultures were negative for herpes
simplex and varicella zoster viruses, in addition to bacterial, fungal, and mycobacterial infections. Behçet’s syndrome classically
manifests with oral and genital ulcerations and pathergy, whereas
reactive arthritis manifests with uveitis, arthritis, and urethritis.
Our patient did not have any of these features during evaluation.
His cutaneous eruption may be considered a distinct clinical entity or can be alternatively thought of as an example of pustular
PG, as it has been described in the past.
The histopathologic features of the pustular eruption of Crohn’s
disease are not diagnostic.
Nonetheless, a skin biopsy is necessary to exclude other infectious and noninfectious causes. Skin biopsy demonstrates subcorneal and dermal neutrophilic infiltration with subepidermal
edema that indicate a range of changes within the same disease,
reflecting the timing of the biopsy in disease evolution.1
Conclusions
The diagnosis of pustular eruption of Crohn’s disease is difficult to
prove, as is pustular PG, because of the lack of specificity of the
cutaneous clinical and histopathologic signs. Exclusion of the fundamental pustular eruptions leaves a clinical scenario in which the
physician can be comfortable diagnosing and treating the acutely febrile patient with bloody diarrhea and pustules for Crohn’s disease.
References
1 Chia MW, Teo L, Tay YK, Poh WT. Pustular pyoderma gangrenosum: an uncommon variant which is easily misdiagnosed. Dermatol Online J. 2008;14:21.
2 Lazarov A, Amichai B, Halevy S. Pustular vasculitis and superficial bullous pyoderma gangrenosum in a patient with ulcerative
colitis. Cutis. 1995;56:297–300.
3 Havemann BD. A pustular skin rash in a woman with 2 weeks of
diarrhea. MedGenMed. 2005;7:11.
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Figure 2.The back of our patient revealing scattered erythematous papulopustules (A). Single 8-mm papulopustule with a
rim of erythema and central necrosis and early ulceration (B).
4 Shankar S, Sterling JC, Rytina E. Pustular pyoderma gangrenosum. Clin Exp Dermatol. 2003;28:600–603.
5 O’Loughlin S, Perry HO. A diffuse pustular eruption associated
with ulcerative colitis. Arch Dermatol. 1978;114:1061–1062.
6 Powell FC, Si D, Perry HO. Pyoderma gangrenosum: classification
Cutaneous Manifestation of Crohn’s Disease
May/June 2011
CASE STUDY
Figure 3. Skin biopsy from a papulopustule on the central upper back showing a subcorneal pustule with areas of eroded epidermis (hematoxylin-eosin stain, original magnification ×4) and dermal infiltration (A). Dermal infiltrate consisting predominantly of
neutrophils (hematoxylin-eosin stain, original magnification ×20) (B).
and management. J Am Acad Dermatol. 1996;34:395–409.
occurring in adults. Arch Dermatol. 1930;22:655–680.
7 Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma gangrenosum: clinical and experimental observations in five cases
8 Basler RSW, Dubin HV. Ulcerative colitis and the skin. Arch Dermatol. 1976;112:531–534.
VINTAGE LABEL
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Cutaneous Manifestation of Crohn’s Disease
May/June 2011
CASE STUDY
Cutaneous Manifestations of Strongyloides stercoralis
Hyperinfection in an HIV-Seropositive Patient
Stephanie J. Martin, BA;1 Philip R. Cohen, MD;2,3,4 Deborah F. MacFarlane, MD, MPH;2,3 Marc E. Grossman, MD5
A 41-year-old human immunodeficiency virus (HIV)–positive man was hospitalized with complaints of a 4-week history of nausea and
vomiting, associated with decreased oral intake, and a 4-day history of frontal headache and fever. His medical history was significant for a
gunshot wound to the head 3 years prior, with a residual seizure disorder. He also had two previous hospitalizations, both for culture-negative bacterial meningitis; the first episode occurred 12 months before admission and the second episode occurred 5 months later. At that
time, he was found to be positive for serum antibodies against HIV and a CD4+ T-lymphocyte count of 126/mm3. He had no known drug
allergies and was not receiving any medication. On admission, the patient was febrile (104.0°F) and hypotensive (blood pressure, 92/40
mm Hg). Pertinent physical examination findings included cachexia with bitemporal wasting, dry mucus membranes, adherent white
patches on the oral mucosa, and negative Kernig’s and Brudzinski’s signs. His laboratory results revealed macrocytic anemia, a decreased
serum sodium of 125 mEq/L, and a normal total leukocyte count with a CD4+ T-lymphocyte count <50/mm3. Lumbar puncture opening
pressure was elevated at 160 mm Hg, and cerebrospinal fluid analysis showed an increased white cell count of 97/mL (84% lymphocytes),
a decreased glucose level of 26 mg/dL, and a decreased protein level of 42 mg/dL. The patient was started on empiric therapy that included
intravenous ampicillin and cefotaxime, oral Bactrim, and clotrimazole lozenges for thrush. Cerebrospinal fluid culture was positive for
Escherichia coli, sensitive to cefotaxime. Two days later, the patient developed fine, erythematous, nonblanchable macules primarily on his
abdomen, with minimal involvement of his thorax and back. His skin lesions remained unchanged for the next 2 weeks. Repeat lumbar
puncture was performed after 14 days of cefotaxime. The cerebrospinal fluid analysis showed an elevated white cell count of 7/mL (100%
lymphocytes), a decreased glucose level of 53 mg/dL, and a decreased protein level of 33 mg/dL. The cerebrospinal fluid culture was now
positive for Pseudomonas aeruginosa resistant to cefotaxime. The patient was started on imipenem. On day 34 of his admission, the patient
became tachypneic with complaints of dyspnea. A chest roentgenogram revealed bilateral patchy infiltrates. He was transferred to the
intensive care unit and intubated for hypoxemic respiratory failure (arterial blood gas values on 6 L of oxygen: pH, 7.46; bicarbonate, 23;
and oxygen saturation, 37). That evening, the patient was also noted to have diffuse petechiae and purpura in a reticulated pattern over
his abdomen (Figure 1A and 1B), most heavily concentrated in the periumbilical region, extending to the axillae and upper thighs. A
3×3-mm punch biopsy from abdominal skin demonstrated Strongyloides stercoralis larvae in the dermis (Figure 2A and 2B). His sputum
specimen was teeming with adult S stercoralis worms (Figure 3) and, subsequently, numerous S stercoralis larvae were observed not only
from the bronchoalveolar lavage but also from the nasogastric fluid specimen. These findings confirmed the diagnosis of disseminated
strongyloidiasis. On hospital day 35, the patient was doing poorly and was started on thiabendazole (1250 mg twice daily for 28 days).
Nine days later, ivermectin (4.5 mg once daily for 3 days for 2 courses) was also added. He continued to clinically deteriorate. The patient
died 31 days after systemic antihelminthic treatment was initiated.
S
trongyloides stercoralis is an intestinal nematode commonly known as the human threadworm that infects
millions of people worldwide.1 It is endemic to tropical
and subtropical areas of the world, including the southeastern
United States.1,2 The unique life cycle of S stercoralis can result
in cutaneous, gastrointestinal, and pulmonary manifestations in
humans.1 Disseminated strongyloidiasis, also known as hyperinfective strongyloidiasis, develops most commonly in patients
with suppressed immunity, including infection, such as HIV or
tuberculosis; iatrogenic, such as long-term corticosteroid therapy
or patients undergoing chemotherapy; or malignancy, such as
leukemia or lymphoma.3–6
Human infection occurs when the infective larvae penetrate the
skin, enter the bloodstream, and travel to the alveoli of the lungs.
From the lungs, the larvae ascend the tracheobronchial tree, are
From the University of Texas Medical School at Houston, Houston, TX;1 the Department of Dermatology, University of Texas MD Anderson
Cancer Center, Houston, TX;2 the Department of Dermatology, University of Texas Medical School at Houston, Houston, TX;3 the University
of Houston Health Center, University of Houston, Houston, TX;4 and the Department of Dermatology, Dermatology Consultation Service,
College of Physicians and Surgeons of Columbia University, New York Presbyterian Hospital, New York, NY5
Address for Correspondence: Philip R. Cohen, MD, 805 Anderson Street, Bellaire, TX 77401-2806 • E-mail: mitehead@aol.com
SKINmed. 2011;9:199–202
199
May/June 2011
CASE STUDY
The term larva currens was initially coined in 1958 to describe
the swift migration of S stercoralis larvae within the skin.13 The
cutaneous finding is commonly described as a pruritic, erythematous, serpiginous, or linear lesion. It is due to an allergic reaction to the filariform larvae that travel in the skin, producing serpiginous urticaria.15 These lesions are most commonly identified
over the buttocks, proximal thigh region, and lower abdomen
due to the perianal source of autoinfection. The rate of migration has been cited to be 5 to 15 cm/h.13,15 Nondisseminated S
stercoralis infection can also present as chronic urticaria.12,13
Cutaneous manifestations of the disseminated helminthic disease have been described as rapidly progressing petechia and
purpura. Skin lesions most commonly involve the abdomen but
can also occur on the thorax and proximal extremities.13 Massive
numbers of larvae migrate through the intestinal mucosa to disseminate throughout the body.
Figure 1. Distant (A) and closer (B) views of nonpalpable
purpura with extensive involvement of the abdomen in an immunocompromised patient with disseminated strongyloidiasis.
swallowed by the human host, and subsequently localize to the
favored habitat of the small bowel.7 The female nematode produces larvae that are either (1) excreted in the stool of the host
or (2) penetrate the intestinal mucosa or perianal area, resulting
in autoinfection.8 This cycle of autoinfection allows persistence of
the parasite for decades without additional exposure of the host
to exogenous infective larvae.1 Even with chronic infection, however, healthy individuals are usually asymptomatic.9 It is when the
parasite is coupled with a defective cell-mediated immunity that
disseminated disease, or hyperinfection syndrome, can occur.10,11
Disseminated strongyloidiasis is associated most commonly with
severe infection (pneumonia, meningitis, bacteremia) with enteric
organisms from a suspected intra-abdominal source. S stercoralis hyperinfection has also been observed in patients with dermatologic
conditions associated with immunodeficiency such as bullous pemphigoid, pemphigus vulgaris, and systemic lupus erythematosus.12,13
The primary cutaneous manifestations of the parasitic infection
include larva currens and disseminated S stercoralis (Table).2,13–17
SKINmed. 2011;9:199–202
The vascular distribution of the S stercoralis lesions observed in
disseminated disease resembles the clinical picture of caput medusae of chronic liver disease in patients who have portal hypertension. In the setting of portal hypertension, increased portal
pressure results in retrograde flow through the periumbilical
portal systemic anastomoses.18 Our patient was placed on mechanical ventilation before the development of the periumbilical
purpura. As described previously,14 it is thought that there is a
rise in portal pressure secondary to the positive-pressure ventilation. This increase in portal pressure shunts blood, carrying
numerous S stercoralis larvae, through the periumbilical portal
systemic anastomoses. When the larvae reach the dermal vasculature, extravasation of red blood cells occurs, resulting in periumbilical purpura that resembles multiple thumbprints, commonly referred to as the thumbprint sign.4,13,14
The mortality associated with disseminated S stercoralis has been
reported as high as 77% to 85% worldwide, but, in recent years,
endemic areas of the United States have a 31% mortality rate.2,16
A better prognosis is associated with early detection of the parasitic infection and prompt initiation of anthelminthic medication.8 In patients with a negative stool culture, anti-strongyloides immunoglobulin G enzyme immunoassay can be valuable
for early diagnosis of strongyloidiasis. With a sensitivity and
specificity >90%, the rapid test can readily identify the parasitic
infection early in the course of the disease in patients at risk for
disseminated disease.19
Treatment for strongyloidiasis includes the anthelminthic drugs
ivermectin, thiabendazole, and albendazole. Strongyloidiasis
treatment in immunocompetent patients consists of either ivermectin 200 mg/kg orally for 1 day, thiabendazole 25 mg/kg orally
twice a day for 3 days, or albendazole 400 mg orally twice a day
200
Strongyloides stercoralis Hyperinfection
May/June 2011
CASE STUDY
for 3 days.2,8 Ivermectin is considered first-line therapy due to
better tolerance and decreased hepatotoxicity.17 Disseminated S
stercoralis requires multiple-dose treatments for an extended period, usually lasting several weeks until all specimens (nasogastric
aspirates, pulmonary secretions, or stool) are free of nematode.16
Conclusions
The population of immunocompromised patients is increasing with the progressively higher prevalence of HIV infection,
increased organ transplants, and the extensive use of corticosteroids, immunomodulators, and cancer chemotherapy.19,20
Clinicians should maintain a high index of suspicion for strongyloidiasis when an immunocompromised patient presents with
a serious infection caused by enteric organisms and nonspecific
abdominal or pulmonary symptoms.1,2 In the setting of immunosuppression, periumbilical purpura (the thumbprint sign) is
considered diagnostic of disseminated S stercoralis.4,13,14
References
1 Kalb RE, Grossman ME. Periumbilical purpura in disseminated
strongyloidiasis. JAMA. 1986;256:1170–1171.
2 Basile A, Simzar S, Bentow J, et al. Disseminated Strongyloides
stercoralis: hyperinfection during medical immunosuppression.
J Am Acad Dermatol. 2010;63:896–902.
3 Salluh JI, Bozza FA, Pinto TS, et al. Cutaneous periumbilical
purpura in disseminated strongyloidiasis in cancer patients: a
pathognomonic feature of potentially lethal disease? Braz J Infect Dis. 2005;9:419–424.
4 Weiser JA, Scully BE, Bulman WA, Husain S, Grossman ME. Periumbilical parasitic thumbprint purpura: strongyloides hyperinfection
syndrome acquired from a cadaveric renal transplant. Transpl Infect Dis. 2010 May 26. doi 10.1111/j.1399-3062.2010.00516.x.
Figure 2. Longitudinal (A) and cross-sectional (B) views of
Strongyloides stercoralis larvae in the dermis (hematoxylin-eosin
stain, original magnification ×1000 [A] and ×1000 [B]).
5 Patel G, Arvelakis A, Sauter BV, et al. Strongyloides hyperinfection syndrome after intestinal transplantation. Transpl Infect Dis.
2008;10:137–141.
6 Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev. 2004;17:208–217.
7 Reddy TS, Myers JW. Syndrome of inappropriate secretion
of antidiuretic hormone and nonpalpable purpura in a woman
with Strongyloides stercoralis hyperinfection. Am J Med Sci.
2003;325:288–291.
8 Greiner K, Bettencourt J, Semolic C. Strongyloidiasis: a review
and update by case example. Clin Lab Sci. 2008;21:82–88.
9 Concha R, Harrington W, Rogers A. Intestinal strongyloidiasis:
recognition, management, and determinants of outcomes. J
Clin Gastroenterol. 2005;39:203–211.
10 Chaudhary K, Smith RJ, Himelright IM, et al. Case report:
purpura in disseminated strongyloidiasis. Am J Med Sci.
1994;308:186–191.
11 Simpson WG, Gerhardstein DC, Thompson JR. Disseminated Strongyloides stercoralis infection. South Med J. 1993;86:821–825.
12 Jacob CI, Patten SF. Strongyloides stercoralis infection presenting as generalized prurigo nodularis and lichen simplex chroni-
SKINmed. 2011;9:199–202
201
Figure 3. Adult Strongyloides stercoralis worm isolated from
sputum.
cus. J Am Acad Dermatol. 1999;41:357–361.
13 Von Kuster LC, Genta RM. Cutaneous manifestations of strongyloidiasis. Arch Dermatol. 1988;124:1826–1830.
14 Bank DE, Grossman ME, Kohn SR, et al. The thumbprint sign:
May/June 2011
CASE STUDY
Table. Cutaneous Manifestations of Strongyloides stercoralis
Manifestation
Larva Currens
Disseminated S stercoralis
Associated disease2
None
Immunocompromised
Location13,15
Buttocks, proximal thigh region, and lower abdomen
Abdomen primarily, with extension to
thorax and proximal extremities
Morphology15
Pruritic, erythematous, and serpiginous or linear urticarial lesion
Rapidly progressing periumbilical
petechia and purpuraa
Pathology13,15
Allergic reaction from S stercoralis larvae migration; larvae
often missed on biopsy
S stercoralis larvae readily identifiable in
a dermal biopsy
Treatment2,16
Ivermectinb 200 mg/kg PO for 1 dose, thiabendazole 25
mg/kg PO BID for 3 d, or albendazole 400 mg PO BID
for 3 d
Multiple-dose treatment for an extended periodc
Abbreviations: BID, twice daily; PO, orally. aCommonly referred to as the thumbprint sign.4,13,14. bConsidered first-line therapy due to better
tolerance and decreased hepatotoxicity.17 cIvermectin 200 mg/kg PO for 1 dose per day for 1 to 3 days, may repeat treatment weekly for 2 total
courses; thiabendazole 25 mg/kg PO BID or albendazole 400 mg PO BID for 2 to 4 weeks.2,16
rapid diagnosis of disseminated strongyloidiasis. J Am Acad
Dermatol. 1990;23:324–326.
15 Smith JD, Goette DK, Odom RB. Larva currens. Cutaneous
strongyloidiasis. Arch Dermatol. 1976;112:1161–1163.
16 Lam CS, Tong MK, Chan KM, et al. Disseminated strongyloidiasis: a retrospective study of clinical course and outcome. Eur J
Clin Microbiol Infect Dis. 2006;25:14–18.
17 Segarra-Newnham M. Manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. Ann Pharmacother.
2007;41:1992–2001.
18 Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an
overview. Pharmacol Ther. 2001;89:221–231.
19 Bon B, Houze S, Talabani H, et al. Evaluation of a rapid enzymelinked immunosorbent assay for diagnosis of strongyloidiasis. J
Clin Microbiol. 2010;48:1716–1719.
20 Grossman ME, Roth J. Cutaneous Signs of Infection in the Immunocompromised Host. Philadelphia, PA: Lippincott Williams
and Wilkins; 1995:143–147.
VINTAGE LABEL
SKINmed. 2011;9:199–202
202
Locoid Lipocream® Cream, 0.1%
(hydrocortisone butyrate 0.1% cream)
For Topical Use Only
Rx Only
BRIEF SUMMARY
Locoid Lipocream is a topical corticosteroid indicated for: relief of the inflammatory
and pruritic manifestations of corticosteroid-responsive dermatoses in adults and
the treatment of mild to moderate atopic dermatitis in patients 3 months to 18 years
of age.
Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with
the potential for glucocorticosteroid insufficiency. Consider periodic evaluations for
HPA axis suppression if Locoid Lipocream is applied to large surface areas or used
under occlusion. If HPA axis suppression is noted, reduce the application frequency,
discontinue use, or switch to a lower potency corticosteroid.
Systemic effects of topical corticosteroids may also include manifestations of
Cushing’s syndrome, hyperglycemia, and glucosuria.
Pediatric patients may be more susceptible to systemic toxicity due to their larger
skin surface-to-body-mass ratios.
Initiate appropriate therapy if concomitant skin infections develop.
Discontinue use if irritation develops.
ADVERSE REACTIONS
The most common adverse reactions (>1%) are HPA axis suppression and
application site reactions.
The following additional local adverse reactions have been reported infrequently
with topical corticosteroids, and they may occur more frequently with the use of
occlusive dressings and higher potency corticosteroids. These reactions included:
irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis,
allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and
telangiectasia.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Corticosteroids have been shown to be teratogenic in
laboratory animals when administered systemically at relatively low dosage levels.
Some corticosteroids have been shown to be teratogenic after dermal application
in laboratory animals.There are no adequate and well-controlled studies in
pregnant women. Therefore, Locoid Lipocream should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Please refer to full prescribing information for detailed information regarding
systemic embryofetal development studies.
Nursing Mothers
Systemically administered corticosteroids appear in human milk and could
suppress growth, interfere with endogenous corticosteroid production, or cause
other untoward effects. It is not known whether topical administration of
corticosteroids could result in sufficient systemic absorption to produce detectable
quantities in human milk. Because many drugs are excreted in human milk, caution
should be exercised when Locoid Lipocream is administered to a nursing woman.
Pediatric Use
Safety and efficacy in pediatric patients below 3 months of age have not been
established.
Because of higher skin surface-to-body-mass ratios, pediatric patients are at a
greater risk than adults of HPA axis suppression when they are treated with topical
corticosteroids. They are therefore also at a greater risk of glucocorticosteroid
insufficiency after withdrawal of treatment and of Cushing’s syndrome while on
treatment.
Eighty-six (86) pediatric subjects (5 months to less than 18 years of age) with
moderate to severe atopic dermatitis affecting at least 25% of body surface area
(BSA) treated with Locoid Lipocream three times daily for up to 4 weeks were
assessed for HPA axis suppression. The disease severity (moderate to severe
atopic dermatitis) and the dosing regimen (three times daily) in this HPA axis study
were different from the subject population (mild to moderate atopic dermatitis) and
the dosing regimen (two times daily) for which Locoid Lipocream is indicated.
Five of the 82 evaluable subjects (6.1%) demonstrated laboratory evidence of
suppression, where the sole criterion for defining HPA axis suppression was a
serum cortisol level of less than or equal to 18 micrograms per deciliter after
cosyntropin stimulation. Suppressed subjects ranged in age from 5 months to
16 years and, at the time of enrollment, had 25% to 95% BSA involvement. These
subjects did not develop any other signs or symptoms of HPA axis suppression.
At the first follow up visit, approximately one month after the conclusion of
treatment, cosyntropin stimulation results of all subjects had returned to normal,
with the exception of one subject. This last subject recovered adrenal function by
the second post treatment visit, 65 days post-treatment.
Cushing’s syndrome, linear growth retardation, delayed weight gain, and
intracranial hypertension have also been reported in pediatric patients receiving
topical corticosteroids. Manifestations of adrenal suppression in pediatric patients
include low plasma cortisol levels to an absence of response to ACTH stimulation.
Manifestations of intracranial hypertension include bulging fontanelles, headaches,
and bilateral papilledema.
Geriatric Use
Clinical studies of Locoid Lipocream did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects.
No studies were conducted to determine the photococarcinogenic or dermal
carcinogenic potential of Locoid Lipocream.
Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic
potential based on the results of two in vitro genotoxicity tests (Ames test and
L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse
micronucleus assay).
No evidence of impairment of fertility or effect on mating performance was
observed in a fertility and general reproductive performance study conducted in
male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day
(0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals,
such as reduced food consumption and a subsequent reduction in body weight gain,
were seen at doses ≥0.6 mg/kg/day (0.2X MTHD).
Patients using Locoid Lipocream should receive the following information
and instructions:
Apply a thin layer to the affected skin two or three times daily for corticosteroidresponsive dermatoses in adults. Consult with your physician to determine if
treatment is needed beyond 2 weeks. Apply a thin film to the affected skin areas
two times daily for atopic dermatitis in patients 3 months of age and older.
Safety of Locoid Lipocream in pediatric patients has not been established beyond 4
weeks of use.
Rub in gently.
Avoid contact with the eyes.
Do not bandage, otherwise cover, or wrap the affected skin area so as to be
occlusive unless directed by your physician.
Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants may
constitute occlusive dressings.
Do not use Locoid Lipocream on the face, underarms, or groin areas unless
directed by your physician.
If no improvement is seen within 2 weeks, contact your physician.
Do not use other corticosteroid-containing products while using Locoid Lipocream
without first consulting your physician.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature]. Protect from freezing. Keep out of the reach of children.
Manufactured for: Triax Pharmaceuticals, LLC
Cranford NJ 07016
By: Ferndale Laboratories, Inc.
Ferndale MI 48220
Locoid Lipocream is a registered trademark of
Astellas Pharma Europe BV licensed to
Triax Pharmaceuticals, LLC.
Marketed and Distributed By:
Triax Pharmaceuticals, LLC
Cranford NJ 07016
www.Locoid.com
131B301
Rev 11/09
Now younger eczema
patients have something
to smile about
Now approved for use in children
down to 3 months of age
The power of an ointment with the elegance of a cream
Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses,
including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older.
Safety and effectiveness in pediatric patients below 3 months of age have not been established.
Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA
axis suppression if applied to large surface areas or used under occlusion. Systemic effects of topical corticosteroids may also include
manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity
due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use
if irritation develops. Please see full Prescribing Information on adjacent page.
Visit us at www.locoid.com
(hydrocortisone butyrate 0.1%) Cream
©2010 Triax Pharmaceuticals, LLC. All rights reserved. Locoid is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC. LOC-0410-01

May / June, 2011 - SKINmed Journal

Transcription

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