January/February 2011 Volume 9 Issue 1

EDITORIAL DEPARTMENTS
Bed Bugs Revisited New Therapy Update
Lavery and Parish Veltin Gel
(Clindamycin Phosphate 1.2% and Tretinoin 0.025%)
Abramovits, Oquendo, and Gupta
ORIGINAL CONTRIBUTIONS
High Frequency of Psoriasis in Relatives
Perils of Dermatopathology
in a Turkish Multiple Sclerosis Cohort
Why Immunofluorescence?
Dogan, Atakan, Kurne, and Karabudak
Husain, Rojas, Maghari, and Lambert

Advances in Topical Delivery Systems in Acne:

Congress Report
New Solutions to Address Concentration
Scratching the Surface:
Dependent Irritation and Dryness
The History of Skin, Its Diseases and Their Treatment
Ceilley
History of Medicine Unit, University of Birmingham,
October 2930, 2010 [Parallel Publication]
REVIEWS Wynter
The Tzanck Smear Test:
Rediscovery of a Practical Diagnostic Tool CASE STUDIES
Durdu, Sekin, and Baba
Longitudinal Erythronychia:
The Value of Cosmetic Alterations in Nail Findings
Fatigue in Psoriasis With Arthritis
Rashid, Torres-Cabala, and Chon
Carneiro, Chaves, Verardino, Drummond, Ramos-e-Silva, and Carneiro
A Case of Cinderella:
CORE CURRICULUM Erythema Dyschromicum Perstans
Nail Biology, Morphologic Changes, (Ashy Dermatosis or Dermatosis Cinecienta)
and Clinical Ramifications: Muoz and Chang
Part I
Sehgal, Aggarwal, Srivastava, and Chatterjee Bullous-Hemorrhagic Darier Disease
Snchez-Salas, Aranibar, Torres, and Grasa

BOOK REVIEW
Dermatologic Complications With Body Art:
Tattoos, Piercings, and Permanent Make-Up
Reviewed by Parish
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Differin Lotion, 0.1% is indicated for the topical treatment of acne vulgaris in patients 12 years and older. A thin film of
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INDICATIONS AND USAGE
DIFFERIN Lotion is a retinoid product indicated for the topical treatment of
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CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight
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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
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depilation should not be performed on treated skin.
Pregnancy
Pregnancy Category C. There are no well-controlled trials in pregnant women
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Human Data
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Animal Data
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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
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Nursing Mothers
It is not known whether adapalene is excreted in human milk following
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Pediatric Use
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Geriatric Use
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Carcinogenesis, Mutagenesis, Impairment of Fertility
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In the rat study, an increased incidence of benign and malignant
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of pharmacologically similar drugs (e.g. retinoids) when exposed to UV
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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
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PATIENT COUNSELING INFORMATION
Apply a thin film of DIFFERIN Lotion to the affected areas of the skin once
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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
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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.
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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
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Wax depilation should not be performed on treated skin due to the
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This product is for external use only.
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 TABLE OF CONTENTS
January/February 2011 Volume 9 Issue 1

EDITORIAL

Bed Bugs Revisited.......................................................................................................................................... 6

Michael Joseph Lavery; Lawrence Charles Parish, MD, MD (Hon)

ORIGINAL CONTRIBUTIONs

High Frequency of Psoriasis in Relatives in a Turkish Multiple Sclerosis Cohort................................................ 11

Sibel Dogan, MD; Nilgn Atakan, MD; Asli Kurne, MD; Rana Karabudak, MD

Advances in Topical Delivery Systems in Acne:

New Solutions to Address Concentration Dependent Irritation and Dryness ..................................................... 15
Roger I. Ceilley, MD

REVIEWs

The Tzanck Smear Test: Rediscovery of a Practical Diagnostic Tool................................................................. 23

Murat Durdu, MD; Deniz Sekin, MD; Mete Baba, MD
Self-Test Review Questions (p. 32)

Fatigue in Psoriasis With Arthritis .................................................................................................................. 34

Claudio Carneiro, MD; Mario Chaves, MD; Gustavo Verardino, MD; Alessandra Drummond, MD; Marcia Ramos-e-Silva, MD, PhD;
Sueli Carneiro, MD, PhD

CORE CURRICULUM
Virendra N. Sehgal, MD, Section Editor

Nail Biology, Morphologic Changes, and Clinical Ramifications: Part I.............................................................. 39

Virendra N. Sehgal, MD; Ashok K. Aggarwal, MD; Govind Srivastava, MD; Kingsuk Chatterjee, MBBS

Departments

New Therapy Update

William Abramovits, MD; Aditya K. Gupta, MD, Section Editors

Veltin Gel (Clindamycin Phosphate 1.2% and Tretinoin 0.025%)....................................................................... 49

William Abramovits, MD; Marcial Oquendo, MD; Aditya K. Gupta, MD

Perils of Dermatopathology
W. Clark Lambert, MD, PhD, Section Editor

Why Immunofluorescence?............................................................................................................................. 52
Zain Husain, BS; Javier Rojas, MD; Amin Maghari, MD; W. Clark Lambert, MD, PhD

Congress Report
Marcia Ramos-e-Silva, MD, PhD, Section Editor

Scratching the Surface: The History of Skin, Its Diseases and Their Treatment
History of Medicine Unit, University of Birmingham, October 2930, 2010 [Parallel Publication]....................... 56
Rebecca Wynter, MPhil, PhD

3
 January/February 2011 TABLE OF CONTENTS

CASE STUDIES
Vesna Petronic-Rosic, MD, MSc, Section Editor

Longitudinal Erythronychia: The Value of Cosmetic Alterations in Nail Findings................................................ 60

Rashid M. Rashid, MD, PhD; Carlos Torres-Cabala, MD; Susan Chon, MD

A Case of Cinderella: Erythema Dyschromicum Perstans (Ashy Dermatosis or Dermatosis Cinecienta)............. 63

Claudia Muoz, MD, MPH; Anne Lynn S. Chang, MD

Bullous-Hemorrhagic Darier Disease.............................................................................................................. 65

Mara Pilar Snchez-Salas, MD; Francisco Javier Garca Latasa de Aranibar, MD; Rosa Oncns Torres, MD; Paula Gamb Grasa, MD

Book Review
Noah S. Scheinfeld, MD, JD, Section Editor

Dermatologic Complications With Body Art: Tattoos, Piercings, and Permanent Make-Up................................. 68
Reviewed by Lawrence Charles Parish, MD, MD (Hon)

ABOUT OUR JOURNAL Editorial

SKINmed: Dermatology for the Clinician, print ISSN 1540-9740, on- MANAGING EDITOR ASSOCIATE MANAGING EDITOR
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4
 January/February 2011 EDITORIAL BOARD

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon)

Philadelphia, PA

DEPUTY EDITORS
William Abramovits, MD W. Clark Lambert, MD, PhD Larry E. Millikan, MD Jennifer L. Parish, MD
Dallas, TX Newark, NJ Meridian, MS Philadelphia, PA
Marcia Ramos-e-Silva, MD, PhD
Rio de Janeiro, Brazil

EDITORIAL BOARD
Mohamed Amer, MD Howard A. Epstein, PhD Jasna Lipozencic, MD, PhD Vincenzo Ruocco, MD
Cairo, Egypt Gibbstown, NJ Zagreb, Croatia Naples, Italy

Robert L. Baran, MD Ibrahim Hassan Galadari, MD, PhD, FRCP Eve J. Lowenstein, MD, PhD Noah S. Scheinfeld, MD, JD
Cannes, France Dubai, United Arab Emirates New York, NY New York, NY

Anthony V. Benedetto, DO Anthony A. Gaspari, MD George M. Martin, MD Virendra N. Sehgal, MD

Philadelphia, PA Baltimore, MD Kihei, HI Delhi, India

Brian Berman, MD, PhD Michael Geiges, MD David I. McLean, MD Charles Steffen, MD
Miami, FL Zurich, Switzerland Vancouver, British Columbia Oceanside, CA

Jack M. Bernstein, MD Michael H. Gold, MD Marc S. Micozzi, MD, PhD Alexander J. Stratigos, MD
Dayton, OH Nashville, TN Bethesda, MD Athens, Greece

Sarah Brenner, MD Orin M. Goldblum, MD George F. Murphy, MD James S. Studdiford III, MD

Tel Aviv, Israel Abbott Park, IL Boston, MA Philadelphia, PA

Joaquin Calap Calatayud, MD Lowell A. Goldsmith, MD, MPH Oumeish Youssef Oumeish, MD, FRCP Robert J. Thomsen, MD
Cadiz, Spain Chapel Hill, NC Amman, Jordan Los Alamos, NM

Henry H.L. Chan, MB, MD, PhD, FRCP Aditya K. Gupta, MD, PhD, FRCP(C) Joseph L. Pace, MD, FRCP Julian Trevino, MD
Hong Kong, China London, Ontario Naxxar, Malta Dayton, OH

Noah Craft, MD, PhD, DTMH Seung-Kyung Hann, MD, PhD Art Papier, MD Snejina Vassileva, MD, PhD
Torrance, CA Seoul, Korea Rochester, NY Sofia, Bulgaria

Ncoza C. Dlova, MBChB, FCDerm Roderick J. Hay, BCh, DM, FRCP, FRCPath Vesna Petronic-Rosic, MD, MSc Daniel Wallach, MD
Durban, South Africa London, UK Chicago, IL Paris, France

Richard L. Dobson, MD Tanya R. Humphreys, MD Johannes Ring, MD, DPhil Michael A. Waugh, MB, FRCP
Mt Pleasant, SC Philadelphia, PA Munich, Germany Leeds, UK

William H. Eaglstein, MD Camila K. Janniger, MD Roy S. Rogers III, MD Wm. Philip Werschler, MD
Palo Alto, CA Englewood, NJ Rochester, MN Spokane, WA

Boni E. Elewski, MD Abdul-Ghani Kibbi, MD Donald Rudikoff, MD Joseph A. Witkowski, MD

Birmingham, AL Beirut, Lebanon New York, NY Philadelphia, PA

Charles N. Ellis, MD Andrew P. Lazar, MD Robert I. Rudolph, MD Ronni Wolf, MD

Ann Arbor, MI Highland Park, IL Wyomissing, PA Rechovot, Israel

5
 January/February 2011 Volume 9 Issue 1

EDITORIAL

Bed Bugs Revisited

Michael Joseph Lavery;1 Lawrence Charles Parish, MD, MD (Hon)2

Night night, sleep tight

Dont let the bed bugs bite
If they do, squeeze them tight
And they wont bite another night
Irish bedtime verse

T
his nighttime tale and its variations are told to chil-
dren, but are these creatures really taken seriously?
When bed bug infestations were last visited in 2004, it
was postulated whether the then epidemic would fade.1 Many
parasitic diseases can be tamed or adhere to a wax and wane
cycle; eg, scabies and even pediculosis have been considered at
times to be affected by so-called herd immunity, but, alas, this
has not been so with the bed bug.
Incidence
Bed bugs have been known since the Ice Age, when they are
thought to have lived in caves, feeding off both humans and
bats. Currently, there appears to be an epidemic, not just in
hostels but in 5 star hotels, too. For example, known cases in
San Francisco doubled from 300 cases in 2004 to 600 cases in
2006. In New York, 4600 cases were reported for 2006. The
number could be much higher, but the stigma of bed bug in-
festation taints a hotel and even a house that might be for sale,
resulting in under-reporting.2 These figures are so worrying
that the United States hosted the first bed bug conference in
April 2009.3 Philadelphia, like many cities, is currently under
a major attack.
Elsewhere in the world, Danish authorities have reported a
2-fold increase in July and August from 20032007 in the
number of inquiries made to the Danish Pest Infestation
Laboratory (DPIL).4 In Greater London, there was almost
a 25% increase in the number of complaints regarding bed
bugs between 2000 and 2006,5 with an increased incidence in
UK travel hubs (M. T. Siva-Jothy, personal communication,
August 12, 2010).
Contributing Factors
The folklore that bed bugs are present due to poor hygiene and
sanitation is still true, but lack of cleanliness does not account
for reports from homes with good housekeepers or even from
luxury hotels. When dichlorodiphenyltrichloroethane (DDT)
was used, some observers even considered the use of insecti-
cides as creating the presence of bed bugs. This is erroneous,
as the insecticide forced the bed bugs out from their hiding
places in mattresses, upholstered furniture, and the crevices in
plaster walls.6
Could increased air travel be contributing to the problem? Peo-
ple can move from infested areas quickly, bringing bed bugs
with them in their luggage; therefore, suitcases are best kept on
stands and away from the floor. Moreover, recent treatments
may be less effective, due to the development of resistance and
the delayed mechanism of action in the newer agents. DDT
was insecticidal, but its ban in 1972 due to its effects on the
food chain and possible link to cancer resulted in fewer bed
bug deaths. In addition, some bed bugs have undergone muta-
tions, resulting in certain treatments that work in some states
and not in others, eg, bed bugs in Florida are 264 times less
resistant to 1% deltamethrin than are New York bed bugs.7
Entomology
Bed bugs belong to the family Cimicidae and are homeother-
mic ectoparasites, feeding primarily on mammals but also on
poultry and rodents. The most common genus causing the cur-
rent problems is Cimex lenticularius. Other forms include Ci-
mex hemipterus (mainly in the tropics) and Leptocimex bouleti
(mainly in South America and West Africa).8

From Queens University Belfast, Belfast, Northern Ireland;1 and the Department of Dermatology and Cutaneous Biology, Jefferson Center
for International Dermatology, Jefferson Medical College of Thomas Jefferson University,2 Philadelphia, PA
Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103
E-mail: larryderm@yahoo.com

SKINmed. 2011;9:68 6 2011 Pulse Marketing & Communications, LLC

 January/February 2011 EDITORIAL

The butterfly has wings of gold,

The firefly wings of flame,
The bed bug has no wings at all,
But he gets there just the same9

Bed bugs are reddish brown, flat, oval-shaped, wingless, typically

measure 4 to 7 mm, are big enough to be seen, and are small
enough to enter through cracks in the wall or under doorways;
therefore, their spread is not totally confined to the attachment to
clothing and luggage (Figure 1). Common nesting areas are those
where there is minimal light, including behind paintings, under
ripped wallpaper or posters, near couches, around the bed, in the
mattress, on the bed board, on the night stand, or even outside
the house (eg, cars, bus shelters, hospitals, nursing homes, pub- Figure 1. A bed bug disgorged of its recent blood meal.
lic transport systems), anywhere it is well hidden, dark, and close
to a carbon dioxide (CO2) source. They usually remain clustered
but can be 6 times its own weight.12 Some nights, a patient can
together and near the victim, because they are wingless6 and at-
sustain more than 100 bites.6
tracted to the exhaled CO2 (too high a level of CO2 can be fatal).10

Bed bugs can live for about a year without eating,11 if the sur-
rounding conditions are adequate. In a laboratory, they are
known to survive for up to 4 years and even for more than 18
months without any food.1 The optimum temperature for tem-
perate bed bugs is 79oF and for tropical bed bugs 97F, but after
2 weeks at 104F (with no air conditioning), temperate bed bugs
are effectively dead, and they cannot produce viable offspring
(M. T. Siva-Jothy, personal communication, August 12, 2010).
Clinical Features
Treatment
Just as there is the trio of breakfast, lunch, and dinner, so interven-
tion should include another threesome: symptomatic relief, fumi-
gation, and prevention. Relief can be accomplished with topical
steroids. Fumigation is needed, as bed bugs quickly reproduce
with thousands of progeny in just a few weeks.2 Such insecticides
used include deltamethrin, permethrin, and pyrethrin, as well as
newer agents such as chlorfenapyr or hydroprene.12 Washing bed
clothing, cleaning drapes and upholstery, and repairing torn wall-
paper and disreputable plaster are useful preventive measures.

Signs of bed bug bites can take several days to occur, with up to
50% of individuals, showing no reaction.2 The telltale sign of a
bed bug bite is a red macular wheal in clusters of 3: breakfast,
lunch, and dinner on exposed areas (mainly face, arms, hands,
and legs) (Figure 2). There is itching, sometimes severe enough
to cause the victim to excoriate the involved areas, leaving crusts
and possibly leading to superimposed pyoderma. These bites
may cause bleeding, and continual scratching can lead to infec-
tion.6 Other signs of bed bug infestation include blood on the
mattress, dead bed bugs and/or fecal material, and a sweet musty
odor coming from the ventral stink glands of the bed bug.8
Were it not for the expense, trained dogs are able to detect the bed
bug odor and thus their hiding places.13 Studying the female organ
spermalege could result in a new antibiotic for human therapy (M.
T. Siva-Jothy, personal communication, August 12, 2010).
Conclusions
Bed bugs are currently an irritation, but their worldwide increase
in incidence is worrisome. Unsanitary conditions are no longer

Bed bugs usually begin feeding on their prey around an hour

before dawn, using their proboscis to attach to the skinusually
the face, arms, or legsbut any exposed skin can be affected.
Once the bed bug has bitten, it injects its saliva, which contains
an anesthetic that numbs the area and an anticoagulant, which
eases the flow of blood from humans to the bug through the
proboscis more easily.11 Feeding lasts between 3 and 12 minutes,
upon which the bed bug returns to its nesting area to mate, lay Figure 2. A patient who has sustained the breakfast, lunch, and
eggs, or digest its recent meal. The amount of blood drawn varies dinner bites.

SKINmed. 2011;9:68 7 Bed Bugs Revisited

 January/February 2011 EDITORIAL

the only associated factor, with increase in travel and resistance
to drug treatments playing a role. Vigilance and fumigation on
the slightest provocation are advised. Although bed bugs cannot
be exterminated from this earth, their numbers can be controlled
by even the simplest of measures to prevent a full-blown pan-
demic. Prevention is better than cure.
Once bitten, twice shy!
References
1 Parish LC, Witkowski JA. The bedbugs never left. Skinmed.
2004;3:6970.
2 Goddard J, deShazo R. Bed bugs (Cimex lectularius) and clinical
consequences of their bites. JAMA. 2009;301:13581366.
3 US to tackle resurgent bed bugs. BBC News Online. http://
news.bbc.co.uk/2/hi/americas/7999260.stm. Accessed Au-
gust 13, 2010.
4 Kilpinen O, Jensen KM, Kristensen M. Bed bug problems in Den-
mark, with a European Perspective. In: Proceedings of the Sixth
International Conference on Urban Pests. Veszprm, Hungary:
OOK-Press Kft; 2008:395398.
5 Richards L, Boase CJ, Gezan S, et al. Are bed bug infestations
on the increase within Greater London? J Environ Health Res.
2009;9:1724.
6 Rozendaal JA. Bedbugs, fleas, lice, ticks and mice. Vector Con-
trol: Methods for Use by Individuals and Communities. Geneva,
Switzerland: WHO; 1997:237243.
7 Yoon KS, Kwon DH, Strycharz JP, et al. Biochemical and molecu-
lar analysis of deltamethrin resistance in the common bed bug
(Hemiptera: Cimicidae). J Med Entomol. 2008;45:10921101.
8 Crissey JT. Bedbugs: an old problem with a new dimension. Int
J Dermatol. 1981;20:411414.
9 Graham-Brown RAC, Burns T. Lecture notes. Dermatology. 9th
ed. Malden, MA: Blackwell Publishing; 2007:51.
10 Wang C, Gibb T, Bennett GW, et al. Bed bug (Heteroptera: Cimic-
idae) attraction to pitfall traps baited with carbon dioxide, heat,
and chemical lure. J Econ Entomol. 2009;102:15801585.
11 Burns DA. Diseases caused by arthropods and other noxious animals.
In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rooks Textbook of
Dermatology. Oxford, England: Wiley-Blackwell; 2010:38.138.61.
12 How to Manage Pests: Pests of Homes, Structures, People, and
Pets. 2009. http://www.ipm.ucdavis.edu/PMG/PESTNOTES/
pn7454.html. Accessed August 13, 2010.
13 Krause-Parello CA, Sciscione P. Bedbugs: an equal opportunist
and cosmopolitan creature. J Sch Nurs. 2009;25:126132.

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.
DIAGNOSIS: In a fully developed
case there is little likelihood of con-
fusion, though in its early stages the
disease can be distinguished from
papular uticaria only after long obser-
vation. Generalized eczema does not
spare the flexures and is protean and
much less obstinate. Scabies affects
the hands and penis. In pediculosis
corporis the duration of the disease,
the distribution of the lesions, the
long parallel scratch marks and the
presence of the parasites make the
differential diagnosis easy.

TREATMENT: There are no specific

remedies. As a rule the most that can
be accomplished is to mitigate the se-
vere itching. Cannabis indica and po-
tassium bromide are helpful at times.
Frequent warm baths with sapo mol-
lis followed by inunctions with a two
to five per cent betanaphthol salve,
unguentum sulphuris, unguentum sul-
phuris compositum, N. F., or a simple
emollient ointment prove very benefi-
cial in some cases.

SKINmed. 2011;9:68 8 Bed Bugs Revisited

 Introducing VELTIN GelA New Topical Treatment for Patients 12 Years or Older With Acne Vulgaris
Once-daily application in the evening

Combines the acne-fighting properties of tretinoin and clindamycin

VELTIN Gel 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, Clindamycin has been shown to have neuromuscular blocking
ulcerative colitis, or history of antibiotic-associated colitis properties that may enhance the action of other neuromuscular
blocking agents. VELTIN Gel should be used with caution in
Systemic absorption of clindamycin has been demonstrated
patients receiving such agents
following topical use. Diarrhea, bloody diarrhea, and colitis (including
pseudomembranous colitis) have been reported with the use of VELTIN Gel should be used during pregnancy only if the potential
topical clindamycin. VELTIN Gel should be discontinued if significant benefit justifies the potential risk to the fetus
diarrhea occurs. Severe colitis has occurred following oral or
It is not known whether either clindamycin or tretinoin is excreted
parenteral clindamycin administration. Severe colitis may result
in human milk following use of VELTIN Gel. However, orally and
in death
parenterally administered clindamycin has been reported to appear
Avoid exposure to sunlight and sunlamps when using VELTIN Gel. in breast milk. Due to possible serious adverse reactions in nursing
Patients with sunburn should be advised not to use VELTIN Gel until infants, a decision should be made whether to discontinue
fully recovered. Daily use of sunscreen products and protective nursing or the drug. Exercise caution if administering VELTIN Gel
apparel are recommended. Weather extremes (eg, wind and cold) to a nursing woman
also may be irritating to patients using VELTIN Gel
The ecacy and safety have not been established
Observed local treatment-related adverse reactions (1%) in clinical in pediatric patients below the age of 12 years
studies with VELTIN Gel were application site reactions, including
VELTIN Gel is not for oral, ophthalmic,
dryness, irritation, exfoliation, erythema, pruritus, and dermatitis.
or intravaginal use
Sunburn was also reported. Incidence of skin reactions peaked at
week 2 and then gradually decreased
VELTIN Gel should not be used in combination with erythromycin-
containing products due to possible antagonism to the clindamycin
component

Please see brief summary of Prescribing Information on the next page.

 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.
1 INDICATIONS AND USAGE
VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years
or older.
4 CONTRAINDICATIONS
VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis,
or history of antibiotic-associated colitis.
5 WARNINGS AND PRECAUTIONS
5.1 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 antibiotic-
associated colitis.
5.2 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.
6 ADVERSE REACTIONS
6.1 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.
7 DRUG INTERACTIONS
7.1 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.
7.2 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.
8 USE IN SPECIFIC POPULATIONS
8.1 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.
8.3 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.
8.4 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.]
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 g (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.
17 PATIENT COUNSELING INFORMATION
[See FDA-approved Patient Labeling].
17.1 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.
17.2 Skin Irritation
VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
17.3 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.
STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.
VELTIN is a trademark of Astellas Pharma Europe B.V.
VEL:2BRS
Issued July 2010
2010 Stiefel Laboratories, Inc.
2010 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. VEL015R0 September 2010
 January/February 2011 Volume 9 Issue 1

Original Contribution

High Frequency of Psoriasis in Relatives in a

Turkish Multiple Sclerosis Cohort
Sibel Dogan, MD;1 Nilgn Atakan, MD;1 Asli Kurne, MD;2 Rana Karabudak, MD2

Abstract

Psoriasis was recently accepted as an autoimmune T cellmediated disease. Various autoimmune disease associations for psoriasis have
been defined, including multiple sclerosis, a model autoimmune demyelinating neurologic disorder. In this study, the familial frequency of
psoriasis in a Turkish multiple sclerosis cohort was investigated, and a higher frequency of psoriasis was found, supporting the presence of
a complex background of autoimmunity underlying psoriasis. (SKINmed. 2011;9:1113)

P
soriasis is a chronic, recurrent, inflammatory skin disor-
der that has been recently accepted as an autoimmune
disease. The presence of similar pathophysiologic mecha-
nisms within autoimmune diseases has motivated investigators
to search for a common genetic background, association, and
coexistence between these diseases. Multiple sclerosis (MS),
which is accepted as a model T cellmediated autoimmune
disease, has been the subject of several studies showing the as-
sociations with various autoimmune diseases.13 Families with
MS members have also been investigated, and different patterns
of autoimmune diseases have been found in different popula-
tions.46 Recent studies show that psoriasis is one of the autoim-
mune diseases that occur in MS patients families with a higher
frequency.5,6 In this study, we investigated the familial frequency
of psoriasis in a Turkish MS cohort compared with a similar sex-
and age-matched control group.
Materials and Methods
The records of 127 patients (78 women and 49 men; ratio,
1.59:1) with definite MS were included in this study between
2006 and 2007. All of the patients were diagnosed and followed
up in the neurology department of Hacettepe University. The
patients were contacted by phone and were asked whether any
of their first- and/or second-degree relatives had psoriasis. The
control group consisted of 125 patients (77 women and 48 men;
ratio, 1.6:1) who were admitted to the internal diseases outpa-
tient clinic of the same university.
Records of MS patients included age, symptoms and signs at
onset of MS, functional neurologic systems, and disability scor-
ing with the expanded disability status scale of the last visit. In-
formation on a family history of psoriasis within MS patients
was obtained from phone contacts made with the patients them-
selves. Full biological relatives, including first- (parent, sibling,
child) and second-degree relatives (grandparents, uncles/aunts,
nephews/nieces) were considered.
Statistical Analysis
Contingency tables were analyzed by Fisher exact test and chi-
square test. Frequency and descriptive analysis was made on
SPSS 11.0 (SPSS Inc, Chicago, IL).
Results
Demographic characteristics of MS and control groups are given
in Table I. There were no significant differences between the
groups with regard to age and sex. Eight relatives of MS patients
had psoriasis, whereas only one relative had psoriasis in the con-
trol group. Although a higher frequency of psoriasis is found in
MS patients relatives, a statistically significant increased risk of
psoriasis was not obtained (P>.05). All of the psoriatic relatives
had chronic plaque-type psoriasis.
The relatives with psoriasis in MS and control groups are shown
in Table II. Most relatives with psoriasis in the MS population
were fathers (n=2) and brothers (n=2), but this frequency was
not significant with respect to other relatives who were a mother
(n=1), sister (n=1), nephew (n=1), and niece (n=1) (P>.05).
The mean age of MS onset of patients who had a relative with psori-
asis was 31.8 years, while the patients without psoriatic relatives had

From the Department of Dermatology1 and Neurology,2 Hacettepe University, Faculty of Medicine, Ankara, Turkey
Address for Correspondence: Sibel Dogan, MD, Hacettepe University, Faculty of Medicine, Department of Dermatology, Sihhiye, 06100,
Ankara, Turkey E-mail: sibel.dogan@hacettepe.edu.tr

SKINmed. 2011;9:1113 11 2011 Pulse Marketing & Communications, LLC

 January/February 2011 ORIGINAL CONTRIBUTION

Table I. Characteristics of Multiple Sclerosis (MS) and Control Patients

MS Patients Controls
Patients, No. 127 125
Female/male ratio 1.59:1 1.66:1
Age, y 43.710.03 (2069) 42.95.7 (2069)
Age of onset, y 32.49.04 (1562)
Duration of disease, y 11.795.77 (140)
Relatives with psoriasis, No. (%) 8 (6.2) 1 (0.8)
Values are expressed as mean standard deviation (range) unless otherwise indicated.

a mean onset age of 32.3 years. There was no statistically significant
difference in age of onset when MS patients were compared accord-
ing to psoriasis history in relatives (P>.05).
The symptoms and signs at onset of MS patients with and with-
out psoriatic relatives are compared in Table III. There were no
significant differences between patient groups with respect to
signs and symptoms at onset.
Discussion
In this study, although not statistically significant, a higher fre-
quency of psoriasis was found in relatives of MS patients. An
increased risk for psoriasis in MS patients and their relatives
could not be defined. The prevalence of psoriasis in an otherwise
healthy Turkish population has been estimated to be 1% to 2%
in previous reports; therefore, the psoriasis prevalence of 6.2%
within the relatives of MS patients in our study was strikingly
engrossing.7 We believe that there could have been false-negative
family histories, resulting in a probable higher frequency of pso-
riasis in MS families, because the data were retrospectively col-
lected by phone.
Three of the MS patients had psoriasis themselves. Their psoria-
sis onset ages were 15, 20, and 41 years and MS onset ages were
22, 35, and 42 years, respectively. All of the patients who had
psoriasis themselves were diagnosed in the dermatology depart-
ment between 2005 and 2007. The small number of patients
with coexistent psoriasis and MS inhibited the evaluation of
disease interaction on prognosis for each other. In our opinion,
studies and individual cases should be strongly supported to be
reported to understand more adequately these relationships.
In some studies, MS patients with a relative with psoriasis were
found to have a younger age of onset.6 In our study, we found no
difference of age at onset between MS patients with and without
psoriatic relatives. This feature was also not evaluated as a predic-
tor of MS disability because the duration and number of attacks
of MS patient groups were not homogenous when divided ac-
cording to psoriasis family history.
Psoriasis is accepted as an autoimmune T cellmediated disorder.
Like other autoimmune diseases, the associated major histocom-
patibility complex alleles have begun to be expressed for psoria-
sis.8 Activated T cells produce systemic inflammatory cytokines,
including principally interferon gamma. Interferon gamma par-
ticularly induces ectopic class II major histocompatibility complex
expression on keratinocytes and activated cytotoxic T cells. This
pathomechanism supports the probability of self-intolerance in

Table II. Frequency of Psoriasis in Multiple Sclerosis (MS) and Control Families
MS Patients Controls
Relative No. Percentage No. Percentage
Father 2 25
Mother 1 12.5 1 100
Brother 2 12.5
Sister 1 25
Nephew 1 12.5
Niece 1 12.5

SKINmed. 2011;9:1113 12 High Frequency of Psoriasis

 January/February 2011 ORIGINAL CONTRIBUTION

Table III. Signs and Symptoms at Onset in Multiple Sclerosis Patients in Relation to Psoriasis in Relatives
Symptoms/Signs Psoriasis +b Psoriasis c
Visuala 4 (50%) 40 (35.7%)
Pyramidal-cerebellar 4 (50%) 58 (51.7%)
Sensory 14 (12.5%)
Total 8 112
a
Visual symptoms: optic neuritis. bPatients with a relative with psoriasis. cPatients without a relative with psoriasis.

psoriasis, which seems to be the main keystone of autoimmunity.9
Although not fully proved, it was shown that the autoimmunity
in psoriasis could be adopted by means of immune pathomecha-
nisms, when a patient developed psoriasis after receiving syngeneic
bone marrow from a psoriatic donor.10 In view of the evidence
of autoimmunity in psoriasis, the higher frequency of psoriasis in
MS patients relatives may be the outcome of a complex hetero-
genic background of autoimmunity.
Conclusions
Coexistence of psoriasis with autoimmune diseases supports the
upcoming evidence of psoriasis own autoimmune nature. The
underlying self-reactivity remains to be unknown in many auto-
immune diseases, making the coexistence more crucial to define
and investigate. The predictivity of these associations on disease
morbidity and/or mortality requires more investigation consist-
ing of higher numbers of patients.
References
1 Seyfert S, Klapps P, Meisel C, et al. Multiple sclerosis and other
immunologic diseases. Acta Neurol Scand. 1990;81:3742.
2 Warren S, Warren KG. Multiple sclerosis and associated diseases: a
relationship to diabetes mellitus. Can J Neurol Sci. 1981;8:3539.
3 De Keyser J. Autoimmunity in multiple sclerosis. Neurology.
1988;38:371374.
4 Broadley SA, Deans J, Sawcer SJ, et al. Autoimmune diseases
in first degree relatives of patients with multiple sclerosis. A UK
survey. Brain. 2000;123:11021111.
5 Heinzlef O, Alamowitch S, Sazdovitch V, et al. Autoimmune dis-
eases in families of French patients with multiple sclerosis. Acta
Neurol Scand. 2000;101:3640.
6 Annunziata P, Morana P, Giorgio A, Lore F, Guarino E. High
frequency of psoriasis in relatives is associated with early on-
set in an Italian multiple sclerosis cohort. Acta Neurol Scand.
2003;108:327331.
7 Kundakci N, Trsen U, Babiker MO, et al. The evaluation of the
sociodemographic and clinical features of Turkish psoriasis pa-
tients. Int J Dermatol. 2002;41:220224.
8 Bowcock AM. The genetics of psoriasis and autoimmunity. Annu
Rev Genomics Hum Genet. 2005;6:93122.
9 Reeves WH. Autoimmune mechanisms in psoriasis. Semin Der-
matol. 1991;10:217224.
10 Snowden JA, Heaton DC. Development of psoriasis after
syngeneic bone marrow transplant from psoriatic donor:
further evidence for adoptive autoimmunity. Br J Dermatol.
1997;137:130132.

TRICHOMEGALY
Medication reported to cause eyelash growth
Clomid Loniten Sandimmune Topamax
Cosopt Lumigan Simulect Trusopt
Cortisone-like drugs Neoral Soriatane Xalatan
Dilantin Rogaine Timoptic Zyrtec
Erbitux
Adapted from Litt, JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009:164.

SKINmed. 2011;9:1113 13 High Frequency of Psoriasis

 ONE PRESCRIPTION.
TWO POWERFUL EFFECTS.

The power to calm inflammatory acne

Inflammation is an important aspect in the
pathophysiology of acne1
+ The power to eradicate P acnes
Significant reduction in P acnes even up to 3 weeks
after discontinuation2
Both laboratory and clinical studies document the A decrease in P acnes can lead to a drop in
anti-inflammatory effects of minocycline1 pro-inflammatory cytokines and reduced inflammation1
Minimal resistance in an in vitro study
Complementary T 3 Calming Wipes The majority of tetracycline-resistant P acnes
Soothing and alcohol-free were cross-resistant to doxycyclinebut sensitive
part of a complete approach to minocycline*3
to acne treatment

TM C ALM I NG
WI P ES
(30 WIPES) The only pelletized form of Minocycline available...

A dual approach to acne care

For more information, go to www.minocin-kit.com

The most common adverse events associated with MINOCIN are nausea, vomiting, and diarrhea. CNS adverse effects may include
dizziness, vertigo, and headache.

Important Information
The most common adverse events associated with MINOCIN are nausea, vomiting, and diarrhea. Central nervous system adverse events including
light-headedness, dizziness, or vertigo have been reported with minocycline therapy, but are generally transient in nature. Other adverse events
include tinnitus, headache, sedation, and skin pigmentation, particularly on the face and mucous membranes. MINOCIN is contraindicated in persons
who have shown hypersensitivity to any of the tetracyclines or to any of the components of the product formulation. WARNING: MINOCIN Pellet-
Filled Capsules, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman. The use of drugs of the
tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent
discoloration of teeth (yellow-gray-brown). Concurrent use of tetracyclines may render oral contraceptives less effective.

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.
*In vitro activity does not necessarily correlate to in vivo activity.

2010 Triax Pharmaceuticals, LLC All rights reserved. Printed in USA. MN-0810-280
 January/February 2011 Volume 9 Issue 1

Original Contribution

Advances in Topical Delivery Systems in Acne:

New Solutions to Address Concentration Dependent
Irritation and Dryness
Roger I. Ceilley, MD

Abstract

Formulation development is key to the successful treatment of acne. There has been significant progress over the past few years, but not
all developments can be universally applied. An effective topical formulation must provide chemical stability and enhanced penetration
of active ingredients at optimal concentrations for efficacy and safety; be cosmetically acceptable; and not add side effects of its own. Both
retinoids and fixed combinations containing benzoyl peroxide are commonly used to treat acne, but both have the potential to cause
troublesome dose-dependent irritation and dryness. Excipients such as surfactants and alcohol have added to the problem. Two products
have recently been introduced where a combination of micronization skills and well-chosen excipients has minimized irritation and dryness
without compromising efficacy. Results from two major studies are discussed in this article. (SKINmed. 2011;9:1521)

D
eveloping effective topical dermatologic formulations
is challenging, yet key, to many issues in acne treat-
ment.13 Formulation influences the dosage regimen;
it affects efficacy and tolerability and is interactive with compli-
ance. In creating high-performance topicals, we must consider
two formulations. The primary formulation is delivered to the
patient, but once it is applied to the skin, its components (es-
pecially if there is water in the formulation) begin to evaporate.
Some begin to penetrate the skin, blending with the skins natu-
ral hydrolipidic film, resulting in the secondary formulation. It
is often from this changed formulation that the drug is delivered,
and the problems of irritation occur.
Myths
There are a number of myths surrounding formulation develop-
ment. A great vehicle is not great for all drugs or skin conditions.
Optimal vehicles have to be customized for the active ingredient.
There is a view that all gels are drying, resulting from many years
ago when the initial gels used in dermatology were alcohol and
acetone based. Today, there are very few remaining alcohol gels
(eg, Retin-A gel). Another aspect is whether penetration en-
hancers can be put into any formulation. Penetration enhancers
are drug specific and formulation sensitive. Finally, methylpara-
ben, propylparaben, and propylene glycol have been considered
by some as inappropriate in topical formulations. This is not
the case: methylparaben and propylparaben are the most widely
used preservatives, and sensitivity reactions are low and irritation
at low concentrations is rare. Propylene glycol is also a useful
multifunctional ingredient.
Therapeutic options for acne have changed little over the years,
but there has been much progress in their delivery and appli-
cation of therapeutic modalities, increasing both the effective-
ness, as well as patient tolerability and acceptance. An in-depth
understanding of the pathophysiologic mechanisms has lead to
the increased use of combination therapy; however, side effects
associated with various topical antiacne agents and the undesir-
able physicochemical characteristics of certain important agents,
such as tretinoin and benzoyl peroxide (BPO), can affect their
utility and patient compliance.
What Is an Effective Formulation?
A better understanding of the physicochemical effects of both
active ingredients and vehicles has led to the introduction of new
products with enhanced efficacy, tolerability, and cosmetic ac-
ceptability.
An effective topical formulation must satisfy a number of key criteria:
1. Provide a stable chemical environment to accommodate
multiple compounds that may have different, if not in-
compatible, physicochemical characteristics.

From the Department of Dermatology, University of Iowa, Carver College of Medicine, West Des Moines, IA
Address for Correspondence: Roger I. Ceilley, MD, 6000 University Avenue, Suite 450, West Des Moines, IA 50266 E-mail: ricakb@aol.com

SKINmed. 2011;9:1521 15 2011 Pulse Marketing & Communications, LLC

 January/February 2011 ORIGINAL CONTRIBUTION

Table. Degree of Bother From Irritation and Dryness Caused by Fixed-Combination Products Containing 5% Benzoyl Peroxide
Degree of Bother Dry Skin, % Redness, % Flaky/Peeling Skin, % Itchy Skin, % Irritated Skin, %
None 7 14 10 10 12
Mild 26 30 29 32 26
Moderate 34 36 34 34 42
Severe 34 20 27 22 22
Patients were asked to rate how bothersome each of those side effects were while using two clindamycin/benzoyl peroxide 5% marketed prod-
ucts (1 meaning the effects were not at all bothersome and 10 meaning they were extremely bothersome). Scores are grouped into mild (13),
moderate (47), and severe (810).

2. Enhance penetration of the active ingredients into the ex-
tremely lipophilic pilosebaceous unit.
3. Contain concentrations of active ingredients that, in com-
bination with excipients, are effective and well tolerated.
4. Contain excipients that are not drying or irritating, but
are occluding or moisturizing, which, in combination, can
modulate the release of the product at the treatment site.
5. Be cosmetically acceptable and easy to apply.
Therapeutic Options
Current evidence suggests that acne is the result of a combina-
tion of increased sebum production and follicular hyperkeratini-
zation, compounded by the host responses to the pro-inflamma-
tory activities of Propionibacterium acnes.4 Combination therapy,
targeting the multiple components of acne, should provide bet-
ter patient outcomes and is now commonplace; however, con-
centration- and formulation-dependent skin irritation and dry-
ness can limit utility especially with the use of retinoids, BPO,
and some formulation excipients.
Topical retinoids are one of the cornerstones of acne therapy and
are recommended as first-line therapy for all but the most severe
forms. They are used as monotherapy in mild comedonal acne
and in combination with BPO and antimicrobials (topical or
oral) for inflammatory acne.5

2.5
Mean Irritancy Score (Range 04)

2.0

1.5 Slight irritation

Barely perceptible
1.0 irritation

0
5.0% 2.5% 1.0%

Concentration of BPO

Figure 1. Mean cumulative irritation score with varying benzoyl peroxide (BPO) concentrations. Reproduced with permission from
Bucks et al.17

SKINmed. 2011;9:1521 16 Advances in Topical Delivery Systems in Acne

 January/February 2011
Retinoids normalize the abnormal follicular desquamation asso-
ciated with acne, which facilitates penetration of other antiacne
agents6,7 and prevents obstruction of the pilosebaceous orifice.7
As a result, they can be both comedolytic and anticomedogenic,
having been shown to reduce the formation of microcomedones
and comedones.8 Retinoids also have direct and indirect anti-
inflammatory effects, presumably from their actions on toll-like
receptors and cytokine production.9
A major drawback of retinoids is the potential to cause irrita-
tion, a side effect that is generally dose dependent.10 Irritation,
exfoliation, dryness, and scaling with retinoid therapy is partic-
ularly common during the initial 3 to 4 weeks of treatment.10
Irritation can also be a limiting factor for treatment adherence
in many patients.10
In addition to retinoids, two topical acne medications common-
ly used in fixed-combination formulations are clindamycin and
BPO. Clindamycin diminishes signs by reducing the levels of P
acnes and may decrease inflammation.11 BPO is also safe and effec-
tive, with its efficacy being maintained over many years of use and
the distinct advantage of not being associated with antimicrobial
Mean Cumulative Receptor Levels of Benzoic Acid (BPO Metabolite)*
2500
2000
Benzoic Acid, ng/cm2
1500
1000
500
0
0 6 hours
Figure 2. Cumulative benzoic acid levels for 2.5% benzoyl peroxide (BPO)/1.2% clindamycin phosphate compared with two clinda-
mycin/BPO 5% marketed products. *Clinical significance is unknown. Differences between test products were not statistically
significant. Reproduced with permission from Bucks et al.17
SKINmed. 2011;9:1521 17
ORIGINAL CONTRIBUTION
resistance.4 In addition, BPO has keratolytic and anticomedogenic
effects.12,13 As with the retinoids, the primary limitation of BPO
in certain patients is concentration-dependent (and potentially
formulation-dependent) skin dryness and irritation.4
Surfactants, preservatives, and high levels of organic solvents
often used in combination with BPO or for solubilizing reti-
noids are potential irritants. Alcohol and surfactants disrupt
membrane lipid bilayers of the epidermal barrier. Preservatives
are also sensitizing. In addition, the first-generation tretinoin
products, including all the generics that followed, were solubi-
lized formulated into a formulation containing significant levels
of isopropyl myristate or alcohol. The use of these products is
associated with a burst in penetration of tretinoin, when the
medication is applied to the epidermis, causing dryness and peel-
ing that can advance to unwanted scaling and redness.
Resolution
Novel drug delivery strategies play a pivotal role in improving
the topical delivery of antiacne agents by enhancing their dermal
localization with a concomitant reduction in their side effects.
Clindamycin-BPO 2.5%
Commercial Preparation BPO 5%
Commercial Preparation BPO 5%
12 hours 18 hours 24 hours
Advances in Topical Delivery Systems in Acne
 January/February 2011
0%
Median Percentage Change From Baseline
10%
20%
30%
40%
50%
60%
*
70%
Inflammatory
Lesions
Figure 3. Median percentage reduction in lesions at week 12: 64% reduction in inflammatory lesions with 2.5% benzoyl peroxide
(BPO)/1.2% clindamycin phosphate. A new, once-daily, optimized, fixed combination of clindamycin phosphate 1.2% and low-con-
centration BPO 2.5% gel for the treatment of moderate to severe acne. *P<.001 vs clindamycin phosphate 1.2%, BPO 2.5%, and
vehicle. **P<.001 vs clindamycin phosphate 1.2% and vehicle, P=.001 compared with BPO 2.5%. Reprinted from Gold.20
Recognizing the impact of skin irritation and dryness on success-
ful acne management is important.
In a recent survey of 200 patients with acne who had used fixed-
combination products containing 5% BPO and 1% clindamycin
for 6 months, 56% to 68% reported being bothered by dry skin,
redness, flaky/peeling skin, or even irritation (Table). As a result, pa-
tients adopted a variety of coping mechanisms including spot treat-
ment (33%), intermittent use (32%), or discontinuation (10%).14 A
number of patients switched to another product, and many (41%)
applied moisturizers to counteract the redness and dryness.
High concentrations of BPO (5%) are known to result in skin
irritation that may limit patient adherence.15 Two commonly
used fixed-combination products, containing 5% BPO and
clindamycin, may be moderately irritating, but there is a mean-
ingful reduction in irritation scores when the concentration is
reduced from 5% to 2.5%.16,17 By extrapolating this informa-
tion, one could create an ideal fixed-combination acne product
that would be used once daily, contain a low concentration of
SKINmed. 2011;9:1521
ORIGINAL CONTRIBUTION
Clindamycin-BPO
2.5% (n=797)
Clindamycin
Phosphate (n=812)
BPO (n=809)
Vehicle (n=395)
**
*
Noninflammatory Total
Lesions Lesions
Week 12
BPO (<5%), be stable, and be formulated in a vehicle, enhanc-
ing BPO bioavailability and minimizing irritation.18
Acanya Gel
A unique formulation of BPO 2.5% with clindamycin phos-
phate 1.2% (Acanya gel; Coria Laboratories, Aliso Viejo, CA) is
a once-daily, fixed-combination acne product to combine a low
concentration (2.5%) of microdispersed BPO particles, deliv-
ered in a hydrogel with a nonirritating excipient, acting as both
a humectant and a penetration enhancer.
The aqueous gel formulation BPO 2.5%/clindamycin phosphate
1.2% achieves stability between two otherwise incompatible ac-
tive ingredients: solubilized clindamycin phosphate and a mi-
crosuspension of BPO. Low amounts of propylene glycol act as
a humectant-type moisturizer and effective delivery solvent for
the BPO, following application to the skin, and allows for good
bioavailability without compromising cosmetic elegance. In ad-
dition, the uniformly distributed suspended micronized particles
further minimize irritation compared with solubilized BPO.
18 Advances in Topical Delivery Systems in Acne
 January/February 2011 ORIGINAL CONTRIBUTION

Erythema Itching
0.3 0.3 0.2 0.3 0.2 0.3 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

0 4wk 8wk 12wk 0 4wk 8wk 12wk

Scaling Burning

0.1 0.1 0.2 0.2 0.1 0.1 0.1 0.2 0 0 0.1 0.1 0 0 0 0

0 4wk 8wk 12wk 0 4wk 8wk 12wk

Stinging

0 0 0 0 0 0 0 0

0 4wk 8wk 12wk

Figure 4. Cutaneous tolerability of 2.5% benzoyl peroxide (BPO)/1.2% clindamycin phosphate compared with vehicle. Black rectangle
= clindamycin/BPO 2.5%; yellow rectangle = vehicle. All scores were 0.3, where a score of 1 = mild. Mean scores (scale 0 [none]
3 [severe]). Adapted from Thiboutot et al with permission from the American Academy of Dermatology.19

A 21-day cumulative irritation study showed that reducing the micronized particles of tretinoin in a moisturizing hydrogel ve-
BPO concentration from 5% to 2.5% in a series of clindamycin/ hicle to avoid localized hot spots of high tretinoin concentration.
BPO fixed combinations with common vehicle reduced irrita- Also, the gel formulation contains excipients that are commonly
tion by 33% (Figure 1).17 In addition, this gel was shown in an found in skin-hydration and moisturizer products (soluble col-
in vitro percutaneous absorption study to have comparable bio- lagen, sodium hyaluronate, and glycerin). In addition to mini-
availability with other marketed fixed combinations where the mizing irritation, it maximizes efficacy. This was addressed by
concentration of BPO was higher (5%) (Figure 2).17 ensuring that the particles were very small to target follicular
The gel was studied for the once-daily treatment of moderate to se-
vere acne in more than 2800 patients. Unlike many previous studies
on fixed-combination products, almost 19% of patients had severe
acne, based on Evaluator Global Severity Score.19 By week 12, the
median percent reduction in inflammatory lesions with 2.5% BPO/
clindamycin phosphate 1.2% was 64%, compared with a 54% re-
duction with clindamycin phosphate (1.2%), 55% reduction with
BPO 2.5%, and 34% reduction with vehicle (P<.001) (Figure 3).
Median percent reductions in noninflammatory lesions and total
lesions were 49%, 40%, 41%, and 26% and 52%, 45%, 46%, and
27%, respectively.20 Of significance, cutaneous tolerability was ex-
cellent. Mean scores for erythema, scaling, itching, burning, and
stinging at each postbaseline visit were <1 (1 = mild) and compa-
rable with active ingredients and vehicle (Figure 4).19

Atralin Gel
Atralin gel (tretinoin 0.05%; Coria Laboratories, Aliso Viejo, Figure 5. Deposition of micronized particles of tretinoin in
tretinoin gel 0.05%.
CA) uses a low concentration of dispersed controlled-release

SKINmed. 2011;9:1521 19 Advances in Topical Delivery Systems in Acne

 January/February 2011 ORIGINAL CONTRIBUTION

Tretinoin microsphere 0.1% (n=376)

30% Tretinoin gel 0.05% (n=674)

Vehicle (n=487)
Incidence Rate

20%

Rate of new skin-related adverse

events fell below 1% after week 4 and
did not increase for the duration of the study
10%

0%
1 2 3 4 5 6 7 8 9 10 11 12

Treatment Week

Figure 6. Total skin-related adverse events: effect of treatment duration.

penetration and direct uptake into the sebum through the fol-
licular opening (Figure 5).
Tolerability of Atralin gel is excellent. Analyses of the combined stud-
ies demonstrate a low incidence of skin-related adverse events (AEs)
after treatment with tretinoin gel 0.05%; 70% of patients reported
no skin-related AEs.21 The most commonly reported skin-related AE
within the tretinoin gel 0.05% group was dry skin (16%). This is
in comparison with the higher-strength tretinoin 0.1% microsphere,
where the overall incidence of skin-related AEs was 52% (P<.001 vs
0.05% tretinoin) and dry skin occurred in 30% of patients (Figure 6).
In addition, peeling/scaling/flaking skin was reported by 30% of pa-
tients treated with tretinoin 0.1% microsphere (compared with only
12% taking tretinoin gel 0.05%) and erythema in 18% of patients
(compared with 7% taking tretinoin gel 0.05%).
Skin-related AEs generally resolved within the first 4 weeks of
treatment and were similar to baseline at week 12; furthermore,
the incidence rates observed with tretinoin gel 0.05% in the com-
bined analysis were 50% to 75% lower than those rates reported
in the literature for other marketed tretinoin formulations con-
taining half the concentration of tretinoin gel (ie, 0.025%).22,23
Conclusions
Developing topical formulations in dermatology is challenging
but necessary if patient outcomes are to be improved. A bet-
ter understanding of the pathophysiology of acne has helped to
consolidate our views on the best treatment options; however,
retinoids and fixed-combination products containing BPO can
cause dose-dependent and formulation-dependent irritation and
dryness, limiting use in some patients and resulting in a number
of coping mechanisms. Recent advances in formulation technol-
ogy have permitted the development of products that are both
effective and well tolerated.
Acknowledgement and disclosure: Brian Bulley, MSc, assisted in the
development of this manuscript. Dr Ceilley is a consultant for Coria
Laboratories, Aliso Viejo, CA.
References
1 Date AA, Naik B, Nagarsenker MS. Novel drug delivery systems:
potential in improving topical delivery of antiacne agents. Skin
Pharmacol Physiol. 2006;19:216.
2 Katz MA, Cheng CH, Nacht S, inventors. Methods and com-
positions for topical delivery of benzoyl peroxide. US patent
5,879,716. March 9, 1999.
3 Ting WW, Vest CD, Sontheimer RD. Review of traditional and novel
modalities that enhance the permeability of local therapeutics
across the stratum corneum. Int J Dermatol. 2004;43:538547.
4 Gollnick H, Cunliffe W, Berson D, et al. Management of acne:
a report from the alliance to improve outcomes in acne. J Am
Acad Dermatol. 2003;49(suppl):S138.
5 Ghali F, Kang S, Leyden J, et al. Changing the face of acne

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therapy. Cutis. 2009;83(2 suppl):415.
6 Yan AC. Current concepts in acne management. Adolesc Med
Clin. 2006;17:613637.
7 Leyden JJ. A review of the use of combination therapies
for the treatment of acne vulgaris. J Am Acad Dermatol.
2003;49(suppl):S200S210.
8 Thielitz A, Sidou F, Gollnick H. Control of microcomedone forma-
tion throughout a maintenance treatment with adapalene gel,
0.1%. J Eur Acad Dermatol Venereol. 2007;21:747753.
9 Feldman S, Careccia RE, Barham KL, et al. Diagnosis and treat-
ment of acne. Am Fam Physician. 2004;69:21232130.
10 Leyden JJ, Grossman R, Nighland M. Cumulative irritation poten-
tial of topical retinoid formulations. J Drugs Dermatol. 2008;7(8
suppl):s14s18.
11 Webster GF, leyden JJ, McGinley KJ, et al. Suppression of poly-
morphonuclear leucocyte chemotactic factor production in Pro-
pionibacterium acnes by subminimal inhibitory concentrations
of tetracycline, ampicillin, minocycline, and erythromycin. Anti-
microb Agents Chemother. 1982;21:770772.
12 Gupta AK, Lynde CW, Kunynetz RA, et al. A randomized, double-
blind, multicenter, parallel group study to compare relative effica-
cies of the topical gels 3% erythromycin/5% benzoyl peroxide
and 0.025% tretinoin/erythromycin 4% in the treatment of moder-
ate acne vulgaris of the face. J Cutan Med Surg. 2003;7:3137.
13 Waller JM, Dreher F, Behnam S, et al. Keratolytic properties of
benzoyl peroxide and retinoic acid resemble salicylic acid in
man. Skin Pharmacol Physiol. 2006;19:283289.
14 Feldman SF, Chen DM. How patients experience and manage dry-
ness and irritation from acne treatment. J Drugs Dermatol. In press.
15 Waller JM, Dreher F, Behnam S, et al. Keratolytic properties of
VINTAGE LABELs
Courtesy of BuyEnlarge, Philadelphia, PA
SKINmed. 2011;9:1521 21
ORIGINAL CONTRIBUTION
benzoyl peroxide and retinoic acid resemble salicylic acid in
man. Skin Pharmacol Physiol. 2006;19:283289.
16 Dosik J, Varnvakias G. Comparative irritation potential of two com-
bination acne products. Am J Clin Dermatol. 2008;9:313333.
17 Bucks D, Sarpotdar P, Yu K, Angel A, Del Rosso J. The devel-
opment and optimization of a fixed combination of clindamycin
and benzoyl peroxide aqueous gel with minimal irritation and
enhanced bioavailability. J Drugs Dermatol. 2009;8:634638.
18 Stein Gold L. Fixed combination products in the management of
acne vulgaris. Cutis. 2010;85:160167.
19 Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed
combination of clindamycin phosphate 1.2% and benzoyl per-
oxide 2.5% for the once-daily treatment of moderate to severe
acne vulgaris: assessment of efficacy and safety in 2813 pa-
tients. J Am Acad Dermatol. 2008;59:792800.
20 Gold MH. A new once-daily, optimized, fixed combination of
clindamycin phosphate 1.2% and low concentration benzoyl
peroxide 2.5% for the treatment of moderate-to-severe acne. J
Clin Aesth Dermatol. 2009;2:4448.
21 Webster G, Cargill I, Quiring J, et al. A combined analysis of 2
randomized clinical studies of tretinoin gel 0.05% for the treat-
ment of acne. Cutis. 2009;83:146154.
22 Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-
controlled, multicenter comparison of two 0.025% tretinoin
creams in patients with acne vulgaris. J Am Acad Dermatol.
1998;38(suppl):S24S30.
23 Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy
and safety of two 0.025% tretinoin gels: results from a mul-
ticenter double-blind, parallel study. J Am Acad Dermatol.
1998;38(suppl):S17S23.
Advances in Topical Delivery Systems in Acne
 January/February 2011 Volume 9 Issue 1

REVIEW

The Tzanck Smear Test:

Rediscovery of a Practical Diagnostic Tool
Murat Durdu, MD;1 Deniz Sekin, MD;2 Mete Baba, MD1

Abstract

The Tzanck smear test is a simple, rapid, valuable, and cost-effective diagnostic method based on the investigation of characteristics of
individual cells. In this method, materials are obtained by various techniques and then transferred to a glass slide. Slides can be stained with
various dyes and then are examined under a light microscope. To date, cytology has mostly been used in the diagnosis of various erosive-
vesiculobullous and nodular lesions, including many tumors. The sampling methods for Tzanck smears and the cytologic findings of a
broad range of skin diseases that could provide a rapid diagnosis are described. (SKINmed. 2011;9:2332)

C
ytology is a diagnostic method based on the investigation
of characteristics of individual cells. Morphologic features
of cells change in various diseases.1 Cytology examines
these alterations for the early diagnosis and treatment of diseases.2
This diagnostic method has been used for the diagnosis of diseases
of various systems since the mid-19th century.3 For dermatologic
diseases, cytology was first used by Arnault Tzanck in 1947.4 To
date, the Tzanck smear test has been used in the diagnosis of vari-
ous erosive-vesiculobullous, papular, pustular, and nodular lesions
of different etiology, including tumors (Table).522
The Tzanck smear test has some advantages. It is a simple, reli-
able, rapid, and inexpensive (the cost per test is less than $1)
method.16 Obtaining samples for the Tzanck smear test is pain-
less and, therefore, anesthesia is not necessary; moreover, mul-
tiple samples can be taken from different lesions and regions
where taking a biopsy specimen is difficult.5,6 Despite all these
advantages, the use of the Tzanck smear test is usually limited to
a few diseases in daily dermatologic practice.
To emphasize the utility and to expand the use of the Tzanck
smear test, we present the ways of a Tzanck smear preparation
and the cytologic findings of various skin diseases.
Tzanck Smear Preparation
Obtaining Smear Materials
For cytologic examination, materials are obtained by scraping
(abrasion), slit-skin, or touch (imprint) techniques, depend-
ing on the localization and type of the lesions.5,12 To obtain
materials from erosive-vesiculobullous or pustular lesions, the
scraping method is used. The youngest vesicle, bulla, or pustule
should be selected for sampling. Older lesions, even if intact,
may be diagnostically misleading, as secondary infections, cel-
lular degeneration, and epidermal regeneration at the base of
the lesion may be confused with basic pathologic findings.23
The lesions are first gently cleaned with a 70% alcohol swab.
The roof of the vesicle, bulla, or pustule is incised with a scalpel
(No. 15), and then the fluid contents are carefully swabbed
without touching its base. The contents of the vesicle, bulla,
or pustule and the blood should not be included in a sample,
because they dilute and obscure the epithelial or inflammatory
cells. The base of the lesion is scraped with the sharp edge of the
scalpel. A blunt-ended spatula or a brush may be used in oral
mucosa, because they cause less bleeding.2 The cellular mate-
rial obtained is then immediately spread in a thin layer onto at
least 2 microscopic slides (Figure 1A1F). An erosive lesion can
easily bleed. When that happens, the bleeding area should be
compressed with a saline-moistened gauze. In crusted lesions,
the crusts are carefully removed with sterile forceps, and the
base of the lesion is then scraped.12 Solid lesions are grasped be-
tween the thumb and the forefinger of the nondominant hand,
and then a small superficial incision (about 3- to 5-mm long
and 2-mm deep) is made at the edge of the lesions. The tissue
is scraped along the incision by a scalpel (No. 15) and the ma-
terial obtained is gently scraped onto microscopic slides (slit-
skin smear) (Figure 1G1L).24 If the lesion bleeds, it is cleaned

From the Department of Dermatology, Bakent University, Faculty of Medicine, Adana1 and Ankara2 Hospitals, Ankara, Turkey
Address for Correspondence: Deniz Sekin, MD, Professor of Dermatology, Department of Dermatology, Bakent University Faculty of
Medicine, 5. Sokak No: 48, Bahelievler 06490, Ankara, Turkey E-mail: denizs@baskent-ank.edu.tr

SKINmed. 2011;9:2332 23 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Table. Major Indications for a Tzanck Smear Test With Relevant Main Findings
Diseases
Cutaneous infections
Bacterial infections
Bullous impetigo
SSSS
Mycobacterial infections
Bacillary angiomatosis
Fungal infections
Dermatophytic infections
Candidiosis
Aspergillosis
Mucormycosis
Blastomycosis
Sporotrichosis
Viral infections
Herpetic infections
Hand, foot, and mouth disease
Human papillomavirus infections
Molluscum contagiosum
Milkers nodule and orf
Parasitic infestations
Leishmaniasis
Demodicosis
Scabies
Cutaneous amoebiasis
Immunobullous disorders
Pemphigus
Other autoimmune bullous diseases
Erythema multiforme, TEN
Genodermatoses
Hailey-Hailey disease
Dariers disease
Spongiotic dermatitis
Allergic contact dermatitis
Irritant contact dermatitis
SKINmed. 2011;9:2332
REVIEW
Cytologic Findings
Dyskeratotic acantholytic cells, abundant neutrophils, and clusters of cocci1
Dyskeratotic acantholytic cells, absence of abundant neutrophils, and cocci6
Negative images of mycobacteria, acid-fast bacilli7
Clumps of coccobacilli of Bartonella henselae in Warthin-Starrystained smears8
Hyphae and spores9
Pseudohyphae and spores9
Septate hyphae with 45-degree angle branching and/or aspergillus heads9
Ribbon-like, nonseptate, thin-walled hyphae10
Broad-based budding spores10
Spherical, oval, or cigar-shaped yeasts and asteroid bodies11
Acantholytic cells, multinucleated giant cells, and eosinophilic inclusion bodies1
Syncytial nuclei, absence of acantholytic cells1
Koilocytes12
Intracytoplasmic inclusion bodies (Henderson-Pattersons bodies)1
Intracytoplasmic inclusion bodies (Guarnieris bodies)13
Ellipsoid-shaped Leishman-Donovan bodies1
More than 5 Demodex mites/cm2 5
Sarcoptes scabiei with 4 pairs of legs and multiple dorsal cuticular spines14
Trophozoites of Entamoeba histolytica15
Acantholytic cells with direct immunofluorescence positivity12
Nonspesific12
Apoptotic and necrotic cells, absence of acantholytic cells16
Acantholytic cells without direct immunofluorescence positivity16
Acantholytic cells, corps ronds, grains1
Presence of more than 10 tadpole cells at 100 magnification17
Tadpole cells and lymphocytes18
Tadpole cells and polymorphonuclear leukocytes18
table continued on adjacent page
24 The Tzanck Smear Test
 January/February 2011 REVIEW

Granulomatous diseases Granuloma formation and multinucleated giant cells7

Granuloma annulare Palisading granuloma and mucin7
Necrobiosis lipoidica Palisading granuloma and necrobiotic materials7
Foreign body granuloma Foreign body7
Juvenile xanthogranuloma Touton-type giant cells and foamy cells7
Neonatal pustular disease
Acropustulosis of infancy and transient Abundant neutrophils and a few eosinophils19
neonatal pustular melanosis
Erythema toxicum neonatorum Dense accumulation of eosinophils19
Tumors
Benign tumoral lesions
Mastocytoma Abundant mast cells1
Sebaceous hyperplasia Clusters of sebocytes5
Seborrheic keratoses Hyperkeratosis and horny cysts6
Melanocytic nevi Dermal and epidermal type nevoid cells20
Eruptive vellus hair cysts Abundant vellus hairs21
Malignant tumoral lesions Cellular atypia including mitosis, poikilokaryosis, poikilocytosis, nuclear contour irregularity,
prominent nucleoli, and nuclear molding
Basal cell carcinoma Clusters of basaloid cells1
Squamous cell carcinoma Cytologic atypia of keratinocytes5
Melanoma Atypical melanocytes5,12
Lymphoma Atypical lymphocytes12
Pagets disease Isolated or clusters of Pagets cells1
Kaposis sarcoma Cigar-shaped spindle cells22
Abbreviations: SSSS, staphylococcal scalded skin syndrome; TEN: toxic epidermal necrolysis.

with a swab. Ulcerated lesions are gently cleaned to remove the
excess tissue. If the ulcerated lesion has a crust, it is removed
with sterile forceps. The base of the ulcer is then scraped by the
blunt end of a scalpel (Figure 1M and 1N). Touch smear prepa-
ration is usually used for some of the infectious and neoplastic
skin diseases. For a touch smear, the ulcerated tissue is touched
to the glass slides, or the biopsy material is held by forceps and
touched on the glass slides at several points without causing
undue pressure or lateral movement (Figure 1O).23,25
Staining of Samples
The most commonly used stain is May-Grnwald-Giemsa
(MGG) (Bio-optica, Milan, Italy).1 The others include Wright,
Diff-Quick, Papanicolaou, and hematoxylin and eosin (H&E)
stains. Smears can be quickly stained by the MGG (2025 sec-
onds) and Diff-Quick (2 minutes) stains. The Papanicolaou stain
is especially used to demonstrate viral inclusion bodies for the
diagnosis of warts and other viral infections.9
Immediate alcohol fixation is required for both Papanicolaou
and H&E stains. For other staining methods, specimens should
be stained as soon as they have been air-dried. If not, excessive
drying results in cellular swelling and loss of nuclear details;
however, cytoplasmic and background details are protected.9,10
If necessary, other staining methods such as Gram staining for
bacterial infections, acid-fast staining for mycobacterial infec-
tions, methylene blue or toluidine blue stainings for mastocy-
tosis, and periodic acid-Schiff (PAS) or Gomorris methena-
mine silver (GMS) stainings for deep fungal infections can be
used.7,10 If a Tzanck smear test shows only acantholytic cells,
direct immunofluorescence study on smears can be addition-
ally performed.26

SKINmed. 2011;9:2332 25 The Tzanck Smear Test

 January/February 2011
Figure 1. Sampling methods for the Tzanck smear. A vesicular
lesion on the dorsum of the foot (A). Cleaning the lesional area
with an alcohol swab (B). Incising the roof of the vesicle by a scal-
pel (C). Absorbing the fluid content with the swab (D). Scraping
the base of the lesion with the scalpel (E). Spreading the material
onto a glass slide as a thin layer (F). A nodular lesion on the face
(G). Cleaning the lesional area with an alcohol swab (H). Grasp-
ing the lesion between thumb and forefinger of the nondominant
hand (I). Making a small superficial incision at the edge of the
lesion (J). Scraping the tissue along the incision by a scalpel (K).
Spreading the material onto a glass slide as a thin layer (L). Re-
moving the crusts with sterile forceps in noduloulcerative lesions
(M). Scraping the base of the ulcer by a scalpel (N). Touching the
ulcerated nodule to a glass slide (touch smear) (O).
Cytologic Findings
Cutaneous Infections
Cytology can be the first diagnostic tool for detection of various
bacterial, fungal, viral, and parasitic agents. Presence of abundant
macrophages, neutrophils, or multinucleated giant cells with or
without granuloma formation should alarm the cytologist about
the possibility of an infectious process.10
Bacterial Infections
Most bacterial agents can be detected by using routine cytologic
stains, but some bacteria need to be identified by additional stains
SKINmed. 2011;9:2332
REVIEW
such as acid-fast (Mycobacteria and Nocardia species) or Warthin-
Starry (Bartonella henselae and spirochetes) stains. Cytology reveals
morphologic type of bacteria such as bacilli or cocci. Besides, most
bacteria can be classified as Gram-positive or Gram-negative by
Gram staining. Gram-positive bacteria appear purple or deep blue,
whereas Gram-negative bacteria appear red or pink.9
Bullous impetigo. Cytologic features are highly sensitive
(92%) and specific (100%) for bullous impetigo.16 Scraping
smear of bullous impetigo lesions shows acantholytic cells, abun-
dant neutrophils, and clusters of cocci. Some of the acantholytic
cells are dyskeratotic. Gram-stained specimens reveal clusters
of Gram-positive cocci. By contrast, cocci are not observed in
staphylococcal scalded skin syndrome (SSSS), because this dis-
ease is caused by an exfoliative toxin of Staphylococcus aureus that
causes an infection in a distinct area.6,13
Tuberculosis. Mycobacteria cannot be identified by routine
cytologic stainings; therefore, unstained bacilli are observed as
negative images or ghost bacilli. Acid-fast staining discloses
pink or red bacilli. Presence of these acid-fastpositive bacilli is
highly probable in lesions that show caseation necrosis with or
without granulomas.27
Leprosy. Interpretation of cytologic findings is probably most
difficult in leprosy due to the variable morphology of Mycobacteri-
um leprae. Acid-fast bacilli can appear in rod-shaped, fragmented,
or granular forms. The bacilli are easily detected in patients with
lepromatous leprosy; however, they are very few in number in tu-
berculoid leprosy. In reactional leprosy, smears show numerous
foamy macrophages with negative images of M leprae.28
Fungal Infections
Potassium hydroxide (KOH) is usually used for the identification
of superficial fungal infections. The fungal elements of those infec-
tions can also be detected in Papanicolaou, Giemsa, or methylene
bluestained smears. Some deep fungi can be identified according
to the morphologic characteristics of their hyphae on direct micro-
scopic examinations or stained smears (Table).9 In suspected cases,
confirmatory stains such as GMS and PAS can be performed.10
Viral Infections
Viruses cannot be detected by examining smears under a light
microscope, but their cytopathic effects can be observed.9,10
Herpesvirus infections. The most specific but difficult to find
cytologic features of herpetic infections are nuclear changes,
namely prominent eosinophilic inclusion bodies (Cowdry A nu-
clei) resembling eggs in a basket. For detection of these nuclear
changes, Papanicolaou and Romanowsky stains are the most
26 The Tzanck Smear Test
 January/February 2011
valuable cytologic stains.9 The specificity of acantholytic and
multinucleated giant cells (Figure 2A) for herpetic infections has
been reported to be 100%.16 Acantholytic cells are large round
keratinocytes with hyperchromatic nuclei and scanty basophilic
cytoplasm. The basophilic staining is peripherally deeper on the
cell membrane (mourning-edged cells) leading to a perinuclear
halo. Due to cytopathic effects of herpes virus, multinucleated
giant cells contain 3 syncytial nuclei, and they sometimes swell
enormously to a diameter of 60 to 80 mm (ballooning degenera-
tion).1 Presences of acantholytic and multinucleated giant cells
in herpetic infections have been reported between 53.1%29 and
86%.30 These differences are related to the types and duration of
the lesions. Positivity of those cells is decreased after 3 days and
much higher in vesicles than pustules.31 Cytologically, differen-
tiation between herpes simplex and varicella zoster virus infec-
tions can be made by direct immunofluorescence examination
using monoclonal antibodies against herpes simplex virus and
varicella zoster virus.32
Hand, foot, and mouth disease. Coxsackie virus induces syn-
cytial nuclei in epithelial cells and causes vesicles and aphthous le-
sions (Figure 2B). The size of each nucleus in giant cells is uniform.
The number of nuclei is less than that in herpetic infections. Papa-
nicolaou staining may disclose intracytoplasmic inclusion bodies.33
In contrast to herpetic infections, acantholytic cells are not observed
in hand, foot, and mouth disease.1
Human papillomavirus infections. Cytology is useful in
oral or genital warts, but it may be difficult to obtain adequate
materials from cutaneous lesions. Cytologic evidence of human
papillomavirus infections includes koilocytes with basophilic
nucleus and punched-out perinuclear halo surrounded by a
dense peripheral cytoplasm. Small eosinophilic inclusion bod-
ies may seldom be observed in both cytoplasm and nucleus. All
these features can be more easily seen in specimens stained with
Papanicolaou stain than with other stains.12
Molluscum contagiosum. Unlike other DNA viruses, the
Molluscum contagiosum virus replicates in the cytoplasm of ke-
ratinocytes, leading to oval, large (3035 mm), deeply basophilic
intracytoplasmic inclusion bodies, the so-called molluscum bodies
or Henderson-Patterson bodies (Figure 2C). It is difficult to ob-
serve the nuclei of infected cells.1
Milkers nodule and orf. Milkers nodule and orf, caused by
the Parapoxviruses, induce round or oval cytoplasmic eosino-
philic inclusion bodies in keratinocytes known as Guarnieris
bodies, which are usually surrounded by a clear halo (Figure
2D). There are also a variable number of acantholytic cells, ne-
crotic keratinocytes, and inflammatory cells in the background.13
SKINmed. 2011;9:2332 27
REVIEW
Figure 2. Acantholytic cell (red arrows), multinucleated giant
cell (white arrow), and intranuclear inclusion bodies (black
arrows) in herpetic infection (A); syncytial nuclei (arrow) in
hand, foot, and mouth disease (B); Henderson-Pattersons
bodies (arrows) in molluscum contagiosum (C); and Guarnieris
bodies (arrows) in orf (D). Rapid Papanicolaou (cytocolor)
stain, magnification 1000 (A); May-Grnwald-Giemsa stain,
magnification 1000 (BD).
Parasitic Infections
Leishmaniasis. A diagnostic finding for cutaneous leishmaniasis
is ellipsoid-shaped parasites with a 2- to 4-mm, eccentric nucleus
and paranuclear kinetoplast in the cytoplasm of macrophages and
giant cells, also in granulomas or extracellular background. A large
number of parasites within the cytoplasm of macrophages appear in
a swarm of bees formation.1,12 Positive findings of parasites have
been reported to be between 30%34 and 82.6%.35 These differences
are related to the duration of lesions, the smear method, and the
presence of secondary bacterial infections. Positive results of para-
sites are especially high in the first 6 months of infection; afterwards,
it declines.36 The longer the duration of the disease, the higher the
possibility of the presence of granulomas and multinucleated (Lang-
hans type and/or foreign body type) giant cells in the lesions.7
Demodicosis, scabies, and cutaneous ameobiasis. Demo-
dex mites are between 0.3 mm and 0.4 mm and live in hair follicles
of mammals. They have 4 pairs of short legs and cross-striations on
the abdomen. Demodicosis is not usually included in the differential
diagnoses of dermatologists or the diagnosis is frequently masked by
other skin diseases. The diagnosis of demodicosis needs both compat-
ible clinical features and the presence of a high density of mites (>5
mites/cm2). Standardized skin surface biopsy is a better diagnostic tool
for demodicosis than direct microscopic examination of fresh secre-
tions from sebaceous glands.37 Definitive diagnosis of scabies is made
The Tzanck Smear Test
 January/February 2011
Figure 3. A normal keratinocyte (red arrow) and an acantho-
lytic cell (black arrow) (A); acantholytic cells phagocyted by a
multinucleated giant cell (arrows) (B); Sertolis rosette cells,
an epithelial cell at the center surrounded by a ring of leuko-
cytes (arrow) (C); and immunoglobulin G deposition around
the acantholytic cell (arrow) (D) in pemphigus. May-Grnwald-
Giemsa stain, magnification 1000 (AC); direct immunofluo-
rescence examination, magnification 1000 (D).
by microscopic identification of Sarcoptes scabiei (KOH examination)
in skin scrapings taken from the burrows or vesicles. This mite has 4
pairs of legs, multiple cuticular spines, and measures 0.3 mm.14 Direct
specimens or PAS and acid phosphatasestained specimens in cases
with doubtful direct specimens show trophozoites of Entamoeba his-
tolytica (1540 mm) with finger-shaped pseudopods.15,25
Immunobullous Disorders
Pemphigus
Pemphigus is characterized by numerous single or loosely adherent
clumps of acantholytic cells with rounded or ovoid, mostly smooth,
or occasionally serrated surface. The most distinctive features of
those cells are the presence of a large hyperchromatic, usually cen-
trally situated, nucleus and pronounced nucleoli.38 The cytoplasm is
scanty, usually basophilic and darker at the periphery (mourning-
edged cells) (Figure 3A).1 Tadpole cells are usually few in number,
but more than 10 tadpole cells (at 100 magnification) are observed
in pemphigus herpetiformis.16 In chronic cases, multinucleated gi-
ant histiocytes can rarely be seen. These multinucleated giant histio-
cytes frequently phagocytize the acantholytic cells (Figure 3B).39 In-
flammatory cells are mainly neutrophilic and eosinophilic. Sertolis
rosette cells consist of an epithelial cell at the center, surrounded
by a ring of leukocytes, and streptocytes are the chains of white
blood cells (Figure 3C).6 Direct immunofluorescence or immuno-
histochemistry studies in smear show the typical immunoreactant
SKINmed. 2011;9:2332 28
REVIEW
deposition around the acantholytic cells and increase the specificity
of the Tzanck smear test for pemphigus (Figure 3D).26,38
Acantholysis is a typical finding in the pemphigus group of autoim-
mune bullous diseases; however, it can also be observed in other skin
disorders. The specificity of acantholytic cells for pemphigus has been
found to be 43.4%.16 Based on the cytologic findings, an algorithmic
approach to acantholytic dermatoses has previously been proposed.16
Erythema Multiforme
Cytology reveals necrotic epithelial cells, leukocytes, and fibrin
filaments.1 Nuclear pyknosis, karyorrhexis, and fragmentation of
keratinocytes may be present in early lesions.16 A Tzanck smear
may also be a rapid test to distinguish toxic epidermal necrolysis
from SSSS. Toxic epidermal necrolysis shows necrotic cuboidal
basal cells and leukocytes, whereas SSSS specimens reveal large,
superficial squamous cells and dyskeratotic acantholytic cells
without inflammatory cells and cocci.19
Genodermatoses
Hailey-Hailey Disease
Cytology of Hailey-Hailey disease is characterized by numerous ac-
antholytic cells that mostly show round and uniformly hypertrophic
nucleus and basophilic cytoplasm. Occasionally, dyskeratotic cells
with pyknotic nucleus may also be seen.12 Unlike the pemphigus
group, direct immunofluorescence test on smears is negative.16
Dariers Disease
Cytologic findings of Dariers disease are diagnostic. Similar to his-
topathologic examination, cytology reveals dyskeratotic acantholyt-
ic cells, corps ronds, and grains. Corps ronds are pyknotic kera-
tinocytes with a round-shaped and hyaline, acidophilic cytoplasm,
and a pyknotic nucleus surrounded by a clear halo. The grains are
the end-product of the corps ronds. The nuclei of grains are ovoid
and are surrounded by a homogeneous dyskeratotic material.1,13
Spongiotic Dermatitis
In spongiotic dermatitis, the nuclei of keratinocytes that form
the wall of spongiotic vesicles are pushed to one side due to the
pressure of intraepidermal edema, and the cytoplasm takes the
form of a tail (tadpole cells). The presence of tadpole cells in cy-
tologic examination usually refers to contact dermatitis. Tadpole
cells, however, may also be observed in many other skin diseases.
It has been reported that the presence of more than 10 tadpole
cells at 100 magnification is 83% sensitive and 100% specific
for spongiotic dermatitis.17 Lymphocytes are the predominant
cells in the majority (84%) of allergic contact dermatitis cases,
whereas polymorphonuclear leukocytes outnumber the lympho-
cytes in most (82%) irritant contact dermatitis cases.18
The Tzanck Smear Test
 January/February 2011
Granulomatous Diseases
Characteristic cytologic findings of granulomatous dermatitis are
granuloma formation and multinucleated giant cells of Langhans,
foreign body, and/or Touton types (Figure 4A). Cytology may also
reveal various infectious agents (Figure 4B4H). Furthermore,
Touton-type giant cells in juvenile xanthogranuloma (Figure 4I),
a foreign body in foreign body granuloma (Figure 4J), necrobiotic
material in necrobiosis lipoidica (Figure 4K), and mucinous mate-
rial in granuloma annulare (Figure 4L) can also be observed. An al-
gorithmic approach to granulomatous dermatitis based on cytologic
findings has been previously proposed.7
Neonatal Pustular Diseases
The Tzanck smear test is helpful in the differential diagnosis of neo-
natal pustular diseases. In both acropustulosis of infancy and transient
neonatal pustular melanosis, abundant neutrophils and few eosino-
phils are observed. A Tzanck smear of pustules in erythema toxicum
neonatorum, however, reveals a dense accumulation of eosinophils.
All 3 dermatoses show neither bacteria nor fungal agents.19
Tumoral Lesions
Benign Tumoral Lesions
Mastocytoma. The Tzanck smear test is useful for rapid di-
agnosis of mastocytoma in children. Cytology shows abundant
polygonal, triangular, or round mast cells (1520 mm) with
metachromatically stained granules (0.20.5 mm). Granules are
stained basophilic with MGG, while stained reddish purple with
methylene blue (Figure 5A).6
Sebaceous hyperplasia. Scraping smear shows clusters of
large foamy sebaceous cells with abundant cytoplasms (Figure
5B). Unlike sebaceous carcinoma, cellular atypia is absent. Lipid
staining is positive.5
Seborrheic keratosis. Cytologically, a seborrheic keratosis
shows hyperkeratosis, basaloid cells, and horny cystic areas filled
with keratin (Figure 5C). Pigment granules are observed in both
nucleated and enucleated keratinocytes and also in the back-
ground. If lesions are flat or ulcerated, they may be mistaken for
basal cell carcinoma (BCC).6
Melanocytic nevi. Cytologic examination presents epidermal
and dermal type melanocytic cells (Figure 5D); however, cytologic
differentiation of the benign nevoid cells from the malignant ones
may be difficult.20
Malignant Tumors
The Tzanck smear test is useful in differentiating BCC from
other skin tumors such as squamous cell carcinoma (SCC) and
SKINmed. 2011;9:2332
REVIEW
Figure 4. Granuloma (red arrow) and a foreign bodytype
giant cell (black arrow) in scrofuloderma (A); bacterial balls
(arrow) in botryomycosis (B); acid-fast Mycobacterium leprae
(arrows) (C) and negative images (arrows) (D) in leprosy;
pseudohyphae (black arrows) and spores (red arrow) in
candidiosis (E); dichotomous hyphae with 45-degree angle
branching (arrows) in aspergillosis (F); broad-based budding
spores (arrow) in blastomycosis (G); Leishman-Donovan bodies
in a macrophage, swarm of bees fashion (arrow) (H); Touton-
type giant cell (arrow) in juvenile xanthogranuloma (I); foreign
bodies (arrows) in foreign body granuloma (J); necrobiosis
in necrobiosis lipoidica (K); and mucin in granuloma annulare
(L). May-Grnwald-Giemsa stain, magnification 1000 (A, B,
D, HL); Erlich-Ziehl-Nielsen stain, magnification 1000 (C);
Methylene blue stain, magnification 1000 (EG).
melanoma.5 For this reason, it could make a great contribution
to preoperative surgical planning. The Tzanck smear test can also
be used for the investigation of a possible recurrence of a previ-
ously treated neoplasm and for the follow-up of patients with
chronic dermatoses in whom the development of a malignancy is
possible. Furthermore, a previous study showed the effectiveness
of a Tzanck smear test for intraoperative surgical margin control
in the treatment of well-demarcated BCC.40
Basal cell carcinoma. Clusters of basaloid cells are the most
characteristic cytologic pattern for BCC (Figure 6A). This cytologic
finding has high sensitivity (97%) and specificity (86%) for BCC.41
Basaloid cells are uniform in size, elongated, and have a central oval
nucleus usually without nucleoli and scanty, poorly defined baso-
philic cytoplasm. Nuclear dysplasia1,12 and clusters of spindle-shaped
cells5 may rarely be seen. Furthermore, the adenoid type shows small
dark basaloid cells in pseudoglandular arrangement, and the spaces
between the cells are filled with a myxoid substance. Keratotic-type
BCC reveals keratin structures and atypical keratinocytes, whereas
29 The Tzanck Smear Test
 January/February 2011
Figure 5. Mast cells (arrow) in mastocytoma (A); clusters of
sebocytes (arrow) in sebaceous hyperplasia (B); horny cyst
(arrow) in seborrheic keratosis (C); and nevoid cells (arrows)
in compound nevus (D). Methylene blue stain, magnification
1000 (A); May-Grnwald-Giemsa stain, magnification 1000 Kaposis sarcoma. Cytologic examination of lesions in Ka-
(B, D); May-Grnwald-Giemsa stain, magnification 100 (C).
pigmented BCC shows melanin granules in the macrophages and
epithelial cell groups and in the background.22
Squamous cell carcinoma. The characteristic feature is cyto-
logic atypia of keratinocytes, namely, poikilokaryosis, poikilocytosis,
nuclear contour irregularity, prominent nucleoli, nuclear molding,
and mitosis (Figure 6B). In very poorly differentiated tumors, bizarre
nuclei, multinucleated giant cells, and spindle-shaped keratinocytes
may also be observed.5,12 In contrast to BCC, SCC does not show
adherent clusters of small cells.1 These cytologic findings of SCC are
sometimes difficult to differentiate from those of keratoacanthoma
and Bowens disease.5,12 Thus, histopathologic examination should be
made for the definitive diagnosis.6
Melanoma. Cytologically, melanoma is characterized by the
presence of large pleomorphic cells that may be epitheloid, spin-
dle-shaped, rounded or mixed-type (Figure 6C). Binucleated or
multinucleated cells are frequently present. Pathognomonic fea-
tures are binucleated melanocytes with two symmetric and con-
vergent nuclei (fly-eye nuclei).6 The nucleus may be irregular
and include a large eosinophilic nucleolus. Well-defined punched-
out intranuclear inclusions are characteristic of melanoma.12 Mel-
anin granules may be found in the palely basophilic cytoplasm of
cells, melanophages, and in the background.5 Cytologic diagnosis
of amelanotic melanoma is difficult because the tumors can be
mistaken for metastatic carcinoma. Recently, with the advances
in immunohistochemical staining techniques, correct diagnosis
SKINmed. 2011;9:2332 30
REVIEW
is possible in the majority of cases with amelanotic melanoma.
Immunohistochemically, S-100 staining is more sensitive but less
specific, and HMB-45 staining is less sensitive but more specific.42
Cutaneous lymphoma. Patch lesions of mycosis fungoides
show nonspecific features, while plaques and tumors show abun-
dant, noncohesive, atypical lymphocytes with cerebriform nuclei
(Figure 6D).12 Papanicolaou staining discloses folds or irregular nu-
clear membranes of nuclei. A scanty cytoplasm surrounds a round
nucleus, but the cytoplasms are generally abundant and the nuclei
show high mitotic activity in cells of anaplastic large cell lymphoma.
Classification of lymphocytes can be made by performing an im-
munohistochemical study on smears.22
Pagets disease. Cytology helps to make an early diagnosis of
Pagets disease. It reveals isolated or clusters of Pagets cells that
have round to ovoid eccentric nuclei, dense chromatin, and
prominent nucleoli. Cytoplasm contains microvacuoles, mu-
cine, and occasionally granular melanin.1
posis sarcoma shows single or cohesive bundles of cigar-shaped
spindle cells with occasional single prominent nucleolus (Figure
6E). The cytoplasms of the tumor cells are indefinite and baso-
philic. These cells are positive for CD31 and CD34.22
Miscellaneous
Cytology has also been used for the diagnosis of various cuta-
neous malignant tumors such as metastatic carcinoma, Merkel
cell carcinoma, sebaceous carcinoma, and histiocytosis. It is
of utmost importance that the immunohistochemical study is
performed for the cytologic diagnosis of the above-mentioned
diseases (Figure 6F),5,12,22 because cytologic diagnosis of tumoral
lesions can sometimes be difficult due to overlapping cytologic
features of certain tumors and tumor-like conditions.22
Conclusions
The Tzanck smear test can be used not only in the diagnosis but also
in the treatment and follow-up of many skin diseases. The studies
reporting the diagnostic value of a Tzanck smear test in erosive-vesic-
ulobullous lesions are limited in the literature.1618,29 Further cytologic
studies are needed for granulomatous and tumoral diseases. Diagnos-
tic efficacy and utility of the Tzanck smear test can be increased by
performing histochemical, immunohistochemical, or immunofluo-
rescence studies when needed. If the Tzanck smear test is performed
in a laboratory in some countries, such as in the United States, Cana-
da, or Australia, it may be essential to comply with the certain labora-
tory quality regulations and accreditation standards. We believe that
the value of cytology will be better understood in the future by more
frequently using the Tzanck smear test in daily dermatology practice.
The Tzanck Smear Test
 January/February 2011 REVIEW

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pes simplex or zoster virus infections by immunofluorescence:
comparison with Tzanck cell preparations and viral culture. Br
Dent J. 1989;167:235238.
33 Froeschle JE, Nahmias AJ, Feorino PM, et al. Hand, foot, and
mouth disease (Coxsackievirus A16) in Atlanta. Am J Dis Child.
1967;114:278283.
34 Dar NR, Khurshid T. Comparison of skin smears and biopsy
specimens for demonstration of Leishmania tropica bod-
ies in cutaneous leishmaniasis. J Coll Physicians Surg Pak.
2005;15:765767.
35 Rahman S, Bari A. Laboratory profile in patients of cutaneous
leishmaniasis from various regions of Pakistan. J Coll Physicians
Surg Pak. 2003;13:313316.
36 Weigle KA, de Dvalos M, Heredia P, et al. Diagnosis of cutane-
ous and mucocutaneous leishmaniasis in Colombia: a compari-
son of seven methods. Am J Trop Med Hyg. 1987;36:489496.
37 Akin U, Sekin D. Comparison of the two techniques for mea-
surement of the density of Demodex folliculorum: standardized
SELF-TEST REVIEW QUESTIONS
W. Clark Lambert, MD, PhD, Section Editor
Instructions: For each of the following numbered questions, choose the most appropriate lettered response(s).
1) Corps ronds and grains, seen on Tzanck smear test of a
characteristic lesion, are indicative of:
a. bullous pemphigoid
b. Darier disease
c. erythema multiforme
d. Hailey-Hailey disease (benign familial Pemphigus)
e. pemphigus vulgaris
f. None of the above
2) Which of the following, seen on Tzanck smear test, is consistent
with herpesvirus infection but not Coxsackie virus infection?
a. Acantholytic cells.
b. Characteristic inclusions.
c. Multinucleated epidermal giant cells.
d. Visualization of characteristic changes using the Papanico-
laou stain.
e. Visualization of characteristic changes using the Romanowsky
stain.
3) Of the following, a Touton-type giant cell, seen on Tzanck
smear test, is most characteristic of:
a. foreign body granuloma
b. granuloma annulare
c. juvenile xanthogranuloma
d. necrobiosis lipoidica
e. None of the above
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;9:2332 32
REVIEW
skin surface biopsy and direct microscopic examination. Br J
Dermatol. 2010;162:11241126.
38 Kobayashi TK, Kaneko C, Sugishima S, et al. Scrape cytology
of oral pemphigus. Report of a case with immunocytochemistry
and light, scanning electron and transmission electron micros-
copy. Acta Cytol. 1999;43:289294.
39 Medak H, Burlakow P, McGrew EA, et al. The cytology of vesicu-
lar conditions affecting the oral mucosa: pemphigus vulgaris.
Acta Cytol. 1970;14:1121.
40 Baba M, Durdu M, Sekin D. A useful alternative approach for
the treatment of well-demarcated basal cell carcinoma: surgical
excision and margin control with Tzanck smear test. Dermatol
Surg. 2010;36:659664.
41 Bakis S, Irwig L, Wood G, et al. Exfoliative cytology as a diagnos-
tic test for basal cell carcinoma: a meta-analysis. Br J Dermatol.
2004;150:829836.
42 Lai R, Redburn J, Nguyen GK. Cytodiagnosis of metastatic amelanotic
melanomas by fine-needle aspiration biopsy: adjunctival value of immu-
nocytochemistry and electron microscopy. Cancer. 1998;84:9297.
4) A dense accumulation of eosinophils, seen on Tzanck smear test
of a characteristic lesion, is most indicative of:
a. acropustulosis of infancy
b. erythema toxicum neonatorum
c. transient neonatal pustular melanosis
d. All of the above
e. None of the above
5) Which of the following, seen on Tzanck smear test of a character-
istic lesion, are characteristic of toxic epidermal necrolysis (TEN)
but not staphylococcal scalded skin syndrome (SSSS)?
a. Dyskeratotic acantholytic cells without cocci.
b. Epidermal giant cells with hyperchromatic, molded nuclei.
c. Large superficial squamous cells.
d. Leukocytes.
e. Necrotic cuboidal basal cells.
ANSWERS TO SELF-TEST REVIEW QUESTIONS:
1) b, 2) a, 3) c, 4) c, 5) d, e
The Tzanck Smear Test
Available soon...

A New Tretinoin Therapy

From Triax Pharmaceuticals

2010 Triax Pharmaceuticals, LLC. All Rights Reserved. Printed in USA TX-0610-02
 January/February 2011 Volume 9 Issue 1

Review

Fatigue in Psoriasis With Arthritis

Claudio Carneiro, MD; Mario Chaves, MD; Gustavo Verardino, MD; Alessandra Drummond, MD;
Marcia Ramos-e-Silva, MD, PhD; Sueli Carneiro, MD, PhD

Abstract

Patients have frequently described fatigue in association with chronic diseases, including cancer and a host of neurologic, metabolic, and
psychiatric diseases. Fatigue can be influenced by factors such as the activity of the disease, medication, age, sex, and duration of symptoms.
It presents a multidimensional influence with expression on physical, emotional, cognitive, and even social aspects of life. Fatigue also
coexists and often interacts with other factors, including disturbance of mood, anemia, infections, fever, pain, sleep, and stress, making its
evaluation complex. Psoriasis is a systemic inflammatory and chronic disease that can be widespread and recurrent. Patients with psoriatic
arthritis have reduced physical activity (associated with pain, inflammation of joints, muscle hypotrophy, reduced muscular strength, and
resistance), reduction of self-esteem, and depression and reduction of quality of life, leading to common somatic manifestations such as
fatigue and sleep disturbances. (SKINmed. 2011;9:3437)

P
soriasis is a universal, recurrent, chronic, and systemic in-
flammatory disease that affects about 2% of the worlds
population. It is polygenic, with unquestionable genetic
predisposition, and it is influenced by environmental factors. Joint
involvement appears in 40% of patients, and the most common is
the asymmetric oligo/polyarticular form. The articular disease has a
variable evolution, but, in 20% of patients, it is intense, debilitat-
ing, and disabling.13 Among the several systemic manifestations of
the disease, as well as its association with the metabolic syndrome,
fatigue in psoriasis patients has recently drawn great interest.3
In clinical practice, fatigue has frequently been described by patients
with chronic diseases. It is the most common symptom reported
by cancer patients and is almost omnipresent among patients with
other chronic diseases. It may be influenced by factors such as dis-
ease activity, medication, age, sex, and duration of the symptoms.46
Fatigue encompasses a multidimensional expression that influences
on a physical, emotional, and cognitive level, even on the social as-
pects of life.6,7 It frequently coexists and interacts with other fac-
tors, including mood disturbances, anemia, infections, fevers, pain,
sleep, and stress, making its assessment complex.7,8 The importance
and relation between fatigue and quality of life were researched and
documented among various diseases such as cancers, multiple scle-
rosis, systemic lupus erythematosus, chronic viral diseases includ-
ing acquired immune deficiency syndrome, chronic kidney disease,
chronic liver disease, and rheumatoid artrithis.610
Fatigue
In Dorlands Illustrated Medical Dictionary, fatigue is defined as
a state of increased discomfort and decreased efficiency result-
ing from prolonged or excessive exertion and loss of power or
capacity to respond to stimulation.11
Acute fatigue affects healthy individuals, including sport participants
such as speed racers, short-distance swimmers, and speed cyclists. It
arises due to the exaggerated energetic substrate in a low-oxygen in-
take environment and thus results in low performance.6 Another type
of fatigue occurs in marathon runners, resistance swimmers, tour cy-
clists, and long-shift heavy task workers, where the energy production
is made in an aerobic manner, at a high performance rate, and where
the cardiorespiratory conditions are fundamental. There are types of
fatigue associated with chronic diseases, infectious diseases, psychiat-
ric disorders, and exogenous intoxication, in which the manifestations
may be acute or chronic and often overshadow the manifestations of
the main disease.6 Certain medications such as methotrexate, used for
treatment of psoriasis, may present an inexplicable tiredness as an ad-
verse effect, which the patients may refer to as fatigue.1 Besides these fa-
tigue types, there are others in which no physical or mental disease may
be identified, forming a nosologic entity currently referred to as chronic
fatigue syndrome, to which chapters of medical books are dedicated.8
The original fatigue sites may be divided in two areas: one whose com-
pounds are peripheral and another where they are central. Peripheral
mechanisms are scientifically grounded and result from the failure in

From the Sector of Dermatology and Post-Graduation Course in Dermatology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 143/C-32, 22280-020, Rio de Janeiro, Brazil
E-mail: ramos.e.silva@dermato.med.br

SKINmed. 2011;9:3437 34 2011 Pulse Marketing & Communications, LLC

 January/February 2011
the contraction process, such as neuromuscular transmission difficul-
ties.12 Central fatigue, often referred to as psychological factors, like-
ly to affect negatively performance, are based on the impossibility to
explain the muscular failure despite an appropriate fuel offer to an
apparently normal working organ. The fatigue observed in infectious
and post-surgery settings or post-injury recovery is not yet clarified.10
Fatigue manifestations, as observed by the reduction in the ability to
produce a certain strength, appear immediately after the beginning of
intense activity. Where such activity is sustained, fatigue may persist
for days or even weeks. The mechanisms responsible for performance
limitation are several.6,12,13
At the muscular cell level, adenosine-5-triphosphate (ATP) use is dra-
matically accelerated to meet the required energy for excitement and
contraction, leading to metabolic fatigue. Glycogen is the fundamental
fuel, and fatigue will occur when exhausted in cell stocks. The intense
activity may also result from nonmetabolic fatigue as a consequence of
internal structure rupture and cytoskeletal muscular damage.14,15
The sensation of fatigue has been described by many arthritis patients
but was only recently included in the Outcome Measures in Rheu-
matology Clinical Trials (OMERACT) meetings, a nucleus of studies
of clinical measures and models in rheumatology.1618 The Group of
Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has been
including fatigue in its recent discussions.19,20 The relevance of fatigue
in the evolution of disease, however, is unknown, with regard to how
to precisely measure or to what extent treatments may interfere with
it. Concerning rheumatoid arthritis fatigue, some studies point to
predictive factors such as intense pain, bad sleep quality, sedentariness,
and functional limitations being more prevalent in women.21 There is
a lack of studies on the subject of psoriatic arthritis.
Fatigue has been observed in different self-assessment scales that mea-
sure aspects of life, and there is no common view about which would
be more or less reliable.16,18 Thus, quality of life, functional evaluation,
and visual analogical scales have been used.
In 1991, researchers retrospectively analyzed the prevalence of fatigue
in a medical clinic. In 1159 patients who completed the study, 276
(24%) presented fatigue as a primary complaint. Greater prevalence
was found among the female participants (two-thirds of the cases).
In this study, after having discarded the known clinical causes for fa-
tigue, by history, physical examination, and laboratory examinations,
a significant number of patients (in whom nothing physical was
detected) presented with anxiety or depression, symptoms that were
more valued by patients than by their doctors.22
In 1993, investigators analyzed patients seen in emergency departments
of general practice clinics. A total of 995 patients were identified with fa-
tigue complaints lasting more than 6 months, among whom 85 did not
present any clinical or psychiatric condition after careful assessment.23
SKINmed. 2011;9:3437 35
REVIEW
Physiopathology of Fatigue
In humans, fatigue is more central than peripheral and more psycho-
logical than physiological; nevertheless, it is very difficult to quantify
such facts. During very intense exercising, physical fatigue can arise in
a short span of time, while less intense exercises may be extended before
exhaustion voids the muscular work. The determining factor in the
appearance of effort fatigue is the voluntary muscular activity, in which
the feeding substrate is progressively reduced by exhaustion due to
accumulation of metabolites and lack of regulating mechanisms.6
Multiple factors accelerate the appearance of fatigue, which include
heat, humidity, altitude, and muscular fitness. Other factors delay
fatigue, such as pleasure, rhythm, motivation, knowledge of the
steps of a task to be performed, and physical fitness. Sex and age also
interfere in the establishment of fatigue.9,24
Chronic fatigue may appear following long-term activities without
sufficient rest for recovery or as a sensation of tiredness that is not
justified as cause from physical exercise.12
The endoplasmic reticulum of muscular fibers (sarcoplasmic reticu-
lum) stocks Ca2+ ions and has Ca volt-dependent channels. Myosin
has the capacity to hydrolyze ATP, which is enhanced by the Ca2+ ions
and inhibited by the Mg++ ions, and its maximum activity occurs in a
pH of 6.4. Actin also requires presence of Mg++ and Ca2+.25,26
It may be concluded that the alterations in proteins; the sarcolem;
Mg++, Ca2+, and KCl quantities; pH; and energy production (mito-
chondria, glycogen, phosphocreatine, and ATP) interfere with mus-
cular contraction and may thus cause fatigue.2527
From a neurologic point of view, fatigue is studied together with las-
situde. Fatigue would be weariness or exhaustion due to physical or
mental effort, while lassitude has a more restrictive meaning, tending
more to be a lack of capacity to remain physically or mentally active.2628
The intolerance to exercise (tiredness from small efforts) and fatigue
are common manifestations of myopathic diseases, in which the mus-
cles are primarily weakened, as occurs in myasthenia gravis, muscular
atrophy, post-poliomyelitis syndrome, in some glycogen storage dis-
eases, and mitochondrial myopathies. Fatigue is a frequent complaint
in multiple sclerosis. Patients with a neurologic disease characterized
by unresting muscular activity, such as in Parkinson disease, athetosis,
and Huntington chorea, complain about fatigue.2729
The reduction of productivity and work capacity caused by fatigue
was studied by industrial psychologists. In these studies, the impor-
tance of physical or mental motivational factors was clearly dem-
onstrated.14,30 Real muscular weakness cannot be detected in most
individuals who complain about fatigue. The individual affected
by fatigue is unable to handle complex problems and tends to be
less reasonable. The worker affected by fatigue cannot provide the
Fatigue in Psoriasis With Arthritis
 January/February 2011
necessary support to his family and often turns into the tyrant who
returns at night to join the family. Inferiority complexes may surface.
In neurologic and psychiatric departments, anxiety and depression
are frequently diagnosed in fatigued patients.31
Most patients who seek medical help due to unexplained chronic fa-
tigue present some kind of psychiatric disorder. The most frequent
symptoms are unrest, irritability, anxiety, depression, migraine, in-
somnia, drowsiness, and reduction in appetite and libido.31,32
Clinical Aspects of Fatigue
Fatigue may be acute (<1 month) or chronic (>1 month). In the
acute form, the most easily identified causes prevail.22
Almost all chronic diseases may be associated with fatigue. The differ-
ential diagnosis includes infections, anemia, neoplastic diseases, con-
nective tissue diseases, endocrinopathy, neurologic diseases, chronic
kidney diseases, chronic liver diseases, metabolic diseases and ionic
disorders, sleep disorders, psychiatric diseases, and many others.2729
Chronic fatigue syndrome is the current name of the disorder charac-
terized by severe disabling fatigue accompanied by other physical, con-
stitutional, and neurophysiologic complaints. The frequency is higher
among women (2:1), and patients are aged between 25 and 45 years,
although children and eldery patients have also been diagnosed.2729,33
Cases may occur in isolation or in groups. Famous outbreaks in-
clude those in Los Angeles County Hospital (1934), Royal Free
Hospital in London (1955), and Incline Village in Nevada (1985).
The etiology of such outbreaks, although suggestive of an infectious
etiology or other environmental factors, were not established.27,33,34
Chronic fatigue is very common and occurs in up to 20% of
the patients in general emergency clinics. The chronic fatigue
syndrome is far less common and affects between 100 to 300 per
100,000 individuals in the United States.33,34
The pathogenesis of chronic fatigue syndrome is controversial
and the attempted explanations include post-infectious and
post-viral states (Epstein-Barr virus, retrovirus, or enterovirus),
immunologic disorders, somatic worrying, or depression. Anti-
bodies against some of those viruses have already been detected
at a high rate among chronic fatigue syndrome patients, but the
subsequent studies failed to confirm any relation.29,33
Fatigue and Psoriasic Arthritis
Diseases with immune characteristics frequently include fatigue
among its symptoms. Psoriasis is one of the most common dermato-
logic/rheumatologic diseases and bears immunogenetic information
(HLA Cw6, HLA B13, HLA B17, B27, B57) in its physiopathology;
however, the study on the incidence or prevalence of fatigue in pso-
riatic arthritis or psoriasis patients was not found in the literature.2,35
SKINmed. 2011;9:3437
REVIEW
The presence of a psychiatric disorder in patients with skin diseas-
es, or resulting from them, is well known. Depression and anxiety
symptoms are frequent in psoriasis and/or psoriatic arthritis pa-
tients, possibly influencing fatigue symptoms.34 Psychiatric comor-
bidity in skin disease patients may reach 25% and keeps a greater
correlation with the quality of life score than with the clinical gravity
attributed by the doctor. The presence of psychiatric comorbidity
may be responsible, among other factors, for a greater perception of
symptoms, including fatigue.1,36
In rheumatoid arthritis, for example, fatigue is a relatively com-
mon symptom, affecting 90% of patients and, for half of them,
is the most upsetting aspect of the disease.37
Patients with rheumatoid arthritis intensively affected by fatigue
perceive their fatigue as frustrating or exhausting, while those
not intensively affected see fatigue as a normal phenomenon.37,38
The intensity of fatigue has been linked to age, pain, depressive
thoughts, worries, and sleep disorders.38 Fatigue in rheumatoid
arthritis, therefore, is more related to physical factors, depression,
and psychosocial factors than to inflammation. Only a small per-
centage of patients with rheumatoid arthritis can be classified as
being clinically depressed.39
Likewise, as in rheumatoid arthritis, patients with psoriatic arthritis
also experience a decrease in physical activity (due to pain, articu-
lar inflammation, muscle hypotrophy, reduction of strength, and
muscular resistance), reduction of self-esteem, and often depression
and reduction in the quality of life, which leads to common somatic
manifestations such as fatigue and sleep disorders.39 In addition, pa-
tients with psoriasis excessively worry about their disease and are
distrustful about the treatments. Patients with such profiles are the
ones who most complain about pain, pruritus, and fatigue.40
The severity of psoriasis used to be assessed only by the extension of
the dermatitis, leaving aside the assessment of fatigue, the quality
of life and anxiety, and depression symptoms. Psoriasis, however,
can provoke disabling and life-threatening disease.40 These effects
include stress, embarrassment, stigmata, and physical discomfort.
With time, the patients emotional compromise grows, in detri-
ment to his/her social involvement and drop in productivity in
school or work, as well as the loss in self-esteem. Systematic analy-
sis revealed fatigue as superior and different to normal tiredness,
and patients believe that it is linked to the diseases activity, bare
sleep, tension of the articular components, and lack of well-being.
It is considered more important than the articular symptoms.40
Conclusions
Fatigue is therefore a symptom of great relevance that has to be
measured and assessed in arthritis patients, including patients
with psoriasis.
36 Fatigue in Psoriasis With Arthritis
 January/February 2011
References
1 Gudjonsson JE, Elder JT. Psoriasis. In: Wolk K, Goldsmith LA, Katz
SI, Gilchrest BA, Paller AS, eds. Fitzpatricks Dermatology in Gener-
al Medicine. 7th ed. Columbus, OH: McGraw Hill; 2008:169193.
2 Wollina U, Unger L, Heinig B, Kittner T. Psoriatic arthritis. Derma-
tol Ther. 2010;23:123136.
3 Gudjonsson JE, Johnston A. Current understanding of the genetic
basis of psoriasis. Expert Rev Clin Immunol. 2009;5:433443.
4 Reid VL, Gleeson M, Williams N, Clancy RL. Clinical investigation
of athletes with persistent fatigue and/or recurrent infections.
Br J Sports Med. 2004;38:4245.
5 Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fa-
tigue syndrome. Clin Evid. 2004;12:15781593.
6 Skurvydas A, Brazaitis M, Streckis V, Rudas E. The effect of
plyometric training on central and peripheral fatigue in boys. Int
J Sports Med. 2010;31:451457.
7 Hainsworth KR, Davies WH, Khan KA, Weisman SJ. Co-occurring
chronic pain and obesity in children and adolescents: the impact
on health-related quality. Clin J Pain. 2009:25:715721.
8 Brown WJ, Mishra G, Lee C, et al. Leisure time physical activity
in Australian women: relationship with well being and symptoms.
Res Q Exerc Sport. 2000;71:206216.
9 Ishizaki Y, Ishizaki T, Fukuoka H. Changes in mood status
and neurotic levels during a 20-day bed rest. Acta Astronaut.
2002;50:453459.
10 van Hoogmoed D, Fransen J, Bleijenberg G, van Riel P. Physi-
cal and psychosocial correlates of severe fatigue in rheumatoid
arthritis. Rheumatology (Oxford). 2010;49:12941302.
11 Dorlands Illustrated Medical Dictionary. 28th ed. Philadelphia.
PA: Saunders; 1994:612.
12 Puetz TW. Physical activity and feelings of energy and fatigue:
epidemiological evidence. Sports Med. 2006;36:767780.
13 Millet GY, Divert C, Banizette M, et al. Changes in running pattern
due to fatigue and orienteering. J Sports Sci. 2010;28:153156.
14 Kristal-Boneh E, Froom P, Harari G, et al. Fatigue among Israeli in-
dustrial employees. J Occup Environ Med. 1996;38:11451150.
15 Main LC, Dawson B, Heel K, et al. Relationship between inflam-
matory cytokines and self-report measures of training overload.
Res Sports Med. 2010;18:127139.
16 Carr A, Hewlett S, Hughes R, et al. Rheumatology outcomes: the
patients perspective. J Rheumatol. 2003;30:880883.
17 Gladman DD, Mease P, Krueger G, et al. Outcome measures in
psoriatic arthritis: OMERACT VII Psoriatic Arthritis Workshop. J
Rheumatol. 2007;34:11591166.
18 Kirwan JR, Hewlett SE, Heiberg T, et al. Incorporating the patient
perspective into outcome assessment in rheumatoid arthritis
progress at OMERACT 7. J Rheumatol. 2005;32:22502256.
19 Gladman DD, Helliwell P, Mease PJ, et al. Assessment of pa-
tients with psoriatic arthritis: a review of currently available mea-
sures. Arthritis Rheum. 2004;50:2435.
20 Mease PJ, Gladmann DD, Krueger GG. Prologue: Group for
Research and Assessment of Psoriasis and Psoriatic Arthritis
(GRAPPA). Ann Rheum Dis. 2005;64:iilii2.
21 Escobar ME, Gerhardt C, Roesler E, et al. Anemia versus dis-
ease activity as cause of fatigue in rheumatoid arthritis. Acta
Reumatol Port. 2010;35:2428.
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22 Kroenke K. Chronic fatigue syndrome: is it real? Postgrad Med.
1991;89:4455.
23 Bates DW, Schmitt W, Buchwall D, et al. Prevalence of fatigue
and chronic fatigue syndrome in a primary care practice. Arch
Intern Med. 1993;153:27592765.
24 Jakobsson U. The epidemiology of chronic pain in a general
population: results of a survey in southern Sweden. Scand J
Rheumatol. 2010;39:421429.
25 Barbagallo M, Belvedere M, Dominguez LJ. Magnesium homeo-
stasis and aging. Magnes Res. 2009;22:235246.
26 Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C.
Changes in vitamin D levels in patients with systemic lupus ery-
thematosus: effects on fatigue, disease activity and damage.
Arthritis Care Res (Hoboken). 2010:62:11601165.
27 Barohn RJ. Muscles diseases. In: Goldman L, Ausiello D, eds. Cecil
Medicine. 23rd ed. New York, NY: Saunders; 2007: chapter 447.
28 Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity
scale. Application to patients with multiple sclerosis and system-
ic lupus erythematosus. Arch Neurol. 1989;46:1112111123.
29 Wessley S, Powell FR. Fatigue syndrome: a comparison of
chronic postviral fatigue with neuromuscular and disorders. J
Neurol Neurosurg Psychiatry. 1989;52:940.
30 Bultmann U, Kant I, Kasi SV, et al. Lifestyle factors as risk fac-
tors for fatigue and psychological distress in the working popu-
lation: prospective results from the Maastricht Cohort Study. J
Occup Environ Med. 2002;44:116124.
31 Khlat M, Chau N. Social disparities in musculoskeletal disorders
and associated mental malaise: findings from a population-based
survey in France. Scand J Public Health. 2010;38:495501.
32 Resch M. The psychological factors affecting athletic perfor-
mance. Orv Hetil. 2010;15:815821.
33 Bennett RM. Fibromyalgia and chronic fatigue syndrome. In:
Goldman L, Ausiello D. Cecil Medicine. 23rd ed. New York, NY:
Saunders; 2007: chapter 295.
34 Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wes-
selys (bio)psychosocial model versus a bio(psychosocial) mod-
el based on inflammatory and oxidative and nitrosative stress
pathways. BMC Med. 2010;8:35.
35 Winchester R. Psoriatic arthritis. In: Wolk K, Goldsmith LA, Katz SI,
Gilchrest BA, Paller AS, eds. Fitzpatrick`s Dermatology in General
Medicine. 7th ed. Columbus, OH: McGraw Hill; 2008:194206.
36 Gupta M, Gupta A. Psychodermtology: an update. J Am Acad
Dermatol. 1996;36:10301046.
37 Pollard LC, Choy EH, Gonzalez J, et al. Fatigue in rheuma-
toid arthritis reflects pain, not disease activity. Rheumatol.
2006;45:885889.
38 Repping-Wuts H, Fransen J, Van Achterberg T, et al. Persistent
severe fatigue in patients with rheumatoid arthritis. J Clin Nurs.
2007;16:377383.
39 Treharne GJ, Lyons AC, Hale ED, et al. Predictors of fatigue over
1 year among people with rheumatoid arthritis. Psychol Health
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40 Finlay AY. Quality of life measurement in dermatology: a practi-
cal guide. Br J Dermatol. 1997;136:305314.
Fatigue in Psoriasis With Arthritis
 January/February 2011 Volume 9 Issue 1

Core Curriculum
Virendra N. Sehgal, MD, Section Editor

Nail Biology, Morphologic Changes,

and Clinical Ramifications: Part I
Virendra N. Sehgal, MD;1 Ashok K. Aggarwal, MD;2 Govind Srivastava, MD;2 Kingsuk Chatterjee, MBBS2

The nail, a well-recognized and fascinating appendage of the skin, represents an invaluable clinical means to facilitate the diagnosis of a
number of dermatoses; hence, the authors considered it worthwhile to examine the physiopathologic alterations affecting the nail morphol-
ogy, including shape, attachment, surface, and color. The accurate definitions of nail abnormalities in various cutaneous disorders have been
delineated and their clinical ramifications have been recounted.

T
he nail is a dermal appendage formed through the in-
teraction of mesoderm and ectoderm.1 The nails serve
to protect the terminal phalanx and fingertip from trau-
matic impact2 and provide counter-pressure to the pulp that is
essential to the tactile sensation involving the fingers.1,2 Nails are
used for fine manipulations, scratching, protection, and beauti-
fication of the hand.1
Nails are a window to the interior of the body and provide im-
portant clues to an underlying disorder.3 They are often subject-
ed to trauma such as biting, chewing, breaking, or splitting and
exposed to the external environment. The desire for beautiful
nails is a universal phenomenon. The problem of nail trauma
has increased with procedures for adorning nails such as clean-
ing with a brush or removing cuticles with clippers and pushers,
leading to secondary infections. The most common allergens are
found in nail cosmetics such as nail enamel, artificial sculptured
nails, and preformed plastic tips. Contact dermatitis of the nail
unit is not an unusual event. It may present as onychodystrophy,
onycholysis, paronychia, or dermatitis.
Abnormalities of the nail may serve as an important clue to
cutaneous disease and may provide information about disease
or toxic exposures that occurred several months in the past.4 A
complete examination of the nail, therefore, should include the
shape, symmetry, and color of the nail plate, nail fold, cuticle,
and nail bed. Deposits under the nail plate and changes in gross
appearance, color, or shape of the nail unit should be evaluated.
Nail Biology
Anatomy
The nail plate is the permanent component of the nail matrix. Its
normal appearance and growth depends on the integrity of several
constituents: the surrounding tissues or perionychium and the bony
phalanx that contribute to the nail apparatus. The nail is proximally
inserted in an invagination practically parallel to the upper surface
of the skin and laterally in the lateral nail groove. This pocket-like
invagination has a roof, the proximal nail fold, and a floor, the matrix
from which the nail is derived. The germinal matrix forms the bulk
of the nail plate. The proximal element forms the superficial one third
of the nail, whereas the distal element provides its deeper two thirds.
The ventral surface of the proximal nail fold closely adheres to the
nail for a short distance and forms a gradually desquamating tissue.
The cuticle is made of the stratum corneum of the proximal nail fold.
The cuticle seals and therefore protects the ungual cul-de-sac. The nail
plate is bordered by the proximal nail fold, which is continuous with
the similarly structured lateral nail folds on each side. The nail bed
extends from the lunula to the hyponychium. The nail bed presents
parallel longitudinal rete ridges. This area has a firm attachment to
the nail plate, and nail avulsion produces a denudation of the nail
bed. Colorless but translucent, the highly vascular connective tissue
containing glomus organs renders a pink color to the nail (Figure 1).1
Developmental Anatomy
Individual digits are discernible from the 8th week of gestation.
Rudimentary nails appear by the 9th week. Nail field with the

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi,1 and the Skin Institute, School of Dermatology,
Greater Kailash, New Delhi2
Address for Correspondence: Virendra N. Sehgal, MD, Dermato-Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi
110 033 India E-mail: drsehgal@ndf.vsnl.net.in

SKINmed. 2011;9:3946 39 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Epidermis
Lunula
Posterior nail fold
Lateral nail fold
Cuticle
Nail Plate
Metacarpal bone
Vertical collagen fibres Hyponychium
Nail Bed
Nail matrix
Epidermis
Distal margin of lunula
Figure 1. Nail structure depicting its anatomic components.
matrix primordium underlying the proximal nail fold is well
formed by 13th week. The nail plate emerges from beneath the
proximal nail fold during the 14th week, the nail plate covers al-
most the whole nail bed by the 17th week, and the nail unit and
finger grow in tandem in the 20th week of gestation.5
The nail apparatus develops and matures from the primitive epi-
dermis between the 9th and 20th weeks of intra-uterine life. At the
20th week, the matrix cells show a postnatal type of cell division,
differentiation, and keratinization, then the nail plate begins to
move more distally. The nail bed at this stage loses its granular layer.
Physiology
Man has recognized the importance of nails in their finer func-
tions and in their existence as an extension of aesthetic beauty.
Adorning, painting, polishing, sculpturing, and using preformed
plastic tips have all found places in nail cosmetics, and such prac-
tice is at least as old as human civilization.6 While the desire for
beautiful nails is a universal phenomenon, the more humans ma-
nipulate their nails, the more profound the attendant complica-
tions.6 The structure of claws and hooves and their evolutionary
relationship to humans has recently been reviewed.
In generalized integumentary diseases, such as psoriasis, the nail ap-
paratus, hair follicle, and epidermis are affected. The main function
of the nail apparatus is to produce a strong, relatively inflexible, kera-
tinous nail plate over the dorsal surface of the end of each digit. The
nail plate acts as a protective covering for the fingertip. The flat nail
plate, by exerting counterpressure over the volar skin and the pulp,
allows precision and delicacy in many subtle functions of the fingers.7
The rectangular nail plate is the largest structure, resting on and firmly
adherent to the nail bed. Approximately one quarter of the nail is
covered by the proximal nail fold, and a narrow margin of the sides
SKINmed. 2011;9:3946 40
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of the nail plate is occluded by the lateral nail folds. Underlying the
proximal part of the nail is the half-moon lunule (white lunula7). It
is most prominent on the thumb and great toe and is partially/com-
pletely concealed by the proximal nail fold of other digits. The reason
for the white color is unknown. The natural shape of the free margin
of the nail is the same as the contour of the distal border of the lunula.
The nail plate distal to the lunula appears pink from its translucency,
allowing for the redness of the vascular nail bed to be seen through
it. The lateral nail fold and the adjacent tissue lateral to the nail fold
is also termed the nail wall.
The definition of the nail matrix appears debatable.8 It is considered
to be a localized region beneath the proximal nail, which produces the
major part of the normal nail plate, the germinal matrix. The ma-
trix can be subdivided into dorsal, intermediate, and ventral sections,
contributing by a lamellar fashion to the formation of the nail plate.
The nail plate may appear thick up to 30% as it passes from the distal
margin of the lunula to the end of the nail bed. This is not associated
with an increase in cell numbers, yet it may represent compaction of
the nail caused by distal tip trauma and may not be associated with
nail bed or plate production.9
Nail Abnormalities
Morphology
This situation may change with disease, where the nail bed changes
its histologic appearance to gain a granular layer10 and may contribute
a false nail of cornified epithelium to the undersurface of the nail.
At the point of separation of the nail plate from the nail bed, the
proximal part of the hyponychium may be modified as the solehorn.
Solehorn is a central thickened structure with a dermal core, typically
found on the toe of elderly persons, often associated with vascular
anomalies. On close examination, apart from white proximal lunula
and distal pink nail, another narrow, barely perceptible onychodermal
band has been described. Perhaps, its significance is that it has a blood
supply different from the main body of the nail bed. It becomes more
prominent in diseases such as acrocyanosis. If the tip of the finger is
pressed firmly, the band and an area just proximal to it blanch, and if
the pressure is repeated several times the band reddens.
Many changes in color have been described in the onychodermal
band in health and disease. Its structural significance lies in the
attachment of the nail plate and the nail bed. In psoriasis, separa-
tion of the nail plate from the nail bed may become progressive
if there is a breach in the onychodermal band.
The matrix is devoid of the granular layer, and cells may differentiate
with an expression of trichocyte hard keratin as they become incorpo-
rated into the nail plate, alongside normal epithelial keratins.11,12 Dur-
ing the process, the nuclei may be retained and such retained nuclei
Nail Biology
 January/February 2011 CORE CURRICULUM

are called Pertinax bodies. Electron microscopic studies have shown

that the other detail cytologic changes seen in the matrix epithelium
are essentially the same as seen in the epidermis.13,14 Matrix melano-
cytes in the nail are different from those elsewhere by their failure to
produce melanin in the normal circumstances in white persons. This
can change, with melanotic streaks presenting in local inflammatory,
nevoid, or neoplastic disease.15
The nail bed epidermis is only 2- to 3-cells thick, having no granu-
lar layer.10 The transitional zone from living keratinocytes to dead
ones in the ventral nail plate cell is abrupt, occurring in the space
of one horizontal cell layer. The loss of the overlying nail results in
the development of a granular layer, which is otherwise present only
in disease states.10,16 The nail plate comprises 3 horizontal layers,
namely: (1) a thin dorsal lamina, (2) the thicker intermediate layer,
and (3) a ventral lamina arising from the nail bed. Figure 2. Nails showing distal onycholysis, a salient feature of
psoriasis.
A transition between flattened cells dorsally and thicker cells ventral-
ly can be demonstrated at high magnification, while the contents of
each cell appear to show a uniform fine granularity similar to a hair
cuticle. The nail plate flexibility owes itself to significant amounts of
phospholipids, mainly in the dorsal and intermediate layer. The nail
bed dermal collagen is vertically oriented, being directly attached to
the phalange periosteum and the epidermal basal lamina.

Biochemical Changes in Nail Abnormalities

The nail plate is rich in calcium, as phosphate in the form of hydrox-
ylapatite crystals, and is intracellularly bound to phospholipids.17
Nail keratin analysis essentially shows the same fractions as that of
hair: fibrillar, low-sulfur protein; globular, high-sulfur protein; ma-
trix protein; and high glycine-tyrosinerich matrix protein.
Nail amino acid analysis in contrast to hair analysis reveals higher
cysteine, glutamic acid, and serine values but lower tyrosine val-
ues.12 Immunohistochemically trichocyte keratins have been de-
tected within the epithelial structures of the nail unit. In the nail, it
demonstrates a well-demarcated supra-basal region corresponding Figure 3. Fibrosis resulting in blurry cuticle resembling pte-
to the matrix.11 The distribution of the keratins in the nail bed and rygium, similar to that seen in Figures 7 and 9.
matrix has resulted in further understanding the molecular basis of
pachyonychia congenita, where the various nail manifestations are
Koilonychia, most commonly associated with iron deficiency, may be
found to correlate well with mutations within the keratin genes and
persistent in some children with a deficiency of cysteine-rich kera-
corresponding phenotypes.18 The nails are prone to develop ony-
tin.21 In dermatoses, such as psoriasis and dermatophyte infection,
choschizia or lamellar splitting in children younger than 5 years.19
nail bed hyperkeratosis may push the nail up distally to produce a
The subungual area, as a whole, in old age may show thickening of
spoon shaped nail.
blood vessel walls with vascular elastic tissue fragmentation.
Occupational koilonychias result from permanent wave solutions in
The nail plate often shows irregularities in the proximal nail-
hairdressers or from softening of the nail with oil in mechanics.22,23
generative region and thickening of the nail bed blood vessels
(Pertinax bodies). As the nail growth becomes inversely propor- While onychomadesis or nail loss has been associated with local der-
tional to age, the larger corneocytes seen in older age relate to the matoses such as bullous disorders and paronychia, it may manifest as
slower rate of growth of nail plates.20 a feature of generalized dermatoses such as toxic epidermal necrolysis

SKINmed. 2011;9:3946 41 Nail Biology

 January/February 2011
Figure 4. Beaus lines displaying transverse ridging resulting
from endogenous cause(s).
Figure 5. Nails depicting trachyonychia and transverse
grooves, with periunguinal psoriatic lesions and joint swelling
on the proximal interphalangeal joints.
and a rapid-onset pustular psoriasis. Scarring in lichen planus and that
following toxic epidermal necrolysis may result in onychomadesis.
Retinoids and large doses of cloxacillin and cephaloridine have been
known to cause temporary nail loss. In epidermolysis bullosa, nail
loss can be part of an inherited structural defect. Alopecia unguium
or onychoptosis defluvium is a periodic, atraumatic, familial, nonin-
flammatory nail loss, associated with dental amelogenesis imperfecta.
Onycholysis is the distal and/or lateral separation of the nail from
the nail bed.24 Psoriatic onycholysis is typically distal with variable
lateral involvement, and used as reference point for other forms of
onycholysis. Oil spots or a salmon patch appearance of the nail
is due to the accumulation of shed squames, sequestrated debris,
glycoprotein exudates, and air in the nail bed. The border of the
onycholysis appears in the nail bed as reddish brown from the un-
derlying inflammatory changes (Figure 2).
SKINmed. 2011;9:3946 42
CORE CURRICULUM
The diminished adherence of nail to nail bed could be primary and/
or secondary to trauma, fungal infection, eczema, or photo-onychol-
ysis.24,25 It is opined that onycholysis is one of the commonest nail
signs.26 Minor trauma sustained in some occupations could cause sec-
ondary onycholysis. Contact reactions may be because of use of nail
cosmetics or immersion of hands in soap and water resulting in reput-
ed trauma. Psoriasis, fungal infections, and dermatitis are also regarded
as fairly common causes of onycholysis.24 Photo-onycholysis has been
reported to occur during treatment with psoralens, demethylchlortet-
racycline, and doxycycline.27 A winged appearance of nail occurs when
a central fibrotic band proximally divides a nail into two.28 This condi-
tion has since been termed pterygium (Figure 3). The background and
sequence of events of pterygium29 are enumerated:
1. Pterygium formation is preceded by an inflammatory destruc-
tive process.
2. Fusion between the nail fold and the underlying nail bed are
prominent.
3. The fibrotic band, then, obstructs the normal nail growth.
4. Superficial abnormal blood vessels are apparent.
5. Skin markings are absent.
The preceding changes are well documented in lichen planus and
its variants and that following trauma. While longitudinal groove(s)
running across the whole or part of the nails longitudinal axis, of
the thumb in particular, may be normal, they can still be easily dis-
tinguished from pterygium, which prominently stands on the nail
surface and in which full thickness of the nails is involved.28
Dystrophia unguium mediana canaliformis is an entity first described
in 192830 where the nail is split, usually in the midline, with a fir
treelike appearance of ridges angled backward. It has been attrib-
uted to a definite history of trauma in some patients and to oral reti-
noids31 in others.
Transverse grooves, involving either full or partial thickness of the nails,
may be caused by exogenous/endogenous factors. An account of trans-
verse ridging of thumbnails was first described in 1966.32 They may
occur on isolated diseased digits as a result of trauma, inflammation, or
neurologic events. They may be generalized, reflecting a systemic event,
coronary artery disease, measles, mumps, or pneumonia. The trans-
verse grooves resulting from endogenous cause(s) are often referred to
as Beaus lines (Figure 4). Zinc deficiency has also been associated with
the condition. Accordingly, Beaus lines can be used as a useful clinical
marker. The margin of the line matching well with the proximal nail
fold and the distance of the groove from the nail fold represents the
time elapsed since the growth disturbance. Depth and the width of
the groove are proportional with duration and severity of the disease.33
Foci of parakeratosis, reflecting an isolated nail malformation in pso-
riasis, are cardinal.34 Clinically, they appear as punctate erosions on
Nail Biology
 January/February 2011 CORE CURRICULUM

the surface of the nails called pitting (Figure 5). The number, size,
and pattern of nail pits are often taken into account in differentiat-
ing between psoriasis and alopecia areata. Fewer, larger, and randomly
placed pits characterize psoriasis, while a large number of small, uni-
form, shallow pits arranged classically in a cross-hatched pattern are
indicative of alopecia areata (Figure 6), which might not always be the
case.35 When numerous, pitting may appear randomly distributed on
the nail surface or may show a geometric pattern. In the latter, there
may be rippling or a grid of pits. Trachyonychia is a result of exten-
sive pitting combined with other surface irregularities. Elkonyxis is
defined as an isolated large pit due to a localized full thickness defect
in the nail plate. Elkonyxis can result from a nail trauma or may be
associated with Reiter disease or psoriasis.

The term twenty-nail dystrophy (TND) in children was coined in

1977.36 TND is characterized by a pattern of changes affecting all
the nails. The term trachyonychia (from the Greek T paxoo, mean-
ing rough), described in 1979,37 is well suited to convey the clinical
appearance of the affected nails. TND syndrome is classified38 into
two groups: (1) loss of luster in all nails identified by vertical, striated
sand paper, and (2) shiny nails.

The French term sand-blasted nails was coined in 1978,38 wherein

detailed examination was performed on trachyonychia in TND.3946
TND was found to be associated with congenital etiology, autoim-
munity, ichthyosis vulgaris, alopecia areata, vitiligo, lichen planus,
and hematologic disorders.

In a recent overview of TND/trachyonychia,47 it was concluded that

the lesions are fairly representative and are characterized by alternat- Figure 6. Fine pitting in alopecia totalis progressing to universalis.
ing elevation and depression (ridging) and/or pitting, lack of luster,
roughening likened to sand paper, splitting, muddy grayish white
color, and prominent dystrophy (Figure 7). The diagnosis of TND
should primarily be made on the onset in infancy/childhood, occa-
sionally in adults, and confirmed by cardinal clinical features and mi-
croscopic pathology. Earlier, the role of longitudinal nail biopsy was
emphasized in diagnosing TND.48

Common skin diseases such as psoriasis, lichen planus, alopecia area-

ta, and TND often manifest in nail changes. Nail changes are seen
in 12% of psoriasis patients, where 1% to 2% of the general popu-
lation is affected with psoriasis.49 A pathologic basis of nail changes
was later defined in psoriasis, where location such as the cutaneous
surface of the proximal nail fold, undersurface of the proximal nail
fold, nail matrix, nail bed, and the hyponychium sites of inflamma-
tory and hyperkeratotic papule may be considered the mainstay.50 In
Figure 7. Twenty-nail dystrophy with pterygium.
addition, erythematous, scaly papules and plaques seen on the cuta-
neous surface of the proximal nail fold and hyponychium appeared
similar to psoriasis elsewhere on the skin. Accordingly, the lesions in separation of the proximal nail fold from the nail plate. This separa-
these locations do not produce changes in the nail plate. The under- tion may cause a paronychia, the characteristic features of which are
surface of the proximal nail fold, when involved in psoriasis, causes a erythematous, inflamed proximal nail fold, ragged or absent cuticle,

SKINmed. 2011;9:3946 43 Nail Biology

 January/February 2011
Figure 8. (A) Distal and lateral subungual onychomycosis, (B)
candida onychomycosis, and (C) proximal subungual ony-
chomycosis, mycelia, and spores may be demonstrated on
potassium hydroxide mount.
and chronicity perpetuated by maceration and overgrowth of yeast
under the proximal nail fold (Figure 8).
The psoriasis lesions of the matrix can occur both in the proximal and
distal matrix. The proximal matrix contributes orthokeratotic keratin
to the dorsal nail plate, while the distal matrix to the ventral nails plate.
A cluster of abnormal parakeratotic cells are produced in psoriasis, and
the clinical features depend on the matrix area affected. Accordingly, if
SKINmed. 2011;9:3946 44
CORE CURRICULUM
the proximal matrix is involved, the parakeratotic cells are carried to the
dorsal nail plate up to a certain distance and are suddenly lost, produc-
ing a depression or pit (marking the prior location of the parakeratotic
cells), the hallmark of psoriatic nail disease. When the central or distal
matrix is involved, the parakeratotic cells remain trapped within the
nail plate, producing opaque white reflections when examined under
light. Involvement of the nail bed results in an erythematous macule
visible through a translucent nail plate. Glycoproteins produced from
psoriasis accumulate beneath the nail plate and clinically present as a
yellowish nail bed macule that earned the connotation oil drop sign.
Splinter hemorrhages, onycholysis, mounds of keratinous debris, and
complete dystrophy are other worthwhile features.50 In addition, com-
plete dystrophy characterizes severe psoriasis or acrodermatitis conti-
nua of Hallopeau. The severity of nail disease could be well correlated
to severe skin disease(s) and advanced psoriatic arthritis. Beaus lines
may be associated with pustular psoriasis.51 Other less common nail
changes include nail fold telangiectasias, red lunulae, punctate red
spots in the lunula, transverse leuconychia, leukonychia punctata, half-
and-half nail, koilonychia, and onychoschizia.52,53
A multicenter study compared the prevalence of onychomycosis
in psoriatic nails with that of nonpsoriatic nails.54 The study found
that a positive family history; location of lesions on the elbows,
knees, gluteal clefts, and scalp; and nail pitting help to confirm the
diagnosis of psoriasis. A positive potassium hydroxide preparation/
fungal culture may help establish the diagnosis of onychomycosis.
In addition, the evaluation of the clinical pattern of nail abnormal-
ity in onychomycosis manifesting either as distal and lateral subun-
gual onychomycosis (DLSO)(Figure 8A), candida onychomycosis
(Figure 8B), superficial white onychomycosis (SWO), proximal
subungual onychomycosis (PSO) (Figure 8C), or total dystrophic
(destructive) onychomycosis (TDO) may be helpful.55 The presence
of tinea pedis facilitates the diagnosis of onychomycosis.
Coexistence of psoriasis and secondary onychomycosis is intrigu-
ing. A study of 561 patients with psoriasis found that 47% had nail
changes, of whom 27% were positive for mycelia spore on potas-
sium hydroxide mount. Nail plate pitting, a hallmark of psoriasis,
may also be seen in alopecia areata, pityriasis rubra pilaris, and Re-
iter disease. There were certain clinical differences in pits of psoriasis
and alopecia areata, their briefs are outlined in the Table. Deeper
and more irregular pits, similar to those of psoriasis could also be
seen in pityriasis rubra pilaris.56 In children, nail lichen planus may
occur as an isolated finding.57
Several clinical variations, depending on the location of lichenoid in-
flammatory infiltrate, may be seen in lichen planus of the nails. Pri-
marily, lichen planus affects the nail matrix and may result in: (1)
onychorrhexis, recognized by nail plate thinning, ridging and fissur-
ing. (2) Trachyonychia, a rough sand paper appearance of the surface
Nail Biology
 January/February 2011
of the nail plate, gray opacity, and brittle/split nails. The nail plate
might be thrown into folds and may result in complete nail atrophy.
(3) Pterygium, a chief association of lichen planus following intense
lichenoid infiltrate encompassing the proximal nail fold, the nail ma-
trix, and the nail bed. The cul-de-sac under the proximal nail fold may
shorten, the nail plate may progressively result in thinning, and finally
the proximal nail fold may fuse with the matrix and the proximal nail
bed, thus dividing the nail plate into two lateral sections58 (Figure 9).
Pterygium is pathognomonic of nail lichen planus; however, it
could also be a feature of nail patella syndrome. Trauma, peripheral
vascular diseases, Raynauds phenomenon, radiotherapy, infection,
and immunobullous diseases may be the other causes.5964
Alopecia areata could too involve one, multiple, or all 20 nails.65
Pitting of the nails was reported in 21.9% of patients with alo-
pecia areata.63 The probable nature of pitting, vis-a-vis psoriasis,
has already been mentioned (videsupra). Nail plate pitting and
trachyonychia were considered to be characteristic of alopecia
areata,64 while other studies6264 found trachyonychia in only
3.65% of patients with alopecia areata, and in 15.4% patients
with alopecia universalis. Another opinion was that alopecia
areata could affect only the matrix and the spotty absence of the
whiteness of the lunula that might produce the so-called spotted
lunula, diagnostic of alopecia areata.66 The acute onset of alope-
cia areata has also been described to be associated with nail plate
shedding (onychomadesis).62 Nail pitting is a prominent finding
in psoriasis, alopecia areata, dermatitis, HLA-B27 inheritance,
diabetes mellitus, and occupational trauma.6668
Acknowledgement: Asha Singh, MS, PhD, Professor and Head of the
Anatomy Department, SGT Dental College, Gurgaon, reviewed the
section on nail biology. The final text (parts I and II) was reviewed by
Prashant Verma, MD, Senior Resident, Department of Dermatology
and STD, University College of Medical Sciences and Associated Guru
Teg Bahadur Hospital, Shahdara, Delhi.
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41 Peloro TM, Pride HB. Twenty-nail dystrophy and vitiligo: a rare
association. J Am Acad Dermatol. 1999;40:488490.
42 Clegg HW, Prose NS, Greenbag DN. Nail dystrophy in congenital
cutaneous candidiasis. Pediatr Dermatol. 2003;20:342344.
43 Tosti A, Bardazzi F, Piraccini BM, et al. Idiopathic trachyonychia
(twenty nail dystrophy): a pathological study of 23 patients. Br J
Dermatol. 1994;131:866872.
44 Germain-Lee EL, Zinkham WH. Twenty nail dystrophy associ-
ated with hematologic abnormalities. Acta Paediatr Scan.
1991;80:977980.
SKINmed. 2011;9:3946 46
CORE CURRICULUM
45 Wilkinson JD, Dawber RP, Bowers RP, et al. Twenty-nail dystro-
phy of childhood: case report and histopathological findings. Br
J Dermatol. 1979;100:217221.
46 Ohta Y, Katsuoka K. A case report of twenty-nail dystrophy. J
Dermatol. 1997;24:6062.
47 Sehgal VN. Twenty-nail dystrophy trachyonychia: an overview. J
Dermatol. 2007;34:361366.
48 Grover C, Khandpur S, Reddy BS, et al. Longitudinal nail biopsy:
utility in 20-nail dystrophy. Dermatol Surg. 2003;29:11251129.
49 Mallbris L, Larsson P, Bergqvist S, et al. Psoriasis phenotype
at disease onset: clinical characterization of 400 adult cases. J
Invest Dermatol. 2005;124:499504.
50 Zaias N. Psoriasis of the nail. A clinical-pathologic study. Arch
Dermatol. 1969;99:567579.
51 Burkhart CG. Beaus lines: an association with pustular psoriasis
and telogen effluvium. Arch Dermatol. 1980;116:11901191.
52 Ohtsuka T, Yamakage A, Miyachi Y. Statistical definition of nail-
fold capillary pattern in patients with psoriasis. Int J Dermatol.
1994;33:779782.
53 Marino MT. Mees lines. Arch Dermatol. 1990;126:827828.
54 Gupta AK, Lynde CW, Jain HC, et al. A higher prevalence of
onychomycosis in psoriatics compared with non-psoriatics: a
multicentre study. Br J Dermatol. 1997;136:786789.
55 Sehgal VN, Srivastava G, Dogra S, et al. Onychomycosis: Asian
perspective. Skinmed. 2010;8:3845.
56 Griffiths WA. Pityriasis rubra pilarisan historical approach. 2.
Clinical features. Clin Exp Dermatol. 1976;1:3750.
57 Tosti A, Piraccini BM, Cambiaghi S, et al. Nail lichen planus in
children clinical features, response to treatment, and long-term
follow-up. Arch Dermatol. 2001;137:10271032.
58 Caputo R, Prandi G. Pterygium inversum unguis. Arch Dermatol.
1973;108:817818.
59 Pierre M, ed. The Nail. Edinburgh, UK: Churchill Livingstone; 1981.
60 Burge SM, Powell SM, Ryon TJ. Cicatricial pemphigoid with nail
dystrophy. Clin Exp Dermatol. 1985;10:472475.
61 Dhawan SS, Zaias N, Pena J. The nail fold in pemphigus vulgaris.
Arch Dermatol. 1990;126:13741375.
62 Tosti A, Morelli R, Bardazzi F, et al. Prevalence of nail abnor-
malities in children with alopecia areata. Pediatr Dermatol.
1994;11:112115.
63 Tosti A, Fanti PA, Morelli R, et al. Trachyonychia associated with
alopecia areata: a clinical and pathological study. J Am Acad
Dermatol. 1991;25:266270.
64 Dotz WI, Lieber CD, Vogt PJ. Leukonychia punctata and pitted
nails in alopecia areata. Arch Dermatol. 1985;121:14521454.
65 Horn RT Jr, Odom RB. Twenty-nail dystrophy of alopecia areata.
Arch Dermatol. 1980;116:573574.
66 Shelley WB. The spotted lunula. A neglected nail sign associated
with alopecia areata. J Am Acad Dermatol. 1980;2:385387.
67 Pajarre R, Kemo M. Nail changes as the first manifesta-
tion of HLA-B27 inheritance: a case report. Dermatologica.
1977;154:350354.
68 Green RA, Scher RK. Nail changes associated with diabetes mel-
litus. J Am Acad Dermatol. 1987;16:10151021.
Nail Biology
 Introducing VELTIN GelA New Topical Treatment for Patients 12 Years or Older With Acne Vulgaris
Once-daily application in the evening

Combines the acne-fighting properties of tretinoin and clindamycin

VELTIN Gel 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, Clindamycin has been shown to have neuromuscular blocking
ulcerative colitis, or history of antibiotic-associated colitis properties that may enhance the action of other neuromuscular
blocking agents. VELTIN Gel should be used with caution in
Systemic absorption of clindamycin has been demonstrated
patients receiving such agents
following topical use. Diarrhea, bloody diarrhea, and colitis (including
pseudomembranous colitis) have been reported with the use of VELTIN Gel should be used during pregnancy only if the potential
topical clindamycin. VELTIN Gel should be discontinued if significant benefit justifies the potential risk to the fetus
diarrhea occurs. Severe colitis has occurred following oral or
It is not known whether either clindamycin or tretinoin is excreted
parenteral clindamycin administration. Severe colitis may result
in human milk following use of VELTIN Gel. However, orally and
in death
parenterally administered clindamycin has been reported to appear
Avoid exposure to sunlight and sunlamps when using VELTIN Gel. in breast milk. Due to possible serious adverse reactions in nursing
Patients with sunburn should be advised not to use VELTIN Gel until infants, a decision should be made whether to discontinue
fully recovered. Daily use of sunscreen products and protective nursing or the drug. Exercise caution if administering VELTIN Gel
apparel are recommended. Weather extremes (eg, wind and cold) to a nursing woman
also may be irritating to patients using VELTIN Gel
The ecacy and safety have not been established
Observed local treatment-related adverse reactions (1%) in clinical in pediatric patients below the age of 12 years
studies with VELTIN Gel were application site reactions, including
VELTIN Gel is not for oral, ophthalmic,
dryness, irritation, exfoliation, erythema, pruritus, and dermatitis.
or intravaginal use
Sunburn was also reported. Incidence of skin reactions peaked at
week 2 and then gradually decreased
VELTIN Gel should not be used in combination with erythromycin-
containing products due to possible antagonism to the clindamycin
component

Please see brief summary of Prescribing Information on the next page.

 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.
1 INDICATIONS AND USAGE
VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years
or older.
4 CONTRAINDICATIONS
VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis,
or history of antibiotic-associated colitis.
5 WARNINGS AND PRECAUTIONS
5.1 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 antibiotic-
associated colitis.
5.2 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.
6 ADVERSE REACTIONS
6.1 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.
7 DRUG INTERACTIONS
7.1 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.
7.2 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.
8 USE IN SPECIFIC POPULATIONS
8.1 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.
8.3 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.
8.4 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.]
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 g (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.
17 PATIENT COUNSELING INFORMATION
[See FDA-approved Patient Labeling].
17.1 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.
17.2 Skin Irritation
VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
17.3 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.
STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.
VELTIN is a trademark of Astellas Pharma Europe B.V.
VEL:2BRS
Issued July 2010
2010 Stiefel Laboratories, Inc.
2010 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. VEL015R0 September 2010
 January/February 2011 Volume 9 Issue 1

NEW THERAPY UPDATE

William Abramovits, MD; Aditya K. Gupta, MD, Section Editors

Veltin Gel
(Clindamycin Phosphate 1.2% and Tretinoin 0.025%)
William Abramovits, MD;1,2,3 Marcial Oquendo, MD;3 Aditya K. Gupta, MD4

Description Clinical Pharmacology

Veltin gel (clindamycin phosphate and tretinoin), 1.2%/0.025%,
is a fixed combination of two solubilized active ingredients in
an aqueous-based gel. It is manufactured by Stiefel Laborato-
ries, Inc (Research Triangle Park, NC), a GSK company. Veltin
gel was approved by the US Food and Drug Administration on
July 16, 2010.1,2
Clindamycin phosphate is a water-soluble ester of the semi-
synthetic antibiotic produced by a 7(S)-chloro-substitution
of the 7(R)-hydroxyl group of the parent antibiotic lincomy-
cin. The chemical name for clindamycin phosphate is methyl
7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrro-
lidinecarboxamido)-1-thio-L-threo-a-D-galacto-octopyranoside
2-(dihydrogen phosphate).
The chemical name for tretinoin is all-trans 3,7-dimethyl-9-
(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic
acid. It is a member of the retinoid family of compounds.
Veltin gel contains the following inactive ingredients: butylated
hydroxytoluene, carbomer 940, anhydrous citric acid, edetate
disodium, methylparaben, laureth 4, propylene glycol, trometh-
amine, and purified water.
Mechanism of Action
Clindamycin binds to the 50S ribosomal subunit of susceptible bac-
teria and prevents elongation of peptide chains by interfering with
peptidyl transfer, thereby suppressing bacterial protein synthesis.
Although the exact mode of action of tretinoin is unknown,
current evidence suggests that topical tretinoin decreases cohe-
siveness of follicular epithelial cells with decreased microcom-
edo formation. Additionally, it stimulates mitotic activity and
increased turnover of follicular epithelial cells causing extrusion
of the comedones.
Clindamycin has been shown to have in vitro activity against
Propionibacterium acnes, a bacterium that has been associated
with acne vulgaris; however, the clinical significance of this activ-
ity against P acnes was not examined in clinical studies with Vel-
tin gel. P acnes resistance to clindamycin has been documented,
often in association with erythromycin resistance.
Topical tretinoin is used in the treatment of mild to moderate
acne and on skin that has been damaged by excessive sun ex-
posure. Tretinoin causes an increase in cell turnover and death,
which reduces the number of cell layers in the skin. This rapid
turnover may prevent new acne lesions from forming.
Clinical Studies
Three randomized, double-blind, multicenter, 12-week studies
compared the combination product clindamycin 1%tretinoin
0.025% gel with clindamycin gel 1%, tretinoin gel 0.025%, and
vehicle gel in almost 3900 patients 12 years and older with acne.
One trial used the Veltin formulation, while the other two tri-
als used an older, slightly different formulation (Velac). Study
medications were applied once daily in the evening in all trials.
Efficacy was assessed at weeks 2, 4, 8, and 12. The co-primary
end points were the mean absolute change from baseline to week
12 in 2 of 3 (total, inflammatory, and noninflammatory) lesion
counts and the proportion of patients with at least a 2-grade
improvement in Investigators Static Global Assessment (ISGA)
score (a 05 scale) from baseline to week 12.1,35
Efficacy
Based on assessment of the co-primary end points, the newer
formulation was found to be superior to the comparator in terms
of change in ISGA score and in the absolute reduction in at least
2 of 3 lesion counts (total, inflammatory, or noninflammatory).

From the Department of Medicine, Baylor University Medical Center;1 the Departments of Dermatology & Family Practice, University of
Texas Southwestern Medical School,2 Dallas, TX; Dermatology Treatment & Research Center, Dallas, TX;3 and the Division of Dermatology,
Department of Medicine, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Canada4
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;9:4951 49 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Table. Adverse Eventsa in Patients According to Treatment
Adverse Event, ClindamycinTretinoin Gel Clindamycin Gel 1%
No. (%) (n=1104) (n=1091)
Dryness 140 (13)
Desquamation 64 (6)
Burning 50 (5)
Erythema 50 (5)
Pruritus 40 (4)
Sunburn 26 (2)
Irritation 11 (1)
a
All adverse events at application site.
The median time to 50% reduction in total lesion count was sig-
nificantly faster with clindamycintretinoin gel (8 weeks) than with
clindamycin gel alone (12 weeks), tretinoin gel alone (12 weeks), or
vehicle (median time not reached at study completion) (P<.0001).
The proportion of patients who achieved an ISGA score of 0 or 1 at
12 weeks was significantly higher in the clindamycintretinoin gel
group (37%) compared with clindamycin gel alone (27%), treti-
noin gel alone (25%), or vehicle gel (14%) (P.0001).4
Comparing baseline with week 12 data, the combination clinda-
mycintretinoin gel was superior to the other study medications
in terms of decreasing the ISGA score to clear/almost clear and
in decreasing the number of total lesions and inflammatory le-
sions. In one trial, the combination clindamycintretinoin gel
was similar to the tretinoin gel in the reduction of noninflamma-
tory lesions, while the other two trials found clindamycintreti-
noin superior to the other 3 arms of this end point.4,5
In the combined analysis of all studies, clindamycintretinoin
gel was significantly better than clindamycin 1% gel, tretinoin
0.025% gel, and vehicle gel in reducing total inflammatory and
noninflammatory lesions after 12 weeks of treatment (P.0043).1
Adverse Reactions
The completion rate from one of the studies was 1446 of 1649
patients (88%). The most common reason for study discon-
tinuation was withdrawn consent (n=76) and lost to follow-up
(n=73). Few patients withdrew due to adverse events (n=11),
noncompliance (n=10), or lack of efficacy (n=7).
The safety data from the combined studies reflect exposure to
clindamycintretinoin in 1104 patients 12 years or older with
acne vulgaris. Patients were treated once daily in the evening for
12 weeks. Adverse reactions that were reported in 1% of patients
treated with the combination gel are presented in the Table.
SKINmed. 2011;9:4951 50
NEW THERAPY UPDATE
Tretinoin Gel 0.025% Vehicle Gel
(n=1084) (n=552)
38 (3) 141 (13) 17 (3)
12 (1) 62 (6) 3 (1)
4 (<1) 57 (5) 5 (1)
2 (<1) 56 (5) 2 (<1)
6 (1) 39 (4) 3 (1)
7 (1) 23 (2) 6 (1)
6 (1) 7 (1) 3 (1)
Local skin reactions included erythema, scaling, dryness, burn-
ing, and itching. During the 12 weeks of treatment, each local
skin reaction peaked at week 2 and gradually reduced thereafter.
Safety
Systemic absorption of clindamycin has been demonstrated fol-
lowing topical use. Diarrhea, bloody diarrhea, and colitis (in-
cluding pseudomembranous colitis) have been reported with the
use of topical clindamycin. If significant diarrhea occurs, treat-
ment would be discontinued.4
Exposure to sunlight, including sunlamps, should be avoided
during the use of tretinoin, and patients with sunburn should be
advised not to use the product until fully recovered due to height-
ened susceptibility to sunlight as a result of the use of treatment.1
This treatment should not be used in combination with eryth-
romycin-containing products due to possible antagonism to the
clindamycin component. In vitro studies have shown antago-
nism between these 2 antimicrobials. The clinical significance
of this in vitro antagonism is not known. Clindamycin has been
shown to have neuromuscular-blocking effects that may enhance
the action of other neuromuscular-blocking agents; therefore, it
should be used with caution in patients receiving such agents.
This combination gel falls under Pregnancy Category C. There
are no well-controlled studies in pregnant women treated with
clindamycintretinoin. A limited 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. These abnormalities are con-
sistent with retinoid effects and occurred at 16 times the recom-
mended clinical dose assuming 100% absorption and based on
body surface area comparison. Oral tretinoin has been shown to
be teratogenic in mice, rats, hamsters, rabbits, and primates, and
Veltin Gel
 January/February 2011
has also been shown to enhance photocarcinogenicity in studies
involving UV radiation exposure.
Safety and effectiveness of clindamycintretinoin in pediatric
patients younger than 12 years have not been established nor has
it been established in patients 65 years and older.
Indications and Administration
Veltin (clindamycin phosphate and tretinoin) gel, 1.2%/0.025%
is a yellow, opaque topical gel indicated for the treatment of
acne vulgaris in patients 12 years and older. The gel should be
applied once daily in the evening, gently rubbing the medica-
tion to lightly cover the entire affected area. Approximately a
pea-sized amount will be needed for each application. The eyes,
lips, and mucous membranes should be avoided. It is not for
oral, ophthalmic, or intravaginal use. Because it is a combination
of clindamycintretinoin, it is contraindicated in patients with
regional enteritis, ulcerative colitis, or a history of antibiotic-
associated colitis.1,2
Each gram of Veltin gel contains, as dispensed, 10 mg (1%)
clindamycin as clindamycin phosphate and 0.25 mg (0.025%)
tretinoin solubilized in an aqueous-based gel. The tube sizes for
this product are 30 g and 60 g.
Conclusions
This gel (Veltin) represents an alternative to another topical for-
mulation (Ziana; Medicis, Scottsdale, AZ)6 that differs mainly in
FORMULARY OF DR GEORGE C. ANDREWS
Bleach
Bismuth oxychloride ointment
Mercury bichloride
Bismuth oxychloride
Lanolin anhydrous
Aqua rosae ointment q. s.
Oil jasmine
Add mercury bichloride to oil and i ounce of alcohol. Melt
all other ingredients, and when sufficiently cold, slowly add
the oil solution.
Submitted by Douglas D. Altchek, MD, New York, NY
SKINmed. 2011;9:4951
NEW THERAPY UPDATE
the vehicle and in the way the tretinoin is released from it. No
head-to-head studies allow us to recommend one brand over the
other based on superiority of effectiveness vis a vis side effects.
We find the use of these combinations useful to provide a once-
a-day treatment paradigm for acne that utilizes 3 molecules with
different modes of action (with benzoyl peroxide in the form of a
wash, for example) hopefully to optimize compliance and success.
References
1 Veltin (clindamycin phosphate 1.2% and tretinoin 0.025%) gel
[package insert]. Research Triangle Park, NC: Stiefel Laborato-
ries, Inc; 2006.
2 Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/treti-
noin gel formulation in the treatment of acne vulgaris. Expert
Opin Pharmacother. 2008;9:29312937.
3 Tolerability of Veltin Gel in Combination with Benzoyl Peroxide
Gel. Data on file. Research Triangle Park, NC: Stiefel Laborato-
ries; Study W0265306.
4 Efficacy and Safety of Veltin Gel for the Treatment of Acne Vul-
garis. Data on file. Research Triangle Park, NC: Stiefel Labora-
tories; Study W026503.
5 Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-
blind, controlled trials of 2219 subjects to compare the combi-
nation clindamycin/tretinoin hydrogel with each agent alone and
vehicle for the treatment of acne vulgaris. J Am Acad Dermatol.
2006;54:7381.
6 Ziana (clindamycin phosphate 1.2% and tretinoin 0.025%) gel
[package insert]. Scottsdale, AZ. Medicis: The Dermatology
Company; 2006.
grains v
ounces ii
ounces ii
ounces xvi
drops xxx
51 Veltin Gel
 January/February 2011 Volume 9 Issue 1

Perils of Dermatopathology
W. Clark Lambert, MD, PhD, Section Editor

Why Immunofluorescence?
Zain Husain, BS;1 Javier Rojas, MD;2 Amin Maghari, MD;2,3 W. Clark Lambert, MD, PhD2,3

With immunohistochemistry available, why do we still use immunofluorescence?Numerous residents, fellows, and colleagues

I
mmunofluorescence (IF) was first developed in 1941 when
Coons identified pneumococci using a direct fluorescent
method. This was followed by indirect IF, which added
greater specificity and signal amplification. In 1979, immuno-
histochemistry (IHC) was developed with the introduction of
horseradish peroxidase and peroxidase antiperoxidase. This was
soon followed by the use of the avidin and biotin complex in the
early 1980s.1 IHC provided more sensitive results than IF and
quickly began replacing its predecessor in the laboratory setting,
begging the question, why do we still use immunofluorescence?
Current Use
IHC and IF are important laboratory techniques used in current
dermatopathology. They are simple, rapid, and relatively inex-
pensive diagnostic methods with numerous applications. The
development of new antibodies, improvements in detection of
antigens, and automated processing systems have enhanced their
diagnostic utility.2 Each technique has its own inherent strengths
and weaknesses, which should be understood to ensure their
proper and optimal use in diagnostics.
Immunohistochemistry
IHC is a technique used to localize antigens in cells of a tissue
section using monoclonal antibodies to bind to specific antigens
in the tissues and using a method of visualizing this antigen-an-
tibody complex such as linked peroxidase enzyme (Figure 1 and
Figure 2).1 IHC allows the investigator to localize a given protein
within the tissue examined. IHC has numerous applications in
dermatopathology including the detection of markers associated
with neural and neuroendocrine neoplasms, soft tissue neo-
plasms, infectious diseases, melanocytic proliferations, vascular
proliferations, and epidermal and appendageal neoplasms. Me-
lanocytic staining is garnering great interest for both diagnostic
and prognostic value.3 Two general models are used: direct and
indirect methods. The direct method is a one-step staining pro-
cess and uses a labeled antibody that reacts directly with the an-
tigen in tissue sections. It is relatively simple and quick, but there
can be poor sensitivity due to minimal signal amplification. The
indirect method uses an unlabeled primary antibody specific for
the tissue antigen and a labeled secondary antibody, which reacts
with the primary antibody. Signal amplification via several sec-
ondary antibody reactions with different antigenic sites on the
primary antibody provides higher sensitivity than direct IHC. In
addition, it allows the secondary antibody to be used with vari-
ous primary antibodies raised in the same species. The secondary
antibody can be labeled with an enzyme to visualize the reaction,
often seen as a brown stain.2 Formalin-fixed paraffin-embedded
(FFPE) tissue specimens generally use a biotinylated secondary
antibody followed by an avidin-biotin peroxidase complex and
development with a soluble chromogenic substrate. This allows
for high sensitivity and reliable detection of specific antigens
and can be automated for labeling, imaging, and scoring. IHC
also allows the investigator to view cytologic details and tissue
architecture. In addition, the preparations are permanent and
relatively light insensitive. Although IHC is a valuable diagnostic
tool, there are several limitations with its use. First, only one pro-
tein can be detected at a time, since multiple color approaches
combining peroxidase with other development systems are inad-
equate and cannot be used to co-localize two antigens within the
same subcellular compartment. Another limitation is that the
resolution of antigen localization is limited due to the chromo-
genic substrate precipitate and the thickness of the sections im-
aged in the light microscope. Lastly, chromogenic systems easily
saturate, which restricts semiquantitative analysis.4
immunofluorescence
IF is a technique used to visualize a specific protein or antigen
in cells or tissue sections by binding a specific antibody chemi-

From the Division of Plastic Surgery,1 the Department of Pathology,2 and the Department of Dermatology,3 UMDNJ-New Jersey Medical
School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building, UMDNJ-New Jersey Medical School,
Newark, NJ 07101 E-mail: lamberwc@umdnj.edu

SKINmed. 2011;9:5254 52 2011 Pulse Marketing & Communications, LLC

 January/February 2011 Perils of Dermatopathology

Figure 1. Diffuse nonspecific anti-immunoglobulin M immune Figure 2. Anti-immunoglobulin M immune reaction primarily
reaction in adnexa and adipose tissue of the deep dermis. localized to the vessel walls.

cally conjugated with a fluorescent dye (Figure 3). Fluorescence

is a phenomenon in which a substance absorbs light or other
electromagnetic radiation of a different wavelength and emits
light, usually of a longer wavelength and lower energy than the
absorbed radiation. The dyes chosen for IF are excited by light
of one wavelength, usually blue or green, and emit light of a dif-
ferent wavelength in the visible spectrum. The most common
fluorescent dyes are fluorescein, which emits green light; Texas
Red and Peridin chlorophyll protein, which emit red light; and
rhodamine and phycoerythrin, which emit orange/red light.5
By using selective filters, only the light coming from the dye or
fluorochrome used is detected in the fluorescence microscope.
This technique can be used to detect the distribution of any
protein, and if different fluorochromes are attached to different
antibodies, multiple proteins can be identified within the same
cell or tissue section.
IF is a standard procedure for diagnosis of immune-mediated
dermatologic diseases such as immunobullous disease and is also
useful in connective tissue diseases, oral inflammatory diseases,
and vaculitis.6 Similar to IHC, there are direct and indirect IF Figure 3. Anti-immunoglobulin M immunofluorescence indicates
antigen-antibody immune-complex deposition in vessel walls.
methods. In practice, direct IF is often used to detect presence
of autoantibodies, immunoglobulin A (IgA), IgG, IgM, comple-
ment, and fibrin, whereas indirect IF is performed to detect cir- standard immunostaining. It allows for the simultaneous visual-
culating autoantibodies directed against an antigen in the skin.6 ization of multiple antigens, even in the same subcellular com-
IF-stained samples are then examined under a fluorescence or partment. There is also higher resolution because fluorophores
confocal microscope. There are several advantages of IF over are directly conjugated to the antibody. IF also gives quantitative

SKINmed. 2011;9:5254 53 Why Immunofluorescence?

 January/February 2011
signals for analysis. However, IF is not usually used in FFPE
specimens because there is a perception that paraffin sections
are not suitable for fluorescence microscopy because of excessive
background autofluorescence.7 This would make high-quality IF
imaging difficult. In addition, the fluorescence tends to decrease
with time, making it difficult to review IF-stained specimens
at a later time. Experts have proposed a new method for high-
resolution IF labeling of FFPE tissues, which combines antigen
retrieval, indirect IF, and confocal laser scanning microscopy.
This limits autofluorescence and allows investigators to study co-
expression of multiple markers and to detect subcellular antigen
localization within tissue samples.
Conclusions
IHC is a common laboratory procedure that has largely replaced
IF in the laboratory setting due to its higher sensitivity and signal
amplification. It has several limitations in diagnostics, however;
the most serious being the inability to simultaneously visualize
multiple antigens. Although IF may have poorer sensitivity than
IHC, there are several advantages for its use. It can simultaneously
detect multiple antigens, provides higher resolution, and allows
VINTAGE LABEL
Courtesy of BuyEnlarge, Philadelphia, PA
SKINmed. 2011;9:5254 54
Perils of Dermatopathology
for quantitative signals for analysis. Thus, IF remains a valuable
tool in diagnostics and should not be completely replaced by IHC.
References
1 Burnett R, Guichard Y, Barale E. Immunohistochemistry for light
microscopy in safety evaluation of therapeutic agents: an over-
view. Toxicology. 1997;119:8393.
2 Braun-Falco M, Schempp W, Weyers W. Molecular diagnosis in
dermatopathology: what makes sense, and what doesnt. Exp
Dermatol. 2009;18:1223.
3 Wasserman J, Maddox J, Racz M, et al. Update on immunohis-
tochemical methods relevant to dermatopathology. Arch Pathol
Lab Med. 2009;133:10531061.
4 Robertson D, Savage K, Reis-Filho JS, et al. Multiple immunoflu-
orescence labelling of formalin-fixed paraffin-embedded (FFPE)
tissue. BMC Cell Biol. 2008;9:13.
5 Mandy FF, Bergeron M, Minkus T. Principles of flow cytometry.
Transfus Sci. 1995;16:303314.
6 Morrison LH. When to request immunofluorescence: practical
hints. Semin Cutan Med Surg. 1999;18:3642.
7 Gellrich S, Ventura R, Jones M, et al. Immunofluorescent
and FISH analysis of skin biopsies. Am J Dermatopathol.
2004;26:242247.
Why Immunofluorescence?
THE Aesthetic Show 2011

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 January/February 2011 Volume 9 Issue 1

Congress Report
Marcia Ramos-e-Silva, MD, PhD, Section Editor

Scratching the Surface:

The History of Skin, Its Diseases and Their Treatment
History of Medicine Unit, University of Birmingham,
October 2930, 2010 [Parallel Publication]*
Rebecca Wynter, MPhil, PhD

S
ponsored by the Wellcome Trust and the Society for Social
History of Medicine, this international conference gath-
ered postgraduates and scholars from medical, cultural
studies, and histories of medicine and art backgrounds whose re-
search incorporates skin, its diseases, and treatment since 1700.
The organizersJonathan Reinarz (University of Birmingham,
United Kingdom) and Kevin Siena (Trent University, Canada),
with Rebecca Wynter (University of Birmingham)constructed
a program with 21 speakers from 7 nations, divided into 8 pan-
els, garnering an audience with a strong clinical presence.
Reading the Skin
After the opening remarks, Professor Philip K. Wilson (Penn
State College of Medicine, Hershey, PA) gave the keynote ad-
dress, situating the conference papers within the wider terrain of
history in Reading the Skin, Discerning the Landscape: Geo-
historical Descriptions of the Human Surface. Space and place
featured heavily throughout the event (Figures 1 and 2). The
first panel commenced with Italic Scurvy, Pellarina, Pella-
gra: Medical Reactions to a New Disease in Italy, 17701830
by Professor David Gentilcore (University of Leicester, United
Kingdom), and was followed by Timothy J. Peters (University
of Birmingham) The Skin Disease of Admiral Frances Beau-
fort, written with Nick Levell (Norfolk and Norwich University
Hospital, United Kingdom). This panel on diagnostic confusion
highlighted issues that resurfaced throughout the event: skin as
a barrier between practitioners, patients, classes, and nationali-
ties, and skin disease as symptomatic of a deeper malaise, either
physical or of hereditary, social, or cultural taint.
These themes were fused by syphilis, which dominated the second
panel of forgotten skin diseases. Kevin Sienas The Moral Biology
of the Itch in Eighteenth-Century London indicated that the Eng-
lish blamed the immoral poor and located the Itch on the syphi-
litic spectrum and as Scottish (Figure 3). In St Pauls Bay Disease:
Skin and Scourge in Eighteenth-Century Quebec, James Moran
(University of Prince Edward Island, Canada) found contemporary
English etiology pinpointing the Francophone population. The ill-
ness precipitated prophecies of colonial degeneration and public
health measures administered through local priests. The Coming
into Being and Passing Away of the Norwegian Radesyge by Anne
Kveim Lie (University of Oslo, Norway) echoed Quebecois symp-
tomology: lesions, skeletal corrosion, and soft tissue deterioration.
Radesyge was connected with the decent lifestyle of the poor and
the development of independent nationhood.
Visualizing the Skin
The afternoon began with visualizing skin disease. Mechthild
Fend (University College London, United Kingdom) spoke about
Portraying Skin Disease: Robert Carswells Dermatological Wa-
tercolors. Scottish physician Carswell visited Parisian hospitals,
18271829. His paintings were placed within wider medical tax-
onomy, and depicted tensions between representing patients or
their conditions. In Visualizing Venereal Disease: The Functions
of Visual Representations, Harriet Palfreyman (PhD student,
University of Warwick, United Kingdom) incorporated disem-
bodied plastinates and emphasized pedagogy at 18th-century
anatomical schools. Venereal disease also featured in the dubious
practices panel. Fiona Clark (Queens University, Belfast, Nothern

From the Department of History, University of Birmingham, Birmingham, United Kingdom

Address for Correspondence: Rebecca Wynter, MPhil, PhD, Department of History, University of Birmingham, Edgbaston, Birmingham,
United Kingdom E-mail: r.i.wynter@bham.ac.uk
*This report was published in part in The Gazette of the Society for the Social History of Medicine. Wynter R. Scratching the surface: the his-
tory of skin, its diseases and their treatment. History of Medicine Unit, University of Birmingham, 2930 October 2010. The Gazette. No. 52,
December 2010. Conference Reports:68.

SKINmed. 2011;9:5658 56 2011 Pulse Marketing & Communications, LLC

 January/February 2011 CONGRESS REPORT

Ireland) conveyed an Irish surgeons determination to counteract

Catholic hospital administration and a high-profile quack by cam-
paigning for mercury treatment in Scratching Below the Surface:
Politics, Intrigue and Anti-Venereal Clinical Trials, Mexico City
(179091). Adrien Minard (Sciences Po, Paris, France) present-
ed the days final paper, Syphilis and Indigenous Skin Lesions
through French Physicians Eyes in Colonial Maghreb, 1830
1930. The virulence of the Arabian strain was considered a way
to witness Medieval French syphilis and was thought indicative of
foreigners filth and degeneracy.
The early-evening facilitated a viewing of the original medical
texts and dermatological atlases that had informed many of the
papers. The visit to the recently refurbished premises of the Uni-
versitys Special Collections enabled clinicians to locate teach-
ing material and stimulated interdisciplinary exchange. The later Figure 1. Professor Philip K. Wilson delivering the keynote
meal at one of Birminghams famous curry houses was a chance address.
to relax before a second full day of presentations.

Working With the Skin

The morning began with working with skin. Lynda Payne
(Medical Humanities and Bioethics School of Medicine, Kan-
sas City, MO) offered valuable insights into the practice and
pedagogy of men like Percivall Pott in Drain, Blister, Bleed:
Surgeons Open and Close the Skin in Georgian London. These
discussions provided a milieu to Skin Politics: Scrotal Cancer
and the Regulation of Child Labour in Chimney Sweeping in
Britain, c.17751840 by Niels Van Manen (PhD candidate,
University of York, United Kingdom). Pott identified the can-
cerous industrial disease, stimulating the study of labor-related
sickness. This prompted medical and political debate surround-
ing hygiene and working conditions.
Figure 2. Professor Philip K. Wilson looking at the book of
The next panel considered skin as text. Matthew Newsom Kerr Daniel Turner, who received the first MD degree in the United
(Santa Clara University, Santa Clara, CA) provoked complexity in States, degree from Yale College (albeit honorary).
An Alteration in the Human Countenance: Inoculation, Vaccina-
tion and the Face of Smallpox Following Jenner. The 18th-century
tell-tale signs of acquired immunity helped secure employment and
were even considered beautiful in women; notions that fed into later
pox eradication controversies and the success expressed on smooth
faces. Gemma Angel (PhD student, University College London)
then considered 300 preserved skins of sailors, soldiers, and crimi-
nals. Atavistic Marks and Risky Practices: The Tattoo in Medico-
Legal Debate, 18501950 noted the connections made between
tattoos and deviance in anatomizing the criminal and in syphilitic
infection. In a challenging paper, Nikki Halpern (European Insti-
tute for Jewish Studies, Stockholm, Sweden) discussed The Word
Made Flesh: Charcot and Skin-Writing. Here again, at the late
19th-century Salptrire asylum, Paris, complexion was gandered, Figure 3. Dr Kevin Siena viewing one of the rare books in the
University of Birmingham Library.
the capacity to present dermography a stigmata of hysteria.

SKINmed. 2011;9:5658 57 The History of Skin

 January/February 2011 CONGRESS REPORT

Leprosy Conclusions
After lunch, Daniel Ham (University of Cambridge, United There is much more to discuss about the history of skin, its dis-
Kingdom) began the barriers and borders session with An El eases, and their treatmentand much more that can be learned
Dorado for a Leprous Chinaman?: Leprosy in Hong Kong in through dermatologists and historians coming together and
the Late 19th and Early 20th Centuries. Amidst British con- sharing their ideas, expertise, and experience. The conference
cerns that Hong Kong was a beacon for sick Chinese, there successfully achieved what it was designed to do: it scratched the
was local colonial reticence to formulate coherent strategies for surface and will provide a platform on which to build further
the discovery, prevention, and care of leprosy and non-British interest and knowledge.
subjectsa gap addressed by missionary activity. These patterns
were echoed by Kathleen Vongasthorn (University of Oxford,
United Kingdom) in A Disease Apart: Fear and Acceptance
of Leprosy in Mid-Twentieth-Century Uganda. Missionaries
exported leprosy myths (of virulence and stigma) to local eth-
nic groups with varied belief systems. The Bakiga, for example, Wax Moulage
had previously accepted the diseased in their community, rather
than enforcing the isolation of sufferers.

Anthrax and AIDS

The final panel, signs on the skin, opened with Classic, Char-
acteristic or Typical: Cutaneous Anthrax, Lesions and Industrial
Posters in the Early Twentieth Century by James Francis Stark
(University of Leeds and Thackray Museum, United Kingdom).
A color-illustrated 1927 poster generated an examination of
Bradfords woolen industry and Anthrax Investigation Board.
The poster (designed in 1916 and still used in 1952) both in-
formed workers of lesion appearance and warned against self-
diagnosis. Tania Woloshyn (Richmond University and Univer-
sity of Nottingham, United Kingdom) also considered images
in Lupus and Light: The Visual Culture of Nature and Artifi-
cial Light Therapeutics, c.18901930. Through light, doctors
restored patients faces with systems of phototherapy, tanning,
and skin health instituted by the Finsen Light Institute and Bat-
tle Creek Sanitarium. In the last paper, fresh from his successful
viva, Richard McKay (University of Oxford, United Kingdom)
conveyed a darker picture of Sex and Skin Cancer: Kaposis
Sarcoma becomes the Stigmata of AIDS, 19791983. Just as
had been the case in Italy, Britain, Quebec, Norway, France,
Mexico, Maghreb, Hong Kong, Uganda, and America since
c.1700, skin disease was subject to diagnostic confusion and
conflicting nomenclature and was understood as an indicator of
the Otherthe minority or the outsider. The closing discus-
sion by Lesley Hall (Wellcome Trust, London) identified themes
that emerged from the event: skin surface as symptomatic of
something deeper; skin as a microcosm of a socially constructed LeuKod. syphiliticum. Secondary Syphilis, Leukoderma
story, one manifested locally and through the visibility of shape, syphliticum. Moulage No 449 made by Lotte Volger in
the Dermatology Clinic in Zurich in 1927. Museum of Wax
shade, pigment, and sickness; and skin as metaphor and stigma, Moulages Zurich, www.moulagen.ch
concealing, expelling, and being invaded. There were aspects of
skin that remained untouched, such as skin and feeling, aller- Courtesy of Michael Geiges, MD
gies, and rarer conditions.

SKINmed. 2011;9:5658 58 The History of Skin

 January/February 2011 Volume 9 Issue 1

CASE STUDY
Vesna Petronic-Rosic, MD, MSc, Section Editor

Longitudinal Erythronychia:
The Value of Cosmetic Alterations in Nail Findings
Rashid M. Rashid, MD, PhD; Carlos Torres-Cabala, MD; Susan Chon, MD

A 71-year-old man presented to the authors clinic for evaluation of a red line under his right thumb. He noticed a red streak develop during the past year.
It slowly grew in width and become more prominent in color (Figure 1). It did not cause pain. He delayed presentation because he perceived it to be only
a cosmetic issue. Medical history included a metastatic atypical carcinoid tumor to the liver, lung, and the bone diagnosed 9 years ago. He had undergone
multiple debulking surgeries and was currently taking octreotide and zoledronic acid. He had not started any new medications in the past 2 years. Review
of systems was unremarkable. On physical examination, the right thumb nail was noted to have a red streak that began at the distal matrix. The line
ended at the distal nail plate with distal disintegration and subungual hyperkeratosis. A biopsy was performed through the nail plate. The site removed by
biopsy included the area in which the erythronychia visibly started, as well as the preceding normal nail matrix. The ventral nail plate was noted to have a
groove of thinning, with slight purple discoloration. The nail bed/matrix was red in a linear pattern and no clinically apparent hyperkeratosis was noted.
The matrix/bed sample was sent for pathologic evaluation. Notable findings included an acanthotic epidermis with some enlarged nuclei (Figure 2). Mild
capillary dilatation was present in papillary dermis. Focal solar elastosis in the distal portion of the nail bed was identified. In situ hybridization for low- and
high-risk human papillomavirus was negative. An immunohistochemical study using a panmelanocytic cocktail (HMB45, anti-MART1, anti-tyrosinase)
failed to reveal any melanocytic lesion. Perls iron stain was negative. Metastatic carcinoid or primary squamous cell carcinoma were not identified.

M
ost patients and physicians perceive the nail unit as a cos-
metic appendage. The authors believe, however, that the
cosmetic-medical value is dramatically understated. In fact,
alterations in appearance of the nail unit can be signs of more serious
pathology despite the lack of other symptoms. For example, longitu-
dinal erythronychia is an easily overlooked clinical presentation. Many
cases are asymptomatic, and thus managed with minimal intervention.
In fact, this presentation is often only considered a cosmetic issue to
patients and physicians. The underlying changes, however, can be of
utmost clinical concern and biopsy is warranted.14 Here, the authors
present a detailed characterization of a case with clinical changes that
could not be explained despite extensive histologic analysis.
This case and review illustrates the value of careful examination of
the nail unit and the traditionally perceived cosmetic aspect of nail
function. Recently, longitudinal erythronychia has been reported as
a presentation of Bowen disease and may continue to be an under-
reported and often undiagnosed pathology.1 Although clinically iden-
tical to previous reported cases of longitudinal erythronychia, this
presentation illustrates several unusual deviations. Histopathologic
examination of our case showed acanthosis and focal keratinocytic
atypia. Only mild capillary vascular dilation was present. Increased
iron deposition and extravasated red blood cells were not identified.
The term onychopapillomas of the nail bed has been proposed to describe
localized, distal, subungual keratosis with multinucleated cells. This ter-
minology is used to characterize a papilloma with histology that shows
a keratogenous zone identical to the nail matrix (matrix metaplasia).1
Although a common histologic finding in the initial elegantly prepared
reports on longitudinal erythronychia, this histologic change was not
present in our case. Multinucleated giant cells were not present either.
The presence of acanthosis and mild papillomatosis, however, suggests
that this lesion belongs to the spectrum of the distal subungual kera-
tosis. It is possible that the discoloration was primarily produced at the
distal nail matrix and was transferred to the nail plate and distal nail
bed. The color could also be a result of the altered physical features of
the nail plate. Although human papillomavirus was a theorized etiol-
ogy in previous reports, our case ruled out viral presences.
We believe this case illustrates a unique and unusual presentation
of longitudinal erythronychia. It is possible that at least some of the
cases clinically suggestive of subungual keratosis may lack matrix
metaplasia on histologic examination. Despite the apparent idio-
pathic nature of this presentation, however, we still place high value
on the previous reports of longitudinal erythronychia being an initial
presentation of malignancy and thus requiring biopsy. Long-term
follow-up for recurrence and/or resolution is also recommended.

From the Department of Dermatology, MD Anderson Cancer Center, University of Texas Medical School, Houston, TX
Address for Correspondence: Rashid M. Rashid, MD, PhD, Department of Dermatology, MD Anderson Cancer Center, University of Texas
Medical School, Houston, 6655 Travis Street, Suite 980, Houston, TX 77030 E-mail: rrashid@mdanderson.org

SKINmed. 2011;9:6061 60 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Figure 1. Longitudinal band of erythronychia originating at the
distal matrix/lunula.
Finally, differential diagnosis must also be considered, evaluated for,
and ruled out as appropriate. In particular, physicians must consider
amelanotic melanoma, Darier disease, lichen planus, and psoriasis.5
References
1 Baran R, Perrin C. Longitudinal erythronychia with distal subun-
gual keratosis: onychopapilloma of the nail bed and Bowens
disease. Br J Dermatol. 2000;143:132135.
2 de Berker DA, Perrin C, Baran R. Localized longitudinal erythro-
VINTAGE LABEL
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SKINmed. 2011;9:6061 61
CASE STUDY
Figure 2. Nail bed dyskeratosis and acanthosis (hematoxylin-
eosin stain, original magnification 20).
nychia: diagnostic significance and physical explanation. Arch
Dermatol. 2004;140:12531257.
3 Dalle S, Depape L, Phan A, et al. Squamous cell carcinoma of
the nail apparatus: clinicopathological study of 35 cases. Br J
Dermatol. 2007;156:871874.
4 Harwood M, Telang GH, Robinson-Bostom L, et al. Melanoma
and squamous cell carcinoma on different nails of the same
hand. J Am Acad Dermatol. 2008;58:323326.
5 Baran R. Red nailalways benign? Actas Dermosifiliogr.
2009;100(suppl 1):106113.
Longitudinal Erythronychia
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 January/February 2011 Volume 9 Issue 1

CASE STUDY

A Case of Cinderella:
Erythema Dyschromicum Perstans
(Ashy Dermatosis or Dermatosis Cinecienta)
Claudia Muoz, MD, MPH; Anne Lynn S. Chang, MD

A 33-year-old healthy Latina (from either Mexico or Central America) woman with Fitzpatrick type V skin complained of a 2-year his-
tory of progressive hyperpigmentation on the axillary folds, dorsal hands, upper neck spilling onto the jawline area, and lower abdomen.
There was no preceding dermatitis. The lesions were asymptomatic. She did not use any prescription or over-the-counter drugs or any
herbal supplements. She denied contact with any new substances and did not start any new activities. A full review of systems was nega-
tive. Physical examination revealed diffuse symmetric gray patches on the proximal arms radiating from the axillary folds with extension
onto the trunk (Figure 1). This discoloration was also present on the dorsal hands (Figure 2), upper neck and jawline, and lower abdomen.
The lesions were nonpalpable and without erythema. Thyroid function test results and morning cortisol levels were normal. Two adjacent
4-mm punch biopsies were performed on the right axillary skin, one consisted of unaffected skin and one of hyperpigmented skin. Figure
3 shows affected axillary skin with an interface dermatitis and significant pigment dropout. There was no evidence of depositional process
of substances such as heavy metals, drugs, or tattoo. There was no evidence of an actinic process. Differential diagnosis included erythema
dyschromicum perstans (EDP), fixed-drug reaction, or interface drug reaction. As the patient was not taking any medications, the overall
clinical and histologic impression was most consistent with EDP. The patient was started on a low-potency topical steroid twice a day to
the affected areas. In addition, because the patient was concerned about the cosmetic appearance of the hyperpigmentation, a 4% hydro-
quinone cream was started twice daily to the neck area.

E
rythema dyschromicum perstans (EDP) was first reported in EDP is difficult to treat. In the acute inflammatory stages, topi-
El Salvador in 1957 by Ramirez,1 who described his patients cal steroids or other anti-inflammatory agents such as topical
as the ashen. This description was later connected with
cenicienta, or Cinderella, a reference to the storybook character
sitting by the ashes and acquiring a gray appearance on the skin.
EDP has been described in a range of populations, but most cases
have been found in Latin American populations.2 The age of onset
of EDP is almost always before age 40, with a chronic course.3 Le-
sions are typically symmetric and generalized. In a 2007 report of
23 patients, the most common location of lesions was the trunk (in
74% of patients), followed by lesions on the upper limbs (65%). Le-
sions can also affect the face (35%), neck (30%), lower extremities
(30%), and lower abdomen (13%).4 Lesions are ashy gray macules
and patches, although a palpable, fine, erythematous border has
been reported on the periphery of some lesions. This difficult-to-
find, erythematous border is the source of the word erythema in
the term EDP. Lesions are not pruritic. The cause of EDP is un- Figure 1. Diffuse symmetric gray patches on the proximal
known, although the involvement of cell-mediated immunity5 or arms radiating from the axillary folds with extension onto the
trunk. Lesions were nonpalpable and without edema.
certain HLA antigen types4 have been postulated.

From the Department of Dermatology, Stanford School of Medicine, Stanford, CA

Address for Correspondence: Anne Lynn S. Chang, MD, Clinical Instructor, Dept. of Dermatology, Director of Dermatological Clinical Trials,
900 Blake Wilbur Drive, Room W0030, Stanford, CA 94305 E-mail: alschang@stanford.edu

SKINmed. 2011;9:6364 63 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Figure 2. Symmetric gray patches were also present on the
dorsal hands.
Figure 3. Affected axillary skin with an interface dermatitis
and significant pigment dropout (hematoxylin-eosin, original
magnification 200). There was no evidence of depositional
process of substances such as heavy metals, drugs, or tat-
too. There was no evidence of an actinic process.
ERRATUM: September/October 2010 Volume 8 Issue 5 Page 265
Review
Dermatoscopy: An OverviewPart I: Nonmelanocytic Lesions
Jason B. Lee, MD; Dawn Hirokawa, MD, MPH
The name of Dr Leon Goldman (19061997), longtime Professor and Chairman of Dermatology at the University of Cin-
cinnati College of Medicine, was incorrectly identified.
SKINmed. 2011;9:6364
CASE STUDY
tacrolimus have been reported, although no treatments have been
subjected to controlled clinical trials. Older, pigmented lesions do
not respond well to treatment. Clofazimine has been reported to
induce a response in a small number of patients,5 although clofazi-
mine itself may lead to pigmentation. Response to dapsone has
been reported in a few cases as well.6
In the United States, Latinos are the largest minority group, com-
prising 36% of the California population and 15% of the US pop-
ulation according to the US Census Bureau in 2006. The Latino
population is growing at 3% per year and estimated to represent
25% of the US population by the year 2050. Dermatologists are
likely to see more cases of this condition in the future.
References
1 Ramirez C. Los cenicientos: problema clinica. Paper presented
at: Memoria del Primer Congreso Centroamericano de Derma-
tologica; December 58, 1957, San Salvador, El Salvador.
2 Schwartz RA. Erythema dyschromicum perstans: the continu-
ing enigma of Cinderella or ashy dermatosis. Int J Dermatol.
2004;43:230232.
3 Epps RE. Case reports: selected dermatoses in children of
color. J Drugs Dermatol. 2007;6:7882.
4 Correa MC, Memije EV, Vargas-Alarcon G, et al. HLA-DR association
with the genetic susceptibility to develop ashy dermatosis in Mexi-
can Mestizo patients. J Am Acad Dermatol. 2007;56:617620.
5 Piquero-Martin J, Perez-Alfonzo R, Abrusci V, et al. Clinical
trial with clofazimine for treating erythema dyschromicum per-
stans. Evaluation of cell-mediated immunity. Int J Dermatol.
1989;28:198200.
6 Bahadir S, Cobanoglu U, Cimsit G, et al. Erythema dyschromi-
cum perstans: response to dapsone therapy. Int J Dermatol.
2004;43:220222.
64 Erythema Dyschromicum Perstans
 January/February 2011 Volume 9 Issue 1

CASE STUDY

Bullous-Hemorrhagic Darier Disease

Mara Pilar Snchez-Salas, MD; Francisco Javier Garca Latasa de Aranibar, MD;
Rosa Oncns Torres, MD; Paula Gamb Grasa, MD

A 48-year-old man presented with a 4-month history of papular hyperkeratotic diffuse lesions on his trunk, arms, and neck that were
highly pruritic (Figure 1). He also had V-shaped nicks in the nails, mucous white papules on his palate, and diffuse desquamation on
the scalp. Abnormal laboratory values included elevated levels of uric acid and triglycerides. Serum electrolytes, blood sugar, and renal and
liver function test results were within normal range. X-ray film and abdominal ultrasonography findings were also normal. Histopathologic
study of the biopsy from the thorax revealed acantholysis with suprabasal clefting, intraepidermal lacunae, and dyskeratosis with corps
ronds. The clinical features and results of the histopathologic studies suggested a diagnosis of Darier disease (Figure 2), but the course was
not typical of this entity because the patient had no family or personal history of previous cutaneous lesions and the age of onset was older
than usual. In the course of the disease, he developed blisters and small black hemorrhagic macules with jagged borders on the back of his
hands (Figure 3). Nikolskys sign was negative. A biopsy of a blister was performed, which confirmed Darier disease, studied by means of
immunofluorescence. Measurement of porphyrins in the urine was also ordered. Direct immunofluorescence did not show deposition of
immunoglobulins or complement, and the study of porphyrins was normal. The patient was treated with an oral retinoid (acitretin 10 mg
daily), but treatment was stopped because he developed an increase in triglycerides; therefore, control of the disease with oral antihista-
mines, 5-fluorouracil 1% cream, and topical tazarotene was used, with mild improvement.

D
arier-White disease is an autosomal dominant disorder
of keratinization caused by mutations in the ATP2A2
gene, locus 12q23-q24.1, which encodes the sarco/en-
doplasmic reticulum Ca+2ATPase.1 Many cases are considered
new mutations. Darier disease in general starts in the first or
second decade of life, but eruptive forms of late onset have been
described, as well as less frequent forms, including hypertrophic,
linear, vesiculobullous, and hemorrhagic types.
disease. Investigators5 reported hemorrhagic lesions in 6% of
patients with Darier disease but did not comment on familial
incidence of this finding. Another investigator6 did not describe
hemorrhagic lesions in the 79 patients examined. In addition, re-
searchers7 examined 34 patients from three large pedigrees, and
hemorrhagic lesions were limited to one of the pedigrees. This

Discrete vesicular lesions, caused by enlargement of the intraepi-

dermal lacunae, may occur in Darier disease, and blistering may
be precipitated by factors such as high humidity, ultraviolet ra-
diation, surgery, physical stress, and treatment with etretinate.2,3
Our patient had not received retinoids before presentation and
had no evidence of bacterial infection, so the mechanism is un-
certain. Blistering persisted throughout the summer, in exposed
sites, suggesting sunlight and trauma as exacerbating factors.

Hemorrhagic Darier disease was first described in 1964 in 4 pa-

tients, 2 of whom were mother and daughter.4 Biopsy specimens
from these patients showed intraepidermal lacunae filled with
red blood cells; in older lesions (black lesions), the red blood
cells were located higher in the epidermis and were amorphous. Figure 1. Hyperkeratotic papules on the trunk typical of
Darier disease.
Otherwise, the histopathologic findings were typical of Darier

From the Departments of Dermatology and Pathology, Hospital de Barbastro, Carretera N-240, s/n, 22300 Barbastro (Huesca), Spain
Address for Correspondence: Mara Pilar Snchez-Salas, MD, C/Bario Mato, 38, 22314 Salas Altas (Huesca), Spain
E-mail: psanchezsalas@gmail.com

SKINmed. 2011;9:6566 65 2011 Pulse Marketing & Communications, LLC

 January/February 2011
Figure 2. Intraepidermal lacunae and dyskeratosis with corps
ronds (hematoxylin and eosin, original magnification 200).
fact suggests a possible genetic heterogeneity of Darier disease.
Studies to map the genes for Darier disease are in progress and
the molecular basis for this heterogeneity will be of great interest.
We would like to emphasize the atypical and late onset of the
disease in our patient, and the association of two uncommon
clinical features of Darier disease: blistering and hemorrhagic le-
sions. The mechanism remains unclear, but it may be the clinical
expression of suprabasal clefting present histologically.
References
1 Sakuntabhai A, Ruiz-Prez V, Carter S, et al. Mutations in
ATP2A2, encoding a Ca+2 pump, cause Dariers disease. Nat
Genet. 1999;21:271277.
ERRATUM: September/October 2010 Volume 8 Issue 5 Page 306
Case Study
Purpuric Nodules and Macules on the Scalp of an 18-Month-Old Boy
Baris Malbora, MD; Engin Senel, MD; Zekai Avci, MD; Namik Ozbek, MD
Published: Figure 2. Diffuse dermal and subcutaneous infiltration by monomorphic cells (Hematoxylin-eosin stain, original
magnification 10).
Correct: Figure 2. Diffuse monomorphic cell infiltration, bone marrow biopsy (Hematoxylin-eosin stain, original magnification, 10).
SKINmed. 2011;9:6566 66
CASE STUDY
Figure 3. Blisters on the back of the hand.
2 Hori Y, Tsuru N, Nimura M. Bullous Dariers disease. Arch Derma-
tol. 1982;118:278279.
3 Telfer NR, Burge SM, Ryan TJ. Vesiculo-bullous Dariers disease.
Br J Dermatol. 1990;122:831834.
4 Jones WN, Nix TE, Clark WH. Hemorrhagic Dariers disease.
Arch Dermatol. 1964;89:523527.
5 Burge SM, Wilkinson JD. Darier-White disease: a review of
the clinical features in 163 patients. J Am Acad Dermatol.
1992;27:4050.
6 Munro CS. The phenotype of Dariers disease: penetrance
and expressivity in adults and children. Br J Dermatol.
1992;127:126130.
7 Foresman PL, Goldsmith LA, Ginn L. Hemorraghic Dariers dis-
ease. Arch Dermatol. 1993;129:511512.
Bullous-Hemorrhagic Darier Disease
 January/February 2011 Volume 9 Issue 1

Book Review
Noah S. Scheinfeld, MD, JD, Section Editor

Dermatologic Complications With Body Art:

Tattoos, Piercings, and Permanent Make-Up
Edited by Christa de Cuyper and Maria-Luisa Prez-Cotapos
110 pages. New York, NY; Springer; 2010
$99. ISBN 3642032915

Tattoos and body piercings are enjoying a good
deal of popularity in contemporary Western
culture, becoming even more trendy in recent
years.1 Such adornment may look quite allur-
ing in a young person, but as the recipient ap-
proaches middle age or has a change of mind
about the decoration, problems ensuetattoos
blurring, pigment dropping down, or names
of significant others no longer being significant. The initial process may
lead to contact dermatitis, cutaneous infection, or even keloid formation,
which may be immediately evident or delayed in affecting the recipient.
This short multi-authored volume begins with an excellent histori-
cal chapter, well illustrated in color. Neither tattoos nor piercings are
new and can be traced back to antiquity.2 For the record, the first
tattoo parlor opened in New York in 1846, while the introduction of
an electric tattooing apparatus is credited to the innovations of Pro-
fessor Samuel OReilly in 1891. By 1929, modifications were suf-
ficiently advanced that current machines are little changed from then.
This is followed by Materials used in body art, which describes the
components of ink for permanent tattoos and the use of henna for
temporary tattoos. The metals used in piercings include stainless steel,
titanium, silver, and gold. In the chapter on complications arising
from tattooing, the list ranges from molluscum contagiosum to syphi-
lis, and from contact dermatitis to keloids. Immediate problems can
also be related to bleeding and pyogenic infections. Unwanted effects
from piercings, as might be expected, concern similar problems, but
the more unusual are the development of argyrosis and angiofibroma.
Tattoos can also be employed to return pigment to an area of vitiligo
or to make an areola appear more natural following breast surgery.
Cosmetically, tattoos can be used for eyeliners and lip liners, but such
procedures are not without complications of pigment spreading or
the reactivation of a herpes simplex infection.
Because contact dermatitis is one of the most common complications
of both types of body adornment, a chapter is devoted to this prob-
lem. In addition to an eczematous dermatitis, granulomatous derma-
titis is not unknown. Knowing the component of the ink can be help-
ful in determining the offending agent, ie, black: carbon, iron oxide,
or dichromates; brown: ferric oxide; white: zinc or titanium oxide; or
yellow: cadmium sulfide.
Removing a tattoo is fraught with problems, and the fact remains that
the evidence for a tattoo, and for that matter a piercing, can never be
eliminated. Whereas a piercing will leave a scar even without com-
plications, the ink from a tattoo will still be visible, depending upon
the color. Methods have involved salabrasion: rubbing salt, dermabra-
sion, electrodesiccation, excision, application of caustic chemicals
such as trichloracetic acid, and more recently, laser surgery with the
q-switched laser being the most effective.
This thin volume contains a great deal of information, but the publisher
did not do the contributors justice. The use of core messages, when there
are often summaries and conclusions, is annoying. Color pictures are
fine, but they are wasted on showing bottles of ink or sterilization equip-
ment; it would have been better to present more pictures of tattoos or
piercings and their complications. The editing is erratic, with a mixture
of British and American spellings and no uniformity of the references.
References
1 Kazandjieva J, Tsankov N. Tattoos and piercings. Clin Dermatol.
2007;25:363420.
2 Parry A. Tattoo: Secrets of a Strange Art as Practiced Among
the Natives of the United States. New York, NY: Simon and
Schuster; 1922.

Reviewed by Lawrence Charles Parish, MD, MD (Hon)

From the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of
Thomas Jefferson University, Philadelphia, PA
Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103
E-mail: larryderm@yahoo.com

SKINmed. 2011;9:68 68 2011 Pulse Marketing & Communications, LLC

Locoid Lipocream Cream, 0.1% Rx Only
(hydrocortisone butyrate 0.1% cream)
For Topical Use Only

BRIEF SUMMARY

INDICATIONS AND USAGE Geriatric Use

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.
WARNINGS AND PRECAUTIONS
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
Cushings 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 Cushings 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.
Cushings 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.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
PATIENT COUNSELING INFORMATION
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 corticosteroid-
responsive 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 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled
Room Temperature]. Protect from freezing. Keep out of the reach of children.
Manufactured for: Triax Pharmaceuticals, LLC Marketed and Distributed By:
Cranford NJ 07016 Triax Pharmaceuticals, LLC
By: Ferndale Laboratories, Inc. Cranford NJ 07016
Ferndale MI 48220 www.Locoid.com
Locoid Lipocream is a registered trademark of
Astellas Pharma Europe BV licensed to 131B301
Triax Pharmaceuticals, LLC. Rev 11/09
 Now younger eczema
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Now approved for use in children

down to 3 months of age

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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 Cushings 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