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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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Erythema, scaling, stinging and burning may also occur. Excessive exposure to sunlight and sunlamps should be avoided
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DIFFERIN Rx only 9.0 mg/m2/day). In terms of body surface area, the highest dose levels are
(adapalene) Lotion 0.1% 9.8 (mice) and 7.4 times (rats) the MRHD of 2 grams of DIFFERIN Lotion.
For Topical Use Only In the rat study, an increased incidence of benign and malignant
Not For Oral, Ophthalmic, or Intravaginal Use. pheochromocytomas in the adrenal medulla of male rats was observed.
BRIEF SUMMARY No photocarcinogenicity studies were conducted with adapalene. However,
animal studies have shown an increased tumorigenic risk with the use
INDICATIONS AND USAGE of pharmacologically similar drugs (e.g. retinoids) when exposed to UV
DIFFERIN Lotion is a retinoid product indicated for the topical treatment of irradiation in the laboratory or sunlight. Although the significance of these
acne vulgaris in patients 12 years and older. findings to humans is not clear, patients should be advised to avoid or
CONTRAINDICATIONS minimize exposure to either sunlight or artificial irradiation sources.
None. Adapalene did not exhibit mutagenic or genotoxic effects in vitro (Ames test,
WARNINGS AND PRECAUTIONS Chinese hamster ovary cell assay, mouse lymphoma TK assay) or in vivo
Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight (mouse micronucleus test).
and sunlamps. Wear sunscreen when sun exposure cannot be avoided. In rat oral studies, 20 mg adapalene/kg/day (120 mg/m2/day; 98 times the
Erythema, scaling, dryness, and stinging/burning may occur with use of MRHD based on mg/m2/day comparison) did not affect the reproductive
DIFFERIN Lotion. performance and fertility of F0 males and females, or growth, development
ADVERSE REACTIONS and reproductive function of F1 offspring.
Dry skin of mild to moderate severity was the most frequently reported PATIENT COUNSELING INFORMATION
( 1%) treatment related adverse event. Erythema, scaling, dryness, Apply a thin film of DIFFERIN Lotion to the affected areas of the skin once
burning/stinging were also seen during treatment. daily, after washing gently with a mild soapless cleanser. Dispense a nickel
DRUG INTERACTIONS size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the
Concomitant use of topical products with a strong drying effect can increase entire face. Avoid application to the areas of skin around eyes, lips and
skin irritation. Use with caution, especially in using preparations containing mucous membranes. DIFFERIN Lotion may cause irritation such as
sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Lotion. Wax erythema, scaling, dryness, stinging or burning.
depilation should not be performed on treated skin. Advise patients to cleanse the area to be treated with a mild or soapless
Pregnancy cleanser; pat dry. Apply DIFFERIN Lotion to the entire face or other
Pregnancy Category C. There are no well-controlled trials in pregnant women acne affected areas as a thin layer, avoiding the eyes, lips and mucous
treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be membranes.
used during pregnancy only if the potential benefit justifies the potential risk Exposure of the eye to this medication may result in reactions such as
to the fetus. Animal reproduction studies have not been conducted with swelling, conjunctivitis and eye irritation.
DIFFERIN Lotion. Furthermore, such studies are not always predictive of
human response. 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
Human Data results, but may increase irritation.
In clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne
vulgaris, women of childbearing potential initiated treatment only after a Advise patients to minimize exposure to sunlight including sunlamps.
negative pregnancy test. Two women became pregnant while using DIFFERIN Recommend the use of sunscreen products and protective apparel
Lotion, 0.1%. One patient delivered a healthy full term baby and the other (e.g., hat) when exposure cannot be avoided.
patient electively terminated her pregnancy. Moisturizers may be used if necessary; however, products containing alpha
Animal Data hydroxy or glycolic acids should be avoided.
No teratogenic effects were observed in rats treated with oral doses of 0.15 This medication should not be applied to cuts, abrasions, eczematous, or
to 5.0 mg adapalene/kg/day, up to 25 times (mg/m2/day) the maximum sunburned skin.
recommended human dose (MRHD) of 2 grams of DIFFERIN Lotion. Wax depilation should not be performed on treated skin due to the
However, teratogenic changes were observed in rats and rabbits when treated potential for skin erosions.
with oral doses of 25 mg adapalene/kg/day representing 123 and 246 times This product is for external use only.
MRHD, respectively. Findings included cleft palate, microphthalmia,
encephalocele and skeletal abnormalities in rats; and umbilical hernia,
exophthalmos and kidney and skeletal abnormalities in rabbits. Marketed by:
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patients with acne treated with DIFFERIN Lotion applied to the face, chest P51503-0
and back (2 grams applied to 1000 cm of acne-involved skin). Revised: March 2010
Nursing Mothers
It is not known whether adapalene is excreted in human milk following
use of DIFFERIN Lotion. Because many drugs are excreted in human milk,
caution should be exercised when DIFFERIN Lotion is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the
age of 12 have not been established.
Geriatric Use
Clinical studies of DIFFERIN Lotion did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently
from younger subjects. Reference: 1.Dataonfile.GaldermaLaboratories,L.P.
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topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m/day), DIFF-113PrintedinUSA09/10 www.differin.com/HCP
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
Sarah D. Staats Elizabeth Holcomb
line ISSN 1751-7125, is published bimonthly by Pulse Marketing &
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PUBLISHER Associate Publisher
torial Board, neither does the publication of advertisements constitute Art Kalaka James R. Adams
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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- Contributing Factors
dren, but are these creatures really taken seriously? The folklore that bed bugs are present due to poor hygiene and
When bed bug infestations were last visited in 2004, it sanitation is still true, but lack of cleanliness does not account
was postulated whether the then epidemic would fade.1 Many for reports from homes with good housekeepers or even from
parasitic diseases can be tamed or adhere to a wax and wane luxury hotels. When dichlorodiphenyltrichloroethane (DDT)
cycle; eg, scabies and even pediculosis have been considered at was used, some observers even considered the use of insecti-
times to be affected by so-called herd immunity, but, alas, this cides as creating the presence of bed bugs. This is erroneous,
has not been so with the bed bug. as the insecticide forced the bed bugs out from their hiding
places in mattresses, upholstered furniture, and the crevices in
Incidence plaster walls.6
Bed bugs have been known since the Ice Age, when they are Could increased air travel be contributing to the problem? Peo-
thought to have lived in caves, feeding off both humans and ple can move from infested areas quickly, bringing bed bugs
bats. Currently, there appears to be an epidemic, not just in with them in their luggage; therefore, suitcases are best kept on
hostels but in 5 star hotels, too. For example, known cases in stands and away from the floor. Moreover, recent treatments
San Francisco doubled from 300 cases in 2004 to 600 cases in may be less effective, due to the development of resistance and
2006. In New York, 4600 cases were reported for 2006. The the delayed mechanism of action in the newer agents. DDT
number could be much higher, but the stigma of bed bug in- was insecticidal, but its ban in 1972 due to its effects on the
festation taints a hotel and even a house that might be for sale, food chain and possible link to cancer resulted in fewer bed
resulting in under-reporting.2 These figures are so worrying bug deaths. In addition, some bed bugs have undergone muta-
that the United States hosted the first bed bug conference in
tions, resulting in certain treatments that work in some states
April 2009.3 Philadelphia, like many cities, is currently under and not in others, eg, bed bugs in Florida are 264 times less
a major attack.
resistant to 1% deltamethrin than are New York bed bugs.7
Elsewhere in the world, Danish authorities have reported a
2-fold increase in July and August from 20032007 in the Entomology
number of inquiries made to the Danish Pest Infestation Bed bugs belong to the family Cimicidae and are homeother-
Laboratory (DPIL).4 In Greater London, there was almost mic ectoparasites, feeding primarily on mammals but also on
a 25% increase in the number of complaints regarding bed poultry and rodents. The most common genus causing the cur-
bugs between 2000 and 2006,5 with an increased incidence in rent problems is Cimex lenticularius. Other forms include Ci-
UK travel hubs (M. T. Siva-Jothy, personal communication, mex hemipterus (mainly in the tropics) and Leptocimex bouleti
August 12, 2010). (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- Treatment
rounding conditions are adequate. In a laboratory, they are Just as there is the trio of breakfast, lunch, and dinner, so interven-
known to survive for up to 4 years and even for more than 18 tion should include another threesome: symptomatic relief, fumi-
months without any food.1 The optimum temperature for tem- gation, and prevention. Relief can be accomplished with topical
perate bed bugs is 79oF and for tropical bed bugs 97F, but after steroids. Fumigation is needed, as bed bugs quickly reproduce
2 weeks at 104F (with no air conditioning), temperate bed bugs with thousands of progeny in just a few weeks.2 Such insecticides
are effectively dead, and they cannot produce viable offspring used include deltamethrin, permethrin, and pyrethrin, as well as
(M. T. Siva-Jothy, personal communication, August 12, 2010). newer agents such as chlorfenapyr or hydroprene.12 Washing bed
clothing, cleaning drapes and upholstery, and repairing torn wall-
Clinical Features paper and disreputable plaster are useful preventive measures.

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

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 on the increase within Greater London? J Environ Health Res.
to drug treatments playing a role. Vigilance and fumigation on 2009;9:1724.
the slightest provocation are advised. Although bed bugs cannot 6 Rozendaal JA. Bedbugs, fleas, lice, ticks and mice. Vector Con-
trol: Methods for Use by Individuals and Communities. Geneva,
be exterminated from this earth, their numbers can be controlled Switzerland: WHO; 1997:237243.
by even the simplest of measures to prevent a full-blown pan- 7 Yoon KS, Kwon DH, Strycharz JP, et al. Biochemical and molecu-
demic. Prevention is better than cure. lar analysis of deltamethrin resistance in the common bed bug
(Hemiptera: Cimicidae). J Med Entomol. 2008;45:10921101.
Once bitten, twice shy!
8 Crissey JT. Bedbugs: an old problem with a new dimension. Int
J Dermatol. 1981;20:411414.
References
9 Graham-Brown RAC, Burns T. Lecture notes. Dermatology. 9th
1 Parish LC, Witkowski JA. The bedbugs never left. Skinmed. ed. Malden, MA: Blackwell Publishing; 2007:51.
2004;3:6970. 10 Wang C, Gibb T, Bennett GW, et al. Bed bug (Heteroptera: Cimic-
2 Goddard J, deShazo R. Bed bugs (Cimex lectularius) and clinical idae) attraction to pitfall traps baited with carbon dioxide, heat,
consequences of their bites. JAMA. 2009;301:13581366. and chemical lure. J Econ Entomol. 2009;102:15801585.
3 US to tackle resurgent bed bugs. BBC News Online. http:// 11 Burns DA. Diseases caused by arthropods and other noxious animals.
news.bbc.co.uk/2/hi/americas/7999260.stm. Accessed Au- In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rooks Textbook of
gust 13, 2010. Dermatology. Oxford, England: Wiley-Blackwell; 2010:38.138.61.
4 Kilpinen O, Jensen KM, Kristensen M. Bed bug problems in Den- 12 How to Manage Pests: Pests of Homes, Structures, People, and
mark, with a European Perspective. In: Proceedings of the Sixth Pets. 2009. http://www.ipm.ucdavis.edu/PMG/PESTNOTES/
International Conference on Urban Pests. Veszprm, Hungary: pn7454.html. Accessed August 13, 2010.
OOK-Press Kft; 2008:395398. 13 Krause-Parello CA, Sciscione P. Bedbugs: an equal opportunist
5 Richards L, Boase CJ, Gezan S, et al. Are bed bug infestations 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 With widespread use of any drug, a small number of birth defect reports associated
VELTIN (clindamycin phosphate and tretinoin) Gel 1.2%/0.025% temporally with the administration of the drug would be expected by chance alone.
The following is a brief summary only; see full prescribing information for complete Thirty cases of temporally associated congenital malformations have been reported
product information. during two decades of clinical use of another formulation of topical tretinoin.
Although no definite pattern of teratogenicity and no causal association have been
1 INDICATIONS AND USAGE established from these cases, 5 of the reports describe the rare birth defect category,
VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years holoprosencephaly (defects associated with incomplete midline development of the
or older. forebrain). The significance of these spontaneous reports in terms of risk to fetus is
not known.
4 CONTRAINDICATIONS
VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis, 8.3 Nursing Mothers
or history of antibiotic-associated colitis. 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
5 WARNINGS AND PRECAUTIONS to appear in breast milk. Because of the potential for serious adverse reactions in
5.1 Colitis nursing infants, a decision should be made whether to discontinue nursing or to
Systemic absorption of clindamycin has been demonstrated following topical use. discontinue the drug, taking into account the importance of the drug to the mother.
Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have It is not known whether tretinoin is excreted in human milk. Because many drugs are
been reported with the use of topical clindamycin. If significant diarrhea occurs, excreted in human milk, caution should be exercised when VELTIN Gel is administered
VELTIN Gel should be discontinued. to a nursing woman.
Severe colitis has occurred following oral or parenteral administration of clindamycin 8.4 Pediatric Use
with an onset of up to several weeks following cessation of therapy. Antiperistaltic Safety and effectiveness of VELTIN Gel in pediatric patients below the age of 12 years
agents such as opiates and diphenoxylate with atropine may prolong and/or worsen have not been established. Clinical trials of VELTIN Gel included 2,086 patients 12-17
severe colitis. Severe colitis may result in death. years of age with acne vulgaris. [See Clinical Studies (14) of full prescribing information.]
Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-
associated colitis. 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.2 Ultraviolet Light and Environmental Exposure Long-term animal studies have not been performed to evaluate the carcinogenic
Exposure to sunlight, including sunlamps, should be avoided during the use of potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was negative
VELTIN Gel, and patients with sunburn should be advised not to use the product until for mutagenic potential when evaluated in an in vitro Ames Salmonella reversion
fully recovered because of heightened susceptibility to sunlight as a result of the use assay. VELTIN Gel was equivocal for clastogenic potential in the absence of metabolic
of tretinoin. Patients who may be required to have considerable sun exposure due to activation when tested in an in vitro chromosomal aberration assay.
occupation and those with inherent sensitivity to the sun should exercise particular Clindamycin: Once daily dermal administration of 1% clindamycin as clindamycin
caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are phosphate in the VELTIN Gel vehicle (32 mg/kg/day, 13 times the recommended
recommended. Weather extremes, such as wind or cold, also may be irritating to clinical dose based on body surface area comparison) to mice for up to 2 years did
patients under treatment with VELTIN Gel. not produce evidence of tumorigenicity.
6 ADVERSE REACTIONS Tretinoin: In two independent mouse studies where tretinoin was administered
6.1 Adverse Reactions in Clinical Studies topically (0.025% or 0.1%) three times per week for up to two years no
The safety data reflect exposure to VELTIN Gel in 1,104 patients with acne vulgaris. carcinogenicity was observed, with maximum effects of dermal amyloidosis. However,
Patients were 12 years or older and were treated once daily in the evening for 12 in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 g (1.4
weeks. Observed local treatment-related adverse reactions (1%) in clinical studies times the recommended clinical dose based on body surface area comparison) three
with VELTIN Gel were application site reactions, including dryness (6%), irritation (5%), times per week for 20 weeks acted as a weak promoter of skin tumor formation
exfoliation (5%), erythema (4%), pruritus (2%), and dermatitis (1%). Sunburn (1%) following a single application of dimethylbenz[]anthracene (DMBA).
was also reported. Incidence of skin reactions peaked at week 2 and then gradually In a study in female SENCAR mice, papillomas were induced by topical exposure
decreased. to DMBA followed by promotion with 12-O-tetradecanoyl-phorbol 13-acetate or
Local skin reactions were actively assessed at baseline and at the end of 12 weeks of mezerein for up to 20 weeks. Topical application of tretinoin prior to each application
treatment in patients exposed to VELTIN Gel. At baseline (N=476), local skin reactions of promoting agent resulted in a reduction in the number of papillomas per mouse.
included erythema (24%), scaling (8%), dryness (11%), burning (8%), and itching However, papillomas resistant to topical tretinoin suppression were at higher risk for
(17%). At 12 weeks of treatment (N=409), local skin reactions included erythema pre-malignant progression.
(21%), scaling (19%), dryness (22%), burning (13%), and itching (15%). During the Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed
12 weeks of treatment, each local skin reaction peaked at week 2 and gradually specific studies, employing concurrent or intercurrent exposure to tretinoin and UV
reduced thereafter. radiation. The photoco-carcinogenic potential of the clindamycin tretinoin combination
is unknown. Although the significance of these studies to humans is not clear, patients
7 DRUG INTERACTIONS should avoid exposure to sun.
7.1 Erythromycin
VELTIN Gel should not be used in combination with erythromycin-containing products 17 PATIENT COUNSELING INFORMATION
due to possible antagonism to the clindamycin component. In vitro studies have [See FDA-approved Patient Labeling].
shown antagonism between these 2 antimicrobials. The clinical significance of this 17.1 Instructions for Use
in vitro antagonism is not known. 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
7.2 Neuromuscular Blocking Agents (excluding the eyes and lips).
Clindamycin has been shown to have neuromuscular blocking properties that may Patients should be advised not to use more than a pea sized amount to cover
enhance the action of other neuromuscular blocking agents. Therefore, VELTIN Gel the face and not to apply more often than once daily (at bedtime) as this will not make
should be used with caution in patients receiving such agents. for faster results and may increase irritation.
A sunscreen should be applied every morning and reapplied over the course
8 USE IN SPECIFIC POPULATIONS of the day as needed. Patients should be advised to avoid exposure to sunlight,
8.1 Pregnancy sunlamp, ultraviolet light, and other medicines that may increase sensitivity to
Pregnancy Category C. There are no well-controlled studies in pregnant women sunlight.
treated with VELTIN Gel. VELTIN Gel should be used during pregnancy only if the Other topical products with a strong drying effect, such as abrasive soaps or
potential benefit justifies the potential risk to the fetus. A limit teratology study cleansers, may cause an increase in skin irritation with VELTIN Gel.
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 17.2 Skin Irritation
in teratogenic effects. Although no systemic levels of tretinoin were detected, VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
craniofacial and heart abnormalities were described in drug-treated groups. These 17.3 Colitis
abnormalities are consistent with retinoid effects and occurred at 16 times the In the event a patient treated with VELTIN Gel experiences severe diarrhea or
recommended clinical dose assuming 100% absorption and based on body surface gastrointestinal discomfort, VELTIN Gel should be discontinued and a physician should
area comparison. For purposes of comparison of the animal exposure to human be contacted.
exposure, the recommended clinical dose is defined as 1 g of VELTIN Gel applied
daily to a 50 kg person. STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.
Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, VELTIN is a trademark of Astellas Pharma Europe B.V.
rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given VEL:2BRS
orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose Issued July 2010
based on body surface area comparison). However, variations in teratogenic doses 2010 Stiefel Laboratories, Inc.
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. 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- ing with the expanded disability status scale of the last visit. In-
der that has been recently accepted as an autoimmune formation on a family history of psoriasis within MS patients
disease. The presence of similar pathophysiologic mecha- was obtained from phone contacts made with the patients them-
nisms within autoimmune diseases has motivated investigators selves. Full biological relatives, including first- (parent, sibling,
to search for a common genetic background, association, and child) and second-degree relatives (grandparents, uncles/aunts,
coexistence between these diseases. Multiple sclerosis (MS), nephews/nieces) were considered.
which is accepted as a model T cellmediated autoimmune
disease, has been the subject of several studies showing the as- Statistical Analysis
sociations with various autoimmune diseases.13 Families with Contingency tables were analyzed by Fisher exact test and chi-
MS members have also been investigated, and different patterns square test. Frequency and descriptive analysis was made on
of autoimmune diseases have been found in different popula- SPSS 11.0 (SPSS Inc, Chicago, IL).
tions.46 Recent studies show that psoriasis is one of the autoim-
mune diseases that occur in MS patients families with a higher Results
frequency.5,6 In this study, we investigated the familial frequency
Demographic characteristics of MS and control groups are given
of psoriasis in a Turkish MS cohort compared with a similar sex-
in Table I. There were no significant differences between the
and age-matched control group.
groups with regard to age and sex. Eight relatives of MS patients
Materials and Methods had psoriasis, whereas only one relative had psoriasis in the con-
trol group. Although a higher frequency of psoriasis is found in
The records of 127 patients (78 women and 49 men; ratio,
MS patients relatives, a statistically significant increased risk of
1.59:1) with definite MS were included in this study between
psoriasis was not obtained (P>.05). All of the psoriatic relatives
2006 and 2007. All of the patients were diagnosed and followed
had chronic plaque-type psoriasis.
up in the neurology department of Hacettepe University. The
patients were contacted by phone and were asked whether any The relatives with psoriasis in MS and control groups are shown
of their first- and/or second-degree relatives had psoriasis. The in Table II. Most relatives with psoriasis in the MS population
control group consisted of 125 patients (77 women and 48 men; were fathers (n=2) and brothers (n=2), but this frequency was
ratio, 1.6:1) who were admitted to the internal diseases outpa- not significant with respect to other relatives who were a mother
tient clinic of the same university. (n=1), sister (n=1), nephew (n=1), and niece (n=1) (P>.05).
Records of MS patients included age, symptoms and signs at The mean age of MS onset of patients who had a relative with psori-
onset of MS, functional neurologic systems, and disability scor- 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 22, 35, and 42 years, respectively. All of the patients who had
difference in age of onset when MS patients were compared accord- psoriasis themselves were diagnosed in the dermatology depart-
ing to psoriasis history in relatives (P>.05). ment between 2005 and 2007. The small number of patients
with coexistent psoriasis and MS inhibited the evaluation of
The symptoms and signs at onset of MS patients with and with-
disease interaction on prognosis for each other. In our opinion,
out psoriatic relatives are compared in Table III. There were no
studies and individual cases should be strongly supported to be
significant differences between patient groups with respect to
reported to understand more adequately these relationships.
signs and symptoms at onset.
In some studies, MS patients with a relative with psoriasis were
Discussion found to have a younger age of onset.6 In our study, we found no
In this study, although not statistically significant, a higher fre- difference of age at onset between MS patients with and without
quency of psoriasis was found in relatives of MS patients. An psoriatic relatives. This feature was also not evaluated as a predic-
increased risk for psoriasis in MS patients and their relatives tor of MS disability because the duration and number of attacks
could not be defined. The prevalence of psoriasis in an otherwise of MS patient groups were not homogenous when divided ac-
healthy Turkish population has been estimated to be 1% to 2% cording to psoriasis family history.
in previous reports; therefore, the psoriasis prevalence of 6.2%
Psoriasis is accepted as an autoimmune T cellmediated disorder.
within the relatives of MS patients in our study was strikingly
Like other autoimmune diseases, the associated major histocom-
engrossing.7 We believe that there could have been false-negative
patibility complex alleles have begun to be expressed for psoria-
family histories, resulting in a probable higher frequency of pso-
sis.8 Activated T cells produce systemic inflammatory cytokines,
riasis in MS families, because the data were retrospectively col-
including principally interferon gamma. Interferon gamma par-
lected by phone.
ticularly induces ectopic class II major histocompatibility complex
Three of the MS patients had psoriasis themselves. Their psoria- expression on keratinocytes and activated cytotoxic T cells. This
sis onset ages were 15, 20, and 41 years and MS onset ages were 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 2 Warren S, Warren KG. Multiple sclerosis and associated diseases: a
Although not fully proved, it was shown that the autoimmunity relationship to diabetes mellitus. Can J Neurol Sci. 1981;8:3539.
in psoriasis could be adopted by means of immune pathomecha- 3 De Keyser J. Autoimmunity in multiple sclerosis. Neurology.
1988;38:371374.
nisms, when a patient developed psoriasis after receiving syngeneic
4 Broadley SA, Deans J, Sawcer SJ, et al. Autoimmune diseases
bone marrow from a psoriatic donor.10 In view of the evidence in first degree relatives of patients with multiple sclerosis. A UK
of autoimmunity in psoriasis, the higher frequency of psoriasis in survey. Brain. 2000;123:11021111.
MS patients relatives may be the outcome of a complex hetero- 5 Heinzlef O, Alamowitch S, Sazdovitch V, et al. Autoimmune dis-
genic background of autoimmunity. 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
Conclusions
frequency of psoriasis in relatives is associated with early on-
Coexistence of psoriasis with autoimmune diseases supports the set in an Italian multiple sclerosis cohort. Acta Neurol Scand.
upcoming evidence of psoriasis own autoimmune nature. The 2003;108:327331.
underlying self-reactivity remains to be unknown in many auto- 7 Kundakci N, Trsen U, Babiker MO, et al. The evaluation of the
sociodemographic and clinical features of Turkish psoriasis pa-
immune diseases, making the coexistence more crucial to define tients. Int J Dermatol. 2002;41:220224.
and investigate. The predictivity of these associations on disease 8 Bowcock AM. The genetics of psoriasis and autoimmunity. Annu
morbidity and/or mortality requires more investigation consist- Rev Genomics Hum Genet. 2005;6:93122.
ing of higher numbers of patients. 9 Reeves WH. Autoimmune mechanisms in psoriasis. Semin Der-
matol. 1991;10:217224.
10 Snowden JA, Heaton DC. Development of psoriasis after
References
syngeneic bone marrow transplant from psoriatic donor:
1 Seyfert S, Klapps P, Meisel C, et al. Multiple sclerosis and other further evidence for adoptive autoimmunity. Br J Dermatol.
immunologic diseases. Acta Neurol Scand. 1990;81:3742. 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 the case: methylparaben and propylparaben are the most widely
is challenging, yet key, to many issues in acne treat- used preservatives, and sensitivity reactions are low and irritation
ment.13 Formulation influences the dosage regimen; at low concentrations is rare. Propylene glycol is also a useful
it affects efficacy and tolerability and is interactive with compli- multifunctional ingredient.
ance. In creating high-performance topicals, we must consider
Therapeutic options for acne have changed little over the years,
two formulations. The primary formulation is delivered to the
but there has been much progress in their delivery and appli-
patient, but once it is applied to the skin, its components (es-
cation of therapeutic modalities, increasing both the effective-
pecially if there is water in the formulation) begin to evaporate.
ness, as well as patient tolerability and acceptance. An in-depth
Some begin to penetrate the skin, blending with the skins natu-
understanding of the pathophysiologic mechanisms has lead to
ral hydrolipidic film, resulting in the secondary formulation. It
the increased use of combination therapy; however, side effects
is often from this changed formulation that the drug is delivered,
associated with various topical antiacne agents and the undesir-
and the problems of irritation occur.
able physicochemical characteristics of certain important agents,
such as tretinoin and benzoyl peroxide (BPO), can affect their
Myths utility and patient compliance.
There are a number of myths surrounding formulation develop-
ment. A great vehicle is not great for all drugs or skin conditions. What Is an Effective Formulation?
Optimal vehicles have to be customized for the active ingredient. A better understanding of the physicochemical effects of both
There is a view that all gels are drying, resulting from many years active ingredients and vehicles has led to the introduction of new
ago when the initial gels used in dermatology were alcohol and products with enhanced efficacy, tolerability, and cosmetic ac-
acetone based. Today, there are very few remaining alcohol gels ceptability.
(eg, Retin-A gel). Another aspect is whether penetration en-
An effective topical formulation must satisfy a number of key criteria:
hancers can be put into any formulation. Penetration enhancers
are drug specific and formulation sensitive. Finally, methylpara- 1. Provide a stable chemical environment to accommodate
ben, propylparaben, and propylene glycol have been considered multiple compounds that may have different, if not in-
by some as inappropriate in topical formulations. This is not 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- zation, compounded by the host responses to the pro-inflamma-
tremely lipophilic pilosebaceous unit. tory activities of Propionibacterium acnes.4 Combination therapy,
3. Contain concentrations of active ingredients that, in com- targeting the multiple components of acne, should provide bet-
bination with excipients, are effective and well tolerated. ter patient outcomes and is now commonplace; however, con-
centration- and formulation-dependent skin irritation and dry-
4. Contain excipients that are not drying or irritating, but
ness can limit utility especially with the use of retinoids, BPO,
are occluding or moisturizing, which, in combination, can
and some formulation excipients.
modulate the release of the product at the treatment site.
5. Be cosmetically acceptable and easy to apply. Topical retinoids are one of the cornerstones of acne therapy and
are recommended as first-line therapy for all but the most severe
Therapeutic Options forms. They are used as monotherapy in mild comedonal acne
Current evidence suggests that acne is the result of a combina- and in combination with BPO and antimicrobials (topical or
tion of increased sebum production and follicular hyperkeratini- 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 ORIGINAL CONTRIBUTION

Retinoids normalize the abnormal follicular desquamation asso- resistance.4 In addition, BPO has keratolytic and anticomedogenic
ciated with acne, which facilitates penetration of other antiacne effects.12,13 As with the retinoids, the primary limitation of BPO
agents6,7 and prevents obstruction of the pilosebaceous orifice.7 in certain patients is concentration-dependent (and potentially
As a result, they can be both comedolytic and anticomedogenic, formulation-dependent) skin dryness and irritation.4
having been shown to reduce the formation of microcomedones
Surfactants, preservatives, and high levels of organic solvents
and comedones.8 Retinoids also have direct and indirect anti-
often used in combination with BPO or for solubilizing reti-
inflammatory effects, presumably from their actions on toll-like
noids are potential irritants. Alcohol and surfactants disrupt
receptors and cytokine production.9
membrane lipid bilayers of the epidermal barrier. Preservatives
A major drawback of retinoids is the potential to cause irrita- are also sensitizing. In addition, the first-generation tretinoin
tion, a side effect that is generally dose dependent.10 Irritation, products, including all the generics that followed, were solubi-
exfoliation, dryness, and scaling with retinoid therapy is partic- lized formulated into a formulation containing significant levels
ularly common during the initial 3 to 4 weeks of treatment.10 of isopropyl myristate or alcohol. The use of these products is
Irritation can also be a limiting factor for treatment adherence associated with a burst in penetration of tretinoin, when the
in many patients.10 medication is applied to the epidermis, causing dryness and peel-
ing that can advance to unwanted scaling and redness.
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 Resolution
acnes and may decrease inflammation.11 BPO is also safe and effec- Novel drug delivery strategies play a pivotal role in improving
tive, with its efficacy being maintained over many years of use and the topical delivery of antiacne agents by enhancing their dermal
the distinct advantage of not being associated with antimicrobial localization with a concomitant reduction in their side effects.

Mean Cumulative Receptor Levels of Benzoic Acid (BPO Metabolite)*

2500

2000
Benzoic Acid, ng/cm2

1500

1000

Clindamycin-BPO 2.5%
500 Commercial Preparation BPO 5%
Commercial Preparation BPO 5%

0
0 6 hours 12 hours 18 hours 24 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 Advances in Topical Delivery Systems in Acne


January/February 2011 ORIGINAL CONTRIBUTION

0%
Clindamycin-BPO
Median Percentage Change From Baseline

2.5% (n=797)
10%
Clindamycin
Phosphate (n=812)
20% BPO (n=809)

Vehicle (n=395)
30%

40%

50% **
*
60%

*
70%
Inflammatory Noninflammatory Total
Lesions Lesions Lesions

Week 12
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- BPO (<5%), be stable, and be formulated in a vehicle, enhanc-
ful acne management is important. ing BPO bioavailability and minimizing irritation.18

In a recent survey of 200 patients with acne who had used fixed- Acanya Gel
combination products containing 5% BPO and 1% clindamycin A unique formulation of BPO 2.5% with clindamycin phos-
for 6 months, 56% to 68% reported being bothered by dry skin, phate 1.2% (Acanya gel; Coria Laboratories, Aliso Viejo, CA) is
redness, flaky/peeling skin, or even irritation (Table). As a result, pa- a once-daily, fixed-combination acne product to combine a low
tients adopted a variety of coping mechanisms including spot treat- concentration (2.5%) of microdispersed BPO particles, deliv-
ment (33%), intermittent use (32%), or discontinuation (10%).14 A ered in a hydrogel with a nonirritating excipient, acting as both
number of patients switched to another product, and many (41%) a humectant and a penetration enhancer.
applied moisturizers to counteract the redness and dryness.
The aqueous gel formulation BPO 2.5%/clindamycin phosphate
High concentrations of BPO (5%) are known to result in skin 1.2% achieves stability between two otherwise incompatible ac-
irritation that may limit patient adherence.15 Two commonly tive ingredients: solubilized clindamycin phosphate and a mi-
used fixed-combination products, containing 5% BPO and crosuspension of BPO. Low amounts of propylene glycol act as
clindamycin, may be moderately irritating, but there is a mean- a humectant-type moisturizer and effective delivery solvent for
ingful reduction in irritation scores when the concentration is the BPO, following application to the skin, and allows for good
reduced from 5% to 2.5%.16,17 By extrapolating this informa- bioavailability without compromising cosmetic elegance. In ad-
tion, one could create an ideal fixed-combination acne product dition, the uniformly distributed suspended micronized particles
that would be used once daily, contain a low concentration of further minimize irritation compared with solubilized BPO.

SKINmed. 2011;9:1521 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- ter understanding of the pathophysiology of acne has helped to
licular opening (Figure 5). consolidate our views on the best treatment options; however,
retinoids and fixed-combination products containing BPO can
Tolerability of Atralin gel is excellent. Analyses of the combined stud-
cause dose-dependent and formulation-dependent irritation and
ies demonstrate a low incidence of skin-related adverse events (AEs)
dryness, limiting use in some patients and resulting in a number
after treatment with tretinoin gel 0.05%; 70% of patients reported
of coping mechanisms. Recent advances in formulation technol-
no skin-related AEs.21 The most commonly reported skin-related AE
ogy have permitted the development of products that are both
within the tretinoin gel 0.05% group was dry skin (16%). This is
effective and well tolerated.
in comparison with the higher-strength tretinoin 0.1% microsphere,
where the overall incidence of skin-related AEs was 52% (P<.001 vs Acknowledgement and disclosure: Brian Bulley, MSc, assisted in the
0.05% tretinoin) and dry skin occurred in 30% of patients (Figure 6). development of this manuscript. Dr Ceilley is a consultant for Coria
In addition, peeling/scaling/flaking skin was reported by 30% of pa- Laboratories, Aliso Viejo, CA.
tients treated with tretinoin 0.1% microsphere (compared with only
12% taking tretinoin gel 0.05%) and erythema in 18% of patients References
(compared with 7% taking tretinoin gel 0.05%). 1 Date AA, Naik B, Nagarsenker MS. Novel drug delivery systems:
potential in improving topical delivery of antiacne agents. Skin
Skin-related AEs generally resolved within the first 4 weeks of Pharmacol Physiol. 2006;19:216.
treatment and were similar to baseline at week 12; furthermore, 2 Katz MA, Cheng CH, Nacht S, inventors. Methods and com-
the incidence rates observed with tretinoin gel 0.05% in the com- positions for topical delivery of benzoyl peroxide. US patent
bined analysis were 50% to 75% lower than those rates reported 5,879,716. March 9, 1999.
in the literature for other marketed tretinoin formulations con- 3 Ting WW, Vest CD, Sontheimer RD. Review of traditional and novel
modalities that enhance the permeability of local therapeutics
taining half the concentration of tretinoin gel (ie, 0.025%).22,23
across the stratum corneum. Int J Dermatol. 2004;43:538547.
4 Gollnick H, Cunliffe W, Berson D, et al. Management of acne:
Conclusions
a report from the alliance to improve outcomes in acne. J Am
Developing topical formulations in dermatology is challenging Acad Dermatol. 2003;49(suppl):S138.
but necessary if patient outcomes are to be improved. A bet- 5 Ghali F, Kang S, Leyden J, et al. Changing the face of acne

SKINmed. 2011;9:1521 20 Advances in Topical Delivery Systems in Acne


January/February 2011 ORIGINAL CONTRIBUTION

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

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SKINmed. 2011;9:1521 21 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 ing on the localization and type of the lesions.5,12 To obtain
of characteristics of individual cells. Morphologic features materials from erosive-vesiculobullous or pustular lesions, the
of cells change in various diseases.1 Cytology examines scraping method is used. The youngest vesicle, bulla, or pustule
these alterations for the early diagnosis and treatment of diseases.2 should be selected for sampling. Older lesions, even if intact,
This diagnostic method has been used for the diagnosis of diseases may be diagnostically misleading, as secondary infections, cel-
of various systems since the mid-19th century.3 For dermatologic lular degeneration, and epidermal regeneration at the base of
diseases, cytology was first used by Arnault Tzanck in 1947.4 To the lesion may be confused with basic pathologic findings.23
date, the Tzanck smear test has been used in the diagnosis of vari- The lesions are first gently cleaned with a 70% alcohol swab.
ous erosive-vesiculobullous, papular, pustular, and nodular lesions The roof of the vesicle, bulla, or pustule is incised with a scalpel
of different etiology, including tumors (Table).522 (No. 15), and then the fluid contents are carefully swabbed
without touching its base. The contents of the vesicle, bulla,
The Tzanck smear test has some advantages. It is a simple, reli-
or pustule and the blood should not be included in a sample,
able, rapid, and inexpensive (the cost per test is less than $1)
because they dilute and obscure the epithelial or inflammatory
method.16 Obtaining samples for the Tzanck smear test is pain-
cells. The base of the lesion is scraped with the sharp edge of the
less and, therefore, anesthesia is not necessary; moreover, mul-
scalpel. A blunt-ended spatula or a brush may be used in oral
tiple samples can be taken from different lesions and regions
mucosa, because they cause less bleeding.2 The cellular mate-
where taking a biopsy specimen is difficult.5,6 Despite all these
rial obtained is then immediately spread in a thin layer onto at
advantages, the use of the Tzanck smear test is usually limited to
least 2 microscopic slides (Figure 1A1F). An erosive lesion can
a few diseases in daily dermatologic practice.
easily bleed. When that happens, the bleeding area should be
To emphasize the utility and to expand the use of the Tzanck compressed with a saline-moistened gauze. In crusted lesions,
smear test, we present the ways of a Tzanck smear preparation the crusts are carefully removed with sterile forceps, and the
and the cytologic findings of various skin diseases. base of the lesion is then scraped.12 Solid lesions are grasped be-
tween the thumb and the forefinger of the nondominant hand,
Tzanck Smear Preparation 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
Obtaining Smear Materials is scraped along the incision by a scalpel (No. 15) and the ma-
For cytologic examination, materials are obtained by scraping terial obtained is gently scraped onto microscopic slides (slit-
(abrasion), slit-skin, or touch (imprint) techniques, depend- 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 REVIEW

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

table continued on adjacent page

SKINmed. 2011;9:2332 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 is especially used to demonstrate viral inclusion bodies for the
excess tissue. If the ulcerated lesion has a crust, it is removed diagnosis of warts and other viral infections.9
with sterile forceps. The base of the ulcer is then scraped by the
Immediate alcohol fixation is required for both Papanicolaou
blunt end of a scalpel (Figure 1M and 1N). Touch smear prepa-
and H&E stains. For other staining methods, specimens should
ration is usually used for some of the infectious and neoplastic
be stained as soon as they have been air-dried. If not, excessive
skin diseases. For a touch smear, the ulcerated tissue is touched
drying results in cellular swelling and loss of nuclear details;
to the glass slides, or the biopsy material is held by forceps and
however, cytoplasmic and background details are protected.9,10
touched on the glass slides at several points without causing
undue pressure or lateral movement (Figure 1O).23,25 If necessary, other staining methods such as Gram staining for
bacterial infections, acid-fast staining for mycobacterial infec-
Staining of Samples tions, methylene blue or toluidine blue stainings for mastocy-
The most commonly used stain is May-Grnwald-Giemsa tosis, and periodic acid-Schiff (PAS) or Gomorris methena-
(MGG) (Bio-optica, Milan, Italy).1 The others include Wright, mine silver (GMS) stainings for deep fungal infections can be
Diff-Quick, Papanicolaou, and hematoxylin and eosin (H&E) used.7,10 If a Tzanck smear test shows only acantholytic cells,
stains. Smears can be quickly stained by the MGG (2025 sec- direct immunofluorescence study on smears can be addition-
onds) and Diff-Quick (2 minutes) stains. The Papanicolaou stain ally performed.26

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


January/February 2011 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


Figure 1. Sampling methods for the Tzanck smear. A vesicular difficult in leprosy due to the variable morphology of Mycobacteri-
lesion on the dorsum of the foot (A). Cleaning the lesional area um leprae. Acid-fast bacilli can appear in rod-shaped, fragmented,
with an alcohol swab (B). Incising the roof of the vesicle by a scal- or granular forms. The bacilli are easily detected in patients with
pel (C). Absorbing the fluid content with the swab (D). Scraping
the base of the lesion with the scalpel (E). Spreading the material
lepromatous leprosy; however, they are very few in number in tu-
onto a glass slide as a thin layer (F). A nodular lesion on the face berculoid leprosy. In reactional leprosy, smears show numerous
(G). Cleaning the lesional area with an alcohol swab (H). Grasp- foamy macrophages with negative images of M leprae.28
ing the lesion between thumb and forefinger of the nondominant
hand (I). Making a small superficial incision at the edge of the Fungal Infections
lesion (J). Scraping the tissue along the incision by a scalpel (K).
Potassium hydroxide (KOH) is usually used for the identification
Spreading the material onto a glass slide as a thin layer (L). Re-
moving the crusts with sterile forceps in noduloulcerative lesions of superficial fungal infections. The fungal elements of those infec-
(M). Scraping the base of the ulcer by a scalpel (N). Touching the tions can also be detected in Papanicolaou, Giemsa, or methylene
ulcerated nodule to a glass slide (touch smear) (O). bluestained smears. Some deep fungi can be identified according
to the morphologic characteristics of their hyphae on direct micro-
Cytologic Findings scopic examinations or stained smears (Table).9 In suspected cases,
confirmatory stains such as GMS and PAS can be performed.10
Cutaneous Infections
Cytology can be the first diagnostic tool for detection of various Viral Infections
bacterial, fungal, viral, and parasitic agents. Presence of abundant Viruses cannot be detected by examining smears under a light
macrophages, neutrophils, or multinucleated giant cells with or microscope, but their cytopathic effects can be observed.9,10
without granuloma formation should alarm the cytologist about
the possibility of an infectious process.10 Herpesvirus infections. The most specific but difficult to find
cytologic features of herpetic infections are nuclear changes,
Bacterial Infections namely prominent eosinophilic inclusion bodies (Cowdry A nu-
Most bacterial agents can be detected by using routine cytologic clei) resembling eggs in a basket. For detection of these nuclear
stains, but some bacteria need to be identified by additional stains changes, Papanicolaou and Romanowsky stains are the most

SKINmed. 2011;9:2332 26 The Tzanck Smear Test


January/February 2011 REVIEW

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
Figure 2. Acantholytic cell (red arrows), multinucleated giant
using monoclonal antibodies against herpes simplex virus and cell (white arrow), and intranuclear inclusion bodies (black
varicella zoster virus.32 arrows) in herpetic infection (A); syncytial nuclei (arrow) in
hand, foot, and mouth disease (B); Henderson-Pattersons
Hand, foot, and mouth disease. Coxsackie virus induces syn- bodies (arrows) in molluscum contagiosum (C); and Guarnieris
cytial nuclei in epithelial cells and causes vesicles and aphthous le- bodies (arrows) in orf (D). Rapid Papanicolaou (cytocolor)
sions (Figure 2B). The size of each nucleus in giant cells is uniform. stain, magnification 1000 (A); May-Grnwald-Giemsa stain,
magnification 1000 (BD).
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 Parasitic Infections
in hand, foot, and mouth disease.1
Leishmaniasis. A diagnostic finding for cutaneous leishmaniasis
Human papillomavirus infections. Cytology is useful in is ellipsoid-shaped parasites with a 2- to 4-mm, eccentric nucleus
oral or genital warts, but it may be difficult to obtain adequate and paranuclear kinetoplast in the cytoplasm of macrophages and
materials from cutaneous lesions. Cytologic evidence of human giant cells, also in granulomas or extracellular background. A large
papillomavirus infections includes koilocytes with basophilic number of parasites within the cytoplasm of macrophages appear in
nucleus and punched-out perinuclear halo surrounded by a a swarm of bees formation.1,12 Positive findings of parasites have
dense peripheral cytoplasm. Small eosinophilic inclusion bod- been reported to be between 30%34 and 82.6%.35 These differences
ies may seldom be observed in both cytoplasm and nucleus. All are related to the duration of lesions, the smear method, and the
these features can be more easily seen in specimens stained with presence of secondary bacterial infections. Positive results of para-
Papanicolaou stain than with other stains.12 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
Molluscum contagiosum. Unlike other DNA viruses, the possibility of the presence of granulomas and multinucleated (Lang-
Molluscum contagiosum virus replicates in the cytoplasm of ke- hans type and/or foreign body type) giant cells in the lesions.7
ratinocytes, leading to oval, large (3035 mm), deeply basophilic
intracytoplasmic inclusion bodies, the so-called molluscum bodies Demodicosis, scabies, and cutaneous ameobiasis. Demo-
or Henderson-Patterson bodies (Figure 2C). It is difficult to ob- dex mites are between 0.3 mm and 0.4 mm and live in hair follicles
serve the nuclei of infected cells.1 of mammals. They have 4 pairs of short legs and cross-striations on
the abdomen. Demodicosis is not usually included in the differential
Milkers nodule and orf. Milkers nodule and orf, caused by diagnoses of dermatologists or the diagnosis is frequently masked by
the Parapoxviruses, induce round or oval cytoplasmic eosino- other skin diseases. The diagnosis of demodicosis needs both compat-
philic inclusion bodies in keratinocytes known as Guarnieris ible clinical features and the presence of a high density of mites (>5
bodies, which are usually surrounded by a clear halo (Figure mites/cm2). Standardized skin surface biopsy is a better diagnostic tool
2D). There are also a variable number of acantholytic cells, ne- for demodicosis than direct microscopic examination of fresh secre-
crotic keratinocytes, and inflammatory cells in the background.13 tions from sebaceous glands.37 Definitive diagnosis of scabies is made

SKINmed. 2011;9:2332 27 The Tzanck Smear Test


January/February 2011 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,
Figure 3. A normal keratinocyte (red arrow) and an acantho- superficial squamous cells and dyskeratotic acantholytic cells
lytic cell (black arrow) (A); acantholytic cells phagocyted by a without inflammatory cells and cocci.19
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
Genodermatoses
the acantholytic cell (arrow) (D) in pemphigus. May-Grnwald- Hailey-Hailey Disease
Giemsa stain, magnification 1000 (AC); direct immunofluo-
rescence examination, magnification 1000 (D). 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
by microscopic identification of Sarcoptes scabiei (KOH examination) with pyknotic nucleus may also be seen.12 Unlike the pemphigus
in skin scrapings taken from the burrows or vesicles. This mite has 4 group, direct immunofluorescence test on smears is negative.16
pairs of legs, multiple cuticular spines, and measures 0.3 mm.14 Direct
specimens or PAS and acid phosphatasestained specimens in cases Dariers Disease
with doubtful direct specimens show trophozoites of Entamoeba his-
Cytologic findings of Dariers disease are diagnostic. Similar to his-
tolytica (1540 mm) with finger-shaped pseudopods.15,25
topathologic examination, cytology reveals dyskeratotic acantholyt-
ic cells, corps ronds, and grains. Corps ronds are pyknotic kera-
Immunobullous Disorders
tinocytes with a round-shaped and hyaline, acidophilic cytoplasm,
Pemphigus and a pyknotic nucleus surrounded by a clear halo. The grains are
Pemphigus is characterized by numerous single or loosely adherent the end-product of the corps ronds. The nuclei of grains are ovoid
clumps of acantholytic cells with rounded or ovoid, mostly smooth, and are surrounded by a homogeneous dyskeratotic material.1,13
or occasionally serrated surface. The most distinctive features of
those cells are the presence of a large hyperchromatic, usually cen- Spongiotic Dermatitis
trally situated, nucleus and pronounced nucleoli.38 The cytoplasm is In spongiotic dermatitis, the nuclei of keratinocytes that form
scanty, usually basophilic and darker at the periphery (mourning- the wall of spongiotic vesicles are pushed to one side due to the
edged cells) (Figure 3A).1 Tadpole cells are usually few in number, pressure of intraepidermal edema, and the cytoplasm takes the
but more than 10 tadpole cells (at 100 magnification) are observed form of a tail (tadpole cells). The presence of tadpole cells in cy-
in pemphigus herpetiformis.16 In chronic cases, multinucleated gi- tologic examination usually refers to contact dermatitis. Tadpole
ant histiocytes can rarely be seen. These multinucleated giant histio- cells, however, may also be observed in many other skin diseases.
cytes frequently phagocytize the acantholytic cells (Figure 3B).39 In- It has been reported that the presence of more than 10 tadpole
flammatory cells are mainly neutrophilic and eosinophilic. Sertolis cells at 100 magnification is 83% sensitive and 100% specific
rosette cells consist of an epithelial cell at the center, surrounded for spongiotic dermatitis.17 Lymphocytes are the predominant
by a ring of leukocytes, and streptocytes are the chains of white cells in the majority (84%) of allergic contact dermatitis cases,
blood cells (Figure 3C).6 Direct immunofluorescence or immuno- whereas polymorphonuclear leukocytes outnumber the lympho-
histochemistry studies in smear show the typical immunoreactant cytes in most (82%) irritant contact dermatitis cases.18

SKINmed. 2011;9:2332 28 The Tzanck Smear Test


January/February 2011 REVIEW

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- Figure 4. Granuloma (red arrow) and a foreign bodytype
phils are observed. A Tzanck smear of pustules in erythema toxicum giant cell (black arrow) in scrofuloderma (A); bacterial balls
neonatorum, however, reveals a dense accumulation of eosinophils. (arrow) in botryomycosis (B); acid-fast Mycobacterium leprae
All 3 dermatoses show neither bacteria nor fungal agents.19 (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
Tumoral Lesions branching (arrows) in aspergillosis (F); broad-based budding
Benign Tumoral Lesions spores (arrow) in blastomycosis (G); Leishman-Donovan bodies
in a macrophage, swarm of bees fashion (arrow) (H); Touton-
Mastocytoma. The Tzanck smear test is useful for rapid di- type giant cell (arrow) in juvenile xanthogranuloma (I); foreign
bodies (arrows) in foreign body granuloma (J); necrobiosis
agnosis of mastocytoma in children. Cytology shows abundant
in necrobiosis lipoidica (K); and mucin in granuloma annulare
polygonal, triangular, or round mast cells (1520 mm) with (L). May-Grnwald-Giemsa stain, magnification 1000 (A, B,
metachromatically stained granules (0.20.5 mm). Granules are D, HL); Erlich-Ziehl-Nielsen stain, magnification 1000 (C);
stained basophilic with MGG, while stained reddish purple with Methylene blue stain, magnification 1000 (EG).
methylene blue (Figure 5A).6

Sebaceous hyperplasia. Scraping smear shows clusters of melanoma.5 For this reason, it could make a great contribution
large foamy sebaceous cells with abundant cytoplasms (Figure to preoperative surgical planning. The Tzanck smear test can also
5B). Unlike sebaceous carcinoma, cellular atypia is absent. Lipid be used for the investigation of a possible recurrence of a previ-
staining is positive.5 ously treated neoplasm and for the follow-up of patients with
chronic dermatoses in whom the development of a malignancy is
Seborrheic keratosis. Cytologically, a seborrheic keratosis possible. Furthermore, a previous study showed the effectiveness
shows hyperkeratosis, basaloid cells, and horny cystic areas filled of a Tzanck smear test for intraoperative surgical margin control
with keratin (Figure 5C). Pigment granules are observed in both in the treatment of well-demarcated BCC.40
nucleated and enucleated keratinocytes and also in the back-
ground. If lesions are flat or ulcerated, they may be mistaken for Basal cell carcinoma. Clusters of basaloid cells are the most
basal cell carcinoma (BCC).6 characteristic cytologic pattern for BCC (Figure 6A). This cytologic
Melanocytic nevi. Cytologic examination presents epidermal finding has high sensitivity (97%) and specificity (86%) for BCC.41
and dermal type melanocytic cells (Figure 5D); however, cytologic Basaloid cells are uniform in size, elongated, and have a central oval
differentiation of the benign nevoid cells from the malignant ones nucleus usually without nucleoli and scanty, poorly defined baso-
may be difficult.20 philic cytoplasm. Nuclear dysplasia1,12 and clusters of spindle-shaped
cells5 may rarely be seen. Furthermore, the adenoid type shows small
Malignant Tumors dark basaloid cells in pseudoglandular arrangement, and the spaces
The Tzanck smear test is useful in differentiating BCC from between the cells are filled with a myxoid substance. Keratotic-type
other skin tumors such as squamous cell carcinoma (SCC) and BCC reveals keratin structures and atypical keratinocytes, whereas

SKINmed. 2011;9:2332 29 The Tzanck Smear Test


January/February 2011 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
Figure 5. Mast cells (arrow) in mastocytoma (A); clusters of
sebocytes (arrow) in sebaceous hyperplasia (B); horny cyst prominent nucleoli. Cytoplasm contains microvacuoles, mu-
(arrow) in seborrheic keratosis (C); and nevoid cells (arrows) cine, and occasionally granular melanin.1
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). posis sarcoma shows single or cohesive bundles of cigar-shaped
spindle cells with occasional single prominent nucleolus (Figure
pigmented BCC shows melanin granules in the macrophages and 6E). The cytoplasms of the tumor cells are indefinite and baso-
epithelial cell groups and in the background.22 philic. These cells are positive for CD31 and CD34.22

Squamous cell carcinoma. The characteristic feature is cyto- Miscellaneous


logic atypia of keratinocytes, namely, poikilokaryosis, poikilocytosis, Cytology has also been used for the diagnosis of various cuta-
nuclear contour irregularity, prominent nucleoli, nuclear molding, neous malignant tumors such as metastatic carcinoma, Merkel
and mitosis (Figure 6B). In very poorly differentiated tumors, bizarre cell carcinoma, sebaceous carcinoma, and histiocytosis. It is
nuclei, multinucleated giant cells, and spindle-shaped keratinocytes of utmost importance that the immunohistochemical study is
may also be observed.5,12 In contrast to BCC, SCC does not show performed for the cytologic diagnosis of the above-mentioned
adherent clusters of small cells.1 These cytologic findings of SCC are diseases (Figure 6F),5,12,22 because cytologic diagnosis of tumoral
sometimes difficult to differentiate from those of keratoacanthoma lesions can sometimes be difficult due to overlapping cytologic
and Bowens disease.5,12 Thus, histopathologic examination should be features of certain tumors and tumor-like conditions.22
made for the definitive diagnosis.6
Conclusions
Melanoma. Cytologically, melanoma is characterized by the The Tzanck smear test can be used not only in the diagnosis but also
presence of large pleomorphic cells that may be epitheloid, spin- in the treatment and follow-up of many skin diseases. The studies
dle-shaped, rounded or mixed-type (Figure 6C). Binucleated or reporting the diagnostic value of a Tzanck smear test in erosive-vesic-
multinucleated cells are frequently present. Pathognomonic fea- ulobullous lesions are limited in the literature.1618,29 Further cytologic
tures are binucleated melanocytes with two symmetric and con- studies are needed for granulomatous and tumoral diseases. Diagnos-
vergent nuclei (fly-eye nuclei).6 The nucleus may be irregular tic efficacy and utility of the Tzanck smear test can be increased by
and include a large eosinophilic nucleolus. Well-defined punched- performing histochemical, immunohistochemical, or immunofluo-
out intranuclear inclusions are characteristic of melanoma.12 Mel- rescence studies when needed. If the Tzanck smear test is performed
anin granules may be found in the palely basophilic cytoplasm of in a laboratory in some countries, such as in the United States, Cana-
cells, melanophages, and in the background.5 Cytologic diagnosis da, or Australia, it may be essential to comply with the certain labora-
of amelanotic melanoma is difficult because the tumors can be tory quality regulations and accreditation standards. We believe that
mistaken for metastatic carcinoma. Recently, with the advances the value of cytology will be better understood in the future by more
in immunohistochemical staining techniques, correct diagnosis frequently using the Tzanck smear test in daily dermatology practice.

SKINmed. 2011;9:2332 30 The Tzanck Smear Test


January/February 2011 REVIEW

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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 4) A dense accumulation of eosinophils, seen on Tzanck smear test
characteristic lesion, are indicative of: of a characteristic lesion, is most indicative of:
a. bullous pemphigoid a. acropustulosis of infancy
b. Darier disease b. erythema toxicum neonatorum
c. erythema multiforme c. transient neonatal pustular melanosis
d. Hailey-Hailey disease (benign familial Pemphigus) d. All of the above
e. pemphigus vulgaris e. None of the above
f. 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)
2) Which of the following, seen on Tzanck smear test, is consistent but not staphylococcal scalded skin syndrome (SSSS)?
with herpesvirus infection but not Coxsackie virus infection? a. Dyskeratotic acantholytic cells without cocci.
a. Acantholytic cells. b. Epidermal giant cells with hyperchromatic, molded nuclei.
b. Characteristic inclusions. c. Large superficial squamous cells.
c. Multinucleated epidermal giant cells. d. Leukocytes.
d. Visualization of characteristic changes using the Papanico- e. Necrotic cuboidal basal cells.
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 ANSWERS TO SELF-TEST REVIEW QUESTIONS:
e. None of the above
1) b, 2) a, 3) c, 4) c, 5) d, e

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

the contraction process, such as neuromuscular transmission difficul- Physiopathology of Fatigue


ties.12 Central fatigue, often referred to as psychological factors, like- In humans, fatigue is more central than peripheral and more psycho-
ly to affect negatively performance, are based on the impossibility to logical than physiological; nevertheless, it is very difficult to quantify
explain the muscular failure despite an appropriate fuel offer to an such facts. During very intense exercising, physical fatigue can arise in
apparently normal working organ. The fatigue observed in infectious a short span of time, while less intense exercises may be extended before
and post-surgery settings or post-injury recovery is not yet clarified.10 exhaustion voids the muscular work. The determining factor in the
Fatigue manifestations, as observed by the reduction in the ability to appearance of effort fatigue is the voluntary muscular activity, in which
produce a certain strength, appear immediately after the beginning of the feeding substrate is progressively reduced by exhaustion due to
intense activity. Where such activity is sustained, fatigue may persist accumulation of metabolites and lack of regulating mechanisms.6
for days or even weeks. The mechanisms responsible for performance Multiple factors accelerate the appearance of fatigue, which include
limitation are several.6,12,13 heat, humidity, altitude, and muscular fitness. Other factors delay
At the muscular cell level, adenosine-5-triphosphate (ATP) use is dra- fatigue, such as pleasure, rhythm, motivation, knowledge of the
matically accelerated to meet the required energy for excitement and steps of a task to be performed, and physical fitness. Sex and age also
contraction, leading to metabolic fatigue. Glycogen is the fundamental interfere in the establishment of fatigue.9,24
fuel, and fatigue will occur when exhausted in cell stocks. The intense Chronic fatigue may appear following long-term activities without
activity may also result from nonmetabolic fatigue as a consequence of sufficient rest for recovery or as a sensation of tiredness that is not
internal structure rupture and cytoskeletal muscular damage.14,15 justified as cause from physical exercise.12
The sensation of fatigue has been described by many arthritis patients The endoplasmic reticulum of muscular fibers (sarcoplasmic reticu-
but was only recently included in the Outcome Measures in Rheu- lum) stocks Ca2+ ions and has Ca volt-dependent channels. Myosin
matology Clinical Trials (OMERACT) meetings, a nucleus of studies has the capacity to hydrolyze ATP, which is enhanced by the Ca2+ ions
of clinical measures and models in rheumatology.1618 The Group of and inhibited by the Mg++ ions, and its maximum activity occurs in a
Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has been pH of 6.4. Actin also requires presence of Mg++ and Ca2+.25,26
including fatigue in its recent discussions.19,20 The relevance of fatigue
in the evolution of disease, however, is unknown, with regard to how It may be concluded that the alterations in proteins; the sarcolem;
to precisely measure or to what extent treatments may interfere with Mg++, Ca2+, and KCl quantities; pH; and energy production (mito-
it. Concerning rheumatoid arthritis fatigue, some studies point to chondria, glycogen, phosphocreatine, and ATP) interfere with mus-
predictive factors such as intense pain, bad sleep quality, sedentariness, cular contraction and may thus cause fatigue.2527
and functional limitations being more prevalent in women.21 There is From a neurologic point of view, fatigue is studied together with las-
a lack of studies on the subject of psoriatic arthritis. situde. Fatigue would be weariness or exhaustion due to physical or
Fatigue has been observed in different self-assessment scales that mea- mental effort, while lassitude has a more restrictive meaning, tending
sure aspects of life, and there is no common view about which would more to be a lack of capacity to remain physically or mentally active.2628
be more or less reliable.16,18 Thus, quality of life, functional evaluation, The intolerance to exercise (tiredness from small efforts) and fatigue
and visual analogical scales have been used. are common manifestations of myopathic diseases, in which the mus-
In 1991, researchers retrospectively analyzed the prevalence of fatigue cles are primarily weakened, as occurs in myasthenia gravis, muscular
in a medical clinic. In 1159 patients who completed the study, 276 atrophy, post-poliomyelitis syndrome, in some glycogen storage dis-
(24%) presented fatigue as a primary complaint. Greater prevalence eases, and mitochondrial myopathies. Fatigue is a frequent complaint
was found among the female participants (two-thirds of the cases). in multiple sclerosis. Patients with a neurologic disease characterized
In this study, after having discarded the known clinical causes for fa- by unresting muscular activity, such as in Parkinson disease, athetosis,
tigue, by history, physical examination, and laboratory examinations, and Huntington chorea, complain about fatigue.2729
a significant number of patients (in whom nothing physical was
The reduction of productivity and work capacity caused by fatigue
detected) presented with anxiety or depression, symptoms that were
was studied by industrial psychologists. In these studies, the impor-
more valued by patients than by their doctors.22
tance of physical or mental motivational factors was clearly dem-
In 1993, investigators analyzed patients seen in emergency departments onstrated.14,30 Real muscular weakness cannot be detected in most
of general practice clinics. A total of 995 patients were identified with fa- individuals who complain about fatigue. The individual affected
tigue complaints lasting more than 6 months, among whom 85 did not by fatigue is unable to handle complex problems and tends to be
present any clinical or psychiatric condition after careful assessment.23 less reasonable. The worker affected by fatigue cannot provide the

SKINmed. 2011;9:3437 35 Fatigue in Psoriasis With Arthritis


January/February 2011 REVIEW

necessary support to his family and often turns into the tyrant who The presence of a psychiatric disorder in patients with skin diseas-
returns at night to join the family. Inferiority complexes may surface. es, or resulting from them, is well known. Depression and anxiety
In neurologic and psychiatric departments, anxiety and depression symptoms are frequent in psoriasis and/or psoriatic arthritis pa-
are frequently diagnosed in fatigued patients.31 tients, possibly influencing fatigue symptoms.34 Psychiatric comor-
bidity in skin disease patients may reach 25% and keeps a greater
Most patients who seek medical help due to unexplained chronic fa-
correlation with the quality of life score than with the clinical gravity
tigue present some kind of psychiatric disorder. The most frequent
attributed by the doctor. The presence of psychiatric comorbidity
symptoms are unrest, irritability, anxiety, depression, migraine, in-
may be responsible, among other factors, for a greater perception of
somnia, drowsiness, and reduction in appetite and libido.31,32
symptoms, including fatigue.1,36
Clinical Aspects of Fatigue In rheumatoid arthritis, for example, fatigue is a relatively com-
Fatigue may be acute (<1 month) or chronic (>1 month). In the mon symptom, affecting 90% of patients and, for half of them,
acute form, the most easily identified causes prevail.22 is the most upsetting aspect of the disease.37

Almost all chronic diseases may be associated with fatigue. The differ- Patients with rheumatoid arthritis intensively affected by fatigue
ential diagnosis includes infections, anemia, neoplastic diseases, con- perceive their fatigue as frustrating or exhausting, while those
nective tissue diseases, endocrinopathy, neurologic diseases, chronic not intensively affected see fatigue as a normal phenomenon.37,38
kidney diseases, chronic liver diseases, metabolic diseases and ionic The intensity of fatigue has been linked to age, pain, depressive
disorders, sleep disorders, psychiatric diseases, and many others.2729 thoughts, worries, and sleep disorders.38 Fatigue in rheumatoid
arthritis, therefore, is more related to physical factors, depression,
Chronic fatigue syndrome is the current name of the disorder charac-
and psychosocial factors than to inflammation. Only a small per-
terized by severe disabling fatigue accompanied by other physical, con-
centage of patients with rheumatoid arthritis can be classified as
stitutional, and neurophysiologic complaints. The frequency is higher
being clinically depressed.39
among women (2:1), and patients are aged between 25 and 45 years,
although children and eldery patients have also been diagnosed.2729,33 Likewise, as in rheumatoid arthritis, patients with psoriatic arthritis
also experience a decrease in physical activity (due to pain, articu-
Cases may occur in isolation or in groups. Famous outbreaks in-
lar inflammation, muscle hypotrophy, reduction of strength, and
clude those in Los Angeles County Hospital (1934), Royal Free
muscular resistance), reduction of self-esteem, and often depression
Hospital in London (1955), and Incline Village in Nevada (1985).
and reduction in the quality of life, which leads to common somatic
The etiology of such outbreaks, although suggestive of an infectious
manifestations such as fatigue and sleep disorders.39 In addition, pa-
etiology or other environmental factors, were not established.27,33,34
tients with psoriasis excessively worry about their disease and are
Chronic fatigue is very common and occurs in up to 20% of distrustful about the treatments. Patients with such profiles are the
the patients in general emergency clinics. The chronic fatigue ones who most complain about pain, pruritus, and fatigue.40
syndrome is far less common and affects between 100 to 300 per
The severity of psoriasis used to be assessed only by the extension of
100,000 individuals in the United States.33,34
the dermatitis, leaving aside the assessment of fatigue, the quality
The pathogenesis of chronic fatigue syndrome is controversial of life and anxiety, and depression symptoms. Psoriasis, however,
and the attempted explanations include post-infectious and can provoke disabling and life-threatening disease.40 These effects
post-viral states (Epstein-Barr virus, retrovirus, or enterovirus), include stress, embarrassment, stigmata, and physical discomfort.
immunologic disorders, somatic worrying, or depression. Anti- With time, the patients emotional compromise grows, in detri-
bodies against some of those viruses have already been detected ment to his/her social involvement and drop in productivity in
at a high rate among chronic fatigue syndrome patients, but the school or work, as well as the loss in self-esteem. Systematic analy-
subsequent studies failed to confirm any relation.29,33 sis revealed fatigue as superior and different to normal tiredness,
and patients believe that it is linked to the diseases activity, bare
Fatigue and Psoriasic Arthritis sleep, tension of the articular components, and lack of well-being.
Diseases with immune characteristics frequently include fatigue It is considered more important than the articular symptoms.40
among its symptoms. Psoriasis is one of the most common dermato-
logic/rheumatologic diseases and bears immunogenetic information Conclusions
(HLA Cw6, HLA B13, HLA B17, B27, B57) in its physiopathology; Fatigue is therefore a symptom of great relevance that has to be
however, the study on the incidence or prevalence of fatigue in pso- measured and assessed in arthritis patients, including patients
riatic arthritis or psoriasis patients was not found in the literature.2,35 with psoriasis.

SKINmed. 2011;9:3437 36 Fatigue in Psoriasis With Arthritis


January/February 2011 REVIEW

References
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al Medicine. 7th ed. Columbus, OH: McGraw Hill; 2008:169193. 23 Bates DW, Schmitt W, Buchwall D, et al. Prevalence of fatigue
2 Wollina U, Unger L, Heinig B, Kittner T. Psoriatic arthritis. Derma- and chronic fatigue syndrome in a primary care practice. Arch
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4 Reid VL, Gleeson M, Williams N, Clancy RL. Clinical investigation Rheumatol. 2010;39:421429.
of athletes with persistent fatigue and/or recurrent infections. 25 Barbagallo M, Belvedere M, Dominguez LJ. Magnesium homeo-
Br J Sports Med. 2004;38:4245. stasis and aging. Magnes Res. 2009;22:235246.
5 Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fa- 26 Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C.
tigue syndrome. Clin Evid. 2004;12:15781593. Changes in vitamin D levels in patients with systemic lupus ery-
6 Skurvydas A, Brazaitis M, Streckis V, Rudas E. The effect of thematosus: effects on fatigue, disease activity and damage.
plyometric training on central and peripheral fatigue in boys. Int Arthritis Care Res (Hoboken). 2010:62:11601165.
J Sports Med. 2010;31:451457. 27 Barohn RJ. Muscles diseases. In: Goldman L, Ausiello D, eds. Cecil
7 Hainsworth KR, Davies WH, Khan KA, Weisman SJ. Co-occurring Medicine. 23rd ed. New York, NY: Saunders; 2007: chapter 447.
chronic pain and obesity in children and adolescents: the impact 28 Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity
on health-related quality. Clin J Pain. 2009:25:715721. scale. Application to patients with multiple sclerosis and system-
8 Brown WJ, Mishra G, Lee C, et al. Leisure time physical activity ic lupus erythematosus. Arch Neurol. 1989;46:1112111123.
in Australian women: relationship with well being and symptoms.
29 Wessley S, Powell FR. Fatigue syndrome: a comparison of
Res Q Exerc Sport. 2000;71:206216.
chronic postviral fatigue with neuromuscular and disorders. J
9 Ishizaki Y, Ishizaki T, Fukuoka H. Changes in mood status Neurol Neurosurg Psychiatry. 1989;52:940.
and neurotic levels during a 20-day bed rest. Acta Astronaut.
2002;50:453459. 30 Bultmann U, Kant I, Kasi SV, et al. Lifestyle factors as risk fac-
tors for fatigue and psychological distress in the working popu-
10 van Hoogmoed D, Fransen J, Bleijenberg G, van Riel P. Physi- lation: prospective results from the Maastricht Cohort Study. J
cal and psychosocial correlates of severe fatigue in rheumatoid Occup Environ Med. 2002;44:116124.
arthritis. Rheumatology (Oxford). 2010;49:12941302.
31 Khlat M, Chau N. Social disparities in musculoskeletal disorders
11 Dorlands Illustrated Medical Dictionary. 28th ed. Philadelphia. and associated mental malaise: findings from a population-based
PA: Saunders; 1994:612. survey in France. Scand J Public Health. 2010;38:495501.
12 Puetz TW. Physical activity and feelings of energy and fatigue:
32 Resch M. The psychological factors affecting athletic perfor-
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13 Millet GY, Divert C, Banizette M, et al. Changes in running pattern
due to fatigue and orienteering. J Sports Sci. 2010;28:153156. 33 Bennett RM. Fibromyalgia and chronic fatigue syndrome. In:
Goldman L, Ausiello D. Cecil Medicine. 23rd ed. New York, NY:
14 Kristal-Boneh E, Froom P, Harari G, et al. Fatigue among Israeli in- Saunders; 2007: chapter 295.
dustrial employees. J Occup Environ Med. 1996;38:11451150.
34 Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wes-
15 Main LC, Dawson B, Heel K, et al. Relationship between inflam- selys (bio)psychosocial model versus a bio(psychosocial) mod-
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Res Sports Med. 2010;18:127139. pathways. BMC Med. 2010;8:35.
16 Carr A, Hewlett S, Hughes R, et al. Rheumatology outcomes: the
35 Winchester R. Psoriatic arthritis. In: Wolk K, Goldsmith LA, Katz SI,
patients perspective. J Rheumatol. 2003;30:880883.
Gilchrest BA, Paller AS, eds. Fitzpatrick`s Dermatology in General
17 Gladman DD, Mease P, Krueger G, et al. Outcome measures in Medicine. 7th ed. Columbus, OH: McGraw Hill; 2008:194206.
psoriatic arthritis: OMERACT VII Psoriatic Arthritis Workshop. J
Rheumatol. 2007;34:11591166. 36 Gupta M, Gupta A. Psychodermtology: an update. J Am Acad
Dermatol. 1996;36:10301046.
18 Kirwan JR, Hewlett SE, Heiberg T, et al. Incorporating the patient
perspective into outcome assessment in rheumatoid arthritis 37 Pollard LC, Choy EH, Gonzalez J, et al. Fatigue in rheuma-
progress at OMERACT 7. J Rheumatol. 2005;32:22502256. toid arthritis reflects pain, not disease activity. Rheumatol.
2006;45:885889.
19 Gladman DD, Helliwell P, Mease PJ, et al. Assessment of pa-
tients with psoriatic arthritis: a review of currently available mea- 38 Repping-Wuts H, Fransen J, Van Achterberg T, et al. Persistent
sures. Arthritis Rheum. 2004;50:2435. severe fatigue in patients with rheumatoid arthritis. J Clin Nurs.
2007;16:377383.
20 Mease PJ, Gladmann DD, Krueger GG. Prologue: Group for
Research and Assessment of Psoriasis and Psoriatic Arthritis 39 Treharne GJ, Lyons AC, Hale ED, et al. Predictors of fatigue over
(GRAPPA). Ann Rheum Dis. 2005;64:iilii2. 1 year among people with rheumatoid arthritis. Psychol Health
21 Escobar ME, Gerhardt C, Roesler E, et al. Anemia versus dis- Med. 2008;13:494504.
ease activity as cause of fatigue in rheumatoid arthritis. Acta 40 Finlay AY. Quality of life measurement in dermatology: a practi-
Reumatol Port. 2010;35:2428. cal guide. Br J Dermatol. 1997;136:305314.

SKINmed. 2011;9:3437 37 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- Nail Biology
teraction of mesoderm and ectoderm.1 The nails serve
Anatomy
to protect the terminal phalanx and fingertip from trau-
matic impact2 and provide counter-pressure to the pulp that is The nail plate is the permanent component of the nail matrix. Its
essential to the tactile sensation involving the fingers.1,2 Nails are normal appearance and growth depends on the integrity of several
used for fine manipulations, scratching, protection, and beauti- constituents: the surrounding tissues or perionychium and the bony
fication of the hand.1 phalanx that contribute to the nail apparatus. The nail is proximally
inserted in an invagination practically parallel to the upper surface
Nails are a window to the interior of the body and provide im- of the skin and laterally in the lateral nail groove. This pocket-like
portant clues to an underlying disorder.3 They are often subject- invagination has a roof, the proximal nail fold, and a floor, the matrix
ed to trauma such as biting, chewing, breaking, or splitting and from which the nail is derived. The germinal matrix forms the bulk
exposed to the external environment. The desire for beautiful of the nail plate. The proximal element forms the superficial one third
nails is a universal phenomenon. The problem of nail trauma of the nail, whereas the distal element provides its deeper two thirds.
has increased with procedures for adorning nails such as clean- The ventral surface of the proximal nail fold closely adheres to the
ing with a brush or removing cuticles with clippers and pushers, nail for a short distance and forms a gradually desquamating tissue.
leading to secondary infections. The most common allergens are The cuticle is made of the stratum corneum of the proximal nail fold.
found in nail cosmetics such as nail enamel, artificial sculptured The cuticle seals and therefore protects the ungual cul-de-sac. The nail
nails, and preformed plastic tips. Contact dermatitis of the nail plate is bordered by the proximal nail fold, which is continuous with
unit is not an unusual event. It may present as onychodystrophy, the similarly structured lateral nail folds on each side. The nail bed
onycholysis, paronychia, or dermatitis. extends from the lunula to the hyponychium. The nail bed presents
parallel longitudinal rete ridges. This area has a firm attachment to
Abnormalities of the nail may serve as an important clue to the nail plate, and nail avulsion produces a denudation of the nail
cutaneous disease and may provide information about disease bed. Colorless but translucent, the highly vascular connective tissue
or toxic exposures that occurred several months in the past.4 A containing glomus organs renders a pink color to the nail (Figure 1).1
complete examination of the nail, therefore, should include the
shape, symmetry, and color of the nail plate, nail fold, cuticle, Developmental Anatomy
and nail bed. Deposits under the nail plate and changes in gross Individual digits are discernible from the 8th week of gestation.
appearance, color, or shape of the nail unit should be evaluated. 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 CORE CURRICULUM

Epidermis of the nail plate is occluded by the lateral nail folds. Underlying the
Lunula
proximal part of the nail is the half-moon lunule (white lunula7). It
Posterior nail fold
is most prominent on the thumb and great toe and is partially/com-
Lateral nail fold
Cuticle 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
Nail Plate 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,
Metacarpal bone 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
Vertical collagen fibres Hyponychium is also termed the nail wall.
Nail Bed
Nail matrix The definition of the nail matrix appears debatable.8 It is considered
Epidermis to be a localized region beneath the proximal nail, which produces the
Distal margin of lunula
major part of the normal nail plate, the germinal matrix. The ma-
Figure 1. Nail structure depicting its anatomic components.
trix can be subdivided into dorsal, intermediate, and ventral sections,
contributing by a lamellar fashion to the formation of the nail plate.

matrix primordium underlying the proximal nail fold is well The nail plate may appear thick up to 30% as it passes from the distal
formed by 13th week. The nail plate emerges from beneath the margin of the lunula to the end of the nail bed. This is not associated
proximal nail fold during the 14th week, the nail plate covers al- with an increase in cell numbers, yet it may represent compaction of
most the whole nail bed by the 17th week, and the nail unit and the nail caused by distal tip trauma and may not be associated with
finger grow in tandem in the 20th week of gestation.5 nail bed or plate production.9

The nail apparatus develops and matures from the primitive epi- Nail Abnormalities
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, Morphology
differentiation, and keratinization, then the nail plate begins to This situation may change with disease, where the nail bed changes
move more distally. The nail bed at this stage loses its granular layer. its histologic appearance to gain a granular layer10 and may contribute
a false nail of cornified epithelium to the undersurface of the nail.
Physiology At the point of separation of the nail plate from the nail bed, the
Man has recognized the importance of nails in their finer func- proximal part of the hyponychium may be modified as the solehorn.
tions and in their existence as an extension of aesthetic beauty. Solehorn is a central thickened structure with a dermal core, typically
Adorning, painting, polishing, sculpturing, and using preformed found on the toe of elderly persons, often associated with vascular
plastic tips have all found places in nail cosmetics, and such prac- anomalies. On close examination, apart from white proximal lunula
tice is at least as old as human civilization.6 While the desire for and distal pink nail, another narrow, barely perceptible onychodermal
beautiful nails is a universal phenomenon, the more humans ma- band has been described. Perhaps, its significance is that it has a blood
nipulate their nails, the more profound the attendant complica- supply different from the main body of the nail bed. It becomes more
tions.6 The structure of claws and hooves and their evolutionary prominent in diseases such as acrocyanosis. If the tip of the finger is
relationship to humans has recently been reviewed. pressed firmly, the band and an area just proximal to it blanch, and if
the pressure is repeated several times the band reddens.
In generalized integumentary diseases, such as psoriasis, the nail ap-
paratus, hair follicle, and epidermis are affected. The main function Many changes in color have been described in the onychodermal
of the nail apparatus is to produce a strong, relatively inflexible, kera- band in health and disease. Its structural significance lies in the
tinous nail plate over the dorsal surface of the end of each digit. The attachment of the nail plate and the nail bed. In psoriasis, separa-
nail plate acts as a protective covering for the fingertip. The flat nail tion of the nail plate from the nail bed may become progressive
plate, by exerting counterpressure over the volar skin and the pulp, if there is a breach in the onychodermal band.
allows precision and delicacy in many subtle functions of the fingers.7
The matrix is devoid of the granular layer, and cells may differentiate
The rectangular nail plate is the largest structure, resting on and firmly with an expression of trichocyte hard keratin as they become incorpo-
adherent to the nail bed. Approximately one quarter of the nail is rated into the nail plate, alongside normal epithelial keratins.11,12 Dur-
covered by the proximal nail fold, and a narrow margin of the sides ing the process, the nuclei may be retained and such retained nuclei

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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 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:
Figure 4. Beaus lines displaying transverse ridging resulting
from endogenous cause(s). 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
Figure 5. Nails depicting trachyonychia and transverse
grooves, with periunguinal psoriatic lesions and joint swelling treelike appearance of ridges angled backward. It has been attrib-
on the proximal interphalangeal joints. uted to a definite history of trauma in some patients and to oral reti-
noids31 in others.
and a rapid-onset pustular psoriasis. Scarring in lichen planus and that Transverse grooves, involving either full or partial thickness of the nails,
following toxic epidermal necrolysis may result in onychomadesis. may be caused by exogenous/endogenous factors. An account of trans-
Retinoids and large doses of cloxacillin and cephaloridine have been verse ridging of thumbnails was first described in 1966.32 They may
known to cause temporary nail loss. In epidermolysis bullosa, nail occur on isolated diseased digits as a result of trauma, inflammation, or
loss can be part of an inherited structural defect. Alopecia unguium neurologic events. They may be generalized, reflecting a systemic event,
or onychoptosis defluvium is a periodic, atraumatic, familial, nonin- coronary artery disease, measles, mumps, or pneumonia. The trans-
flammatory nail loss, associated with dental amelogenesis imperfecta. verse grooves resulting from endogenous cause(s) are often referred to
as Beaus lines (Figure 4). Zinc deficiency has also been associated with
Onycholysis is the distal and/or lateral separation of the nail from
the condition. Accordingly, Beaus lines can be used as a useful clinical
the nail bed.24 Psoriatic onycholysis is typically distal with variable
marker. The margin of the line matching well with the proximal nail
lateral involvement, and used as reference point for other forms of
fold and the distance of the groove from the nail fold represents the
onycholysis. Oil spots or a salmon patch appearance of the nail
time elapsed since the growth disturbance. Depth and the width of
is due to the accumulation of shed squames, sequestrated debris,
the groove are proportional with duration and severity of the disease.33
glycoprotein exudates, and air in the nail bed. The border of the
onycholysis appears in the nail bed as reddish brown from the un- Foci of parakeratosis, reflecting an isolated nail malformation in pso-
derlying inflammatory changes (Figure 2). riasis, are cardinal.34 Clinically, they appear as punctate erosions on

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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,

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January/February 2011 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-
Figure 8. (A) Distal and lateral subungual onychomycosis, (B) sium hydroxide mount. Nail plate pitting, a hallmark of psoriasis,
candida onychomycosis, and (C) proximal subungual ony- may also be seen in alopecia areata, pityriasis rubra pilaris, and Re-
chomycosis, mycelia, and spores may be demonstrated on iter disease. There were certain clinical differences in pits of psoriasis
potassium hydroxide mount.
and alopecia areata, their briefs are outlined in the Table. Deeper
and more irregular pits, similar to those of psoriasis could also be
and chronicity perpetuated by maceration and overgrowth of yeast seen in pityriasis rubra pilaris.56 In children, nail lichen planus may
under the proximal nail fold (Figure 8). occur as an isolated finding.57
The psoriasis lesions of the matrix can occur both in the proximal and Several clinical variations, depending on the location of lichenoid in-
distal matrix. The proximal matrix contributes orthokeratotic keratin flammatory infiltrate, may be seen in lichen planus of the nails. Pri-
to the dorsal nail plate, while the distal matrix to the ventral nails plate. marily, lichen planus affects the nail matrix and may result in: (1)
A cluster of abnormal parakeratotic cells are produced in psoriasis, and onychorrhexis, recognized by nail plate thinning, ridging and fissur-
the clinical features depend on the matrix area affected. Accordingly, if ing. (2) Trachyonychia, a rough sand paper appearance of the surface

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January/February 2011 CORE CURRICULUM

of the nail plate, gray opacity, and brittle/split nails. The nail plate
Table. Clinical Differences in Pits of Psoriasis and
might be thrown into folds and may result in complete nail atrophy. Alopecia Areata
(3) Pterygium, a chief association of lichen planus following intense
Psoriasis Alopecia Areata
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 Deep pits with rough margin Shallow pits with regular margin
shorten, the nail plate may progressively result in thinning, and finally Fewer in number More in number
the proximal nail fold may fuse with the matrix and the proximal nail No definite pattern Geometric cross-hatched pattern
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 Figure 9. Pterygium with partial anonychia.
with alopecia universalis. Another opinion was that alopecia
areata could affect only the matrix and the spotty absence of the 8 de Berker D, Angus B. Proliferative compartments in normal
whiteness of the lunula that might produce the so-called spotted nail. Br J Dermatol. 1996;135:555559.
lunula, diagnostic of alopecia areata.66 The acute onset of alope- 9 De Berker D, Mawhinney B, Sviland L. Quantification of regional
cia areata has also been described to be associated with nail plate matrix production. Br J Dermatol. 1996;34:10831086.
shedding (onychomadesis).62 Nail pitting is a prominent finding 10 Fanti PA, Tosti A, Cameli N, et al. Nail matrix hypergranulosis.
Am J Dermatopathol. 1994;16:607610.
in psoriasis, alopecia areata, dermatitis, HLA-B27 inheritance,
11 de Berker D, Wojnarowska F, Sviland L, et al. Keratin expression
diabetes mellitus, and occupational trauma.6668 in the normal nail unit: markers of regional differentiation. Br J
Dermatol. 2000;142:8996.
Acknowledgement: Asha Singh, MS, PhD, Professor and Head of the
12 Westgate GE, Tidman N, De Berker D, et al. Characterization
Anatomy Department, SGT Dental College, Gurgaon, reviewed the
of LH Tric-1, a new monospecific monoclonal antibody to the
section on nail biology. The final text (parts I and II) was reviewed by trichocyte keratin Ha1. Br J Dermatol. 1997;137:2430.
Prashant Verma, MD, Senior Resident, Department of Dermatology 13 Hashimoto K. Ultrastructure of the human toenail. 1. Proximal
and STD, University College of Medical Sciences and Associated Guru nail matrix. J Invest Dermatol. 1971;56:235246.
Teg Bahadur Hospital, Shahdara, Delhi. 14 Hashimoto K. Ultrastructure of the human toenail. II. Keratini-
zation and formation of the marginal band. J Ultrastruct Res.
1971;36:391410.
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38 Baran R, Dupre A, Christol B, et al. Vertical striated sand-pa-
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39 Arias AM, Yung CW, Rendler S, et al. Familial severe twenty nail 63 Tosti A, Fanti PA, Morelli R, et al. Trachyonychia associated with
dystrophy. J Am Acad Dermatol. 1982;7:349352. alopecia areata: a clinical and pathological study. J Am Acad
40 Barth JH, Telfer NR, Dawber RP. Nail abnormalities and autoim- Dermatol. 1991;25:266270.
munity. J Am Acad Dermatol. 1988;18:10621065. 64 Dotz WI, Lieber CD, Vogt PJ. Leukonychia punctata and pitted
41 Peloro TM, Pride HB. Twenty-nail dystrophy and vitiligo: a rare nails in alopecia areata. Arch Dermatol. 1985;121:14521454.
association. J Am Acad Dermatol. 1999;40:488490. 65 Horn RT Jr, Odom RB. Twenty-nail dystrophy of alopecia areata.
42 Clegg HW, Prose NS, Greenbag DN. Nail dystrophy in congenital Arch Dermatol. 1980;116:573574.
cutaneous candidiasis. Pediatr Dermatol. 2003;20:342344. 66 Shelley WB. The spotted lunula. A neglected nail sign associated
43 Tosti A, Bardazzi F, Piraccini BM, et al. Idiopathic trachyonychia with alopecia areata. J Am Acad Dermatol. 1980;2:385387.
(twenty nail dystrophy): a pathological study of 23 patients. Br J 67 Pajarre R, Kemo M. Nail changes as the first manifesta-
Dermatol. 1994;131:866872. tion of HLA-B27 inheritance: a case report. Dermatologica.
44 Germain-Lee EL, Zinkham WH. Twenty nail dystrophy associ- 1977;154:350354.
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1991;80:977980. litus. J Am Acad Dermatol. 1987;16:10151021.

SKINmed. 2011;9:3946 46 Nail Biology


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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 With widespread use of any drug, a small number of birth defect reports associated
VELTIN (clindamycin phosphate and tretinoin) Gel 1.2%/0.025% temporally with the administration of the drug would be expected by chance alone.
The following is a brief summary only; see full prescribing information for complete Thirty cases of temporally associated congenital malformations have been reported
product information. during two decades of clinical use of another formulation of topical tretinoin.
Although no definite pattern of teratogenicity and no causal association have been
1 INDICATIONS AND USAGE established from these cases, 5 of the reports describe the rare birth defect category,
VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years holoprosencephaly (defects associated with incomplete midline development of the
or older. forebrain). The significance of these spontaneous reports in terms of risk to fetus is
not known.
4 CONTRAINDICATIONS
VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis, 8.3 Nursing Mothers
or history of antibiotic-associated colitis. 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
5 WARNINGS AND PRECAUTIONS to appear in breast milk. Because of the potential for serious adverse reactions in
5.1 Colitis nursing infants, a decision should be made whether to discontinue nursing or to
Systemic absorption of clindamycin has been demonstrated following topical use. discontinue the drug, taking into account the importance of the drug to the mother.
Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have It is not known whether tretinoin is excreted in human milk. Because many drugs are
been reported with the use of topical clindamycin. If significant diarrhea occurs, excreted in human milk, caution should be exercised when VELTIN Gel is administered
VELTIN Gel should be discontinued. to a nursing woman.
Severe colitis has occurred following oral or parenteral administration of clindamycin 8.4 Pediatric Use
with an onset of up to several weeks following cessation of therapy. Antiperistaltic Safety and effectiveness of VELTIN Gel in pediatric patients below the age of 12 years
agents such as opiates and diphenoxylate with atropine may prolong and/or worsen have not been established. Clinical trials of VELTIN Gel included 2,086 patients 12-17
severe colitis. Severe colitis may result in death. years of age with acne vulgaris. [See Clinical Studies (14) of full prescribing information.]
Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-
associated colitis. 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.2 Ultraviolet Light and Environmental Exposure Long-term animal studies have not been performed to evaluate the carcinogenic
Exposure to sunlight, including sunlamps, should be avoided during the use of potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was negative
VELTIN Gel, and patients with sunburn should be advised not to use the product until for mutagenic potential when evaluated in an in vitro Ames Salmonella reversion
fully recovered because of heightened susceptibility to sunlight as a result of the use assay. VELTIN Gel was equivocal for clastogenic potential in the absence of metabolic
of tretinoin. Patients who may be required to have considerable sun exposure due to activation when tested in an in vitro chromosomal aberration assay.
occupation and those with inherent sensitivity to the sun should exercise particular Clindamycin: Once daily dermal administration of 1% clindamycin as clindamycin
caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are phosphate in the VELTIN Gel vehicle (32 mg/kg/day, 13 times the recommended
recommended. Weather extremes, such as wind or cold, also may be irritating to clinical dose based on body surface area comparison) to mice for up to 2 years did
patients under treatment with VELTIN Gel. not produce evidence of tumorigenicity.
6 ADVERSE REACTIONS Tretinoin: In two independent mouse studies where tretinoin was administered
6.1 Adverse Reactions in Clinical Studies topically (0.025% or 0.1%) three times per week for up to two years no
The safety data reflect exposure to VELTIN Gel in 1,104 patients with acne vulgaris. carcinogenicity was observed, with maximum effects of dermal amyloidosis. However,
Patients were 12 years or older and were treated once daily in the evening for 12 in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 g (1.4
weeks. Observed local treatment-related adverse reactions (1%) in clinical studies times the recommended clinical dose based on body surface area comparison) three
with VELTIN Gel were application site reactions, including dryness (6%), irritation (5%), times per week for 20 weeks acted as a weak promoter of skin tumor formation
exfoliation (5%), erythema (4%), pruritus (2%), and dermatitis (1%). Sunburn (1%) following a single application of dimethylbenz[]anthracene (DMBA).
was also reported. Incidence of skin reactions peaked at week 2 and then gradually In a study in female SENCAR mice, papillomas were induced by topical exposure
decreased. to DMBA followed by promotion with 12-O-tetradecanoyl-phorbol 13-acetate or
Local skin reactions were actively assessed at baseline and at the end of 12 weeks of mezerein for up to 20 weeks. Topical application of tretinoin prior to each application
treatment in patients exposed to VELTIN Gel. At baseline (N=476), local skin reactions of promoting agent resulted in a reduction in the number of papillomas per mouse.
included erythema (24%), scaling (8%), dryness (11%), burning (8%), and itching However, papillomas resistant to topical tretinoin suppression were at higher risk for
(17%). At 12 weeks of treatment (N=409), local skin reactions included erythema pre-malignant progression.
(21%), scaling (19%), dryness (22%), burning (13%), and itching (15%). During the Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed
12 weeks of treatment, each local skin reaction peaked at week 2 and gradually specific studies, employing concurrent or intercurrent exposure to tretinoin and UV
reduced thereafter. radiation. The photoco-carcinogenic potential of the clindamycin tretinoin combination
is unknown. Although the significance of these studies to humans is not clear, patients
7 DRUG INTERACTIONS should avoid exposure to sun.
7.1 Erythromycin
VELTIN Gel should not be used in combination with erythromycin-containing products 17 PATIENT COUNSELING INFORMATION
due to possible antagonism to the clindamycin component. In vitro studies have [See FDA-approved Patient Labeling].
shown antagonism between these 2 antimicrobials. The clinical significance of this 17.1 Instructions for Use
in vitro antagonism is not known. 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
7.2 Neuromuscular Blocking Agents (excluding the eyes and lips).
Clindamycin has been shown to have neuromuscular blocking properties that may Patients should be advised not to use more than a pea sized amount to cover
enhance the action of other neuromuscular blocking agents. Therefore, VELTIN Gel the face and not to apply more often than once daily (at bedtime) as this will not make
should be used with caution in patients receiving such agents. for faster results and may increase irritation.
A sunscreen should be applied every morning and reapplied over the course
8 USE IN SPECIFIC POPULATIONS of the day as needed. Patients should be advised to avoid exposure to sunlight,
8.1 Pregnancy sunlamp, ultraviolet light, and other medicines that may increase sensitivity to
Pregnancy Category C. There are no well-controlled studies in pregnant women sunlight.
treated with VELTIN Gel. VELTIN Gel should be used during pregnancy only if the Other topical products with a strong drying effect, such as abrasive soaps or
potential benefit justifies the potential risk to the fetus. A limit teratology study cleansers, may cause an increase in skin irritation with VELTIN Gel.
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 17.2 Skin Irritation
in teratogenic effects. Although no systemic levels of tretinoin were detected, VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
craniofacial and heart abnormalities were described in drug-treated groups. These 17.3 Colitis
abnormalities are consistent with retinoid effects and occurred at 16 times the In the event a patient treated with VELTIN Gel experiences severe diarrhea or
recommended clinical dose assuming 100% absorption and based on body surface gastrointestinal discomfort, VELTIN Gel should be discontinued and a physician should
area comparison. For purposes of comparison of the animal exposure to human be contacted.
exposure, the recommended clinical dose is defined as 1 g of VELTIN Gel applied
daily to a 50 kg person. STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.
Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, VELTIN is a trademark of Astellas Pharma Europe B.V.
rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given VEL:2BRS
orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose Issued July 2010
based on body surface area comparison). However, variations in teratogenic doses 2010 Stiefel Laboratories, Inc.
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. 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%, Clindamycin has been shown to have in vitro activity against
is a fixed combination of two solubilized active ingredients in Propionibacterium acnes, a bacterium that has been associated
an aqueous-based gel. It is manufactured by Stiefel Laborato- with acne vulgaris; however, the clinical significance of this activ-
ries, Inc (Research Triangle Park, NC), a GSK company. Veltin ity against P acnes was not examined in clinical studies with Vel-
gel was approved by the US Food and Drug Administration on tin gel. P acnes resistance to clindamycin has been documented,
July 16, 2010.1,2 often in association with erythromycin resistance.
Clindamycin phosphate is a water-soluble ester of the semi- Topical tretinoin is used in the treatment of mild to moderate
synthetic antibiotic produced by a 7(S)-chloro-substitution acne and on skin that has been damaged by excessive sun ex-
of the 7(R)-hydroxyl group of the parent antibiotic lincomy- posure. Tretinoin causes an increase in cell turnover and death,
cin. The chemical name for clindamycin phosphate is methyl which reduces the number of cell layers in the skin. This rapid
7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrro- turnover may prevent new acne lesions from forming.
lidinecarboxamido)-1-thio-L-threo-a-D-galacto-octopyranoside
2-(dihydrogen phosphate). Clinical Studies
The chemical name for tretinoin is all-trans 3,7-dimethyl-9- Three randomized, double-blind, multicenter, 12-week studies
(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic compared the combination product clindamycin 1%tretinoin
acid. It is a member of the retinoid family of compounds. 0.025% gel with clindamycin gel 1%, tretinoin gel 0.025%, and
vehicle gel in almost 3900 patients 12 years and older with acne.
Veltin gel contains the following inactive ingredients: butylated One trial used the Veltin formulation, while the other two tri-
hydroxytoluene, carbomer 940, anhydrous citric acid, edetate als used an older, slightly different formulation (Velac). Study
disodium, methylparaben, laureth 4, propylene glycol, trometh- medications were applied once daily in the evening in all trials.
amine, and purified water. Efficacy was assessed at weeks 2, 4, 8, and 12. The co-primary
end points were the mean absolute change from baseline to week
Mechanism of Action
12 in 2 of 3 (total, inflammatory, and noninflammatory) lesion
Clindamycin binds to the 50S ribosomal subunit of susceptible bac- counts and the proportion of patients with at least a 2-grade
teria and prevents elongation of peptide chains by interfering with improvement in Investigators Static Global Assessment (ISGA)
peptidyl transfer, thereby suppressing bacterial protein synthesis. score (a 05 scale) from baseline to week 12.1,35
Although the exact mode of action of tretinoin is unknown,
current evidence suggests that topical tretinoin decreases cohe- Efficacy
siveness of follicular epithelial cells with decreased microcom- Based on assessment of the co-primary end points, the newer
edo formation. Additionally, it stimulates mitotic activity and formulation was found to be superior to the comparator in terms
increased turnover of follicular epithelial cells causing extrusion of change in ISGA score and in the absolute reduction in at least
of the comedones. 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 NEW THERAPY UPDATE

Table. Adverse Eventsa in Patients According to Treatment


Adverse Event, ClindamycinTretinoin Gel Clindamycin Gel 1% Tretinoin Gel 0.025% Vehicle Gel
No. (%) (n=1104) (n=1091) (n=1084) (n=552)
Dryness 140 (13) 38 (3) 141 (13) 17 (3)
Desquamation 64 (6) 12 (1) 62 (6) 3 (1)
Burning 50 (5) 4 (<1) 57 (5) 5 (1)
Erythema 50 (5) 2 (<1) 56 (5) 2 (<1)
Pruritus 40 (4) 6 (1) 39 (4) 3 (1)
Sunburn 26 (2) 7 (1) 23 (2) 6 (1)
Irritation 11 (1) 6 (1) 7 (1) 3 (1)
a
All adverse events at application site.

The median time to 50% reduction in total lesion count was sig- Local skin reactions included erythema, scaling, dryness, burn-
nificantly faster with clindamycintretinoin gel (8 weeks) than with ing, and itching. During the 12 weeks of treatment, each local
clindamycin gel alone (12 weeks), tretinoin gel alone (12 weeks), or skin reaction peaked at week 2 and gradually reduced thereafter.
vehicle (median time not reached at study completion) (P<.0001).
The proportion of patients who achieved an ISGA score of 0 or 1 at Safety
12 weeks was significantly higher in the clindamycintretinoin gel Systemic absorption of clindamycin has been demonstrated fol-
group (37%) compared with clindamycin gel alone (27%), treti- lowing topical use. Diarrhea, bloody diarrhea, and colitis (in-
noin gel alone (25%), or vehicle gel (14%) (P.0001).4 cluding pseudomembranous colitis) have been reported with the
use of topical clindamycin. If significant diarrhea occurs, treat-
Comparing baseline with week 12 data, the combination clinda-
ment would be discontinued.4
mycintretinoin gel was superior to the other study medications
in terms of decreasing the ISGA score to clear/almost clear and Exposure to sunlight, including sunlamps, should be avoided
in decreasing the number of total lesions and inflammatory le- during the use of tretinoin, and patients with sunburn should be
sions. In one trial, the combination clindamycintretinoin gel advised not to use the product until fully recovered due to height-
was similar to the tretinoin gel in the reduction of noninflamma- ened susceptibility to sunlight as a result of the use of treatment.1
tory lesions, while the other two trials found clindamycintreti-
This treatment should not be used in combination with eryth-
noin superior to the other 3 arms of this end point.4,5
romycin-containing products due to possible antagonism to the
In the combined analysis of all studies, clindamycintretinoin clindamycin component. In vitro studies have shown antago-
gel was significantly better than clindamycin 1% gel, tretinoin nism between these 2 antimicrobials. The clinical significance
0.025% gel, and vehicle gel in reducing total inflammatory and of this in vitro antagonism is not known. Clindamycin has been
noninflammatory lesions after 12 weeks of treatment (P.0043).1 shown to have neuromuscular-blocking effects that may enhance
the action of other neuromuscular-blocking agents; therefore, it
Adverse Reactions should be used with caution in patients receiving such agents.
The completion rate from one of the studies was 1446 of 1649
This combination gel falls under Pregnancy Category C. There
patients (88%). The most common reason for study discon-
are no well-controlled studies in pregnant women treated with
tinuation was withdrawn consent (n=76) and lost to follow-up
clindamycintretinoin. A limited teratology study performed in
(n=73). Few patients withdrew due to adverse events (n=11),
Sprague Dawley rats treated topically with Veltin gel or 0.025%
noncompliance (n=10), or lack of efficacy (n=7).
tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15
The safety data from the combined studies reflect exposure to did not result in teratogenic effects. These abnormalities are con-
clindamycintretinoin in 1104 patients 12 years or older with sistent with retinoid effects and occurred at 16 times the recom-
acne vulgaris. Patients were treated once daily in the evening for mended clinical dose assuming 100% absorption and based on
12 weeks. Adverse reactions that were reported in 1% of patients body surface area comparison. Oral tretinoin has been shown to
treated with the combination gel are presented in the Table. be teratogenic in mice, rats, hamsters, rabbits, and primates, and

SKINmed. 2011;9:4951 50 Veltin Gel


January/February 2011 NEW THERAPY UPDATE

has also been shown to enhance photocarcinogenicity in studies the vehicle and in the way the tretinoin is released from it. No
involving UV radiation exposure. head-to-head studies allow us to recommend one brand over the
other based on superiority of effectiveness vis a vis side effects.
Safety and effectiveness of clindamycintretinoin in pediatric
patients younger than 12 years have not been established nor has We find the use of these combinations useful to provide a once-
it been established in patients 65 years and older. a-day treatment paradigm for acne that utilizes 3 molecules with
different modes of action (with benzoyl peroxide in the form of a
Indications and Administration wash, for example) hopefully to optimize compliance and success.
Veltin (clindamycin phosphate and tretinoin) gel, 1.2%/0.025%
is a yellow, opaque topical gel indicated for the treatment of References
acne vulgaris in patients 12 years and older. The gel should be
1 Veltin (clindamycin phosphate 1.2% and tretinoin 0.025%) gel
applied once daily in the evening, gently rubbing the medica- [package insert]. Research Triangle Park, NC: Stiefel Laborato-
tion to lightly cover the entire affected area. Approximately a ries, Inc; 2006.
pea-sized amount will be needed for each application. The eyes, 2 Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/treti-
lips, and mucous membranes should be avoided. It is not for noin gel formulation in the treatment of acne vulgaris. Expert
Opin Pharmacother. 2008;9:29312937.
oral, ophthalmic, or intravaginal use. Because it is a combination
3 Tolerability of Veltin Gel in Combination with Benzoyl Peroxide
of clindamycintretinoin, it is contraindicated in patients with
Gel. Data on file. Research Triangle Park, NC: Stiefel Laborato-
regional enteritis, ulcerative colitis, or a history of antibiotic- ries; Study W0265306.
associated colitis.1,2 4 Efficacy and Safety of Veltin Gel for the Treatment of Acne Vul-
garis. Data on file. Research Triangle Park, NC: Stiefel Labora-
Each gram of Veltin gel contains, as dispensed, 10 mg (1%) tories; Study W026503.
clindamycin as clindamycin phosphate and 0.25 mg (0.025%) 5 Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-
tretinoin solubilized in an aqueous-based gel. The tube sizes for blind, controlled trials of 2219 subjects to compare the combi-
this product are 30 g and 60 g. nation clindamycin/tretinoin hydrogel with each agent alone and
vehicle for the treatment of acne vulgaris. J Am Acad Dermatol.
2006;54:7381.
Conclusions
6 Ziana (clindamycin phosphate 1.2% and tretinoin 0.025%) gel
This gel (Veltin) represents an alternative to another topical for- [package insert]. Scottsdale, AZ. Medicis: The Dermatology
mulation (Ziana; Medicis, Scottsdale, AZ)6 that differs mainly in Company; 2006.

FORMULARY OF DR GEORGE C. ANDREWS


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

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

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SKINmed. 2011;9:5254 54 Why Immunofluorescence?


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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 These themes were fused by syphilis, which dominated the second
History of Medicine, this international conference gath- panel of forgotten skin diseases. Kevin Sienas The Moral Biology
ered postgraduates and scholars from medical, cultural of the Itch in Eighteenth-Century London indicated that the Eng-
studies, and histories of medicine and art backgrounds whose re- lish blamed the immoral poor and located the Itch on the syphi-
search incorporates skin, its diseases, and treatment since 1700. litic spectrum and as Scottish (Figure 3). In St Pauls Bay Disease:
The organizersJonathan Reinarz (University of Birmingham, Skin and Scourge in Eighteenth-Century Quebec, James Moran
United Kingdom) and Kevin Siena (Trent University, Canada), (University of Prince Edward Island, Canada) found contemporary
with Rebecca Wynter (University of Birmingham)constructed English etiology pinpointing the Francophone population. The ill-
a program with 21 speakers from 7 nations, divided into 8 pan- ness precipitated prophecies of colonial degeneration and public
els, garnering an audience with a strong clinical presence. health measures administered through local priests. The Coming
into Being and Passing Away of the Norwegian Radesyge by Anne
Reading the Skin Kveim Lie (University of Oslo, Norway) echoed Quebecois symp-
After the opening remarks, Professor Philip K. Wilson (Penn tomology: lesions, skeletal corrosion, and soft tissue deterioration.
State College of Medicine, Hershey, PA) gave the keynote ad- Radesyge was connected with the decent lifestyle of the poor and
dress, situating the conference papers within the wider terrain of the development of independent nationhood.
history in Reading the Skin, Discerning the Landscape: Geo-
historical Descriptions of the Human Surface. Space and place Visualizing the Skin
featured heavily throughout the event (Figures 1 and 2). The The afternoon began with visualizing skin disease. Mechthild
first panel commenced with Italic Scurvy, Pellarina, Pella- Fend (University College London, United Kingdom) spoke about
gra: Medical Reactions to a New Disease in Italy, 17701830 Portraying Skin Disease: Robert Carswells Dermatological Wa-
by Professor David Gentilcore (University of Leicester, United tercolors. Scottish physician Carswell visited Parisian hospitals,
Kingdom), and was followed by Timothy J. Peters (University 18271829. His paintings were placed within wider medical tax-
of Birmingham) The Skin Disease of Admiral Frances Beau- onomy, and depicted tensions between representing patients or
fort, written with Nick Levell (Norfolk and Norwich University their conditions. In Visualizing Venereal Disease: The Functions
Hospital, United Kingdom). This panel on diagnostic confusion of Visual Representations, Harriet Palfreyman (PhD student,
highlighted issues that resurfaced throughout the event: skin as University of Warwick, United Kingdom) incorporated disem-
a barrier between practitioners, patients, classes, and nationali- bodied plastinates and emphasized pedagogy at 18th-century
ties, and skin disease as symptomatic of a deeper malaise, either anatomical schools. Venereal disease also featured in the dubious
physical or of hereditary, social, or cultural taint. 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- The term onychopapillomas of the nail bed has been proposed to describe
metic appendage. The authors believe, however, that the localized, distal, subungual keratosis with multinucleated cells. This ter-
cosmetic-medical value is dramatically understated. In fact, minology is used to characterize a papilloma with histology that shows
alterations in appearance of the nail unit can be signs of more serious a keratogenous zone identical to the nail matrix (matrix metaplasia).1
pathology despite the lack of other symptoms. For example, longitu- Although a common histologic finding in the initial elegantly prepared
dinal erythronychia is an easily overlooked clinical presentation. Many reports on longitudinal erythronychia, this histologic change was not
cases are asymptomatic, and thus managed with minimal intervention. present in our case. Multinucleated giant cells were not present either.
In fact, this presentation is often only considered a cosmetic issue to The presence of acanthosis and mild papillomatosis, however, suggests
patients and physicians. The underlying changes, however, can be of that this lesion belongs to the spectrum of the distal subungual kera-
utmost clinical concern and biopsy is warranted.14 Here, the authors tosis. It is possible that the discoloration was primarily produced at the
present a detailed characterization of a case with clinical changes that distal nail matrix and was transferred to the nail plate and distal nail
could not be explained despite extensive histologic analysis. bed. The color could also be a result of the altered physical features of
the nail plate. Although human papillomavirus was a theorized etiol-
This case and review illustrates the value of careful examination of
ogy in previous reports, our case ruled out viral presences.
the nail unit and the traditionally perceived cosmetic aspect of nail
function. Recently, longitudinal erythronychia has been reported as We believe this case illustrates a unique and unusual presentation
a presentation of Bowen disease and may continue to be an under- of longitudinal erythronychia. It is possible that at least some of the
reported and often undiagnosed pathology.1 Although clinically iden- cases clinically suggestive of subungual keratosis may lack matrix
tical to previous reported cases of longitudinal erythronychia, this metaplasia on histologic examination. Despite the apparent idio-
presentation illustrates several unusual deviations. Histopathologic pathic nature of this presentation, however, we still place high value
examination of our case showed acanthosis and focal keratinocytic on the previous reports of longitudinal erythronychia being an initial
atypia. Only mild capillary vascular dilation was present. Increased presentation of malignancy and thus requiring biopsy. Long-term
iron deposition and extravasated red blood cells were not identified. 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 CASE STUDY

Figure 1. Longitudinal band of erythronychia originating at the Figure 2. Nail bed dyskeratosis and acanthosis (hematoxylin-
distal matrix/lunula. eosin stain, original magnification 20).

Finally, differential diagnosis must also be considered, evaluated for, nychia: diagnostic significance and physical explanation. Arch
and ruled out as appropriate. In particular, physicians must consider Dermatol. 2004;140:12531257.
amelanotic melanoma, Darier disease, lichen planus, and psoriasis.5 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.
References
4 Harwood M, Telang GH, Robinson-Bostom L, et al. Melanoma
1 Baran R, Perrin C. Longitudinal erythronychia with distal subun- and squamous cell carcinoma on different nails of the same
gual keratosis: onychopapilloma of the nail bed and Bowens hand. J Am Acad Dermatol. 2008;58:323326.
disease. Br J Dermatol. 2000;143:132135. 5 Baran R. Red nailalways benign? Actas Dermosifiliogr.
2 de Berker DA, Perrin C, Baran R. Localized longitudinal erythro- 2009;100(suppl 1):106113.

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SKINmed. 2011;9:6061 61 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 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
Figure 2. Symmetric gray patches were also present on the 1 Ramirez C. Los cenicientos: problema clinica. Paper presented
dorsal hands. 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.

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

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 CASE STUDY

Figure 2. Intraepidermal lacunae and dyskeratosis with corps


ronds (hematoxylin and eosin, original magnification 200). Figure 3. Blisters on the back of the hand.

fact suggests a possible genetic heterogeneity of Darier disease. 2 Hori Y, Tsuru N, Nimura M. Bullous Dariers disease. Arch Derma-
Studies to map the genes for Darier disease are in progress and tol. 1982;118:278279.
the molecular basis for this heterogeneity will be of great interest. 3 Telfer NR, Burge SM, Ryan TJ. Vesiculo-bullous Dariers disease.
Br J Dermatol. 1990;122:831834.
We would like to emphasize the atypical and late onset of the
4 Jones WN, Nix TE, Clark WH. Hemorrhagic Dariers disease.
disease in our patient, and the association of two uncommon Arch Dermatol. 1964;89:523527.
clinical features of Darier disease: blistering and hemorrhagic le- 5 Burge SM, Wilkinson JD. Darier-White disease: a review of
sions. The mechanism remains unclear, but it may be the clinical the clinical features in 163 patients. J Am Acad Dermatol.
expression of suprabasal clefting present histologically. 1992;27:4050.
6 Munro CS. The phenotype of Dariers disease: penetrance
References and expressivity in adults and children. Br J Dermatol.
1992;127:126130.
1 Sakuntabhai A, Ruiz-Prez V, Carter S, et al. Mutations in
ATP2A2, encoding a Ca+2 pump, cause Dariers disease. Nat 7 Foresman PL, Goldsmith LA, Ginn L. Hemorraghic Dariers dis-
Genet. 1999;21:271277. ease. Arch Dermatol. 1993;129:511512.

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 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 procedures are not without complications of pigment spreading or
deal of popularity in contemporary Western the reactivation of a herpes simplex infection.
culture, becoming even more trendy in recent
Because contact dermatitis is one of the most common complications
years.1 Such adornment may look quite allur-
of both types of body adornment, a chapter is devoted to this prob-
ing in a young person, but as the recipient ap-
lem. In addition to an eczematous dermatitis, granulomatous derma-
proaches middle age or has a change of mind
titis is not unknown. Knowing the component of the ink can be help-
about the decoration, problems ensuetattoos
ful in determining the offending agent, ie, black: carbon, iron oxide,
blurring, pigment dropping down, or names
or dichromates; brown: ferric oxide; white: zinc or titanium oxide; or
of significant others no longer being significant. The initial process may
yellow: cadmium sulfide.
lead to contact dermatitis, cutaneous infection, or even keloid formation,
which may be immediately evident or delayed in affecting the recipient. 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
This short multi-authored volume begins with an excellent histori- eliminated. Whereas a piercing will leave a scar even without com-
cal chapter, well illustrated in color. Neither tattoos nor piercings are plications, the ink from a tattoo will still be visible, depending upon
new and can be traced back to antiquity.2 For the record, the first the color. Methods have involved salabrasion: rubbing salt, dermabra-
tattoo parlor opened in New York in 1846, while the introduction of sion, electrodesiccation, excision, application of caustic chemicals
an electric tattooing apparatus is credited to the innovations of Pro- such as trichloracetic acid, and more recently, laser surgery with the
fessor Samuel OReilly in 1891. By 1929, modifications were suf- q-switched laser being the most effective.
ficiently advanced that current machines are little changed from then.
This thin volume contains a great deal of information, but the publisher
This is followed by Materials used in body art, which describes the did not do the contributors justice. The use of core messages, when there
components of ink for permanent tattoos and the use of henna for are often summaries and conclusions, is annoying. Color pictures are
temporary tattoos. The metals used in piercings include stainless steel, fine, but they are wasted on showing bottles of ink or sterilization equip-
titanium, silver, and gold. In the chapter on complications arising ment; it would have been better to present more pictures of tattoos or
from tattooing, the list ranges from molluscum contagiosum to syphi- piercings and their complications. The editing is erratic, with a mixture
lis, and from contact dermatitis to keloids. Immediate problems can of British and American spellings and no uniformity of the references.
also be related to bleeding and pyogenic infections. Unwanted effects
from piercings, as might be expected, concern similar problems, but References
the more unusual are the development of argyrosis and angiofibroma. 1 Kazandjieva J, Tsankov N. Tattoos and piercings. Clin Dermatol.
2007;25:363420.
Tattoos can also be employed to return pigment to an area of vitiligo
2 Parry A. Tattoo: Secrets of a Strange Art as Practiced Among
or to make an areola appear more natural following breast surgery. the Natives of the United States. New York, NY: Simon and
Cosmetically, tattoos can be used for eyeliners and lip liners, but such 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 Clinical studies of Locoid Lipocream did not include sufficient numbers of subjects
and pruritic manifestations of corticosteroid-responsive dermatoses in adults and aged 65 and over to determine whether they respond differently from younger
the treatment of mild to moderate atopic dermatitis in patients 3 months to 18 years subjects.
of age. Carcinogenesis, Mutagenesis, Impairment of Fertility
WARNINGS AND PRECAUTIONS No studies were conducted to determine the photococarcinogenic or dermal
Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with carcinogenic potential of Locoid Lipocream.
the potential for glucocorticosteroid insufficiency. Consider periodic evaluations for Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic
HPA axis suppression if Locoid Lipocream is applied to large surface areas or used potential based on the results of two in vitro genotoxicity tests (Ames test and
under occlusion. If HPA axis suppression is noted, reduce the application frequency, L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse
discontinue use, or switch to a lower potency corticosteroid. micronucleus assay).
Systemic effects of topical corticosteroids may also include manifestations of No evidence of impairment of fertility or effect on mating performance was
Cushings syndrome, hyperglycemia, and glucosuria. observed in a fertility and general reproductive performance study conducted in
Pediatric patients may be more susceptible to systemic toxicity due to their larger male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day
skin surface-to-body-mass ratios. (0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals,
Initiate appropriate therapy if concomitant skin infections develop. such as reduced food consumption and a subsequent reduction in body weight gain,
Discontinue use if irritation develops. were seen at doses 0.6 mg/kg/day (0.2X MTHD).
ADVERSE REACTIONS PATIENT COUNSELING INFORMATION
The most common adverse reactions (>1%) are HPA axis suppression and Patients using Locoid Lipocream should receive the following information
application site reactions. and instructions:
The following additional local adverse reactions have been reported infrequently Apply a thin layer to the affected skin two or three times daily for corticosteroid-
with topical corticosteroids, and they may occur more frequently with the use of responsive dermatoses in adults. Consult with your physician to determine if
occlusive dressings and higher potency corticosteroids. These reactions included: treatment is needed beyond 2 weeks. Apply a thin film to the affected skin areas
irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, two times daily for atopic dermatitis in patients 3 months of age and older.
allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and Safety of Locoid Lipocream in pediatric patients has not been established beyond 4
telangiectasia. weeks of use.
USE IN SPECIFIC POPULATIONS Rub in gently.
Pregnancy Avoid contact with the eyes.
Pregnancy Category C. Corticosteroids have been shown to be teratogenic in Do not bandage, otherwise cover, or wrap the affected skin area so as to be
laboratory animals when administered systemically at relatively low dosage levels. occlusive unless directed by your physician.
Some corticosteroids have been shown to be teratogenic after dermal application Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants may
in laboratory animals.There are no adequate and well-controlled studies in constitute occlusive dressings.
pregnant women. Therefore, Locoid Lipocream should be used during pregnancy Do not use Locoid Lipocream on the face, underarms, or groin areas unless
only if the potential benefit justifies the potential risk to the fetus. directed by your physician.
Please refer to full prescribing information for detailed information regarding If no improvement is seen within 2 weeks, contact your physician.
systemic embryofetal development studies. Do not use other corticosteroid-containing products while using Locoid Lipocream
Nursing Mothers without first consulting your physician.
Systemically administered corticosteroids appear in human milk and could
suppress growth, interfere with endogenous corticosteroid production, or cause Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled
other untoward effects. It is not known whether topical administration of Room Temperature]. Protect from freezing. Keep out of the reach of children.
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. Manufactured for: Triax Pharmaceuticals, LLC Marketed and Distributed By:
Cranford NJ 07016 Triax Pharmaceuticals, LLC
Cushings syndrome, linear growth retardation, delayed weight gain, and By: Ferndale Laboratories, Inc. Cranford NJ 07016
intracranial hypertension have also been reported in pediatric patients receiving Ferndale MI 48220 www.Locoid.com
topical corticosteroids. Manifestations of adrenal suppression in pediatric patients
include low plasma cortisol levels to an absence of response to ACTH stimulation. Locoid Lipocream is a registered trademark of
Manifestations of intracranial hypertension include bulging fontanelles, headaches, Astellas Pharma Europe BV licensed to 131B301
and bilateral papilledema. Triax Pharmaceuticals, LLC. Rev 11/09
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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