Sep / Oct 2011 by jo-ann kalaka-Adams

September/October 2011 • Volume 9 • Issue 5

EDITORIAL The Wax Model Parish and Geiges

ORIGINAL CONTRIBUTIONS The Role of Nutrition in Acne Pathogenesis: YouTube as a Reflection of Current Popular Thought Qureshi and Lowenstein

An Open-Label Study of Naftifine Hydrochloride 1% Gel in the Treatment of Tinea Versicolor Gold, Bridges, Avakian, Plaum, Pappert, Fleischer, and Hardas

DEPARTMENTS HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER A History of Sulfur Mustard Lowenstein

HISTORICAL VIGNETTE Claude Huriez and His Syndrome Aboud and Khachemoune

CASE STUDIES Nodular Cutaneous Amyloidosis Borowicz, Shama, and Miller

The Impact of Dermatology in Premier Medicine Journals Kheterpal and Ellis

REVIEW Phototoxicity of Oriental Medicinal Plants: Measurement and Possible Applications Bark, Sun, Yoon, and Kim

CORE CURRICULUM Noninsulin-Dependent, Type II Diabetes Mellitus–Related Dermatoses: Part II Sehgal, Srivastava, Aggarwal, Gupta, Bhattacharya, and Verma

Livedo Reticularis From Amantadine Xu, Liu, and Kerr

Nodule on the Scrotum Narang, Singh, and Singh

CORRESPONDENCE Longitudinal Erythronychia Associated With Graft-Versus-Host Disease Cohen

Segmental Vitiligo May Not Be Associated With Risk of Autoimmune Thyroiditis Silverberg

Author’s Response Sehgal

DIFFERIN® (adapalene) LOTION, 0.1% — THE ONLY RETINOID IN A LOTION FORMULATION

ON THE JOB WITH GENTLE EFFICACY1

58.2% MEDIAN TOTAL LESION COUNT REDUCTION BY WEEK 121* TOLERABILITY PROFILE SIMILAR TO DIFFERIN® (adapalene) CREAM, 0.1%1† AVAILABLE IN AN EASY-TO-USE PUMP DISPENSER

RESULTS PATIENTS WANT IN A FORMULATION THAT DOES THE WORK—

PRESCRIBE DIFFERIN® LOTION, 0.1% TODAY!

A 12-week, multicenter, randomized, double-blind, parallel-group study of patients 12 to 18 years of age with acne vulgaris (N=1075). The most frequent adverse event reported was dryness. Erythema, stinging/burning, and scaling may also occur.1

* †

Important Safety Information Differin® Lotion, 0.1% is indicated for the topical treatment of acne vulgaris in patients 12 years and older. A thin ﬁlm of Differin® Lotion, 0.1% should be applied once per day to the face and other areas of the skin affected by acne. In clinical trials, the most common adverse event (>1%) reported with use of Differin® Lotion, 0.1% was mild to moderate skin dryness. Erythema, scaling, stinging and burning may also occur. Excessive exposure to sunlight and sunlamps should be avoided during treatment, and use of sunscreen products and protective clothing is recommended. Concomitant use of drying or irritating topical products (like products containing resorcinol, salicylic acid or sulfur) should be used with caution. Instruct patients to avoid the eyes, lips and mucous membranes when applying Differin® Lotion, 0.1%, and not to apply to areas that have been depilated with wax products. Differin® Lotion, 0.1% has not been tested in pregnant or nursing women, or with the elderly. Pregnancy Category C. www.differin.com/HCP Please see Brief Summary of Prescribing Information on adjacent page.

DIFFERIN®

Rx only

(adapalene) Lotion 0.1% For Topical Use Only Not For Oral, Ophthalmic, or Intravaginal Use. BRIEF SUMMARY INDICATIONS AND USAGE DIFFERIN Lotion is a retinoid product indicated for the topical treatment of acne vulgaris in patients 12 years and older. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight and sunlamps. Wear sunscreen when sun exposure cannot be avoided. Erythema, scaling, dryness, and stinging/burning may occur with use of DIFFERIN Lotion. ADVERSE REACTIONS Dry skin of mild to moderate severity was the most frequently reported (≥ 1%) treatment related adverse event. Erythema, scaling, dryness, burning/stinging were also seen during treatment. DRUG INTERACTIONS Concomitant use of topical products with a strong drying effect can increase skin irritation. Use with caution, especially in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Lotion. Wax depilation should not be performed on treated skin. Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with DIFFERIN Lotion. Furthermore, such studies are not always predictive of human response. Human Data In clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne vulgaris, women of childbearing potential initiated treatment only after a negative pregnancy test. Two women became pregnant while using DIFFERIN Lotion, 0.1%. One patient delivered a healthy full term baby and the other patient electively terminated her pregnancy. Animal Data No teratogenic effects were observed in rats treated with oral doses of 0.15 to 5.0 mg adapalene/kg/day, up to 25 times (mg/m2/day) the maximum recommended human dose (MRHD) of 2 grams of DIFFERIN Lotion. However, teratogenic changes were observed in rats and rabbits when treated with oral doses of ≥ 25 mg adapalene/kg/day representing 123 and 246 times MRHD, respectively. Findings included cleft palate, microphthalmia, encephalocele and skeletal abnormalities in rats; and umbilical hernia, exophthalmos and kidney and skeletal abnormalities in rabbits. Dermal teratology studies conducted in rats and rabbits at doses of 0.66.0 mg adapalene/kg/day [25-59 times (mg/m2) the MRHD] exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits. Systemic exposure (AUC 0-24h) to adapalene at topical doses (6.0 mg/kg/day) in rats represented 101 times the exposure to adapalene in patients with acne treated with DIFFERIN Lotion applied to the face, chest and back (2 grams applied to 1000 cm² of acne-involved skin). Nursing Mothers It is not known whether adapalene is excreted in human milk following use of DIFFERIN Lotion. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN Lotion is administered to a nursing woman. Pediatric Use Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the age of 12 have not been established. Geriatric Use Clinical studies of DIFFERIN Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity and impairment of fertility studies were conducted with DIFFERIN Lotion. Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m²/day),

and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3.0, and 9.0 mg/m2/day). In terms of body surface area, the highest dose levels are 9.8 (mice) and 7.4 times (rats) the MRHD of 2 grams of DIFFERIN Lotion. In the rat study, an increased incidence of benign and malignant pheochromocytomas in the adrenal medulla of male rats was observed. No photocarcinogenicity studies were conducted with adapalene. However, animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g. retinoids) when exposed to UV irradiation in the laboratory or sunlight. Although the significance of these findings to humans is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial irradiation sources. Adapalene did not exhibit mutagenic or genotoxic effects in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) or in vivo (mouse micronucleus test). In rat oral studies, 20 mg adapalene/kg/day (120 mg/m2/day; 98 times the MRHD based on mg/m2/day comparison) did not affect the reproductive performance and fertility of F0 males and females, or growth, development and reproductive function of F1 offspring. PATIENT COUNSELING INFORMATION • Apply a thin film of DIFFERIN Lotion to the affected areas of the skin once daily, after washing gently with a mild soapless cleanser. Dispense a nickel size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the entire face. Avoid application to the areas of skin around eyes, lips and mucous membranes. DIFFERIN Lotion may cause irritation such as erythema, scaling, dryness, stinging or burning. • Advise patients to cleanse the area to be treated with a mild or soapless cleanser; pat dry. Apply DIFFERIN Lotion to the entire face or other acne affected areas as a thin layer, avoiding the eyes, lips and mucous membranes. • Exposure of the eye to this medication may result in reactions such as swelling, conjunctivitis and eye irritation. • Patients should be advised not to use more than the recommended amount and not to apply more than once daily as this will not produce faster results, but may increase irritation. • Advise patients to minimize exposure to sunlight including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided. • Moisturizers may be used if necessary; however, products containing alpha hydroxy or glycolic acids should be avoided. • This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin. • Wax depilation should not be performed on treated skin due to the potential for skin erosions. • This product is for external use only. Marketed by: GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Manufactured by: Galderma Production Canada Inc., Baie d’Urfé, QC, H9X 3S4 Canada Made in Canada. GALDERMA is a registered trademark. P51503-0 Revised: March 2010

Reference: 1. Data on ﬁle. Galderma Laboratories, L.P. Galderma is a registered trademark. ©2010 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 DIFF-113 Printed in USA 09/10

www.differin.com/HCP

TABLE OF CONTENTS September/October 2011 • Volume 9 • Issue 5

EDITORIAL The Wax Model ........................................................................................................................................... 275 Lawrence Charles Parish, MD, MD (Hon); Michael L. Geiges, MD

ORIGINAL CONTRIBUTIONS The Role of Nutrition in Acne Pathogenesis: YouTube as a Reflection of Current Popular Thought .................. 279 Naema Qureshi, MS; Eve J. Lowenstein, MD, PhD

An Open-Label Study of Naftifine Hydrochloride 1% Gel in the Treatment of Tinea Versicolor ......................... 283 Michael H. Gold, MD; Tancy Bridges, NP-C; Edward Avakian, MA, PhD; Stefan Plaum, MD; Eric J. Pappert, MD; Alan B. Fleischer, Jr, MD; Bhushan Hardas, MD, MBA

The Impact of Dermatology in Premier Medicine Journals ............................................................................ 288 Meenal K. Kheterpal, MD; Charles N. Ellis, MD

REVIEW Phototoxicity of Oriental Medicinal Plants: Measurement and Possible Applications ....................................... 294 Ki-Min Bark, PhD; Young-Woo Sun, MD; Tae-Jin Yoon, MD, PhD; Tae-Heung Kim, MD, PhD Self-Test Review Questions (p. 300)

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Noninsulin-Dependent, Type II Diabetes Mellitus–Related Dermatoses: Part II ................................................ 302 Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Megha Gupta, MBBS; Sambit N. Bhattacharya, MD; Prashant Verma, MD

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve J. Lowenstein, MD, PhD, Section Editor

A History of Sulfur Mustard ......................................................................................................................... 310 Elie B. Lowenstein, MD

HISTORICAL VIGNETTE Charles Steffen, MD, Section Editor

Claude Huriez and His Syndrome................................................................................................................. 313 Khalid Al Aboud, MD; Amor Khachemoune, MD

270

TABLE OF CONTENTS September/October 2011 • Volume 9 • Issue 5

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

Nodular Cutaneous Amyloidosis .................................................................................................................. 316 Jessica Borowicz, DO; Leah Shama, DO; Richard Miller, DO

Livedo Reticularis From Amantadine ............................................................................................................ 320 Lisa Y. Xu, MD; Austin Liu, MD; Holly A. Kerr, MD

Nodule on the Scrotum ............................................................................................................................... 323 Tarun Narang, MD; Varinder Singh, MD; Jasbir Singh, MD

CORRESPONDENCE Longitudinal Erythronychia Associated With Graft-Versus-Host Disease ......................................................... 327 Philip R. Cohen, MD

Segmental Vitiligo May Not Be Associated With Risk of Autoimmune Thyroiditis ............................................ 329 Nanette Silverberg, MD

Author’s Response....................................................................................................................................... 330 Virendra N. Sehgal, MD

Editorial

ABOUT OUR JOURNAL

EDITORIAL DIRECTOR Sarah D. Staats sstaats@skinmedjournal.com

SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760.

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Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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Abstracting & Indexing: The journal is indexed in Index Medicus/ MEDLINE.

271

September/October 2011

EDITORIAL BOARD

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD Dallas, TX

W. Clark Lambert, MD, PhD Newark, NJ

Larry E. Millikan, MD Meridian, MS

Vesna Petronic-Rosic, MD, MSc Chicago, IL

Marcia Ramos-e-Silva, MD, PhD Rio de Janeiro, Brazil

Jennifer L. Parish, MD Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Gibbstown, NJ

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Noah S. Scheinfeld, MD, JD New York, NY

Robert L. Baran, MD Cannes, France

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Eve J. Lowenstein, MD, PhD New York, NY

Virendra N. Sehgal, MD Delhi, India

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

Marc S. Micozzi, MD, PhD Bethesda, MD

Alexander J. Stratigos, MD Athens, Greece

Jack M. Bernstein, MD Dayton, OH

Michael H. Gold, MD Nashville, TN

George F. Murphy, MD Boston, MA

James S. Studdiford III, MD Philadelphia, PA

Sarah Brenner, MD Tel Aviv, Israel

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Robert J. Thomsen, MD Los Alamos, NM

Joaquin Calap Calatayud, MD Cadiz, Spain

Aditya K. Gupta, MD, PhD, FRCP(C) London, Ontario

Joseph L. Pace, MD, FRCP Naxxar, Malta

Julian Trevino, MD Dayton, OH

Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China

Seung-Kyung Hann, MD, PhD Seoul, Korea

Art Papier, MD Rochester, NY

Snejina Vassileva, MD, PhD Sofia, Bulgaria

Noah Craft, MD, PhD, DTMH Torrance, CA

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Johannes Ring, MD, DPhil Munich, Germany

Daniel Wallach, MD Paris, France

Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa

Tanya R. Humphreys, MD Philadelphia, PA

Roy S. Rogers III, MD Rochester, MN

Michael A. Waugh, MB, FRCP Leeds, UK

Richard L. Dobson, MD Mt Pleasant, SC

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Wm. Philip Werschler, MD Spokane, WA

William H. Eaglstein, MD Palo Alto, CA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Joseph A. Witkowski, MD Philadelphia, PA

Boni E. Elewski, MD Birmingham, AL

Andrew P. Lazar, MD Highland Park, IL

Vincenzo Ruocco, MD Naples, Italy

Ronni Wolf, MD Rechovot, Israel

Charles N. Ellis, MD Ann Arbor, MI

272

VELTIN Gel—A Topical Treatment for Patients 12 Years or Older With Acne Vulgaris Once-daily application in the evening

VELTIN Gel

Combines the acne-fighting properties of tretinoin and clindamycin Contains tretinoin, solubilized in an aqueous-based gel Combats inflammatory and noninflammatory acne

Important Safety Information for VELTIN Gel VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis Systemic absorption of clindamycin has been demonstrated following topical use. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. VELTIN Gel should be discontinued if signiﬁcant diarrhea occurs. Severe colitis has occurred following oral or parenteral clindamycin administration. Severe colitis may result in death Avoid exposure to sunlight and sunlamps when using VELTIN Gel. Patients with sunburn should be advised not to use VELTIN Gel until fully recovered. Daily use of sunscreen products and protective apparel are recommended. Weather extremes (eg, wind and cold) also may be irritating to patients using VELTIN Gel Observed local treatment-related adverse reactions (≥1%) in clinical studies with VELTIN Gel were application site reactions, including dryness, irritation, exfoliation, erythema, pruritus, and dermatitis. Sunburn was also reported. Incidence of actively assessed local skin reactions peaked at week 2 and then gradually decreased VELTIN Gel should not be used in combination with erythromycincontaining products due to possible antagonism to the clindamycin component Please see brief summary of Prescribing Information on the next page.

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. VELTIN Gel should be used with caution in patients receiving such agents VELTIN Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus It is not known whether either clindamycin or tretinoin is excreted in human milk following use of VELTIN Gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Due to possible serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug. Exercise caution if administering VELTIN Gel to a nursing woman The efficacy and safety have not been established in pediatric patients below the age of 12 years VELTIN Gel is not for oral, ophthalmic, or intravaginal use

BRIEF SUMMARY VELTIN™ (clindamycin phosphate and tretinoin) Gel 1.2%/0.025% The following is a brief summary only; see full prescribing information for complete product information. INDICATIONS AND USAGE VELTIN Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. CONTRAINDICATIONS VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. WARNINGS AND PRECAUTIONS Colitis Systemic absorption of clindamycin has been demonstrated following topical use. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. If significant diarrhea occurs, VELTIN Gel should be discontinued. Severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death. Studies indicate a toxin(s) produced by clostridia is one primary cause of antibioticassociated colitis. Ultraviolet Light and Environmental Exposure Exposure to sunlight, including sunlamps, should be avoided during the use of VELTIN Gel, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with VELTIN Gel. ADVERSE REACTIONS Adverse Reactions in Clinical Studies The safety data reflect exposure to VELTIN Gel in 1,104 patients with acne vulgaris. Patients were 12 years or older and were treated once daily in the evening for 12 weeks. Observed local treatment-related adverse reactions (≥1%) in clinical studies with VELTIN Gel were application site reactions, including dryness (6%), irritation (5%), exfoliation (5%), erythema (4%), pruritus (2%), and dermatitis (1%). Sunburn (1%) was also reported. Incidence of skin reactions peaked at week 2 and then gradually decreased. Local skin reactions were actively assessed at baseline and at the end of 12 weeks of treatment in patients exposed to VELTIN Gel. At baseline (N=476), local skin reactions included erythema (24%), scaling (8%), dryness (11%), burning (8%), and itching (17%). At 12 weeks of treatment (N=409), local skin reactions included erythema (21%), scaling (19%), dryness (22%), burning (13%), and itching (15%). During the 12 weeks of treatment, each local skin reaction peaked at week 2 and gradually reduced thereafter. DRUG INTERACTIONS Erythromycin VELTIN Gel should not be used in combination with erythromycin-containing products due to possible antagonism to the clindamycin component. In vitro studies have shown antagonism between these 2 antimicrobials. The clinical significance of this in vitro antagonism is not known. Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, VELTIN Gel should be used with caution in patients receiving such agents. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no well-controlled studies in pregnant women treated with VELTIN Gel. VELTIN Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A limit teratology study performed in Sprague Dawley rats treated topically with VELTIN Gel or 0.025% tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15 did not result in teratogenic effects. Although no systemic levels of tretinoin were detected, craniofacial and heart abnormalities were described in drug-treated groups. These abnormalities are consistent with retinoid effects and occurred at 16 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison. For purposes of comparison of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of VELTIN Gel applied daily to a 50 kg person. Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose based on body surface area comparison). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomologous monkey, a species in which tretinoin metabolism is closer to humans than in other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (324 times the recommended clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related teratogenic effects and increased abortion rates were reported in pigtail macaques.

With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to fetus is not known. Nursing Mothers It is not known whether clindamycin is excreted in human milk following use of VELTIN Gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VELTIN Gel is administered to a nursing woman. Pediatric Use Safety and effectiveness of VELTIN Gel in pediatric patients below the age of 12 years have not been established. Clinical trials of VELTIN Gel included 2,086 patients 12-17 years of age with acne vulgaris. [See Clinical Studies (14) of full prescribing information.] NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was negative for mutagenic potential when evaluated in an in vitro Ames Salmonella reversion assay. VELTIN Gel was equivocal for clastogenic potential in the absence of metabolic activation when tested in an in vitro chromosomal aberration assay. Clindamycin: Once daily dermal administration of 1% clindamycin as clindamycin phosphate in the VELTIN Gel vehicle (32 mg/kg/day, 13 times the recommended clinical dose based on body surface area comparison) to mice for up to 2 years did not produce evidence of tumorigenicity. Tretinoin: In two independent mouse studies where tretinoin was administered topically (0.025% or 0.1%) three times per week for up to two years no carcinogenicity was observed, with maximum effects of dermal amyloidosis. However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 μg (1.4 times the recommended clinical dose based on body surface area comparison) three times per week for 20 weeks acted as a weak promoter of skin tumor formation following a single application of dimethylbenz[␣]anthracene (DMBA). In a study in female SENCAR mice, papillomas were induced by topical exposure to DMBA followed by promotion with 12-O-tetradecanoyl-phorbol 13-acetate or mezerein for up to 20 weeks. Topical application of tretinoin prior to each application of promoting agent resulted in a reduction in the number of papillomas per mouse. However, papillomas resistant to topical tretinoin suppression were at higher risk for pre-malignant progression. Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to tretinoin and UV radiation. The photoco-carcinogenic potential of the clindamycin tretinoin combination is unknown. Although the significance of these studies to humans is not clear, patients should avoid exposure to sun. PATIENT COUNSELING INFORMATION [See FDA-approved Patient Labeling in full prescribing information.] Instructions for Use • At bedtime, the face should be gently washed with a mild soap and water. After patting the skin dry, apply VELTIN Gel as a thin layer over the entire affected area (excluding the eyes and lips). • Patients should be advised not to use more than a pea sized amount to cover the face and not to apply more often than once daily (at bedtime) as this will not make for faster results and may increase irritation. • A sunscreen should be applied every morning and reapplied over the course of the day as needed. Patients should be advised to avoid exposure to sunlight, sunlamp, ultraviolet light, and other medicines that may increase sensitivity to sunlight. • Other topical products with a strong drying effect, such as abrasive soaps or cleansers, may cause an increase in skin irritation with VELTIN Gel. Skin Irritation VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging. Colitis In the event a patient treated with VELTIN Gel experiences severe diarrhea or gastrointestinal discomfort, VELTIN Gel should be discontinued and a physician should be contacted. VELTIN is a trademark of Astellas Pharma Europe B.V. ©2010 Stiefel Laboratories, Inc. VEL:2BRS July 2010

September/October 2011

Volume 9 • Issue 5

EDITORIAL

The Wax Model Lawrence Charles Parish, MD, MD (Hon);1 Michael L. Geiges, MD2

ith the advent of PowerPoint presentations and digital photography, the slide, sometimes referred to as a Kodachrome or diapositive, has been relegated to the attic or, even worse, the recycling bin. Glass projection transparencies have long since disappeared from department collections, with a few water-colored illustrations clinging on in an occasional clinic as a reminder of the past; yet, one vehicle survives, even with its rocky history, the wax model.1 The wax model, sometimes referred to as a moulage, provides a wonderful three-dimensional view of skin disease. The coloring can be so realistic that the model is almost life-like.* While significant collections remain extant at institutions such as l’Hôpital St Louis in Paris,2 “Andreas Sygros” Hospital in Athens,3 and the University of Zurich,4 other collections of yesteryear are nowhere to be found or have been markedly reduced in numbers and prominences.5 A REBIRTH Dermatologists and historians have begun to rediscover the almost-forgotten three-dimensional models of the skin.6 Many

have been molded from patients with the use of a plaster cast to provide unique exhibits of skin diseases, often of yesteryear. In some cases, the patient histories have also survived to provide a window into earlier times.7 In the early 1960s, Kodachromes had replaced the moulages at Zurich as teaching aids, but then an exhibition in the Museum of Medical History in Zurich changed the course of wax model history.8 The exhibit drew new attention to the nearly forgotten medical wax figures. By 1993, the growing public interest finally led to the opening of the modern Museum of Wax Moulages of the University Hospital and the University of Zurich. A CURRENT EDUCATIONAL TOOL After showing several special exhibitions on historical topics, the Museum of Wax Moulages in Zurich now provides a complete tour for the specialty of dermatology and venereology (Figure 2, Figure 3). This is based on the Swiss catalogue of learning objectives for undergraduate medical training. Despite the objections of some who view new as good and old as bad, this, being the oldest of dermatologic teaching aids, has proven to be of great

Figure 1. An exhibit of the Collection of Wax Models of the University of Pennsylvania at the 30th Annual Meeting of the American Academy of Dermatology, Chicago, IL, December 4–9, 1971. *When the Duhring models were exhibited at the American Academy of Dermatology Meeting in 1971, the porters were afraid to approach the booth for fear of contracting the diseases depicted10 (Figure 1).

From Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;1 and the Museum of Wax Moulages and Department of Dermatology, University of Zurich, Zurich, Switzerland2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Jefferson Medical College of Thomas Jefferson University, Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, 1760 Market Street, Philadelphia, PA l9103 • E-mail: larryderm@yahoo.com

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Figure 2. Wax moulages being made at the University of Zurich: A) how the moulage is casted and B) the painting process. Copyright Tine Edel (tine.edel@freesurf.ch).

Figure 3. An exhibit at the University of Zurich.

value for the medical students.4 The collection complements the teaching of skin diseases, providing a more realistic approach, along with e-learning and digital imagery.9 For more than 5 years, the introduction to dermatologic training has taken place in the museum itself and has been met with great success. These wax moulages have regained their position as important teaching aids, thanks to their outstanding quality and quantity, with there being more than 1800 models in the collection (600 on display). Pictures of some of these models are currently published in many issues of SKINmed. THE FUTURE We recognize that not all dermatology programs have or will have wax models; however, we believe that they are highly useful for teaching students and dermatologic neophytes (Figure 4). Where else can the morphology of various skin diseases be introduced so well?

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Figure 4. Wax models at the MĂźtter Museum of the College of Physicians of Philadelphia.

The Wax Model

September/October 2011

EDITORIAL

REFERENCES 1

Haviland TN, Parish LC. A brief account of the use of wax models in the study of medicine. J Hist Med Allied Sci. 1970;25: 52–75.

Rudlinger R, Stoiber E. The Bloch era as reflected in the moulages collection at the Zurich Dermatological University Clinic 1917-1933 [in German]. Hautarzt. 1988;39:314–317.

Geiges ML, Holzer R. Three dimensional documents. Moulages showing animal experiments, self-experiments and clinical research. Moulagenmuseum. Zurich, Switzerland: University and University Hospital of Zurich; 2006.

Geiges ML. Renaissance of Zurich moulages [in German]. Gesnerus. 2001;58:249–258.

Tilles G, Wallach D. Le musèe de moulages de l´Hôpital SaintLouis. Velizy, France: Doin; 1996:105.

Worm AM, Hadjivassiliou M, Katsambas A. The Greek moulages: a picture of skin diseases in former times. J Eur Acad Dermatol Venereol. 2007;21:515–519.

Geiges M. The Museum of Wax Moulages in Zurich—current relevance for dermatology, history of medicine and the general public [in German]. J Dtsch Dermatol Ges. 2007;5:953–957.

Geiges ML. A hundred glances on a “pimple.” Historical wax moulages as modern teaching aids. In: Lang J, Mühlenberend S, Rössiger S, eds. Bodies in Wax-Moulages in Research and Restoration. Dresden, Germany: Deutsches Hygiene Museum; 2010:21–25.

Parish LC, Worden G, Witkowski JA, et al. Wax models in dermatology. Trans Stud Col Physic Phila. 1991;13:29–74.

10 Parish LC, Rubin MB. Dermatology 100 Years Ago. Chicago, IL: American Academy of Dermatology; 1971.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2011;9:275–277

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The Wax Model

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September/October 2011

Volume 9 • Issue 5

ORIGINAL CONTRIBUTION

The Role of Nutrition in Acne Pathogenesis: YouTube as a Reflection of Current Popular Thought Naema Qureshi, MS;1 Eve J. Lowenstein, MD, PhD1,2 ABSTRACT Although studies have yet to prove definitively a causal relationship between diet and acne, the lay public has traditionally held that such causality exists. The authors’ study aims to determine which nutritional elements are thought to be related to acne, both positively and negatively. YouTube, a popular video-sharing Web site, was used to survey the views of the lay public. The keywords “acne,” “acne diet,” and “acne food” were searched in YouTube in July and August of 2009, and 87 videos were included in the study. More than 85% of videos suggest at least a moderate correlation between diet and acne. Dairy products and oily and greasy foods were viewed as aggravating factors, while fruits, vegetables, and supplements were regarded as alleviating factors. Generally regarded “truths” can affect patient compliance with treatment regimens, and a knowledgeable physician is better able to address these issues with his or her patients. (SKINmed. 2011;9:279–280)

here is a prevalent belief in the lay public that there exists a connection between diet and acne. Although much has been elucidated about the pathogenesis of acne, the role of diet has long been debated. Several studies have implicated dairy products or high-glycemic–loaded foods with prevalence and/or severity of acne.1–6 Based on these data, some researchers have suggested that patients with acne eliminate all dairy products from their diet and eat only foods with a low glycemic index. Such a diet is suggested in the Clear Skin Diet Book, for instance.7 Although such ideas may be popular or prevalent, it is important to keep in mind that these studies are not evidence-based. Many patients may expect information from their doctors on what foods they should eat or avoid to improve their acne; however, evidence is lacking to make any recommendation in regard to diet and acne.8 YouTube is a popular video-sharing Web site. A search of the term acne on YouTube yields more than 30,000 videos.9 Discussed are a broad range of topics in relation to acne, oftentimes with the maker of the video offering their personal advice regarding prevention and treatment options. This study uses YouTube to elicit public opinion on the role of diet and nutrition in acne pathogenesis. METHODS During July and August of 2009, YouTube was searched with the following keywords: “acne diet,” “acne nutrition,” and “acne food.” Videos were included only if they mentioned or discussed

a component of diet as it related to acne. Videos that appeared under more than one keyword were included only once. Advertisements were omitted. Most videos were excluded as they did not discuss nutrition and its relation to acne. Videos were assessed in terms of strength of correlation between acne and nutrition, and classified as “none,” “minimal,” “moderate,” and “strong.” The specific nutritional components that were discussed were noted. The number of times a video had been viewed and the video’s rating, as determined by viewers, were also noted. RESULTS Of the 87 videos included in the study, more than 85% suggested at least a moderate correlation between diet and acne. Specifically, 50% of videos suggested a strong correlation, while 37% suggested moderate, 3% suggested minimal, and 9% suggested no correlation. Fruits and vegetables, as well as nutritional supplements, were suggested as alleviating factors. Dairy products were generally regarded as aggravating factors. Sugary and oily/greasy foods were generally regarded as aggravating factors, although a significant percentage stated that these foods had no effect on acne (Table). Very popular videos had been viewed more than 10,000 times. The three most popular videos, which had been viewed more than 100,000 times, all suggested a strong correlation between acne and nutrition. All three recommended increased consumption of fruits and vegetables. Two videos suggested that dairy products

From the Department of Dermatology, SUNY Health Science Center at Brooklyn, NY;1 and the Department of Medicine, Brookdale Hospital Medical Center,2 Brooklyn, NY Address for Correspondence: Naema Qureshi, MS, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: naema.qureshi@downstate.edu

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Table. Percentage of Videos That Discussed Nutritional Components and Their Relation to Acne

NUTRITIONAL COMPONENT

ALLEVIATING, %

NO EFFECT, %

AGGRAVATING, %

TOTAL, %

Dairy

2.3

29.9

33.3

Fruits and vegetables

34.5

Supplements

Sugar

9.2

21.8

Oily or greasy foods

5.7

13.8

19.5

should be avoided, while one video suggested that dairy products can help alleviate acne. Two videos suggested that sugar and sweets should be avoided, and one video suggested that oily foods should be avoided.

data are available, an open mind on this topic can only help in treating our patients. REFERENCES

DISCUSSION Despite the long-running controversy regarding acne and diet, dermatologists as a rule do not manage acne by modifying diet. Yet, more than 85% of videos viewed on YouTube suggest at least a moderate correlation between diet and acne, even though little scientific proof of this exists. This is noted to be a source of frustration in some videos. Indeed, many people who stated that there was a strong correlation between diet and acne also suggested that viewers “not waste time and money” visiting dermatologists, whom they felt were not treating the source of the problem. Awareness of this perception is important, as it may play a role in patient compliance. CONCLUSIONS The controversy about the role of nutrition in acne remains unresolved. Studies continue on the subject, and, until better

Spencer EH, Ferdowsian HR, Barnard ND. Diet and acne: a review of the evidence. Int J Dermatol. 2009;48:339–347.

Danby FW. Acne and milk, the diet myth, and beyond. J Am Acad Dermatol. 2005;52:360–362.

Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol. 2008;58:787–793.

Clement A, Spiegelman D, Berkey CS, et al. Milk consumption and acne in adolescent girls. Dermatol Online J. 2006;12:1.

Smith RN, Mann NJ, Braue A, et al. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr. 2007;86:107–115.

Danby FW. Nutrition and acne. Clin Dermatol. 2010;28:598– 604.

Danby FW. Diet and acne. Clin Dermatol. 2008;26:93–96.

Logan AC, Treloar V. The Clear Skin Diet. Nashville, TN: Cumberland House; 2007.

www.YouTube.com. Accessed July, August 2009.

URTICARIA A-G Drugs that may cause urticaria A-G Abbokinase

Calan

Duragesic

Flagyl

Atarax

Celebrex

Eidel

Fosmax

Bactrim

Claritin

Elavil

Gabitril

Benadryl

Darvon

Erythromcyin

Geodon

Beniacar

Diamox

Feldene

Glucophage

Caffeine Adapted from Litt, JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009: 126–128.

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cy… Delivers on efﬁca

Handles Patients With Care

the topical l is indicated for DUAC Topic al Ge ammator y acne vulgaris. ve any infl of t en treatm mons trated to ha e l has not been de alone in the sam ide DUAC Topic al Ge rox pe yl nzo . h be flammator y acne en compared wit nin wh t no fi of ne t be en al atm ion addit d for the tre vehicle when use

DUAC Topical Gel is the once-daily clindamycin/benzoyl peroxide combination with a patented formula containing both glycerin and dimethicone The contribution to efﬁcacy by individual components of the vehicle has not been established. • No therapeutically equivalent generic substitute1 • More than 6 million prescriptions of DUAC Topical Gel dispensed since launch2

PLEASE NOTE: The soap-free cleanser is no longer included in the package. Please prescribe DUAC Topical Gel 45 g.

DUAC 45 g

Apply once daily Dispense as written

Important Safety Information for DUAC Topical Gel • DUAC Topical Gel is contraindicated in patients who have shown hypersensitivity to any of its components or lincomycin • DUAC Topical Gel is contraindicated in patients with a history of regional enteritis, ulcerative colitis, pseudomembranous colitis, or antibiotic-associated colitis • Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus • For dermatologic use only; not for ophthalmic use • Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents • The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms, including fungi. If this occurs, discontinue use of this medication and take appropriate measures • Clindamycin- and erythromycin-containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical signiﬁcance of this in vitro antagonism is not known • DUAC Topical Gel may bleach hair and colored fabrics • Excessive or prolonged exposure to sunlight should be limited. To minimize exposure to sunlight, a hat or other clothing should be worn • DUAC Topical Gel should be given to a pregnant woman only if clearly needed • It is not known whether DUAC Topical Gel is secreted into human milk after topical application. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother • Safety and effectiveness of this product in pediatric patients below the age of 12 have not been established • Adverse reactions may include erythema, peeling, burning, and dryness • Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with DUAC Topical Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Please see brief summary of Prescribing Information on following page. References: 1. Electronic Orange Book. US Food and Drug Administration Web site. http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm. Accessed February 25, 2011. 2. SDI. VectorOne: National (VONA). October 2009.

BRIEF SUMMARY DUAC ® Topical Gel (clindamycin, 1% - benzoyl peroxide, 5%) The following is a brief summary only; see full prescribing information for complete product information. For Dermatological Use Only. Not for Ophthalmic Use. Rx Only INDICATIONS AND USAGE DUAC Topical Gel is indicated for the topical treatment of inflammatory acne vulgaris. DUAC Topical Gel has not been demonstrated to have any additional benefit when compared to benzoyl peroxide alone in the same vehicle when used for the treatment of non-inflammatory acne. CONTRAINDICATIONS DUAC Topical Gel is contraindicated in those individuals who have shown hypersensitivity to any of its components or to lincomycin. It is also contraindicated in those having a history of regional enteritis, ulcerative colitis, pseudomembranous colitis, or antibiotic-associated colitis. WARNINGS ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEEN ASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENT DEATH. USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTS IN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE. DIARRHEA, BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUS COLITIS) HAVE BEEN REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRODUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF ANTIBIOTIC-ASSOCIATED COLITIS. THE COLITIS IS USUALLY CHARACTERIZED BY SEVERE PERSISTENT DIARRHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE ASSOCIATED WITH THE PASSAGE OF BLOOD AND MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDOMEMBRANOUS COLITIS. STOOL CULTURE FOR Clostridium difficile AND STOOL ASSAY FOR Clostridium difficile TOXIN MAY BE HELPFUL DIAGNOSTICALLY. WHEN SIGNIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE DISCONTINUED. LARGE BOWEL ENDOSCOPY SHOULD BE CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS IN CASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS SUCH AS OPIATES AND DIPHENOXYLATE WITH ATROPINE MAY PROLONG AND/OR WORSEN THE CONDITION. DIARRHEA, COLITIS AND PSEUDOMEMBRANOUS COLITIS HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL WEEKS FOLLOWING CESSATION OF ORAL AND PARENTERAL THERAPY WITH CLINDAMYCIN. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. PRECAUTIONS General: For dermatological use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms, including fungi. If this occurs, discontinue use of this medication and take appropriate measures. Avoid contact with eyes and mucous membranes. Clindamycin and erythromycin containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known. Information for Patients: Patients using DUAC Topical Gel should receive the following information and instructions: 1.

DUAC Topical Gel is to be used as directed by the physician. It is for external use only. Avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as this product may be irritating.

This medication should not be used for any disorder other than that for which it was prescribed.

Patients should not use any other topical acne preparation unless otherwise directed by their physician.

Patients should report any signs of local adverse reactions to their physician. Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue use and contact their physician immediately.

DUAC Topical Gel may bleach hair or colored fabric.

DUAC Topical Gel can be stored at room temperature up to 25°C (77°F) for up to 2 months. Do not freeze. Keep tube tightly closed. Keep out of the reach of small children. Discard any unused product after 2 months.

Before applying DUAC Topical Gel to affected areas, wash the skin gently, rinse with warm water, and pat dry.

Excessive or prolonged exposure to sunlight should be limited. To minimize exposure to sunlight, a hat or other clothing should be worn.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced squamous cell skin tumors in transgenic TgAC mice in a study using 20 weeks of topical treatment. The clinical signiﬁcance of this is unknown. In a 2-year dermal carcinogenicity study in mice, treatment with DUAC Topical Gel at doses up to 8000 mg/kg/day (16 times the highest recommended adult human dose of 2.5 g DUAC Topical Gel, based on mg/m2) did not cause an increase in skin tumors. However, topical treatment with another formulation containing 1% clindamycin and 5% benzoyl peroxide at doses of 100, 500, or 2000 mg/kg/day caused a dose-dependent increase in the incidence of keratoacanthoma at the treated skin site of male rats in a 2-year dermal carcinogenicity study in rats. In a 52-week photocarcinogenicity study in hairless mice (40 weeks of treatment followed by 12 weeks of observation), the median time to onset of skin tumor formation decreased and the number of tumors per mouse increased relative to controls following chronic concurrent topical treatment with DUAC Topical Gel and exposure to ultraviolet radiation. Genotoxicity studies were not conducted with DUAC Topical Gel. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in Salmonella typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells. Studies have not been performed with DUAC Topical Gel or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in the highest recommended adult human dose of 2.5 g DUAC Topical Gel, based on mg/m2) revealed no effects on fertility or mating ability. Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with DUAC Topical Gel or benzoyl peroxide. It is also not known whether DUAC Topical Gel can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DUAC Topical Gel should be given to a pregnant woman only if clearly needed. Developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times the amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) revealed no evidence of teratogenicity. Nursing Women: It is not known whether DUAC Topical Gel is secreted into human milk after topical application. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of this product in pediatric patients below the age of 12 have not been established. ADVERSE REACTIONS During clinical trials, all patients were graded for facial erythema, peeling, burning, and dryness on the following scale: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The percentage of patients that had symptoms present before treatment (at baseline) and during treatment were as follows: Local reactions with use of DUAC Topical Gel % of patients using DUAC Topical Gel with symptom present Combined results from 5 studies (n = 397) Before Treatment (Baseline) During Treatment Mild Moderate Severe Mild Moderate Severe Erythema 28% 3% 0 26% 5% 0 Peeling

<1%

17%

Burning

<1%

Dryness

<1%

15%

(Percentages derived by # subjects with symptom score/# enrolled DUAC Topical Gel subjects, n = 397). Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in post-marketing use with DUAC Topical Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. ©2010 Stiefel Laboratories, Inc. DUA:2BRS January 2011

September/October 2011

Volume 9 • Issue 5

ORIGINAL CONTRIBUTION

An Open-Label Study of Naftifine Hydrochloride 1% Gel in the Treatment of Tinea Versicolor Michael H. Gold, MD;1 Tancy Bridges, NP-C;1 Edward Avakian, MA, PhD;2 Stefan Plaum, MD;2 Eric J. Pappert, MD;2 Alan B. Fleischer, Jr, MD;2 Bhushan Hardas, MD, MBA2 ABSTRACT Tinea versicolor (TV) is a superficial cutaneous fungal infection characterized by cutaneous pigment changes, pruritus, scaling, and erythema. This open-label, single-center pilot study evaluated the efficacy and safety of naftifine 1% gel applied twice daily for 2 weeks in 10 men and women (median age 38 years) with TV. Baseline mycology status was determined by potassium hydroxide (KOH) and microscopy and clinical symptom severity (CSS) scored by the investigator using a 0 to 9 scale (0=absent, 9=worst). Patients applied naftifine HCl 1% gel to the affected area twice daily for 14 days. They returned for follow-up efficacy and safety assessments at the end of treatment (week 2), 2 weeks after treatment (week 4), and 6 weeks after treatment (week 8). All patients had a positive mycology at baseline; one was KOH negative at week 2, two were negative at week 4, and five (50%) were negative at week 8. Mean investigator total CSS score decreased from a baseline value of 4.7 to 3.2 at week 2 (32% improvement), 2.6 at week 4 (45% improvement), and 2.7 at week 8 (43% improvement). The patients rated their symptoms to be improved at all follow-up visits. There were no treatment-related adverse events during the study. These results suggest that naftifine 1% gel is a safe and efficacious topical treatment for TV. (SKINmed. 2011;9:283–286)

inea versicolor (TV) is a superficial cutaneous fungal infection characterized by pigment changes resulting from colonization of various yeasts and lipophilic fungi of the genus Malassezia, of which there are three dominant species: M globosa, M sympodialis, and M furfur.1 The frequency of TV is estimated to be as high as 30% in humid tropical zones.2,3 It may occur at any age but is more common during adolescence and young adulthood, suggesting a relationship with androgeninduced sebaceous activity.2 In the United States from 1990 to 1999, TV was diagnosed at 2.9 million office visits, corresponding to a frequency of 110 visits per 100,000 population per year.3 Topical antifungal therapy, including zinc pyrithione and selenium sulfide shampoos, is often recommended initially or for limited cases of TV.4 Non-creamy forms of antifungal agents such as gels or sprays are generally preferred for treatment due to their lack of messiness and ability to be used under clothing areas.4 Naftifine HCl 1% gel is a topical broad-spectrum fungicidal agent of the allylamine class. In the United States, naftifine 1% gel is indicated for the treatment of tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans,

and Epidermophyton floccosum. The purpose of this open-label exploratory study was to obtain preliminary data on the safety and efficacy of 2 weeks of twice-daily application of naftifine 1% topical gel in the treatment of TV. METHODS

PATIENT SELECTION This was a single-center, open-label study conducted in the United States from November 2007 to April 2008. To participate, patients had to be at least 18 years of age, have a clinical diagnosis of TV by microscopy/potassium hydroxide (KOH) by virtue of identification of yeast under the microscope, and a total clinical symptom severity (CSS) score for erythema, scaling, and pruritus ≥3 on a 0 to 9 scale, where 0 was absent and 9 was worst. Evaluation of hypopigmented and hyperpigmented patches, although commonly associated with TV, was not an objective of this clinical trial. Women were either postmenopausal for at least 1 year or had agreed to use an approved method of birth control throughout the study. Study exclusion criteria included known allergy or sensitivity to the ingredients in the study drug formulation or similar chemical structures; psoriasis; atopic dermatitis or any clinically significant systemic or dermatologic disorder

From Gold Skin Care Center, Tennessee Clinical Research Center, Nashville, TN;1 Merz Pharmaceuticals, LLC, Greensboro, NC2 Address for Correspondence: Michael H. Gold, MD, Tennessee Clinical Research Center, 2000 Richard Jones Road, Suite 223, Nashville, TN 37215 • E-mail: goldskin@goldskincare.com

SKINmed. 2011;9:283–286

283

September/October 2011

ORIGINAL CONTRIBUTION

that could interfere with the study results; uncontrolled diabetes mellitus; Parkinson’s disease; drug or alcohol abuse; a mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study; and use of any of the following medications: other topical antifungal treatments for TV, topical retinoids or corticosteroids within 4 weeks of screening, topical medication containing tar, selenium sulfide, zinc pyrithione, salicylic acid or sulfur within 2 weeks of screening; systemic use of corticosteroids, retinoids, erythromycin, tetracycline or their derivatives, trimethoprim/sulfamethoxazole, cytostatic or immunomodulating drugs, or other antimycotic drugs within 4 weeks of screening; inhaled/intranasal corticosteroids >800 μg/d 4 weeks prior to screening; or participation in any investigational drug or device study within 30 days of screening. Participants signed a voluntary informed consent and Health Insurance Portability and Accountability Act authorization prior to screening. The protocol and consent form were approved by Independent Investigational Review Board, Inc, and the study was conducted in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice.

DESIGN AND PROCEDURES The study consisted of a screening/baseline visit at week 0, twice-daily application of naftifine 1% gel for 14 days, and follow-up visits at week 2 (last treatment day), week 4 (14 days

post-treatment), and week 8 (42 days post-treatment) for efficacy and safety assessments. At visit 1, after screening and enrollment, baseline CSS score and mycology status were obtained. The patients were then given two 40-g tubes of naftifine gel 1% to apply to the affected area twice daily for 14 days. Mycology analysis was performed by scraping the epidermis of the periphery of the affected area with a sterile scalpel blade, placing the scrapings onto a microscope slide, adding 1 or 2 drops of 10% KOH solution onto the slide to dissolve epithelial tissue and keep the fungal hyphae intact, and visual inspection by light microscopy. CSS scoring was performed by the investigator by visual examination using the following 4-point scale: for erythema and scaling, 0 = absent, 1 = minimal involvement, 2 = distinctive presence, and 3 = marked/intense; and for pruritus, 0 = absent, 1 = at least occasionally present but not bothersome to patient, 2 = present and bothersome some of the time, and 3 = present and so bothersome that the patient thinks about it much of the time. Individual CSS scores were summed to obtain a total CSS score graded from 0 (absent) to 9 (worst). Each patient also rated his/her improvement from baseline at each follow-up visit using a 4-point scale: 0 = worse, 1 = no change, 2 = improved, 3 = much improved. Safety was assessed at each follow-up visit by the frequency and severity of adverse events. Due to the exploratory nature of the study and small sample size, data were analyzed with descriptive statistics.

Table. Combined Mean CCS and KOH Mycology Status for All Patients at Baseline and at Follow-Up Visits

BASELINE PATIENT

WEEK 2

WEEK 4

WEEK 8

AGE

SEX

YEAR

LOCATION

CSS

KOH

CSS

KOH

CSS

KOH

CSS

KOH

1999

Back, arms, shoulders

1990

Chest, arms, shoulders

–

1990

Trunk

1999

Neck

2004

Chest

–

2003

Back, chest, shoulders

2005

Back, flanks, shoulders

1990

Neck, chest, back, abdomen

1998

Chest

2005

Back, chest

Abbreviations: CSS, clinical symptom severity score for erythema, scaling, and pruritus combined (scale for total symptom score ranged from 0 to 9 where 0 was absent and 9 was worst); F, female; KOH, potassium hydroxide; M, male; week 2, end of treatment; week 4, 2 weeks after treatment; week 8, 6 weeks after treatment. SKINmed. 2011;9:283–286

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60%

are in agreement with those of a 1986 efficacy study with naftifine 1% solution.5 To our knowledge, no other published data are available on naftifine therapy in TV. By week 4, nine of ten (90%) patients had >2-grade improvement from baseline in CSS score. Mycological cure at week 8 (42 days post-treatment) was achieved by 50% of the patients. There were no treatmentrelated adverse events during the study, which is consistent with the well-established safety profile for naftifine 1% topical cream and gel.

50% 50%

Patients, %

40% 30% 20%

20% 10% 0%

10%

Week 2

Week 4

Week 8

Figure. Mycological cure rate at the end of treatment (week 2), 14 days post-treatment (week 4), and 6 weeks post-treatment (week 8). All patients were positive for potassium hydroxide at baseline.

RESULTS Ten patients (7 men and 3 women) with a median age of 38 years (range 29–53 years) were enrolled and all completed the study. The median time since diagnosis of TV was 9 years (range 2–18 years). Two weeks of naftifine 1% gel treatment lowered CSS scores from baseline in 9 of 10 patients at week 2, week 4, and week 8 (Table). The lower CSS scores corresponded with individual improvements ranging from 25% to 75% over baseline. Mean total CSS score for the 10 patients (all symptoms combined) was 4.7 at baseline, 3.2 at week 2, 2.6 at week 4, and 2.7 at week 8. The follow up scores at week 2, week 4, and week 8 corresponded to an improvement over baseline of 32%, 45%, and 43%, respectively, for combined clinical symptoms. The proportion of patients who achieved mycological cure (negative KOH) at each follow-up visit is illustrated in the Figure. All patients were KOH positive at baseline prior to treatment. At the end of the 2-week treatment regimen (week 2), 1 patient (10%) was KOH negative, 2 (20%) were KOH negative at week 4, and 5 (50%) achieved mycological cure at week 8. The patients rated their clinical symptoms to be “improved,” 1.7 grades over baseline at weeks 2 and 4, and 1.9 at week 8 (0- to 4-grade scale). Two treatment-emergent adverse events, low-grade fever and inflammation in the right hip, were reported in 2 patients during the study, but neither was considered related to naftifine treatment. DISCUSSION The efficacy responses observed in the present open-label study suggest that naftifine 1% gel applied twice daily for 14 days is an effective topical agent for the treatment of TV. These findings SKINmed. 2011;9:283–286

The 2-week treatment regimen for naftifine 1% gel is half the recommended duration for treatment of TV and other cutaneous fungal infections such as tinea pedis and tinea cruris.6 Higher cure rates for TV are generally associated with longer durations (>4 weeks) of daily antimycotic treatment.7 CSS scores and mycological cure rate after 2 weeks of treatment with naftifine 1% gel, however, were comparable with those reported for other topical therapies for TV including selenium sulfide and zinc pyrithione shampoos, topical terbinafine, ketoconazole, and clotrimazole formulations.8–10 The progressive increase in mycological cure rate from 10% at week 2 (end of treatment) to 50% at week 8 (6 weeks posttreatment) is characteristic of naftifine’s therapeutic actions.11 Extended fungicidal activity and a delay in maximal treatment response have been consistently observed in previous clinical studies of naftifine 1% gel and cream topical therapy for tinea pedis, tinea cruris, and tinea corporis.11–18 The basis for these effects appears to be pharmacokinetic. Human radiolabeled drug distribution studies have shown that with daily topical application, naftifine accumulates and forms a depot in the stratum corneum at the application site.11 This depot effect, in turn, functions to maintain a continuous exposure of dermatophyteinfected epithelial tissue to naftifine for several weeks after treatment, resulting in a residual increase in mycological and clinical cure rate over time.6,11 CONCLUSIONS The results of this open-label pilot study suggest that naftifine 1% gel may be efficacious as topical therapy for TV. Disclosures: Naftifine HCl 1% gel is marketed as Naftin gel by Merz Pharmaceuticals, LLC. This study was sponsored by Merz Pharmaceuticals, LLC, Greensboro, NC. Joy Willard, RN, BSN of Merz Pharmaceuticals, LLC, participated in study design and regulatory issues. Michael H. Gold, MD: clinical investigator with no conflicts of interest disclosed; Tancy Bridges, N-PC: research coordinator with no conflicts of interest disclosed; Edward Avakian, MA, PhD, Alan B. Fleischer Jr, MD, Stefan Plaum, MD, Eric J. Pappert, MD, and Bhushan Hardas, MD, MBA: employees of Merz Pharmaceuticals, LLC.

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REFERENCES 1

Bonifaz A, Gomez-Daza F, Paredes V, Ponce RM. TV, tinea nigra, white piedra, and black piedra. Clin Dermatol. 2010;28: 140–145.

Mendez-Tovar LJ. Pathogenesis of dermatophytosis and tinea versicolor. Clin Dermatol. 2010;28:185–189.

Roberts SO. Pityriasis versicolor. In: Verbow JL, ed. Superficial Fungal Infections: New Clinical Applications in Dermatology. Lancaster, England: MTP Press; 1986:47–72.

Mellen LA, Vallee J, Feldman SR, Fleischer AB, Jr. Treatment of pityriasis versicolor in the United States. J Dermatolog Treat. 2004;15:189–192.

Hira SK, Abraham MS, Mwinga A, Kamanga J, Schmidt C. Naftifine solution (1%) in the treatment of pityriasis versicolor in Zambia. Mycoses. 1986;29:378–381.

Merz Pharmaceuticals, LLC. Naftifine 1% Gel. Product Monograph, 2010.

Hu SW, Bigby M. Pityriasis versicolor: a systematic review of intervention. Arch Dermatol. 2010;146:1132–1139.

Roberts SO. Pityriasis versicolor: a clinical and mycological investigation. Br J Dermatol. 1969;81:315–326.

DiFonzo EM, Martini P, Mazzatenta C, Lotti L, Alvino S. Comparative efficacy and tolerability of ketomousse® (ketoconazole foam 1%) and ketoconazole cream 2% in the treatment of pityriasis versicolor; results of a perspective, multicenter, randomized study. Mycoses. 2008;51:532–535.

10 Savin R, Eisen D, Fradin MS, Lebwohl M. Tinea versicolor treated with terbinafine 1% solution. Int J Dermatol. 1999;38:863–865. 11 Monk JP, Brogden RN. Naftifine: a review of its antimicrobial activity and therapeutic use as in superficial dermatomycoses. Drugs. 1991;42:659–672. 12 Gupta AK, Saunder DN, Shear NH. Antifungal agents: an overview. Part II. Am Acad Dermatol. 1994;30:911–933. 13 Kagawa S. Comparative clinical trial of naftifine and clotrimazole in tinea pedum, tinea cruris, and tinea corporis. Mykosen. 1987;30(suppl 1):63–69. 14 Smith EB, Wiss K, Hanifin JM, et al. Comparison of once- and twice-daily naftifine cream regimens with twice-daily clotrimazole in the treatment of tinea pedis. J Am Acad Dermatol. 1990;22(6 pt 1):1116–1117. 15 Ablon G, Rosen T, Spedale J. Comparative efficacy of naftifine, oxiconazole, and terbinafine in short-term treatment of tinea pedis. Int J Dermatol. 1996;35:591–593. 16 Schachner L, Bagatell F, Whittington C, et al. The safety and efficacy of naftifine cream 1% in the treatment of tinea pedis. Adv Ther. 1990;7:148–152. 17 Jordon RE, Rapini RP, Rex IH Jr, et al. Once-daily naftifine cream 1% in the treatment of tinea cruris and tinea corporis. Int J Dermatol. 1990;29:441–442. 18 Gip L, Brundin G. A double-blind, two group multicentre study, comparing naftifine 1% cream with placebo cream in the treatment of tinea cruris. Mykosen. 1987;30(suppl 1):38–41.

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The Impact of Dermatology in Premier Medicine Journals Meenal K. Kheterpal, MD; Charles N. Ellis, MD ABSTRACT In the past 15 years, research in dermatology has significantly increased. Dermatology-related contributions in premier medical journals such as The New England Journal of Medicine (NEJM) and The Journal of the American Medical Association (JAMA) are the representation of our field in the medical world. To analyze this representation, incidence of dermatology-related contributions in NEJM and JAMA during 3 separate years (during a 15-year period) was calculated. (SKINmed. 2011;9:288–292)

he number of journals in dermatology published worldwide increased from 107 in 1993 to 161 in 2008.* The number of contributions published with a Medline major subject heading of “Skin Diseases” rose from 12,352 in 1993–1994 to 18,649 in 2007–2008,† a 51% increase that reflects advances within our field as well as a better understanding of skin diseases. We believe that reading relevant case reports and research contributions regarding skin conditions may be beneficial to other specialties of medicine, at all levels of medical training— whether it is learning the skin examination technique as a medical student, treating skin conditions as a primary care physician, or understanding dermatologic manifestations of various systemic diseases as a specialist; hence, we investigated whether the advances in dermatology are reaching other medical professionals. Dermatology has its foundation deeply rooted in internal medicine. General medicine journals, such as The New England Journal of Medicine (NEJM) and The Journal of the American Medical Association (JAMA) have wide readership, and contributions published in these journals have a broad interest and application in the medical world. Representation of dermatology research in widely read general medicine journals such as NEJM and JAMA is, therefore, one way to gauge the impact of our field on the world of medicine.

MATERIALS AND METHODS To assess whether the overall growth in dermatology literature is represented in two premier general medicine journals, we studied the incidence of dermatology-related contributions in NEJM and JAMA using a retrospective, cross-sectional study. Using a retrospective, cross-sectional analysis, we searched 3 years (June 1, 1993–May 31, 1994; June 1, 1999–May 31, 2000; and June 1, 2007–May 31, 2008) of publications in NEJM and JAMA during a span of 15 years. We did not include Editorials and Commentaries, Book Reviews, Correspondence, or any nonacademic contributions. For NEJM, full text was accessed online for academic publications. Original Articles, Review Articles (Reviews, Clinical Therapeutics, Clinical Practice), and Case Reports (Case Records of Massachusetts General Hospital and Clinical Problem Solving) were evaluated via a word stem search using NEJM’s online search engine. The word stems used for all searches were skin, derm, rash, ulcer, purpura, petechiae, urticaria, pemph, psor, and erythema. All contributions that were identified by the word stem search were categorized into Original Articles, Review Articles, and Case Report categories and graded as levels 1 (highest relevance to dermatology) through 3 (lowest relevance) (Table I). Images in the Images in Medicine section (including the Electronic Images) were graded as either related (level 1) or not related (level 3) to dermatology.

*Analysis conducted via Ulrich’s Periodicals Directory Online. † Searched via PubMed using “Skin Diseases” as Major Subject Heading and limits of time periods.

From the Department of Dermatology, University of Michigan Medical School and the Dermatology Service, Department of Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI Address for Correspondence: Charles N. Ellis, MD, Department of Dermatology, University of Michigan Medical School, 1500 East Medical Center Drive SPC 5314, Ann Arbor, MI 48109-5314 • E-mail: cellis@med.umich.edu

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In JAMA, the percentages of contributions related to dermatology were much lower than those in NEJM, particularly in the Original Article and Review Article categories, in which the representation of dermatology was negligible. The percentages of Case Reports rated as level 1 or 2 were higher in all 3 years, although still lower than those in NEJM (Table II). No trends over time could be assessed because of the small number of dermatologyfocused contributions.

Table I. Grading Scheme for Relevance to Dermatology

LEVEL DESCRIPTION 1

Dermatology is the sole focus of the contribution.

Dermatology is a key focus of the contribution with regard to diagnosis and management, although topics are included that are highly relevant to other medical specialties.

The contribution is mainly focused on topics relevant to other medical specialties; however, some aspect of dermatology is critical to either diagnosis or management, and those dermatologic aspects are covered in detail.

Dermatologic aspects are mentioned but the aspects are either not covered in detail or not key to diagnosis or management.

Not relevant to dermatology.

DISCUSSION

For purposes of presentation in the text, levels 3a–c are presented as level 3.

A similar evaluation was conducted for JAMA, using the same periods and JAMA’s online search engine for the years 2007–2008 and 1999–2000. Original Articles (Original Contributions, Preliminary Communications, Clinical Investigations), Review Articles (Reviews, Clinical Reviews, Consensus Statements), and Case Reports (Clinical Crossroads, Caring for the Critically Ill Patient, Grand Rounds, The Rational Clinical Exam) were searched using identical word stems as above. Due to lack of electronic full texts of the contributions, the search for the year 1993–1994 was conducted by examining printed copies of the journals. All contributions were graded by one of the authors (MK); contributions that were difficult to grade for level of relevance were reviewed by both authors to reach consensus. RESULTS In NEJM, not including contributions appearing in Images in Medicine, the overall incidence of level 1 contributions in NEJM was 2.7% in 1993–1994, 3.1% in 1999–2000, and 2.9% in 2007–2008 (not significant, P >.7; c2 for all comparisons). For the 3 years combined, 4% of the Original Articles, 8% of the Review Articles, and 8% of the Case Reports in NEJM were graded as level 1 or 2 in their relevance to dermatology. The percentage of level 1 Original Articles decreased from 3.3% in 1993–1994 to 1% in 2007–2008 (P=.09; Table III). Compared with results from 1993–1994, the percentages of level 1 Review Articles and level 1 Case Reports increased in 1999–2000 and 2007–2008. The representation of dermatology was highest in the Images in Medicine section during the 3 years (25% in 2007–2008, 19% in 1999–2000, and 33% in 1993–1994). SKINmed. 2011;9:288–292

We found that the overall percentage of level 1 dermatology contributions was stable during the selected time periods, with about a 3% incidence each year in NEJM, despite varying percentages in the individual categories of contributions. The stable representation of dermatology over time in NEJM despite growth of the dermatology literature worldwide may be due to various factors, the most likely being competition from other advancing medical fields for limited publication space. Even so, is dermatology over- or under-represented in NEJM? According to the American Medical Association’s Physician Characteristics and Distribution in the United States, 1.2% of physicians in 2005 as well as in 1993 were self-designated as dermatologists.1 Comparing the percentage of dermatology-focused contributions (about 3%) with the percentage of dermatologists in the United States (1.2%) suggests that dermatology is well represented in NEJM. The continued over-representation of dermatology in NEJM is a reflection of interest of the medical community in the diagnostic and management issues posed by dermatologic conditions. While we should have pride in this, Case Reports had one of the highest representations (8%) in the various categories of contributions graded as level 1 and 2 in their relevance to dermatology for the 3 selected years. Case Reports usually are of limited, if any, value as models of research efforts in dermatology. Research papers in dermatology are declining as a percentage of published contributions. A reader of NEJM during 2007–2008 was exposed to only two Original Articles and three Review Articles graded as level 1. The decreasing trend of published level 1 Original Articles over time (Table II) along with a low number of level 1 Review Articles is concerning. Does it represent a declining interest in dermatological clinical research? Or does it reflect decreasing quality of well-designed clinical trials with potential to make an impact on the world of medicine? The answer is unclear; however, increasing the number of well-designed clinical trials to study, understand, and manage dermatologic and systemic diseases is the most natural solution.

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Table II. Relevance of Contributions to Dermatology by Journal and Type of Contribution

THE NEW ENGLAND JOURNAL OF MEDICINE (NEJM) 2007–2008 (N = 335) CATEGORIES

ORIGINAL ARTICLES (N = 208)

REVIEW ARTICLES (N = 75)

CASE REPORTS (N = 52)

IMAGES IN MEDICINE (N = 100)

TOTAL (N = 335)

25 (25%)

10 (2.9%)

Level 1

2 (1%)

3 (4%)

5 (9.6%)

Level 2

7 (3.4%)

3 (4%)

2 (3.9%)

Level 3

199 (95.7%)

69 (92%)

45 (86.5%)

75 (75%)

313 (93.1%)

ORIGINAL ARTICLES (N = 206)

REVIEW ARTICLES (N = 70)

CASE REPORTS (N = 45)

IMAGES IN MEDICINE (N = 52)

TOTAL (N = 321)

10 (19.2%)

12 (3.6%)

1999–2000 (N = 321) CATEGORIES Level 1

2 (1.5%)

6 (10%)

0 (0%)

Level 2

2 (0.5%)

2 (1.4%)

1 (2.2%)

8 (3.1%)

Level 3

202 (98%)

62 (88.6%)

44 (97.8%)

42 (80.8%)

308 (96%)

ORIGINAL ARTICLES (N = 243)

REVIEW ARTICLES (N = 70)

CASE REPORTS (N = 64)

IMAGES IN MEDICINE (N = 52)

TOTAL (N = 377)

Level 1

8 (3.3%)

0 (0%)

2 (3.1%)

17 (32.7%)

10 (2.7%)

Level 2

4 (1.6%)

3 (4.3%)

3 (4.7%)

Level 3

231 (95%)

67 (95.7%)

59 (92.2%)

5 (0.9%)

1993–1994 (N = 377) CATEGORIES

10 (2.7%) 35 (67.3%)

357 (94.6%)

THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (JAMA) 2007–2008 (N = 215) ORIGINAL ARTICLES (N = 154)

REVIEW ARTICLES (N = 33)

CASE REPORTS (N = 28)

TOTAL (N = 215)

Level 1

0 (0%)

1 (3.5%)

1 (0.4%)

Level 2

0 (0%)

Level 3

154 (100%)

33 (100%)

27 (96.5%)

214 (99.6%)

ORIGINAL ARTICLES (N = 210)

REVIEW ARTICLES (N = 53)

CASE REPORTS (N = 34)

TOTAL (N = 297)

Level 1

0 (0%)

1 (2.9%)

1 (0.3%)

Level 2

1 (0.5%)

0 (0%)

1 (2.9%)

2 (0.7%)

Level 3

209 (99.5%)

53 (100%)

32 (95.2%)

294 (99%)

ORIGINAL ARTICLES (N = 222)

REVIEW ARTICLES (N = 17)

CASE REPORTS (N = 27)

TOTAL (N = 266)

Level 1

2 (0.9%)

0 (0%)

2 (0.8%)

Level 2

0 (0%)

1 (3.7%)

1 (0.4%)

Level 3

220 (99.1%)

17 (100%)

26 (96.3%)

263 (98.8%)

CATEGORIES

27 (2.6%) 152 (74.5%)

978 (94.7%)

JAMA, ALL 3 YEARS CATEGORIES

For definition of levels (relevance to dermatology), see Table I. For purposes of presentation, levels 3a–c are presented as level 3. Contributions appearing in Images in Medicine are not included in totals.

To ensure an uptrend in dermatology literature reaching the medical community, we need a continuous supply of physician-scientists. Yet, the number of physician-scientists has been decreasing in our country for the past 2 decades. From 1983 to 2003, the percentage of physicians engaged in research decreased from 4.6% to 1.8%.2 In dermatology, the growth rate of full-time academic dermatologists has been estimated to have decreased from 4.3% in 1994–1995 to 2.8% in 2001–2002.3 The decrease in original research is especially concerning because early exposure to well-designed research projects could be a means to stimulate interest in dermatology among research-oriented medical students.4–9 If exposure to dermatology research articles would bring our specialty to the attention of medical students, the declining representation of such contributions in NEJM and their virtual absence in JAMA could be leading research-oriented students to explore other fields. For the month of July 2010, 0.9% of JAMA recipients were dermatologists and 27% were family practice physicians. This was significantly higher compared with NEJM (0.6% and 3%, respectively; P<.0001; c2 test).10,11 This is surprising in view of the significantly lower representation of dermatology-related articles in JAMA. The low representation of dermatology in JAMA is important because of its wide circulation within the medical community, including the Student American Medical Association.

SKINmed. 2011;9:288–292

LIMITATIONS Our search of dermatology contributions in general medicine journals was not meant to be exhaustive. We limited ourselves to only two general medicine journals and we searched 3 selected years, which may not be representative of the 15-year span. Any suggestion of a trend was applicable only to NEJM, and we are unable to evaluate the effects, if any, of changes in editors or editorial policies. We did not search journals with predominantly international circulations that might demonstrate a different incidence of dermatology contributions. We focused on clinical medicine journals, because the information is more directly applicable to medical practice. Quantifying the incidence of dermatology-related articles in prominent basic science journals, such as Nature, is an unexamined aspect of the manifestation of dermatology in the medical literature. CONCLUSIONS Representation of our field in premier general medicine journals is a medium to enlighten practicing physicians, as well as residents and medical students, about the breadth and depth of dermatology research, clinical diagnosis, and management. The overall over-representation of dermatology in NEJM, which has been stable throughout the 3 years selected for analysis, reflects ongoing and undisputed interest of the medical community toward clinical issues and research advances in dermatology, and we hope this will continue in a similar direction in the future.

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Disclosures: Supported by the clinical funds of and alumni donations to the University of Michigan Department of Dermatology.

Wu JJ, Ramirez CC, Alonso CA, et al. Dermatology residency program characteristics that correlate with graduates selecting an academic dermatology career. Arch Dermatol. 2006;142: 845–850.

REFERENCES

Lynch PJ, Harrell ER. Factors in the choice of an academic career. Arch Dermatol. 1971;103:328.

Kirsner RS, Kerdel FA, Falanga V, Trent J, Eaglstein WH. The role of mandated research during dermatology residency. J Invest Dermatol. 1999;112:400–401.

Wu JJ. Current strategies to address the ongoing shortage of academic dermatologists. J Am Acad Dermatol. 2007; 56:1065–1066.

Smart DR. Physician Characteristics and Distribution in the US, 2006 Edition. Chicago, IL: AMA Press; 2006.

Ley TJ, Rosenberg LE. Build it, and they will come. JAMA. 2005;294:1343–1351.

Loo DS, Liu CL, Geller AC, Gilchrest BA. Academic dermatology manpower; issues of recruitment and retention. Arch Dermatol. 2007;143:341–347.

Kia KF, Gielczyk RA, Ellis CN. Academia is the life for me, I’m sure. Arch Dermatol. 2006;142:911–913.

10 Business Publication Circulation Statement for the 6 month period ended July 2010 [JAMA]. http://pubs.ama-assn.org/ misc/jamacirc.pdf. Accessed March 24, 2011.

Reck SJ, Stratman EJ, Vogel C, Mukesh BN. Assessment of residents’ loss of interest in academic careers and identification of correctable factors. Arch Dermatol. 2006;142:855–858.

11 Business Publication Circulation Statement for the 6 month period ended July 2010 [NEJM]. http://www.nejmadsales.org/ downloads/July2010BPA.pdf. Accessed March 24, 2011.

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REVIEW

Phototoxicity of Oriental Medicinal Plants: Measurement and Possible Applications Ki-Min Bark, PhD;1 Young-Woo Sun, MD;2 Tae-Jin Yoon, MD, PhD;3 Tae-Heung Kim, MD, PhD2 ABSTRACT Phototoxicity can be either harmful and induce adverse skin reactions or beneficial and be used therapeutically as in psoralen and UV-A or photodynamic therapy. Hundreds of medicinal plants are widely used in Asia and Western countries in oriental medicine, yet the phototoxicity of oriental medicinal plants is an understudied area. In this contribution, the authors discuss some methods used to measure the phototoxicity of plants and give an overview of the results of their previous and ongoing studies into the phototoxicity of medicinal plants. The authors argue that because they found that more than a quarter of oriental medicinal plants can be phototoxic, such research is helpful for dermatologists and that active phototoxic components extracted from oriental medicinal plants may be used therapeutically. (SKINmed. 2011;9:294–300)

hotochemical reactions are adverse skin reactions to the combined actions of chemical agents such as drugs, plants or chemicals (photosensitizers), and UV or visible radiation.1,2 Photochemical reactions may be phototoxic or photoallergic. Phototoxicity is a double-edged sword. On one hand, it induces sunburn, pigmentation, and melasma; in the long-term, it may also cause photoaging and skin cancers.3 On the other hand, it can be used therapeutically. For example, photochemotherapy using psoralen and UV-A (PUVA) and photodynamic therapy (PDT) are used widely in dermatology.4 Dermatologists tend to be familiar with phototoxic medications (psoralen, porphyrin, hydrochlorothiazide, quinolone antibiotics, phenothiazines), cosmetic ingredients (balsam of Peru, musk ambrette, hexachlorophene, tetrachlorosalicylanilide, fenticlor, benzophenone), and foods (lime, celery, St John’s wort).2,4,5 Even in Asia, however, most dermatologists know very little—if anything—about photosensitizers in oriental medicinal plants. Yet, oriental herbal medicine is used widely in China, Korea, Japan, and many other countries in the world. In Korea, oriental medicinal plants have been used for more than 2000 years, and their names and clinical applications are similar to those found in traditional Chinese or Japanese medicine. In most cases, oriental medicines come in the form of decoctions, a method of extraction by boiling of dried medicinal plants, or are eaten as vegetables or salads. Dermatologists occasionally observe photosensitivity or

aggravation of melasma that is suspected to have been induced by oriental medicines. They find it difficult to investigate such cases, however, because oriental medicines come in decocted mixtures of several medicinal plants, and information about the phototoxicity of those plants is scarce. Consequently, the phototoxic potential of oriental medicines has remained understudied.6 The main ingredient of phytophotodermatitis—a phototoxic dermatitis induced by photosensitizers in plants, vegetables, and fruits that are absorbed or have come into contact with the human body—is furocoumarin.5 Other components, however, are also involved.7,8 The main families of phototoxic plants include Chenopodiaceae, Compositae, Convolvulaceae, Cruciferae, Hypericaceae, Leguminosae, Moraceae, Ranunculaceae, Rosaceae, Rutaceae, and Umbeliferae.9 We studied the phototoxicity of drugs or oriental medicinal plants by Wood light screening, fluorescence spectroscopy, Candida albicans test, photohemolysis test, and in vivo mouse experiments. In our studies, we found that more than a quarter of oriental medicinal plants can be phototoxic in vitro, and we were able to confirm the phototoxicity in mice experiment in 5 medicinal plants tested.6,9,10 PHOTOTOXIC SKIN LESIONS In phototoxicity, once the photosensitizer is activated by light, it directly damages the subcellular target. The damage is manifested in sunburn-like skin lesions such as tender erythema or edema

From the Department of Chemical Education, Gyeongsang National University, Jinju, Kyungnam, Korea;1 White-Line Skin Clinic & Research Center, Changwon, Kyungnam, Korea;2 and the Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, Kyungnam, Korea3 Address for Correspondence: Tae-Heung Kim, MD, PhD, White-Line Skin Clinic & Research Center, Fl-5. Handok-B/D, 15-2 Sangnam-Dong, Seongsan-Ku, Changwon, Kyungnam 641-832, Korea • E-mail: derkim@paran.com

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Acorus gramineus, root, 1/2 Panax ginseng, root, 1/1 Platycodon grandiflorum, root, 1/20 Atractylodes japonica, root, 1/10 Xanthium strumarium, leaf, 1/1 Dioscorea batatas, root, 1/1 Anemarrhena asphodeloides, root, 1/10 Polygonatum sibiricum, root, 1/1 Cocculus trilobus, stem, 1/1 Ficus carica, leaf, 1/5 Chelidonium majus, stem, 1/1 C majus, root, 1/2 Pulsatilla koreana, root, 1/5 Agrimonia pilosa, leaf, 1/1 Zanthoxylum schinifolium, seed oil, 1/2 Angelica gigas, stem, 1/1 A gigas, leaf, 1/1 A gigas, root, 1/1 Cnidium offocinale, root, 1/1 Ledebouriella seseloides, root, 1/10 0

% Hemolysis values (Mean±SEM) Figure 1. Results of the photohemolysis test for the extracts of medicinal plants. The fractional number indicates further dilution from original solutions. The experiments were repeated 3 times and the mean values were used as a final data (mean ± standard error of the mean [SEM]). Reprinted with permission from Bark et al.6

and bullae after exposure to light (particularly UV). Phototoxicity can occur if there are sufficient amounts of physical and chemical factors. It is more common and different from photoallergy, which is mediated by a type IV delayed-type hypersensitivity reaction in which a photosensitizer becomes a complete antigen by binding to a carrier protein after activation by light. When photosensitivity due to an exogenous factor persists for a longer period, it can progress to a more chronic type of photosensitivity, such as chronic actinic dermatitis.1–3,5 In our clinics, we encountered many patients showing features of photosensitivity mediated by exogenous factors, and, in some of those cases, oriental medicinal plants were suspected as the cause. One of these patients took Zanthoxylum schinifolium seed oil, which was proved by oral provocation test revealing markedly decreased minimal erythemal dose to UV-A. It was that experience which led us to investigate the phototoxicity of oriental medicinal plants.11 Phototoxicity also affects some diseases that are sensitive to UV, such as melasma. If melasma patients take photosensitizers orally or apply them on the skin, they can easily aggravate their melasma, even SKINmed. 2011;9:294–300

if they apply quality sunscreen diligently. Melasma is an important issue for Asian women, as it is difficult to control completely even through combination treatment with the Kligman formula, intense pulsed light or laser treatments, chemical peels with glycolic or lactic acid, and other supportive treatments.12,13 In patients with severe melasma, oriental medicinal herbs or plant extracts that are phototoxic can easily aggravate melasma, and information and recommendations may prevent risks of aggravation. In view of studies of melasma that suggest the importance of the dermal milieu and stem cell factors,14 as well as the possible importance of visual light,15 it is possible that phototoxicity may play more important roles as it is induced by longer-wavelength UV-A or visual light that can penetrate deeper.6,10 Finally, long-term exposure to phototoxicity may increase chronic unwanted effects of UV such as photoaging and photocarcinogenesis. Photoaging is an important cosmetic problem in middle-aged to older populations. Phototoxicity may increase photocarcinogenesis by combined actions of mutation, sunburn apoptosis, and immune suppression.6,10

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MEASUREMENT OF PHOTOTOXICITY Most photosensitizers are photochemically unstable. When they receive physical energy sufficient to induce structural change, they usually show significant fluorescence. In the subcellular level, it can damage the cell wall, nuclei, or other subcellular targets.3,5,16 In in vivo experiments, they induced sunburn erythema and edema, induction of sunburn cells, and immune suppression.6,10 Many experimental models have measured phototoxicity.

FLUORESCENCE SCREENED BY WOOD’S LIGHT EXAMINATION AND FLUORESCENCE SPECTROSCOPY Because photosensitizers are photochemically unstable,4,5,16 they emit fluorescence. Dermatologists can perform a Wood’s light examination to screen oriental medicinal plants for fluorescence. In the case of extracted solution or crushed live oriental medicinal plants, those materials can be screened by definite change of color or evident fluorescence in Wood’s light.9 Another approach to measuring fluorescence is to measure the absorption and fluorescence spectra. Chemicals have their own absorption spectra, and when those chemicals are hit by the same wavelengths in the absorption spectra, photosensitizers frequently emit strong fluorescence. This method proved efficient in screening dried oriental medicinal plants for phototoxicity.9

CANDIDA ALBICANS TEST AND OTHER MICROORGANISMS

Groups

Phototoxicity affects many different microorganisms such as C albicans, Salmonella typhimurium, or Pseudomonas or cells such as fibroblasts. Consequently, such microorganisms or cells can be used to measure phototoxicity in vitro.17 Two sets of culture plates containing those microorganisms or cells and photosensitizer are prepared, and light (usually UV-A) is irradiated to

one of them. In light-irradiated plates, cellular destruction by phototoxicity occurs, which decreases the number of microorganisms or cells.17 The Candida albicans test is an inexpensive, efficient, and easy method to measure photosensitizers that target cellular nuclei. A disadvantage is that it frequently shows false-negative results to photosensitizers that target subcellular structures other than cellular nuclei. For example, quinacrine, nalidixic acid, ofloxacin, mequitazine, and chlorpromazine are positive to the Candida albicans test, but sulfonamides or thiazide diuretics show negative results.17 Among the screening methods using cells, photohemolysis is a useful and easy method to screen photosensitizers. Since a red blood cell (RBC) does not have a nucleus, it is sensitive to a photosensitizer that targets the cellular membrane. In photohemolysis, most photosensitizers do not induce spontaneous hemolysis of RBC. It facilitates the experiment, but this is difficult to follow.17 The MTT assay is another useful method to measure phototoxicity. The MTT assay using cultured fibroblast is used widely in various experiments to measure apoptosis, and it can be useful to measure phototoxicity that targets cellular mitochondria. It is suitable for large samples because it can use 96 well enzymelinked immunosorbent assay plates. The disadvantage of the MTT assay is that repeated and detailed pilot experiments are needed for every sample to prevent spontaneous apoptosis.18

LIPID PEROXIDATION When unsaturated fatty acid is exposed to phototoxic reaction, it undergoes oxidation by reactive oxygen species and can be

Ledebouriella seseloides + UV-A Xanthium strumarium + UV-A Zanthoxylum schinifolium + UV-A Chelidonium majus + UV-A Atractylodes japonica + UV-A UV-A only No Treatment 0

Back Skin Swelling (0.01 mm) Figure 2. Dorsal skin swellings in mice irradiated with 50 J/cm2 of UV-A. Mice groups treated with medicinal plants showed increased swelling of dorsal skin compared with mice that received only UV-A. *P<.05 compared with UV-A–only control. Reprinted with permission from Bark et al.6 SKINmed. 2011;9:294–300

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September/October 2011 120 100

REVIEW PHOTOTOXICITY OF ORIENTAL MEDICINAL PLANTS

MTT Assay

100

FLUORESCENCE SPECTROSCOPIC STUDY OF ORIENTAL MEDICINAL PLANTS

71.5

80 60 40 20 0

Control

UV-control

No UV-A

22.4

20.1

Psoralen 0.01%

PTS-A 0.01%

We screened 62 live oriental medicinal plants for their potential phototoxicity by Wood’s light examination. We crushed live plants and observed them with Wood’s light. If there was evident fluorescence or change of color, we selected them for fluorescence spectroscopy.

13.6 PTS-B 0.001%

Seventeen oriental medicinal plants out of the 62 tested showed fluorescence or change of color in the Wood’s light examination. All of them showed significant absorption peaks in the UV range and showed strong fluorescence when they were excited by the corresponding wavelengths of the absorption spectra in that study (Table).9

UV-A 30 J/cm2

Figure 3. MTT assay result of the extracted photosensitizing materials from two different medicinal plants. Fibroblasts were irradiated with 30 J/cm2 of UV-A1 and two compounds show strong phototoxicity that is stronger than 8-methoxy psoralen. Abbreviation: PTS, photosensitizer.

PHOTOHEMOLYSIS AND CANDIDA ALBICANS TEST

measured by spectrophotometer. Linoleic acid, cholesterol, or squalene can be used for that purpose.17,18

IN VIVO EXPERIMENT TO MEASURE PHOTOTOXICITY In vivo experiments for photoxicity include the measurement of skin swellings of the ears, tail, or back skin; colorimetric or visual scoring of erythema in hairless mice; evaluation of sunburn apoptosis cells by hematoxylin and eosin stain (H&E) stain or terminal deoxynucleotidyl transferase dUTP nick end labeling assay; depletion of Langerhans cell count in epidermal sheet; and suppression of local immune response measured by contact hypersensitivity (CHS).6,10,17 Sunburn includes sunburn edema and formation of dyskeratotic sunburn cell in the epidermis. Dorsal skin swelling in mice is a good in vivo method to measure the inflammation induced by sunburn. Sunburn cells are keratinocytes, undergoing apoptosis when the skin is exposed to UV irradiation.10,17 Langerhans cells are dendritic cells present in the epidermis. When UV-B is irradiated, the number of these cells decrease and a loss of dendrite is observed. Langerhans cells play important roles in antigen presentation and in the suppression of immune response by UV irradiation. When mice were irradiated with photosensitizer and UV-A, the number of Langerhans cells significantly decreased.10,17 The observation of CHS, which is a model of allergic contact dermatitis using haptens, is a popular method for evaluating UV-induced suppression of cell-mediated immunity in vivo. The local suppression of CHS is mainly concerned with antigen-presenting cells,19 and phototoxic reaction suppressed local CHS.6,10 SKINmed. 2011;9:294–300

We examined the phototoxicity in vitro by using the photohemolysis and Candida albicans tests. In the photohemolysis test, 16 of 17 plants showed positive results. Cocculus trilobus was negative in the photohemolysis test (Table and Figure 1) but showed a definite fluorescence response. The results suggested that C trilobus may not be phototoxic or that it may have a different mechanism of phototoxicity involving subcellular targets other than DNA or cell membrane.6,17 As most medical plants that had strong fluorescence showed positive in vitro phototoxicity in the photohemolysis test except C trilobus, phototoxicity screening by measuring absorption and fluorescent emission spectra may be better because it is more convenient, does not need blood experiment, and covers various subcellular targets. In the Candida albicans test, 5 medicinal plants showed significant phototoxicity (Table). According to the results, the 16 species of medicinal plants showed significant photohemolysis indicating that the tested medicines show phototoxicity targeting the cellular membrane. Because a marked suppression of growth of fungi was observed for 5 medicinal plants in the Candida albicans test, it appears that these plants also target the cellular nuclei.6,18 These data suggest that more than a quarter of oriental medicinal plants can be phototoxic. As a typical dose of medicine given to a patient includes a mixture of 5 to 10 medicinal herbs, many oriental medicines will probably raise the possibilities of phototoxicity.6

IN VIVO EXPERIMENT We performed an in vivo mouse experiment for 5 medicinal plants that showed phototoxicity in the photohemolysis and Candida albicans test. Models included in the in vivo experiment were swellings of back skin, evaluation of sunburn cells by H&E

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stain, depletion of Langerhans cell count in the epidermal sheet, and suppression of local immune response measured by CHS to dinitro-fluoro-benzene.6 When the mice received 50 J/cm2 UV-A, all the treated groups showed significantly increased dorsal skin swellings compared with the UV-A–only irradiated group (Figure 2). Compared with the UV-A–only irradiated group, a significant increase in sunburn cells showing dark and crushing nucleus and eosinophilic cytoplasm were observed in the treated groups.6 In the Langerhans cell study, the treated groups showed a decreased number of Langerhans cells, and the number of dendrites and the ATPase activity of Langerhans cells were also markedly decreased by UV-A irradiation compared with the UV-A–only irradiated group (50 J/cm2). Local CHS decreased significantly in all the UV-A irradiated groups. The medicine-treated groups showed significant decrease of local CHS, however, compared with the UV-A–only group.6 SIGNIFICANCE OF PHOTOTOXICITY FROM A CLINICAL PERSPECTIVE For clinical dermatologists, researching the phototoxicity of oriental medicines can be fruitful on two accounts. Not only can

it enlighten dermatologists regarding the adverse side effects of herbal medicines in terms of their phototoxicity, but it can also indicate positive ways in which phototoxic reactions can be used in some treatments.3,6 On the negative side, the phototoxicity of oriental medicinal plants may induce sunburn, pigmentation, and melasma, and may also cause photoaging and skin cancers in the long-term.4 Because a doctor’s precise recommendation is important for patients to prevent not only the aggravation of disease but also legal conflict for doctors, information about oriental medicinal plants is important. A fluorescence spectroscopic study using 162 available dried oriental medicinal plants will give more detailed information (TH Kim, EM Gil, HB Liu, et al. Ultraviolet/visible absorption and fluorescence emission spectra of extracts from oriental medicinal plants using ethanol, in preparation). Alisma orientale (␸ᬡ), Artemisia asiatica (ᵩḶ ᫼᜜ ⍠), Angelica dahurica (ᨂ≒), Angelica tenuissimum (ᓍᩦ), Amomum costatum (⍠ᓿ), Belamcanda chinensis (ᬒᎶ), Caesalpinia sappan L. (ᰦᤴ), Cimicifuga simplex (ᶁ᳄ᢷ), Citrus unshiu (⍀ⓕ), Chrysanthemum morifolium (ᖐ◧ Ꮮᖐ), Ephedra sinica (ᢷ☠), Epimedium koreanum (᭐≃ᕚḶ⍠ Ὺᶡᔋ), Eugenia caryophyllata (ⅉ╍), Forsythia koreana Nakai (Ḗᕎ), Gardenia jasminoides (⏌⁯), Gleditsia

Table. Result of Photohemolysis and Candida albicans Test in 17 Medicinal Plants That Showed Significant Fluorescence

FAMILY

SPECIES NAME

ORIENTAL NAME

PHOTOHEMOLYSIS

CANDIDA ALBICANS

Araceae

Acorus gramineus

᮰⋤⒰

(+)

–

Araliaceae

Panax ginseng

‵᭖

(+)

–

Campanulaceae

Platycodon grandiflorum

ᙊᑿ

(+)

–

Compositae

Atractylodes japonica

⋥⎦

(+)

Xanthium strumarium

⋥†⁯

(+)

–

Dioscoreaceae

Dioscorea batatas

ᭁᶉ

(+)

–

Haemodoraceae

Anemarrhena asphodeloides

≉ᤧ

(+)

–

Liliaceae

Polygonatum sibiricum Red

☠Ⅿ

(+)

–

Menispermaceae

Cocculus trilobus

ᤴ᧧ᘕ

–

Moraceae

Ficus carica

ᥗ◧ᓿ

(+)

Papaveraceae

Chelidonium majus var. asiaticum

ᨂᖛ⋮

(+)

Ranuculaceae

Pulsatilla koreana

ᨂ᝽Ầ

(+)

–

Rosaceae

Agrimonia pilosa

἖ᴨ⍠

(+)

–

Rutaceae

Zanthoxylum schinifolium

ᭁ⍓

(+)

Umbelliferae

Angelica gigas

ᜍᖻ

(+)

Ledebouriella seseloides

᧧ⓐ

(+)

–

Cnidium officinale

⌍ᖢ

(+)

–

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japonica (ⱖᎯ⁫ ⱖ▀), Glycyrrhiza glabra (Ꮮ⍠; licorice), Loranthus parasiticus (᭫ᘒᮄ), Morus alba L. (᭫ᨂⓕ), Myristica fragrans (῅᝹㬆), Poncirus trifoliata (≄ᗕ ᕬᗕ), Psoralea corylifolia L. (ᩑᓫ≏ ①ᒼ≍), Rheum coreanum (↤ᯔ᜔☠), Scutellaria baicalensis Georgi (☠ᗵ), Schisandra chinensis (ṷᥳ ⁯), Schizonepeta tenuifolia (▐ᐔ), Thuja orientalis (⏀ᨀ), Uncaria sinensis (⇁ᖇដ) showed significantly strong fluorescence and could be regarded as possible photosensitizers (precise data are not shown here). The phototoxic reaction induced by medicinal plants can also be harnessed as a positive side effect. For example, photochemotherapy using PUVA and PDT are widely used in dermatology.3 In Korea, oriental therapists use Xanthium strumarium and Atractylodes japonica in the treatment of vitiligo that exhibit strong phototoxicity. This example shows that the phototoxic reaction induced by plants can constitute some of the therapeutic value of oriental medicine. Another example is PUVA therapy. Psoralen, which is used in PUVA therapy, is widely distributed in medicinal plants, and some of the oriental medicinal herbs contain a large amount of furocoumarin (psoralen).5,8,20 Other photosensitizers can also exhibit the therapeutic effect of phototoxicity. PDT is yet another model of treatment that uses phototoxic reaction. In PDT, porphyrin is the main photosensitizer and several additional photosensitizers are under investigation. Porphyrin has a major absorption peak at UV-A to blue light range and a minor peak at longer-wavelength visual light.3,20 When we measured oriental medicinal plants with fluorescence spectroscopy, we obtained very interesting findings. Some of the plants showed emission spectra in the red light range, such as porphyrin,9 and others at the infrared range (TH Kim et al, in preparation). We personally suggest that screening of strong fluorescence and emission spectra enables us to find newer therapeutic phototoxic materials.

epoxycollinin, estragole, N-methylschinifoline, schinifoline, schinilenol, schininallyol, and schinindiol.21 Taking the chemical components of oriental medicines into consideration, phototoxicity can be induced by similar chemicals or by different chemicals. Somewhat prospective results will be obtained if the extracted samples are separated into several ingredients and the phototoxicity of these fractions are examined (study in progress). When we measured the phototoxicity of purified ingredients from two oriental medicinal plants, they showed stronger phototoxicity compared with 8-methoxy psoralen (Figure 3). The difference between these materials is their fluorescence emission spectra, one in the red light and the other in the infrared range. CONCLUSIONS In previous studies, we showed that more than a quarter of oriental medicinal plants can be phototoxic in vitro or in vivo and that strong fluorescence measured by absorption and fluorescence spectra can be an easier way to screen for phototoxicity. Phototoxicity can not only have a negative side effect but can also constitute a therapeutic effect of oriental medicines. Photosensitizers present in oriental medicinal plants may be responsible for the therapeutic effect of some of these drugs. Further studies regarding the phototoxicity of active components extracted from oriental medicinal plants in progress may be useful to find newer therapeutic materials. Finally, since the experiments in previous studies were limited to the live herbs obtainable from the Medicinal Plant Institute, further experiments for evaluating phototoxic potentials of dried plants used in oriental medicinal shops, which are extracted by ethanol or hot water, will also give more informative data. Acknowledgments: Professor Marie J. Guilloteaux, Department of English Education, Gyeongsang National University, provided many suggestions and copyedited the manuscript. REFERENCES

Four medicinal plants, Agrimonia pilosa, Cnidium officinale, Xanthium strumarium, and C trilobus showed absorption bands at the UV-A or blue region of visible light, and a strong fluorescence emission at red light in our previous study.3 Oral intake of these plants and exposure to sunlight filtered with window glass for 30 minutes was effective for the supportive treatments of atopic dermatitis and keloid (TH Kim’s personal experience).

Harber LC, Baer RL. Pathogenic mechanisms of drug-induced photosensitivity. J Invest Dermatol. 1972;58:327–342.

Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol. 1995;33:551–573.

Hönigsmann H, Szeimies R-M, Knober R, et al. Photochemotherapy and photodynamic therapy. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003;2477–2493.

At the present time in Korea, research is actively progressing to analyze the components of oriental medicinal herbs. For example, the investigated components of Zanthoxylum schinifolium are Asarinin, 3,7,8-trimethoxy-2H-1-benzopyran-2one, acetoxyauraptene, acetoxycollinin, a-sanshool, bergaptan,

Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003:1298–1307.

Harber LC, Bickers DR. Photosensitivity Diseases. 2nd ed. Toronto, Canada: BC Decker Inc; 1989:160–202.

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Bark KM, Heo EP, Han KD, et al. Evaluation of the phototoxic potential of plants used in oriental medicine. J Ethnopharmacol. 2010;127:11–18.

14 Kang HY, Hwang JS, Lee JY, et al. The dermal stem cell factor and c-kit are overexpressed in melasma. Br J Dermatol. 2006;154:1094–1099.

Oodyke DL. Monographs on fragrance raw materials. Food Cosmet Toxicol. 1974;12:385–405.

Carlsen K, Weismann K. Phytophotodermatitis in 19 children admitted to hospital and their differential diagnoses: child abuse and herpes simplex virus infection. J Am Acad Dermatol. 2007;57:s88–s91.

15 Verallo-Rowell VM, Pua JM, Bautista D. Visible light photopatch testing of common photocontactants in female filipino adults with and without melasma: a cross-sectional study. J Drugs Dermatol. 2008;7:149–156.

16 Sasaki M, Matsuo I, Fujita H. Hydrophobicity-dependent fluorescence properties and intracellular fluorospectroscopic behavior of phototoxic drugs. Photochem Photobiol. 1991;53:385–389.

Han KD, Bark KM, Lee JK, et al. Evaluation of the phototoxic potential of some medicinal plants for Korean traditional medicine I. Kor J Invest Dermatol. 1999;6:221–226.

17 Kang JS, Kim TH. Meaning and application of phototoxic reaction. Kor J Invest Dermatol. 2001;8:129–136.

10 Sun YW, Heo EP, Cho YH, et al. Pefloxacin and ciprofloxacin increase UVA-induced edema and immune suppression. Photodermatol Photoimmunol Photomed. 2001;17:172–177.

18 Agrawal N, Ray RS, Farooq M, et al. Photosensitizing potential of ciprofloxacin at ambient level of UV radiation. Photochem Photobiol. 2007;83:1226–1236.

11 Lee SH, Yoon TJ, Kim TH. Clinical review of the photosensitivity patients. Kor J Dermatol. 2001;39:972–978.

19 Gil EM, Kim TH. UV-induced immune suppression and sunscreen. Photodermatol Photoimmunol Photomed. 2000;16:101–110.

12 Rendon M, Berneburg M, Arellano I, et al. Treatment of melasma. J Am Acad Dermatol. 2006;54:s272–s281.

20 Davis IC, Stiller MJ, Shupack JL. Pharmacology of therapeutic agents in photomedicine. In: Lim HW and Soter NA, eds. Clinical Photomedicine. New York, NY: Dekkar; 1993:59–74.

13 Jeong SY, Shin JB, Yeo UC, et al. Low-fluence Q-switched neodymium-doped yttrium aluminum garnet laser for melasma with pre- or post-treatment triple combination cream. Dermatol Surg. 2010;36:909–918.

21 Natural Products Research Institute, Seoul National University. Treatise on Asian Herbal Medicines. Seoul, Korea: Haksulpyeonsukwan; 2003:1–216.

SELF-TEST REVIEW QUESTIONS W. Clark Lambert, MD, PhD, Section Editor Instructions: For each of the following numbered questions, choose the appropriate lettered response(s). Unless directed to choose only one lettered response, all, some, or none of the responses may be correct.

Decoctions are: (Choose the single best response.) a. distilled from residues of dried medicinal plants. b. extracted by boiling of dried medicinal plants. c. precipitated from acidic residues of dried medicinal plants. d. precipitated from basic residues of dried medicinal plants. e. separated from residues of dried medicinal plants using organic solvents. The main ingredient(s) of photosensitizers that induce phytophotodermatitis is (are): (Choose the single best response.) a. furocoumarin. b. glucoseaminoglycans. c. histones. d. membrane phospholipids. e. unsaturated fatty acids. Dermatologists can best perform an examination using which of the following instruments/methods to screen oriental medicinal plants for fluorescence? (Choose the single best response.) a. Dermatoscope b. Dioscopy c. Light microscope

d. Magnifying glass e. Wood’s lamp 4)

Which of the following may be useful to screen for photoreactive medicinal substances? (Answer as many as apply.) a. Candida albicans test b. MTT assay c. Hubble telescope d. Photohemolysis e. Spectrophotometer

In photodynamic therapy (PDT), the main photosensitizer(s) is (are): (Choose the single best response.) a. furocoumarin. b. glycoseaminoglycans. c. membrane phospholipids. d. porphyrin. e. unsaturated fatty acids.

ANSWERS TO SELF-TEST REVIEW QUESTIONS: 1) b; 2) a; 3) e; 4) a, b, d, e; 5) d

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

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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 PelletFilled 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

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September/October 2011

Volume 9 • Issue 5

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Noninsulin-Dependent, Type II Diabetes Mellitus–Related Dermatoses: Part II Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Megha Gupta, MBBS; Sambit N. Bhattacharya, MD; Prashant Verma, MD

Cutaneous complications of noninsulin-dependent, type II diabetes mellitus are reviewed, including diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic bullae (bullosis diabeticorum), certain acquired perforating dermatoses, diabetic thick skin, scleredema adultorum, Dupuytren’s contractures, certain xanthomas, carotenoderma, rubeosis faciei, and acanthosis nigricans.

hile the fascinating and precise account of necrobiosis lipoidica (NL) and granuloma annulare, noninsulin-dependent, diabetes mellitus (DM)-related dermatoses, formed the contents of Part I,1 the brief review of the other dermatoses is the subject of the current contribution. DIABETIC DERMOPATHY

HISTORY In 1964, Melin observed that his chief, Nils Tornblom, described characteristic, atrophic, circumscribed brown patches on the front and sides of the lower portion of the legs in diabetic patients.2 The term diabetic dermopathy (DD), however, was coined by Binkley in 1965. He believed that these lesions were etiologically related to diabetic microangiopathy and were as diagnostic as the associated nephropathy, neuropathy, and retinopathy. It was further labeled pigmented pretibial patches (PPP), shin spots, and spotted leg sydrome.3 Bauer and Levan believed that DD and NL were variants of the same cutaneous disorder, which they termed diabetic dermangiopathy.4

EPIDEMIOLOGY DD is the most common cutaneous manifestation in diabetics. The male to female ratio is 2:1.5,6 The frequency and specificity of these lesions in diabetics depend on the number of pretibial plaques, which is accepted as indicating dermopathy.7,8

CLINICAL APPEARANCE The primary lesion of DD, preceding the pigmented atrophic patches of PPP, has not been clearly defined.9 Lesions may be either discrete or grouped, and round to oval. Shin spots appear as multiple, bilateral, asymmetrical, annular, or irregular red papules/plaques on the extensor surface of the lower leg10 (Figure). The borders are well-defined and sloped and evolve into atrophic, thin, hyperpigmented macules. The lesions disappear in one or more years, while new lesions may develop.11 Lesions are asymptomatic and often overlooked by the patient and physician alike.12 Rarely, a bullous stage may exist.13

PATHOPHYSIOLOGY The genesis of shin spots is unclear. Similar lesions develop in patients who had preexisting DD after experimental thermal trauma.5 Patients who develop the lesions are typically elderly or young patients with diabetes of long duration.14 The frequency of changes over bony prominences, and reports linking dermatosis to peripheral neuropathy suggest that trauma may be a modifying/triggering factor but blunt trauma does not elicit lesions.2,10

HISTOPATHOLOGY The epidermis in patients with DD is thin, with thickened vessels in the papillary dermis showing increased periodic acidSchiff–positive diastase-resistant material. There are often mild

From the DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India; Skin Institute, School of Dermatology, Greater Kailash New Delhi, India; Department of Dermatology and STD, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 India • E-mail: drsehgal@ndf.vsnl.net.in

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CORE CURRICULUM erythema. It is largely painless and nonpruritic21 and usually resolves after 3 to 6 weeks.

PATHOPHYSIOLOGY Mechanical trauma or UV radiation in conjunction with nephropathy may be a cofactor in the evolution of diabetic lesions. There has been speculation about the role of altered carbohydrate, calcium, or magnesium metabolism, or vascular insufficiency, microangiopathy, or reaction imbalance secondary to renal failure in many patients with diabetic bullae.13,22–24

EPIDEMIOLOGY

Figure. Diabetic dermopathy: multiple discrete/grouped, round to oval shin plaques.

perivascular lympho-histiocytic infiltrates and scattered hemosiderin deposits15 following extravasation of red blood cells from the vessel wall. Acute lesions, however, show edema of the epidermis and papillary dermis.12 The incidence of DD increases not only with each of the three complications (retinopathy, nephropathy, and neuropathy), but also in relation to the number of complications in each patient.14 As these lesions precede abnormal glucose metabolism, their presence in nondiabetics should alert a physician to possible early diabetes.5 DD does not, however, correlate with obesity or hypertension in patients with DM.16 The differential diagnosis includes NL, stasis dermatitis, pigmented purpuric dermatoses, and post-traumatic scarring.

TREATMENT The lesions associated with DD are largely asymptomatic. They do not respond to any treatment nor to control of hyperglycemia.17 DIABETIC BULLAE

HISTORY In 1963, Rocca and Pereya18 described bullous lesions of the feet that developed without trauma in 14 diabetics. The name bullosis diabeticorum was coined by Cantwell and Marts in 1967.19 Approximately 0.5% of diabetics develop diabetic bullae.9 Although not common, it is considered a clinically distinct diabetic marker.

CLINICAL APPEARANCE Spontaneous and sudden appearance of bullae on the hand and forearm is characteristic. The bullae are several millimeters to several centimeters in size and may be recurrent. Typically, the blister starts as a tense lesion, but, as it enlarges, it becomes flaccid.20 The blister contains clear sterile fluid and is not surrounded by SKINmed. 2011;9:302–308

Diabetic bullae have only been reported in adults aged 40 to 77 years. They are commonly seen in men22 with longstanding,2 established peripheral neuropathy affecting the extremities.5 Spontaneous nonscarring bullae containing clear sterile fluid are the most common clinical features.

HISTOPATHOLOGY These lesions may show intraepidermal cleavage without acantholysis,25 and may be hemorrhagic. Subepidermal cleavage without acantholysis may also be seen. The third type, as reported in this case, consisted of multiple, tender, nonscarring blisters on sun-exposed and deeply tanned skin of the feet, legs, and arms. Immunofluoresence and porphyrin studies are negative and the cleavage plane is seen at the level of the lamina lucida.24 This bullous disease runs a benign course without involvement of large body surface areas. Secondary infection may be the only complication, which may be managed with appropriate antibiotics.16 Separation between the cell membrane and basal lamina, preceded by almost complete disappearance of anchoring filaments and hemidesmosomes, has been demonstrated on electron microscopy.18 Differential diagnosis includes bullous pemphigoid, epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous impetigo, bullous erythema multiforme and blisters from barbiturate, carbon monoxide poisoning, and insect bite reaction. Bullosis diabeticorum remains a diagnosis of exclusion with negative immunofluorescence studies, porphyrin levels, and cultures.2,10

TREATMENT Treatment is conservative and based on symptoms using aluminum subacetate or saline compresses.26 ACQUIRED PERFORATING DERMATOSIS

HISTORY Cohen and Auerbach described the acquired reactive perforating collagenosis associated with severe DM and chronic renal

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failure.27 The term acquired perforating dermatosis (APD) was proposed by Rapini and colleagues in 1989.28

CLINICAL APPEARANCE Cutaneous perforating disorders, characterized by the transepidermal elimination of altered components of the dermis, have been divided into 4 classic types5: (1) elastosis perforans serpiginosa, (2) reactive perforating collagenosis, (3) Kyrle’s disease, and (4) perforating folliculitis.10 The degenerated altered dermal material consists mainly of collagen and elastic fibers.16 APDs are seen in patients with chronic renal failure and DM with or without hemodialysis.29 Other associations are abnormal glucose metabolism, hepatic insufficiency, albuminuria, and congestive heart failure.5 APD consists of 2- to 10-mm pruritic, hyperkeratotic, dome-shaped, often umbilicated papules and nodules,10 some of which may coalesce as a result of severe pruritus and rubbing to form small verrucous plaques. They may be either clustered or arranged in a linear distribution. The smallest lesions are pinhead-sized follicular or perifollicular papules, while the largest lesions are dark brown nodules with a central crust, filling a central depression.30 Koebner’s phenomenon may occur. Lesions present chiefly on the legs; however, the trunk and face may also be involved.20 Spontaneous resolution is unlikely. Most patients with APD are middle-aged black men.2

PATHOPHYSIOLOGY The metabolic derangements caused by chronic renal failure and diabetes lead to superficial dermal connective tissue change and trigger transepidermal elimination.31 There may be deposition of uremic substances such as uric acid or hydroxyapatite that induces a foreign body inflammatory reaction resulting in transepidermal elimination.29 Pruritus caused by uremia or diabetes may result in epidermal injury secondary to scratching, whereas the altered blood supply of diabetic vasculopathy results in localized dermal necrosis and extrusion of dead tissue through the epidermis.10 Microangiopathy and dysregulation of vitamin A or D have also been proposed.29

HISTOPATHOLOGY APD shows an area of basophilic staining of the papillary connective tissue and atrophy of the suprapapillary plate. The basophilic collagen bundles are gradually taken into the epidermis through the intercellular spaces and foci of epidermal disruption. This forms a crateriform invagination of the epidermis filled by a parakeratotic plug and basophilic cellular debris.32–34

TREATMENT Treatment of APD is largely unsuccessful. The patient is advised to avoid scratching and trauma. Retinoic acid, topical SKINmed. 2011;9:302–308

keratolytics, topical and systemic retinoids, psoralen–UV-A (PUVA), UV-B, topical and intralesional steroids, and oral antihistamines have been used with partial success.29,31,35 DIABETIC THICK SKIN

CLINICAL APPEARANCE Diabetics, in general, have an asymptomatic, often unnoticed but measurable increase in skin thickness. At least 20% of diabetic patients have such measurable skin thickness.36 Using the technique of palpation and tenting of the area, thickening has been demonstrated in both type 1 and type II diabetes. The pathogenesis of diabetic thick skin has not yet been fully elucidated; however, potential explanations include the monoenzymatic glycosylation of collagen, making it less soluble; collagen hydration secondary to polyol accumulation; and nonenzymatic glycosylation of albumin resulting in endothelial cell extravasation.37,38 The diabetic hand syndrome is characterized by limited joint mobility, cheiroarthropathy, waxy skin and stiff joints, scleroderma-like syndrome, and diabetic sclerodactyly. It presents as stiffness, primarily of the small joints of the hands. It begins in the metacarpophalangeal and proximal interphalangeal joints. It is bilateral, symmetrical, and painless.39–41 The limitation of movement initially in active and later even in passive extension may less frequently involve larger joints of the wrist, elbow, and the spine.2 Despite the name, the joints themselves are not directly involved. Microvascular complications such as retinopathy, nephropathy, and peripheral neuropathy have been associated.42–44 Diabetic scleredema10 is the association between scleredema and diabetes and was emphasized for the first time by Fleischmajer and colleagues in 1970.45 Diabetic scleredema is present in 2.5% of patients with type II diabetes. Insulin acting as a growth factor in combination with decreased local oxygen pressure secondary to microangiopathy may increase collagen and glycosaminoglycan synthesis by fibroblasts.10 Diabetic hand syndrome or digital sclerosis of DM is a syndrome that generally affects the 5th digit and may then progress laterally to involve other fingers. Stiffening of the collagen in periarticular tissue is common.2 The degree of skin collagen fluorescence correlates with these complications.39 According to one study,40 thick skin, like glycosylated hemoglobin, is a marker of glycemic control, which has been demonstrated by a decrease in skin thickness toward normal following pump administration of insulin and achievement of tighter control. The most accurate sign, however, is limitation of extension with the examiner passively testing the interphalangeal and metacarpophalangeal joints. Thickening can also be demonstrated by

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ultrasound scanning,2 microscopic measurement, caliper measurement, and radiological investigations.12 Due to the miniature cobblestone-like appearance, this velvety skin is described as having finger pebbles or knuckle pebbles. It occurs in 10% to 39% of diabetics and is found in patients with both type I and type II DM. Decreased ability to produce tenting of the skin and wrinkling following immersion in water is characteristic of diabetic thick skin. Histopathology shows epidermal hyperkeratosis and hypertrophy of the papillary dermis. The collagen in the papillary dermis is vertically oriented and streaked.41 SCLEREDEMA ADULTORUM

CLINICAL APPEARANCE Scleredema adultorum (SA) is characterized by a marked increase in dermal thickness on the upper back and nape of the neck in overweight, middle-aged patients with longstanding severe DM.44,45 The onset of SA is insidious, with loss of skin markings, which may extend to the face, arm, chest, and abdomen. SA is usually asymptomatic; however, neck discomfort and back pain may occur in severe cases.9 Patients may experience decreased sensation to pain and light touch over the affected area. SA does not correlate with retinopathy, nephropathy, neuropathy, or peripheral vascular disease.7

HISTOPATHOLOGY Patients with SA may show a thickened dermis with swollen collagen bundles separated by wide-clear spaces previously occupied by mucin and by an increased number of mast cells.46

diabetic patients. Serum triglyceride levels are increased in patients with eruptive xanthoma and serum is turbid. Increased serum triglycerides are also found in familial type I, II, IV, and V lipoproteinemias, nephrosis, pancreatitis, alcohol-induced lipemia, myxedema, hemochromatosis, and glycogen storage diseases.14 The common factor in hyperlipidemic states is decreased lipoprotein lipase activity or increased hepatic products of lowdensity lipoproteins, making chylomicrons less able to compete with low-density lipoproteins for lipoprotein lipase.48 There is some evidence that eruptive xanthomas in diabetics result from macrophages incorporating plasma lipoproteins forming foamy or xanthoma cells.2 Polyphagia in uncontrolled diabetes accelerates the formation of very low-density lipoprotein and chylomicrons.9 Xanthelasma may be associated with hypercholesterolemia and hypertriglyceridemia. Palmar/plantar xanthomas show a yellow discoloration of the palmar creases.49 Typical skin involvement is the sudden onset of crops of yellow papules, each with an erythematous rim,5 often presenting as Koebner’s phenomenon. The lesions are located mostly over the extensor surfaces, knees, elbows, back, and buttocks.20 Papules may coalesce to form tuberous xanthomas and lesions may be pruritic/tender.2 Tendon xanthomas are more persistent, tender on pressure, and often seen over pressure areas. The lesions are yellow thick nodules attached to the underlying subcutaneous tissues.49

HISTOPATHOLOGY

TREATMENT Treatment of SA is usually unsuccessful; however, radiotherapy, low-dose methotrexate, prostaglandin E1, topical/intralesional steroids, penicillamine, intralesional insulin, bath PUVA, and pentoxifylline have been advocated.47 DUPUYTREN’S CONTRACTURE Dupuytren’s contracture exhibits fibrosis and thickening of the palmar fascia, usually involving the aponeurosis over the 4th and 5th metacarpals. A gradual flexion deformity develops, which may extend to other digits. On microscopic examination, there are dense collections of fibroblasts, which mature into thick avascular collagen bundles. Pain may be relieved by heat, stretching exercises, or local steroid injection. Repeated surgical procedures may be necessary. ERUPTIVE XANTHOMA

CLINICAL APPEARANCE Eruptive xanthoma mainly appears in patients with severe, poorly controlled DM. Xanthomas occur in about 0.1% of SKINmed. 2011;9:302–308

Foamy, lipid-laden histiocytes, with a mixed lymphocytic and neutrophilic infiltrate accumulation in the dermis are characteristic of eruptive xanthoma.9

TREATMENT It is imperative to control diabetes or underlying inherited hyperlipidemia, which includes weight reduction, if indicated, and carbohydrate restriction. It may be necessary to add clofibrate.49 CAROTENODERMIA (CAROTENEMIA/CAROTENOSIS) Up to 10% of diabetic patients have carotenodermia (yellowing of skin), where blood levels of carotene exceed 0.2 mg/100 mL to 0.8 mg/100 mL for carotenemia to become evident in the skin.30 In the past, carotenemia was considered to be a manifestation of the diabetic diet (carrot, spinach, apricots, yellow vegetables).7,14 Yellow discoloration of the skin, however, may be the result of nonenzymatic glycosylation and its products.50 They are apparently yellow, long-lived proteins. Dermal collagen could become glycosylated to eventually appear yellow.7 The impaired

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Table. Acanthosis Nigricans (AN): Clinical Variants

STUDY NO.

VARIANTS

CLINICAL FEATURES

Benign AN

A rare genodermatosis that may be unilateral and present at birth or in early childhood, has a familial pattern, and may be seen in association with multiple melanocytic nevi.

Pseudoacanthosis nigricans

Obesity-associated AN. It is the most common type of AN and regresses completely with weight loss.

Syndromic AN

Similar to the type A syndrome found in girls and young women, which shows signs of virilization and accelerated growth. A genetic defect at the insulin receptor or in a postreceptor pathway has been postulated. Type B syndrome has been seen in older women with signs of immunologic dysfunction in whom anti-insulin receptor antibodies have been found. Conditions other than these two syndromes may also feature AN and insulin resistance. Pathogenesis involves genetic and acquired defects of the classic glycoprotein insulin receptor or post-receptor pathway causing resistance to the action of insulin. This results in a compensatory secretion of excessive amounts of insulin into the circulation. Large amounts of unbound insulin is then available for binding to insulin-like growth factor receptors. Such binding of insulin to receptors on keratinocytes or fibroblasts may lead to increased metabolism, growth, and proliferation of epidermal cells, expressed clinically as AN.54–56

Malignant AN

Characterized by its sudden onset and rapid progression. AN occurs with malignancy from secretion of tumor products with insulin-like activity at the cell receptor level.52,57

Acral AN

The velvety hyperkeratosis of the dorsa of the hands and feet.

Drug-induced AN

Induced by systemic corticosteroids, nicotinic acid, and estrogens, such as diethylstilbestrol, insulin, pituitary extract, oral contraceptives, and fusidic acid.52,58

Unilateral AN/nevoid AN

See above.

Mixed type

When two of the above types occur together.

conversion of carotene to vitamin A in the diabetic liver30 may have a similar outcome. In carotenodermia, deposits of yellow pigment may be found in the nasolabial folds, on the forehead and axillae, and areas that are rich in sebaceous glands. The palms, soles, nostrils, and bony prominences have a thickened stratum corneum and also show this yellow discoloration; however, it does not cause scleral icterus as in jaundice.49 RUBEOSIS FACIEI Although difficult to quantify, flushed face or rubeosis faciei has been reported in 3% to 59% of diabetics.9 In a study7 comparing facial redness with diabetic parameters, 59% of patients had markedly red faces. Rosy color of the face and occasionally the hands and feet is seen even in mild diabetics as well as in latent diabetic patients. There seems to be a familial tendency.30 The red color may be caused by microangiopathy evident as decreased tone and dilatation of venules in the cheek mucosa, increased solar sensitivity, or dehydration.51 This facial blush lacks the warmth and elevated border of erysipelas and the telangiectasia of carcinoid flush.30 Tighter glucose control may improve the appearance of rubeosis faciei.9 SKINmed. 2011;9:302–308

ACANTHOSIS NIGRICANS

HISTORY AND CLINICAL APPEARANCE The term acanthosis nigricans (AN) was coined by Unna in 1889.52 In one study of the condition,53 50% of patients in their 5th decade of life had type II DM. AN is characterized by symmetric, velvety to verrucous, hyperkeratotic, and hyperpigmented plaques that have a predilection for the axillae, anterior and posterior neck, umbilicus, areola, hands, and especially flexural areas such as in the groin, submammary regions, and antecubital and popliteal fossae.54,55 The degree of cutaneous involvement varies from subtle hyperpigmentation and papillary thickening affecting a few areas to a deeply pigmented and verrucoid process that involves the entire integument including the mucous membrane56–58 (Table). CONCLUSIONS DM, an endocrine disorder, is characterized by dysfunctional metabolism of sugar. It is a scourge of all the communities at global level. Most diabetics manifest cutaneous lesions at some point in time. These cutaneous lesions are not only a marker of the disease, but they may also reflect the status of blood

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sugar control. It is, therefore, imperative to understand these cutaneous manifestations of diabetes. Besides, necrobiosis lipoidica diabeticorum, diabetic bullae (bullosis diabeticorum), certain acquired perforating dermatoses, diabetic thick skin, SA, Dupuytren’s contractures, certain xanthomas, carotenoderma, rubeosis faciei, and AN are the other important diabetes related dermatoses. REFERENCES

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33 Hong SB, Park JH, Ihm CG, et al. Acquired perforating dermatosis in patients with chronic renal failure and diabetes mellitus. J Korean Med Sci. 2004;19:283–288.

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34 Sehgal VN, Jain S, Thappa DM, et al. Perforating dermatoses: a review and report of four cases. J Dermatol. 1993;20:329–340. 35 Sehgal VN, Singh N. Chondrodermatitis nodularis. Am J Otolaryngol. 2009;30:331–336. 36 Mendelsohn S, Verbov J. Diabetes and the skin: a review. Br J Clin Pract. 1983;37:85–94. 37 Paron NG, Lambert PW. Cutaneous manifestation of diabetes mellitus. Prim Care. 2000;27:371–383. 38 Buckingham BA, Uitto J, Sandborg C, et al. Scleroderma like changes in insulin dependent diabetes mellitus: clinical & biochemical studies. Diabetes Care. 1984;7:163–169. 39 Rosenbloom L: Diabetic thick skin and stiff joints. Diabetologia. 1989;32:74–76. 40 Huntley AC. Finger pebbles: a common finding in diabetes mellitus. J Am Acad Dermatol. 1986;14:612–617. 41 Huntley AC, Walter RM. Quantitative determination of skin thickness in diabetes mellitus: relationship to diseasese parameters. J Med. 1990;21:257–264.

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42 Krakowski A, Covo J, Berlin C. Diabetic scleredema. Dermatologica. 1973;146:193–198. 43 Cole GW, Headley J, Skowsky R. Scleredema dibeticorum: a common and distinct cutaneous manifestation of diabetes mellitus. Diabetes Care. 1983;6:189–192. 44 Cohn BA, Wheeler CE, Briggaman RA. Scleredema adultorum of Buschke and diabtes mellitus. Arch Dermatol. 1970;101: 27–35.

58 Teknetzis A, Lefaki I, Joannides D, et al. Acanthosis nigricans like lesions after local application of fusidic acid. J Am Acad Dermatol. 1993;28:501–502.

WAX MOULAGE

45 Fleischmajer R, Faludi G, Krol S. Scleredema and diabetes mellitus. Arch Dermatol. 1970;101:21–26. 46 Hanna W, Friesen D, Bombardier C, et al. Pathologic features of diabetic thick skin. J Am Acad Dermatol. 1987;16:546–553. 47 Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol. 2006;24:237–246. 48 Cruz PD Jr, East C, Berstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19:95–111. 49 Weedon D, Struton G. Skin Pathology. 2nd ed. Churchill Livingstone. Edinburgh, 2002:193–221. 50 Sueki H, Nozaki S, Numazawa S, et al. Effect of non-enzymatic glycosylation and heating on browning of human stratum corneum and nail. Dermatologica. 1991;183:197–202. 51 Haroon TS. Diabetes and skin–a review. Scott Med J. 1974; 19:257–267. 52 Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol. 1994;31:1–19. 53 Stuart CA, Gilkison CR, Smith MM, et al. Acanthosis nigricans as a risk factor for noninsulin dependent diabetes mellitus. Clin Pediatr (Phila). 1998;37:73–80. 54 Rendon MI, Cruz PD, Sontheimer RD, et al. Acanthosis nigricans: a cutaneous marker of tissue resistance to insulin. J Am Acad Dermatol. 1989;21:461–469. 55 Flier JS. Metabolic importance of acanthosis nigricans. Arch Dermatol. 1985;121:193–194. 56 Barth JH, Ng LL, Wojnarowska F, Dawber RP. Acanthosis nigricans, insulin resistance and cutaneous virilism. Br J Dermatol. 1988;118:613–619. 57 Schwartz RA, Burgess GH. Florid cutaneous papillamatosis. Arch Dermatol. 1978;114:1803–1806.

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Gonoblenorrhoea. Moulage No 304, made by Lotte Volger in the Dermatology Clinic in Zurich, 1925. Museum of Wax Moulages Zurich, www.moulagen.ch. Courtesy of Michael Geiges, MD

Type II Diabetes Mellitus–Related Dermatoses

September/October 2011

Volume 9 • Issue 5

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve J. Lowenstein, MD, PhD, Section Editor

A History of Sulfur Mustard Elie B. Lowenstein, MD Gas! GAS! Quick, boys! – An ecstasy of fumbling, Fitting the clumsy helmets just in time; But someone still was yelling out and stumbling, And flound’ring like a man in fire or lime… Dim, through the misty panes and thick green light, As under a green sea, I saw him drowning. In all my dreams, before my helpless sight, He plunges at me, guttering, choking, drowning. —Wilfred Owen, “Dulce Et Decorum Est [pro patria mori]”, 1917 (Wilfred Owen was a British soldier who died on the front lines in World War I.)

ulfur mustard is a vesicant with a mustard-like odor that can affect the skin, eyes, respiratory and gastrointestinal tracts, and bone marrow, and can be lethal at certain doses.1 Throughout its years of use, various names have been used for this infamous gas. “S-mustard” distinguishes it from nitrogen mustard, “Lost” or “S-Lost,” represent contractions of the names of two chemists who suggested it be used as a war gas (Lommel and Steinkopf ), and “Yellow cross” as the identifying mark on World War I (WWI) shells containing the chemical. It has also been called “Yperite,” the name of the site of its first use in 1917 during WWI.1 The German Imperial Army began using chlorine, phosgene, and sulfur mustard gas as weapons in WWI, vesicants producing chemical burns, to drive the Allied Forces from the relative safety of their trenches.1 The German Army launched their first sulfur mustard gas attack on July 12, 1917, against British troops in Ypres, Belgium (hence “Yperite” as a name used for the gas). The gas was loaded into large artillery shells marked with a yellow cross (hence referred to as the “Yellow cross” or “Gelbkreuz”).

a very important role as a portal of entry for sulfur mustard.1,4 The potential for blindness, disfiguring slow-healing lesions of the skin, and the rather painful death of those who had inhaled significant amounts (Figure), caused a significant blow to both sides. As a result of its effects, sulfur mustard became known as the “King of the Battle Gases,” as it was responsible for more chemical casualties than chlorine, phosgene, and cyanogen chloride combined.5 FUTILE PREVENTION Despite efforts to prevent further use of chemical weapons at the Chemical Convention Talks as part of the Geneva Protocol in 1925 and as recently as the Chemical Weapons Convention in 1993, history continues to repeat itself with its use.1 Mustard gas was used in the War of the Rif in Morocco (1925), the Second Italo-Abyssinian War in Ethiopia (1935), World War II,

The introduction of sulfur mustard to the German’s armamentarium provided several advantages over the previous agents. In addition to its colorless and mustard/garlic-like odor, making it less detectable, sulfur mustard is a vesicant capable of sticking to and penetrating most clothing, therefore rendering gas masks ineffective.2,3 The gas is highly lipophilic, with the skin playing

Figure. “Gassed” by John Singer Sargent, 1918: a pictorial account of the effects of gas warfare during World War I.

From the Department of Dermatology, Mount Sinai School of Medicine, New York, NY Address for Correspondence: Elie B. Lowenstein, MD, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1047, New York, NY, 10029 • E-mail: elielowenstein@gmail.com

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The Yemini Civil War (1962–1970), and most recently in the Iran-Iraq War (1980–1988).1 Much of the information on the toxic effects of mustard gas that we have today come from studies of victims of the Iran-Iraq conflict. Presented at the 37th Annual Meeting of the History of Dermatology Society, Miami Beach, FL, March 4, 2010. REFERENCES 1

Pechura CM, Rall DP; from the Committee on the Survey of the Health Effects of Mustard Gas and Lewisite, Institute of

Medicine. Veterans at Risk: The Health Effects of Mustard Gas and Lewisite. 1st ed. Washington, DC: National Academies Press; 1993. 2

Guthrie F. On some derivations from the Olefins. Q J Chem Soc. 1860;13:129–135.

Momeni AZ, Enshaeih S, Meghdadi M, Amindjavaheri M. Skin manifestations of mustard gas. A clinical study of 535 patients exposed to mustard gas. Arch Dermatol. 1992;128:775–780.

Cullumbine H. Medical aspects of mustard gas poisoning. Nature. 1947;159:151–153.

Fitzgerald GJ. Chemical warfare and medical response during World War I. Am J Public Health. 2008;98:611–625.

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September/October 2011

Volume 9 • Issue 5

HISTORICAL VIGNETTE Charles Steffen, MD, Section Editor

Claude Huriez and His Syndrome Khalid Al Aboud, MD;1 Amor Khachemoune, MD2 Claude Huriez (1907–1984) was a well-known French dermatologist. In the 1960s, Huriez and colleagues reported two families from northern France with a rare congenital genodermatosis—later known as Huriez syndrome. This syndrome is characterized by scleroatrophy of the hands and feet, nail hypoplasia, mild palmoplantar keratoderma, and hypohidrosis and is a cancer-prone genodermatosis. This report sheds light on Huriez and the syndrome that bears his name.

laude Huriez (1907–1984) (Figure 1) was a worldrenowned French professor of dermatology and venerology.1–4 Among his great contributions to dermatology, he is credited for describing a syndrome,5,6 later known as Huriez syndrome.7–12 HURIEZ SYNDROME

Scleroatrophic syndrome of Huriez, also called sclerotylosis,11 is a rare autosomal-dominant condition, with which few families are affected worldwide.11 It is characterized by congenital scleroatrophy of the distal extremities, palmoplantar keratoderma, and hypoplastic nail changes.12 Huriez initially described this condition in 42 of 132 members of two families from northern France. Subsequently, sporadic and familial cases developed in Germany, England, Morocco, India, Tunisia, Japan, Italy, and Scandinavia.13 The term sclerotylosis was proposed, based on the pseudosclerodermatous appearance of the hands and digits.8 Additional hallmarks of this syndrome include poikiloderma-like changes on the nose, flexion contractures of the little finger, a distinctive nodule on the little finger, and telangiectasia of the lips.10

examination at the end of high school before entrance to college and university. He received his doctoral degree in medicine in early adulthood, and in 1943, he was appointed professor of clinical dermatology.1 His work in public health was considerable, particularly in decreasing mortality from venereal diseases.4 He was a pioneer, believing that a cortisone-like cream that consisted of vitamin D had beneficial effects on many dermatoses. Cortisone was discovered a quarter of a century after his use of vitamin D–containing topical preparations. As determined later, these two have the same mode of action on nuclear receptors. Huriez was at the forefront of investigational new drugs, using penicillin that he obtained from the US Army before it was available for regular use in any French hospital.1–4 He was interested in many dermatologic diseases, but syphilis was one of his favorite topics. He is credited with first describing lipodermatosclerosis as hypodermite sclerodermiforme in his report on 1000 patients with leg ulcers of venous etiology.14

CLAUDE HURIEZ (1907–1984)

Hureiz was a diligent man with many endeavors. He saw patients very early in the morning at his home before making his hospital rounds between 10 am and 1 pm. He would see patients at the hospital every day of the week, and later in the afternoon he would confer with his associates. Huriez designed a sliding cabinet of kodachromes for filing slides for teaching and presenting at meetings, dubbing it the “Kodatheque.” He used films and humorous drawings to illustrate diseases and concepts.

Claude Huriez, born in 1907 in France, was precocious.1 At the age of 15, he passed his baccalaureate—a mandatory

Huriez published 795 scientific articles and 48 monographs, 5 of which won a prize by the Academy of Medicine. For years

Aggressive squamous cell carcinoma (SCC) of the affected skin can develop in this syndrome, occurring in approximately 15% of affected individuals.12 SCC in Huriez syndrome is characterized by early onset and metastasis.10

From King Faisal Hospital, Saudi Arabia;1 and the Service of Dermatology, Veterans Affairs Medical Center, Brooklyn, NY2 Address for Correspondence: Khalid Al Aboud, MD, King Faisal Hospital, PO Box 5440, Makkah 21955, Saudi Arabia • E-mail: amoa65@ hotmail.com

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HISTORICAL VIGNETTE More notably, Dr Huriez was known for his eloquence, creativity, and leadership in northern France, where he was chairman of the Department of Dermatology at the chief hospital in Lille, the largest city in the province. Huriez was later the vice president of the hospital committee, which led the development of the most important university hospital in Lille, where a building was named after him.1–4 REFERENCES

Figure. Claude Huriez (1907–1984). Reprinted with kind permission from the Museum Association, Regional Hospital of Lille, France.

during the 1950s, Huriez taught venereology every Friday (Veneris Dies—as he said) from 2 pm to 6 pm. Huriez used to organize weekly patient presentations in a lecture room with projections of patient lesions in an adjacent room. These highly instructive sessions were called “the circus” by his associates. Huriez sat on many boards and committees in northern France and nationwide, but the project of which he was most proud was the building that he called the “Medicopolis,” encompassing the Cité Hospitalière. This structure, of which he was vice president for 20 years, was later renamed Hopital Claude-Huriez, comprising a geriatric hospital, nursing homes, a rehabilitation center, and a labor and delivery hospital. Huriez visited 55 countries and more than 100 university hospitals to learn and gather information on how to build and organize the Medicopolis. CONCLUSIONS Dr Claude Huriez was an eminent professor of dermatology and a pioneer in the management of leg ulcers and skin diseases.

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HURIEZ, Claude (1907–1984). Pôle ressources du Patrimoine Hospitalier et Médical du Nord: Biographies de médecins du Nord. http://www.patrimoinehospitalierdunord.fr/biographies/ page18.html Accessed July 9, 2010.

Martin P. Claude Huriez’ 65th anniversary [in German]. Dermatol Monatsschr. 1972;158:918–919.

Debeyre J. Eulogy for Claude Huriez 1907–1984 [in French]. Bull Acad Natl Med. 1984;168:509–515.

Agache P, Thomas P. History of the Lille University Dermatology Clinic. In: Wallach D, Tilles G, eds. Dermatology in France. Privat: Pierre-Fabre Dermo-Cosmetique; 2002:583–586. http:// www2.biusante.parisdescartes.fr/livanc/?p=579&cote=extwall 00001&do=page. Accessed February 2, 2011.

Huriez C, Deminati M, Agache P, Delmas-Marsalet Y, Mennecier M. Génodermatose scléro-atrophiante et kératodermique des extrémités. Ann Dermatol Syphiligr (Paris). 1969;96:135–146.

Huriez C, Deminatti M, Agache P, Mennecier M. A gene dysplasia not previously known: frequently degenerative scleroatrophying and keratodermic genodermatosis of the extremities [in French]. Sem Hop. 1968;44:481–488.

Patrizi A, Di Lernia V, Patrone P. Palmoplantar keratoderma with sclerodactyly (Huriez syndrome). J Am Acad Dermatol. 1992;26(5 pt 2):855–857.

Delaporte E, N’guyen-Mailfer C, Janin A, et al. Keratoderma with scleroatrophy of the extremities or sclerotylosis (Huriez syndrome): a reappraisal. Br J Dermatol. 1995;133:409–416.

Hamm H, Traupe H, Bröcker EB, Schubert H, Kolde G. The scleroatrophic syndrome of Huriez: a cancer-prone genodermatosis. Br J Dermatol. 1996;134:512–518.

10 Kavanagh GM, Jardine PE, Peachey RD, Murray JC, De Berker D. The scleroatrophic syndrome of Huriez. Br J Dermatol. 1997;137:114–118. 11 Downs AM, Kennedy CT. Scleroatrophic syndrome of Huriez in an infant. Pediatr Dermatol. 1998;15:207–209. 12 Sekar SC, Srinivas CR. Huriez syndrome. Indian J Dermatol Venereol Leprol. 2008;74:409–410. 13 Guldbakke KK, Huldt-Nystrøm T, Mjønes P. An unusual case of palmoplantar keratoderma. Arch Dermatol. 2010;146: 1419–1424 14 Huriez C, Legache G, Desmons F, Pelce P. Ulceres de jambes et trouble trophiques d’origine veineuse (donnes tirees de l’etude d’un millier d‘ulcereuz trophiques d’origine veineuse (donnes tirees de l’etude d’un millier d‘ulcereuz hospitalizes). Rev Prat. 1955;5:2703–2721.

Claude Huriez and His Syndrome

September/October 2011

Volume 9 • Issue 5

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

Nodular Cutaneous Amyloidosis Jessica Borowicz, DO; Leah Shama, DO; Richard Miller, DO A 56-year-old white man presented with a lesion on the right shoulder. The lesion developed during a short period and recently became irritated with occasional bleeding and mild pruritus. The patient denied pain. Medical history included melanoma, nonmelanoma skin cancer, diabetes mellitus type II, hyperlipidemia, multinodular thyroid goiter, and obesity. Medications and family and social history were noncontributory. Review of systems was negative. Examination revealed a slightly raised, friable yellow-pink waxy plaque located on the right shoulder (Figure 1). There was no evidence of excoriation, secondary infection, drainage, scale, crust, atrophy, lichenification, or telangiectasia. The patient had no mucosal or nail changes and the remainder of his skin examination was normal. A shave biopsy on the right shoulder revealed a nodular deposit of homogenous eosinophilic material associated with extravasated erythrocytes within the dermis. An infiltrate of lymphocytes and plasma cells was associated with the deposits. Immunohistochemical stains revealed positive plasma cells with kappa light chain and negative with lambda light chain. Congo red stain was positive and supported the diagnosis. The findings were consistent with nodular cutaneous amyloidosis (NCA) of the amyloid light–type. Initial work-up included referrals to hematology/oncology and to general surgery. The patient had a complete blood cell count (CBC), complete metabolic profile (CMP), serum protein electrophoresis (S-PEP), urine protein electrophoresis (U-PEP), 24-hour urine creatinine clearance, and protein, serum immunoglobulins and b2 microglobulin. These were all within normal limits. Abdominal/pelvic computed tomography and positron emission tomography scan also were within normal limits. Bone marrow biopsy showed no abnormalities. The patient underwent both an abdominal fat pad biopsy as well as a colonoscopy with rectal biopsy. Both were negative for amyloidosis. Initially, the patient’s cutaneous amyloidosis remained localized and mild pruritus was controlled with low potency topical steroids. The patient was closely monitored by hematology/oncology and general surgery on a biannual basis to assess the possibility of progression to systemic amyloidosis. Over the course of the subsequent two years, the patient developed multiple similar lesions across the back, shoulders, and chest, which were biopsied and found to be consistent with NCA. Progression of the cutaneous nodules led to disfiguring, painful, and friable pink to yellow waxy papules coalescing into plaques with obvious hemorrhage diffusely over the trunk (Figure 2). In lieu of the painful and disfiguring progression of disease, the patient desired a more aggressive treatment plan. At present, the treatment option recommended to the patient is carbon dioxide laser ablation. Hematology/oncology recommendation consists of a general systemic amyloid reevaluation annually, including CBC, CMP, S-PEP, U-PEP, 24-hour urine collection with creatinine clearance, and history and physical examination.

he amyloidoses are a group of several diseases sharing the feature of abnormal deposition of insoluble amyloid protein fibrils in the body leading to changes in tissue architecture and function. The disorders can be classified both clinically and biochemically, although most modern classification is based on the nature of the precursor plasma proteins that form the amyloid fibril deposits, since approximately 18 distinct forms of precursor protein-derived amyloid fibers have been identified. Dermatologists consider amyloidosis to be a depositional dermatosis, and generally classify disease states as systemic (with primary myeloma-associated and secondary forms), cutaneous (primary and secondary forms), and heredofamilial amyloidosis.1–3 A specific fibril protein, such as keratin or immunoglobin, is the major constituent of amyloid. Minor components of the

amyloid protein fibril include amyloid P protein, glycosaminoglycans, and apoE lipoprotein.1,3 The precursor amyloid proteins are initially soluble. Unknown factors cause the amyloid proteins to undergo changes that lead to their aggregation and polymerization, and ultimately lead to insoluble fibril formation and tissue deposition. Deposition of the protein fibrils in the skin and other organs affects normal functioning, leading to pathology. The exact disease pathophysiology has not yet been fully elucidated. Proposed mechanisms for the development of primary cutaneous amyloidosis include prolonged friction, Epstein-Barr virus infection, genetic predisposition, and environmental factors.3–5 Primary cutaneous amyloidosis is generally restricted to the skin. The most common forms include macular, lichen, and biphasic amyloidosis. A less common entity is NCA. All are characterized

From Largo Medical Center, Largo, FL Address for Correspondence: Jessica Borowicz, DO, 1104 South Missouri Avenue #301, Clearwater, FL 33756 • E-mail: drjflowers@hotmail.com

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CASE STUDY PSA and NCA share a common precursor protein derived from kappa and/or lambda types of immunoglobin light chain proteins, termed “AL.” AL is unrelated to the keratinocyte-derived amyloid, as in macular and lichen amyloidosis, or to AA amyloid (acute-phase reactant protein), as in secondary cutaneous amyloidosis. In PSA, paraproteins circulate, deposit, and accumulate within tissues systemically and interfere with normal functioning. In NCA, local skin plasma cells produce aberrant immunoglobulin light chain amyloid proteins producing skin disease.3,12 The commonality of the amyloid protein derivation explains the relationship of NCA to PSA and warrants close follow-up of patients diagnosed with NCA to exclude progression to systemic disease.3,4,7,9

Figure 1. Slightly raised, friable yellow-pink waxy plaque on the right shoulder.

by epidermal and dermal deposition of amyloid proteins, either of keratinocyte or immunoglobin light chain (amyloid light) derivation. NCA is the rarest form of cutaneous amyloidosis. The fibrils are composed of amyloid light proteins of immunoglobin light chains or b2-microglobulin subtype. NCA presents as single, or less commonly, multiple pink to yellowish brown waxy nodules preferentially located on acral surfaces, although they may also be found on the trunk, genitalia, and face.4,6 Lesions may resemble large bullae (bullous amyloidosis), or the epidermis may appear atrophic or anetodermic.7 The nodules may have superficial telangiectasias and, as presented in this case, may be quite friable and hemorrhagic, as a result of perivascular deposition of amyloid. Epidemiologically, women in the sixth to seventh decade of life were thought to be predominately affected, but more recent studies suggest that both sexes of middle age are affected.4,8 It is important to recognize NCA, because the lesions are indistinguishable from those of primary systemic amyloidosis (PSA). Rarely, NCA has been shown to progress to PSA and subsequent myeloma. NCA alone follows a relatively benign course, but the prognosis is poor for PSA, with a median survival of 1 to 2 years if untreated.6,9,10 There has been controversy regarding the risk of progression to PSA in patients with NCA. Earlier studies suggested this rate to be as high as 50%,6 although a recent case report by demonstrated that the rate of progression might be as low as 7%.11 Systemic disease should be ruled out in patients newly diagnosed with NCA, and these patients should be assessed annually for progression to PSA. Studies include CBC, CMP, urinalysis (proteinuria is not a feature of NCA), S-PEP, U-PEP, chest radiography, and electrocardiography.6,9,10 SKINmed. 2011;9:316–318

The diagnosis and differentiation of NCA from other types of cutaneous amyloidosis is established via tissue biopsy. Biopsy specimens should include full thickness skin into subcutaneous fat. In NCA, the locally produced immunologlobin light chain– derived amyloid fibrils deposit in the dermis and subcutis and within blood vessel walls. In contrast, keratinocyte-derived amyloid deposits are more superficial, rarely extending beyond the upper dermal layer.13 Additionally, several studies have demonstrated a perivascular infiltrate of plasma cells within the lesions of NCA, suggesting that the amyloid AL protein deposits result from local plasma cell production of immunoglobin light chain precursors. Therefore, some may consider NCA a form of plasmacytoma or plasma cell dyscrasia.3,12 Staining amyloid with hematoxylin and eosin (H&E) demonstrates amorphous, eosinophilic, fissured masses of amyloid protein fibril deposition at variable levels in the epidermis and dermis. Since amyloid proteins are often difficult to visualize with standard H&E staining, the most frequently utilized stain to highlight amyloid is Congo red. A common feature of all the amyloidoses is visualization of apple-green birefringence in polarized light with Congo red staining. This is due to the cross b-pleated sheet structure of amyloid.1,2,9 Immunohistochemical studies of the NCA lesions may demonstrate positivity for immunoglobin light chains (kappa and/or lambda) as well as for b2-microglobulin partially modified by advanced glycation end products.13 Cytokeratin stains will generally be negative, as these stains would highlight the altered keratin proteins in the keratinocyte-derived forms of primary cutaneous amyloidosis. Electron microscopy reveals 7- to 10-nm–thick straight fibrils aggregated in an irregular network while x-ray crystallography and infrared spectroscopy show the cross b-pleated sheet conformation characteristic of amyloid.3,9,14 Treatment of cutaneous amyloidosis lesions is individualized, based upon the clinical presentation. Variable success has

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CASE STUDY

been accomplished through treatment of amyloid lesions with physical removal or destruction of the lesions by shaving and desiccation or use of the carbon dioxide laser.15 A challenge in the treatment of NCA lesions is control of hemostasis due to tissue friability, imparted by perivascular deposition of amyloid. Additionally, local recurrence following surgical excision is common.5,16 Other modalities for treatment include dermabrasion and pulsed dye laser.8,17 Intralesional corticosteroid injection has been shown to exacerbate the lesions and should be avoided.15 CONCLUSIONS NCA is rare and has the ability to progress to systemic amyloidosis.3,6,11 Annual follow-up studies to exclude progression to PSA should be performed for patients diagnosed with NCA. The clinician should pay close attention to the evolution of current skin lesions and the formation of new lesions, as amyloidosis can lead to significant morbidity for the patient. REFERENCES 1

Buxbaum JN, Tagoe CE. The genetics of the amyloidoses. Annu Rev Med. 2000;51:543–569.

Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909.

Black MM, Albert S. Amyloidosis. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. Cambridge, England: Mosby Elsevier Limited; 2003:659–667.

Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol. 2003;139:1157–1159.

Figure 2. Friable pink to yellow waxy papules coalescing into plaques with obvious hemorrhage diffusely over the trunk. 10 Schwendiman MN, Beachkofsky TM, Wisco OJ, et al. Primary cutaneous nodular amyloidosis: case report and review of the literature. Cutis. 2009;84:87–92. 11 Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: long-term follow-up study and treatment. Br J Dermatol. 2001;145:105–109. 12 Hagari Y, Mihara M, Konohana I, et al. Nodular cutaneous amyloidosis: further demonstration of monoclonality of infiltrating plasma cells in four additional Japanese patients. Br J Dermatol. 1998;138:652–654. 13 Fujimoto N, Yajima M, Ohnishi Y, et al. Advanced glycation end product-modified beta2-microglobulin is a component of amyloid fibrils of primary localized cutaneous nodular amyloidosis. J Invest Dermatol. 2002;118:479–484.

Vestey JP, Tidman MJ, Mclaren KM. Primary nodular cutaneous amyloidosis long-term follow-up and treatment. Clin Exp Dermatol. 1994;19:159–162.

Brownstein MH, Helwig EB. The cutaneous amyloidosis 1. Localized forms. Arch Dermatol. 1970;102:8–19.

14 Horiguchi Y, Takahashi C, Imamura S. A case of nodular cutaneous amyloidosis. Amyloid production by infiltrating plasma cells. Am J Dermatopathol. 1993;15:59–63.

Criado PR, Silva CS, Vasconcellos C, et al. Extensive nodular cutaneous amyloidosis: an unusual presentation. J Eur Acad Dermatol Venereol. 2005;19:481–483.

15 Truhan AP, Garden JM. Nodular primary localized cutaneous amyloidosis: immunochemical evaluation and treatment with the carbon dioxide laser. J Am Acad Dermatol. 1986;14:1058–1062.

Lien MH, Railan D. The efficacy of dermabrasion in treatment of nodular amyloidosis. J Am Acad Dermatol. 1997;36:315–316.

16 Mun KS, Pailoor J, Reddy SC. Primary localised deep cutaneous amyloidosis of the eyelid. Malays J Pathol. 2005;27:113–115.

Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol. 1988;18:1–16.

17 Alster TS, Manaloto RP. Nodular amyloidosis treated with pulsed dye laser. Dermatol Surg. 1999;25:133–135.

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September/October 2011

Volume 9 • Issue 5

CASE STUDY

Livedo Reticularis From Amantadine Lisa Y. Xu, MD;1 Austin Liu, MD;2 Holly A. Kerr, MD2 A 70-year-old Caucasian man with a medical history of Parkinson’s disease presented with a 3-month history of violaceous reticulated patches on his upper and lower extremities. The lesions were asymptomatic. The patient did not have a history of cardioembolic events or autoimmune disorders. No new medications were started before the onset of the lesions. Review of systems was unremarkable. On examination, large erythematous to violaceous patches were present in a reticulated net-like pattern on the patient’s upper and lower extremities (Figure 1 and Figure 2). No edema, erosions, or ulcerations were noted. An extensive workup for autoimmune, infectious, and hematologic causes of livedo reticularis was performed. Complete blood cell count, anti-nuclear antibodies (ANAs), anti-Ro and anti-La antibodies, antiphospholipid antibodies, protein C and S levels, cryoglobulin screen, rheumatoid factor, and hepatitis screen were all within normal limits. After these potential other causes were excluded, the patient was diagnosed with amantadine-induced livedo reticularis (LR), a medication he had been taking for 2 years for Parkinson’s disease. The patient’s dose of amantadine was decreased from 100 mg to 50 mg twice daily and over the next few months, his lesions gradually faded. Because his neurologic condition benefited from amantadine and his lesions were asymptomatic, his neurologist continued the medication.

mantadine is a synthetic antiviral agent initially developed to prevent and treat infection by influenza A. It is currently used to treat Parkinson’s disease, druginduced extrapyramidal symptoms, fatigue associated with multiple sclerosis, and chronic hepatitis C resistant to standard treatments. Known side effects of the medication include nausea, dizziness, insomnia, LR, and lower extremity edema, possibly secondary to increased vascular permeability. Leg edema can be seen as an isolated finding1 but has also been documented by some to occur only when LR is concurrently present.2 LR is a cutaneous finding that presents as a mottled network of erythematous to violaceous discoloration. LR can be physiologic, primary, or secondary to intravascular obstruction or vessel wall disease. Physiologic LR, also known as cutis marmorata, is a transient response to cold exposure. Primary LR is idiopathic and a diagnosis of exclusion. Secondary LR may be a result of a wide range of conditions including hematologic, autoimmune, embolic, neoplastic, infectious, and iatrogenic factors. An extensive workup should be performed to rule out these possibilities, including a complete blood cell count, biochemical profile, ANAs, antineutrophil cytoplasmic antibodies, complement levels, coagulation profile, and antiphospholipid antibodies. Amantadine-induced LR has been documented in the medical literature since the early 1970s.2 The reported incidence is highly variable, ranging from 2% to 90%. Most cases involve the use of

amantadine in patients with Parkinson’s disease or fatigue caused by multiple sclerosis. One report of LR was noted after treatment of chronic hepatitis C with amantadine.3 The exact mechanism of amantadine-induced LR is unclear. Amantadine is known to cause the release and depletion of vasoactive compounds (epinephrine, norepinephrine, and dopamine) from nerve terminals. Proposed mechanisms include amantadine-induced vasoconstriction causing decreased blood flow in arterioles, with secondary dilatation of dermal blood vessels. Since amantadine is also an N-Methyl-D-aspartate (NMDA) receptor antagonist, other authors believe that its vasoactive effects may involve cutaneous NMDA receptors.4 Interestingly, another proposed mechanism involves the development of antiphospholipid antibodies in response to amantadine treatment.5 The authors documented a high incidence of antiphospholipid antibodies in patients with Parkinson’s disease being treated with amantadine; however, a causal relationship was not identified and larger studies with inclusion of other thrombotic risk factors were recommended. Amantadine-induced LR is generally asymptomatic and has been reported to occur from 1 month to 4 years after drug initiation.1,3,6 Dosages prescribed in these cases have ranged from 100 mg 3 times weekly to 400 mg daily.1,2,6,7 The lower extremities are most commonly affected, although lesions can be generalized and involve the trunk and upper extremities. Women

From Indiana University School of Medicine, Indianapolis, IN;1 and the Department of Dermatology, Henry Ford Hospital, Detroit, MI2 Address for Correspondence: Lisa Y. Xu, MD, Indiana University School of Medicine, 550 North University Boulevard, UH 3240, Indianapolis, IN 46202 • E-mail: lisaxu@iupui.edu

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Figure 1. Photograph showing reticular net-like cyanotic patches symmetrically distributed on bilateral upper extremities.

appear to be more predisposed to developing this condition than men. LR is a reversible side effect of amantadine and lesions typically resolve a few weeks after drug cessation. Development of LR does not necessarily warrant discontinuation of amantadine, especially if the medication is beneficial for the patient. In severe cases, however, peripheral edema and ulceration can occur. Rimantadine, an a-methyl derivative of amantadine, has been proposed by investigators as an appropriate substitute for amantadine in patients with significant adverse effects.1 These authors documented 7 cases where amantadine was replaced by rimantadine, with 4 patients experiencing significant improvement in peripheral side effects of LR and ulcerating leg edema. REFERENCES 1

Singer C, Papapetropoulos S, Gonzalez MA, et al. Rimantadine in Parkinson’s disease patients experiencing peripheral adverse effects from amantadine: report of a case series. Mov Disord. 2005;20:873–877. Vollum DI, Parkes JD, Doyle D. Livedo reticularis during amantadine treatment. Br Med J. 1971;2:627–628.

Figure 2. Photograph showing similar reticular net-like violaceous patches on lower extremities. 3

Minutilli E, Pompili M, Pelecca G, Rapaccini GL, et al. Amantadineinduced livedo reticularis occurring during treatment of chronic hepatitis C. J Eur Acad Dermatol Venereol. 2008;22:1368–1370.

Kraemer M, Linden D, Berlit P. The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa. A literature review. J Neurol. 2005;252:1155–1166.

Paulson GW, Brandt JT. Amantadine, livedo reticularis, and antiphospholipid antibodies. Clin Neuropharmacol. 1995;18: 466–467.

Hayes BB, Cook-Norris RH, Miller JL, et al. Amantadine-induced livedo reticularis: a report of two cases. J Drugs Dermatol. 2006;5:288–289.

Sladden MJ, Nicolaou N, Johnston GA, et al. Livedo reticularis induced by amantadine. Br J Dermatol. 2003;149:656–658.

FORMULARY OF DR GEORGE C. ANDREWS Perspiration Corrective II Boric acid

1 ounce

Bismuth subcarbonate

1 ounce

Salicylic acid

½ ounce

Zinc stearate

3 ounces

15 drops to one ounce formalin being 40% solution of formaldehyde Submitted by Douglas D. Altchek, MD, New York, NY

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Invited Press Paul Winnington Editor, Practical Dermatology Sharon Finch Publisher, Cutis Amy Stankiewicz Managing Editor, Dermatology Times, Cosmetic Surgery Times Amy Pfeiffer Editor, Skin and Allergy News Rick Ehrlich Group Publisher, Skin and Aging Jo-Ann Kalaka-Adams Executive Publisher/Owner, SKINmed

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September/October 2011

Volume 9 • Issue 5

CASE STUDY

Nodule on the Scrotum Tarun Narang, MD;1 Varinder Singh, MD;1 Jasbir Singh, MD2 A 39-year-old Sikh businessman of Asian origin was referred to us with complaints of a painless scrotal lesion that had enlarged over a 2-year period and was causing him discomfort. There was no history of trauma, inflammation, or infection, and no significant urologic history. Physical examination revealed a 2×2 cm skin-colored nodule of rubbery consistency on the left side of the scrotum (Figure 1), which was separate from the testicles or epididymis. There was no inguinal lymphadenopathy. Scrotal ultrasonography demonstrated that the testicles and epididymis were normal. The scrotal mass and surrounding skin were surgically resected using a vertical elliptical incision and sent for histopathology. Histologic examination was consistent with leiomyoma. The epidermis was normal with a prominent proliferation of intertwined smooth muscle fibers with interlacing collagen bundles in the dermis. At higher magnification, the cells were spindle-shaped with eosinophilic cytoplasm and long nuclei. These interweaving bundles of cells surrounded the vessels and the pilosebaceous apparatus. There was no evidence of atypia and the mitotic index was low (Figure 2 and Figure 3). Some normal dartoic muscle fibers were seen in the periphery of the tumor. The patient’s postoperative recovery was uneventful. On follow-up visit 10 days later, he did not have any complications, and the sutures were removed. At his last visit 6 months after the procedure, he was still asymptomatic and did not have any recurrence.

utaneous leiomyomas are uncommon benign smooth muscle neoplasms of skin that are frequently unrecognized by clinicians.1 These tumors are classified into four categories depending upon their respective sites of origin: (1) multiple piloleiomyomas, (2) solitary piloleiomyoma, (3) angioleiomyoma, and (4) genital leiomyoma.2 The genital group includes masses arising from the dartos muscle of the scrotum or from the labia majora, as well as those derived from the mammillary muscle of the nipple in either sex. The most common type of presentation of leiomyoma is that of multiple piloleiomyomas. The lesions occur as grouped, linear, or dermatomal arrangements of firm, red to brown intradermal nodules that are fixed to the skin but not to the deeper tissues. Solitary piloleiomyoma and genital leiomyomas are clinically similar.1

Leiomyomas of the genitourinary tract may originate from any structure containing smooth muscle.2–5 These benign tumors have been described in the kidneys, ureters, bladder, urethra, prostate, seminal vesicles, spermatic cord, testis, epididymis, penis, and scrotum.4 Due to their rarity, scrotal leiomyomas are often confused with fibroma or an epidermal inclusion cyst and are nearly always preoperatively misdiagnosed.6 Scrotal leiomyoma appear most often between the fourth and sixth decades of life.2,7 They are typically

painless, noninflamed, small cutaneous lesions usually present for an average of 7.6 years between patient recognition and surgical removal.2,8 They tend to be solitary, asymptomatic lesions measuring 1 to 14 cm, with a mean length of 6.4 cm.2 Histologically, vulvar and scrotal leiomyomas are larger, asymptomatic, and histologically deeper and better delimited exhibiting characteristic elongated, blunt-ended smooth muscle nuclei (cigar-shaped) and eosinophilic cytoplasm. Smooth-muscle fiber bundles interlace with variable amounts of collagen. Masson trichrome, aniline blue, van-Gieson, phosphotungstic acidhematoxylin, and desmin and actin immunohistochemical stains facilitate the histologic recognition of smooth muscle. Although multiple cutaneous leiomyomas can be associated with internal tumors,1 no known association exists for solitary genital leiomyoma, and thus no further workup for the patient was required. As a result of its location and symptoms, it is essential that the differential diagnosis with other benign and malignant paratesticular tumors be carried out, as malignancies occur in up to 20% of the cases.5 Although some leiomyosarcomas have been reported in genital skin, there is no evidence of malignant change in preexisting benign lesions. Sonography is a widely used imaging

From the Department of Dermatology, Venereology & Leprology1 and Pathology,2 Gian Sagar Medical College & Hospital, Ram Nagar, Banur, Patiala, India Address for Correspondence: Tarun Narang, MD, Department of Dermatology, Venereology & Leprology, Gian Sagar Medical College & Hospital, Ram Nagar, Banur, Patiala, India • E-mail: narangtarun@yahoo.co.in

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Figure 3. Smooth muscle fiber bundles interlace with variable amounts of collagen, appearing cigar-shaped (hematoxylin and eosin stain, 40× original magnification).

Figure 1. Well-defined nodule on the scrotum.

myxoma, hemangioma, lymphangioma, liposarcoma, rhabdomyosarcaroma, leiomyosarcoma, epidermal inclusion cyst, and leiomyoma.6,9 Surgical excision or ablation of a solitary mass is another treatment option for painful lesions2,3 and carbon dioxide–laser ablation has also been employed in cases of symptomatic cutaneous masses.2 The prognosis for isolated lesions is excellent, particularly following surgical excision. Recurrences have been reported, however, following incomplete excision.5 There is no documented tendency toward malignant degeneration in cutaneous leiomyomas. Although rare, leiomyoma should be considered in the differential diagnosis of a scrotal mass. If there is any doubt regarding the extent for surgical excision of scrotal masses not associated with the testicle or epididymis, ultrasonography and pathologic frozen sections should be used to confirm the clinical suspicion of a benign vs malignant scrotal lesion.

Figure 2. A poorly circumscribed dermal tumor exhibiting characteristic elongated, blunt-ended smooth-muscle nuclei and eosinophilic cytoplasm (hematoxylin and eosin stain, scanning magnification).

REFERENCES modality for patients with suspected scrotal abnormalities. Both solid and multicystic lesions have been described in scrotal leiomyomas. As a rule, solid intratesticular lesions have a high likelihood of malignancy (about 90%–95%), while extratesticular lesions are usually benign. A review of the latter in the urology literature shows a malignancy rate of 3%.5 Another important role of sonography is that it can easily distinguish intratesticular from extratesticular lesions with an accuracy of 95%–100%.7,8 The differential diagnosis of scrotal lesions distinctly separate from the testis and adnexal structures includes squamous cell carcinoma, basal cell carcinoma, Paget’s disease, fibroma, lipoma,

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Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46:477–490.

Newman PL, Fletcher CD. Smooth muscle tumors of the external genitalia: clinicopathological analysis of a series. Histopathology. 1991;18:523–529.

Wolf DI. Solitary nodule of the scrotum. Leiomyoma. Arch Dermatol. 1989;125:416–419.

Livne PM, Nobel M, Savir A, et al. Leiomyoma of the scrotum. Arch Dermatol. 1983;119:358–359.

Lioe TF, Bigart JD. Tumours of the spermatic cord and paratesticular tissue. A clinicopathological study. Br J Urol. 1993;71:600–606.

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CASE STUDY

Das AK, Bolick D, Little NA, et al. Pedunculated scrotal mass: leiomyoma of the scrotum. Urol. 1992;39: 376–379.

Frates MC, Benson CB, DiSalvo DN, et al. Solid extratesticular masses evaluated with sonography: pathologic correlation. Radiology. 1997;204:43–46.

Krone KD, Carroll BA. Scrotal ultrasound. Radiol Clin North Am. 1985;23:121–139.

Tomera KM, Gaffey TA, Goldstein I, Zincke H. Leiomyoma of the scrotum. Urol. 1981;18:388–389.

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.

SCLERODERMA SYNONYMS: Dermatosclerosis; Sclerema; Scleroma; Scleriasis; Hide bound disease. DIAGNOSIS: The most characteristic feature of scleroderma is, as the name indicates, a hardening of the skin, and this may be the only feature in common between the two most widely separated varieties. The lesions may develop rapidly, or as is more common, very gradually; they may be single or multiple, diffuse and ill defined or localized and sharply circumscribed, level with

SKINmed. 2011;9:323–325

the normal skin or slightly elevated or depressed, of an ivory like whiteness or a translucent yellow, or pigmented diffusely or in blotches. The patches sometimes have a characteristic violaceous areola. Their surface is usually smooth but may be slightly scaly or somewhat nodular and is often traversed by a network of dilated capillaries. TREATMENT: It is difficult to estimate the value of various remedies. General symptomatic and tonic treatment is indicated. Thyroid extract has seemed to benefit some cases. Local massage with oil or a mildly stimulating ointment is usually employed.

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Volume 9 • Issue 5

CORRESPONDENCE

Longitudinal Erythronychia Associated With Graft-Versus-Host Disease To the Editor:

Table I. Classification of Longitudinal Erythronychia

I read with interest the recent report in SKINmed of idiopathic longitudinal erythronychia in a 71-year-old man.1 Longitudinal erythronychia has recently been classified into subtypes depending on the number of nails affected and the number of linear red bands on these nails (Table I).2,3 Similar to the patient described by Rashid and colleagues,1 nail findings in other patients with idiopathic monodactylous longitudinal erythronychia have previously been published.4 In addition to an idiopathic etiology for a single linear red band of the nail of only one digit, monodactylous longitudinal erythronychia has been observed in patients with either a benign or malignant-associated nail bed tumor (Table II).2–5

Type Ia: Monodactylous-single red band per nail Type Ib: Monodactylous-bifid red bands per nail Type IIa: Polydactylous-single red band per nail Type IIb: Polydactylous-multiple red bands per nail Table II. Conditions Associated With Monodactylous Longitudinal Erythronychia Glomus tumor Hemiplegia Idiopathic Malignant melanoma

In contrast to monodactylous longitudinal erythronychia, polydactylous longitudinal erythronychia presents with one or more nails that have either a single longitudinal red band or multiple linear red streaks. A 59-year-old man developed chronic graftversus-host disease of the gastrointestinal tract and the skin following a matched unrelated donor stem cell transplant to treat his acute myeloid leukemia. His gastrointestinal and lichenoid skin changes of graft-versus-host disease essentially resolved after prolonged treatment with triple therapy including low-dose methyl prednisone, tacrolimus, and mycophenolate mofetil. In addition to his skin changes, however, he also developed chronic graft-versus-host disease nail changes that persisted: lamellar splitting of both great toenails (Figure 1), thinning with a central linear split of both thumbnails (Figure 2), and longitudinal erythronychia of the remaining 8 fingernails (Figure 3). Additional nail changes, that have previously also been associated with longitudinal erythronychia, are most prominent at the distal border of the red band on the free edge of the right middle fingernail (V-shaped distal nick) and the left middle fingernail (onycholysis and nail breaking) (Figure 4). In addition to graft-versus-host disease,3 polydactylous longitudinal erythronychia can be a nail manifestation found in patients with systemic conditions such as amyloidosis and pseudobulbar syndrome.3,6 In addition, linear red bands on multiple nails have been observed in some individuals who have certain dermatologic conditions: acantholytic dyskeratotic epidermal nevus, acantholytic epidermolysis bullosa, acrokeratosis verruciformis of Hopf, keratosis follicularis (Darier’s disease), and lichen

Onychopapilloma Scar (postsurgical) Squamous cell carcinoma Systemic conditions associated with polydactylous longitudinal erythronychia (initial stage) Warty dyskeratoma

Figure 1. Lamellar splitting of the great toenails in a man with graft-versus-host disease.

planus.2 Also, albeit less commonly, polydactylous longitudinal erythronychia has been reported as an idiopathic finding with no associated etiology.7–9

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Figure 2. The thumbnails in a man with graft-versus-host disease show thinning and central splitting.

B Figure 4. Longitudinal erythronychia-associated nail changes located at the distal border of the broad red linear band in a man with graft-versus-host disease include a V-shaped distal nick at the free edge of the right middle fingernail (a) and onycholysis with breaking of the nail at the free edge of the left middle fingernail (b).

B Figure 3. Graft-versus-hostâ&#x20AC;&#x201C;associated longitudinal erythronychia: the fingernails on the right (a) and left (b) hands show individual broad red longitudinal bands that extend from the distal lunula to the free edge of the nail. Thin red bands, originating at the proximal nailfold are also present on the lateral right and left middle fingernails.

Longitudinal erythronychia can involve either a single nail or multiple nails, where one or more linear red bands are present on the affected nails. Indeed, this nail finding may be an associated manifestation of a local condition or a clinical feature related to an underlying systemic disease. Similar to the patient reported by Rashid and colleagues,1 monodactylous longitudinal erythronychia may be idiopathic. Involvement of only one red band on the nail of a single digit, however, raises the possibility of either a benign tumor or a malignant neoplasm of the respective nail bed. Multiple nails with longitudinal red bands may result from either a primary dermatologic disorder (most commonly either Darierâ&#x20AC;&#x2122;s disease or lichen planus) or a systemic condition (such as graft-versus-host disease in the described patient). Alternatively, polydactylous longitudinal erythronychia may be an idiopathic finding.

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REFERENCES 1

Rashid RM, Torres-Cabala C, Chon S. Longitudinal erythronychia: the value of cosmetic alterations in nail findings. Skinmed. 2011;9:60–61. Cohen PR. Longitudinal erythronychia: individual or multiple linear red bands of the nail plate—a review of clinical features and associated conditions. Am J Clin Dermatol. 2011;12:217–231.

Jellinek NJ. Longitudinal erythronychia: suggestions for evaluation and management. J Am Acad Dermatol. 2011;37:74–79.

de Berker DA, Perrin C, Baran R. Localized longitudinal erythronychia: diagnostic significance and physical explanation. Arch Dermatol. 2004;140:1253–1257.

Baran R, Perrin C. Longitudinal erythronychia with distal subungual keratosis: onychopapilloma of the nail bed and Bowen’s disease. Br J Dermatol. 2000;143:132–135.

Siragusa M, Del Gracco S, Ferri R, Schepis C. Longitudinal red streaks on the big toenails in a patient with pseudobulbar syndrome. J Eur Acad Dermatol Venereol. 2001;15:85–86.

Baran R, Dawber RP, Perrin C, Drape JL. Idiopathic polydactylous longitudinal erythronychia: a newly described entity. Br J Dermatol. 2006;155:219–221.

Baran R. The red nail—always benign? Actas Dermosifiliogr. 2009;100(suppl 1):106–113.

Cohen PR. Idiopathic polydactylous longitudinal erythronychia. J Clin Aesthet Dermatol. 2011;4:22–28. —Philip R. Cohen, MD, Houston, TX • E-mail: mitehead@aol.com

Segmental Vitiligo May Not Be Associated With Risk of Autoimmune Thyroiditis To the Editor: I read with interest the contribution entitled “Vitiligo and Alopecia Areata Associated With Subclinical/Clinical Hypothyroidism” by Dr VN Sehgal.1 The contribution describes 5 cases of concurrent vitiligo and alopecia areata with marked thyroid function abnormalities in patients ranging in age from 11 to 64 years. The author, however, does not address all the subtleties of overlapping autoimmune diatheses. Overlapping alopecia areata and vitiligo can coexist in either a generalized or segmental distribution and is especially noticeable in the scalp area (men and women) and the beard area (men). The primary determinant of whether the generalized autoimmune risk exists is whether the overlap is segmental (autoimmune twin spotting/agminated type), which is caused by postzygotic mutations vs concurrent, generalized disease states, which would imply a generalized autoimmune risk. The overlap of vitiligo and alopecia in a segmental area is a common phenomenon and is unlikely to be associated with autoimmune thyroid disease. Figure 1 demonstrates an example of such a patient. A 13-year-old African American boy presented with a few months’ history of a linear strip of vitiligo in which localized hair loss occurred overlying the vitiligo shortly after onset of the hypopigmentation. Figure 2 demonstrates partial repigmentation and hair regrowth following 3 months’ application of tacrolimus 0.03% ointment twice daily. This individual has had normal thyroid function for the past 7 years. In a cohort of 28 children with vitiligo, 7 (25%) had active thyroid disease2; of the 7 children with segmental vitiligo, none had signs

Figure 1. A 13-year-old boy with linear alopecia and depigmentation of the right temple.

of thyroid autoimmunity. Other studies during the past 10 years have confirmed that the association of vitiligo with hypothyroidism appears to be unique to the generalized3,4 not the segmental forms. The presence of localized alopecia areata within a segmental case of vitiligo is likely caused by the common presence of antibodies to the melanocytes that are within the hair follicle and the epidermis, and is not part of generalized alopecia areata; furthermore, localization of the immune process to a single segment of skin suggests that a somatic mutation in this genetic segment resulted in localized autoimmune susceptibility. While generalized cases of vitiligo can occur concurrent with segmental disease caused by localized loss of heterozygosity, the majority of segmental vitiligo cases lack the generalized

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CORRESPONDENCE propensity.5 Coexistence of autoimmune thyroid disease is only a risk when either the vitiligo and/or alopecia areata are generalized but not when both are in the agminated segmental form. Thyroid function screening, hence, is not needed in overlapping segmental alopecia areata/vitiligo but rather should be reserved for cases where one or both diseases are generalized and especially in the presence of two or more generalized cutaneous autoimmune illnesses.

REFERENCES 1

Sehgal VN. Vitiligo and alopecia areata associated with subclinical/clinical hypothyroidism. Skinmed. 2011;9:192–194.

Pagovich OE, Silverberg JI, Freilich E, Silverberg NB. Thyroid abnormalities in pediatric patients with vitiligo in New York City. Cutis. 2008;81:463–466.

Mazereeuw-Hautier J, Bezio S, Mahe E, et al. Segmental and nonsegmental childhood vitiligo has distinct clinical characteristics: a prospective observational study. J Am Acad Dermatol. 2010;62:945–949.

Iacovelli P, Sinagra JL, Vidolin AP, et al. Relevance of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology. 2005;210:26–30.

Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest. 2004;114:1467–1474.

Figure 2. The same patient after therapy with tacrolimus 0.03% ointment for 3 months.

—Nanette Silverberg, MD, New York, NY. nsilverb@chpnet.org

Author’s Response REFERENCES

To the Editor: 1

The comments on the paper are welcomed and are in order. Indeed, they are well-conceived, outstanding, illustrated, and are laudable, once again reiterating the prevalent overtones on coexistence or overlap of vitiligo alopecia areata and subclinical/ clinical hypothyroidsim of autoimmune origin.1,2 Nonsegmental vitiligo alone has also been reported to occur in multinodulor goiter with euthyroid status.3 The contents of the communication form a viable focus for the future execution. It is, therefore, mandatory to determine the status of thyroid in such cases through thyroid panel/capsule comprising tridothyronine, total thyroxine, and thyroid-stimulating hormone irrespective of segmental and/ or nonsegmental vitiligo in the current context.4 In resourcecrunched countries, however, the discretion is exercised by the treating clinician; nonetheless, it is claimed to be more useful in generalized and progressive vitiligo. This modality is indispensable, and may prove invaluable in evolving the future treatment strategies for vitiligo and alopecia areata in children in particular.5,6

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Sehgal VN. Vitiligo and alopecia areata associated with subclinical/clinical hypothyroidism. Skinmed. 2011;9:192–194.

Sehgal VN, Srivastava G. Vitiligo: auto-immunity and immune responses. Int J Dermatol. 2006;45:583–590.

Sehgal VN, Singh A. Vitiligo occurring in multinodulor goiter with euthyroid status. J Eur Acad Dermatol Venereol. 1996;6:94.

Sehgal VN, Srivastava G. Vitiligo: compendium of clinicoepidemiological features. Indian J Dermatol Venereol Leprol. 2007;73:149–156.

Sehgal VN, Srivastava G. Vitiligo treatment options: an evolving scenario. J Dermatolog Treat. 2006;17:262–275.

Sehgal VN. Role of tacrolimus (FK506) 0.1% ointment WW in vitiligo in children and imperatives of combine therapy with Trioxsalen and Silymarin suspension in progressive vitiligo. J Eur Acad Dermatol Venereol. 2009;23:1218–1219. —Virendra N. Sehgal, MD, Panchwati, Delhi, India • E-mail: drsehgal@ndf.vsnl.net.in

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

Rx Only

BRIEF SUMMARY INDICATIONS AND USAGE Locoid Lipocream is a topical corticosteroid indicated for: relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in adults and the treatment of mild to moderate atopic dermatitis in patients 3 months to 18 years of age. WARNINGS AND PRECAUTIONS Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with the potential for glucocorticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if Locoid Lipocream is applied to large surface areas or used under occlusion. If HPA axis suppression is noted, reduce the application frequency, discontinue use, or switch to a lower potency corticosteroid. Systemic effects of topical corticosteroids may also include manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infections develop. Discontinue use if irritation develops. ADVERSE REACTIONS The most common adverse reactions (>1%) are HPA axis suppression and application site reactions. The following additional local adverse reactions have been reported infrequently with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions included: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and telangiectasia. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.There are no adequate and well-controlled studies in pregnant women. Therefore, Locoid Lipocream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Please refer to full prescribing information for detailed information regarding systemic embryofetal development studies. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Locoid Lipocream is administered to a nursing woman. Pediatric Use Safety and efficacy in pediatric patients below 3 months of age have not been established. Because of higher skin surface-to-body-mass ratios, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are therefore also at a greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing’s syndrome while on treatment. Eighty-six (86) pediatric subjects (5 months to less than 18 years of age) with moderate to severe atopic dermatitis affecting at least 25% of body surface area (BSA) treated with Locoid Lipocream three times daily for up to 4 weeks were assessed for HPA axis suppression. The disease severity (moderate to severe atopic dermatitis) and the dosing regimen (three times daily) in this HPA axis study were different from the subject population (mild to moderate atopic dermatitis) and the dosing regimen (two times daily) for which Locoid Lipocream is indicated. Five of the 82 evaluable subjects (6.1%) demonstrated laboratory evidence of suppression, where the sole criterion for defining HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Suppressed subjects ranged in age from 5 months to 16 years and, at the time of enrollment, had 25% to 95% BSA involvement. These subjects did not develop any other signs or symptoms of HPA axis suppression. At the first follow up visit, approximately one month after the conclusion of treatment, cosyntropin stimulation results of all subjects had returned to normal, with the exception of one subject. This last subject recovered adrenal function by the second post treatment visit, 65 days post-treatment. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have also been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Geriatric Use Clinical studies of Locoid Lipocream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carcinogenesis, Mutagenesis, Impairment of Fertility No studies were conducted to determine the photococarcinogenic or dermal carcinogenic potential of Locoid Lipocream. Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse micronucleus assay). No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day (0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals, such as reduced food consumption and a subsequent reduction in body weight gain, were seen at doses ≥0.6 mg/kg/day (0.2X MTHD). PATIENT COUNSELING INFORMATION Patients using Locoid Lipocream should receive the following information and instructions: Apply a thin layer to the affected skin two or three times daily for corticosteroidresponsive dermatoses in adults. Consult with your physician to determine if treatment is needed beyond 2 weeks. Apply a thin film to the affected skin areas two times daily for atopic dermatitis in patients 3 months of age and older. Safety of Locoid Lipocream in pediatric patients has not been established beyond 4 weeks of use. Rub in gently. Avoid contact with the eyes. Do not bandage, otherwise cover, or wrap the affected skin area so as to be occlusive unless directed by your physician. Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants may constitute occlusive dressings. Do not use Locoid Lipocream on the face, underarms, or groin areas unless directed by your physician. If no improvement is seen within 2 weeks, contact your physician. Do not use other corticosteroid-containing products while using Locoid Lipocream without first consulting your physician. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from freezing. Keep out of the reach of children.

Manufactured for: Triax Pharmaceuticals, LLC Cranford NJ 07016 By: Ferndale Laboratories, Inc. Ferndale MI 48220 Locoid Lipocream is a registered trademark of Astellas Pharma Europe BV licensed to Triax Pharmaceuticals, LLC.

Marketed and Distributed By: Triax Pharmaceuticals, LLC Cranford NJ 07016 www.Locoid.com

131B301 Rev 11/09

Now younger eczema patients have something to smile about

Now approved for use in children down to 3 months of age

The power of an ointment with the elegance of a cream Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older. Safety and effectiveness in pediatric patients below 3 months of age have not been established. Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if applied to large surface areas or used under occlusion. Systemic effects of topical corticosteroids may also include manifestations of Cushingâ&#x20AC;&#x2122;s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use if irritation develops. Please see full Prescribing Information on adjacent page. Visit us at www.locoid.com (hydrocortisone butyrate 0.1%) Cream ÂŠ2010 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