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July/August 2011 • Volume 9 • Issue 4

EDITORIAL Pressure, Time, and Soft Tissue Trauma Lowthian and Parish

COMMENTARY Cholera Allen

DEPARTMENTS COSMETIC SCIENCE The Next Frontier of Sunscreen Protection: Beyond Sunscreens Epstein

PERILS OF DERMATOPATHOLOGY The Three Faces of Cylindroma Zaleski, Dabaghian, Maghari, and Lambert

ORIGINAL CONTRIBUTIONS Unusual Variants of Mycosis Fungoides Abeldaño, Arias, Benedetti, Ochoa, Maskin, Pelleran, Kien, and Chouela

NEW TO THE CLINIC Natroba (Spinosad) 0.9% Suspension Topical Suspension for Head Lice Scheinfeld

A Pentad of Vancomycin Reactions O’Brien, Shah, and Allen

REVIEW Mobile Teledermatology: As Doctors and Patients Are Increasingly Mobile, Technology Keeps Us Connected Farshidi, Craft, and Ochoa

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

CASE STUDIES Multiple Miliary Osteoma Cutis of the Face After Initiation of Alendronate Therapy for Osteoporosis Riahi and Cohen

Significance of Gram’s Stain Smear, Potassium Hydroxide Mount, Culture, and Microscopic Pathology in the Diagnosis of Acrodermatitis Continua of Hallopeau Sehgal and Sharma

Refractory Hailey-Hailey Disease Successfully Treated With Sandpaper Dermabrasion LeBlanc, Wharton, and Sheehan

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

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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

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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.

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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),

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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

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TABLE OF CONTENTS July/August 2011 • Volume 9 • Issue 4

EDITORIAL Pressure, Time, and Soft Tissue Trauma ...................................................................................................... 211 Peter T. Lowthian, MPhil, SRN; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARY Cholera ...................................................................................................................................................... 215 Samuel H. Allen, MD

ORIGINAL CONTRIBUTIONS Unusual Variants of Mycosis Fungoides ........................................................................................................ 218 Alejandra Abeldaño, MD; Mariana Arias, MD; Adriana Benedetti, MD; Karina Ochoa, MD; Matías Maskin, MD; Graciela Pellerano, MD; María Cristina Kien, MD; Edgardo Chouela, MD, PhD

A Pentad of Vancomycin Reactions .............................................................................................................. 225 Meghan O’Brien, MD; Avnee Shah, MD; Herbert B. Allen, MD

REVIEW Mobile Teledermatology: As Doctors and Patients Are Increasingly Mobile, Technology Keeps Us Connected ................................................................................................................. 231 Dina Farshidi, BA; Noah Craft, MD, PhD, DTM&H; Maria Teresa Ochoa, MD

CORE CURRICULUM Noninsulin-Dependent, Type II Diabetes Mellitus–Related Dermatoses: Part I ................................................. 240 Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Megha Gupta, MBBS; Sambit N. Bhattacharya, MD; Prashant Verma, MD Self-Test Review Questions (p. 245)

DEPARTMENTS COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor The Next Frontier of Sunscreen Protection: Beyond Sunscreens ................................................................... 247 Howard A. Epstein, PhD

PERILS OF DERMATOPATHOLOGY

W. Clark Lambert, MD, PhD, Section Editor

The Three Faces of Cylindroma ................................................................................................................... 252 Theresa A. Zaleski, DO; Laurie Dabaghian, BA; Amin Maghari, MD; W. Clark Lambert, MD, PhD

NEW TO THE CLINIC

Noah S. Scheinfeld, MD, JD, Section Editor

Natroba (Spinosad) 0.9% Suspension Topical Suspension for Head Lice ........................................................ 256 Noah S. Scheinfeld, MD, JD

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TABLE OF CONTENTS July/August 2011 • Volume 9 • Issue 4

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

Multiple Miliary Osteoma Cutis of the Face After Initiation of Alendronate Therapy for Osteoporosis .............. 258 Ryan R. Riahi, BS; Philip R. Cohen, MD

Significance of Gram’s Stain Smear, Potassium Hydroxide Mount, Culture, and Microscopic Pathology in the Diagnosis of Acrodermatitis Continua of Hallopeau ............................................................. 260 Virendra N. Sehgal, MD; Sonal Sharma, MD

Refractory Hailey-Hailey Disease Successfully Treated With Sandpaper Dermabrasion .................................. 263 Keith G. LeBlanc, Jr, MD; Joshua B. Wharton, MD; Daniel J. Sheehan, MD

Editorial

ABOUT OUR JOURNAL

MANAGING EDITOR 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.

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July/August 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

Vincenzo Ruocco, MD Naples, Italy

Robert L. Baran, MD Cannes, France

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

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

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

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

George M. Martin, MD Kihei, HI

Virendra N. Sehgal, MD Delhi, India

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

David I. McLean, MD Vancouver, British Columbia

Charles Steffen, MD Oceanside, CA

Jack M. Bernstein, MD Dayton, OH

Michael H. Gold, MD Nashville, TN

Marc S. Micozzi, MD, PhD Bethesda, MD

Alexander J. Stratigos, MD Athens, Greece

Sarah Brenner, MD Tel Aviv, Israel

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

George F. Murphy, MD Boston, MA

James S. Studdiford III, MD Philadelphia, PA

Joaquin Calap Calatayud, MD Cadiz, Spain

Aditya K. Gupta, MD, PhD, FRCP(C) Oumeish Youssef Oumeish, MD, FRCP London, Ontario Amman, Jordan

Robert J. Thomsen, MD Los Alamos, NM

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

Seung-Kyung Hann, MD, PhD Seoul, Korea

Joseph L. Pace, MD, FRCP Naxxar, Malta

Julian Trevino, MD Dayton, OH

Noah Craft, MD, PhD, DTMH Torrance, CA

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

Art Papier, MD Rochester, NY

Snejina Vassileva, MD, PhD Sofia, Bulgaria

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

Tanya R. Humphreys, MD Philadelphia, PA

Johannes Ring, MD, DPhil Munich, Germany

Daniel Wallach, MD Paris, France

Richard L. Dobson, MD Mt Pleasant, SC

Camila K. Janniger, MD Englewood, NJ

Roy S. Rogers III, MD Rochester, MN

Michael A. Waugh, MB, FRCP Leeds, UK

William H. Eaglstein, MD Palo Alto, CA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Donald Rudikoff, MD New York, NY

Wm. Philip Werschler, MD Spokane, WA

Boni E. Elewski, MD Birmingham, AL

Andrew P. Lazar, MD Highland Park, IL

Robert I. Rudolph, MD Wyomissing, PA

Joseph A. Witkowski, MD Philadelphia, PA

Charles N. Ellis, MD Ann Arbor, MI

Ronni Wolf, MD Rechovot, Israel

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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

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

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.

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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.

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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

©2011 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. VEL049R0 April 2011

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July/August 2011

Volume 9 • Issue 4

EDITORIAL

Pressure, Time, and Soft Tissue Trauma Peter T. Lowthian, MPhil, SRN;1 Lawrence Charles Parish, MD, MD (Hon)2 In the 21st century, it might seem reasonable to expect that the pathophysiology of the decubitus ulcer would be understood or, at least, many workers in this field might have reached agreement about causation. Alas, this is not the case, as illustrated in this essay.

A

2010 publication called “International Review. Pressure Ulcer Prevention: Pressure, Shear, and Microclimate in Context,”1 attempts to provide a global concensus about the extrinsic causes and prevention of decubitus ulcers (DUs). This is a laudable aim, because these lesions remain a major health care problem. Witness the penalties inflicted when a hospital patient develops even a lone DU. The document in question is a useful distillation of many recent contributions that discuss the causes and prevention of the DU. Even so, parts of the new document are questionable, and this particularly applies to some comments on the pressuretime curve devised by Reswick and Rogers (R&R curve).2 Pressure in this context means “uniaxial” pressure3 (pressure in one direction). Arguably, prolonged tissue distortion by pressure (or related forces) is the chief extrinsic factor in the etiology of the DU. It is important to know in healthy persons just what levels of pressure and their duration are critical. The R&R curve attempted to do this, and it appeared to be showing an inverse relationship between pressure and time. The R&R curve was neither complete nor absolute,2 with their published figure (Figure 1) indicating their degree of uncertainty about a definitive curve; however, the new idea about a sigmoid function curve1,4,5 merits our consideration.

distance above the rabbits’ hearts, thereby, acting on a reduced blood pressure, when compared with the recumbent dogs used by Kosiak, who had applied pressure to the dogs’ femoral trochanters. With this insight, a new curve was drawn (Figure 2).9 It resembled the R&R curve but was largely based on Kosiak’s own pressure-time curve.8 This has been considered relevant to humans, even though dogs were used. As with the R&R curve, the 1995 curve was not absolute; yet, it was criticized (anonymously), because it was not a true geometric (hyperbolic) curve. This, however, was not a claim made for it. Similarly, no such claim appears to have been made for the R&R curve.2 Despite this, Gefen has shown a curve that purports to be similar to the R&R curve but is more precise.4 More bizarre is the fact that this new hyperbolic curve is then criticized for predicting DUs at 25 mm Hg, which is, of course, unlikely (see below)!3

PROBLEMS WITH CURVES

We assume that Gefen is attempting to make a case for a pressure-time curve shaped like a reversed “S,” this contention being based on skeletal muscle experiments. In short, at very high pressures, the upper part of the R&R curve ought to change direction, so that it curves toward zero on the time scale. While we agree with this, it does not affect the usefulness of either the R&R curve or the 1995 curve. In addition, the reversed S curve supports our contention that many DUs are caused by overstretching of the microcirculation.10

Developing a practical pressure-time curve is problematic. For instance, in 1995 one of us (PTL) showed how the experimental pressure work of Lindan on rabbit ears6 could be reconciled with the similar work by Kosiak7,8 (Lindan and Kosiak were mid20th century pioneers in the field). Briefly, Lindan’s pressure indenters, which were rigid but smooth pads, were placed a short

In explaining this, we should consider that, in Gefen’s work, as well as in similar publications,1 there appears to be no clear conviction as to why prolonged uniaxial pressure (exacerbated, or not, by related forces, such as tissue shear and tension) produces pressure necrosis. Possibly, these investigators have not fully appreciated what pressure can do to the microcirculation.

Independent Specialist in Pressure Area Care, Watford, United Kingdom;1 and from the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Peter T. Lowthian, MPhil, SRN, 134 Villiers Road, Watford, WD19 4FJ, United Kingdom • E-mail: peterlowthian@btinternet.com

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EDITORIAL death, then occurs in the plaque of compressed tissue, which is now almost completely devoid of circulation. Of course, if the pressure is high enough, capillaries and other small blood vessels will be ripped by the distraction effect so that a contusion results. At even higher pressures, the skin and subcutaneous tissue are torn apart, producing a laceration. In summation, DUs, contusions, and lacerations are all related. As these very high pressures are applied to soft tissues, pressuretime curves will change direction: toward zero on the time scale. This change will occur at pressures higher than the 650 mm Hg shown on the 1995 curve (Figure 2). Such pressures are not generally encountered in normal clinical situations. Additionally, various tissues (eg, flaccid muscle and skin) will be disrupted at different levels of pressure. Unfortunately, the data for plotting such extended pressure-time curves are currently lacking.

Figure 1. Allowable pressure vs time of application under bony prominences. Reproduced with permission from Reswick and Rogers.2

When it comes to determining the pressure to which a patient is being subjected, both the R&R curve and the 1995 curve assume that measurements will be taken at the patient/support interface, using a small pressure sensor.13,14 If the patient’s bony prominence is close to the skin surface, such readings should be reliable; however, on some subjects, measurements over deep-seated prominences will register a pressure lower, at the interface, than will occur near the prominence. Groth demonstrated this principle in 1942.15 It follows that these deep pressures will need estimating.3 Groth also demonstrated that a rigid pressure indenter the same size and shape as a bony prominence will produce the same soft tissue pressures throughout the depth of tissue separating the prominence and the indenter.15 This points out that Kosiak’s experimental results, using pressure indenters similar in size and shape to the dogs’ femoral trochanters, must be very close to the actual tissue pressures the dogs experienced. It follows that the 1995 curve, being largely based on Kosiak’s curve, should indicate the maximum pressure levels and times under such pressures that can be allowed (in humans) to avoid pressure necrosis; this being for normotensive patients, at heart level.

Figure 2. Estimated pressure-time curve of uniaxial pressure, at heart level, which can lead to soft tissue destruction or tissue atrophy, in normotensive adults. Reproduced with permission from Lowthian.9

ADDITIONAL PRESSURE-TIME CURVES

TRAUMA FROM PRESSURE As described in previous papers,10–12 we maintain that many DUs, especially deep ones, are caused when the pressure under a bony prominence is both high enough and sufficiently prolonged to produce distortion and lateral distraction of the soft tissues. This takes time, partly because tissue fluids and gels have to migrate through tight tissue interstices.12 These distorted tissues contain the microcirculation. In consequence, this is also distracted, until it is overstretched. Then, to seal these leaking vessels, platelets are activated and so produce multiple microthrombi, surrounding the region of maximum pressure. Acidosis, followed by tissue SKINmed. 2011;9:211–213

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We still await pressure-time curves for tissues situated some distance below the heart; likewise, we have no pressure-time curves for either hypotensive or hypertensive patients. Estimates are possible using data from a suitable textbook.16 Interestingly, Reswick and Rogers, along with some other researchers, probably did not appreciate that normal tissue pressures at some distance below the heart register higher than those at heart level.16,17 This may account for some of the uncertainty in their results.3 At the lower end of the 1995 pressure-time curve, there comes a point where long-continued pressures (below 50 mm Hg but

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above 32 mm Hg) should result in tissue atrophy, rather than in pressure necrosis9; hence the reference to atrophy in Figure 2. As a result, we maintain that the R&R curve, and particularly the 1995 curve, gives useful indications of the pressures and times needed to cause pressure necrosis, or tissue atrophy, in humans.

5

Gefen A. Reswick and Rogers pressure-time curve for pressure ulcer risk. Part 2. Nurs Stand. 2009;23(46):40–44.

6

Lindan O. Etiology of decubitus ulcers. Arch Phys Med Rehabil. 1961;42:774–783.

7

Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehabil. 1959;40:62–69.

8

Kosiak M. Etiology of ischemic ulcers. Arch Phys Med Rehabil. 1961;42:19–29.

9

Lowthian PT. An investigation of the uncurling forces of indwelling catheters. Br J Nurs. 1995;4:328–334.

PRESSURE ON MUSCLES In the 2010 document, and in other papers by Gefen, some emphasis is placed on the trauma to muscle cells caused by pressure. We agree that damaged muscle cells can result from prolonged pressure. Even so, the microanatomy of skeletal muscle illustrates that muscle capillaries mostly run between the fibrils.18 With the muscle relaxed (or flaccid) they are straight rather than convoluted. As a result, they can be easily overstretched when pressure is applied, which is an important consideration. In practice, however, many DUs (eg, on the heels and the femoral trochanters) do not involve skeletal muscle. Similarly, this applies to the ischia because, when seated, the gluteal muscles normally slip sideways so that the specialized panniculus adiposus of the buttocks is positioned under the ischia.19 Even so, if an indenter is pressed against muscle tissue,20 we should expect to get traumatized muscle. In clinical practice, skeletal muscle may become involved in serious DUs, but our experience reveals that this is mostly after the initial necrosis in connective tissues. It is also reasonable to conclude that the ulcers developing in Kosiak’s dogs were mostly in connective tissue over their femoral trochanters.

10 Lowthian PT. Trauma and thrombosis in the pathogenesis of pressure ulcers. Clin Dermatol. 2005;23:116–123. 11 Parish LC, Lowthian PT, Witkowski JA. The decubitus ulcer: many questions but few definitive answers. Clin Dermatol. 2007;25:101–108. 12 Lowthian PT, Parish LC. Decubitus ulcers: definitions, disagreements, and deductive etiology. Skinmed. 2010;8:67–69. 13 Robertson JC, Shah J, Amos H, et al. An interface pressure sensor for routine clinical use. Eng Med. 1980;9:151–156. 14 Shaw BH. Pneumatic capsules as pressure transducers—effect of size on tissue bearing pressure readings. BRADU Report. Oxford, England; 1979:140–144. 15 Groth KE. Klinische beobachtungen und experimentelle studien uber die entstehung des dekubitus. Acta Chir Scand. 1942;LXXXVII (suppl 76). 16 Ganong WF. Review of Medical Physiology. 12th ed. Los Altos, CA: Lange Medical Publications; 1985:477–484. 17 Browse NL. The Physiology and Pathology of Bed Rest. Springfield, Il: Charles C. Thomas; 1965:14–15. 18 Elias H, Pauly JE. Human Microanatomy. 3rd ed. Philadelphia, PA: FA Davis; 1966.

CONCLUSIONS

19 Elson RA. Anatomical aspects of pressure sores and their treatment. Lancet. 1965;I:886.

Why dig into all of these data? Well, we believe that some past mistakes and misunderstandings continue to confound this area of study, so that specialists in DU pathogenesis continue to hold very divergent views. Indeed, the differing and even contradictory information found in some papers defeats attempts at any reconciliation. How can clinicians develop appropriate patient care guidelines when the basics are still not clear?

20 Linder-Ganz E, Engelberg S, Scheinowitz M, et al. Pressuretime  cell death threshold for albino rat skeletal muscles as related to pressure sore biomechanics. J Biomech. 2006;39: 2725–2732.

REFERENCES 1

Takahashi M, Black J, Dealey C, et al. Pressure in context. In: International Review. Pressure Ulcer Prevention: Pressure, Shear, Friction and Microclimate in Context. A Consensus Document. London, England: Wounds International; 2010:2–10.

2

Reswick JB, Rogers JE. Experience at Rancho Los Amigos Hospital with devices and techniques to prevent pressure sores. In: Kenedi RM, Cowden JM, Scales JT, eds. Bed Sore Biomechanics. London, England: Macmillan; 1976:301–310.

3

Lowthian PT. Notes on the pathogenesis of serious pressure sores. Br J Nurs. 1997;6:907–912.

4

Gefen A. Reswick and Rogers pressure-time curve for pressure ulcer risk. Part 1. Nurs Stand. 2009;23(45):64–68.

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When she asks about her scar, recommend Mederma® with confidence. In a clinical study,1 77% of subjects noted moderate to significant improvement in scars treated with Mederma® in terms of redness, texture and overall appearance. 98% of patients completed the study without any adverse events.

1 Draelos, Z., The ability of onion extract gel to improve the cosmetic appearance of postsurgical scars, Cosmetic Dermatology, June 2008. 2 IMS Health, NDTI, December 2008. 3 Pharmacy Times, OTC Guide, June 2010.

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Volume 9 • Issue 4

COMMENTARY

Cholera Samuel H. Allen, MD “A disease worse than death, which begins where others end, with death.� — Magendie, Paris, 1831

C

holera is a severe and often fatal secretory diarrhea caused by the bacterium Vibrio cholerae. Man is the only known natural host, but the organism can exist in shellfish. Transmission is through ingestion of contaminated water or food. The infectious dose varies between 105 and 108 organisms, with an incubation period to clinical disease from a few hours to 5 days. For each symptomatic case, there may be 5 to 40 asymptomatic or mildly symptomatic carriers that can lead to rapid spread of disease, especially when living conditions are cramped and safe water supply is inadequate. There are no prodromal symptoms associated with cholera, and fever is unusual. The onset of diarrhea is usually abrupt and begins as mild diarrhea that rapidly gives way to passage of copious opalescent â&#x20AC;&#x153;rice-waterâ&#x20AC;? stool. The stool is nonodorous or has a slight fishy smell. Vomiting of fluid of similar composition may occur as a later feature. The massive fluid lossâ&#x20AC;&#x201D;up to 20 L dailyâ&#x20AC;&#x201D;leads to rapid hypovolemia, with up to 10% of a personâ&#x20AC;&#x2122;s body weight being lost in a few hours. Untreated, the disease is associated with a 20% to 80% mortality rate. This can be reduced to <1% with adequate rehydration.

V cholerae is not invasive in the gut but exerts its effect by means of an enterotoxin. The toxin has two components: B (binding) and A (active). Binding of B subunit toxin to the small intestinal epithelial cell membrane enables the A subunit to migrate into the cell and activate adenylyl cyclase, inhibiting sodium chloride absorption. Stimulating chloride excretion leads to hypersecretion of water and chloride ions, producing a small intestinal watery diarrhea. The organism is a motile (Vibrio from the Latin â&#x20AC;&#x153;to moveâ&#x20AC;?), comma-shaped, gram-negative organism, and can be cultured on thiosulfate-citrate-bile salts-sucrose agar. EPIDEMIOLOGY The annual global disease burden of cholera is estimated to be between 3 and 5 million cases, with approximately 120,000 deaths per annum. Although eliminated as a major public health concern in developed countries, there has been no decline in incidence in developing countries, despite efforts to ensure provision of clean water and adequate sanitation.

MICROBIOLOGY

Massive assemblies of pilgrims along the Ganges river led to 6  pandemics of cholera between 1817 and 1823. In 1961, V cholerae serotype O1 El Tor emerged as the seventh pandemic and continues to spread to the present day. Symptomless carriers, who may represent 75% of those infected with the El Tor biotype, are very important in the epidemiology of this disease, as they may transport the organisms over long distances and from country to country.

V cholerae was first demonstrated by Koch in 1883. The species is now divided into several distinct serovars, according to their somatic (O) antigen, the most important being O1. There are two biotypes, namely classical and El Tor, the latter being first isolated from pilgrims at the El Tor quarantine station in Sinai, Egypt, in 1906.

In 1992, a hitherto unknown toxigenic serovar, designated O139, was identified in Madras, India and Bangladesh. The high attack rate of O139 among adults suggests that previous exposure to O1 serotype does not confer protection. This type of cholera is now spreading in the Far East, where it is replacing the El Tor serotype, raising concerns that it may lead to the eighth pandemic.

Rapid fluid loss leads to thirst, muscle cramps, anuria, electrolyte loss, metabolic acidosis, and hypovolemic shock. Severe hyponatremia and hypokalemia can result in cardiac arrhythmia and paralytic ileus. Typical â&#x20AC;&#x153;choleric faciesâ&#x20AC;? are presented as deeply sunken cheeks and eyes, dry skin, and dry mucous membranes.

From the Department of Infectious Diseases, Crosshouse Hospital, Kilmarnock, Scotland, United Kingdom Address for Correspondence: Samuel H. Allen, MD, Carlung House, West Kilbride, KA23 9PU, Scotland, United Kingdom â&#x20AC;˘ E-mail: sam.allen@nhs.net

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HAITI CHOLERA OUTBREAK On January 12, 2010, Haiti experienced a massive earthquake that resulted in the loss of approximately 220,000 lives and made more than 1 million people homeless. On October 20, 2010, 60 cases of acute watery diarrhea were reported at Lâ&#x20AC;&#x2122;HĂ´pital de Saint Nicolas, more than 55 miles from the nearest displacedpersons camp, and were later confirmed as cholera. The outbreak has continued to spread, with almost 179,000 reported cases and 3759 reported deaths to January 7, 2011.1 Although shocking, the reported number of cases is likely to represent only a fraction of the epidemicâ&#x20AC;&#x2122;s true toll. Although cholera has been present in Latin America since 1991, it has not been epidemic in Haiti for at least 100 years. Paradoxically, it now appears that the Haitian strain of the disease was imported, probably through one of the aid agencies that may have inadvertently dumped waste from their camp into a nearby river used as a source for drinking water. This strain appears to have a higher relative fitness and pathogenicity compared with previous cholera cases in the region and raises concern that this will now spread to neighboring countries.2 TREATMENT

REHYDRATION Rapid rehydration with electrolyte replacement proportionate to fluid and electrolyte loss is the key to successful treatment. A rapid assessment of fluid loss can be made by collecting the watery stool in a graduated bucket placed under the large central hole in a waterproof disposable sheet upon which the patient lies. Oral rehydration works well in all but severe cases. Oral rehydration salts to replace electrolyte loss (eg, Dioralyte) or locally prepared cereal-based formulations can dramatically reduce mortality. Luminal glucose absorption mechanism is not affected by the cholera toxin. A simple oral replacement solution can be made from 1 teaspoon of table salt and 4 heaping teaspoons of sugar added to 1 L of safe water. Intravenous fluids are indicated in persons in shock or with other signs of severe hypovolemia.

ANTIBIOTIC THERAPY Effective antibiotic therapy not only shortens the duration of excretion of V cholerae in the stool, but also shortens the duration of illness and reduces the bacterial shedding to the environment. Effective antibiotic therapy, therefore, has both individual and communal benefits that maximize the effectiveness of limited resources while optimizing patient care.

azithromycin has been shown to be highly effective, leading to dramatic resolution of diarrhea after 24 hours.3 If antimicrobials are to be used, this will require close monitoring for emergence of antibiotic resistance. Single plasmid-mediated resistance genes have been shown to spread with antibiotic pressure. The epidemic strain in Haiti is susceptible to tetracycline (a proxy for doxycycline) and azithromycin but is resistant to nalidixic acid (ciprofloxacin) and cotrimoxazole. PREVENTION Cholera vaccines confer only short-lived limited protection and are, therefore, not particularly effective as pre-exposure prophylaxis in outbreak management. Although they may prevent up to 50% of clinical cases, they do not lower the number of infected and therefore infectious persons. Vaccination is, therefore, likely to lead to a false sense of security both among vaccinees and the authorities. Contacts with patients with proven disease, however, should receive vaccine as post-exposure prophylaxis. All faeces and bed linen of patients with known cases should be destroyed. Toxoid vaccines using inactivated toxin have so far been shown to be ineffective. As our understanding of the pathophysiology of cholera improves, it is anticipated that the efficacy of newer cholera vaccines will increase. The challenge is the emergence of more virulent and antibiotic-resistant strains of cholera such as those that are appearing in Bangladesh and have now appeared in Haiti. Breaking the link between safe drinking water and sewerage remains the key to prevention and control, as it was when Dr John Snow identified the Broad Street pump as the source of the Soho outbreak in London in 1854. This epidemic was immediately halted when the pump handle was removed.4 As an increasingly interconnected global population surpasses 7 billion, the potential for further cholera outbreaks and pandemics will increase. A â&#x20AC;&#x153;good Samaritanâ&#x20AC;? stockpile of cholera vaccine for rapid deployment to countries in need has been proposed as a lever in â&#x20AC;&#x153;vaccineâ&#x20AC;? diplomacy.5 FIVE BASIC CHOLERA PREVENTION MESSAGES

Several antimicrobials are effective in the treatment V cholerae, including doxycycline, chloramphenicol, cotrimoxazole, azithromycin, and ciprofloxacin. Administration of single-dose SKINmed. 2011;9:215â&#x20AC;&#x201C;217

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1. Drink and use safe water: piped water sources, drinks sold in cups or bags, or ice may not be safe and should be boiled or treated with chlorine. 2. Wash your hands often with soap and water: if no soap is available, scrub hands often with ash or sand and rinse with safe water. 3. Use latrines or bury your feces; do not defecate in any body of water. Cholera

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COMMENTARY

4. Cook food well, keep it covered, eat it hot, and peel fruit and vegetables (“boil it, cook it, peel it, or forget it”).

3

Saha D, Karim MM, Khan WA, et al. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med. 2006;354:2452–2462.

5. Clean up safely—in the kitchen and in places where the family bathes and washes clothes.

4

Snow J. On the Mode of Communication of Cholera. London, England: Churchill; 1855.

5

Waldor MK, Hotez PJ, Clemens JD. A national cholera stockpile—a new humanitarian and diplomatic resource. N Engl J Med. 2010;363:2279–2282.

REFERENCES 1

2

The Gazette. Haiti cholera toll tops 3,750. http://www.montrealgazette.com/news/Haiti+cholera+toll+tops/4103074/story. html. Accessed January 24, 2011.

BIBLIOGRAPHY

Chin CS, Sorenson J, Harris JB, et al. The origin of the Haitian cholera outbreak strain. N Engl J Med. 2010;364:33–42.

Gabriel García Márquez. Love in the Time of Cholera. Grossman E, trans. New York, NY: Alfred A. Knopf; 1988.

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.

(continued on page 222) SKINmed. 2011;9:215–217

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Volume 9 â&#x20AC;˘ Issue 4

ORIGINAL CONTRIBUTION

Unusual Variants of Mycosis Fungoides Alejandra AbeldaĂąo, MD; Mariana Arias, MD; Adriana Benedetti, MD; Karina Ochoa, MD; MatĂ­as Maskin, MD; Graciela Pellerano, MD; MarĂ­a Cristina Kien, MD; Edgardo Chouela, MD, PhD ABSTRACT Unusual variants of mycosis fungoides (MF) differ substantially from the classical presentation, and most of them resemble other dermatologic diseases. The authors reviewed files of patients with MF who consulted our clinic between November 1995 and June 2010 to evaluate the relative frequency and clinical behavior of these variants. Among 98 patients with MF, 32 (32.65%) had unusual variants. The most common types included follicular MF (31.25%), hypopigmented MF (18.75%), poiquilodermic MF (15.6%), and erythrodermic MF (12.5%). Less common variants included unilesional MF, bullosa MF, ichthyosiform MF, granulomatous slack skin, and pigmented purpura-like MF. Progressive disease and MF-related death were most commonly associated with follicular MF, bullosa MF, and erythrodermic MF. (SKINmed. 2011;9:218â&#x20AC;&#x201C;222)

M

ycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphomas (CTCLs), representing 44% of newly diagnosed primary cutaneous lymphomas in the Dutch experience, 82% at three academic dermatology departments in the United States, and 72% in a multicenter study conducted in Argentina.1â&#x20AC;&#x201C;3

As first described by Alibert and Bazin in the 19th century, clinicopathologic manifestations of MF include multiple patches and plaques that may progress to tumors. The classical Alibert-Bazin disease (cMF) is now recognized as an indolent cutaneous lymphoma with three well-defined variants: follicular MF, pagetoid reticulosis, and granulomatous slack skin. Many variants of this lymphoma differ substantially from cMF, and are, therefore, sometimes referred to as atypical or unusual forms of MF, most of which resemble other dermatologic diseases.4,5 The objective of this investigation was to evaluate the prevalence of infrequent variants of MF among patients with a diagnosis of MF and to estimate the clinical course in relation to their stage at the time of diagnosis, disease progression, and response to initial treatment. This was an observational, descriptive, retrospective cohort analysis. Between November 1995 and June 2010, all patients with a clinicopathologic and immunophenotypic diagnosis of CTCL (World Health Organization/European Organization for Research and Treatment of Cancer, 20051) seen in our department were included in a database. Follow-up data

were collected yearly. The following variables were recorded: sex, age, date of definitive diagnosis, stage, type, response to initial treatment, and disease course. Among 135 patients with primary cutaneous lymphomas, 130 had CTCL. Of the latter, 98 (75.38%) had MF (56 men). The mean age at diagnosis was 51.97 years (range, 12â&#x20AC;&#x201C;77 years). From the group of MF patients, 32 (32.65%) had atypical variants (20 men), with a mean age of 44.91 years (range, 12â&#x20AC;&#x201C;76 years). These cases included 10 follicular MF (FMF), 6 hypopigmented MF (HMF), 5 poiquilodermic MF (PMF), 4 erythrodermic MF (EMF), 3 unilesional MF (UMF), and 1 case each of granulomatous slack skin (GSS), ichthyosiform MF (IMF), pigmented purpura-like MF (PPMF), and bullosa MF (BMF) (Figure 1). Staging evaluation of these atypical variants revealed that 15 (47%) were at an advanced stage (IIB to IV), while 17 (53%) were at stage IA to IIA at the time of diagnosis. We evaluated response to therapy and found that 15 patients (47%) achieved complete response to initial treatment and 12 patients (37%) achieved partial response. The analysis of the group with complete response revealed that 5 patients (33.3%) were treated with psoralenâ&#x20AC;&#x201C;UV-A (PUVA) and low doses of interferon (IFN) a, and 5 (33.3%) were treated with sun irradiation and topical corticosteroids. The remaining 5 patients were taking IFN combined with total skin electron beam therapy, retinoids with PUVA, sun exposure associated with topical corticosteroids

From the Department of Dermatology, School of Medicine, University of Buenos Aires, Argentina Address for Correspondence: Alejandra AbeldaĂąo, MD, Unidad de DermatologĂ­a, Hospital General de Agudos Dr Cosme Argerich, Pi y Margall 750 (C1155AHD), Ciudad AutĂłnoma de Buenos Aires, Argentina â&#x20AC;˘ E-mail: dermatoargerich@gmail.com

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ORIGINAL CONTRIBUTION DISCUSSION In a previous report,6 we found 17 cases until August 2007. During the later years we could identify 15 cases, allowing us to infer that unusual variants of MF are more frequent than we expected or that an accurate grade of suspicion at the time of diagnosis was developed. FMF was the most frequent variant of MF, representing 31.25%. Clinical features in FMF are hair loss in the affected area, hyperkeratotic follicular papules, and cyst-like lesions (Figure 2). The face, neck, and trunk are the most commonly affected areas, and there is a significantly higher male to female ratio.4,5,7,8 All cases were consistent with these features. Dense folliculocentric infiltrates are the histopathologic hallmark in FMF (Figure 3). Cells are small to medium and mucin deposition is common. While 4 patients with this variant had a poor clinical course, the other 6 patients had stable disease with good response to initial treatment, although sustained remission could not be achieved.

Figure 1. Distribution of atypical variants in our series of cases. FMF indicates follicular mycosis fungoides (MF); EMF, erythrodermic MF; PMF, poiquilodermic MF; HMF, hypopigmented MF; UMF, unilesional MF; IMF, ichthyosiform MF; GSS, granulomatous slack skin; BMF, bullosa MF; PPMF, pigmented purpura-like MF.

To define EMF, a previous history of cMF is required, together with absent or minimum blood involvement.9 The 4 patients in this series were men. We could observe a progressive disease state with lymph node spread in one of them. Clinical features in PMF include hypopigmentation or hyperpigmentation, dryness, skin atrophy, and telangiectasias. Histopathologic examination shows atrophy of the epidermis, vacuolar alteration of the basal layer, melanophages, and dilatation of superficial blood vessels.4,5,10 There were 5 patients (15.62%) with a diagnosis of PMF in our group, and 4 were men. All patients had a stable disease with very good response to initial treatment (in most of cases, sun exposure plus topical corticosteroids) and sustained remission. Figure 2. Follicular mycosis fungoides: erythematous tumor lesions and multiple follicular hyperkeratotic papules in trunk.

and thalidomide, and topical corticosteroids alone. The disease course was mild for most variants and disease progression was followed-up in 4 patients with FMF: 1 patient had visceral involvement and death related to the disease, 1 had rapid progressive-stage disease followed by death, and 2 had transformation to large-cell lymphoma. Another patient with BMF showed rapid cutaneous spread also with transformation to an anaplastic large T-cell lymphoma followed by death 22 months after diagnosis. One of the patients with EMF showed a positive lymph node. The mean follow-up period after diagnosis of lymphoma was 37.49 months (range, 3â&#x20AC;&#x201C;128 months).

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A total of 6 patients (18.75%) from the group of atypical MF had a diagnosis of HMF. Mean age of this group was 26.07 years. The youngest 5 patients were aged between 12 and 28 years, and hypopigmentation was the only feature of the disease (Figure 4). The remaining patient, a man aged 68, developed this unusual variant after cMF and had an advanced stage at diagnosis. Classical features of MF can be seen in the histopathology. There are no histopathologic markers for this type.4,5,11 This variant affected patients at a younger age, most of whom had stable disease with a good response to treatment, but recurrences were frequent. Unilesional MF is defined by single typical MF lesions, or lesions limited to an isolated individual area involving <5% of the body surface. The breasts, axilla, and buttocks are the most commonly

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ORIGINAL CONTRIBUTION

affected areas.12 There were a total of 3 patients (9.37%) with UMF in our study, all of whom were women who had very good response to topical corticosteroids. Granulomatous slack skin (GSS) occurs most frequently in flexural areas in women. There is a high association with Hodgkin disease. It is characterized by slowly developing bulky, infiltrated folds of atrophic skin in flexural areas. Apart from the epidermotropic infiltrates, the specific finding is the presence of a granuloma with multinucleated giant cells containing lymphocytes and elastic fibers in their cytoplasm. Elastic fibers are almost totally absent.4,5,13 We had only one patient with GSS, a 44-year-old woman with a previous history of patch-stage cMF but with a fluctuating course and a poor response to treatment until she developed this variant (Figure 5). Vesiculobullous lesions are an extremely rare manifestation of MF. Kaposi reported the first case of BMF in 1887 and described it as pemphigus-like MF. BMF commonly presents in elderly patients (with an average age of approximately 66 years) and has no sex predominance. Blisters can superimpose on typical skin lesions of classic MF and Sezary syndrome. The trunk and limbs are predominantly affected. Bullous lesions usually appear months to years after classic MF patches and plaques, but, in some cases, they are present as the primary manifestation.14 The presence of epidermotropism and cerebriform atypical lymphocytes in microscopic studies of the bullous tissue samples, are the cardinal guide to the diagnosis of BMF. Blisters can be seen in different locations on the skin, including subcorneal, intraepithelial, and subepidermal. Immunofluorescence studies are negative. Other bullous diseases must be excluded before the diagnosis of BMF can be established.

Figure 3. Follicular mycosis fungoides: atypical lymphocyte infiltrate with marked folliculotropism (hematoxylin-eosin stain, original magnification Ă&#x2014;100).

BMF represents a particularly aggressive form of MF and is associated with a poor prognosis.15 Only 1 patient (3.12%) in our series had BMF. The patient was a man with classical clinical features (Figure 6). We performed multiple biopsies, all with an unspecific histopathology until reaching a definitive diagnosis. Later, he underwent rapid transformation to an anaplastic large cell lymphoma CD30+ and died 22 months after diagnosis, during chemotherapy, due to sepsis. In IMF, we find widespread ichthyosiform lesions, comedo-like lesions, and or follicular keratotic papules, most frequently seen on the extremities. Pruritus is the rule.16 One patient (3.12%) in our series had IMF, a 65 year-old man with a 4-year history of xeroderma and pruritus until a final diagnosis of MF was made (Figure 7). Complete and sustained remission was achieved with PUVA and IFN-a.

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Figure 4. Hypopigmented mycosis fungoides: hypopigmented lesions on the legs.

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Figure 7. Ichthyosiform mycosis fungoides: adherent scales and erythematosquamous plaques on the legs.

Figure 5. Granulomatous slack skin: hanging fold of slack skin located in the axilla.

It is important to rule out purpuric drug eruptions in association with PPMF, which can be monoclonal, and therefore a close follow-up is required.4,5

CONCLUSIONS Among 98 patients with MF, 32 were unusual variants, with FMF, EMF, PMF, and HMF being the most frequent types. As in the classical disease, we found a male predominance (62.5%) but at a younger age. The youngest patients were those with HMF. Most variants had an indolent course. Recurrence was common in HMF. A total of 47% were at an advanced stage, probably because of the 10 patients with FMF who were considered to have tumorstage disease, regardless of their clinical appearance, as it has been proposed by the Dutch group. Another 47% achieved complete response after initial treatment. Among complete responders, 33.3% were treated with PUVA and low doses of IFNa and 33.3% with sun irradiation and topical corticosteroids. Although there was good response to initial treatment in FMF, most patients could not achieve sustained complete remission. Disease progression and MF-related death were almost entirely restricted to FMF, BMF, and EMF. There is a wide range of clinical presentations in MF. It is important to recognize these unusual variants of MF, because misdiagnosis in the early stages could delay the correct diagnosis and prompt treatment with prognostic and therapeutic implications. REFERENCES

Figure 6. Bullosa mycosis fungoides (MF): tense blister and erosion on skin lesions of MF.

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1

Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–3785.

2

Zackheim HS, Vonderheid EC, Ramsay DL, et al. Relative frequency of various forms of primary cutaneous lymphomas. J Am Acad Dermatol. 2000;43:793–796.

3

Abeldaño A, Blaustein A, Azcune R, et al. Frecuencia relativa de varias formas de linfomas cutáneos primarios de células T. Una serie retrospectiva de 91 pacientes. Dermatol Argent. 2004;10:215–227.

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4

Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397–415.

11 Akaraphanth R, Douglass MC, Lim HW. Hypopigmented mycosis fungoides: treatment and a 6 ½-year follow-up of 9 patients. J Am Acad Dermatol. 2000;42:33–39.

5

Nashan D, Faulhaber D, Ständer S, et al. Mycosis fungoides: a dermatological masquerader. Br J Dermatol. 2007;156:1–10.

12 Hodak E, Phenig E, Amichai B, et al. Unilesional mycosis fungoides: a study of seven cases. Dermatology. 2000;201:300–306.

6

Abeldaño A, Arias M, Ochoa K, et al. Micosis fungoide más allá de la forma clásica de Alibert-Bazin: comunicación de diecisiete variantes atípicas. Dermatol Argent. 2008;14:124–133.

7

Van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a distinct disease with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol. 2002;138:191–198.

8

Cristina Muniesa C, Estrach T, Pujol RM et al. Folliculotropic mycosis fungoides: clinicopathological features and outcome in a series of 20 cases. J Am Acad Dermatol. 2010;62:418–426.

13 Kempf W, Ostheeren-Michaelis S, Paulli M, et al. Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC). Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer. Arch Dermatol. 2008;144: 1609–1617.

9

Vonderheid E, Bernengo M, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. 2002;46:95–106.

14 Bowman PH, Hogan DJ, Sanusi ID. Mycosis fungoides bullosa: report of a case and review of the literature. J Am Acad Dermatol. 2001;45:934–939. 15 Kneitz H, Bröcker E-B, Becker JC. Mycosis fungoides bullosa: a case report and review of the literature. J Med Case Reports. 2010;4:78. 16 Badawy E, D’Incan M, Majjaour SE, et al. Ichthyosiform micosis fungoides. Eur J Dermatol. 2002;12:594–596.

10 Bukhari IA. Poikilodermatous variant of mycosis fungoides. J Drugs Dermatol. 2006;5:190–192.

HISTORICAL DIAGNOSIS & TREATMENT: SARCOMA (continued from page 217)

S

arcomas are malignant connective tissue tumors which may have their origin in any organ of the body and are only occasionally primary, but not infrequently secondary, in the skin. They may be classified as non-pigmented and melanotic. There is little difference in the clinical course of the two except that the melanotic form is much more malignant. A sarcoma may arise in the skin without any visible antecedent lesion, but more often it develops from a nevus, especially from one that has been irritated by trauma, cauterization or electrolysis. When the original nevus is pigmented the malignant growth is apt to reproduce the pigment but not necessarily in the same degree. Melanotic sarcomas vary in color from grayish brown to bluish black. The skin over a non-pigmented sarcomatous node may be normal in color but is often reddish or purplish on account of its increased vascularity. A nevus that has undergone malignant transformation first gives evidence of the fact, as a rule, by an increase in size or change of color. About a pigmented mole a dark areola may spread out, or clusters of black puncta develop in close proximity. Occasionally without noticeable change in the mole there occurs a swelling of adjacent lymph glands which on microscopic examination may be found to contain groups of tumor cells similar to those of the original growth. A melanotic sarcoma sometimes develops primarily in a nail fold and has the appearance of a chronic paronychia with pigmented spots suggestive of silver nitrate stains. Sarcomatous tumors occasionally, though rarely, attain the size of an orange. They are usually sessile and hemispheroidal or lobulated and may be firm and elastic or somewhat doughy and compressible. They are at times slightly tender. Some non-pigmented growths are very much more slow

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to spread by metastasis than the melanotic tumors, and being less malignant are more apt to reach a large size. Sarcomas are always quite vascular and therefore when not situated in a region in which they are particularly exposed to trauma are little inclined to ulcerate. But over a large tumor the epidermis in time becomes thinned and abraded and a granulated vascular surface is exposed. The skin about the tumor may be diffusely infiltrated and discolored. By the time a growth has reached this stage there are usually numerous metastatic tumors in the skin and viscera. Sarcomatosis cutis or generalized sarcoma of the skin may arise thus from a primary cutaneous growth, but is more often secondary to disease of a deeper organ. Multiple melanotic growths spring not infrequently from a sarcoma of the choroid, as in the case illustrated, in which there was exophthalmia on the right due to the presence of the tumor in the orbit. Nodes develop in various regions but rarely reach any considerable size because death soon ensues. The duration of life may be many years from the onset of the least malignant non-pigmented form, but with the melanotic variety it rarely exceeds three years and may be only four or five months. The disease may occur at any age.

TREATMENT: Excision of a slow growing non-pigmented primary growth may be curative, but nothing short of early amputation of the limb on which a melanotic sarcoma has started will prevent its becoming generalized. Multiple growths of both kinds are hopeless, although cures have been reported from the hypodermic administration of arsenic, and from injections of the combined toxins of Streptococcus pyogenes and B. prodigiosus.

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Unusual Variants of Mycosis Fungoides

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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 treatment of infl mons trated to ha l has not been de the same in ne alo ide DUAC Topic al Ge rox d with benzoyl pe tor y acne. fit when compare t of noninflamma additional bene d for the treatmen 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.

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30


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.

2.

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

3.

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

4.

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

5.

DUAC Topical Gel may bleach hair or colored fabric.

6.

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

7.

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

8.

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

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

6%

<1%

0

17%

2%

0

Burning

3%

<1%

0

5%

<1%

0

Dryness

6%

<1%

0

15%

1%

0

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

©2011 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. DUA063R0 March 2011

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A Pentad of Vancomycin Reactions Meghan Oâ&#x20AC;&#x2122;Brien, MD; Avnee Shah, MD; Herbert B. Allen, MD ABSTRACT Vancomycin is used in the treatment of infections caused by gram-positive bacteria resistant to b-lactam antibiotics. It is also used in the treatment of enterococci, although this use has been limited due to resistance. The authors report the clinical and pathological presentations of 5 different vancomycin hypersensitivity reactions, including morbilliform eruption, erythroderma, acute generalized exanthematous pustulosis, linear immunoglobulin A bullous dermatosis, and toxic epidermal necrolysis. With the increased prevalence of b-lactamâ&#x20AC;&#x201C; resistant bacteria, reliance on vancomycin continues to increase; thus, the recognition of reactions to this drug will be helpful in caring for patients who require this medication in the future. (SKINmed. 2011;9:225â&#x20AC;&#x201C;229)

D

eveloped in the 1950s, vancomycin is a glycopeptide antibiotic that inhibits peptidoglycan biosynthesis within the bacterial cell wall. Vancomycin has the distinct advantage of having activity against b-lactamâ&#x20AC;&#x201C;resistant bacteria. Since then, its use has increased as a result of the increase in the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections. In the United States today, 58% of S aureus isolates are methicillin resistant.1 In addition, the mortality associated with MRSA infections is greater than that associated with methicillin-sensitive S aureus infections.1 Even though increasing numbers of vancomycin-resistant cases have been documented, vancomycin remains the antibiotic of choice in the hospital setting when a MRSA infection is suspected or has been diagnosed in patients who do not have severe renal impairment. Here, we present 5 cases of vancomycin-induced eruptions to highlight the many skin reactions to this antibiotic, some of which can be serious or fatal. In reporting these reactions, we hope to place vancomycin in the differential diagnosis of these eruptions in patients who have received this medication. REPORT OF CASES We reviewed the clinical information for 5 patients with apparent vancomycin sensitivity. The Table presents the patient information and the histopathologic findings. CASE 1 A 45-year-old African American man with a medical history significant for end-stage renal failure, end-stage liver disease, hepatitis B virus infection, and human immunodeficiency virus

(HIV) infection was treated with vancomycin for Clostridium difficile colitis. After 2 days of treatment, the patient developed a blistering, exfoliative eruption on his arms and legs (Figure 1). Linear immunoglobulin A (IgA) bullous dermatosis was clinically suspected. The eruption subsided after vancomycin therapy was discontinued and camphorylated moisturizing lotion was applied. CASE 2 A 54-year-old white woman was initially admitted for an intracerebral hemorrhage. Her hospital course was complicated by fever, leukocytosis, and aspiration pneumonia, prompting treatment with vancomycin. After treatment, the patient developed an eruption on the neck and body that became more severe over time, causing edematous, dusky red plaques studded with pustules on the trunk and extremities (Figure 2). Discontinuation of vancomycin resulted in amelioration of the eruption. CASE 3 A 46-year-old African American woman with chronic stage II renal failure was admitted for worsening edema and shortness of breath. The patient subsequently developed respiratory failure and vancomycin was started. Within a few days, the patient exhibited expansive purpura on her abdomen, groin, thighs, and left breast, which also had areas of denuded skin (Figure 3). Epidermal sloughing, erosions, and blisters covered more than 40% of her body surface area. The patient also had a positive Nikolsky sign. A biopsy specimen from the left breast showed focal subepidermal bullae formation with patchy, mild, perivascular, inflammatory cell infiltrate. Discontinuation of vancomycin and

From the Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA Address for Correspondence: Herbert B. Allen, MD, Department of Dermatology, Drexel University College of Medicine, 219 North Broad Street, Philadelphia, PA 19107 â&#x20AC;˘ E-mail: hallen@drexelmed.edu

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Table. Patient Demographics, Diagnoses, Medical Histories, and Histopathologic Findings

CASE

NATIONALITY/SEX/AGE

DIAGNOSIS

SIGNIFICANT MEDICAL HISTORY

HISTOPATHOLOGIC FINDINGS

1

African American man (45 y)

Linear IgA bullous dermatosis

End-stage renal failure, end-stage liver failure, hepatitis B virus, and human immunodeficiency virus infection

Subepidermal bulla, neutrophilic and eosinophilic infiltrate; direct immunofluorescence demonstrated a linear pattern of IgA along the epidermal basement membrane

2

White woman (54 y)

Acute generalized exanthematous pustulosis

Intracerebral hemorrhage, deep vein thrombosis, diabetes mellitus, atrial fibrillation, hypertension

Intraepidermal pustule, papillary dermal edema, mixed neutrophilic infiltrate with eosinophils, rare apoptotic keratinocytes, mixed lymphocytic and eosinophilic infiltrate with exocytosis

3a

African American woman (46 y)

Toxic epidermal necrolysis

Chronic renal failure, atrial fibrillation, cerebrovascular accident/ transient ischemic attack

Epidermal necrosis, subepidermal cleft, minimal interface, and perivascular lymphocytic infiltrate

4

White man (84 y)

Morbilliform eruption

Myocardial infarction, congestive heart failure, hyperlipidemia

Focal spongiosis and exocytosis, papillary dermal edema, perivascular lymphocytic and eosinophilic infiltrate

5

White woman (18 y)

Erythroderma

Arnold-Chiari syndrome

Lymphocytic and eosinophilic dermatitis

Abbreviation: IgA, immunoglobulin A. aFigure 6.

treatment of denuded skin with petroleum jellyâ&#x20AC;&#x201C;impregnated gauze was prescribed. Unfortunately, the patient was terminally ill and died.

his arms, trunk, and legs (Figure 4). Papules also formed that coalesced into plaques in his groin. Discontinuation of vancomycin and application of topical steroids alleviated the reaction.

CASE 4

CASE 5

An 84-year-old white man who had an anterior myocardial infarction and rhabdomyolysis was admitted to the hospital. The patient was intubated 2 weeks after admission secondary to respiratory failure, and vancomycin and piperacillinâ&#x20AC;&#x201C;tazobactam were subsequently started. By day 2 of antibiotic treatment, the patient developed a blanchable, pink, morbilliform eruption on

An 18-year-old white woman with a medical history of ArnoldChiari syndrome who had a shunt placed was initially started on cefepime. Vancomycin was added 1 week later. Approximately 11 days after the start of vancomycin therapy, the patient presented with fever and lymphadenopathy. Shortly thereafter, she developed a diffuse eruption of bright pink-red, excoriated papules that coalesced into large plaques (Figure 5). This eruption affected the entire body, sparing only the face. Erythroderma was diagnosed. The eruption improved with the discontinuation of vancomycin, application of topical steroids, and administration of antihistamine. DISCUSSION

Figure 1. A blistering and exfoliative eruption is depicted on this patientâ&#x20AC;&#x2122;s arm. SKINmed. 2011;9:225â&#x20AC;&#x201C;229

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Adverse drug reactions are a major cause of morbidity and mortality around the world. Adverse events to medications have been reported to occur in nearly 30% of hospitalized patients, and even more astounding is the finding that up to 28% of hospital admissions are associated with adverse drug eruptions.2 A variety of adverse reactions to vancomycin have been reported that affect multiple organ systems. Rapid infusion of the drug has been documented to cause side effects such as nausea, colitis, interstitial

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nephritis, renal failure, hematologic reactions, ototoxicity, and thrombophlebitis. Vancomycin-induced drug reactions specific to the skin include exfoliative dermatitis, toxic epidermal necrolysis, hypersensitivity reactions, linear IgA bullous dermatosis (LABD), and â&#x20AC;&#x153;red man syndrome.â&#x20AC;?3 LABD, a rare blistering disease, has been well documented to occur in association with intravenous vancomycin administration. LABD is a disease of subepidermal blistering due to the deposition of IgA in a linear array at the dermal-epidermal interface. Immunofluorescence shows a characteristic linear pattern of IgA deposition along the basement membrane zone. A subgroup of LABD cases are known to be drug-induced. Although numerous medications have been associated with LABD including diclofenac, captopril, and phenytoin,4 intravenous vancomycin is the most well-documented drug to cause this reaction.5 Interestingly, on rechallenge, the reaction will have a shorter time to presentation and a longer total course.6 Other studies have indicated that a vancomycin-induced LABD response is not dose-dependent and may be due to an autoantibody to BP120 and LAD285.7â&#x20AC;&#x201C;9

Figure 2. Edematous red plaques studded with pustules can be seen on this patientâ&#x20AC;&#x2122;s right lateral arm.

Acute generalized exanthematous pustulosis (AGEP) is a wellknown adverse cutaneous drug reaction consisting of numerous small sterile pustules against a background of edema and erythema that usually begins on the face or around large skin folds. Systemically, this cutaneous eruption is associated with fever and leukocytosis. The incidence of AGEP has been approximated at 1 to 5 cases per million annually.10 An analysis of 63 cases of AGEP showed that drugs (b-lactam and macrolide antibiotics most frequently) were the cause in 87%; other causes included viral infections, UV radiation, and mercury poisoning.10 AGEP secondary to drugs may take 1 to 3 weeks to become visible after new drug administration, but latency periods can decrease to only 2 to 3 days on rechallenge.11 Toxic epidermal necrolysis (TEN) is an eruption of the skin that usually begins as very tender, pink-red patches, plaques, or target-like macules that subsequently evolve into full-thickness necrosis of the epidermis. The epidermis then peels off in sheets. On physical examination, the Nikolsky sign, bulla formation, and expansive areas of denuded skin may be observed. Medications are often cited as the most likely cause of this reaction. Drugs with a high risk of causing epidermal necrolysis include allopurinol, sulfamethoxazole, carbamazepine, lamotrigine, and phenytoin.12 Although few reports of vancomycin-induced TEN have been documented, we believe that vancomycin treatment should be considered as a possible cause in patients presenting with epidermal necrolytic reactions. The literature includes SKINmed. 2011;9:225â&#x20AC;&#x201C;229

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Figure 3. Epidermal sloughing and large erosions can be seen on this patientâ&#x20AC;&#x2122;s trunk.

reports of patients in renal failure treated with vancomycin who develop TEN reactions, just as in the case we describe here.13,14 Vancomycin-induced TEN has also been seen in patients with HIV infection.15 Interestingly, cases of vancomycin-induced LABD mistaken as TEN reactions have also been documented.16 Morbilliform eruptions of the skin, so named to describe their similarity in appearance to the viral exanthem of measles, represent the most commonly encountered cutaneous drug reaction. Clinically, these eruptions manifest as pink maculopapular

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Figure 4. A blanchable, pink, maculopapular eruption is seen on this patientâ&#x20AC;&#x2122;s trunk and abdomen.

Figure 6. The epidermis is totally necrotic and is separated from the dermis.

cause a morbilliform variant of LABD in which deposition of IgA at the dermoepidermal junction is present but bullae are not formed.18 Reports of systemic absorption of oral vancomycin resulting in maculopapular eruptions have been published as well, supporting the notion that oral vancomycin can occasionally reach therapeutic systemic levels.19,20 Erythroderma can be described as diffuse erythema and scaling of more than 90% of the skinâ&#x20AC;&#x2122;s surface area. Systemic physical findings such as fever, tachycardia, peripheral edema, and generalized lymphadenopathy are often present as well.21 Medication classes well known to cause this type of reaction include antibiotics, antiepileptic agents, and calcium channel blockers. Vancomycin-induced erythroderma has been reported in patients with renal compromise, often causing prolongation of the reaction because the patientâ&#x20AC;&#x2122;s ability to clear the drug from the body is inhibited.22â&#x20AC;&#x201C;24 Vancomycin-induced erythroderma can be readily distinguished from the â&#x20AC;&#x153;red man syndromeâ&#x20AC;? because the latter is an infusion reaction.24

Figure 5. A diffuse eruption of bright pink-red, excoriated papules coalescing into large plaques can be seen on this patientâ&#x20AC;&#x2122;s right arm.

rashes on the trunk 1 day to 4 weeks after initiation of treatment. Within hours, this eruption can spread to involve the face and extremities, although it usually spares the mucous membranes and acral surfaces.17 Classically, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole cause this reaction. Vancomycin has recently been shown to SKINmed. 2011;9:225â&#x20AC;&#x201C;229

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We have reported here the cases of 5 patients with cutaneous reactions to vancomycin treatment. Our purpose in reporting these cases is to increase awareness and aid in the diagnosis of cutaneous manifestations attributable to vancomycin. Use of vancomycin, a drug best known for treating invasive S aureus infections in hospitalized patients, has become more widespread

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with the rise of methicillin resistance. Clinicians should keep this medication in mind as a cause of cutaneous eruptions, especially when evaluating hospitalized patients who have recently started vancomycin treatment. Acknowledgement: Presented at the 2010 Spring meeting of the Section on Dermatology of the College of Physicians of Philadelphia. REFERENCES 1

Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillinresistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763â&#x20AC;&#x201C;1771.

2

Beltrani VS. Allergic dermatoses. Med Clin North Am. 1998;82:1105â&#x20AC;&#x201C;1133.

3

Vancocin CP [package insert]. Bangalore, India: AstraZeneca; 2006.

4

Cerottini JP, Ricci C, Guggisberg D, et al. Drug-induced linear IgA bullous dermatosis probably induced by furosemide. J Am Acad Dermatol. 1999;41:103â&#x20AC;&#x201C;105.

5

10 Beylot C, Doutre MS, Beylot-Barry M. Acute generalized exanthematous pustulosis. Semin Cutan Med Surg. 1996;15:244â&#x20AC;&#x201C;249. 11 Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127:1333â&#x20AC;&#x201C;1338. 12 Wolff K, Goldsmith L, Katz SI, et al, eds. Fitzpatrickâ&#x20AC;&#x2122;s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2008. 13 Bouaziz JD, Valeyrie-Allanore L, Damak H, et al. Toxic epidermal necrolysis after vancomycin in a patient with terminal renal insufficiency: interest for intensive haemodialysis? J Eur Acad Dermatol Venereol. 2006;20:1011â&#x20AC;&#x201C;1013. 14 Hannah BA, Kimmel PL, Dosa S, et al. Vancomycin-induced toxic epidermal necrolysis. South Med J. 1990;83:720â&#x20AC;&#x201C;722. 15 Vidal C, GonzĂĄlez Quintela A, Fuente R. Toxic epidermal necrolysis due to vancomycin. Ann Allergy. 1992;68:345â&#x20AC;&#x201C;347. 16 Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol. 2004;29:633â&#x20AC;&#x201C;636. 17 Habif TP. Clinical Dermatology. 4th ed. St. Louis, MO: Mosby; 2003. 18 Billet SE, Kortuem KR, Gibson LE, et al. A morbilliform variant of vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol. 2008;144:774â&#x20AC;&#x201C;778.

Nousari HC, Kimyai-Asadi A, Caeiro JP, et al. Clinical, demographic, and immunohistologic features of vancomycin-induced linear IgA bullous disease of the skin. Report of 2 cases and review of the literature. Medicine (Baltimore). 1999;78:1â&#x20AC;&#x201C;8.

19 Osawa R, Kaka AS. Maculopapular rash induced by oral vancomycin. Clin Infect Dis. 2008;47:860â&#x20AC;&#x201C;861.

6

Baden LA, Apovian C, Imber MJ, et al. Vancomycin-induced linear IgA bullous dermatosis [letter]. Arch Dermatol. 1988;124:1186â&#x20AC;&#x201C; 1188.

20 McCullough JM, Dielman DG, Peery D. Oral vancomycinâ&#x20AC;? induced rash: case report and review of the literature. DICP. 1991;25:1326â&#x20AC;&#x201C;1328.

7

Neughebauer BI, Negron G, Pelton S, et al. Bullous skin disease: an unusual allergic reaction to vancomycin. Am J Med Sci. 2002;323:273â&#x20AC;&#x201C;278.

21 Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 1st ed. St. Louis, MO: Mosby; 2003.

8

Kuechle MK, Stegemeir E, Maynard B, et al. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol. 1994;30(2 pt 1):187â&#x20AC;&#x201C;192.

9

Palmer RA, Ogg G, Allen J, et al. Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285. Br J Dermatol. 2001;145:816â&#x20AC;&#x201C;820.

22 Gutfeld MB, Reddy PV, Morse GD. Vancomycin-associated exfoliative dermatitis during continuous ambulatory peritoneal dialysis. Drug Intell Clin Pharm. 1988;22:881â&#x20AC;&#x201C;882. 23 Forrence EA, Goldman MP. Vancomycin-associated exfoliative dermatitis. DICP. 1990;24:369â&#x20AC;&#x201C;371. 24 Richards AL, Cleland H. Exfoliative dermatitis, fever and acute renal failure in a 60% burns patient. Burns. 2005;31:1056â&#x20AC;&#x201C;1060.

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Mobile Teledermatology: As Doctors and Patients Are Increasingly Mobile, Technology Keeps Us Connected Dina Farshidi, BA;1 Noah Craft, MD, PhD, DTM&H;2 Maria Teresa Ochoa, MD1 ABSTRACT With advancements in electronics and health informatics, telemedicine has emerged as a cost-effective tool capable of increasing care to remote regions, facilitating specialist consults, supporting self-management by patients, and sharing knowledge over great distances. In this review, the authors discuss existing telemedicine modalities, highlight examples of mobile systems documented in the literature to date, and emphasize the data supporting the feasibility of telecommunication technologies to deliver dermatology services and education remotely. While many studies have suggested the potential for teledermatology to increase access to care in developing countries with few dermatologists, the authors share some of the most recent developments, including the use of diagnostic decision support software. The authors encourage a thriving and open network that will enhance the ongoing research and development of innovative and useful products. This network will also connect dermatologists willing to volunteer their consultation to health care workers in remote areas lacking specialists. (SKINmed. 2011;9:231–238)

T

he collision of electronics and information technology within the field of medicine has resulted in the revolution we call eHealth. Telemedicine is one manifestation of eHealth with the potential to increase care to remote regions, to facilitate specialist consultultations, to support self-management by patients, and to share knowledge over great distances. These advances may greatly benefit patient care, medical education, and postgraduate training in cost-effective ways. Today, telemedicine may be as simple as two health care professionals discussing a case over the telephone or as complex as using satellite technology and videoconferencing equipment to conduct real-time consultations between medical specialists in two different countries. Most recently, the soldiers in the eHealth revolution have left their examination rooms and their offices to become completely mobile (Table I). This practice is loosely called mHealth, for Mobile Health. TELEDERMATOLOGY: ITS EVOLUTION AND CLASSIFICATION Despite reports of dermatologists evaluating employees at Boston’s Logan Airport through a live black-and-white video link

in 1972,1 the term teledermatology (TD) was not coined until 1995. Since then, a plethora of different modalities have been developed (Table II). Early TD was classified as either synchronous or asynchronous. Synchronous TD refers to videoconferencing between two doctors with a patient at the remote site. Asynchronous refers to “store-and-forward” technology where one health care provider captures a digital image of a patient at a remote site and sends it electronically to a specialist. The specialist can review the consultation request at a convenient location and time. Most recently, TD has been more broadly categorized based on technology tools, the health care professionals involved, and special areas of TD application.2 MOBILE TD: FROM TEXT MESSAGES TO DERMATOSCOPES One technology included in modern classification schemes is mobile TD (MTD). MTD is defined as the use of portable devices, such as mobile phones with built-in cameras, to capture, compute, and share information through wireless networks. Depending on the sophistication of the mobile device, MTD can serve a variety of purposes.

From the Division of Dermatology, David Geffen School of Medicine at the University of California, Los Angeles,1 and the Division of Dermatology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance,2 CA Address for Correspondence: Noah Craft, MD, PhD, DTM&H, LA BioMed, Building HH-207, 1124 West Carson Street, Torrance, CA 90502 • E-mail: ncraft@ucla.edu

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Table I. Existing Examples of Mobile Telemedicine

DISCIPLINE

PURPOSE

SOFTWARE

Medicine (cardiology, endocrine)37

Self-care for diabetes and cardiovascular disease

MediNet software: makes personalized recommendations to patients based on readings from monitoring devices and information known about the patient

Medicine (cardiology)38

Out-of-hospital follow-up of cardiac patients

Portable recording software: supports data transmission via mobile smart phones

Medicine (cardiology)39

Remote electrocardiographic (ECG) monitoring

Recording system: records and transmits ECG data via mobile smart phones

Medicine (cardiology)40

Monitoring patient ECG and movement during daily activities

Java-based system: includes chest electrode and recording system connected to mobile phone

Medicine (endocrine)41

Self-management for type 2 diabetes

Few touch application: includes off-the-shelf blood glucose meter, tailor-made step counter, and food habits recorder and offers user feedback and guidance

Medicine (endocrine)42

Intensive self-insulin therapy

Intelligent neural network: indicates how much insulin to inject in accordance with lifestyle and individual glucose level inputs

Medicine (endocrine)43

Self-management of type 1 diabetes

Real-time telemedicine system: based around transmission and feedback of data to and from a mobile phone

Medicine (intensive care)44

Remote monitoring system to support telediagnosis for intensive/critical care unit patients

Mobile remote monitoring system: includes real-time waveform monitoring, list trend monitoring, graph trend monitoring, and patient information checking

Medicine45

Remote patient monitor

MIMOSA architecture and open development platform: includes ambient intelligence applications (ie, ECG acquisition and glucose level monitoring)

Medicine46

Remote monitoring and management of chronic disease

MOTOHEALTH mobile health care solution: connectivity interface based on the HL7 standards

Medicine47

Remote patient monitoring and data retrieval

Store-and-forward software: transfers patient information

Medicine48

Medical professional educational assistance

Medical decision support system: collects, analyzes, and distributes diagnostic information

Medicine (geriatrics)49

Home support

Case report creation support system: allows for case creation and communication through mobile phones

Medicine (geriatrics)50

Safety support to assist in the care of elderly patients

Safety support system: identifies patient location via mobile phone

Medicine (geriatrics)51

Home health requests by patients

Home welfare and care services support system: allows patients to use a pen-type image sensor to request products and services

Medicine (geriatrics)52

Monitoring mobility trends of elderly patients

Custom-designed mobility alert software: monitors and records patient mobility via mobile phone

Medicine (home health)53

Around the clock communication between patients and contact center personnel

Citizen health system: modules allow for communication between the patient and the contact center using mobile phone

Medicine (preventative medicine)54

Self-monitoring health behaviors interventions

Mobile diary and support system: records and monitors health-related self-observations and offers solutions to patient via mobile phone

Medicine (oncology)55

Symptom and quality-of-life monitoring

Wireless health outcomes monitoring system: allows communication between patient and provider via mobile phone

Medicine (hematology and infectious disease)56

Bacillus counting for diagnostic purposes

Microscopy system with image analysis software: capable of brightfield and fluorescence imaging and automating bacillus counting

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Dermatology57

Self-management for psoriasis patients

Telemedical compliance management system: allows patients to share health parameters, take photos of lesions, and report adverse effects with physician who can respond with feedback

Obstetrics/gynecology (endocrine)58

Intensive insulin treatment of pregnant type 1 diabetic out-clinic patients

Telematic system: consists of a patient teletransmission module with one-box blood glucose meter and electronic logbook and a central clinical control unit with DIAPRET (insulin monitor)

Obstetrics/gynecology (oncology)34

Cervical cancer screening

Telemedical system: remote doctor sends clinical images of cervix with mobile phone in conjunction human papilloma virus results to central gynecologist

Emergency medicine (trauma)59

Teleconsultation for trauma patients presenting to the emergency department

Teletrauma system: simultaneous transmission of a patient’s video, medical images, and ECG signals

Surgery (orthopedics)60

Remote radiology consultation for orthopedic trauma patients

Teleradiology system: includes sending station, transmission network, storage device, viewing station, and software package

Neurology/radiology61

Teleconsultation for patients with suspected stroke

Toolbar software: transmits emergency information including head computer tomography via mobile phone

Neurology/radiology62

Remote teleradiology consultation for brain trauma patients

Wireless system: sends imagines to personal digital assistant

In its simplest form, mobile phone text messages have been used in dermatology to encourage preventative health measures. As one example, in a 6-week randomized, controlled trial, the use of daily text messages detailing local weather information and suggesting sunscreen application significantly increased sunscreen application.3

have demonstrated a concordance of 70% to 94% between the opinions of teledermatologists and face-to-face dermatologists.5–8

For more advanced uses, several feasibility studies using MTD have been conducted. Because clinical visual observation is the gold standard for many dermatologic diagnoses, dermatology is arguably the most suitable specialty for the use of information and telecommunication technologies to deliver services from a distance. In one early study, the concordance of diagnoses of dermatologic conditions using digital images, live examinations, and skin biopsies were compared and showed the use of digital images to be accurate and reliable.4 As with many nascent technologies, early studies must not be accepted as static facts since more recent technologic advances may have already overcome some of the limitations identified by these studies. For example, early pilot studies suggested that low image quality was a major limitation; however, the usability and feasibility of MTD improved along with the optics and macroimaging capabilities of inbuilt cameras. Examples of images sent from recent applications are shown in Figure 1. Various studies

Figure 1. Examples of images sent using the Nexus One phone and ClickDerm software (A–C). Example of a clinical image sent using a commercial camera and store-and-forward e-mail–based software (D).

Table II. Classification of Teledermatology Synchronous

Real-time video consultation

Video conferencing equipment; satellite equipment (very small aperture terminal)

Asynchronous

Store-and-foreward consultation

Conventional e-mail; Web-based integration model; mobile phones

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These early studies demonstrated that TD is very feasible, and support the notion that the technology could be useful for offsite dermatologic consultations. Another example of MTD utility is the mobile phone–based telemedicine compliance management system for patients with psoriasis.9 Using mobile phones with inbuilt 3.2-megapixel cameras, patients were prompted to answer questions relative to their history and take photos of their psoriasis lesions. Size and color reference markers were included close to their skin lesions to help standardize the photography. The data were then automatically sent to the patient’s physician who could easily track the evolution of the lesion via a Web browser and send feedback to the patient through a dedicated messaging system. In case of an adverse event, a Short Message Service (SMS) or e-mail alert was sent to the dermatologist to expedite action. From the physician’s point of view, this application simplifies the patient-physician communication, shortens the mean duration of regular outpatient follow-up, and facilitates individual therapy adjustment based on the availability of photos from all lesions at regular intervals. For patients, this application empowers them to become increasingly involved in their own care. A similar patient-driven mobile home monitoring system for patients with moderate to severe psoriasis was recently developed and tested.10 There was a 71% to 98% correlation between the face-to-face physicians and teledermatologists. Differences were attributed mainly to an inability to see the entire body and, therefore, estimate total body involvement, as well as to palpate lesions and thus estimate the induration of lesions. To provide images with greater detail and thus more clinical information, several groups have also introduced the practice of teledermatoscopy. This approach enables the electronic transfer of images captured with mobile phones coupled with a pocket dermatoscope. Because teledermatoscopy is most useful for the evaluation of pigmented lesions, most research has focused on using teledermatoscopy as a triaging or screening tool. In one study, there was a 91% concordance rate between face-to-face and teledermatoscopic diagnosis of pigmented skin tumors.11 Others found a diagnostic accuracy of 83% for teledermatoscopy compared with conventional histopathologic diagnosis.12 Regarding management decisions, there was also significant agreement between clinic-based dermatologists and remote teledermatologists regarding the diagnosis and management of pigmented lesions (k=0.68–0.92),13,14 In contrast, when focused on “equivocal melanomas,” dermatoscopy without contact with the patient was associated with improper management in about 30% of cases in one study.15 Although

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the future of teledermatoscopy appears promising for triaging patients, it is an unlikely complete substitute for face-to-face definitive examination of patients with lesions suspicious for malignancy. While no studies have specifically evaluated the cost-effectiveness of MTD, several studies have indicated store-and-forward systems to be both accurate and cost-effective.16,17 In separate studies, TD services decreased the cost of care in both a rural US community and in Norway.18,19 Due to decreasing equipment costs, much of the existing work on the economic viability of TD services has become obsolete and must be updated. Additionally, potential complicating factors in economic analyses such as these include factors that are difficult to quantify such as the opportunity cost of a patient’s time vs the intangible benefit of an earlier correct diagnosis and wider geographic reach. CROSSING BOUNDARIES: TO INCREASE CARE AND MEDICAL EDUCATION RESOURCES IN DEVELOPING COUNTRIES Many studies have suggested the potential for TD to increase access to care in developing countries with few dermatologists.20,21 More than 3 billion people live in areas with no access to basic skin treatment. In these regions, 90% of skin diseases are diagnosed and treated by health workers with no formal dermatologic training. The socioeconomic and health implications of TD are significant.22 Some valuable efforts have been made to demonstrate the feasibility of TD and MTD in various parts of Africa.23–26 The sustainable expansion of efforts such as this are encouraged by the fact that patients found this form of dermatology acceptable.27 This expansion, however, will rely on governmental or private agencies to supply equipment, educate participants, and establish relationships between local health care workers and remote dermatologists willing to volunteer in many cases. Efforts to educate additional dermatologists within these regions are also critical at this time.28–30 In addition, efforts must be made in both developed and developing countries to overcome the deficiency of dark skin representation in current medical education resources.31 Together, these efforts would improve the dermatologic care of people with darker skin. Fortunately, mobile phones with the necessary features for MTD are becoming increasingly affordable. These portable devices are also particularly suitable for developing countries because they have the ability to send data and images from areas where Internet connection is not readily available or is too costly. With store-and-forward capabilities, smart phones make the problem of weak and intermittent network coverage less problematic.

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TODAY AND TOMORROW: NOTABLE DEVELOPMENTS AND THE FUTURE OF TD The advantages of specialized software for the purpose of remote MTD are multifold. First, it provides health care workers an easy-to-follow model to assist them through the TD process. Second, it could include applications that automatically standardize, organize, and share information and images. Interface with electronic medical records will be important as these come online universally.32 Finally, additional resources can be included to encourage education and the sharing of knowledge with the primary care doctors who send the consults. In Botswana, a pilot program is using SMS texting to search the National Library of Medicine to return disease information to clinicians by phone.33 Additionally, one member of our group (NC) has recently pioneered the use of diagnostic decision support software

(VisualDx, Logical Images, Inc, Rochester, NY), in conjunction with TD and MTD (Figure 2A–C and Figure 3). This integrated combination provides a trusted source of basic skin disease information (including standard diagnostic techniques, management options, and a wide range of comparable images in various skin tones). Importantly, this mobile resource combination also results in empowerment of the primary care doctor both before and after formal consultation with the expert. In a separate pilot project organized through the University of Pennsylvania and sponsored by the American Academy of Dermatology (AAD), MTD projects are underway that use specialized Android phones (Figure 2D). These phones were supplied with both MTD software (ClickDerm, ClickDiagnostics, Inc, Lexington, MA) and visual diagnostic decision support software (VisualDx, Logical Images, Inc, [Figure 2 A–C]) and are being distributed

Figure 2. Example of VisualDx diagnostic decision support-based differential diagnosis page-view on IPad (A). Example of VisualDx disease information page for pemphigus vulgaris (B). Examples of using VisualDx on the IPhone (C). Example of the Nexus One phone use in the American Academy of Dermatology pilot teledermatology program for safety net clinics (D). SKINmed. 2011;9:231–238

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Figure 3. Test patient as an example of ClickDiagnostics software and interface.

to free clinics in underserved areas of the United States. Volunteer dermatologists who are members of the AAD are providing free consultations using the ClickDerm software. An example of the Web-based software interface is shown in Figure 3.

dermatologists who are willing to volunteer their consultation to health care workers in remote areas lacking specialists.

Additional programs using variations of mobile telemedicine are currently underway in various stages. ClickDoc software on the Samsung Soul U900 phone with 5-megapixel cameras is being used effectively for mobile telegynecology in Botswana as a cervical cancer screening study.34 The similar ClickDerm platform is being used in Egypt and Ghana for MTD with good diagnostic concordance.35,36 As robust MTD and diagnostic decision support systems are developed and come online, additional challenges will be discovered. Despite these challenges, multiple groups will continue working on TD applications. Several groups have been established, including The Community for Teledermatology (www. telederm.com), the Africa Teledermatology Project (www.africa. telederm.org), the International Society of Dermoscopy (www. dermoscopy.telederm.org), and Leprosy & Global Dermatology (leprosy.telederm.org). These groups provide free membership and moderated platforms for teleconsultation discussions and services. Currently, these groups are still small and would benefit from greater participation and collaboration. A thriving and open network will enhance development of useful products and services by reducing inefficient redundancies and encouraging collaborations. Similar to the AAD initiative, these groups can also connect

The future of MTD remains promising. With continual technologic advancements of MTD devices, the quality and accuracy of care delivered by this modality has constantly increased. Indeed, with improvements of computer-vision science, it will not be long before mobile devices are assisting in diagnosis directly. TD has already been demonstrated to be an effective tool for triage, patient self-management, and remote consultation. As the TD community grows, the practice of MTD will likely be more readily available as a cost-effective means to deliver specialty services and public health interventions to remote regions around the world.

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Disclosures: Drs Craft and Ochoa are editors for Logical Images, the makers of VisualDx software. REFERENCES

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Murphy RL Jr, Fitzpatrick TB, Haynes HA, et al. Accuracy of dermatologic diagnosis by television. Arch Dermatol. 1972;105:833–835.

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Kanthraj GR. Classification and design of teledermatology practice: What dermatoses? Which technology to apply? J Eur Acad Dermatol Venereol. 2009;23:865–875.

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Armstrong A, Watson AJ, Makredes M, et al. Text-message reminders to improve sunscreen use, a randomized, controlled trial using electronic monitoring. Arch Dermatol. 2009;145:1230– 1236.

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Scheinfeld N, Kurz J, Tepplitz E. A comparison of the concordance of digital images, live examinations and skin biopsies for the diagnosis of hospitalized dermatology consultation patients. Skinmed. 2003;2:14–19.

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Braun RP, Vechietti JL, Thomas L, et al. Telemedical wound care using a new generation of mobile phones: a feasibility study. Arch Dermatol. 2005;141:254–258.

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Chung P, Thomas Y, Scheinfeld N. Using cellphones for teledermatology, a preliminary study. DOJ. 2007;13:2.

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Ebner C, Wurm EM, Binder B, et al. Mobile teledermatology: a feasibility study of 58 subjects using mobile phones. J Telemed Telecare. 2008;14:2–7.

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Massone C, Lozzi GP, Wurm E, et al. Cellular phones in clinical teledermatology. Arch Dermatol. 2005;141:1319–1320.

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Scheinfeld N. Creating and utilizing a multimedia dermatology medical record for pocket PC personal digital assistant. Skinmed. 2005;4:33–37.

10 Frühauf J, Schwantzer G, Ambros-Rudolph CM, et al. Pilot study using telederamtology to manage high-need patients with psoriasis. Arch Dermatol. 2010;146:200–201. 11 Piccolo D, Smolle J, Wolf IH, et al. Face-to-face diagnosis vs telediagnosis of pigmented skin tumors: a teledermoscopic study. Arch Dermatol. 1999;135:1467–1471. 12 Ferrara G, Argenziano G, Cerroni L, et al. A pilot study of a combined dermoscopic-pathological approach to the telediagnosis of melanocytic skin neoplasms. J Telemed Telecare. 2004;10:34–38. 13 Di Stefani A, Zalaudek I, Argenziano G, et al. Feasibility of a two-step teledermatologic approach for the management of patients with multiple pigmented skin lesions. Dermatol Surg. 2007;33:686–692.

22 Morrone A. Poverty, dignity, and forgotten skin care: dermatology in the stream of human mobile population. Dermatol Clin. 2008;26:245–256. 23 Schmid-Grendelmeier P, Masenga EJ, Haeffner A, et al. Teledermatology as a new tool in sub-saharan Africa: an experience from Tanzania. J Am Acad Dermatol. 2000;42(5 pt 1):833–835. 24 Schmid-Grendelmeier P, Doe P, Pakenham-Walsh N. Teledermatology in sub-Saharan Africa. Curr Probl Dermatol. 2003;32:233–246. 25 Caumes E, Le Bris V, Couzigou C, et al. Dermatoses associated with travel to Burkina Faso and diagnosed by means of teledermatology. Br J Dermatol. 2004;150:312–316. 26 Kaddu S, Soyer HP, Gabler G, et al. The Africa Teledermatology Project: Preliminary experience with a sub-Saharan teledermatology and e-learning program. J Am Acad Dermatol. 2009;61:155–157. 27 Azfar R, Weinberg J, Cavric G, et al. HIV+ patients in Botswana find mobile teledermatology an acceptable method for receiving dermatologic care. JID. www.jidonline.org. Accessed September 06, 2010. 28 US DHHS Health Resources and Services Administration. Office for the Advancement of Telehealth Web site. http://www.hrsa. gov/telehealth. Accessed September 06, 2010. 29 Perez OA, Berman B, Hodson DS, et al. Teledermatology: an educational tool for resident training. Telemed J E Health. 2007;13:220–236. 30 Hu J, McKoy K, Papier A, et al. Dermatology care and HIV/AIDS in Africa. J Glob Infect Dis. In press. 31 Ebede T, Papier A. Disparities in dermatology education resources. J Am Acad Dermatol. 2006;55:687–690. 32 Armstrong A, Sanders C, Farbstein AD, et al. Evaluation and comparison of store-and-forward teledermatology applications. Telemed J E Health. 2010;16:424–438.

14 Massone C, Hofmann-Wellenhof R, Ahlgrimm-Siess V, et al. Melanoma screening with cellular phones. PLoS ONE. 2007;2:e483.

33 Armstrong K, Liu F, Seymour A. Design and evaluation of TXT2Medline and SMS optimized, searchable clinical guidelines for clinicians in Botswana presenters & contributing authors. Telemed J E Health. 2010;16:S-93.

15 Carli P, de Giorgi V, Chiargui A, et al. Addition of demoscopy to conventional naked-eye examination in melanoma screening: a randomized study. J Am Acad Dermatol. 2004;50:683–689.

34 Gormley R, Quinley K, Shih T, et al. Use of mobile telemedicine for cervical cancer screening in Gaborone, Botswana. Telemedicine and e-Health. 2010;16:S-91.

16 Whited JD, Hall RP, Simel DL, et al. Reliability and accuracy of dermatologsits’ clinic-based and digital image consultations. J Am Acad Dermatol. 1999;41:693–702.

35 Tran K, Ayad M, Weinberg J, et al. Mobile teledermatology in the developing world: implications of a feasibility study on 30 Egyptian patients with common skin diseases. J Am Acad Dermatol. 2011;64:302–309.

17 Tait CP, Caly CD. Pilot study of store and forward teledermatology services in Perth, Western Australia. Aust J Dermatol. 1999;40:190–193. 18 Burgiss SG, Julius CE, Watson HW, et al. Telemedicine for dermatology care in rural patients. Telemed J. 1997;3:227–233. 19 Bergmo TS. A cost minimization analysis of a realtime teledermatology service in northern Norway. J Telemed Telecare. 2000;6:273–277. 20 Norton SA, Burdick AE, Phillips CM, et al. Telederamtology and underserved populations. Arch Dermatol. 1997;133:197–200. 21 Ducker I, Elsner P. Dermatology in telemedicine. Possibilities and limits [in German]. Hautarzt. 2002;53:11–17.

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36 Rosen A, Osei-Tutu A, Kovarik C. Mobile teledermatology in Ghana: sending and answering consults via mobile platform presenters & contributing authors. Telemed J E Health. 2010;16(1):S126. 37 Mohan P, Marin D, Sultan S, Deen A. MediNet: personalizing the self-care process for patients with diabetes and cardiovascular disease using mobile telephony. Conf Proc IEEE Eng Med Biol Soc. 2008;755–758. 38 Salvador CH, Pascual Carrasco M, Gonzalez de Mingo MA, et al. Airmed-cardio: a GSM and Internet services-based system for out-of-hospital follow-up of cardiac patients. IEEE Trans Inf Technol Biomed. 2005;9:73–85.

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39 Iwamoto J, Yonezawa Y, Maki H, et al. A mobile phone-based ECG monitoring system. Biomed Sci Instrum. 2006;42:217â&#x20AC;&#x201C; 222. 40 Iwamoto J, Yonezawa Y, Ogawa HM, et al. A new mobile phone-based ECG monitoring system. Biomed Sci Instrum. 2007;43:318â&#x20AC;&#x201C;323. 41 Arsand E, Tatara N, Stengen G, et al. Mobile phone-based selfmanagement tools for type 2 diabetes: the few touch application. J Diabetes Sci Technol. 2010; 4:328â&#x20AC;&#x201C;336.

57 Schreier G, Hayn D, Kastner P, et al. A mobile-phone based teledermatology system to support self-management of patients suffering from psoriasis. Conf Proc IEEE Eng Med Biol Soc. 2008;2008:5338â&#x20AC;&#x201C;5341. 58 LadyzyĂąski P, WĂłjcicki JM, KrzymieĂą J, et al. Teletransmission system supporting intensive insulin treatment of out-clinic type 1 diabetic pregnant women. Technical assessment during 3 yearsâ&#x20AC;&#x2122; application. Int J Artif Organs. 2001;24:157â&#x20AC;&#x201C;163. 59 Chu Y, Ganz A. A mobile teletrauma system using 3G networks. IEEE Trans Inf Technol Biomed. 2004;8:456â&#x20AC;&#x201C;462.

42 Curran K, Nichols E, Xie E, et al. An intensive insulinotherapy mobile phone application built on artificial intelligence techniques. J Diabetes Sci Technol. 2010;4:209â&#x20AC;&#x201C;220.

60 Ricci WM, Borrelli J. Teleradiology in orthopaedics. Clin Orthop Relat Res. 2004;421:64â&#x20AC;&#x201C;69.

43 Farmer A, Gibson O, Hayton P, et al. A real-time, mobile phonebased telemedicine system to support young adults with type 1 diabetes. Inform Prim Care. 2005;13:171â&#x20AC;&#x201C;177.

61 Phabphal K, Hirunpatch S. The effectiveness of low-cost teleconsultation for emergency head computer tomography in patients with suspected stroke. J Telemed Telecare. 2008;14:439â&#x20AC;&#x201C;442.

44 Bajracharya A, Gale TJ, Stack CR, et al. 3.5G based mobile remote monitoring system. Conf Proc IEEE Eng Med Biol Soc. 2008;783â&#x20AC;&#x201C;786.

62 Yaghmai V, Salehi SA, Kuppuswami S, et al. Rapid wireless transmission of head CT images to a personal digital assistant for remote consultation. Acad Radiol. 2004;11:1291â&#x20AC;&#x201C;1293.

45 Quero JM, Tarrida CL, Santana JJ, et al. Health care applications based on mobile phone centric smart sensor network. Conf Proc IEEE Eng Med Biol Soc. 2007;6299â&#x20AC;&#x201C;6302. 46 De Toledo P, Lalinde W, Del Pozo F, et al. Interoperability of a mobile health care solution with electronic healthcare record systems. Conf Proc IEEE Eng Med Biol Soc. 2006;1:5214.

VINTAGE LABEL

47 Hung K, Zhang YT. Implementation of a WAP-based telemedicine system for patient monitoring. IEEE Trans Inf Technol Biomed. 2003;7:101â&#x20AC;&#x201C;107. 48 Eren A, Subasi A, Coskun O. A decision support system for telemedicine through the mobile telecommunications platform. J Med Syst. 2008;32:31â&#x20AC;&#x201C;35. 49 Ogawa H, Yonezawa Y, Maki H, et al. A Java mobile phone-based â&#x20AC;&#x153;Home Helperâ&#x20AC;? care report creation support system. Biomed Sci Instrum. 2004;40:76â&#x20AC;&#x201C;79. 50 Ogawa H, Yonezawa Y, Maki H, et al. An electronic location safety support system. Biomed Sci Instrum. 2007;43:122â&#x20AC;&#x201C;127. 51 Ogawa H, Yonezawa Y, Maki H, et al. Web-based home welfare and care services support system using a pen type image sensor. Biomed Sci Instrum. 2003;39:199â&#x20AC;&#x201C;203. 52 Scanaill CN, Ahearne B, Lyons GM. Long-term telemonitoring of mobility trends of elderly people using SMS messaging. IEEE Trans Inf Technol Biomed. 2006;10:412â&#x20AC;&#x201C;413. 53 Maglaveras N, Koutkias V, Chouvarda I, et al. Home care delivery through the mobile telecommunications platform: the Citizen Health System (CHS) perspective. Int J Med Inform. 2002;68:99â&#x20AC;&#x201C;111. 54 Koskinen E, Salminen J. A customizable mobile tool for supporting health behavior interventions. Conf Proc IEEE Eng Med Biol Soc. 2007;2007:5908â&#x20AC;&#x201C;5911. 55 Bielli E, Carminati F, La Capra S, et al. A Wireless Health Outcomes Monitoring System (WHOMS): development and field testing with cancer patients using mobile phones. BMC Med Inform Decis Mak. 2004;4:7. 56 Breslauer DN, Maamari RN, Switz NA, et al. Mobile phone based clinical microscopy for global health applications. PLoS ONE. 2009;4:e6320.

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Volume 9 • Issue 4

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

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

Diabetes mellitus is a worldwide public health problem. It manifests as either insulin-dependent or noninsulin-dependent diabetes mellitus. It is associated with several dermatoses, which need to be addressed individually. Dermatoses often provide clues to the status of diabetes. The presence of dermatoses may compound the challenges confronted by the treating physician to modify the management of each patient. Several noninfective and infective dermatoses can act as a forewarning that a particular individual is likely to develop diabetes. This association is highlighted by specific entities, such as necrobiosis lipoidica and granuloma annulare and will be discussed below.

D

iabetes mellitus (DM) is a well-documented “iceberg” disease. Its worldwide prevalence in adults is 4%,1 which is likely to rise to 5.4% by 2025,2 In India, however, the prevalence of DM is 2.4% in rural and 4% to 11.6% in urban dwellers.3 DM is a heterogeneous group of disorders of carbohydrate and lipid metabolism.4 There are 3 major types of DM: (1) type I, insulin-dependent diabetes mellitus (IDDM), or juvenile-onset DM, characterized by abrupt onset of symptoms, insulinopenia, dependence on insulin injections, proneness to ketoacidosis, and lack of ability to produce C peptide; (2) type II, noninsulin-dependent diabetes mellitus (NIDDM), or adult-onset diabetes), is recognized by lack of ketoacidosis except under stressful circumstances, ability to produce C peptide, tendency to obesity, and improvement following loss of weight; and (3) type III, secondary diabetes, which occurs as a complication of pancreatic, hormonal, or genetic disorder(s) and/or following ingestion of certain drugs or chemical compounds.5 A total of 90% of diabetics have type II diabetes (NIDDM), whereas only 10% have type I diabetes (IDDM).2 Diabetes is important to study by practicing physicians, including dermatologists, because of the numerous, variedly associated skin manifestations. According to previous estimates, at least 30% to 70% of persons with diabetes have some type of cutaneous involvement during the course of this chronic disease.4,6–8 The prevalence of

skin manifestations in diabetics reaches almost 100%, especially when metabolic effects on microcirculation and changes in skin collagen are considered.9 Although the overall prevalence of cutaneous disorders does not seem to differ between type I and type II diabetes,2 type II patients develop more frequent cutaneous infections, whereas type I patients frequently develop autoimmune-type cutaneous lesions.10 Some skin findings can be the presenting manifestation of the disease, while other findings may indicate a serious, even life-threatening issue; furthermore, there are also relatively minor skin manifestations that can potentiate major complications. Recognition of the preceding manifestations is a key to treatment and prevention.11 Dermatologic disorders associated with DM generally appear after the disease has developed, but they may signal or appear concomitantly with its onset or even precede diabetes by many years.12 We shall describe the details of diabetes-related dermatoses in parts II and III of this paper to cover the subject in its entirety. CLASSIFICATION Understanding DM and its various cutaneous and systemic effects entails knowledge on the part of the treating physician, which starts with prompt and early diagnosis, adequate treatment, and control of diabetes throughout the patient’s life. This management will prevent or ameliorate complications in the

From the Dermato-Venerology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi; Skin Institute, School of Dermatology, Greater Kailash New Delhi; 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

Table I. Classification of Related and/or Associated Dermatoses Major associations: necrobiosis lipoidica, diabetic foot, infection, localized pruritus, and bullae Minor associations: shin spots, granuloma annulare, lichen planus, vitiligo, hair disorder, pathological gustatory sweating, acanthosis nigricans, scleredema, and other rare conditions Disorders associated with treatment: oral hypoglycemic agents and insulin Systemic disease and diabetes: porphyria, secondary xanthomatosis, hemochromatosis, lipodystrophies, carotenemia, Werner’s syndrome, and glucagonoma syndrome13 Syndromes associated with diabetes mellitus: acromegaly, hemochromatosis; xanthomatosis porphyria cutanea tarda; Cushing’s syndrome; Werner’s syndrome; Dupuytren’s contracture; progressive lipodystrophy; Acharad-Heir’s syndrome; Peyronies’ disease; Kaposi’s sarcoma; lipoid proteinosis; pseudoxanthoma elasticum; and atherosclerosis Dermatoses related to diabetes mellitus: benign acanthosis nigricans, scleredema, Kyrle’s disease; anhidrosis and/or oligohidrosis, vitiligo granuloma annulare, necrobiosis lipoidica diabeticorum, shin spots, rubeosis faciei, bullous diabeticorum, and carotenemia Skin signs of diabetes or its therapy: Mal perforans, insulin lipodystrophy; neuropathic joint; diagonal earlobe crease; xerosis, pruritus, and cutaneous infections14

future. Classifying the various dermatoses associated with DM assists in assessing the impact of the disease on body organs and systems at micro and macro levels, providing insight to the treating physician for individualizing treatment for both conditions. Cutaneous markers can also act as a warning that such management has been ignored, thus warranting an immediate reassessment of the patient both clinically and therapeutically to bring the condition under control. Accordingly, it is worthwhile to consider related and/or associated dermatoses in order to manage DM (Table I and Table II).6,12–14 CLINICAL CONNOTATION OF RELATED DERMATOSES

NECROBIOSIS LIPOIDICA

commonly seen in patients with type I diabetes, but may also occur in patients with type II diabetes.17

Clinical Appearance Typical lesions associated with NL occur on pretibial skin as firm, dull, red, papules or plaques, which may enlarge to form irregular, ovoid plaques with a violaceous, indurated periphery and a yellow atrophic center (Figure 1).15 Lesions on the hands, forearms, abdomen, face, and scalp may also be associated with diabetes.18 Spontaneous remission occurs in 13% to 19% of patients. NL-associated lesions are usually asymptomatic but may involve anesthesia, pain, pruritus, and hypohidrosis of the affected skin.19,20 Ulceration21,22 and squamous cell carcinoma have rarely been reported in areas of NL.23,24

Historical Necrobiosis lipoidica (NL) was first described by M. Oppenheim in 1930, and was subsequently named Necrobiosis lipoidica diabeticorum (NLD) by E. Urbach in 1932.5 Hyperlipidemia seems to play a major role in DM. Goldsmith is quoted to have reported the first case of NL in a nondiabetic patient15; however, it is now well-known that NL is not limited to diabetics.16

Epidemiology NL appears in only 0.3% to 1.6% of patients with diabetes.2 Only 11% to 65% of patients with NL may have DM at the time of diagnosis.16 Of patients without diabetes, 90% eventually develop diabetes and have abnormal glucose tolerance. The female to male ratio is 3:1. The age of onset ranges from birth to 76 years, with an average of 30 years in diabetics and 41 years in nondiabetics. Patients with IDDM develop NL considerably earlier, at a mean age of 22 years, whereas NIDDM and nondiabetic patients develop NL at a mean age of 49 years.12 It is most SKINmed. 2011;9:240–244

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Pathophysiology NL may be associated with microangiopathic changes consisting of thickened basement membranes and capillary walls, particularly in lesions located in the pretibial region. Other proposed causative factors include endarteritis obliterans, immune-mediated vasculitis, delayed hypersensitivity, nonenzymatic glycosylation and other defects in collagen trauma, platelet aggregation, defective mobility of neutrophils, and vascular insufficiency.12,25 A human leukocytic antigen (HLA) correlation has also been found in the form of high frequencies of HLA-DR4, HLA-B8, and HLA-CW 3, and low frequencies of HLA-DR5 and HLADR7.15,26

Histopathology Two patterns are seen in NL. The first, usually presenting in patients with DM, is called palisading granulomatous, while the second, called tuberculoid, is predominant in the nondiabetic

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Table II: Classification of Directly/Indirectly Associated Dermatoses Cutaneous manifestations of vascular abnormalities: microangiopathy, macroangiopathy; gangrene; erysipelas-like erythema Cutaneous manifestations of neurologic abnormalities: motor neuropathy, sensory neuropathy; autonomic neuropathy, diabetic foot; eye-foot syndrome Cutaneous infections: candidiasis, nonclostridial gas gangrene; dermatophytosis, malignant external otitis; zygomycosis; erythrasma Other distinct findings: necrobiosis lipoidica diabeticorum, disseminated granuloma annulare; diabetic neuropathy, diabetic bullae; waxy skin, stiff joints, yellow skin; scleredema of diabetes mellitus, eruptive xanthoma of diabetes Less distinct skin findings: skin tags, yellow nails; red face; pigmented purpuric dermatoses; oral findings; peripheral edema Cutaneous findings in secondary diabetes: hemochromatosis, the lipodystrophies; the cutaneous porphyrias, acanthosis nigricans Dermatoses associated with an increased incidence of diabetes mellitus: Werner’s syndrome, scleroderma; Kaposi’s sarcoma, cutaneous perforating disease; lipoid proteinosis, vitiligo; lichen planus Other possible associations with diabetes: alopecia, Dupuytren’s contracture, psoriasis; Degos’ disease, pseudoxanthoma elasticum pruritus; pustulosis palmaris et plantaris; intracutaneous herniation of fat Cutaneous reactions to antidiabetic drugs: oral hypoglycemic agents, insulin

group.27 Large areas of necrobiotic collagen are present in the lower two thirds of the dermis, surrounded by a cellular infiltrate of histiocytes, fibroblasts, and lymphoid cells. Extracellular lipid deposits are also seen. Plasma cells are scattered between degenerating fibers with variable numbers of Langhans’ foreign body giant cells, and blood vessels show endothelial proliferation with wall thickening.5 Atypical lesions have been reported on the face and scalp.28 Miescher’s granuloma of the face has been suggested for lesions similar to NL but with absence of necrobiosis histopathologically. This has been included in the spectrum of necrobiotic disease.29 NL has also been seen in association with Crohn’s disease, ulcerative colitis, and following jejunal bypass surgery.15 An interesting association between NL and GA30 has been noted and has also been reported to occur with ataxia telangiectasia and sarcoidosis.5 Early NL and GA are difficult to differentiate. Late-stage GA lacks the epidermal change, atrophy, or yellow color of NL. GA is typically located on the dorsa of the hands, fingers, and feet.31 Pigmented pretibial patches associated with diabetes may present as flat, atrophic, hyperpigmented lesions, in contrast to the red or yellow lesions associated with NL.32 Sarcoidosis may also mimic NL as annular or serpiginous groups of red-brown papules on the scalp, face, or extremities.16 Rheumatoid nodules can have a clinical appearance similar to NL.33 Red/yellow indurated plaques and nodules with atrophy and ulceration that involve the periorbital areas characterize necrobiotic xanthogranuloma. It is consistently associated with paraproteinemia.34

first-line therapy.35 Other treatment modalities include pentoxifylline, chloroquine, and cyclosporine.36,37

GRANULOMA ANNULARE Historical GM was first described by T. Colcott Fox in 1895, and was established as a specific entity by H. Radcliffe Crocker.5 Several studies38 support the view that generalized GA, especially in older patients, is associated with diabetes. Reports of association of DM with localized variants or localized nodular GA showed that the majority of patients had IDDM.5 Another study39 suggested that type II DM and GA have no other association.

Pathophysiology GA represents a reaction pattern to various triggering factors such as insect bites, waxing-induced pseudofolliculitis, tuberculin

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Figure 1. Necrobiosis lipoidica on the right leg. Type II Diabetes Mellitus–Related Dermatoses

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CORE CURRICULUM CONCLUSIONS NIDDM is a widely-acclaimed entity across the globe with far reaching ramifications. The prevalence of skin manifestations in diabetics reaches almost 100%, especially when metabolic effects on microcirculation and changes in skin collagen are considered. NLD and GA are frequently encountered cutaneous expressions. They may either precede or occur during the course of diabetes. It is imperative to take cognizance of these entities, as they may be a forerunner of diabetes and serve as markers of its subsequent management. Acknowledgments: Dr Sandipan Dhar, MD, editor of the Indian Journal of Dermatology, Kolkata, India supplied Figure 1, and Dr V. Ramesh, MD, the head of the Department of Dermatology and STD, Vardhman Mahavir Medical College and associated Safdarjang Hospital New Delhi, India supplied Figure 2.

Figure 2. Granuloma annulare over the right cheek and neck.

test, Bacille Calmette-Guérin vaccination, or hepatitis B vaccination. Infections such as the human papilloma virus, varicella/ zoster virus, Epstein-Barr virus, hepatitis C virus, and human immunodeficiency virus have been associated with GA.5,40–43 A hypersensitivity mechanism has been implicated due to elevated levels of migration inhibition factor. Lymphocytes, when trapped in the dermis between collagen bundles, may release toxic lysosomal enzymes that cause collagen and elastin degeneration.44 A tissue inactivator of neutrophil chemotaxis has also been demonstrated.45 Correlation between IDDM and GA has been demonstrated through an HLA-B8 association.46

REFERENCES

Epidemiology and Clinical Appearance GA presents as one or more localized annular or arciform lesions with flesh-colored papular borders and flat centers (Figure 2), most often on the dorsal and lateral aspects of the hand and feet of children and young adults.12 Other variants include localized, generalized, perforating, and subcutaneous.47 The majority of affected individuals are younger than 30 years; however, the mean age at onset is 51.7 years.48 It is twice as common in women as in men.5

Histopathology Necrobiotic granuloma is seen in three patterns: (1) necrobiotic palisading, (2) interstitial, and (3) sarcoidal or tuberculoid.49 There are foci of degenerated collagen in the upper dermis and histiocytes between collagen bundles and around degenerated collagen. The colloidal-iron stain shows abundant mucin in involved areas.6 The vessel changes are not predominant, and there are few giant cells.50 There is a marked reduction or absence of elastic fibers.5 Epidermal changes in perforating GA, in the form of superficial areas of necrobiosis surrounded by palisading histiocytes seen below a perforation in the epidermis, have been documented.27,51,52 SKINmed. 2011;9:240–244

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Freinkel RK. Skin manifestation of alteration and disorders of the endocrine system. In: Fitzpatrick TB, Eisen AZ, Wolf K, et al eds. Dermatology in General Medicine. 5th ed. New York, NY: McGraw Hill; 2006:1651–1661.

10 Romano G, Moretti G, Di Benedetto A, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Res Clin Pract. 1998;39:101–106. 11 Huntley AC. Cutaneous manifestation of diabetes mellitus. Dermatol Clin. 1989;7:531–546. 12 Jelinek JE. Cutaneous manifestation of diabetes mellitus. Int J Dermatol. 1994;33:605–617. 13 Mendelsohn S, Verbov J. Diabetes and the skin: a review. Br J Clin Pract. 1983;37:85–94. 14 Gouterman IH, Sibrack LA. Cutaneous manifestation of diabetes. Cutis. 1980;25:45–54.

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15 Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991;25:735–748. 16 O’Toole EA, Kennedy U, Nolan JJ. Necrobiosis lipodica: only a minority of patients have diabetes mellitus. Br J Dermatol. 1999;140:283–286. 17 Shall L, Millard LG, Stevens A. Necrobiosis lipoidica: the footprint not the foot step. Br J Dermatol. 1990;123(suppl 37):47.

34 Jorizzo JL, Olansky AJ, Stanley RJ. Superficial ulcerating necrobiosis in rheumatoid arthritis. A variant of the necrobiosis lipoidica: rheumatoid nodule spectrum? Arch Dermatol. 1982;118:255–259. 35 Macfarlane AW, Verbov JL. Necrobiotic xanthogranuloma with paraproteinemia. Br J Dermatol. 1985;113:339–343.

18 Huntley AC. Cutaneous manifestation of diabetes mellitus. Diabetes Metab Rev. 1993;9:161–176.

36 Goette DK. Resolution of necrobiosis lipoidica with exclusive clobetasol propionate treatment. J Am Acad Dermatol. 1990;22:855–856.

19 Boulton AJ, Cutfield RG, Abouganeum D, et al. Necrobiosis Lipodica diabeticorum: a clinicopathologic study. J Am Acad Dermatol. 1988;18:530–537.

37 Nguyen K, Washenik K, Shupack J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol. 2002;46:s34–s36.

20 Mann RJ, Harman RR. Cutaneous anaesthesia in necrobiosis lipodica. Br J Dermatol. 1984;110:323–325.

38 Darvay A, Acland KM, Russell-Jones R. Persistent ulcerated necrobiosis lipoidica responding to treatment with cyclosporine. Br J Dermatol. 1999;141:725–727.

21 Feingold KR, Elias PM. Endocrine skin interactions. J Am Acad Dermatol. 1984;17:921–940. 22 Lowitt MH, Dover JS. Necrobiosis lipodica. J Am Acad Dermatol. 1991;25:735–748.

39 Haim S, Friedman Birnbaum R, Shafrir A. Generalized granuloma annulare: relationship to diabetes mellitus as revealed in 8 cases. Br J Dermatol. 1970;83:302–305.

23 Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long standing necrobiosis lipoidica. J Cutan Pathol. 2006;33:581–583.

40 Nebrio CL, Lewis C, Chuang TY. Lack of association between granuloma annulare and type II diabetes mellitus. Br J Dermatol. 2002;146:122–124.

24 Santos-Juanes J, Galache C, Curto JR, et al. Squamous cell carcinoma arising in long standing necrobiosis lipoidica. J Eur Acad Dermatol Venereol. 2004;18:199–200.

41 Kakurai M, Kiyosawa T, Ohtsuki M, et al. Multiple lesions of granuloma annulare following BCG vaccination: case report and review of the literature. Int J Dermatol. 2001;40:579–581.

25 Quimby SR, Muller SA, Schroeter AL. The cutaneous immunopathology of necrobiosis lipoidica diabeticorum. Arch Dermatol. 1988;124:1364–1370.

42 Toro JR, Chu P, Yen TS, et al. Granuloma annulare and human immunodeficiency virus infection. Arch Dermatol. 1999;135:1341–1346.

26 Tuomilehto-Wolf E, Tuomilehto J, Hitman GA, et al. Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA retion. BMJ. 1993;307:155–159.

43 Granel B, Serratrice J, Rey J, et al. Chronic hepatitis C virus infection associated with a generalized granuloma annulare. J Am Acad Dermatol. 2000;43:918–919.

27 Glusac EJ, Shapiro PE. Noninfectious granulomas. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF, eds. Levers’ Histopathology of the Skin. 9th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2004:373–379.

44 Sibbald RG, Schachter RK. The skin and diabetes mellitus. Int J Dermatol. 1984;23:567–584.

28 Imakado S, Satomi H, Iskikawa M, et al. Diffuse necrobiosis lipoidica diabeticorum associated with non-insulin-dependent diabetes mellitus. Clin Exp Dermatol. 1998;23:271–273.

46 Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare: Histopathology and direct immunofluorescence. Arch Dermatol. 1977;113:463–467.

29 Mehregan AH, Altman J. Miescher’s granuloma of the face: a variant of the necrobiosis lipoidica-granuloma annulare spectrum. Arch Dermatol. 1973;197:62–64.

47 Anderson BL, Verdich J. Granuloma annulare and diabetes mellitus. Clin Exp Dermatol. 1979;4:31–37.

30 Schwartz ME. Necrobiosis lipoidica and granuloma annulare. Simultaneous occurrence in a patient. Arch Dermatol. 1982;118:192–193. 31 Cohen IJ. Necrobiosis lipodica and granuloma annulare. J Am Acad Dermatol. 1984;10:123–124. 32 Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 5th ed. New York, NY: McGraw Hill Medical Publishing Divison; 2005:438–440. 33 Bauer M, Levan NE. Diabetic dermangiopathy. A spectrum including pigmented pretibial patches and necrobiosis lipoidica diabeticorum. Br J Dermatol. 1970;83:528–535.

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45 Umbert P, Winkelmann RK. Granuloma annulare: direct immunofluorescence study. Br J Dermatol. 1976;95:487–492.

48 Smith MD, Downie JB, Dicostanjo D. Granuloma annulare. Int J Dermatol. 1997;36:326–333. 49 Dabski K, Winkelmann RK. Generalised granuloma annulare: clinical and laboratory finding in 100 patients. J Am Acad Dermatol. 1989;20:39–47. 50 Weedon D, Struton G. Skin Pathology. 2nd ed. Edinburgh, England: Churchill Livingstone; 2002:193–221. 51 Sibbald RG, Schachter RK. The skin and diabetes mellitus. Int J Dermatol. 1984;23:567–584. 52 Penas PF, Jones Caballero M, Frage J, et al. A perforating granuloma annulare. Int J Dermatol. 1997;36:340–348.

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SELF-TEST REVIEW QUESTIONS

SELF-TEST REVIEW QUESTIONS W. Clark Lambert, MD, PhD, Section Editor Instructions: For each of the following numbered questions, choose the appropriate lettered response(s). Unless directed to choose only one lettered response, all, some, or none of the responses may be correct. 4) Which of the following entities is more common in women? (Choose the single best response.) a. Acquired perforating dermatosis b. Bullosis diabeticorum (diabetic bullae) c. Diabetic dermopathy d. All of the above e. None of the above

Cutaneous complications of noninsulin-dependent, type 2 diabetes mellitus include: (Answer as many as apply.) a. acanthosis nigricans. b. acquired perforating dermatosis. c. bulla. d. carotenoderma. e. Dupuytrenâ&#x20AC;&#x2122;s contractures. f. eruptive xanthomas. g. rubeosis faceii.

2)

Each of the following statements regarding diabetic dermopathy is correct, except: (Choose the single best response.) a. bullous lesions are seen very early in most cases. b. it is also known as â&#x20AC;&#x153;pigmented pretibial purpura.â&#x20AC;? c. it is also known as â&#x20AC;&#x153;shin spots.â&#x20AC;? d. it is also known as â&#x20AC;&#x153;spotted leg syndrome.â&#x20AC;? e. it characteristically precedes evidence of abnormal glucose metabolism.

3)

Which of the following locations is least likely to show yellow dyspigmentation in Carotenoderma? (Choose the single best response.) a. Axillae b. Brow c. Nasolabial folds d. Nostrils e. Palms and soles f. Sclerae g. Sebaceous areas.

5) In Rubeosis faceii, one may observe: (Answer as many as apply.) a. calor (warmth). b. elevated borders. c. reddening of the face. d. reddening of the hands and feet. e. telangiectasias.

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

1)

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 â&#x20AC;˘ 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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Volume 9 • Issue 4

COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor

The Next Frontier of Sunscreen Protection: Beyond Sunscreens Howard A. Epstein, PhD

T

he Food and Drug Administration (FDA) has proposed a final sunscreen monograph that is intended to address photostability of sunscreen products. SPF, formerly known as “skin protection factor,” will become “sunburn protection factor.” SPF label claim will be capped at 50+. The FDA has addressed UV-A exposure and package labeling by proposing two methods of UV-A testing. One method is in vitro and the other is in vivo. On June 17, 2011 the FDA issued a revised notice in the Federal Register rules and regulations advising that the package label claim will not require the four star rating system. The revision will now contain a “broad spectrum” label claim. This will indicate to the consumer that the sunscreen provides UV-B and UV-A protection. To establish a broad spectrum claim the sunscreen will have to pass a critical wavelength test. The threshold for critical wavelength is set at 370 nm. The FDA has concluded that most of the harmful effects from the sun are caused by UV radiation in the range of 290–370 nm. This testing will be referred to as the “broad spectrum test.” The prior FDA proposal required a package UV-A label claim requiring a zero to four star rating. A four star rating would have indicated maximum UV-A protection including the UV-A1 spectrum. Achieving a four star rating with a high SPF formulation is extremely challenging using the limited UV-A sunscreens currently permitted by the FDA. Butyl methoxydibenzoylmethane (avobenzone) is the most commonly used organic UV-A sunscreen in the United States. Avobenzone is a photo-unstable agent and must be properly stabilized in sunscreen formulations to provide adequate UV-A protection. The revised FDA requirement acknowledges difficulty achieving protection in the UV-A1 spectrum (340–400 nm) and will no longer propose the four star requirement. The broad spectrum claim with the 370 nm requirement is believed to provide adequate protection based on review of submitted studies.

WHY IS THERE A NEED FOR SKIN PROTECTION BEYOND SUNSCREENS? UV filter molecules absorb and dissipate energy through transfer of energy. When a particle of UV radiation (a photon) transfers its energy, electrons in avobenzone “jump” to a higher energy orbit that is further away from the nuclear framework. The initial jump is frequently to a singlet excited state. The molecule may quickly return to the ground state or go to a triplet excited state. Sunscreen molecules that do not return to the ground state are no longer effective as sunscreen agents. The loss of stability follows a pattern of decline known as an exponential decay curve and is well documented in the literature. Inappropriate formulation of sunscreens, formulating avobenzone with octinoxate, can hasten photoinstability by destroying molecules in both sunscreens. The role of a photostabilizer is to minimize the rate of decay. In addition to rendering a sunscreen formulation ineffective, singlet oxygen is implicated in photosensitization and formation of destructive reactive oxygen species (ROS). This reaction with skin has been associated with textile workers who developed itching, burning sensation, erythema, roughness, dryness, and pigmentation of skin after being in contact with textile dyes that developed singlet oxygen on exposure to light.1–3 Singlet oxygen formation is associated with oxidative damage to amino acids, specifically histidine, tryptophan, and cysteine, as well as nucleic acids, proteins, and lipids. ANTIOXIDANTS A study was performed4 using two-photon fluorescence imaging of sunscreen formulations containing octocrylene (10%), octylmethoxycinnamate (7.5%), and benzophenone-3 (6.0%) formulated in a simple water-in-oil emulsion. Each sunscreen was tested as a single entity in separate emulsions. Two-photon fluorescence microscopy was used to image UV-induced ROS

From EMD Chemicals Inc, Gibbstown, NJ Address for Correspondence: Howard A. Epstein, PhD, EMD Chemicals Inc, 480 South Democrat Road, Gibbstown, NJ 08027 • E-mail: howard.epstein@emdchemicals.com

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COSMETIC SCIENCE Two examples are bis-ethylhexyl hydroxydimethoxy benzylmalonate and diethylhexyl syringylidene malonate (Figure 1). Avobenzone undergoes a photoketonization reaction where the enol is converted to its diketone form. This reaction is reversible; however, a Norrish type 1 reaction can occur, which is irreversible, and can lead to an energy transition to a photodegradative singlet electron or triplet electron excited state leading to singlet oxygen formation. Both bis-ethylhexyl hydroxydimethoxy benzylmalonate and diethylhexyl syringylidene malonate function as antioxidants, with the former shown to be a triplet energy quencher and the latter a singlet energy quencher.8,9 Formulating both materials with avobenzone results in a redox pair providing a high level of photostabilization and quenching of ROS that tends to form in unstable sunscreen formulations. This observation was confirmed using electron spin resonance studies with pig skin explants.8 These types of studies provide in vitro demonstration that a mixture of both materials can provide a prolonged antioxidant benefit over time.

Figure 1A. Bis-ethylhexyl hydroxydimethoxy benzylmalonate.

PHYTOCHEMICALS AS BIOACTIVE SUNSCREEN BOOSTERS AND ANTIOXIDANTS

Figure 1B. Diethylhexyl syringylidene malonate.

generation in the epidermal skin model Epiderm (MatTek Corp, Ashland, MA). The investigators found that the sunscreen molecules can act as sources for ROS generation if they can penetrate skin. The investigators point out that their conclusions were different from a previous study5,6 showing that avobenzone formulated with octylmethoxycinnamate reduced ROS generation over time. The authors note that different tissue (breast and facial tissue) and a different UV source (UV-B and UV-A) were used in the prior studies and their study used a UV-B light source. In the body, ROS form naturally as a result of the respiratory chain and metabolism of xenobiotics. In skin, the single most important source of ROS is UV radiation. Excessive ROS generation is thought to be related to the development of skin cancer, UV-induced immunosuppression, and premature skin aging.7

Modified flavonoids can function as UV absorbers and possess radical quenching activity. Structure activity studies have shown that the degree of efficacy of a flavonoid as an antioxidant depends on the flavonoid structure.10 The investigators showed that chemical modifications to vinylogous compounds can be synthesized to provide useful UV-A absorbers with moderate to good singlet oxygen-quenching activity. The structure of polyphenolic compounds found in various species of plants is structurally similar to organic UV filters. Polyphenolic compounds are associated with antiallergic, anti-inflammatory, antioxidant, freeradical savaging activity and other beneficial medicinal properties. Green tea extract is perhaps the best known polyphenolic compound with more yet to be discovered. Rutin, a flavonoid, was shown to provide enhanced UV-A protection when formulated in a suitable sunscreen base. The Boots Star Rating system was used for the study. It was interesting to note that when the plant extract was tested with another plant extract, Plantago incarnate in the same sunscreen base, the effect was lost. When another sunscreen base was used, the combination was found to enhance critical wavelength, which is another measure of sunscreen efficacy over the broad UV spectrum. The sunscreens used in the test bases were 7.0% ethylhexyl methoxycinnamate, 2.0% benzophenone-3, and 2.0% titanium dioxide.11

AVOBENZONE SOLUBILIZERS WITH ANTIOXIDANT ACTIVITY

PLANT-BASED ANTIOXIDANTS

Avobenzone is known to crystallize if formulated in an inappropriate solvent or in an insufficient amount of cosolvent. Solvents for avobenzone with antioxidant activity are currently available.

Panoxatriol (Figure 2), a fatty alcohol found in ginseng, was shown to have antioxidant activity when tested in vitro using human keratinocytes exposed to UV-B irradiation.12 Phyllanthus

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emblica (Emblica officinalis) has been used for more than 4000 years for a variety of human ailments. P emblica has antioxidant activity believed to be related to its high content of low molecular weight tannins. A standardized extract of P emblica fruit was evaluated in an SPF 30 sunscreen tested on 39 volunteers who applied the sunscreen formulation at least once per day in place of a moisturizer or sunscreen they would normally use. A positive control group of volunteers used a sunscreen formulation and other moisturizing facial products that they normally used. Evaluation was at baseline and weeks 8 and 12. In addition to the clinical study, an in vitro measurement for matrix metalloproteinase enzyme (MMP)-1, an acute and early biomarker of photoaging, was performed. Test material was Melanoderm skin equivalents (Mat Tek Corporation, Ashland, MA). Melanoderm was exposed to 10 J/cm2 UV, a dose equivalent to 2 minimal erythema doses. Enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) was used to evaluate for MMP-1. Wrinkle and fine-line reduction on the volunteers was documented with evaluation of a trained evaluator who was blinded to location of test and control products. A statistically significant reduction in attenuation of MMP-1 expression was measured in the test material containing sunscreen with the P emblica extract. The study included an SPF 30 broad-spectrum sunscreen without antioxidants. This formulation showed MMP-1 production virtually equivalent to a placebo lotion without sunscreens. Comparable MMP-1 attenuation was also observed with a sunscreen formulation containing diethylhexyl syringylidene malonate. In the in vivo clinical study, the SPF 30 sunscreen lotion containing diethylhexyl syringylidene malonate and the SPF sunscreen formulation containing 0.01% Emblica fruit extract both showed visibly reduced wrinkle and fine-line formation compared with the control sunscreens without these ingredients.13 HISTORY OF ANTIOXIDANTS In the 1950s, Denham Harman proposed a “free-radical theory” of aging. His hypothesis was that endogenous oxygen radicals were generated in cells, resulting in a pattern of cumulative damage. At the time, this was considered a controversial theory. Approximately 10 years after publication of the free-radical theory, superoxide dismutase, an enzyme with the sole function that seemed to be the removal of superoxide anions, was identified. This discovery provided credence to the Harman theory. The free-radical theory of aging suggested that targets of ROS were random. Current thinking is that ROS act as specific signaling molecules under both physiologic and pathophysiologic conditions. In this regard, ROS are necessary to maintain homeostasis of the body. With regard to photoprotection, the generation of singlet oxygen (1O2) is of particular concern. Singlet oxygen is not considered a free radical as it has no unpaired electron. Rather, SKINmed. 2011;9:247–250

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Figure 2. Panoxatriol.

it is a highly reactive and potent oxidant as such classified as an ROS. Due to overlapping oxidizing effects, the methods to assess individual ROS lack specificity. The use of several approaches is necessary to obtain insight regarding the relative concentrations and roles antioxidants play in biological systems.14 Singlet oxygen production is of specific interest to the sunscreen formulator because singlet oxygen in the presences of UV-A radiation has been shown to produce deleterious biological effects. In skin, it will react with urocanic acid resulting in photosensitization and skin aging. The singlet oxygen reaction is short-lived in skin, creating a challenge to measure and establish efficacy claims for the cosmetics industry. It is established that avobenzone, the most commonly used UV-A sunscreen, will form singlet oxygen as a by-product of instability on exposure to UV radiation. Given this possibility, it is important for the formulator to stabilize avobenzone appropriately to minimize this possibility. Current theory regarding oxidants in the body is that they serve as signal mechanisms important for the organism’s homeostasis. The mechanism of ROS “crosstalk” is not well understood and cannot be easily measured. This is an area currently under scientific investigation. CONCLUSIONS The proposed final sunscreen monograph establishes standards for testing the effectiveness of sunscreen products and will require labeling that reflects the required test results. Under the

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COSMETIC SCIENCE

new regulations a “broad-spectrum” label claim will indicate that the product provides UV-B and UV-A protection. Conceptually the objective is to protect the skin against all types of suninduced damage. Given that few UV-A sunscreens are available in the United States and it is a challenge to formulate a highly effective sunscreen product that will provide the highest UV-A and UV-B ratings, it is desirable to find additional technologies to help protect skin from solar damage. An example being the need to stabilize avobenzone. The proposed final monograph does not address the potential damaging effects of ROS that are generated in the body as a result of exposure to UV radiation. This is an area of science yet to be fully understood. Our limited ability to measure the biological consequences of excessive ROS production and the resulting paracrine crosstalk are a challenge currently being investigated. Understanding the antioxidant conundrum and developing appropriate antioxidants is indeed the next frontier of photoprotection.

5

Walters KA, Roberts MS. Percutaneous Absorption of Sunscreens. In: Bronaugh RL, Maibach HI, eds. Topical absorption of dermatological products. New York, NY: Dekker; 2002:465– 481.

6

Treffel P, Gabard B. Skin penetration and SPF of ultraviolet filters from two vehicles. Pharm Res. 1996;13:770–774.

7

Steenvoorden DP, van Henegouwen GM. The use of endogenous antioxidants to improve photoprotection. J Photochem Photobiol B. 1997;41:1–10.

8

Rudolph T, Pan J, Scheurich R, et al. Superior two step approach to completely photoprotect avobenzone with a designed organic redox pair. SOFW Journal. 2009;135:14–18.

9

Chaudhuri RK, Lascu Z, Pucetti G, et al. Design of a photostabilizer having built-in antioxidant functionality and its utility in obtaining broad-spectrum sunscreen formulations. Photochen Photobiol. 2006;82:823–828.

10 Martin HD, Beutner S, Frixel S, et al. Modified flavonoids as strong photoprotecting UV-absorbers and antioxidants. Koninklijke Vlaamse Chemische Vereniging. 2006;1:288– 291. 11 Velasco MVR, Sarruf FD, Salgado-Santos IMN, et al. Broad spectrum bioactive sunscreens. 2008;363;50–57.

REFERENCES 1

Kumar V, Tripathi MR, Kumar M, et al. Studies on production and chemical property of singlet oxygen and superoxide radical by dyestuffs. E-Journal of Chem. 2009;6(S1):S79–S86.

12 Jin GH, Liu Y, Jin SZ, Liu SZ. UVB induced oxidative stress in human keratinocytes and protective effect of antioxidant agents. Radiat Environ Biophys. 2007;46:61–68.

2

Prayer WA. Free Radicals in Biology. New York, NY: Academic Press; 1976.

3

Krinsky NI. Singlet oxygen in biological systems. Trends in Biochem Sci. 1977;2:35–38.

4

Hanson KM, Gratton E, Bardeen CJ. Sunscreen enhancement of UV-induced reactive oxygen species in the skin. Free Radic Biol Med. 2006;41:1205–1212.

13 Meyer TA, Beasley DG, Erixon A, et al. Cosmetic efficacy benefits of topical broad-spectrum sunscreens containing antioxidants. Poster P3104, presented at: American Academy of Dermatology Annual Meeting; March 5–9, 2010; Miami Beach, FL. 14 Mukhtar H, ed. Pharmacology of the Skin. Boca Raton, FL: CRC Press; 1991.

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Volume 9 • Issue 4

PERILS OF DERMATOPATHOLOGY W. Clark Lambert, MD, PhD, Section Editor

The Three Faces of Cylindroma Theresa A. Zaleski, DO;1 Laurie Dabaghian, BA;2 Amin Maghari, MD;3 W. Clark Lambert, MD, PhD3 “What’s in a name? That which we call a rose by any other name would smell as sweet.” —William Shakespeare. Romeo and Juliet. Act 2, scene 2.

T

he term cylindroma was first used in 1856 by Billroth to describe an orbital tumor with a glassy appearance.1 The term was derived from the cylindrical appearance of a lesion on cross-section.2 Today, three forms of cylindromas are recognized: a malignant salivary cylindroma also known as adenoid cystic carcinoma, a benign cutaneous cylindroma that occurs in both single and multiple forms, and a malignant cylindroma that usually occurs in the setting of Brooke-Spiegler syndrome.3 While the nomenclature of these lesions may be identical, the clinical behavior and prognosis can vary drastically. It is rare for a benign cutaneous cylindroma to become malignant, but a cylindroma of the salivary glands is almost always malignant. CYLINDROMA OF THE SALIVARY GLAND

Adenoid cystic carcinomas, formerly known as salivary gland cylindromas, are the second most common malignancy in salivary glands, comprising 22% of salivary gland malignancies.4 These tumors are known to have a poor long-term prognosis with a high risk for recurrence.5 The carcinoma may be found in the parotid, submaxillary, and sublingual glands and can develop in any of the minor or major glands of the head, neck, lips, mouth, pharynx, and respiratory tract.6 Histologic findings determine the grade of the tumor. Classically, basaloid cells are found in tubular, solid, or cribriform patterns, and globules of hyaline are interspersed within the cells. Through studying aspirate smears, findings of pleomorphic cells with higher expressions of p53 and Ki-67 and loss of myoepithelial markers suggest a more aggressive and high-grade tumor.7 A tier rank may be used to determine different grades of tumors and help with the differential diagnosis and patient prognosis. Grade I tumors are found in a tubular pattern, grade II tumors are in a cribriform pattern with less than 30% solid areas, and grade III tumors have more than 30% solid basaloid growth

(Figure 1).8 The most important histologic feature is the presence and amount of solid areas in the tumor. The carcinomas that contain larger amounts of solid areas and basaloid growth are considered high-grade, and patients have shorter survival rates. Tumors that contain cells in a mixture of tubular and cribriform patterns are more easily excised and have a better prognosis.8 The location of the tumor is also important in the prognosis. Tumors in the palate and parotid gland have a better prognosis, with survival rates at 15 years of 38% and 21%, respectively. Lower survival rates are found in patients with tumors in the submaxillary gland or antrum. The size of the tumor and metastasis may also influence patient prognosis.8 Treatment for this carcinoma is a combination of surgery and radiation therapy. Although radiation therapy has a 96% response rate, it is often not used alone since ACCs have been found to have a 94% local recurrence.5 The survival rate in patients is variable, and metastasis of the tumor has an incidence of 40%.9 Metastasis most commonly takes place in the lungs but can be found in the liver and bone.4 Patients who have metastasis in the lungs have a longer survival rate than those with bone involvement. No major breakthroughs in chemotherapy have been found to treat this tumor. BENIGN CUTANEOUS CYLINDROMA OF THE SKIN Cutaneous cylindroma is a rare tumor originating from the skin appendages of the scalp and face.10 Benign cylindromas, which are twice as common in women than in men, can occur in both the solitary and multiple form, the latter usually inherited in an autosomal-dominant fashion.10 The observance of multiple cylindromas was first made by Brooke in 1892 and then by Spiegler in 1899.11 Today, the presence of multiple cylindromas is also known as Brooke-Spiegler syndrome, turban tumor, or familial cylindromatosis.12 Brooke-Spiegler syndrome is classified by the appearance of cylindromas, trichoepitheliomas, and occasionally

From UMDNJ, School of Osteopathic Medicine, Stratford, NJ;1 UMDNJ—New Jersey Medical School, Class of 2012, Newark, NJ;2 and the Departments of Dermatology and Pathology, UMDNJ—New Jersey Medical School, Newark, NJ3 Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building UMDNJ—New Jersey Medical School, Newark, NJ 07101 • E-mail: lamberwc@umdnj.edu

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PERILS OF DERMATOPATHOLOGY spiradenomas located on the head and neck beginning as early as the second decade of life.12,13 The mutation responsible for this syndrome is postulated to be the CLYD gene located on chromosome 16 which displays variable expression but absolute penetrance.12 On clinical examination, cylindromas appear as slow-growing, firm, pinkish red skin nodules measuring from 2 mm to 6 mm.13 Histopathologically, benign dermal cylindromas display a jigsaw pattern of epithelial basaloid cell islands with a biphasic cellular distribution surrounded by a thick hyaline-rich stroma, with little or no mitotic figures or nuclear pleomorphism (Figure 2).14

Figure 1. Adenoid cystic carcinoma. Cribriform and tubular pattern. Small bland myoepithelial cells with scant cytoplasm and dark compact angular nuclei palisading against basement membrane (hematoxylin-eosin stain, original magnification ´10).

The recommended treatment for benign cutaneous cylindromas is surgical excision with wide margins because of the likelihood of local tumor recurrence.3,10,15 Patients, especially those with multiple cylindromas, should be closely followed, however, even after surgical excision to rule out the possibility of recurrence with malignant progression and to undergo early surgical excision before extensive tumor growth.12 Occasionally, benign dermal cylindromas grow large enough to warrant surgical excision with or without a graft, especially in the case of multiple cylindromas.3,15 MALIGNANT CYLINDROMA OF THE SKIN Although cutaneous cylindromas are for the most part benign, rarely, cylindromas may become malignant. The first malignant cylindroma was identified by Ancell in 1842.3 Since that time, only 30 or so cases of malignant cylindroma have been described. When malignant cylindromas do occur, it is usually in the setting of multiple cylindromatosis, a condition seen in Brooke-Spiegler syndrome.2,16 Histopathologically, malignant cylindromas differ from their benign counterparts by demonstrating loss of the usual jigsaw pattern seen in benign cylindromas, loss of hyaline sheaths, loss of biphasic cellular distribution, and pronounced cellular pleomorphism with an increased mitotic rate (Figure 3).10 Clinically, these lesions are heralded by rapid growth, ulceration, and pain, with a propensity for extensive local growth up to 20 cm as well as local recurrence and even the possibility for metastases.10 Unlike their benign counterpart, malignant cylindromas have the ability to metastasize and may even result in death, thus making early and complete surgical excision with close patient follow-up crucial.3 CONCLUSIONS

Figure 2. Dermal eccrine cylindroma. Jigsaw-puzzle patterns of epithelial nests surrounded by deposition of basal lamina. Some cell nests with membrane droplets. Also note the peripheral palisading of the nuclei (hematoxylin-eosin stain, original magnification ´10).

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Although the above three types of cylindromas are categorized under a common name, it is evident that major differences are present that have to be considered when deciding on a treatment plan and prognosis. While it is common thought to associate the term cylindroma with a benign course, this is not always

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PERILS OF DERMATOPATHOLOGY

true, depending on the type of cylindroma. Even with all three cylindromas having a high likelihood of recurrence, only salivary gland and malignant cutaneous cylindromas have the possibility of metastasis. The initial treatment of the three cylindromas is surgical excision, with close follow-up due to the possibility of recurrence, but in the case of salivary gland carcinomas, radiation is also used as a means of therapy. Prognosis depends on the success of surgical excision, and, in the cases of salivary and malignant cutaneous cylindromas, the extent of metastasis. Above all, the clinician must understand clearly what the pathologist means by a diagnosis of cylindroma. REFERENCES 1

Ahued S. Cylindroma of the epiglottis. AMA Arch Otolaryngol. 1956;63:366–371.

2

Batsakis JG, Brannon RB. Dermal analogue tumours of major salivary glands. J Laryngol Otol. 1981;95:155–164.

3

Kuklani RM, Glavin FL, Bhattacharyya I. Malignant cylindroma of the scalp arising in a setting of multiple cylindromatosis: a case report. Head Neck Pathol. 2009;3:315–319.

4

Tetsu O, Phuchareon J, Chou A, et al. Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands. Neoplasia. 2010;12:708–717.

5

Spiers AS, Esseltine DL, Ruckdeschel JC, et al. Metastatic adenoid cystic carcinoma of salivary glands: case reports and review of literature. Cancer Control. 1996;3:336–342.

6

Rosenfeld L, Sessions DG, McSwain B, et al. Malignant tumors of salivary gland origin: 37-year review of 184 cases. Ann Surg. 1966;163:726–735.

7

Malhotra KP, Agrawal V, Pandey R. High grade transformation in adenoid cystic carcinoma of the parotid: report of a case with cytologic, histologic and immunohistochemical study. Head Neck Pathol. 2009;3:310–314.

8

Szanto PA, Luna MA, Tortoledo ME, et al. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer. 1984;54:1062–1069.

9

Mithani SK, Shao C, Tan M, et al. Mitochondrial mutations in adenoid cystic carcinoma of the salivary glands. PLoS ONE. 2009;4:e8493.

10 Gerretsen AL, van der Putte SC, Deenstra W, van Vloten WA. Cutaneous cylindroma with malignant transformation. Cancer. 2006;72:1618–1623.

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Figure 3. Malignant cylindroma. Compact nests of tumor cells showing a jigsaw pattern surrounded by thick basement membrane but no biphasic cellular distribution (hematoxylineosin stain, original magnification ´10). 11 Gutiérrez PP, Eggermann T, Höller D, et al. Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CLYD underlies different tumors of skin appendages. J Invest Dermatol. 2002;119:527–531. 12 Liavaag PG, Bang G. Dermal type cylindroma of the parotid gland with malignant transformation. J Laryngol Otol. 1985;99:1049– 1053. 13 Layegh P, Sharifi-Sistani N, Abadian M, et al. Brooke-Spiegler syndrome. Indian J Dermatol Venereol Leprol. 2008;74:632– 634. 14 Gokaslan ST, Carlile B, Duak M, et al. Solitary cylindroma (dermal analog tumor) of the breast: a previously undescribed neoplasm at this site. Am J Surg Pathol. 2001;25:823–826. 15 Fabian RL, Shugar MA. Florid dermal cylindroma (turban tumor). Head Neck. 2006;4:165–169. 16 Hosnuter M, Babuccu O, Kargi E, et al. Malignant solitary cylindroma of the scalp. Eur J Plast Surg. 2004;27:246–248.

The Three Faces of Cylindroma

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July/August 2011

Volume 9 • Issue 4

NEW TO THE CLINIC Noah S. Scheinfeld, MD, JD, Section Editor

Natroba (Spinosad) 0.9% Suspension Topical Suspension for Head Lice Noah S. Scheinfeld, MD, JD

N

atroba (spinosad) 0.9% topical suspension (ParaPRO LLC, Carmel, IN) was approved by the Food and Drug Administration in January 2011 as a pediculicide indicated for the topical treatment of head lice infestations in patients 4 years and older.1 In the pivotal studies of Natroba, 552 patients were studied and used the medication with a reapplication in 1 week if lice remained; 86% patients were lice free at 14 days, compared with 44% in the placebo control group.2

Spinosad is an antibiotic derived from soil microbes and has long been used for controlling flies that affect animals, killing caterpillars, drywood termites, and preventing infestations of sheep. The spinosyns have a unique mechanism of action involving disruption of nicotinic acetylcholine receptors. When compared with many other insecticides, the spinosyns generally show greater selectivity toward target insects and lesser activity against many beneficial predators as well as mammals and other aquatic and avian animals. Spinosad causes neuronal excitation in insects. After periods of hyperexcitation, lice become paralyzed and die.

needed to cover the scalp and hair, (3) rinse off with warm water after 10 minutes, and (4) repeat treatment if live lice are seen 7 days after first treatment. As compared with permethrin 1% (Nix), the current standard treatment for head lice, spinosad requires fewer retreatments. In addition, spinosad does not require nit combing and was significantly more effective than permethrin in 2 studies reflecting actual-use conditions, where most spinosad-treated participants required only 1 application. Spinosad is a more convenient and effective treatment for pediculosis capitis than permethrin. Natroba is contained in a benzyl alcohol base. Benzyl alcohol also has pediculicidal effects. Benzyl alcohol should not be used in neonates/low-weight children, as it can be systemically absorbed with toxic effect. The most common adverse events (>1%) were application site erythema and ocular erythema. REFERENCES

Spinosad 0.9% suspension topical suspension (available in 120-mg bottles) is to be used as follows: (1) shake bottle well, (2) apply product to dry scalp and hair using only the amount

1

FDA Approves Head Lice Treatment for Children and Adults. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm240302.htm. Accessed January 18, 2011.

2

Stough D, Shellabarger S, Quiring J, et al. Efficacy and safety of spinosad and permethrin creme rinses for pediculosis capitis (head lice). Pediatrics. 2009;124:e389–e395.

From the Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY Address for Correspondence: Noah S. Scheinfeld, MD, JD, 150 West 55th Street, New York, NY 10019 • E-mail: scheinfeld@earthlink.net

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July/August 2011

Volume 9 â&#x20AC;˘ Issue 4

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

Multiple Miliary Osteoma Cutis of the Face After Initiation of Alendronate Therapy for Osteoporosis Ryan R. Riahi, BS;1 Philip R. Cohen, MD2,3,4 A 62-year-old Asian woman presented with multiple small, rock-hard papular lesions on her face (Figure). She had no previous history of acne vulgaris or cutaneous malignancy. She had been diagnosed with breast cancer in 1995 and was treated with left lumpectomy followed by combination chemotherapy consisting of cyclophosphamide, 5-fluorouracil, and methotrexate. In 1995, at age 50, she also began therapy with systemic alendronate to treat osteoporosis. Within 1 year, she noticed the development of asymptomatic indurated dermal papules on her cheeks. Topical treatment with 12% lactic acid lotion did not improve her condition. Clinical examination revealed numerous 1- to 2-mm, brown dermal nodules on the malar cheeks bilaterally. Normal laboratory data included complete blood cell count, alkaline phosphatase, serum calcium, and serum phosphate. A lesional punch biopsy from the left cheek revealed lamellar bone within the dermis. Correlation of the clinical presentation, laboratory data, and pathology established the diagnosis of multiple miliary osteoma cutis of the face.

O

steoma cutis represents a disorder characterized by bone formation within the dermis and subcutaneous tissues. Multiple miliary osteoma cutis is a form of osteoma cutis that presents with multiple bony nodules on the face. The disorder can be classified as primary or secondary depending on the absence or presence of associated cutaneous disorders.1 Primary osteoma cutis is seen mostly in light-skinned, middle-aged to older women without preexisting acne, cutaneous neoplasms, or inflammatory dermatoses.2 It has also been associated with syndromes such as Albrightâ&#x20AC;&#x2122;s hereditary osteodystrophy, Gardnerâ&#x20AC;&#x2122;s syndrome, and McCune-Albright syndrome.1

In contrast, secondary osteoma cutis is more common and is typically associated with an underlying disorder such as acne vulgaris, basal cell carcinoma, cutaneous inflammation, dermatomyositis, nevi, scleroderma, sebaceous adenoma, trauma, and/ or venous stasis.3 Our patient has primary osteoma cutis of the face. The temporal association of initiating osteoporosis treatment with alendronate and the subsequent development of osteoma cutis raises the possibility that bisphosphonates may be associated with the pathogenesis of this condition in our patient. While the pathogenesis of osteoma cutis remains unclear, two theories have been proposed to explain the development of the osteomas. One theory suggests that there is a disordered embryo-

logic process that permits mesenchymal cells to differentiate into osteoblasts and migrate to the skin.3 The second theory speculates that undifferentiated or already mature mesenchymal cells, such as fibroblasts, undergo metaplasia to become osteoblasts.3 Treatment of multiple miliary osteoma cutis of the face has been difficult. Topical treatments have been used with varying success. Subjective improvement was described in a 75-year-old African American woman who used 0.1% adapalene gel for 6 months.1 Also, topical tretinoin therapy for multiple miliary osteoma cutis of the face demonstrated gradual improvement in 3 patients over the course of 3 to 6 months.4 Our patient did not achieve any significant improvement of her osteoma lesions after applying 12% lactic acid lotion. Systemic agents have not been successful in the management of this condition. A middle-aged Asian woman with multiple miliary osteomas was treated with oral isotretinoin and did not achieve any improvements.5 Systemic etidronate disodium treatment was unsuccessful in a 57-year-old woman with osteoma cutis.6 Similarly, we observed that our patientâ&#x20AC;&#x2122;s lesions appeared after she received bisphosphonate therapy. There are several reports of successful treatment of miliary osteoma of the face with surgical techniques that remove the bone

From the University of Texas Medical Branch, Medical School, Galveston;1 The University of Houston Health Center, University of Houston, Houston;2 the Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston;3 and the Department of Dermatology, University of Texas-Houston Medical School, Houston,4 TX Address for Correspondence: Philip R. Cohen, MD, 805 Anderson Street, Bellaire, TX 77401-2806 â&#x20AC;˘ E-mail: mitehead@aol.com

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CASE STUDY continuous wave laser followed by gentle removal of the osteomas with a curette demonstrated resolution of lesions with minimal scarring.6 Also, dermabrasion followed by punch biopsy removal of the bony lesions was used in 3 patients with multiple miliary osteoma cutis secondary to acne vulgaris with favorable cosmetic results.8 CONCLUSIONS Multiple miliary osteomas of the face can be primary or secondary depending on the absence or presence, respectively, of an antecedent cutaneous disorder in the affected area. In contrast to the secondary form, which results from dystrophic calcification, primary miliary osteomas are less common and not related to a preexisting skin condition. We describe an Asian woman who developed multiple miliary osteomas after beginning systemic therapy with bisphosphonates for osteoporosis. The temporal association between initiation of alendronate and the subsequent development of her facial osteoma cutis raises the possibility that interference with bone absorption may have contributed to pathogenesis of this condition in our patient. REFERENCES

Figure. Multiple miliary osteoma cutis of the face presenting as numerous, 1- to 2-mm brown, firm papules on the malar cheeks after the patient began treatment with alendronate for osteoporosis.

either from intact skin or following removal of the overlying epidermis. A 46-year-old woman with miliary osteoma cutis unresponsive to topical treatments was treated with a needle microincision-extirpation technique that provided good results that were cosmetically acceptable.7 Similarly, treatment with incision, curettage, and primary closure showed significant cosmetic improvement with no postinflammatory hyperpigmentation after 10 months in a 64-year-old American Indian/African American woman.3 Some investigators have elected to surgically eliminate the epidermis to facilitate osteoma removal. The use of a carbon dioxide

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1

Bowman PH, Lesher JL. Primary multiple miliary osteoma cutis and exogenous ochronosis. Cutis. 2001;68:103â&#x20AC;&#x201C;106.

2

Bergonse FN, Nico MM, Kavamura MI, et al. Miliary osteoma of the face: a report of 4 cases and review of the literature. Cutis. 2002;69:383â&#x20AC;&#x201C;386.

3

Altman JF, Nehal KS, Busam KJ, et al. Treatment of primary military osteoma cutis with incision, curettage, and primary closure. J Am Acad Dermatol. 2001;44:96â&#x20AC;&#x201C;99.

4

Cohen AD, Chetov T, Cagnano E, et al. Treatment of multiple miliary osteoma cutis of the face with local application of tretinoin (all-trans-retinoic acid): a case report and review of the literature. J Dermatolog Treat. 2001;12:171â&#x20AC;&#x201C;173.

5

Thielen AM, Stucki L, Braun RP, et al. Multiple cutaneous osteomas of the face associated with chronic inflammatory acne. J Eur Acad Dermatol Venereol. 2006;20:321â&#x20AC;&#x201C;326.

6

Baginski DJ, Arpey CJ. Management of multiple miliary osteoma cutis. Dermatol Surg. 1999;25:233â&#x20AC;&#x201C;235.

7

Baskan EB, Turan H, Tunali S, et al. Miliary osteoma cutis of the face: treatment with the needle microincision-extirpation method. J Dermatolog Treat. 2007;18:252â&#x20AC;&#x201C;254.

8

Fulton JE. Dermabrasion-loo-punch-excision technique for the treatment of acne-induced osteoma cutis. J Dermatol Surg Oncol. 1987;13:655â&#x20AC;&#x201C;659.

Multiple Miliary Osteoma Cutis of the Face

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July/August 2011

Volume 9 â&#x20AC;˘ Issue 4

CASE STUDY

Significance of Gramâ&#x20AC;&#x2122;s Stain Smear, Potassium Hydroxide Mount, Culture, and Microscopic Pathology in the Diagnosis of Acrodermatitis Continua of Hallopeau Virendra N. Sehgal, MD; Sonal Sharma, MD A 21-year-old housewife presented to the authorsâ&#x20AC;&#x2122; clinic in 2009 with recurrent papulovesicular and pustular eruptions on the index and ring fingers of the left hand accompanied by throbbing pain that had been active for the past 10 years. The condition did not respond to topical and/or systemic treatment. There was neither a personal/family history of psoriasis nor any other systemic disease. The skin surface of the patientâ&#x20AC;&#x2122;s left hand was marked by the presence of multiple pustules located over an erythematous background, affecting the ring and adjoining middle fingers, with crusting prominent in places along the tips (Figure 1). Gram-stained smears prepared from the purulent specimen revealed Gram-positive cocci in clusters. Potassium hydroxide (KOH) examination of the pustules did not show any fungal elements. In vitro culture of the same specimen yielded growth of Staphylococcus aureus, which was found to be sensitive to almost all conventional antibiotics on aerobic culture. Sections prepared from the skin of the tip of the patientâ&#x20AC;&#x2122;s finger showed marked epithelial hyperplasia with uniform elongation of rete ridges and supra-papillary thinning of the epidermis. There was hyperkeratosis with foci of mounds of parakeratosis. Spongiosis with neutrophilic infiltration and microabscess formation were prominent. The dermis showed perivascular lymphohistiocytic infiltrate (Figure 2A and 2B). No organism was identified on special stains. Results from hemography and liver and renal function tests were within normal limits. The diagnosis of acrodermatitis continua of Hallopeau (ACH) was made, in keeping with the findings. The patient received ceftriaxone 1.0 g and tazobactam 125 mg by slow intravenous infusion for 3 consecutive days, following which there was complete regression of the lesions. After cessation of therapy, there was complete recurrence.

A

crodermatitis continua is a peculiar pustular eruption of the fingers and toes, variously attributed to dyshidrosis, pustular psoriasis, and bacterial infection. It is also known as acrodermatitis perstans, dermatitis repens, Hallopeauâ&#x20AC;&#x2122;s disease, and pustulosis palmaris et plantaris.1,2 The entity is typically seen as localized pustular psoriasis, initially affecting the tips of the fingers or toes, extending slowly, and being more common in the elderly. It may ultimately evolve into generalized pustular psoriasis. The skin over the distal phalanx becomes red, scaly, and pustular. Desiccation of pustules may leave a crusted bright red, glazed, very sore, and painful digit. Involvement of the nail folds and nail bed may lead to nail dystrophy.3 While sterile pustules characterize it, paronychia and atrophic skin changes, onychodystrophy, and osteolysis of the distal phalanges of the fingers and toes (a variant of pustular psoriasis

Figure 1. Multiple pustules and crusting over an erythematous background.

From the Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Delhi; and the University College of Medical Sciences and Associated GTB Hospital, Delhi, India Address for Correspondence: Virendra N. Sehgal MD, Dermato-Venerology (Skin/VD) Center Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India â&#x20AC;˘ E-mail: drsehgal@ndf.vsnl.net.in

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CASE STUDY is important to evaluate the diagnosis of ACH by performing a Gram stain smear; a bacterial culture of the pustules in vitro, which may either be sterile or grow saprophytic flora that include the Streptococcus viridans group, Enterococcus species, and diphtheroids9,10; and KOH examination to exclude the presence of fungus. Similarly, it is necessary to study the microscopic pathology,2 the details of which were beautifully presented, described, and illustrated by Barber in 193011 and subsequently reiterated in 1994.2 CONCLUSIONS Excluding other possible etiologies of pustular eruptions involving the fingertips is important before arriving at a diagnosis of ACH. This should ensure an optimal outcome, especially in the setting of current biologics, including tumor necrosis factor b blockers.1,7,8

Figure 2A. Section of skin from the tip of the patientâ&#x20AC;&#x2122;s finger showing epithelial hyperplasia, orthokeratosis, and mounds of parakeratosis with a central area of spongiform pustule. Note the fragment of subcutaneous tissue with numerous Pacinian corpuscles (hematoxylin-eosin stain, original magnification Ă&#x2014;40).

REFERENCES

Figure 2B. A higher-power view of the same section showing numerous neutrophils forming microabscesses in the epidermis (hematoxylin-eosin stain, original magnification Ă&#x2014;200).

having a chronic relapsing course) may be its eventual clinical expression.3 Discrepancy of a wide variety of clinical symptoms reported for ACH is a diagnostic dilemma that may require a meticulous workup to exclude several other clinical conditions in its differential diagnosis,4 including fingertip dermatitis.5 This seems to be a glaring fallout of recent publications,3,6,7 and many other articles published in the past, as revealed through a Medlar search8 of more than 100 published articles. As a result, it

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1

Hallopeau MH. Sur une asphyxie locale des extremities avec polydactylite suppurative chronique et pousseâ&#x20AC;&#x2122;s ephemeres de dermatite pustuleuse disseminee et symetrique. Soc Fr Dermatol Syph Bull. 1890;1:39â&#x20AC;&#x201C;45.

2

Piraccini BM, Fanti PA, Morelli R, et al. Hallopeauâ&#x20AC;&#x2122;s acrodermatitis continua of the nail apparatus: a clinical and pathological study of 20 patients. Acta Derm Venereol. 1994;74:65â&#x20AC;&#x201C;67.

3

Puig L, Barco D, Vilarrasa E, et al. Treatment of acrodermatitis continua of Hallopeau with TNF-blocking agents: case report and review. Dermatology. 2010;220:154â&#x20AC;&#x201C;158.

4

Mooser G, Pillekamp H, Peter RU. Suppurative acrodermatitis continua of Hallopeau. A differential diagnosis of paronychia. Dtsch Med Wochenschr. 1998;123:386â&#x20AC;&#x201C;390.

5

Sehgal VN, Srivastava G, Aggarwal AK, et al. Hand dermatitis/eczema: current management strategy. J Dermatol. 2010;37:593â&#x20AC;&#x201C;610.

6

Brill TJ, Elshorst-Schmidt T, Valesky EM, et al. Successful treatment of acrodermatitis continua of Hallopeau with sequential combination of calcipotriol and tacrolimus ointments. Dermatology. 2005;211:351â&#x20AC;&#x201C;355.

7

Gokdemir G, Kutlu S, KĂśslĂź A. Acrodermatitis continua resistant to etanercept: therapeutic challenge and unfortunate outcome. J Eur Acad Dermatol Venereol. 2009;23:345â&#x20AC;&#x201C;347.

8

Sehgal VN, Verma P, Sharma S, et al. Acrodermatitis continua of Hallopeau: evolution of treatment options. Int J Dermatol. In press.

9

Post CF, Hopper ME. Dermatitis repens: a report of 2 cases with bacteriologic studies. AMA Arch Derm Syphilol. 1951;63:220â&#x20AC;&#x201C;223.

10 Lockshin NA. Escherichia coli infection of the finger. A possible cause of dermatitis repens. Cutis. 1980;26:274. 11 Barber HW. Acrodermatitis continua VEL perstans (dermatitis repens) and psoriasis pustulosa. Br J Dermatol Syphilol. 1930;42:500â&#x20AC;&#x201C;518.

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Grand Wailea, Maui • February 4–8, 2012

20 12 Register Now for the 8th Annual Conference! February 4–8, 2012

Grand Wailea : Maui, Hawaii

Plan to attend the 8th Annual Maui Derm Conference! “Cutting edge, a great blend of science and clinical medicine and a world class faculty” describe Maui Derm 2012. Our faculty will share with you the most important developments in medical and cosmetic dermatology vital to your practice. Our live patient demonstration workshops in lasers, Botulinum Toxin A and fillers have set the standard for “hands on” workshops. Our format has been specifically designed to allow optimal time for discussion with our faculty.We are certain that you will find this to be an outstanding and memorable educational event that you will not want to miss. Put Maui Derm on your calendar for 2012!

Featured Lectures

Hot Topics • Cases for the Panel • Seminars • Workshops • Basic Science

Medical Dermatology: Basic Science, Hot Topics, Cases for the Panel, Point:Counterpoint, Seminars, “How I Do It” Cutaneous Oncology • Acne/Rosacea • Pediatric Dermatology • Infectious Diseases Psoriasis • Skin of Color • Life Threatening Dermatoses • Master’s CPC • Office Surgery • Practice Management

Cosmetic Dermatology: From Basic Science to Case Based Discussion and “How I Do It” Botulinum Toxin A and Fillers • Lasers • Sclerotherapy

2012 Faculty * Matthew Avram, MD Neal Bhatia, MD Andrew Blauvelt, MD Valerie Callender, MD Joel Cohen, MD Lawrence Eichenfield, MD Rebecca Fitzgerald, MD Keith T. Flaherty, MD Sheila Friedlander Fallon, MD Ilona Frieden, MD Michael Gold, MD Mitchel Goldman, MD Pearl Grimes. MD Derek Jones, MD Arthur Kavanaugh, MD Suzanne Kilmer, MD David Laub, MD Philip LeBoit, MD Craig Leonardi, MD Stuart Maddin, MD Ashfaq Marghoob, MD

Chairman: Dr. George Martin Sam Moschella, MD Stuart Nelson, MD Kevin Pinski, MD Phoebe Rich, MD Ted Rosen, MD E. Vic Ross, MD Alan Shalita, MD Ava Shamban, MD Daniel Siegel, MD Eggert Stockfleth, MD Bruce Strober, MD, PhD Neil Swanson, MD James Treat, MD Hensin Tsao, MD Sandy Tsao, MD Guy Webster, MD, PhD Wm. Philip Werschler, MD John Zone, MD * Subject to Change

MAUI DERM 2012 HAS SPECIAL/REDUCED RATES AT THE

Grand Wailea and the Wailea Marriott “Lunch with the Faculty” – Controversial Topics, Case-based Discussions For more details, visit our website at

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Small Group, Live Patient, Hands-On Demonstrations: Botulinum Toxins/Fillers, Sclerotherapy

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July/August 2011

Volume 9 â&#x20AC;˘ Issue 4

CASE STUDY

Refractory Hailey-Hailey Disease Successfully Treated With Sandpaper Dermabrasion Keith G. LeBlanc, Jr, MD; Joshua B. Wharton, MD; Daniel J. Sheehan, MD A 53-year-old woman presented with a 20-year history of pruritic dermatitis on the groin, axillae, inframammary folds, posterior aspect of the neck, and popliteal fossae. She was referred to our clinic by an outside facility after results from a punch biopsy diagnosed Hailey-Hailey disease (HHD). The patient had previously attempted treatment with many traditional noninvasive options with no success. Topical treatment modalities included corticosteroids, immunomodulators, antifungals, retinoids, and antibiotic preparations. Intralesional corticosteroids, as well as botulinum toxin and carbon dioxide laser, were also unsuccessful. Failed systemic treatment modalities included antibiotics, antihistamines, prednisone, azathioprine, mycophenolate mofetil, acitretin, isotretinoin, adalimumab, and etanercept. Of note, cyclosporine was successful in clearing the cutaneous involvement in our patient, but elevation of creatinine and exacerbated hypertension precluded continued use. The decision was made to treat the patient by dermabrasion with sandpaper. The patient was prepped in a sterile fashion, and a field block with 1% lidocaine with epinephrine was performed. This was followed by abrasion down to the superficial dermis with 3M Sandblaster fine sandpaper (3M, St. Paul, MN) and hyfrecation between rounds of dermabrasion. The treated areas were then covered with petrolatum and sterile gauze, and antibiotics and pain medication were prescribed. This treatment was initially performed on the patientâ&#x20AC;&#x2122;s posterior aspect of the neck and later to the bilateral popliteal fossae and axillae. Three months post-treatment, desirable functional and cosmetic results of the treated areas had been achieved (Figure 1 and Figure 2). While no recurrence of clinically active HHD has been seen in the dermabraded areas of the neck and popliteal fossae, the patient continues to have active disease in the axillae despite sandpaper dermabrasion. To quantify our results, we performed two biopsies in the dermabraded sites of the popliteal fossae as healing occurred: a shave biopsy from an obviously active area, and a punch biopsy from a peripheral inactive border. The biopsy from the active area showed diffuse epidermal acantholysis similar to that seen in untreated HHD, while the healing periphery showed only scattered acantholytic areas and a sparse perivascular infiltrateâ&#x20AC;&#x201D;a marked improvement from the untreated areas.

H

ailey-Hailey disease or familial benign chronic pemphigus, is an uncommon autosomal-dominant genodermatosis caused by mutations in the ATP2C1 gene. The disorder is characterized by malodorous, often painful erosions in intertriginous sites. Dysfunction in the protein product hSPCA1 leads to decreased Ca2+ within the Golgi lumen, which may subsequently impair the processing of junctional proteins important in cell-cell adhesion.1 Clinically, patients present with malodorous, macerated patches of acantholytic epidermis, typically in intertriginous areas, that are worsened by heat and diaphoresis. CONCLUSIONS The dermatology literature has very little supportive evidence for eradication of HHD by dermabrasion. No reported cases

of the efficacy of sandpaper for dermabrasion, which we performed in our patient, were found in a literature review2,3 Although successful in only the reported patient, we propose that sandpaper dermabrasion may be a well-tolerated, cost-effective, minimally invasive in-office surgical treatment option for HHD. Further studies and prospective, comparative trials in the future are necessary to confirm or deny this assertion. Sandpaper dermabrasion seemingly offers long-term disease-free results with minimal recurrences. The main side effects are pain and potential pigmentary changes and scarring in the treated areas. We experienced more success in treating areas not involving skin folds, making sandpaper dermabrasion more difficult to recommend for areas such as the axillae in HHD.

From the Division of Dermatology, Medical College of Georgia, Augusta, GA Address for Correspondence: Keith G. LeBlanc, Jr, MD, Medical College of Georgia, Division of Dermatology, 1004 Chafee Avenue, FH-100, Augusta, GA 30904 â&#x20AC;˘ E-mail: keleblanc@mail.mcg.edu

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CASE STUDY

Figure 2. Popliteal fossa, 6 months post-treatment.

Figure 1. Popliteal fossa, pre-treatment.

REFERENCES 1

Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and HaileyHailey disease. Br J Dermatol. 2004;150:821–828.

2

Hamm H, Metze D, Bröcker EB. Hailey-Hailey disease: eradication by dermabrasion. Arch Dermatol. 1994;130:1143–1149.

3

Kirtschig G, Gieler U, Happle R. Treatment of Hailey-Hailey disease by dermabrasion. J Am Acad Dermatol. 1993;28:784–786.

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Registration and Agenda at

New Sessions With Beauty Editors and PR Experts! t Media Relations 101: Tips on how to catch a reporters eye and be a useful resource for their stories. t Meet the Press: Top beauty editors from key national outlets will be on-hand to provide tips on how to increase exposure in the current media landscape. t Generating Publicity for Your Practice: Tools you can use to increase exposure of your practice in local and national media outlets. For more details please contact: Pam Storey at (402) 697-6566 or Info@CosmeticSurgeryForum.com

Live Demos/Case Discussions With a Multispecialty Approach and Practice Management Sessions

t t t t t t t t t

NEW! 1/2 Day MOC Board Review Course! Cosmeceuticals: What’s new? Top 10 list of cosmeceuticals! Cosmetic Surgery: What’s new? What should you avoid? What’s a waste of money? New Frontiers: What’s the next ‘big thing’ in cosmetic surgery? Lasers and Hand-held Devices: How do you compete against Nordstroms? Lightening Skin: Is it safe and does it work? Can it be done without hydroquinone? Mole Mapping Versus the Dermatogist: Are melanoma detection devices a good idea? Electronic Medical Records: Costs, risks and implementation for full service practices. Defending Your Reputation: Keeping your reputation intact in an electronic world. This meeting will be commercially supported by unrestricted educational grants.

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Invited Speakers Carl Thornfeldt, MD Heidi Waldorf, MD Hema Sundaram, MD Cory Maas, MD Steven Dayan, MD Vivian Bucay, MD Ira Berman, MD Mimi Cummings, MD Doris Day, MD Marc Darst, MD Haines Ely, MD Ben Treen, MD Candace Spann, MD Cheryl Burgess, MD S. Manjula Jegasothy, MD Jeanette Graf, MD Barry Lycka, MD Michael Gold, MD Mike Kluska, DO Rhett Drugge, MD Adam Rotunda, MD Jeanine Downie, MD Julie Woodward, MD Jason Michaels, MD Joe Eastern, MD Mitch Goldman, MD Michael Persky, MD Roslyn Rivkah Isseroff, MD Pamela Basuk, MD Jo Bohannon-Grant, MD Gregory Buford, MD FACS Curtis Samlaska, MD Leon Kircik, MD Art Huntley, MD Founder of Dermchat and RxDerm

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

Course Director Joel Schlessinger MD, FAAD, FAACS Past President, American Society of Cosmetic Dermatology and Aesthetic Surgery

CME Information This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dulaney Foundation, Practical Dermatology and Cosmetic Surgery Forum, LLC. The Dulaney Foundation is accredited by the ACCME to provide continuing medical education for physicians. The Dulaney Foundation designates this live activity for a maximum of 18 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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CANCUN 2012 January 31st to February 4th Cancun Quintana Roo, Mexico

www.WCOCD2012.com info@WCOCD2012.com + (52 55) 5531- 0865 + (52 55) 5203- 6454 Abstract submission deadline:

O c tober 30 th, 2011

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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.

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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

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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 Š2010 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

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Jul / Aug 2011