Nov / Dec 2011 by jo-ann kalaka-Adams

November/December 2011 • Volume 9 • Issue 6

EDITORIAL Germophobia: The Dilemma of Hand Washing and Protection From Germs Parish, Wolf, and Parish

DEPARTMENT MYTHS AND MISCONCEPTIONS Alcohol-Based Disinfectants Irritate and Damage Skin More Than Ordinary Soap—True or False? Wolf, Parish, and Parish

COMMENTARIES Mesotherapy Galadari and Al Faresi

The Problem With “Depressed Plaque”

CASE STUDIES Segmental Lesions in Pityriasis Rosea: A Rare Presentation Zawar and Godse

Thomas

Neutrophilic Dermatosis Caused by Azathioprine ORIGINAL CONTRIBUTION Skin Needling in the Treatment of the Aging Neck Fabbrocini, De Vita, Di Costanzo, Pastore, Mauriello, Monfrecola, Annunziata, di Santolo, Cameli, and Monfrecola

REVIEWS General Features and Treatment of Notalgia Paresthetica Pérez-Pérez

Nicotinamide in Dermatology and Photoprotection Surjana and Damian

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

Valentine and Walsh

CORRESPONDENCE Wells on Natural Selection: Right for the Wrong Reason—Described a Giant Congenital Nevus Goldsmith

Propranolol as a Novel Addition to Anti–Kaposi Sarcoma Armamentarium: A Hypothesis Feily, Pazyar, and Namazi

Rosette Sign in Dermatoscopy: A Polarized Finding Marques-da-Costa, Campos-do-Carmo, Ormiga, Ishida, Cuzzi, and Ramos-e-Silva

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

ON THE JOB WITH GENTLE EFFICACY1

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

RESULTS PATIENTS WANT IN A FORMULATION THAT DOES THE WORK—

PRESCRIBE DIFFERIN® LOTION, 0.1% TODAY!

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

* †

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

DIFFERIN®

Rx only

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

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

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

www.differin.com/HCP

TABLE OF CONTENTS November/December 2011 • Volume 9 • Issue 6

EDITORIAL Germophobia: The Dilemma of Hand Washing and Protection From Germs ................................................... 339 Lawrence Charles Parish, MD, MD (Hon); Ronni Wolf, MD; Jennifer L. Parish, MD

COMMENTARIES Mesotherapy............................................................................................................................................... 342 Hassan Galadari, MD; Fatima Al Faresi, MD

The Problem With “Depressed Plaque” ......................................................................................................... 344 Brendan Thomas, MD

ORIGINAL CONTRIBUTION Skin Needling in the Treatment of the Aging Neck ........................................................................................ 347 Gabriella Fabbrocini, MD; Valerio De Vita, MD; Luisa Di Costanzo, MD; Francesco Pastore, MD; Maria Chiara Mauriello, MD; Ambra Monfrecola; Maria Carmela Annunziata, MD; Maria Gabriella Scotto di Santolo, MD; Norma Cameli, MD; Giuseppe Monfrecola, MD

REVIEWS General Features and Treatment of Notalgia Paresthetica ............................................................................ 353 Lidia Comba Pérez-Pérez, MD Self-Test Review Questions (p. 359)

Nicotinamide in Dermatology and Photoprotection ....................................................................................... 360 Devita Surjana, MBBS; Diona L. Damian, MBBS, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Noninsulin-Dependent, Type II Diabetes Mellitus–Related Dermatoses: Part III ............................................... 367 Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Megha Gupta, MBBS; Sambit N. Bhattacharya, MD; Prashant Verma, MD Core Curriculum Review Questions (pp. 375–376)

DEPARTMENT MYTHS AND MISCONCEPTIONS Ronni Wolf, MD, Section Editor

Alcohol-Based Disinfectants Irritate and Damage Skin More Than Ordinary Soap—True or False? .................. 378 Ronni Wolf, MD; Jennifer L. Parish, MD; Lawrence Charles Parish MD, MD (Hon)

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

Segmental Lesions in Pityriasis Rosea: A Rare Presentation ......................................................................... 382 Vijay Zawar, MD; Kiran Godse, MD

Neutrophilic Dermatosis Caused by Azathioprine ......................................................................................... 386 Mark C. Valentine, MD; John S. Walsh, MD

334

TABLE OF CONTENTS November/December 2011 • Volume 9 • Issue 6

CORRESPONDENCE Wells on Natural Selection: Right for the Wrong Reason—Described a Giant Congenital Nevus ...................... 390 Lowell A. Goldsmith, MD, MPH

Propranolol as a Novel Addition to Anti–Kaposi Sarcoma Armamentarium: A Hypothesis ............................... 391 Amir Feily, MD; Nader Pazyar, MD; Mohammad R. Namazi, MD

Rosette Sign in Dermatoscopy: A Polarized Finding ...................................................................................... 392 Juliana Marques-da-Costa, MD; Gabriella Campos-do-Carmo, MD; Patricia Ormiga, MD; Cleide Eiko Ishida, MD; Tullia Cuzzi, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

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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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335

November/December 2011

EDITORIAL BOARD

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD Dallas, TX

W. Clark Lambert, MD, PhD Newark, NJ

Larry E. Millikan, MD Meridian, MS

Vesna Petronic-Rosic, MD, MSc Chicago, IL

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

Jennifer L. Parish, MD Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Gibbstown, NJ

Jasna Lipozencic, MD, PhD Zagreb, Croatia

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

Robert L. Baran, MD Cannes, France

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

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

Virendra N. Sehgal, MD Delhi, India

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

Marc S. Micozzi, MD, PhD Bethesda, MD

Alexander J. Stratigos, MD Athens, Greece

Jack M. Bernstein, MD Dayton, OH

Michael H. Gold, MD Nashville, TN

George F. Murphy, MD Boston, MA

James S. Studdiford III, MD Philadelphia, PA

Sarah Brenner, MD Tel Aviv, Israel

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Robert J. Thomsen, MD Los Alamos, NM

Joaquin Calap Calatayud, MD Cadiz, Spain

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

Joseph L. Pace, MD, FRCP Naxxar, Malta

Julian Trevino, MD Dayton, OH

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

Seung-Kyung Hann, MD, PhD Seoul, Korea

Art Papier, MD Rochester, NY

Snejina Vassileva, MD, PhD Sofia, Bulgaria

Noah Craft, MD, PhD, DTMH Torrance, CA

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

Johannes Ring, MD, DPhil Munich, Germany

Daniel Wallach, MD Paris, France

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

Tanya R. Humphreys, MD Philadelphia, PA

Roy S. Rogers III, MD Rochester, MN

Michael A. Waugh, MB, FRCP Leeds, UK

Richard L. Dobson, MD Mt Pleasant, SC

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Wm. Philip Werschler, MD Spokane, WA

William H. Eaglstein, MD Palo Alto, CA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Joseph A. Witkowski, MD Philadelphia, PA

Boni E. Elewski, MD Birmingham, AL

Andrew P. Lazar, MD Highland Park, IL

Vincenzo Ruocco, MD Naples, Italy

Ronni Wolf, MD Rechovot, Israel

Charles N. Ellis, MD Ann Arbor, MI

336

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

VELTIN Gel

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

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

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

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

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

November/December 2011

Volume 9 • Issue 6

EDITORIAL

Germophobia: The Dilemma of Hand Washing and Protection From Germs Lawrence Charles Parish, MD, MD (Hon);1 Ronni Wolf, MD;2 Jennifer L. Parish, MD1

e are fast becoming a society of “germophobics,” if we are not already there. Hand washing and wearing protective gloves are a crucial part of this obsession that is playing a significant role in the 21st century. There is hardly a person, let alone a household pet, who is not affected by the situation. Let us pause to consider the ramifications. HAND WASHING Not since the days of Ignaz Semmelweis (1818–1865) and the subsequent adherents of hand washing has so much emphasis been placed on appropriate cleansing of the hands.1 There is hardly an office building that does not have the alcohol handwashing dispenser in a prominent place, and hospitals have placed these devices at elevators, nurses’ stations, and patient rooms. The obsession with cleanliness can reach the point of absurdity: ie, dispensers for paper for covering restroom doorknobs. Elsewhere in this issue, we discuss the question of irritation from alcohol-based disinfectant usage.2 Curiously, such alcohol-cleansing had been suggested as early as 1888. Much to our surprise, use of the alcohol-based washes is not irritating. In fact, this procedure may reduce the irritation from scrubbing with soap by eliminating more of the irritant than simple rinsing with water might accomplish. This is not to say that there is not the uncommon person who may be allergic to the alcohol in the dispenser, but these devices are not the terror once presumed. Consuming the alcohol-based washes is not recommended, needless to say.3 Until we searched the literature, we had not even imagined that the alcohol-based washings might also affect an alcohol intoxication test. Fortunately, two studies have shown that the absorption of ethanol from these washes is negligible and does not affect any breathalyzer testing used to determine whether someone is driving under the influence of alcohol. In fact, even

countries whose religious laws forbid alcohol consumption have not found alcohol-based hand washing contradictory to their regulations and mores.4,5 VINYL GLOVES The use of vinyl gloves has mushroomed, as well, during recent years. While the adoption of protective gloves has been a part of medical practice for some time, we have witnessed with relief their implementation by food handlers and bathroom attendants. Curiously, airport screeners seem wedded to vinyl gloves, even when the apparent exposure to pathogens is limited, if nonexistent. More questionable is the fact that bank tellers do not use such protection. There has always been the thought that money is dirty, and famous dermatologists such as Louis A. Duhring (1845–1913) and Henry W. Stelwagon (1853–1919) had a fear of handling money. While money may seem to be inundated with germs, there have been no studies to prove that disease has been transmitted by coins or even paper currency6 (Figure). Similarly, the mail, even when hysteria prompted disinfection, particularly from leprosy, was never found to transmit germs, unless laced maliciously with anthrax spores.7 In the rush to adopt protective measures, the medical community embraced latex gloves 2 decades ago. With dramatic increase in the use of latex gloves, nosocomial infections may have been reduced but the incidence of latex allergy and the subsequent development of latex cripples increased dramatically. With the restrictions on the use of latex-based products and powdered gloves, the problem has fortuitously diminished.8 CONCLUSIONS The traditional proverb “cleanliness is next to godliness” is a worthwhile motto. Being appropriately clean can be recommended, but being crazy clean may be another story.

From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;1 the Dermatology Unit, Kaplan Medical Center, Rechovot, Israel, Affiliated to The School of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem, Israel2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

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EDITORIAL REFERENCES 1

Noakes TD, Borresen J, Hew-Butler T, Lambert MI, Jordaan E. Semmelweis and the aetiology of puerperal sepsis 160 years on: an historical review. Epidemiol Infect. 2008;136:1–9.

Wolf R, Parish LC, Parish JL. Alcohol-based disinfectants irritate and damage skin more than ordinary soap—true or false? SKINmed. 2011;9:378–380.

Henry-Lagarrigue M, Charbonnier M, Bruneel F, et al. Severe alcohol hand rub overdose inducing coma, watch after H1N1 pandemic. Neurocrit Care. 2010;12:400–402.

Brown TL, Gamon S, Tester P, et al. Can alcohol-based hand-rub solutions cause you to lose your driver’s license? Comparative cutaneous absorption of various alcohols. Antimicrob Agents Chemother. 2007;51:1107–1108.

Kramer A, Below H, Bieber N, et al. Quantity of ethanol absorption after excessive hand disinfection using three commercially available hand rubs is minimal and below toxic levels for humans. BMC Infect Dis. 2007;7:117.

Dirty Paper Money. Can Med Assoc J. 1924;14:331.

Ambrose CT. Osler and the infected letter. Emerg Infect Dis. 2005;11:689–693.

Meyer KK, Beezhold DH. Latex allergy: how safe are your gloves? Bull Am Coll Surg. 1997;82:13–15, 72.

PARESTHESIA (burning, tingling, prickling of the skin) Medication known to cause such symptoms Arsenic

Cyproheptadine

Diphenhydramine

Disopyramide

Furosemide

Hydroxyzine

Isotretinoin

Losartan

Minocycline

Quinapril

Valsartan

Adapted from Litt, JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009:108–113.

Figure. Germophobia can assume various poses.

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Adalimumab

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Germophobia: The Dilemma of Hand Washing

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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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November/December 2011

Volume 9 • Issue 6

COMMENTARY

Mesotherapy Hassan Galadari, MD;1,2 Fatima Al Faresi, MD2

hile Michel Pistor (1924–2003) coined the term mesotherapy to describe a technique that used a cocktail of ingredients injected in the dermis and/ or subcutaneous layer of the skin, historically, the procedure was first performed in 1931, when Drs Jose Salvador Gallardo and Jose Coenjo Mir described the treatment of alopecia areata by intradermally injecting milk. Although initially used for pain relief, modern use of mesotherapy has included many cosmetic conditions. The ingredients used depend on the condition being treated and may vary between natural plant extracts, homeopathic agents, pharmaceuticals, vitamins, botanicals, and other bioactive substances. With the exception of local anesthetics, calcitonin, hyaluronidase, and collagenase (all of which were used off-label), the US Food and Drug Administration (FDA) has not approved or granted orphan drug designation to any other mesotherapy ingredients by subcutaneous delivery1; furthermore, manufacturers fail to disclose the ingredients and their concentration. Although one might argue against its use, mesotherapy’s popularity has seen a rise. This has been attributed to the ease of injection and the popularity of affordable minimally invasive procedures. In 1987, the French National Academy of Medicine acknowledged mesotherapy as an official specialty of medicine, and fellowship training has also become available.1 It has received wide acceptance in Europe and South America, and has recently begun to gain popularity in the United States. To lobby for its legitimacy and use, practitioners of mesotherapy, who range from having medical and nonmedical backgrounds, have started forming societies, organizing meetings, and setting up fellowship training programs on the field. INDICATIONS

INJECTION LIPOLYSIS OR LIPODISSOLVE This is perhaps the most popular indication of mesotherapy and it is mainly used for the treatment of fat aggregates, cellulite, and body sculpting. This occurs by the theoretical promotion

of dissolution of fat deposits. The basic ingredients that are frequently used in the solution mixture for this purpose are phosphatidylcholine and/or deoxycholate. The FDA has yet to approve the use of these two substances for treatment and for safety.2 The cosmetic use of phosphatidylcholine, extracted from soybean lecithin, for body contouring began in the mid-1990s as off-label use in Brazil.3 Additionally, phosphatidylcholine was mixed with many other “fat-dissolving” substances. The mechanism of localized fat reduction is unknown. Some authors have theorized that the lipolytic effect of these subcutaneous injections relies on its lipid-modulating effects in the blood and liver and activation of cyclic monophosphate.4,5 There are no standardized trials or research studies reporting clinical, histopathological, and laboratory data that prove the effectiveness of phosphatidylcholine in the treatment of localized fat areas.3 Although reports indicate its use in specific indications such as buffalo humps, lipomas, submental fat, and infraorbital fat herniation, no study has been able to standardize for dose.5–10 After many reported cases of scarring, dyspigmentation, and body contour irregularities, the Brazilian National Agency of Health Inspection (ANVISA), which regulates the use of medications in Brazil, published a resolution in January 2003 prohibiting the use of the agent in this form.3 This was later reaffirmed by the American Society of Plastic Surgeons in a statement warning against the use of these chemical compounds as an alternative to liposuction. Recently, investigators have identified sodium deoxycholate, an emulsifier of phosphatidylcholine and a detergent that produces nonspecific destruction of cell membranes, as a major active ingredient in injection lipolysis.11 Injection of deoxycholate into lipomas causes focal necrosis, acute inflammation, and hemorrhage histologically.11 This has led some to believe that deoxycholate is the main cause of fat dissolution and not phosphatidylcholine, as previously noted.

FACIAL REJUVENATION For mesotherapy to achieve rejuvenation, it should be able to increase dermal hydration and create a favorable environment to

From the Faculty of Medicine and Health Sciences, United Arab Emirates University,1 and Tawam Hospital/Johns Hopkins Medicine,2 Al Ain, United Arab Emirates Address for Correspondence: Hassan Galadari, MD, Tawam Hospital/Johns Hopkins Medicine, PO Box 17666, Al Ain, United Arab Emirates • E-mail: hgaladari@uaeu.ac.ae

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COMMENTARY

facilitate fibroblast activation. Most cocktail solutions used for facial rejuvenation contain hyaluronic acid (HA). Rejuvenation is achieved by the hydrating effects of HA in tissue or the trauma caused by repeated injections into the dermis triggering the healing process, activating fibroblasts and thus neocollagen. Investigators evaluated two patients at different time intervals before and after injection.12 The authors reported no significant clinical and histologic changes after multivitamin and hyaluronic acid solution mesotherapy for skin rejuvenation.

published, the use of mesotherapy is not recommended. Due to a lack of data claiming efficacy and the rising barrage of possible complications, it is advised that the use of mesotherapy for whatever indication using untested ingredients be limited and practiced with extreme caution. REFERENCES

ALOPECIA AND HAIR LOSS Despite the fact that there are no controlled published studies about mesotherapy’s efficacy in hair disease, it has been used as a treatment for androgenetic alopecia and hair loss.13 Finasteride and minoxidil are possible components of the injected solution. These agents are the only FDA-approved agents for the treatment of androgenetic alopecia, when they are administered orally and topically, respectively. Data reporting efficacy of these agents in the form of mesotherapy have not been published and are not yet approved. In addition, manufacturers fail to disclose other ingredients used for the treatment of androgenetic alopecia and their concentrations. Publications of the use of mesotherapy in alopecia revealed many possible complications caused by treatment ranging from cicatricial alopecia to multifocal scalp abscesses.13 CONCLUSIONS Given the ease of treatment and little-to-no downtime, mesotherapy has garnered great attention and has become extremely popular.14,15 Despite its growing popularity, which has relied primarily on marketing the treatment to lower-tier cosmetic outlets such as spas and beauty salons, it is postulated that 18,000 licensed mesotherapists exist in France alone, some of whom have no medical background. The lack of a precise treatment protocol, the unpredictable outcome, and the risk of localized adverse events has made many health regulatory bodies, including the FDA, slow to embrace the treatment modality. In April 2010, the FDA went further, to shut down outlets marketing mesotherapy under false pretenses and claims. These concerns have also been voiced by international societies, such as the American Society of Plastic Surgeons, which has expressed concern about the procedure and the chemicals used in it as an alternative to liposuction.14,15 The American Society for Dermatologic Surgery has stated that until further studies are

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Rotunda AM, Kolodney MS. Mesotherapy and phosphatidylcholine injections: historical clarification and review. Dermatol Surg. 2006;32:465–480.

Wright TI, Davis MD. Noninfectious granulomatous panniculitis: a complication of mesotherapy—two cases and a review. J Am Acad Dermatol. 2009;60:AB188.

Hexsel D, Serra M, Mazzuco R, et al. Phosphatidylcholine in the treatment of localized fat. J Drugs Dermatol. 2003;2:511–518.

Rittes PG, Rittes JC, Carriel Amary MF. Injection of phosphatidylcholine in fat tissue: experimental study of local action in rabbits. Aesthetic Plast Surg. 2006;30:474–478.

Khan MH, Victor F, Rao B, et al. Treatment of cellulite: part II. Advances and controversies. J Am Acad Dermatol. 2010;62:373–384.

Brown SA. The science of mesotherapy: chemical anarchy. Aesthet Surg J. 2006;26:95–98.

Rittes PG. The use of phosphatidylcholine for correction of lower lid bulging due to prominent fat pads. Dermatol Surg. 2001;27:391–392.

Albon G, Rotunda AM. Treatment of lower eyelid fat pads using phosphatidylcholine: clinical trial and review. Dermatol Surg. 2004;30:422–427.

Nabavi CB, Minckler DS, Tao JP. Histologic features of mesotherapy-induced orbital fat inflammation. Ophthal Plast Reconstr Surg. 2009;25:69–70.

10 Co AC, Abad-Casintahan MF, Espinoza-Thaebtharm A. Submental fat reduction by mesotherapy using phosphatidylcholine alone vs. phosphatidylcholine and organic silicium: a pilot study. J Cosmet Dermatol. 2007;6:250–257. 11 Rotunda AM, Ablon G, Kolodney MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol. 2005;53:973–978. 12 Amin SP, Phelps RG, Goldberg DJ. Mesotherapy for facial skin rejuvenation: a clinical, histologic, and electron microscopic evaluation. Dermatol Surg. 2006;32:1467–1472. 13 Dunque-Estrada B, Vincenzi C, Misciali C, et al. Alopecia secondary to mesotherapy. J Am Acad Dermatol. 2009;61:707–709. 14 Al Faresi F, Galadari H. Mesotherapy: myth and reality. Expert Rev Dermatol. 2011;6:157–162. 15 Atiyeh BS, Ibrahim AE, Dibo SA. Cosmetic mesotherapy: between scientific evidence, science fiction and lucrative business. Aesthetic Plast Surg. 2008;32:842–849.

Mesotherapy

November/December 2011

Volume 9 • Issue 6

COMMENTARY

The Problem With “Depressed Plaque” Brendan Thomas, MD

utaneous conditions often present with characteristic primary lesions whose morphology can be described using a number of generally accepted terms. “Plaque” represents one such term and is used to denote an elevated, plateau-like area of integument that is greater in its diameter than in its depth, most often ≥0.5 or 1 cm in diameter.1–3 Regardless of the specific definition one uses, “plaque” always denotes an elevated lesion. Occasionally, the term “depressed plaque” is used to describe the morphology of a primary lesion, an inherently confusing term suggesting a depressed elevation of integument. Herein is an analysis of the prevalence and usage of the term “depressed plaque” within the medical literature. METHODS On May 30, 2010, an electronic literature search was performed on PubMed using the search term “depressed plaque.” Quotation marks were used around the term to force a phrase search.4 Titles and abstracts from all articles retrieved were included in the analysis. Each article was classified as dermatology- or nondermatologyrelated in nature. From the dermatology-related article abstracts the sentence using the term “depressed plaque” was recorded.

cutaneous lesion; therefore, given this infrequent use and that it represents an oxymoron, this author recommends avoiding the term. As an alternative, when a cutaneous lesion meets one’s criteria for a plaque, while also having a central depression or dell, describe the lesion as such (ie, a plaque with central depression or dell). If the cutaneous lesion is characterized only by depression without any areas of accompanying elevation, then the term “atrophy” would be most appropriate. Disclosure: Dr Brendan Thomas had full access to all of the data in the commentary and takes responsibility for the integrity of the data and the accuracy of the data analysis. The commentary concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content were created and/or performed solely by Dr Thomas. Dr Thomas has no ﬁnancial disclosures to report, having no relationships to industry, sponsors, or other sources of funding/support. REFERENCES 1

Callen JP, Greer KE, Paller AS, Swinyer LJ. Color Atlas of Dermatology. 2nd ed. Philadelphia, PA: WB Saunders; 2000.

The search results consisted of 3 dermatology- and 4 nondermatology-related articles. The 3 dermatology-related articles were all case reports, each discussing a diﬀerent cutaneous condition. The following are sentences from those articles using the aforementioned term: “The patient had a markedly deformed and depressed plaque surrounded by erythema on the right cheek.”5 “A 29-year-old man presented with a large, asymptomatic, brown, hyperpigmented, depressed plaque over his left upper back….”6 “[Premalignant circumscribed palmar hypokeratosis] presents clinically with a sharply circumscribed annular erythematous depressed plaque rimmed by a slightly hyperkeratotic border….”7

James WD, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA: WB Saunders; 2005.

Wolff K, Johnson R, Suurmond R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. New York, NY: McGraw-Hill Medical Publishing Division; 2005.

PubMed Help. http://www.ncbi.nlm.nih.gov/books/NBK3827/. Accessed May 30, 2010.

Nakazawa A, Matsuo I, Ohkido M. Progressive facial hemiatrophy with localized scleroderma. Tokai J Exp Clin Med. 1992;17:85–87.

Lee A, Heidary N, Altiner A, et al. Neurovascular hamartoma. Dermatol Online J. 2009;15:21.

COMMENT

Kanitakis J, Lora V, Balme B, Roby J. Premalignant circumscribed palmar hypokeratosis: a new form of circumscribed palmar hypokeratosis? Case report and literature review. Dermatology. 2010;220:143–146.

RESULTS

The term “depressed plaque” is infrequently used within the medical literature to describe the morphology of a primary

From the Department of Dermatology, University of Illinois College of Medicine at Chicago, Chicago, IL Address for Correspondence: Brendan Thomas, MD, University of Illinois College of Medicine at Chicago, Department of Dermatology, 808 South Wood Street, Chicago, IL 60612 • E-mail: bmthomas@uic.edu

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cy… Delivers on efﬁca

Handles Patients With Care

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

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

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

DUAC 45 g

Apply once daily Dispense as written

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

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

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

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

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

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

DUAC Topical Gel may bleach hair or colored fabric.

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

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

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

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

<1%

17%

Burning

<1%

Dryness

<1%

15%

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

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November/December 2011

ORIGINAL CONTRIBUTION

Skin Needling in the Treatment of the Aging Neck Gabriella Fabbrocini, MD;1 Valerio De Vita, MD;1 Luisa Di Costanzo, MD;1 Francesco Pastore, MD;1 Maria Chiara Mauriello, MD;1 Ambra Monfrecola;1 Maria Carmela Annunziata, MD;1 Maria Gabriella Scotto di Santolo, MD;2 Norma Cameli, MD;3 Giuseppe Monfrecola, MD12 ABSTRACT ɨF BJN PG UIJT TUVEZ XBT UP FTUJNBUF UIF FïDBDZ PG TLJO OFFEMJOH JO UIF USFBUNFOU PG UIF BHJOH OFDL &JHIU QBUJFOUT XJUI BHJOH OFDLT XFSF JODMVEFE JO UIF TUVEZ &BDI QBUJFOU XBT USFBUFE XJUI TFTTJPOT PG OFFEMJOH ɨF FWBMVBUJPO PG USFBUNFOU FêFDUJWFOFTT XBT CBTFE PO DIBOHFT GSPN CBTFMJOF PO UIF (MPCBM "FTUIFUJD *NQSPWFNFOU 4DBMF UIF 8SJOLMF 4FWFSJUZ 3BUJOH 4DBMF QIPUPHSBQIJD BOE VMUSBTPOPHSBQIJD JNBHFT BOE TJMJDPOF SVCCFS NJDSPSFMJFG JNQSFTTJPOT PG B TFMFDUFE OFDL SFHJPO CFGPSF BOE BGUFS UIFSBQZ "OBMZTJT PG UIF QIPUPHSBQIT UIF EFHSFF PG JSSFHVMBSJUZ PG UIF TVSGBDF NJDSPSFMJFG BOE UIF VMUSBTPVOE JNBHFT TIPXFE UIBU BGUFS TFTTJPOT UIF MFTJPOT TFWFSJUZ HSBEF XBT SFEVDFE JO BMNPTU PG UIF QBUJFOUT ɨF QSFTFOU TUVEZ QSFTFOUT FWJEFODF GPS UIF FïDBDZ PG TLJO OFFEMJOH GPS UIF BHJOH OFDL SKINmed o

LJO OFFEMJOH PS NJDSPOFFEMJOH PS DPMMBHFO JOEVDUJPO UIFSBQZ JT B EFSNBUPMPHJD USFBUNFOU QFSGPSNFE UP BDIJFWF QFSDVUBOFPVT DPMMBHFO JOEVDUJPO 1$* UP TNPPUI XSJOLMFT JNQSPWF EFQSFTTFE BDOF TDBSSJOH BOE SFEVDF UIF BQQFBSBODF PG TUSFUDI NBSLT *U JT DBSSJFE PVU VTJOH B TLJO SPMMFS UIBU DBVTFT NVMUJQMF UJOZ QJO QPJOU QVODUVSF XPVOET JOUP UIF EFSNJT ɨJT EFSNBM EBNBHF JOEVDFT UIF SFMFBTF PG HSPXUI GBDUPST UIBU TUJNVMBUF UIF QSPEVDUJPO PG OFX DPMMBHFO BOE FMBTUJO JO UIF VQQFS EFSNJT 4LJO OFFEMJOH DSFBUFT EFSNBM EBNBHF XJUIPVU UIF SFNPWBM PG UIF IFBMUIZ FQJEFSNJT ɨFSF JT QSPPG UIBU UIF OFFEMJOH QSPDFEVSF BMTP TUJNVMBUFT ëMMJOH PG DVUBOFPVT XSJOLMFT SFWBTDVMBSJ[BUJPO BOE SFQJHNFOUBUJPO PG TUSFUDI NBSLT #FDBVTF UIF FQJEFSNJT JT MFGU JOUBDU UIF IFBMJOH QFSJPE EVSJOH TLJO OFFEMJOH JT TXJGU BOE UIF TLJO EPFT OPU SJTL QFSNBOFOU TUSVDUVSBM EBNBHF TVO TFOTJUJWJUZ IZQPQJHNFOUBUJPO PS IZQFSQJHNFOUBUJPO 3 6MUSBTPVOE IBT CFFO XJEFMZ VTFE TJODF UIF T UP EFUFSNJOF XIPMF TLJO UIJDLOFTT BOE UP FWBMVBUF BHF SFMBUFE EFSNBM DIBOHFT 4 ɨF BJN PG UIF QSFTFOU TUVEZ XBT UP FWBMVBUF UIF FïDBDZ PG TLJO OFFEMJOH JO UIF USFBUNFOU PG UIF BHJOH OFDL MATERIAL AND METHODS ɨJT TUVEZ XBT DBSSJFE PVU JO BDDPSEBODF XJUI UIF )FMTJOLJ %FDMBSBUJPO PG "O FUIJDBM DPNNJUUFF BQQSPWFE UIF TUVEZ 3 4 8SJUUFO BOE TJHOFE JOGPSNFE DPOTFOU XBT PCUBJOFE

GSPN BMM QBSUJDJQBOUT *O UPUBM QBUJFOUT XFSF FOSPMMFE JO UIF TUVEZ ΉXPNFO BOE NFO BHFE o ZFBST #FGPSF UIF USFBUNFOU CBTFMJOF 50 UIF TFWFSJUZ PG XSJOLMFT JO FBDI QBUJFOU XBT TDPSFE CZ B EFSNBUPMPHJTU XJUI ZFBST DMJOJDBM FYQFSJFODF JOWPMWFE JO UIF TUVEZ VTJOH UIF 8SJOLMF 4FWFSJUZ 3BUJOH 4DBMF 8434 5 5BCMF * "MM QBUJFOUT XFSF SBUFE PO UIF (MPCBM "FTUIFUJD *NQSPWFNFOU 4DBMF ("*4 5BCMF ** /FDL ëOF MJOFT BOE XSJOLMF EFQUIT XFSF DBQUVSFE CZ QIPUPHSBQIJD EJHJUBM UFDIOPMPHZ 1IPUPHSBQIT PG UIF OFDL BSFB PG FBDI QBUJFOU XFSF UBLFO CZ B EFSNBUPMPHJTU OPU JOWPMWFE JO UIF TUVEZ BOE ëMFE JO B EBUBCBTF "U CBTFMJOF BOE BU TUVEZ FOE GPS FBDI QBUJFOU TJMJDPOF SVCCFS NJDSPSFMJFG JNQSFTTJPOT PG B TFMFDUFE OFDL SFHJPO XFSF PCUBJOFE BOE VTFE UP NBLF DPNQVUFSJ[FE EJHJUBM JNBHFT BOE GPS PQUJDBM QSPëMPNFUSZ 'VSUIFSNPSF BU UIF CFHJOOJOH BOE FOE PG UIF USFBUNFOU TLJO VMUSBTPTPOPHSBQIZ XBT QFSGPSNFE PO UIF QBUJFOU JO UIF TBNF TQPU GSPN XIJDI UIF SFQMJDB XBT UBLFO ɨF TFDPOE USFBUNFOU 52 XBT DPOEVDUFE XFFLT BGUFS UIF ëSTU USFBUNFOU BOE HJWFO JO UIF TBNF NBOOFS BT UIF ëSTU USFBUNFOU " ëOBM GPMMPX VQ WJTJU XBT DPOEVDUFE XFFLT BGUFS UIF TFDPOE USFBUNFOU 53 1IPUPHSBQIT XFSF UBLFO BOE DPNQBSFE XJUI UIPTF UBLFO CFGPSF UIF ëSTU USFBUNFOU &BDI QBUJFOU XBT HJWFO B OFX 8434 TDPSF BOE ("*4 SBUJOH *O BEEJUJPO XF BTTFTTFE UIF JNQSPWFNFOUT JOEVDFE CZ TLJO OFFEMJOH PO OFDL XSJOLMFT BGUFS UXP TFTTJPOT PG USFBUNFOU "U UIJT GPMMPX VQ WJTJU B TFDPOE TLJO SFQMJDB XBT NBEF PO UIF TBNF TQPU BT UIF QSFWJPVT POF BOE

From the Department of Systematic Pathology, Division of Dermatology,1 and the Biomorphological and Functional Sciences, Radiology Institute,2 University of Naples Federico II, Naples, Italy; and the San Gallicano Dermatologic Institute, Rome, Italy3 Address for Correspondence: Gabriella Fabbrocini, MD, Università degli Studi di Napoli “Federico II,” via S. Pansini 5, 80131 Naples, Italy t & NBJM HBGBCCSP!VOJOB JU

SKINmed. 2011;9:347–351

347

ª 1VMTF .BSLFUJOH $PNNVOJDBUJPOT --$

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November/December 2011

BSFBT BÃªFDUFE CZ XSJOLMFT 3PMMJOH FOUBJMT NPWJOH UJNFT JO EJSFDUJPOT IPSJ[POUBMMZ WFSUJDBMMZ BOE EJBHPOBMMZ SJHIU BOE MFGU BOE XIFSF OPU QPTTJCMF KVTU JO EJSFDUJPOT IPSJ[POUBMMZ BOE WFSUJDBMMZ É¨JT FOTVSFT BO FWFO iQSJDLJOHw QBUUFSO XIJDI SFTVMUT JO BCPVU UP QSJDLT DN2 #MFFEJOH GPS B TIPSU UJNF JT FYQFDUFE BGUFS UIF USFBUNFOU 8IFO UIF CMFFEJOH IBT TUPQQFE UIF TFSPVT PP[F GPSNFE JT SFNPWFE GSPN UIF TLJO TVSGBDF XJUI B TUFSJMF TBMJOF TPMVUJPO 'VSUIFS XPVOE USFBUNFOU JT OPU OFDFTTBSZ BOE OP ESFTTJOH PS UPQJDBMT XFSF VTFE QPTU OFFEMJOH

Table I. Wrinkle Severity Rating Scale5

SCORE DESCRIPTION 5

&YUSFNF FYUSFNFMZ EFFQ BOE MPOH GPMET EFUSJNFOUBM UP UIF GBDJBM BQQFBSBODF UP NN WJTJCMF 7 TIBQFE GPMET XIFO TUSFUDIFE

4FWFSF WFSZ MPOH BOE EFFQ GPMET QSPNJOFOU GBDJBM GFBUVSFT NN WJTJCMF GPMET XIFO TUSFUDIFE

.PEFSBUF NPEFSBUFMZ EFFQ GPMET DMFBS GBDJBM GFBUVSFT WJTJCMF BU OPSNBM BQQFBSBODF CVU OPU XIFO TUSFUDIFE

.JME TIBMMPX CVU WJTJCMF GPMET XJUI B TMJHIU JOEFOUBUJPO NJOPS GBDJBM GFBUVSFT

"CTFOU OP WJTJCMF GPMET DPOUJOVPVT TLJO MJOF

" XFFL MBUFS FBDI QBUJFOU XBT FYBNJOFE UP HBVHF UIFJS SFTQPOTF UP TLJO OFFEMJOH BOE UP EFUFSNJOF BOZ TJEF FÃªFDUT UIBU NBZ IBWF PDDVSSFE

STATISTICAL ANALYSIS

Table II. Global Aesthetic Improvement Scale6

RATING

DESCRIPTION

7FSZ NVDI JNQSPWFE

0QUJNBM DPTNFUJD SFTVMU GPS OFFEMJOH JO UIJT QBUJFOU

.VDI JNQSPWFE

.BSLFE JNQSPWFNFOU JO BQQFBSBODF GSPN JOJUJBM DPOEJUJPO CVU OPU DPNQMFUFMZ PQUJNBM GPS UIJT QBUJFOU

*NQSPWFE

0CWJPVT JNQSPWFNFOU JO BQQFBSBODF GSPN UIF JOJUJBM DPOEJUJPO CVU SFUSFBUNFOU JOEJDBUFE

/P DIBOHF

"QQFBSBODF FTTFOUJBMMZ UIF TBNF BT UIF PSJHJOBM DPOEJUJPO

8PSTF

"QQFBSBODF XPSTF UIBO UIF PSJHJOBM DPOEJUJPO

%JHJUBM QIPUPHSBQIJD EBUB XFSF BOBMZ[FE VTJOH B UFTU GPS OPOQBSBNFUSJD EBUB TJHO UFTU GPS QBJSFE EBUB É¨F OVMM )0 JT UIBU UIF NFEJBO PG UIF EJÃªFSFODF JT [FSP 1 1Â¦ BOE UIF BMUFSOBUJWF IZQPUIFTFT )" JT UIBU UIF NFEJBO PG UIF EJÃªFSFODFT JT OFHBUJWF 1 1Â¦ a É¨F SFTVMU JT HJWFO CZ DPNQVUJOH UIF CJOPNJBM QSPCBCJMJUZ

SKIN REPLICA AND IMAGE ANALYSIS É¨F BDRVJTJUJPO PG TLJO DBTUT XBT DBSSJFE PVU VTJOH B TUFSFPNJDSPTDPQF DPOOFDUFE UP BO BOBMPH WJEFP DBNFSB

BOBMZ[FE VTJOH PQUJDBM QSPÃ«MPNFUSZ BOE DPNQBSFE XJUI UIPTF PG UIF Ã«STU USFBUNFOU BOE XF BTTFTTFE UIF EFHSFF PG JSSFHVMBSJUZ JO UIF DBTUT CZ NFBOT PG DPNQVUFSJ[FE JNBHF BOBMZTJT 7 5P FWBMVBUF DIBOHFT JO UIF EFSNJT JOEVDFE CZ UIF USFBUNFOU TLJO VMUSBTPOPHSBQIZ XBT QFSGPSNFE JO UIF TBNF TQPU GSPN XIJDI UIF SFQMJDB XBT UBLFO GPS FBDI QBUJFOU

É¨F NPSQIPNFUSJD TUVEZ PG TLJO TVSGBDF NBLFT JU QPTTJCMF UP FWBMVBUF UIF TVSGBDF T JSSFHVMBSJUZ TLJO TVSGBDF UFYUVSF BOE UP EFUFSNJOF BOZ WBSJBUJPO DBVTFE CZ UIF USFBUNFOU É¨F NJDSPSFMJFG T JSSFHVMBSJUZ EFHSFF XBT EFUFSNJOFE CZ TUVEZJOH UIF 'PVSJFS TQFDUSVN 'BTU 'PVSJFS 5SBOTGPSN PO TLJO DBTU JNBHFT *O EFUBJM VTJOH TQFDJBM TPGUXBSF UP QSPDFTT UIF TLJO UFYUVSF T JNBHFT NBLFT JU QPTTJCMF UP FWBMVBUF UIF BWFSBHF WBMVFT PG iHSFZw PCUBJOFE BMPOH UIF 9 BYJT BOE : BYJT UIF FTUJNBUFE JOEFYFT *4*wY BOE *4*wZ *SSFHVMBS 4LJO *OEFY PG wY BYJT BOE wZ BYJT BSF UIF JOUFHSBMT PGÎ&#x2030;BSFBT CPVOEFE CZ UIF DVSWFT SFTVMUJOH GSPN UIF QJYFMT EJTUSJCVUJPO BMPOH UIF 9 BOE : BYFT

&BDI QBUJFOU XBT USFBUFE XJUI B UPQJDBM QSPEVDU DPOUBJOJOH a PNFHB IZESPYZM BDJET PNFHB IZESPYZM BDJET FOPYPMPOF BOE *NBHF QSPDFTTJOH XBT DBSSJFE PVU CZ DPNQVUFSJ[FE JNBHF BOBMZ[JOD GPS XFFLT QSFQBSBUJPO QIBTF CFGPSF TLJO OFFEMJOH XBT TJT É¨F TLJO DBTUT BSF TVCKFDUFE UP MJHIU BU B EFHSFF BOHMF UP TUBSUFE DSFBUF TIBEPXT BMPOH UIF SJEHFT OFHBUJWF JNBHF PG XSJOLMFT &BDI QBUJFOU XBT QSFQBSFE JO B NBOOFS TJNJMBS UP B TVSHJDBM É¨F TIBEPXT BSF DPOWFSUFE JOUP B HSBZ TDBMF XIPTF JOUFOTJUZ JT QSPDFEVSF UIF OFDL TLJO XBT EJTJOGFDUFE BOE B UPQJDBM BOFTUIFUJD EJSFDUMZ QSPQPSUJPOBM UP UIF TIBEPXT JOUFOTJUZ BOE UP UIF XSJO FVUFDUJD NJYUVSF PG MPDBM BOFTUIFUJDT XBT BQQMJFE GPS NJOVUFT LMF EFQUI 0ODF UIF JNBHFT BSF EJTQMBZFE PO UIF TDSFFO BOE UIF &BDI BSFB XBT USFBUFE XJUI B IJHIMZ TQFDJÃ«D UPPM %FSNBSPMMFS BSFB UP CF TUVEJFE JT JEFOUJÃ«FE GPS FBDI QBUJFOU UIF QJYFM CZ .' %FSNBSPMMFS --$ É¨PVTBOE 0BLT $" B NN XJEF QJYFM EFÃ«OJUJPO PG B TFSJFT PG MJOFT TDBOOJOH UIBU QFSQFOEJDVSPMMJOH CBSSFM FRVJQQFE XJUI OFFEMFT JO SPXT É¨F OFFEMFT MBSMZ QBTT UISPVHI UIJT BSFB JT JOJUJBUFE É¨F BWFSBHF JOUFOTJUZ PG VTFE IBWF B MFOHUI PG NN BOE B EJBNFUFS PG NN HSBZ GPS FBDI QJYFM JO UIF JOUFSDFQUFE BSFB JT PCUBJOFE 5P BDIJFWF "DDPSEJOH UP UIF QSFTTVSF BQQMJFE UIF OFFEMFT QFOFUSBUF UIF TLJO SFQSPEVDJCMF TDBOOJOH VODFSUBJOUZ MFWFM DBSF NVTU CF UP CFUXFFO NN BOE NN É¨F EJBNFUFS BU NBYJNVN UBLFO JO PCUBJOJOH UIF TLJO DBTUT É¨F VODFSUBJOUZ JT DBMDVMBUFE QFOFUSBUJPO MFWFM JT NN É¨F TQFDJBM UPPM JT SPMMFE PWFS UIF JO BDDPSEBODF XJUI &/ SVMFT É¨F GPMMPXJOH QSPÃ«MPNFUSJD SKINmed. 2011;9:347â&#x20AC;&#x201C;351

4LJO /FFEMJOH JO UIF 5SFBUNFOU PG UIF "HJOH /FDL

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November/December 2011 QBSBNFUFST BSF DBMDVMBUFE 3B BWFSBHF SPVHIOFTT XIJDI JT UIF BSJUINFUJD NFBO JO BCTPMVUF WBMVF PG BMM WBSJBUJPOT PG UIF NFBO 3U XIJDI JT UIF NBYJNVN EFQUI PG UIF XSJOLMFT JO UIF DPOTJEFSFE BSFB 3[ XIJDI JT UIF BWFSBHF EFQUI PG UIF XSJOLMFT 3NBY XIJDI JT UIF NBYJNVN IFJHIU PG UIF Ã«MUFSFE QSPÃ«MF BOE 3NJO XIJDI JT UIF NJOJNVN IFJHIU PG UIF Ã«MUFSFE QSPÃ«MF

Table III. Wrinkle Severity Rating Scale Data

PATIENT

SKIN ULTRASONOGRAPHY 4LJO VMUSBTPOPHSBQIZ XBT DBSSJFE PVU VTJOH 7PMVTPO & 435 B UP .)[ VMUSBTPVOE TZTUFN (& )FBMUIDBSF 8BVLFTIB 8* É¨F VMUSBTPOJD XBWF JT QBSUJBMMZ SFÃ¬FDUFE BU UIF CPVOEBSZ CFUXFFO BEKBDFOU TUSVDUVSFT BOE HFOFSBUFT FDIPFT PG EJÃªFSFOU BNQMJUVEFT UIF JOUFOTJUZ PG SFÃ¬FDUFE FDIPFT FDIPHFOJDJUZ JT FWBMVBUFE CZ B NJDSPQSPDFTTPS BOE WJTVBMJ[FE BT B EJNFOTJPOBM JNBHF É¨F XBUFS Ã«MMFE UBOL XJUI UIF USBOTEVDFS JT DMPTFE CZ B NFNCSBOF BOE BUUBDIFE PO UIF TLJO TVSGBDF XJUI B MBZFS PG HFM É¨F BYJT PG UIF QSPCF JT UBLFO TUSJDUMZ QFSQFOEJDVMBS UP UIF TVSGBDF PG UIF TLJO 8F UIFO NFBTVSF UIF OFDL XSJOLMFT É¨F UIJDLOFTT PG UIF HFM MBZFS JT BEKVTUFE UP B IPSJ[POUBM QPTJUJPO BU E# É¨F UIJDLOFTT PG UIF EFSNJT JT EFUFSNJOFE JO UIF # NPEF FYDMVEJOH UIF IZQFSFDIPHFOJD FOUSBODF FDIP BOE UIF IZQPFDIPHFOJD TVCDVUJT &DIPEFOTJUZ UIF BWFSBHF BNQMJUVEF PG UIF FDIPFT JO B EFÃ«OFE BSFB PG UIF JNBHF JT EFUFSNJOFE JO B SFHJPO PG JOUFSFTU *O B DIPTFO BSFB JODMVEJOH UIF XIPMF EFSNJT UIF BNQMJUVEFT PG UIF FDIPFT PG UIF TJOHMF JNBHF FMFNFOUT QJYFMT JT BTDSJCFE UP B OVNFSJDBM TDBMF 7BMVFT BSF HJWFO XJUIPVU EJNFOTJPO

T0, BEFORE TREATMENT

T3, 32 WEEKS AFTER TREATMENT

50 FRVBM UP 8JUI SFHBSE UP UIF BWFSBHF EFQUI PG XSJOLMFT BOE UIF NBYJNVN IFJHIU PG UIF Ã«MUFSFE QSPÃ«MF UIF QSPÃ«MPNFUSJD FWBMVBUJPO EJE OPU TIPX TJHOJÃ«DBOU WBSJBUJPOT DPNQBSFE XJUI CBTFMJOF 'JHVSF BOE 'JHVSF É¨F OFDL VMUSBTPOJD JNBHFT TIPXFE Ã«STU FQJEFSNJT BT B IZQFSFDIPHFOJD CBOE XIJUF BSFB VOEFS UIJT [POF UXP QPPS FDIP CBOET CMBDL BSFBT SFQSFTFOUJOH TVQFSÃ«DJBM EFSNJT BOE EFFQ

6MUSBTPOJD NFBTVSFNFOUT XFSF QFSGPSNFE CZ UIF TBNF JOWFTUJHBUPS VOEFS DPOTUBOU FOWJSPONFOUBM DPOEJUJPOT JO FBDI USFBUNFOU RESULTS É¨F SFTVMUT BDIJFWFE BGUFS UXP TFTTJPOT PG USFBUNFOU XFSF BTTFTTFE "GUFS FBDI TFTTJPO UIF OFDL TLJO BQQFBSFE SFEEFOFE BOE TXPMMFO CVU UIF SFEOFTT BOE TXFMMJOH EJTBQQFBSFE JO PS EBZT BT OPUFE CZ UIF QBUJFOUT /P TJEF FÃªFDUT XFSF SFQPSUFE "U UIF FOE PG UIF TUVEZ UIF QIPUPHSBQIJD DPNQBSJTPO BOE UIF BOBMZTJT PG UIF 8434 TDPSFT TIPXO JO 5BCMF *** IJHIMJHIUFE UIBU JO BMNPTU BMM QBUJFOUT UIF SFMBUJWF XSJOLMF EFQUI XBT TJHOJÃ«DBOUMZ SFEVDFE P "DDPSEJOH UP ("*4 QBUJFOU XBT WFSZ NVDI JNQSPWFE QBUJFOUT XFSF NVDI JNQSPWFE QBUJFOUT XFSF JNQSPWFE BOE QBUJFOU TIPXFE OP JNQSPWFNFOU "OBMZTJT PG UIF TVSGBDF NJDSPSFMJFG GSPN TLJO SFQMJDBT TIPXFE B SFEVDUJPO JO UIF EFHSFF PG JSSFHVMBSJUZ PG TLJO UFYUVSF JO BMNPTU BMM UIF QBUJFOUT XJUI BO BWFSBHF SFEVDUJPO PG JO CPUI BYFT 8SJOLMF JNBHF QSPDFTTJOH TIPXFE B TJHOJÃ«DBOU SFEVDUJPO JO UIF BWFSBHF SPVHIOFTT BOE UIF NBYJNVN EFQUI PG UIF XSJOLMFT JO UIF DPOTJEFSFE BSFB XJUI SFTQFDU UP UIF CBTBM DPSSFTQPOEJOH UP GPS UIF BWFSBHF SPVHIOFTT BOE UP GPS UIF NBYJNVN EFQUI PG UIF XSJOLMFT *O BEEJUJPO B DMJOJDBMMZ SFMFWBOU JODSFBTF JO UIF NJOJNVN IFJHIU PG UIF Ã«MUFSFE QSPÃ«MF XBT FTUJNBUFE BU SKINmed. 2011;9:347â&#x20AC;&#x201C;351

349

Figure 1. Cutaneous replica at T0 (before skin needling). 4LJO /FFEMJOH JO UIF 5SFBUNFOU PG UIF "HJOH /FDL

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November/December 2011

Figure 4. &DIPHSBQIJD JNBHF PG UIF TLJO PG UIF OFDL JO B ZFBS PME XPNBO BU 53 (32 weeks after skin needling): the whole epidermal and dermal thickness appears increased compared with that in Figure 3.

Figure 2. Cutaneous replica at T3 (32 weeks after skin needling): a reduction in the degree of irregularity of skin texture can be observed just by the naked eye.

UIF Ã«STU XIJUF CBOE UP UIF Ã«STU CMBDL CBOE EFSNBM UIJDLOFTT XBT NFBTVSFE GSPN UIF Ã«STU CMBDL CBOE UP UIF TFDPOE XIJUF CBOE "GUFS UIFTF NFBTVSFNFOUT XF EFUFSNJOFE UIF UIJDLOFTT PG UIF XIPMF FQJEFSNJT BOE EFSNJT MBZFST GSPN UIF Ã«STU XIJUF CBOE UP UIF TFDPOE XIJUF CBOE 8F DPNQBSFE 50 FDIP JNBHFT XJUI 53 FDIP JNBHFT BOE FNQIBTJ[FE UIBU UIF XIPMF FQJEFSNBM BOE EFSNBM UIJDLOFTT XBT JODSFBTFE BT TIPXO JO 'JHVSF BOE 'JHVSF É¨JT JODSFBTF SFQSFTFOUT B TLJO UFYUVSF JNQSPWFNFOU *O QBSUJDVMBS XF PCTFSWFE B TUBUJTUJDBMMZ TJHOJÃ«DBOU P JODSFBTF JO EFSNBM UIJDLOFTT JO BMM QBUJFOUT XJUI BO BWFSBHF WBMVF PG NN DPNQBSJOH UIF VMUSBTPOJD JNBHFT CFGPSF BOE XFFLT BGUFS UIF USFBUNFOU BT SFQPSUFE JO 5BCMF *7 DISCUSSION

Figure 3. /FDL TLJO T FDIPHSBQIJD JNBHF JO B ZFBS PME woman at T0 (before skin needling): epidermis appears as a hyperechogenic band (white area); under this zone, two poor echo bands (black areas), representing superficial dermis and deep dermis, respectively, are observable.

0VS SFTVMUT EFNPOTUSBUF UIF FÃªFDUJWFOFTT PG TLJO OFFEMJOH JO UIF USFBUNFOU PG UIF BHJOH OFDL 8F DPODMVEF PVS Ã«OEJOHT BSF OPU SFMBUFE UP UIF UPQJDBM DIFNJDBM USFBUNFOUT VTFE FWFO JG FBDI QBUJFOU XBT USFBUFE XJUI B UPQJDBM QSPEVDU DPOUBJOJOH a PNFHB IZESPYZM BDJET PNFHB IZESPYZM BDJET FOPYPMPOF BOE [JOD GPS XFFLT CFGPSF TLJO OFFEMJOH XBT TUBSUFE É¨F SFBTPO UP CFMJFWF UIBU PVS Ã«OEJOHT DBO CF DPOTJEFSFE BT USVF JO UIF BCTFODF PG DPOUSPMT BOE OPU SFMBUFE UP UIF UPQJDBM DIFNJDBM USFBUNFOUT JT CBTFE PO QSFWJPVT TUVEJFT É¨FTF TUVEJFT EFNPOTUSBUFE UIBU a PNFHB IZESPYZM BDJET PNFHB IZESPYZM BDJET FOPYPMPOF BOE [JOD BSF OPU BCMF UP QSPEVDF SFTVMUT TVDI BT XF IBWF PCTFSWFE EVSJOH PVS TUVEZ 9

/FFEMJOH FÃ¯DBDZ EFQFOET PO JUT DBQBDJUZ UP JOEVDF BOE UIFO EFSNJT SFTQFDUJWFMZ XFSF QJDLFE PVU "EJQPTF MBZFS XBT EJT- TUSPOHMZ TUJNVMBUF UIF OFP DPMMBHFOPHFOFTJT QSPDFTT BOE UIF QMBZFE VOEFS EFFQ EFSNJT BT B UIJDL IZQPFDIPHFOJD CBOE XJUIJO OPSNBM XPVOE IFBMJOH QSPDFTT EFWFMPQJOH JO QIBTFT JOÃ¬BNIZQFSFDIPHFOJD TUSFBLT &QJEFSNBM UIJDLOFTT XBT NFBTVSFE GSPN NBUJPO QSPMJGFSBUJPO BOE SFNPEFMJOH 11 É¨F JOÃ¬BNNBUJPO SKINmed. 2011;9:347â&#x20AC;&#x201C;351

350

4LJO /FFEMJOH JO UIF 5SFBUNFOU PG UIF "HJOH /FDL

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November/December 2011

D PNQBSFE XJUI DPOWFOUJPOBM NFUIPET PG UIFSBQZ É¨F NPTU JNQPSUBOU JT UIBU UIF FQJEFSNJT SFNBJOT JOUBDU FMJNJOBUJOH NPTU PG UIF SJTLT BOE OFHBUJWF TJEF FÃªFDUT PG DIFNJDBM QFFMJOH PS MBTFS SFTVSGBDJOH

Table IV. Skin Ultrasonography Data

PATIENT

DERMAL THICKNESS AT T0 (BEFORE NEEDLING), MM

DERMAL THICKNESS AT T3 (32 WEEKS AFTER NEEDLING), MM

"WFSBHF WBMVF

REFERENCES 1

Ferdandes D. Minimally invasive percutaneous collagen induc tion. Oral Maxillofac Surg Clin North Am. 2005;17:51â&#x20AC;&#x201C;63.

Aust MC, Fernandes D, Kolokythas P, et al. Percutaneous col lagen induction therapy. An alternative treatment for scars, wrinkles, and skin laxity. Plast Reconstr Surg. 2008;121: 1421â&#x20AC;&#x201C;1429.

Aust MC, Reimers K, Repenning C, et al. Percutaneous colla gen induction: minimally invasive skin rejuvenation without risk of hyperpigmentationâ&#x20AC;&#x201D;fact or fiction? Plast Reconstr Surg. 2008;122:1553â&#x20AC;&#x201C;1563.

Lacarrubba F, Tedeschi A, Nardone B, et al. Mesotherapy GPS TLJO SFKVWFOBUJPO BTTFTTNFOU PG UIF TVCFQJEFSNBM MPX FDIPHFOJD CBOE CZ VMUSBTPVOE FWBMVBUJPO XJUI DSPTT TFDUJPOBM # NPEF TDBOOJOH Dermatol Ther. 2008;21(suppl 3):S1â&#x20AC;&#x201C;S5.

'BSBHF ." .JMMFS ,8 &MTOFS 1 FU BM 5IF XSJOLMF TFWFSJUZ SBUJOH scale: a validation study. Am J Clin Dermatol. 2004;5:49â&#x20AC;&#x201C;52.

/BSJOT 34 #SBOEU ' -FZEFO + FU BM " SBOEPNJ[FE EPVCMF blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29:588â&#x20AC;&#x201C;595.

8BUTPO 3& 0HEFO 4 $PUUFSFMM -' FU BM " DPTNFUJD ABOUJ BHFJOH QSPEVDU JNQSPWFT QIPUPBHFE TLJO B EPVCMF CMJOE SBOEPNJ[FE controlled trial. Br J Dermatol. 2009;161:419â&#x20AC;&#x201C;426.

7BO 4DPUU &+ %JUSF $. :V 3+ "MQIB IZESPYZBDJET JO UIF USFBU ment of signs of photoaging. Clin Dermatol. 1996;14:217â&#x20AC;&#x201C;226.

(SFFO #" :V 3+ 7BO 4DPUU &+ $MJOJDBM BOE DPTNFDFVUJDBM VTFT of hydroxyacids. Clin Dermatol. 2009;27:495â&#x20AC;&#x201C;501.

QIBTF TUBSUT TPPO BGUFS UIF JOKVSZ QMBUFMFUT PODF BDUJWBUFE SFMFBTF DIFNPUBDUJD GBDUPST XIJDI DBVTF BO JOWBTJPO PG PUIFS QMBUFMFUT OFVUSPQIJMT BOE Ã«CSPCMBTUT %VSJOH UIF QSPMJGFSBUJWF QIBTF OFVUSPQIJMT BSF SFQMBDFE CZ NPOPDZUFT UIBU DIBOHF JOUP NBDSPQIBHFT BOE SFMFBTF TFWFSBM HSPXUI GBDUPST JODMVEJOH QMBUFMFU EFSJWFE HSPXUI GBDUPS Ã«CSPCMBTU HSPXUI GBDUPST USBOTGPSNJOH HSPXUI GBDUPS 5(' a BOE 5(' b XIJDI TUJNVMBUF UIF NJHSBUJPO BOE QSPMJGFSBUJPO PG Ã«CSPCMBTUT É¨FZ TUBSU QSPEVDJOH BMM UIF DPNQPOFOUT UP SFFTUBCMJTI UIF CBTFNFOU NFNCSBOF XJUI MBNJOJO BOE DPMMBHFO FTQFDJBMMZ DPMMBHFO UZQF *** 'JOBMMZ UIF SFNPEFMJOH QIBTF TUBSUT BOE DPOUJOVFT GPS TFWFSBM NPOUIT DPMMBHFO UZQF *** JT MBJE EPXO JO UIF VQQFS EFSNJT KVTU CFMPX UIF CBTBM MBZFS PG UIF FQJEFSNJT BOE JT HSBEVBMMZ SFQMBDFE CZ DPMMBHFO UZQF * 12 CONCLUSIONS 0VS QSFMJNJOBSZ TUVEZ TVHHFTUT UIBU TLJO OFFEMJOH NBZ CF BO FÃªFDUJWF BOE TBGF USFBUNFOU GPS UIF BHJOH OFDL *O QBSUJDVMBS TLJO OFFEMJOH JO UIF BHJOH OFDL IBT VOEJTQVUBCMF BEWBOUBHFT

10 Fernandes D. Minimally invasive percutaneous collagen induc tion. Oral Maxillofac Surg Clin North Am. 2005;17:51â&#x20AC;&#x201C;63. 11 Aust MC, Reimers K, Kaplan HM, et al. Percutaneous collagen inductionâ&#x20AC;&#x201D;regeneration in place of cicatrisation? J Plast Reconstr Aesthet Surg. 2010;64:97â&#x20AC;&#x201C;107. 12 Cohen KI, Diegelmann RF, Lindbland WJ. Wound Healing, Biochemical, and Clinical Aspects. Philadelphia, PA: WB Saunders Co; 1992.

FORMULARY OF DR GEORGE C. ANDREWS Bleach Carbon tetrachloride 25% in alcohol as a bleach 4VCNJUUFE CZ %PVHMBT % "MUDIFL .% /FX :PSL /:

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General Features and Treatment of Notalgia Paresthetica Lidia Comba Pérez-Pérez, MD ABSTRACT Notalgia paresthetica is a neurocutaneous disorder that most commonly manifests as pruritus and a brownish macula in the patient’s upper back. Pain, burning, and paresthesias to a variable degree have also been reported. Although the physiopathology of notalgia paresthetica is still obscure, it is currently considered a sensory neuropathy caused by damage to the spinal nerves. To date, no definitive treatment has been described for this disorder. Alternatives, including physical therapies and topical, systemic, and intralesional drugs, have been tested with diverse results. A review of the current knowledge on notalgia paresthetica and its treatment is provided. (SKINmed. 2011;9:353–358)

n 1934, Astwazaturow took “notalgia” from the Greek “notos” and “algos” meaning “back” and “pain,” respectively, to describe a skin disorder combining pain and hypoesthesia.1–3

Notalgia paresthetica (NP) is currently considered a sensitive neuropathy restricted to the upper portion of the back, affecting the posterior rami of the spinal nerves of the dorsal segments T2 through T6.3 Brachioradial pruritus (affecting the dorsal cutaneous antebrachii nerve), meralgia paresthetica (lateral femoral cutaneous nerve), gonyalgia paresthetica (infrapatellar branch of saphenous nerve of foot), cheiralgia paresthetica (superficial branch of radial nerve), digitalgia paresthetica (digital nerve), thoracolumbar radiculopathy (radicular nerves), intercostal neuropathy (radicular nerves), and incisura scapulae syndrome (suprascapular nerve) are other well-known sensory mononeuropathies.3,4 GENERAL FEATURES

Since the first descriptions of NP, different authors have coined other terms (Table I) to describe similar clinicohistopathologic pictures.1,5,7,8 The possible relation among NP, macular amyloidosis (MA), and macular posterior pigmentary incontinence (MPPI) is not currently clear. Some authors state that NP and MA are two different and independent conditions,6,8,9 while others suggest a probable overlap.2

The term macular posterior pigmentary incontinence was proposed to describe a group of patients showing pruritic pigmented macules in their back with no dermal amyloid deposits. The relation among NP, MA, and MPPI was discussed, but no clear differential definitions of these three entities or information on radiologic or neurologic studies performed were provided.6 In view of the data available to date, it seems probable that NP and MPPI are the same entity. Histopathology is necessary to distinguish between NP and MA. The former shows unspecific findings including mild hyperkeratosis, pigmentary incontinence, a mild inflammatory infiltrate in the papillary dermis, and necrotic keratinocytes to a variable amount.4,10 These features may also be seen in MPPI. MA shows deposits of amyloid in the dermal papillae, which are not present in NP; however, there is no consensus on the presence of amyloid in NP, since it has been found in some patients with NP.1 Detection of dermal amyloid deposits can be difficult, as they are sometimes scarce and may go unnoticed.11 It is, therefore, probable that many of the patients diagnosed with NP would show amyloid deposits, if studied with more sensible histopathology methods. A skin biopsy is also helpful in differentiating NP from other cutaneous disorders, including tinea versicolor, tinea corporis, neurodermatitis, parapsoriasis, contact dermatitis, cutaneous amyloidosis, fixed-drug eruption, leprosy, and postinflammatory hyperpigmentation.

From the Department of Dermatology, University Hospital Complex of Vigo, Vigo, Spain Address for Correspondence: Lidia Comba Pérez-Pérez, MD, Consultant Dermatologist, Department of Dermatology, University Hospital Complex of Vigo, C/Porriño 5, 36209 Vigo, Spain • E-mail: lidiacomba@yahoo.es

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Table I. Notalgia Paresthetica and Clinically Similar Disorders1,5,6

the spinal muscles, making them more sensitive to mechanical trauma or entrapment by muscles.3,14

NOMENCLATURE OF DISORDERS MANIFESTING WITH PRURITUS AND A BROWNISH MACULA IN THE PATIENT’S BACK

Spinal pathologies were present in the majority of patients studied, principally degenerative changes, disk herniation, and scoliosis. Cervical fibrous bands, muscle spasm, injury to the long thoracic nerve, or the cervical roots C5–C7 with serratus anterior dysfunction, dysfunction of other scapular stabilizers (rhomboid, trapezius), and injury to other nerves that stabilize the scapula such as the spinal accessory nerve may also contribute to the development of NP.9,14

Notalgia paresthetica Friction melanosis Towel melanosis Nylon clothes friction melanosis Macular posterior pigmentary incontinence Puzzling posterior pigmented pruritic patches

Underlying individual predisposing factors might also play a role in the pathogenesis of NP.3

Peculiar spotty pigmentation Localized shoulder pruritus

An association with multiple endocrine neoplasia type 2A in hereditary NP has been suggested in the literature.2,3 This association has also been described in patients with cutaneous amyloidoses.15

Localized pigmentation Macular amyloidosis Friction amyloidosis Cutaneous dorsal amyloidosis

PHYSIOPATHOLOGY OF NP The exact cause of NP is still unknown, but localized trauma and spinal nerve impingement have been suggested to be the principal predisposing and etiologic factors9,12,13 (Table II). The spinal nerves that branch out from the spinal cord in the dorsal segments (T2–T6) follow a right-angle course through Table II. Factors That Play a Role in the Pathogenesis of Notalgia Paresthetica2,3,6,9,12–14

FACTORS

OBSERVATIONS

Localized trauma, spinal nerve impingement

Disk herniation Muscle contractures Fibrous bands Vertebral arthrosis Spinal stenosis Scoliosis Spinal tumours Dysfunction of scapular stabilizer muscles

Genetic factors

Familial cases Young patients Association with multiple endocrine neoplasia 2A

Predisposing factors Internal

Individual factors (not yet identified)

External (anecdotal reports)

Saccharin intake Psychological trauma Vaccination Prolonged bed rest Gastroesophageal reflux Sunburn reaction

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Some precipitating factors have been anecdotally reported to promote the development of NP, including saccharin intake, psychological trauma, vaccination, prolonged bed rest, gastroesophageal reflux,3 and sunburn reaction.6 The pruritus in patients with NP may be caused directly by compression of the unmyelinated C fibers (responsible for the transmission of itch and pain)16 or indirectly by mast cell degranulation secondary to substance P release.17 Relevant qualitative or quantitative changes in the cutaneous innervation of the affected area in NP are not constant.12,18–20 The skin hyperpigmentation might be the result of chronic rubbing and scratching.17 The latter has been suggested as a mechanical stimulus that might induce the apoptosis of the basal keratinocytes and subsequent amyloid K deposition21; however, a consensus as to whether amyloid deposition might be a primary feature or the consequence of the chronic rubbing has still not been reached. CLINICAL PICTURE NP may manifest with neuropathic itch, pain, paresthesias, tingling, burning, and hypoesthesia/hyperesthesia.22 One or more (Figures 1–3) ill-defined hyperpigmented macules can be seen in the affected area (unilaterally or bilaterally), but they are not always present.4,9 A reticulated pattern similar to that seen in MA, scaling, lichenification,9 and excoriations can sometimes be observed. The symptoms typically appear affecting the T2–T6 dorsal segments in the patient’s back (interscapular, subscapular, and dorsal paravertebral regions). Affectation of lower regions has been described in some patients,1 but these cases are probably thoracolumbar radiculopathies or intercostal neuropathies rather than true NP.

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REVIEW Women are more frequently affected than men. The sex ratio can be as high as 9:1 (personal observation) but it is usually around 2 to 3:1.1 The median age of onset is around 54 to 62 years,1 but it may be much earlier in hereditary cases. No racial differences have been detected. MANAGEMENT AND TREATMENT The evaluation of a patient with suspicion of NP is usually an interdisciplinary process that may require assessment by different specialists (dermatologists, neurologists, orthopedic surgeons, neurosurgeons). The recommended work-up in patients with suspicion of NP is summarized in Table III.

Figure 1. Ill-defined brownish macule affecting a 53-year-old man’s left subscapular area.

The treatment of NP is still a challenge for clinicians. Different therapeutic alternatives have been used (Table IV), most of which only provide transient benefits. Topical corticosteroids have shown little benefit in patients with NP.1 Topical capsaicin (0.025% and 0.075% cream) is known Table III. Recommended Work-Up in Patients With Notalgia Paresthetica

PROCEDURES

OBSERVATIONS

Detailed anamnesis

Figure 2. Notalgia parasthetica affecting a 58-year-old woman’s right upper scapular area.

Inquire about history of osteoarthritis, vertebral trauma, vehicle accident, vertebral malignancy, sports, surgical procedures in the affected area, familial cases Dermatologic Location and affected dermatomes examination Size and number of the macules Associated findings: lichenification, excoriations, scaling Severity of the symptoms (VAS score) Neurologic examination Sensitivity, sweat test, motor function Complementary tests Skin biopsy Hematoxylin-eosin Search for dermal amyloid deposits (Congo Red, crystal violet, thioflavine T, CK monoclonal antibodies, electronic microscopy) EMG Blood analysis

Figure 3. Brownish macule affecting the left T2–T6 segment, coexisting with other lesions affecting different anatomic areas, in a 67-year-old woman’s back. SKINmed. 2011;9:353–358

It may be normal or reveal neuropathy Complete blood count

Blood biochemistry In hereditary cases/young patients1: serial blood to determine calcitonine levels and screening for medullary thyroid carcinoma Image tests Anteroposterior and lateral entire column x-ray MRI (if possible or if doubtful or inconclusive findings in x-ray) Abbreviations: CK, cytokeratin; EMG, electromyography; MRI, magnetic resonance imaging; VAS, visual analog scale.

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Table IV. Therapeutic Alternatives for the Treatment of Notalgia Paresthetica

TREATMENT

OBSERVATIONS

Topical Corticoids1 Capsaicin23,24 Anesthetics

0.025%, 0.075% cream

Lidocaine plus prilocaine cream

Intralesional Intradermal botulinum toxin A32 Corticoids4

4 UI injected in the selected points, 2 cm apart Triamcinolone: 2.5 mg/mL

Oral Oxcarbazepine26

Initial dose: 300 mg bid Increase: 600 mg bid or 900 mg bid, according to the benefits achieved

Gabapentin28–30

Initial dose: 100–300 mg at bedtime Increase: 100–300 mg tid Maximum: 3600 mg/d Reduce if renal insufficiency

Pregabalin28

Initial dose: 50 mg tid or 75 mg bid Increase by 150 mg every 3–7 d Maximum dose: 600 mg/d Reduce if renal insufficiency

TENS33

5 sessions a wk for 2 wk 50–100 Hz TENS applications of 20-min duration, pulse width 40–75 μs

EMS14

30 s on and 30 s off for 15 min bid 70 Hz with a pulse width of 300 μs

Paravertebral anesthetic block31 36

Bupivacaine 0.75% plus 40 mg of methylprednisolone Surgical decompression, discectomy

Surgical

Narrow band UV-B

3 sessions per wk, following a phototype protocol Mean: 32.8 sessions

Ostheopathic manipulative treatment34

Suboccipital decompression, inhibition and soft tissue techniques, rib raising and scapulothoracic fascial release 20-min session

Other alternatives1,13,16

Acupuncture, massage, multimodal physiotherapy, nonsteroidal anti-inflammatory drugs, antidepressants (selective serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants), oral muscle relaxants

Abbreviations: bid, twice a day; EMS, electrical muscle stimulation; TENS, transcutaneous electrical nerve stimulation; tid, three times a day.

to deplete C fibers of their neuropeptides. It has been successfully used to control pruritus, but the symptoms relapse shortly after the treatment has been stopped.23,24 The most common side effect is a burning sensation on the treated areas, which disappears with repeat applications. Topical anesthetics (pramocaine, 2.5% lignocaine and 2.5% prilocaine cream)25 have also induced partial relief and control of the symptoms, but relapse after withdrawal is common. A topical formulation of 1% naltrexone has shown a significant reduction of the pruritus in more than 70% of patients with SKINmed. 2011;9:353–358

different itchy skin disorders treated in one study,26 and thus could be an interesting topical option to test in patients with NP. Oxcarbazepine is an analog of carbamazepine that possibly acts by decreasing repetitive charges, blocking membrane sodium currents, and increasing the firing threshold in Aδ fibers. Partial relief of the pain and pruritus was observed in a group of patients with NP treated with oral oxcarbazepine for 6 months.27 Dizziness, headache, and gastric upset may be seen in some patients at the beginning of the treatment and resolve with withdrawal of the drug.

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Gabapentin and pregabalin bind to the α2δ subunits of the voltage-gated calcium channel and block neurotransmitter release.28 Resolution of the symptoms was observed with oral gabapentin (100–300 mg at bedtime; increase by 100–300 mg 3 times daily, to a maximum of 3600 mg/d).28,29 Pregabalin is used in the treatment of neuropathic pain and might also be useful in NP. Both gabapentin and pregabalin must be used carefully in patients with renal insufficiency.28,30 A local paravertebral block with bupivacaine (0.75%) and 40 mg of methylprednisolone acetate cleared the pruritus in one patient.31 One year after the procedure, the patient was symptom-free. Resolution of pruritus and a decrease in hyperpigmentation was obtained in 2 women who received intradermal injections of botulinum toxin type A.32 Transcutaneous electrical nerve stimulation (TENS) is a simple and safe therapy that consists of the application of electrical stimulation to the skin for pain control. It has been reported to partially relieve pruritus in a group of 15 patients with NP who received 10 high-frequency 20-minute applications.33 Five of the patients also received hot pack administration and an additional 20-minute cervical traction prior to TENS application. Transcutaneous electrical muscle stimulation (EMS) of the serratus anterior muscle seems to be useful in patients with long thoracic nerve injury and has been proposed as a long-acting and effective treatment for NP.14 Osteopathic manipulative treatment is another alternative that has shown benefit in patients with NP34; however, no data about long-term benefits are available. Narrow-band UV-B also appears to be an effective, safe, and very well-tolerated alternative treatment for NP, as shown in a recently published small series of 5 patients.35 The doses were administered following a phototype protocol in a UV 7002 cabinet (Waldmann, Herbert Waldmann GmbH & Co, Schwenningen, Germany). A significant improvement in the pruritus was achieved after a mean of 32.8 sessions and a mean cumulative dose of 33.76 J ⁄cm2.

selected according to their individual picture and condition. The steps of a reasonable therapeutic approach might be as follows: (1) start with topical measures; (2) addition of oral antihistamines (sedative H1 or/plus nonsedative H1 antihistamines); (3) change to oral oxcarbazepine/gabapentin/pregabalin or physiotherapy or osteopathic manipulative treatment or phototherapy; (4) TENS/ EMS; (5) intradermal botulinum toxin; (6) paravertebral block; or (7) other measures including surgery or acupuncture. Combination of several different alternatives is also possible. Although NP is not a rare disorder in medical practice, only a small series of patients and anecdotal cases have been reported in the literature to date. The underreporting of this entity may have something to do with the fact that (1) a great number of patients do not consult their physician when they have symptoms, and (2) many cases are considered irrelevant or benign by primary care physicians and patients are not subsequently referred for assessment to a specialist. The diagnosis is easily established on clinical grounds and is reinforced with the histopathologic and radiologic findings; however, misdiagnosis may be a problem when physicians are not aware of the typical features. CONCLUSIONS NP may be a cutaneous sign of an underlying spine disease. Dermatologists and other physicians should recognize the disease in order to conduct a proper work-up and assign treatment, which may restore their patient’s quality of life to some degree. REFERENCES

Other therapies including surgical procedures,36 acupuncture,16 multimodal physiotherapy (radar, short waves, infrared and ultrasound physiotherapy),1 spinal manipulation, nonsteroidal anti-inflammatory drugs, antidepressants (selective serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants), and oral muscle relaxants may also be effective.13 A therapeutic protocol for NP is not yet available and because results in only a small series of patients have been reported, it is quite difficult to offer a definitive approach. Patients must be informed of the possible options, and treatment can then be SKINmed. 2011;9:353–358

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Raison-Peyron N, Meunier L, Acevedo M, Meynadier J. Notalgia paresthetica: clinical, physiopathological and therapeutic aspects. A study of 12 cases. J Eur Acad Dermatol Venereol. 1999;12:215–221.

Corral de la Calle M, Arranz Sánchez DM, Casado Jiménez M. Notalgia parestesica. Piel. 2006;21:395–398.

Massey EW. Sensory mononeuropathies. Semin Neurol. 1998; 18:177–183.

Weber PJ, Poulos EG. Notalgia paresthetica. Case reports and histologic appraisal. J Am Acad Dermatol. 1988;18:25–30.

Siragusa M, Ferri R, Cavallari V, Schepis C. Friction melanosis, friction amyloidosis, macular amyloidosis, towel melanosis: many names for the same clinical entity. Eur J Dermatol. 2001;11:545–548.

Westermark P, Ridderström E, Vahlquist A. Macular posterior pigmentary incontinence: its relation to macular amyloidosis and notalgia paresthetica. Acta Derm Venereol. 1996;76:302–304.

Venkataram MN, Bhushnurmath SR, Muirhead DE, Al-Suwaid AR. Frictional amyloidosis in Omam: a study of 10 cases. Indian J Dermatol Venereol Leprol. 2002;68:28–32.

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Misery L. What is notalgia paresthetica? Dermatology. 2002; 204:86–87.

23 Wallengren J. Treatment of notalgia paresthetica with topical capsaicin. J Am Acad Dermatol. 1991;24:286–288.

Savk E, Savk O, Bolukbasi O, et al. Notalgia paresthetica: a study on pathogenesis. Int J Dermatol. 2000;39:754–759.

24 Wallengren J, Klinker M. Successful treatment of notalgia paresthetica with topical capsaicin: vehicle-controlled, double-blind, crossover study. J Am Acad Dermatol. 1995;32:287–289.

10 Allegue F, Rocamora A. Prurito localizado en región interescapular. Piel. 1989;4:345–346. 11 Cheung ST, Maheshwari MB, Tan CY. A comparative study of two Congo red stains for the detection of primary cutaneous amyloidosis. J Am Acad Dermatol. 2006;55:363–364. 12 Eisenberg E, Barmeir E, Bergman R. Notalgia paresthetica associated with nerve root impingement. J Am Acad Dermatol. 1997;37:998–1000. 13 Alai NN, Skinner HB, Nabili ST, et al. Notalgia paresthetica associated with cervical spinal stenosis and cervicothoracic disk disease at C4 through C7. Cutis. 2010;85:77–81. 14 Wang CK, Gowda A, Barad M, Mackey SC, Carroll IR. Serratus muscle stimulation effectively treats notalgia paresthetica caused by long thoracic nerve dysfunction: a case series. J Brachial Plex Peripher Nerve Inj. 2009;4:17. 15 Verga U, Fugazzola L, Cambiaghi S, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf). 2003;59:156–161. 16 Stellon A. Neurogenic pruritus: an unrecognised problem? A retrospective case series of treatment by acupuncture. Acupunct Med. 2002;20:186–190. 17 Steinhoff M, Ständer S, Seeliger S, et al. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol. 2003;139:1479–1488. 18 Springall DR, Karanth SS, Kirkham N, Darley CR, Polak JM. Symptoms of notalgia paresthetica may be explained by increased dermal innervation. J Invest Dermatol. 1991;97:555–561. 19 Savk E, Dikiciog ˘lu E, Culhaci N, Karaman G, Sendur N. Immunohistochemical findings in notalgia paresthetica. Dermatology. 2002;204:88–93. 20 Savk O, Savk E. Investigation of spinal pathology in notalgia paresthesica. J Am Acad Dermatol. 2005;52:1085–1087. 21 Schmerl S, Szeimies RM, Vogt T, et al. Cutaneous amyloidoses and systemic amyloidoses with cutaneous involvement. Eur J Dermatol. 2010;20:152–160. 22 Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547.

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25 Layton AM, Cotterill JA. Notalgia paraesthetica—report of three cases and their treatment. Clin Exp Dermatol. 1991;16:197–198. 26 Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol. 2007;56:979–988. 27 Savk E, Bolukbasi O, Akyol A, Karaman G. Open pilot study on oxcarbazepine for the treatment of notalgia paresthetica. J Am Acad Dermatol. 2001;45:630–632. 28 Dworkin RH, O’Connor AB, Audette J et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85:S3– S14. 29 Loosemore MP, Bordeaux JS, Bernhard JD. Gabapentin treatment for notalgia paresthetica, a common isolated peripheral sensory neuropathy. J Eur Acad Dermatol Venereol. 2007;21:1440–1441. 30 Manenti L, Vaglio A. Gabapentin for uraemic pruritus. Nephrol Dial Transplant. 2005;20:1278–1279. 31 Goulden V, Toomey PJ, Highet AS. Successful treatment of notalgia paresthetica with a paravertebral local anesthetic block. J Am Acad Dermatol. 1998;38:114–116. 32 Weinfeld PK. Successful treatment of notalgia paresthetica with botulinum toxin type A. Arch Dermatol. 2007;143:980–982. 33 Savk E, Savk O, Sendur F. Transcutaneous electrical nerve stimulation offers partial relief in notalgia paresthetica patients with a relevant spinal pathology. J Dermatol. 2007;34:315–319. 34 Richardson BS, Way BV, Speece AJ 3rd. Osteopathic manipulative treatment in the management of notalgia paresthetica. J Am Osteopath Assoc. 2009;109:605–608. 35 Perez-Perez L, Allegue F, Fabeiro JM, et al. Notalgia paresthetica successfully treated with narrow band UVB: report of five cases. J Eur Acad Dermatol Venereol. 2010;24:730–732. 36 Williams EH, Rosson GD, Elsamanoudi I, Dellon AL. Surgical decompression for notalgia paresthetica: a case report. Microsurgery. 2010;30:70–72.

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Volume 9 • Issue 6

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.

Meralgia paresthetica affects the: (Choose the single best response.) a. digital nerve. b. dorsal cutaneous antebrachial nerve. c. infrapatellar branch of the saphenous nerve. d. lateral femoral cutaneous nerve. e. radicular nerves. Notalgia paresthetica may manifest with: (Answer as many as apply.) a. burning. b. hypoesthesia/hyperesthesia. c. itch (pruritus). d. paresthesias. e. tingling.

Which of the following histological characteristics is least characteristic of notalgia paresthetica? (Choose the single best response.) a. Amyloid in the papillary dermis b.

Hyperkeratosis

Inflammatory infiltrate in the papillary dermis

Necrotic keratinocytes

Pigment incontinence

The clinical relevance of notalgia paresthetica is that it may be a cutaneous sign of an underlying: (Choose the single best response.) a. blood dyscrasia. b.

congestive heart failure.

diabetes mellitus.

kidney failure.

spine disease.

Appropriate treatment strategies for notalgia paresthetica may include: (Answer as many as apply.) a. intradermal botulinum toxin. b. oral antihistamines. c. oral oxcarbazepine/gabapentin/pregabalin. d. surgery. e. transcutaneous electrical nerve stimulation.

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

From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101 • E-mail: lamberwc@umdnj.edu

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Nicotinamide in Dermatology and Photoprotection Devita Surjana, MBBS;1 Diona L. Damian, MBBS, PhD1,2 ABSTRACT Nicotinamide (the amide form of vitamin B3) has been used in dermatology for more than 40 years for a diverse range of conditions including acne, rosacea, autoimmune bullous dermatoses, and now the treatment and prevention of photoaging and photoimmunosuppression. The broad clinical effects of nicotinamide may be explained by its role as a cellular energy precursor, a modulator of inflammatory cytokines, and an inhibitor of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase-1, which plays a significant role in DNA repair, maintenance of genomic stability, and cellular response to injury including inflammation and apoptosis. This review outlines the use of nicotinamide for inflammatory dermatoses and photoaging and focuses on its emerging role in photoprotection. (SKINmed. 2011;9:360–365)

icotinamide (niacinamide), an amide form of vitamin B3 (niacin or nicotinic acid) (Figure 1), is widely available in foods such as yeast, meats, liver, legumes, cereals, green leafy vegetables, milk, fish, coffee, and tea.1 Nicotinamide is also used in food fortification and is widely available as a nutritional supplement at doses of 20 mg/d to 500 mg/d. The adult recommended daily allowance for niacin (nicotinamide equivalent from food sources) is approximately 15 mg.2 The amino acid tryptophan, which constitutes approximately 1% of dietary protein, can also be converted into niacin in the liver, with 60 mg of tryptophan equivalent to approximately 1 mg of niacin.1 Excess nicotinamide is metabolized in the liver. Metabolites are renally excreted and can be measured in urine to diagnose nicotinamide deficiency. NICOTINAMIDE DOSAGE AND SAFETY PROFILE Nicotinamide has a high safety profile and is generally well tolerated at doses of 1 g/d to 3 g/d.2 Higher doses, up to 3.5 g/d, have been well tolerated in trials of type I diabetes prevention.3 Potential side effects, including nausea, vomiting, heartburn, headache, and fatigue, are rare even with these high doses.4 Unlike niacin, nicotinamide is not a vasodilator, and does not cause flushing or alteration in blood pressure, pulse rate, or body temperature.5 Nicotinamide does cross the placenta but is not teratogenic in mice6 and there is no reported teratogenicity in humans.4 Lifelong administration of 1% nicotinamide in drinking water (300-fold above requirements) is not carcinogenic in animals,7 with no evidence of carcinogenicity in humans.4

Because nicotinamide is an inhibitor of P450 enzymes, it may decrease carbamazepine clearance,8 although its interactions with other drugs and oral contraceptives have not been reported. Nicotinamide is used in a variety of cosmetic formulations at concentrations of 0.0001% to 3%, without evidence of skin irritation, sensitization, or photosensitization.6 CELLULAR FUNCTIONS OF NICOTINAMIDE Nicotinamide is the main dietary precursor for nicotinamide adenine dinucleotide (NAD) synthesis, an essential coenzyme in oxidation/reduction reactions for the production of cellular energy, adenosine triphosphate (ATP). Cellular NAD content determines p53 expression and malignant phenotype in human skin cancers.9 The role of NAD in carcinogenesis is tightly linked to the nuclear enzyme, poly(adenosine diphosphate[ADP]-ribose) polymerase 1 (PARP-1), which catalyses cleavage of NAD into nicotinamide and ADP ribose.10 Poly(ADP)ribosylation of nuclear proteins has been implicated in chromatin remodelling, DNA repair, and transcriptional regulation to maintain genomic stability.10 PARP-1 has been shown to control cell replication and telomerase activity, which is increasingly recognized to be involved in regulation of cellular senescence, aging, and cancer.10 PARP-1 also plays a key role in nuclear factor-kB (NF-kB)–mediated expression of proinflammatory cytokines including tumor necrosis factor a (TNF-a), interleukin (IL) 1b, IL-6, IL-8, and inflammatory

From the Department of Dermatology, Sydney Cancer Centre, Bosch Institute, University of Sydney at Royal Prince Alfred Hospital, Camperdown;1 and Melanoma Institute Australia, North Sydney, New South Wales,2 Australia Address for Correspondence: Diona L. Damian, MBBS, PhD, Department of Dermatology, Gloucester House Level 3, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia • E-mail: diona.damian@sswahs.nsw.gov.au

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Figure 1. Both nicotinamide and niacin are water-soluble forms of vitamin B3. Nicotinamide is more stable in water and alcohol than niacin and is therefore more commonly used in topical preparations.

mediators including inducible nitric oxide synthase, intercellular adhesion molecule 1, major histocompatibility complex class II, and macrophage migration inhibition factor.11 Nicotinamide, which is an endogenous inhibitor of PARP-1,10 dose-dependently prevented the release of proinflammatory cytokines IL-1b, IL-6, IL-8, and TNF-a in ex vivo human blood.11 NICOTINAMIDE IN THE TREATMENT OF AUTOIMMUNE BLISTERING DISORDERS Nicotinamide, as monotherapy or in combination with tetracycline, has been effective in the treatment of various inflammatory conditions, including granuloma annulare and erythema elevatum diutinum,2 but it is most frequently used as a steroid-sparing regimen in autoimmune blistering disorders. To date, there is only one open-labelled randomized trial comparing the efficacy of oral nicotinamide (1.5 g daily) plus tetracycline (2 g daily) with oral prednisone (40–80 mg/d) in 20 patients with bullous pemphigoid (BP), which showed that the combined therapy gave at least comparable efficacy.12 Although there are numerous case reports on the efficacy of combined oral nicotinamide and tetracycline in the treatment of BP, pemphigus, linear immunoglobulin A bullous dermatosis, lichen planus pemphigoides, dermatitis herpetiformis, and cicatricial pemphigoid (reviewed in Niren 20062), only one case report has claimed efficacy of oral nicotinamide as monotherapy (1.5 g/d) in a patient with localized BP.13 Topical nicotinamide may also be useful adjunctive therapy for pemphigus vulgaris. Eight pemphigus patients, all taking concomitant prednisone and azathioprine, were randomized to apply either 4% nicotinamide gel or vehicle gel once daily for 30 days. The percentage of the re-epithelialized area at day 30 was significantly greater with nicotinamide.14 Although the exact mechanisms of action of nicotinamide in these dermatoses are largely unknown, it does have inhibitory effects on the release of proinflammatory cytokines11 and neutrophil chemotaxis and SKINmed. 2011;9:360–365

A multicenter open-label cohort study of 198 patients with moderate to severe acne vulgaris and/or rosacea found that oral nicotinamide (1.5 g) given in combination with 50 mg of zinc and 1 mg of folic acid daily for 8 weeks significantly reduced inflammatory lesions compared with no treatment, and no added benefit of concomitant oral antibiotics was found.16 Randomized double-blinded studies in patients with inflammatory acne compared 4% nicotinamide gel with 1% clindamycin gel applied twice daily for 8 weeks. There was comparable efficacy in reducing inflammatory lesion counts, acne severity rating, and Physician’s Global Evaluation scale.17 A double-blinded randomized, controlled trial comparing 4% nicotinamide gel and 4% erythromycin gel (twice daily for 8 weeks) in 160 patients with inflammatory acne also found equivalent regression of inflammatory lesions and a greater decrease in cystic lesions and seborrhoea scores in the nicotinamide arm.18 Acne pathogenesis involves multiple factors including hyperkeratinization and reduced desquamation of follicular keratinocytes, leading to comedone formation, excess sebum production, inflammation, and Propionibacterium acnes. There is increasing evidence that keratinocytes and sebocytes within the pilosebaceous unit are able to recognize pathogens and be activated by P acnes via toll-like receptors (TLRs) and CD14 and CD1 molecules, producing inflammatory cytokines in response to these stimuli. P acnes activation of TLR-2 on the surface of keratinocytes, monocytes, and macrophages induces nuclear translocation of the transcription factor NF-kB, which then leads to the transcription of many immune response genes. In human keratinocytes, nicotinamide prevents P acnes–induced activation of TLR-2 via inhibition of NF-kB and mitogen-activated protein kinase pathways, resulting in down-regulation of proinflammatory IL-8 production.19 Nicotinamide may also inhibit sebaceous lipogenesis. In an ex vivo study of human skin, nicotinamide was shown to dosedependently inhibit sebaceous triglyceride and fatty acid synthesis, which, in excess, are important contributors to acne pathogenesis.20 In a double-blind, placebo-controlled trial and a parallel, randomized split-face study, 2% nicotinamide gel reduced facial sebum production in 130 volunteers.21 NICOTINAMIDE IMPROVES EPIDERMAL BARRIER FUNCTION Topical nicotinamide, which has been investigated as a potential treatment for atopic dermatitis and dry skin associated with aging, has been shown to improve skin barrier function and

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increase skin resistance to irritants such as sodium lauryl sulfate and dimethyl suflfoxide.22 In a right/left comparison study in 12 male volunteers with dry skin, 2% nicotinamide was evaluated against its vehicle.23 After twice-daily application of nicotinamide or vehicle for 4 weeks, transepidermal water loss (TEWL) was measured and the stratum corneum was stripped for lipid analysis. Nicotinamide reduced TEWL by 27% compared with its vehicle and increased stratum corneum free fatty acid and ceramide levels by 67% and 34%, respectively.23 An in vitro study with human keratinocytes showed that nicotinamide dose-dependently increased ceramide and other sphingolipids by stimulating the activity and gene expression of serine palmitoyltransferase, the rate-limiting enzyme in de novo sphingolipid synthesis.23 Nicotinamide may also improve skin barrier function by increasing involuncrin, filaggrin, and keratin.22 In 28 patients with atopic dermatitis, 2% nicotinamide cream was significantly more effective in decreasing TEWL and increasing stratum corneum hydration than petrolatum.24 Topical nicotinamide is a potentially useful adjunctive treatment for sensitive dry skin associated with rosacea and irritated and dry skin associated with retinoic acid treatment for photoaging. In a randomized investigator-blinded study of 50 women with rosacea, moisturizer containing 2% nicotinamide applied twice daily decreased facial erythema, dryness and peeling/scaling, and inflammatory lesion counts and significantly improved stratum corneum barrier function and hydration as measured by TEWL and skin capacitance, respectively.25 An in vitro study with human HaCaT keratinocytes provides further insight into the mechanism of nicotinamide prevention of TEWL. Aquaporin 3 (AQP3) mediates keratinocyte water transport, and in cultured human keratinoctyes, nicotinamide treatment dose-dependently prevented retinoid-induced AQP3 overexpression.26 TREATMENT OF PHOTOAGING Topical nicotinamide at concentrations of 2% to 5% has been evaluated for the treatment of photoaging, characterized by fine lines and wrinkles, poor texture, and hyperpigmentation. In a split-face randomized, double-blinded, vehicle-controlled study of 50 women, 5% nicotinamide cream applied twice daily for 12 weeks was more effective than vehicle in reducing facial wrinkles, red blotchiness, hyperpigmented spots, and skin sallowness and in improving skin elasticity.27 In 30 healthy Japanese women with periorbital wrinkles (randomized split-face study), 4% nicotinamide cream applied twice daily for 8 weeks significantly reduced wrinkle grades compared with its vehicle.28 In vitro, nicotinamide inhibits melanosome transfer from melanocytes to SKINmed. 2011;9:360–365

keratinocytes. Twice-daily application for 8 weeks of 5% and 2% nicotinamide cream was significantly more effective than vehicle in reducing facial hyperpigmentation.29 PROTECTION FROM PHOTOCARCINOGENESIS Both UV-A (320–400 nm) and UV-B (290–320 nm) are complete carcinogens in that they are involved in the initiation, promotion, and progression of skin carcinogenesis. UV-B induces DNA adducts including cyclobutane pyrimidine dimers (CPDs) and (6–4) photoproducts in epidermal cells, whereas UV-A largely exerts its deleterious effects through reactive oxygen species–induced oxidative damage to DNA, proteins, and lipids.30 In BALB/c mice treated with topical 2.5% nicotinamide or vehicle before chronic UV-B irradiation, tumor incidence (predominantly squamous cell carcinomas) was 75% with vehicle but only 43% with nicoitnamide. Tumor numbers per mouse were also reduced by almost 50%.31 Supplementation with 0.1%, 0.5%, or 1% dietary niacin in mice irradiated with UV-B over 22 weeks dose-dependently decreased both tumor incidence (by 8%, 20%, and 40%, respectively) and tumor numbers (by 17%, 33%, and 44%).32 NICOTINAMIDE PROTECTS FROM CELLULAR ENERGY LOSS DURING UV IRRADIATION UV radiation depletes NAD levels and cellular energy in the skin.33 Cellular NAD content determines cell survival in UVirradiated human fibroblasts, and addition of nicotinamide to the culture medium, which replenishes intracellular NAD, increases cell survival dose-dependently.33 We have also shown that in cultured human keratinocytes, nicotinamide prevented ATP depletion and reduction in glycolytic rate after UV irradiation.34 NICOTINAMIDE, DNA REPAIR, AND MAINTENANCE OF GENOMIC STABILITY In vitro studies with various human cell types have shown that nicotinamide enhances repair of irradiation or chemically induced DNA damage and that cultured human keratinocytes depleted of NAD showed increased DNA damage even without UV irradiation.20 Maintenance of adequate cellular energy is therefore critical in preserving genomic stability of skin cells.33 As well as its energy-replenishing effects, nicotinamide may enhance repair of UV-induced DNA damage by providing a substrate for PARP-1, which is activated by both CPDs and oxidative damage induced by UV-B irradiation, which triggers nuclear binding of PARP-1 and activates its catalytic activity and consumes NAD, forming nicotinamide and ADP-ribose polymers.10 Binding of the negatively charged ADP-ribose polymers

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REVIEW Mantoux-positive volunteers with low-dose solar simulated (ss)UV, corresponding to approximately 0.35, 0.7, and 1 average minimal erythema doses (MEDs) for the group. Fifteen minutes before each of 3 daily ssUV exposures, 5% topical nicotinamide or its vehicle was applied to separate skin sites. Irradiation with the two highest UV doses significantly suppressed Mantoux-induced erythema and induration. At the sites of nicotinamide application, suppression of Mantoux responses no longer occurred. Nicotinamide was also immune protective when applied immediately after UV exposure, thus excluding the possibility of a sunscreening (UV filtering) effect of nicotinamide.37 Concentrations of nicotinamide as low as 0.2% were also protective against single or multiple UV irradiations.36 Using the same model, oral nicotinamide (500 mg or 1500 mg daily for 1 week) also protected against ssUV-induced suppression of Mantoux reactions.38 Despite preventing photoimmune suppression, nicotinamide does not prevent UV-induced erythema; it had no effect on MED when applied before or after irradiation.37

Figure 2. UV radiation induces DNA damage, which triggers poly(adenosine diphosphate-ribose) polymerase 1 (PARP-1) activation and facilitation of DNA repair. Excessive PARP-1 activation results in nicotinamide adenine dinucleotide (NAD) depletion, glycolytic failure, and necrosis. One pathway by which nicotinamide may prevent cellular energy failure and necrotic cell death is by providing NAD for PARP-1 activation and also blocking PARP-1 overactivation.

to nuclear proteins has been suggested to loosen chromatin compact structure, which not only allows DNA regulatory and repair enzymes access to the damage sites, but also facilitates transcription of genes involved in cellular response to injury.10 In a negative feedback manner, nicotinamide also acts as a PARP-1 inhibitor.10 Excessive PARP-1 activation, for example, by high-dose UV irradiation, depletes cellular energy and leads to energy failure and necrotic cell death35 (Figure 2). Inhibition of PARP-1 overactivation by nicotinamide therefore serves as cellular damage control, preventing necrosis and preserving the remaining energy for DNA repair. PROTECTION FROM PHOTOIMMUNE SUPPRESSION Both UV-A and UV-B radiation are potent suppressors of skin immunity, which plays a critical role in preventing skin cancer progression, even at suberythemal doses corresponding to less than 6 minutes of noon summer sunlight.36 DNA damage, particularly CPDs, has been recognized as a key molecular trigger for UV-induced immunosuppression.30 In recent years, there has been growing interest in the use of naturally occurring, nontoxic compounds with immune-protective, anti-inﬂammatory, and antioxidant eﬀects for protection against UV radiation. Nicotinamide was previously found to be immune protective in mice, when used topically or supplied in the diet.31,32 In humans, we have shown that both topical and oral nicotinamide prevent UV suppression of delayed-type hypersensitivity responses to intradermal tuberculin (Mantoux reactions). UV irradiation dose-dependently suppresses Mantoux-induced induration and erythema, and these measures can be used to assess UV immunosuppression.36–38 We irradiated the lower backs of 20 healthy SKINmed. 2011;9:360–365

Nicotinamide protects against the immune suppressive effects of both UV-B and UV-A. We irradiated Mantoux-positive volunteers with narrowband UV-A (385 nm) or UV-B (300 nm), which both significantly reduced Mantoux reactions. Topical 5% nicotinamide appeared to provide equivalent immune protection from both wavebands36; hence, the broad-spectrum immune protection afforded by nicotinamide could complement the use of sunscreens, which tend to provide relatively less protection against longwave UV-A (and hence immune suppression)39 near the visible light interface. FUTURE DIRECTIONS We found photoprotective effects of nicotinamide in vitro and in vivo in healthy volunteers. Premalignant actinic keratoses (AKs) provide a useful surrogate measure of skin cancer to enable assessment of chemopreventive agents within relatively short timeframes. Recently, we conducted a double-blind placebocontrolled study in 26 heavily sun-damaged patients with multiple AKs randomized to apply either 1% topical nicotinamide or its vehicle to face, forearms, and scalp twice daily for 6 months. At 3 months, we found a significant reduction in AKs of 22% with nicotinamide, compared with a nonsignificant 10% reduction with vehicle. At 6 months, however, there was no longer a significant difference in AKs (22% reduction with vehicle vs 25% reduction with nicotinamide). Instead, seasonal regression of AKs was likely observed in both groups as participants moved from summer to winter.40 CONCLUSIONS In this pilot study, nicotinamide appeared to enhance or accelerate the rate of AK regression, possibly by providing photoimmune protection during the summer and autumn months. Studies

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using oral nicotinamide are now indicated. Nicotinamide is an inexpensive compound with a high safety profile. Given its significant photoprotective effects, nicotinamide is a promising agent for skin cancer chemoprevention. Disclosure: New South Wales Cancer Council, Dermatology Research Foundation, and Cancer Institute New South Wales were funding sources. The authors have no conflict of interest to declare. REFERENCES

17 Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne-vulgaris. Int J Dermatol. 1995;34:434–437. 18 Weltert Y, Chartier S, Gibaud C, et al. Double-blind clinical evaluation of the efficacy of nicotinamide gel versus 4% erythromycin gel in the treatment of moderate acne in predominantly inflammatory component. Les Nouvelles Dermatologiques. 2004;23:385–394. 19 Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-KB and MAPK pathways. J Dermatol Sci. 2009;56:106–112.

Jacob RA. Niacin. In: Bowman BA, Rusell RM, eds. Present Knowledge in Nutrition. 8th ed. Washington DC: ILSI Press; 2001:199–206.

20 Surjana D, Halliday GM, Damian DL. Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. J Nucleic Acids. 2010 Jul 25; pii: 157591.

Niren NM. Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis. 2006;11(1 suppl):11–16.

21 Draelos ZD, Matsubara A, Smiles K. The effect of 2% niacinamide on facial sebum production. J Cosmet Laser Ther. 2006;8:96–101.

Visalli N, Cavallo MG, Signore A, et al. A multi-centre randomized trial of two different doses of nicotinamide in patients with recent-onset type 1 diabetes (the IMDIAB VI). Diabetes Metab Res Rev. 1999;15:181–185.

22 Bissett D. Topical niacinamide and barrier enhancement. Cutis. 2002;70:8–12.

Knip M, Douek IF, Moore WP, et al. Safety of high-dose nicotinamide: a review. Diabetologia. 2000;43:1337–1345.

23 Tanno O, Ota Y, Kitamura N, Katsube T, Inoue S. Nicotinamide increases biosynthesis of ceramides as well as other stratrum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol. 2000;143:524–531.

Hankes LV. Nicotinic acid and nicotinamide. In: Machelin LJ, ed. Handbook of Vitamins. New York, NY: Marcel Dekker; 1984:329–377.

24 Soma Y, Kashima M, Imaizumi A, et al. Moisturizing effects of topical nicotinamide on atopic dry skin. Int J Dermatol. 2005;44:197–202.

Final report of the safety assessment of niacinamide and niacin. Int J Toxicol. 2005;24:1–31.

Toth B. Lack of carcinogenicity of nicotinamide and isonicotinamide following lifelong adminstration to mice. Oncology. 1983;40:72–75.

25 Draelos ZD, Ertel K, Berge C. Niacinamide-containing facial moisturizer improves skin barrier and benefits subjects with rosacea. Cutis. 2005;76:135–141.

Drugdex Drug Evaluations. Niacinamide. In: Klasco R, ed. DrugDex(R) System: Thomsom Micromedex. Colorado: Greenwood Village; 2006.

Jacobson EL, Shieh WM, Huang AC. Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Molecular and Cellular Biochemistry. 1999;193:69–74.

26 Song XZ, Xu A, Pan W, et al. Nicotinamide attenuates aquaporin 3 overexpression induced by retinoic acid through inhibition of EGFR/ERK in cultured human skin keratinocytes. Int J Mol Med. 2008;22:229–236. 27 Bissett DL, Oblong JE, Berge CA. Niacinamide: a B vitamin that improves aging facial skin appearance. Dermatol Surg. 2005;31(7 pt 2):860–865; discussion 865.

10 Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002;54:375–429.

28 Kawada A, Konishi N, Oiso N, Kawara S, Date A. Evaluation of anti-wrinkle effects of a novel cosmetic containing niacinamide. J Dermatol. 2008;35:637–642.

11 Ungerstedt JS, Blomback M, Soderstrom T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol. 2003;131:48–52.

29 Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147:20–31.

12 Fivenson DP, Breneman DL, Rosen GB, et al. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol. 1995;130:753–758.

30 Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res. 2005;571:107–120.

13 Honl BA, Elston DM. Autoimmune bullous eruption localized to a breast reconstruction response to niacinamide. Cutis. 1998;62:85–86.

31 Gensler HL. Prevention of photoimmunosuppression and photocarcinogenesis by topical nicotinamide. Nutr Cancer. 1997;29:157–162.

14 Iraji F, Banan L. The efficacy of nicotinamide gel 4% as an adjuvant therapy in the treatment of cutaneous erosions of pemphigus vulgaris. Dermatol Ther. 2010;23:308–311.

32 Gensler HL, Williams T, Huang AC, Jacobson EL. Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice. Nutr Cancer. 1999;34:36–41.

15 Daniel J, Marechal Y, Van Gool F, Andris F, Leo O. Nicotinamide inhibits B lymphocyte activation by disrupting MAPK signal transduction. Biochem Pharmacol. 2007;73:831–842.

33 Jacobson EL, Giacomoni PU, Roberts MJ, Wondrak GT, Jacobson MK. Optimizing the energy status of skin cells during solar radiation. J Photochem Photobiol B. 2001;63:141–147.

16 Niren NM, Torok HM. The nicomide improvement in clinical outcomes study (NICOS): results of an 8-week trial. Cutis. 2006;77(suppl 1):17–28.

34 Park J, Halliday GM, Surjana D, Damian DL. Nicotinamide prevents ultraviolet radiation-induced cellular energy loss. Photochem Photobiol. 2010;86:942–948.

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35 Farkas B, Magyarlaki M, Csete B, et al. Reduction of acute photodamage in skin by topical application of a novel PARP inhibitor. Biochem Pharmacol. 2002;63:921–932.

38 Yiasemides E, Sivapirabu G, Halliday GM, Park J, Damian DL. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101–105.

36 Sivapirabu G, Yiasemides E, Halliday GM, Park J, Damian DL. Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans Br J Dermatol. 2009;161:1357–1364.

39 Poon TS, Barnetson RS, Halliday GM. Prevention of immunosuppression by sunscreens in humans is unrelated to protection from erythema and dependent on protection from ultraviolet A in the face of constant ultraviolet B protection. J Invest Dermatol. 2003;121:184–190.

37 Damian DL, Patterson CRS, Stapelberg M, et al. Ultraviolet radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. J Invest Dermatol. 2008;128:447–454.

40 Moloney F, Vestergaard M, Radojkovic B, Damian D. Randomized, double-blinded, placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratoses. Br J Dermatol. 2010;162:1138–1139.

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.

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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

Printed in USA.

MN-0810-280

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Volume 9 • Issue 6

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

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

iabetes mellitus (DM) related and/or associated dermatoses warrant periodic attention, and should be taken stock of both in insulin-dependent and noninsulindependent diabetes. Accordingly, the salient briefs of necrobiosis lipoidica (NL), and granuloma annulare (GA) formed the contents of Part I,1 while conditions like diabetic dermopathy, diabetic bullae, acquired perforating dermatosis (APD), diabetic thick skin, scleredema adultorum, eruptive xanthoma, carotenodermia (carotenemia/carotenosis), rubeosis faciei, and acanthosis nigricans (AN) are described in Part II.2 Whereas, insulin dependent diabetes mellitus ([IDDM] juvenile)3 type 1-related dermatoses form the subject matter of another exclusive dissertation. The current paper reviews the final part of this 3-part series. Associated infectious bacterial diseases include impetigo, erysipelas, cellulitis, ecthyma, folliculitis, furuncles and carbuncles, necrotizing fasciitis, malignant otitis externa, erythrasma, and nonclostridial gas gangrene. Associated fungal infections include candidosis (including vulvovaginitis, paronychia, thrush, and balanitis), dermatophytoses, zygomytes infections, and rhinocerebral mucormycosis. Associated inflammatory mucodermatoses include lichen planus (including oral lichen planus), other oral lesions, vitiligo, psoriasis, pigmented purpuric dermatosis, bullous pemphigoid, dermatitis herpetiformis, and other pruritic dermatoses. Associated metabolic/genetic associations include cutaneous porphyrias and lipoid proteinosis. Nail changes include onychomycosis, bacterial infections, Beau’s lines, onychauxis, pterygium, pterygium inversum unguuis, yellow nails, vascular changes, Rosenau’s depression, onychomadesis, and leukonychia. Cutaneous and diabetic therapy, including insulin, are also reviewed.

CUTANEOUS INFECTIONS Skin infections occur in 20% to 75% of diabetic patients. They are more frequently seen in noninsulin dependent, type II diabetes mellitus (NIDDM) and are classically associated with poor blood glucose control. The infectious lesions may be either fungal or bacterial; however, the former are more common.4 The lesions may be a precursor of diabetes and should prompt investigation for possible occult, early, or insulin-resistant DM.5 BACTERIAL INFECTIONS The most common bacterial infections of the skin in diabetic patients are often caused by Staphylococcus aureus and beta-hemolytic Streptococcus. They include impetigo, erysipelas, cellulitis, ecthyma, folliculitis, furuncles, and carbuncles.6 Increased rates of nasal colonization by staphylococci have been reported in diabetics, especially in patients with poor metabolic control.7 Secondary infection of a leg ulcer can culminate in gangrene and amputation.8

NECROTIZING FASCIITIS Approximately 10% to 60% of all cases of necrotizing fasciitis occur in patients with DM. It is a bacterial infection of soft tissue that spreads along fascial planes. The causative organisms are facultative gram-negative bacilli such as Escherichia coli and anaerobes such as bacteroids, peptostreptococcus, and clostridium species. The perineum, trunk, abdomen, and upper extremities are commonly involved. The clinical presentation is characterized by erythema, swelling, induration, and necrosis of the affected area. There is a high degree of pain and toxicity associated with necrotizing fasciitis.8 Treatment includes urgent abscess drainage, surgical debridement, and appropriate antibiotics.9

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

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MALIGNANT OTITIS EXTERNA Malignant otitis externa is an uncommon but serious infection of the external ear canal that is caused most commonly by Pseudomonas aeruginosa. It apparently begins after minor trauma in the external auditory canal, mostly in elderly diabetics. Through the natural cleavage of the external auditory canal, pseudomonas gains access to deeper tissues, invades the cartilage, and ultimately reaches the bone. Diabetic patients are more susceptible, either because of the presence of small vessel occlusive disease or the defective chemotaxis of diabetic leukocytes.10

ERYTHRASMA Corynebacterium minustissimum is the causative organism in erythrasma. It starts as an erythematous plaque, which turns into brown, hyperpigmented, fine scaly patches over body folds such as the groin, axillae, and submammary creases. The infection is confirmed by observing coral red fluorescence by Wood’s lamp examination. The organism can ferment glucose, which may be the cause of the higher than normal incidence of this condition reported in diabetics. Topical or systemic erythromycin or tetracycline is usually adequate treatment.11

Candida albicans is the most commonly detected species.14 Treatment for candida infection includes normalization of blood sugar and use of topical and oral antifungal medications.15

DERMATOPHYTOSES Many studies have reported a statistically significantly higher frequency of dermatophyte infection with main risk factors including age, male sex, obesity duration of diabetes, type II DM, and levels of blood glucose. Tinea pedis and onychomycosis were the most common type of infections seen in these studies. The most frequently isolated fungi were Trichophyton mentagrophytes and Trichophyton rubrum.16,17 Onychomycosis can cause hypertrophic and deformed nails that may damage adjacent skin and their pressure can result in decubitus ulceration of neighboring fingers or nail beds. Combination of systemic treatment with itraconazole, terbinafine, and atraumatic chemical ablation with subsequent local treatment is required.18–22

ZYGOMYCETES INFECTION

NONCLOSTRIDIAL GAS GANGRENE The causative organisms of nonclostridial gas gangrene are Escherichia coli, Klebsiella, pseudomonas, enterococcus, anaerobic streptococci, and bacteroides, often in combination. Gas, detectable as crepitus on palpation or as radiolucent bubbles on x-ray examination, is formed within necrotic tissue.12 FUNGAL INFECTIONS

CANDIDOSIS Candidosis infection may be an early indicator of undiagnosed DM. It frequently causes symptoms such as vulvovaginitis, which is a common cause of localized itching in this region. There is vulval erythema with fissuring and satellite pustules. In a study, yeasts were isolated from the vagina of 35.5% of diabetic women, with Candida glabrata as the commonest yeast species isolated. Paronychia begins at the lateral nail fold and is characterized by erythema, swelling, and separation of the fold from the lateral margin of the nail. Thrush affects the buccal mucosa and tongue, and increased salivary glucose reportedly accounts for the Candida overgrowth. The white curd-like material adheres to erythematous and fissured areas. Balanitis is frequently seen in the elderly and uncircumcized men. It presents clinically as an erythematous, slightly indurated, and/or eroded red patch on the glans penis. Phimosis may occur in patients with chronic or recurrent balanoposthitis.7,12

HISTOPATHOLOGY There are small collections of neutrophils in the stratum corneum with associated yeast and pseudomycelial phases of the SKINmed. 2011;9:367–376

organisms. A mixed dermal inflammatory infiltrate may exist that can become granulomatous.13

Hyperglycemia can allow usually nonpathogenic organisms to establish infection and gangrene in traumatized areas. Diabetics with leg ulcers, open wounds, or surgical incisions not responding to therapy may have either primary or complicating phycomycetes infections. Diagnosis is confirmed by culture and by histologic demonstrations of fungal elements invading vascular channels. Treatment consists of debridement of all necrotic tissue, administering intravenous amphotericin B, correction of acid-based imbalance, and control of hyperglycemia.12

RHINOCEREBRAL MUCORMYCOSIS This is caused by zygomycetes. It presents with headache, fever, lethargy, nasal congestion, and facial/ocular pain and swelling. Later, the patient develops unilateral proptosis, ophthalmoplegia, and palate or nasocutaneous necrosis. Approximately 75% to 80% of all such cases occur in patients with DM.23 It is imperative to draw attention to the facts that it is invariably associated with ketoacidosis, that it is severe, and that therapeutic success is related to prompt recognition and correction of ketoacidosis. LICHEN PLANUS The incidence of diabetes in lichen planus (LP) ranges from 28% to 36%.24,25 The reported rates vary from 0.55% to 5.76% of diabetics having clinical and less often histologic evidence of oral lichen planus (OLP).26 LP is characterized by pruritic, flat-topped, violaceous papules over the flexor aspects of the forearm, wrists, lower leg, and lower part of the back. Mucous membranes of the oral

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cavity and genitalia are involved in two thirds of patients.27 In past studies, the prevalence of OLP was 5.76% in type 1 DM patients, 2.83% in type II DM patients, and 1.82% in controls.28–30 When LP is associated with glucose intolerance, however, no particular human leukocyte antigen (HLA) phenotype is found.31

VITILIGO Vitiligo is an acquired idiopathic depigmentation of the skin characterized by ivory/chalky white macules.30 It is associated with both NIDDM and IDDM.13 Vitiligo has a high incidence in patients with DM, ranging from 9% to 16%.32 Researchers33 found that 4.8% of diabetics have vitiligo, while a few reports have demonstrated a high incidence of DM in the families of patients with vitiligo.33,34 Both diabetes and vitiligo are considered to be of autoimmune origin,35 and a common risk factor is familial predisposition. Both are associated with HLA-DR3 and HLA-DR4. The correlation of diabetic neuropathy and a neurologic etiopathogenesis of vitiligo has been demonstrated by dysfunction of sympathetic nerves in dermatomal vitiligo in particular.36

PSORIASIS Psoriasis, a chronic inflammatory skin disorder, is characterized by a variety of immunologic and inflammatory changes and may similarly predispose patients for disorders such as type II diabetes, arterial hypertension, hyperlipidemia, and coronary heart disease.37 There have been various recent studies38,39 confirming the association between DM and psoriasis. A few other studies40,41 have reported an incidence of diabetes as high as 16% to 27.9% in patients with psoriasis.

PRURITUS The relationship between generalized pruritus and DM is debatable. Most of the studies42,43 are inconclusive; however, a couple

of studies44,45 have shown an incidence of 14% to 20%. Diabetic anhidrosis and oligohidrosis may contribute to xerosis.46 Pruritus in diabetics is usually intense and localized, and may result in prurigo nodularis (Figure 1). Pruritus vulvae is significantly more common in diabetics, mostly associated with candida infection,47 followed by other causes such as neurodermatitis or contact allergic/irritant dermatitis.13 Localized pruritus is also common in the perineal area and lower extremities.46

CUTANEOUS PORPHYRIAS Diabetes has been reported among patients with most forms of hepatic porphyria, including acute intermittent porphyria, variegate porphyria, and porphyria cutanea tarda (PCT).12,48,49 The cutaneous manifestations include bullae on light-exposed areas, excess skin fragility, hypertrichosis, melanosis, scarring alopecia, and scleroderma-like plaques.50 Histologically, there is a subepidermal bulla with a sparse underlying inflammatory infiltrate. Immunoglobulins, especially immunoglobulin G, and complement deposits have been demonstrated at the dermoepidermal junction and around superficial blood vessels.49 The diagnosis is confirmed by a marked elevation of urinary uroporphyrin levels, with a less-pronounced increase in coproporphyrins. Serum ferritin as well as hepatocellular iron stores are increased.13,51

SKIN TAGS Skin tags, or acrochordons, are small exophytic growths of skin that have a predilection for the neck, axillae, and eyelids of middle-aged patients. They are 1 mm to 1 cm in diameter and are either skin or brownish colored. The male to female ratio is 1:2.12,52 The correlation between diabetes and skin tags varies from 26.38% to 72.34%. The plausible mechanism for evolution of skin tags in diabetic patients is hyperinsulinemia, which elevates serum concentration of free insulin-like growth factor 1, while reducing insulin-like growth factor–binding protein 3. These endocrine shifts alter cellular proliferation and growth, which may manifest as skin tags.41 NAIL CHANGES

INFECTION

Figure 1. Incessant pruritus resulting in prurigo nodularis with fissuring and scaling. SKINmed. 2011;9:367–376

Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Proteus vulgaris are the prime culprits. Acute paronychia involving proximal and/or lateral nail folds may result in partial or total matrix destruction, followed by a permanent abnormality of the nail plate. Onycholysis and greenish black discoloration of the nail caused by Pseudomonas colonization are the

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other features. Fungal infection initiates chronic paronychia, resulting in invasion of the nail plate leading to onychomycosis.

VASCULAR LESIONS Beau’s lines develop as a result of occasional spasms in digital arteries, which may produce a period of relative ischemia in the nail matrix, resulting in a reduction or cessation of nail growth and transverse depression across the nail plate(s). Onychauxis, hypertrophic thickening, darkening, and surface irregularity may be caused by vascular insufficiency. Pterygium, a result of arterial spasm, leads to fusion of the undersurface of the proximal nail fold to the underlying matrix and nail bed epithelium. Pterygium inversum unguis, epithelium of the hyponychium, and distal nail bed remains attached to the undersurface of the nail plate. Proximal nail fold capillary microscopic changes may show dilated small vessels in the form of isolated homogenous enlargement of the venular limbs. Other vascular features such as tortuosity, hemorrhages, and ischemic areas have been seen in DM. Splinter hemorrhages of arterial emboli may occlude terminal digital arteries and result in hemorrhage distal to their impaction. Yellow discoloration of the nails is a result of vascular impairment. This may occur in all of the nails but most commonly on the distal aspect of the nail of the hallux seen in half of diabetics.7

MISCELLANEOUS NAIL CHANGES Additional nail changes include Rosenau’s depression (small pitted craters on the surface of the nail plate), onychocryptosis (ingrown toenails), pincer nail deformity (overcurvature of the nail plate), onychomadesis (where the nail plate separates from the nail bed at a proximal site and then proceeds distally), and leukonychia (white areas on the nail plate).53

ORAL LESIONS Angular stomatitis, gingival tenderness, xerostomia, burning mouth, acute gingival abscesses, subgingival perforation, and heavy supragingival deposits of tartar are a few manifestations of oral lesions.12

PIGMENTED PURPURIC DERMATOSIS Pigmented purpuric dermatosis results from red blood cell extravasation of the superficial vascular plexus. It is characterized by the presence of patches of orange to tan pigmentation, and “Cayenne pepper” spots on the shins (Figure 2).54 Approximately half of these patients have associated diabetic dermopathy. This condition may be a marker for microangiopathy in patients with diabetes.15

HEMOCHROMATOSIS This is a clinical disorder referred to as bronze diabetes, with a classical triad of diabetes, hepatic cirrhosis, and hyperpigmentation. Other features may be cardiac disease, joint involvement, and hypogonadism. Excessive iron accumulation in the liver, SKINmed. 2011;9:367–376

Figure 2. Pigmented purpuric dermatoses with presence of patches of orange to tan pigmentation and “Cayenne pepper” spots on the shins.

pancreas, and heart damages these organs.12,13 The incidence of frank diabetes in patients with hemochromatosis ranges from 14% to 78%. A proposed mechanism for diabetes in this disease is the development of cirrhosis, which may interfere with a hepatic factor that enhances peripheral glucose utilization.12 Skin manifestations of liver failure are present in the form of palmar erythema, loss of hair, purpura, and spider telangiectasias.13 Histopathologically, Perls’ stain shows hemosiderin deposits around the blood vessels and sweat glands. Heavy metal deposits of various types stimulate melanin transfer from melanocytes to keratinocytes. This causes a general increase in epidermal melanization, suggesting that hyperpigmentation is not caused by iron but by melanin.12

LIPODYSTROPHY LAWRENCE-SEIP SYNDROME Lawrence-Seip syndrome (total lipoatrophy) may either be congenital or acquired. In both, there is complete loss of adipose tissue,

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hepatomegaly, and hyperlipidemia.55 Diabetes usually develops after the first decade of life and is insulin-resistant and nonketotic. Cutaneous abnormalities include acanthosis nigricans, generalized hypertrichosis, and curly scalp hair. In the congenital form, inheritance is usually autosomal recessive; such children are sometimes products of a consanguineous marriage. The acquired form may develop after bacterial infections, such as pertussis, or after viral infections. Women are affected more commonly than men. Partial lipodystrophy is an insidious symmetrical loss of facial fat tissue that may spread to affect the arms and upper part of the trunk. In some cases, there may be coincidental hypertrophy of subcutaneous fat of the lower part of the body.

BULLOUS PEMPHIGOID Bullous pemphigoid is a chronic blistering dermatosis characterized by subepidermal separation within the lamina lucida of the epidermal basement membrane zone (Figure 3). In two studies investigating the association between bullous pemphigoid and DM, the incidence of bullous pemphigoid was found to be 41% and 20%, respectively.56,57 The proposed mechanism for increased association is that diabetics have a lower threshold than healthy individuals for suction-induced blister since autoimmune mechanisms are active in both bullous pemphigoid and type 1 DM. The other theory is that glucosylated skin collagen, which increases during nonenzymatic glucosylation of collagen in diabetics, is capable of inducing the production of autoantibodies with specificity directed against the modified collagen.

KAPOSI’S SARCOMA/MULTIPLE IDIOPATHIC HEMORRHAGIC SARCOMA Kaposi’s sarcoma (KS)/multiple idiopathic hemorrhagic sarcoma is a neoplasm that usually begins on the lower part of the legs as

multiple, purple macules, nodules, and/or plaques, and is seen most often in elderly Jewish and Italian men. Later, other areas of skin, mucous membranes, and internal organs may be involved. The occurrence of DM has been studied in the older, more classic group of patients with this disease, in whom the incidence varies from 27% to 46% in various studies. KS seen in the acquired immunodeficiency syndrome bears no relation to diabetes.7,12

WERNER SYNDROME Premature aging affects tissues. Werner syndrome develops in the first or second decade of life and is characterized by short stature, premature graying of the hair, alopecia, cataract, skin atrophy, hyperkeratosis, and sharpening of the nose. Indolent ulcers occur on the feet and ankles. In these cases, diabetes ranges from 33% to 44.4% and is characterized by mild degree, absence of ketosis, relative insulin insensitivity, and a tendency for the fasting blood sugar level to be within normal limits.47,58

GLUCAGONOMA SYNDROME First described by Becker in 1942, this syndrome is usually caused by tumors of the alpha cell-glucagon–secreting portion of the pancreas. It manifests itself with four major components: (1) hypersecretion of glucagon; (2) diabetes, usually mild (85% of patients have diabetes or at least abnormal glucose tolerance), but there is neither associated ketoacidosis nor does the diabetes in these patients result in the usual degenerative changes; (3) weight loss; and, (4) necrolytic migratory erythema. This chronic fluctuating dermatosis is characterized by an annular and figurative erythema that forms bullae and erosions. It is mainly seen in the intertrigenous and periorificial regions and on the extremities. Painful glossitis, intermittent diarrhea, mood changes, and thrombosis have also been reported.7,13

LIPOID PROTEINOSIS This is a recessively inherited disease characterized by hyalin deposits in the skin and the mucous membranes. Papules, bullae, pustules, hyperkeratotic areas, and scars involve the skin. Characteristic yellow, ivory, waxy papules have a predilection for the dorsal aspect of the neck, hands, fingers, and free margins of the eyelids. Abnormalities in glucose tolerance among patients with lipoid proteinosis have been reported.12

CLEAR CELL SYRINGOMA

Figure 3. Bullous pemphigoid depicting multiple tense vesicles and blisters.

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Clear cell syringoma is clinically similar to syringoma but differs in two features. It has a histologic preponderance of clear cells and frequent coexistence of DM. This may be the result of phosphorylase deficiency secondary to elevated glucose levels in diabetics that in turn results in the formation of the clear cells.7

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DERMATITIS HERPETIFORMIS The HLA associations such as HLA, DR3, and DRW2 of dermatitis herpetiformis and insulin-dependent diabetes may be a possible explanation of the two diseases appearing together more frequently than expected.7

HAIR DISORDERS Diffuse thinning of the scalp hair is not unusual in uncontrolled diabetes, and fine lanugo hair on the back and arms may be seen in undernourished diabetic patients. Achard–Thiers syndrome, characterized by obesity, hirsutism, hypertension, and diabetes31 is another entity. Alopecia areata, totalis, and universalis (Figure 4), a unique manifestation of NIDDM, has recently been reported.59

CUTANEOUS REACTION TO DIABETIC THERAPY First-generation sulfonylureas such as chlorpropamide and tolbutamide are most commonly associated with hypersensitivityrelated cutaneous manifestations. They may develop in 1% to 5% of patients within the first 1 to 2 months of treatment. The most common is a maculopapular eruption, but morbilliform eruption, erythema, or urticarial lesions may also be seen. They often disappear with discontinuation of therapy. Photosensitive reactions, lichenoid lesions, and rosacea-like eruptions are also seen.5 Generalized pruritus may herald a diffuse exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome with marked mucous membrane involvement, or toxic epidermal necrolysis.13,60 Chlorpropamide may cause a disulfiram-like reaction consisting of marked flushing, headache, tachycardia, and shortness of breath beginning 15 minutes after alcohol consumption and

gradually resolving over the following hour.61 This distinct entity occurs in one third of type II diabetes patients taking this drug and it is inherited as an autosomal-dominant trait.12 Cutaneous reactions such as erythema, exanthems, photosensitivity, pruritus, and urticaria have been reported with increasing use of second-generation sulfonylureas such as glyburide, glipizide, and glimepride. Similar reactions have also been reported with metformin.61

INSULIN CUTANEOUS REACTIONS The incidence of insulin reaction varies from 10% to 56%, which may be immediate local, immediate general, delayed, or biphasic and occurs within the first month of insulin therapy.13 Allergic reactions may be caused by reaction to impurities in the insulin preparation consisting of beef or pork proteins, to the insulin molecule itself, or to additional polypeptides, preservatives, or additives. Use of the newer monocomponent porcine insulins and purified human insulins has made these skin side effects very rare, with an incidence of 0.1% to 0.2%.61 Insulin-induced lipoatrophy and lipohypertrophy is jointly referred to as lipodystrophy. It occurs at the site of injection or occasionally at distant sites. It presents as a depressed circumscribed area of skin, possibly reflecting a localized immune reaction to the insulin with associated loss of subcutaneous fat.27 This reaction is more common in women in areas of substantial fat deposition.13 Lipohypertrophy presents as soft dermal nodules, clinically resembling lipomas, at the site of frequent injections. It may be a response to the lipogenic action of insulin. Chronically injected sites become hypoesthetic, and this results in a delayed absorption rate.

DIABETIC FOOT Lower extremity complications are common in diabetic patients and include neuropathy, ulceration, infection, and peripheral arterial disease. The term diabetic foot is used to include all cutaneous manifestations in the foot that occur as a result of the above complications.47 Proper evaluation of the diabetic foot identifies peripheral neuropathy (60% to 70%), peripheral ischemic vascular disease (15% to 20%), and combined clinically significant neuropathy and vascular disease (15% to 20%) as the cause of ulcerations60 (Figure 5A and 5B).

ISCHEMIA

Figure 4. Alopecia areata with well-defined local hair loss and folliculitus following indigenous topical therapy. SKINmed. 2011;9:367–376

Ischemia results from premature peripheral vascular insufficiency secondary to atherosclerosis of large and medium vessels and microangiopathy. Clinically, the skin shows atrophic changes with cool, shiny skin, dystrophic nails, and hair loss. This may progress to ulceration and gangrene commencing at the tips of the toes.47

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A Figure 6. Trophic ulcer on the planter aspect of the big toe.

melum perforans. A small ulcer can belie considerable deep tissue destruction and even osteomyelitis.47 Ulcers are typically circular and punched out (Figure 6) and associated with callus and concomitant loss of temperature and pain sensation and absence of ankle reflexes.12 Neuropathic joint disease can cause painless disorganized Charcot-type joints.47 The foot has accelerated plantar arches and hammer toes.13 Topical treatment must include the debridement of the ulcer with removal of necrotic tissue. Stimulants of granulation tissue-like membranes, benzyl peroxide, or absorbent dressings may be used. Neurotrophic ulcers require redistribution of weight of the metatarsal heads with special orthopedic shoes. Amputation is indicated when vascular flow is inadequate or cannot be restored by modern surgical procedures.

B Figure 5. Diabetic foot with dry scaly skin and nail deformities (A). Ulcer over dorsum of the left foot (B).

REFERENCES

INFECTION There is an increased frequency of soft tissue infections of the lower extremities in diabetics. A mixture of organisms in the infected tissue is usually found and nonclostridial gas gangrene can occur. Maceration between the fourth and fifth toe is common, leading to marked bacterial and fungal colonization.13

Sehgal VN, Srivastava G, Aggarwal AK, Gupta M, Bhattacharya SN, Verma P. Noninsulin-dependent, type II diabetes mellitus-related dermatoses: part I. Skinmed. 2011;9:240–244.

Sehgal VN, Srivastava G, Aggarwal AK, Gupta M, Bhattacharya SN, Verma P. Noninsulin-dependent, type II diabetes mellitus-related dermatoses: part II. Skinmed. 2011;9:302–308.

Sehgal VN, Bhattacharya SN, Verma P. Juvenile, insulindependent diabetes mellitus, type 1-related dermatoses. J Eur Acad Dermatol Venereol. 2011;25:625–636.

Bhat YJ, Gupta V, Kudyar RP. Cutaneous manifestation of diabetes mellitus. Int J Diab Dev Ctries. 2006;26:152–155.

Park K. Park’s Textbook of Preventive Social Medicines. 17th ed. Jabalpur, India: m/s Bharasidas Bhanot Publishers; 2002:294–298.

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Paron NG, Romano G, Moretti G, Di Benedetto. Skin lesion in diabetes mellitus: prevalence and clinical correlation. Diab Res Clin Pract. 1998;39:101–106.

NEUROPATHY The peripheral neuropathy in diabetes is thought to be caused by microangiopathy, affecting the intraneural blood vessels.47 In the early stages of neuropathy, the foot is frequently warm with good peripheral circulation. Numbness and pain may be present in a glove and stocking distribution prior to the loss of sensation.13 The neuropathy may result in blisters and ulcers developing over pressure areas usually as a result of painless trauma. Callosities along with dry, scaly fissured skin are commonly seen as a result of hypohidrosis from autonomic neuropathy. The characteristic lesion in diabetic neuropathy is the perforating plantar ulcer or SKINmed. 2011;9:367–376

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10 Petrozzi JW, Warthan TL. Malignant external otitis. Arch Dermatol. 1974;110:258–260.

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

11 Montes LF, Dobson H, Dodge BG, et al. Erythrasma and diabetes mellitus. Arch Dermatol. 1969;99:674–680.

32 Gopal KV, Rama Rao GR, Kumar YH, et al. Vitiligo: a part of a systemic autoimmune process. Indian J Dermatol Venereol Leprol. 2007;73:162–165.

12 Huntley AC. The cutaneous manifestation of diabetes mellitus. J Am Acad Dermatol. 1982;7:427–455.

33 Dawber RP, Bleehen SS, Vallace-Owen J. Vitiligo and diabetes mellitus. Br J Dermatol. 1971;84:600.

13 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.

34 Gould IM, Gray RS, Urbaniak SJ, et al. Vitiligo in diabetes mellitus. Br J Dermatol. 1985;113:153–155.

14 Dorko E, Barnova Z, Jenca A, et al. Diabetes mellitus and candidiasis. Folia Microbiol (Praha). 2005;50:255–261. 15 Perez MI, Kohn SR. Cutaneous manifestation of diabetes mellitus. J Am Acad Dermatol. 1994;30:519–531. 16 Sehgal VN, Aggarwal AK, Srivastava G, et al. Onychomycosis: a 3-year clinicomycologic hospital-based study. Skinmed. 2007;6:11–17. 17 Sarma S, Capoor MR, Deb M, et al. Epidemiologic and clinicomycologic profile of onychomycosis from north India. Int J Dermatol. 2008;47:584–587. 18 Skorepova M. Mycoses and diabetes. Vnitr Lek. 2006;52:470–473. 19 Macura AB, Gasinska T, Pawlik B, et al. Nail susceptibility to fungal infection in patients with type 1 and type 2 diabetes under long term poor glycaemia control. Przegl Lek. 2007;64:406– 469. 20 Eckhard M, Lengler A, Liersch J, et al. Fungal foot infections in patients with diabetes mellitus—results of two independent investigations. Mycoses. 2007;50 Suppl 2:14–19. 21 Jain S, Sehgal VN. Itraconazole versus terbinafine in the management of onychomycosis: an overview. J Dermatol Treat. 2003;14:30–42. 22 Baran R, Hayn RJ, Garduno JI. Review of antifungal therapy and the severity index for assessing onychomycosis: part I. J Dermatol Treat. 2008;19:72–81. 23 Freinkel RK. Skin manifestation of alteration and disorders of the endocrine system. In: Fitzpatrick TB, Eisen AZ, Wollf K, eds. Dermatology in General Medicine. 5th ed. New York, NY: McGraw Hill; 2006:1651–1661. 24 Lundstrom IM. Incidence of diabetes mellitus in patients with oral lichen planus. Int J Oral Surg. 1983;12:147–152. 25 Halevy S, Feuerman EJ. Abnormal glucose tolerance associated with lichen planus. Acta Dermatovener. 1979;59:167–170. 26 Albrecht M, Banoczy J, Dinya E, et al. Occurrence of oral leukoplakia and lichen planus in diabetes mellitus. J Oral Pathol Med. 1992;21:364–366. 27 Paron NG, Lambert PW. Cutaneous manifestation of diabetes mellitus. Prim Care. 2000;27:371–383. 28 Petrou-Amerikanou C, Makopoulas AK, et al. Prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. Oral Dis. 1998;4:37–40. 29 Bagan JV, Donat JS, Penarrocha M, et al. Oral lichen planus and diabetes mellitus. A clinico-pathological study. Bull Group. Int Rech Sci Stomatol Odontol. 1993;36(1–2):3–6. 30 Mendelsohn S, Verbov J. Diabetes and the skin—a review. Br J Clin Pract. 1983;37:85–94.

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35 Sehgal VN, Srivastava G. Vitiligo: auto-immunity and immune responses. Int J Dermatol. 2006;45:583–590. 36 Olasode OA. Why vitiligo in diabetes? Egypt Dermatol Online J. 2005;1:8. 37 Sommer DM, Jenisch S, Suchan M, et al. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res. 2006:298;321–328. 38 Cohen AD, Dreiher J, Shapiro Y, et al. Psoriasis and diabetes: a population based cross-sectional study. J Eur Acad Dermatol Venereol. 2008 22:585–589. 39 Shapiro J, Cohen AD, David M, et al. The association between psoriasis, diabetes mellitus and atherosclerosis in Israel: a case control study. J Am Acad Dermatol. 2007;56:629–634. 40 Cohen AD, Gilutz H, Henkin Y, et al. Psoriasis and the metabolic syndrome. Acta Derm Venereol. 2007;87:506–509. 41 Alexander E, Pinto J, Pal GS, et al. Disease concomitance in psoriasis: a clinical study of 61 cases. Indian J Dermatol Venereol Leprol. 2001;67;66–68. 42 Kantor GR, Lookingbill DP. Generalized pruritus and systemic disease. J Am Acad Dermatol. 1983;9:375–382. 43 Polat M, Oztas P, Ilhan MN, et al. Generalized pruritus: a prospective study concerning etiology. Am J Clin Dermatol. 2008;9:39–44. 44 Neilly JB, Martin A, Simpson N, et al. Pruritus in diabetes mellitus: investigation of prevalence and correlation with diabetes control. Diabetes Care. 1986;9:273–275. 45 Mishra VN, Mansharmani GG. Diabetes mellitus in geriatric females. J Indian Med Assoc. 1989;87:138–139. 46 Peer AK, Hoosen AA, Seedat MA, et al. Vaginal yeast infections in diabetic women. S Afr Med J. 1993;83:727–729. 47 Gouterman IH, Sibrack LA. Cutaneous manifestation of diabetes. Cutis. 1980;25:45–54. 48 Naidenov E, Ivanov E, Polonov K, Turkolev N, et al. Carbohydrate metabolic disorders in porphyria cutanea tarda. Vutr Boles. 1987;26;62–65. 49 Grossman ME, Bickers DR, Poh–Ffitzpatrick MB, et al. Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients. Am J Med. 1979;67;277–286. 50 Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991;25:735–748. 51 Cabellero F, Gerez E, Polo C, et al. Changes in the heme metabolic pathway in diabetic patients. Medicina (B Aires). 1995;55:117–124. 52 Abbas R, Razieh SA, Nasim S. Skin tags as a cutaneous marker for impaired carbohydrate metabolism: a case control study. Int J Dermatol. 2008,2:18–22.

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53 Greene RA, Scher RK. Nail changes associated with diabetes mellitus. J Am Acad Dermatol. 1987;16:1015–1021.

58 Sehgal VN, Bhattacharya SN, Sharma S, et al. Alopecia areata progressing to totalis/universalis in non-insulin dependent diabetes mellitus (type II): failure of dexamethasone-cyclophosphamide pulse therapy. Indian J Dermatol Venereol Leprol. 2008;74: 171–173.

54 Sardana K, Sarkar R, Sehgal VN. Pigmented purpuric dermatoses: an overview. Int J Dermatol. 2004;43:482–488. 55 Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl. 1996;413:2–28.

59 Schweiz R. Skin manifestation of diabetes mellitus. Med Prax. 2002;91:1011–1018.

56 Bernstein JE, Medenica M, Soltani K, Griem SF. Bullous eruption of diabetes mellitus. Arch Dermatol. 1979;115: 324-–325.

60 Sehgal VN, Srivastava G. Toxic epidermal necrolysis (TEN) Lyell’s syndrome. J Dermatol Treat. 2005;16:278–286.

57 Chuang TV, Korkij W, Soltani Keyoumars, et al. Increased frequency of diabetes mellitus in patients with bullous pemphigoid: a case control study. J Am Acad Dermatol. 1984;11:1099–1102.

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

CORE CURRICULUM REVIEW QUESTIONS Noninsulin Dependent, Type II Diabetes Mellitus Related Dermatoses: Parts I, II, and III Instructions: For each of the following numbered questions, choose the most appropriate lettered response. 1)

What percentage of patients having necrobiosis lipoidica diabeticorum without diabetes may eventually develop diabetes mellitus? a. 20% b. 50% c. 60% d. 90% e. 100% What percentage of patients with necrobiosis lipoidica diabeticorum might undergo spontaneous remission? a. 13%–19% b. 33%–49% c. 43%–59% d. 20%–30% e. 50%–70% What is the mean age of presentation of necrobiosis lipoidica diabeticorum in insulin dependent diabetics? a. 22 years b. 34 years c. 12 years d. 50 years e. 40 years

The term diabetic dermopathy was coined by: a. Melin. b. Nils Tornblom. c. Binkley. d. T. Colcott Fox. e. M. Oppenheim.

Which of the following cutaneous manifestations has been reported to occur following hepatitis B and Bacille CalmetteGuérin vaccination? a. Necrobiosis lipoidica b. Granuloma annulare c. Diabetic dermopathy

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d. e.

Diabetic bullae Scleredema

What are the characteristic sites for presentation of diabetic bullae? a. Head and neck b. Back c. Hands and forearms d. Chest e. Oral mucosa

Which of the following is a histopathological feature of bullous diabeticorum? a. Linear or thready pattern of immunofluorescence b. Intraepidermal cleft c. Caterpillar cells d. Eosinophilic spongiosis e. Neutrophilic infiltration of dermal papillae

Diabetic cheiroarthropathy is characterized by: a. waxy skin and limitation of movements at joints. b. arthritis. c. joint effusion. d. commonly involving the feet. e. synovitis.

Scleredema adultorum is characterized by: a. Marked decrease in dermal thickness. b. involvement of hands and feet. c. correlating with nephropathy and retinopathy. d. swollen collagen bundles separated by wide, clear spaces. e. occurring only in diabetes.

10) The pathological basis of rubeosis faciei is likely to be: a. microangiopathy. b. neuropathy. c. hypersensitivity reaction.

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CORE CURRICULUM c. d. e.

streptococcal infection. photo-allergic reaction.

11) How many patients with type II diabetes develop acanthosis nigricans by the 5th decade? a. 10% b. 20% c. 70% d. 50% e. 80% 12) The most common causative organism for malignant external otitis is: a. Pseudomonas aeruginosa b. Staphylococcus aureus c. Streptococcus pyogens d. Klebsiella granulomatis e. Corynebacterium

fibroblast growth factor. insulin-like growth factor-1. tumor necrosis factor.

15) Which of the following disorders is known to be associated with diabetes? a. Hartnup’s disease b. Wilson’s disease c. Hemochromatosis d. Acrodermatitis enteropathica e. Sickle cell disease 16) Melum perforans is the result of: a. infection. b. neuropathy. c. vasculitis. d. impaired neutrophil chemotaxis. e. increased venous pressure.

13) What is the incidence of diabetes in lichen planus? a. 28%–36% b. 10%–15% c. 44%–53% d. 1%–8% e. 60%–80%

ANSWERS TO THE CORE CURRICULUM REVIEW QUESTIONS:

14) Skin tags are attributed to: a. vascular endothelial growth factor. b. tissue growth factor.

1) d, 2) a, 3) a, 4) c, 5) b, 6) c, 7) b, 8) a, 9) d, 10) a, 11) d, 12) a, 13) a, 14) d, 15) c, 16) b

HISTORICAL DIAGNOSIS & TREATMENT: SCLERODERMA (continued from page 365) SYNONYMS: DERMATOSCLEROSIS; SCLEREMA; SCLEROMA; SCLERIASIS; HIDE BOUND DISEASE

The most characteristic feature of scleroderma is, as the name indicates, a hardening of the skin, and this may be the only feature in common between the two most widely separated varieties. The lesions may develop rapidly, or as is more common, very gradually; they may be single or multiple, diffuse and ill defined or localized and sharply circumscribed, level with the normal skin or slightly elevated or depressed, of an ivory like whiteness or a translucent yellow, or pigmented diffusely or in blotches. The patches sometimes have a characteristic violaceous areola. Their surface is usually smooth but may be slightly scaly or somewhat nodular and is often traversed by a network of dilated capillaries. The evolution of the patches may be quite insidious or preceded or accompanied by moderate burning pain or pruritis. Neighboring plaques may coalesce and sometimes enclose islands of normal skin. In all cases the integument feels thick and is often leathery and so bound down to the deeper structures that it cannot be pinched up in folds. In the diffuse form the progressive thickening and shrinking of the skin may greatly interfere with the function and nutrition of the parts beneath. On a limb the muscles may atrophy and the joints become ankylosed. In the condition termed sclerodactylia the hands and fingers are rendered stiff, immobile and useless. When the integument of the chest is involved respiration

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may be greatly interfered with. On the face the natural folds disappear, movements of the mouth and eyelids are much inhibited and the face assumes an expressionless and cadaveric appearance. When the condition is very extensive it usually causes marasmus and death. In some cases after months or years the infiltration disappears gradually and leaves the skin thin, dry, wrinkled and parchment like. The more common circumscribed variety, also known as morphoea, is usually slower in its development and more prone to recover in time and leave either a scar like atrophy or merely depressions caused by loss of subcutaneous structures, or no traces at all. New patches may develop while others disappear. Sometimes the disease limits itself chiefly to one side of the face and produces a more or less marked facial hemiatrophy. The course of scleroderma is variable, there may be periods of improvement and recrudescence and the disease may become arrested at any stage. The etiology is obscure. The disease occurs three times as frequently in women as in men and is most common in youth and middle age.

TREATMENT: It is difficult to estimate the value of various remedies. General symptomatic and tonic treatment is indicated. Thyroid extract has seemed to benefit some cases. Local massage with oil or a mildly stimulating ointment is usually employed.

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Volume 9 • Issue 6

MYTHS AND MISCONCEPTIONS Ronni Wolf, MD, Section Editor

Alcohol-Based Disinfectants Irritate and Damage Skin More Than Ordinary Soap—True or False? Ronni Wolf, MD;1 Jennifer L. Parish, MD;2 Lawrence Charles Parish MD, MD (Hon)2

e are all familiar with the stinging sensation of disinfecting our hands with alcohol-based hand rubs (ABHRs). It is an open secret that we doctors and other health care personnel do not like using them, because we have a lingering suspicion that if they are really doing their job of killing germs, they are probably doing nasty things to our skin in the process. In an interesting study on this subject,1 nurses’ perceptions of adverse effects of conventional hygienic handwashing vs alcohol-based hand rubs were surveyed by a self-administered multicenter questionnaire study. The majority (69.5%) of nurses considered alcoholic disinfection to be more damaging than handwashing by ordinary soap products. The prevalence of hand dermatitis was 13.4% by self-diagnosis and 22.4% by symptombased questions.

less dryness and less irritation than regular hand soap. This trend in favor of ABHRs was confirmed by a multivariate analysis, which appeared to show that ABHRs even offered protection against their occurrence. The authors found that the greater the frequency of handwashing with soap, the greater the risk of dryness or irritation, while the risk of dryness and irritation was relatively stable at low (3–5 times daily), average (6–10 times daily), or frequent (11–20 times daily) ABHR use. Interestingly, members of the staff who used an ABHR very frequently (>20 times daily) enjoyed a distinct protective effect.

The aim of this paper is to analyze the dermatologic aspects of ABHRs and help put to rest the confusion surrounding any possible deleterious effects they have been alleged to have on skin during handwashing.

This large, well-designed, qualitative, and convincing French study serves to support previous investigations that yielded similar findings. Two of them had been published 5 years earlier. One of them was conducted in Germany,5 and it measured the biological response of regular human skin to ABHRs and detergents in repetitive patch testing and wash testing on 45 volunteers. The ABHR preparations were associated with minimal irritation comparable to the application of water alone. On the other hand, sodium lauryl sulfate (SLS), produced a stronger barrier disruption, erythema, and dryness. There was no additional irritation with the combined use of SLS and disinfectants. In contrast, there was a decrease in barrier disruption and erythema induced by the combined application of SLS followed by ABHR compared with the use of SLS alone. That study thus showed that the combination of washing and disinfection appears to have a protective advantage compared with washing alone.

Skin tolerance to ABHRs or classic handwashing with mild soap and water of the hands of workers in health care facilities was evaluated in a recent prospective multicenter study in France.4 That study was conducted in a large population in 9 health care facilities that comprised 1932 assessments and took into account numerous individual and environmental risk factors. A univariate analysis showed that the use of an ABHR appeared to cause

A large American study published in the same year showed similar results.6 The authors carried out single and repetitive patch testing with 60% to 100% alcohols, a positive control (SLS), and negative controls. Wash tests were also performed with 80% ethanol and 0.5% SLS on forearms with each agent alone and with both agents in a tandem design. The results showed no significant change in skin barrier or erythema induced by

DISCUSSION Preventing nosocomial infections is high on the list of health care priorities worldwide, and complying with the “Clear Care is Safer Care”2,3 campaign is one of the main concerns of the World Health Organization.

From The Dermatology Unit, Kaplan Medical Center, Rechovot, Israel, Affiliated to The School of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem;1 and the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Ronni Wolf, MD, Dermatology Unit, Kaplan Medical Center, 76100 Rechovot, Israel • E-mail: wolf_r@netvision.net.il

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the alcohols in the patch tests, whereas skin hydration decreased significantly. Application of alcohols to previously irritated skin did not show a stronger skin barrier disruption than application of SLS alone. Wash tests demonstrated that the application of alcohol caused significantly less skin irritation than washing with a detergent. Surprisingly, all the evaluated skin physiological parameters were less impaired by the combination of SLS with ethanol compared with SLS alone. This suggested that the application of ethanol after handwashing may reduce irritant skin changes caused by washing, meaning that ethanol use after skin washing had a protective effect. The authors’ rationale and explanation for this apparent paradox of the protective effect of alcohol was that it was caused by a washout of detergent molecules left on and in the stratum corneum and which may lead to prolonged skin irritation. The importance of these studies is that alcohols used in ABHRs did not induce further skin irritation but may have even reduced the irritation caused by detergents. Interestingly, a protective role of ABHRs was demonstrated in a study performed more than 20 years ago.7 It should be noted that the researchers were associated with the Dermal Research Department of the S. C. Johnson & Son, Inc Company. They evaluated the effects of an antimicrobial hand gel that contained 60% ethanol plus emollients on the condition of the skin, when the gel was used as a supplement to handwashing. Volunteers washed their hands with a bar soap 10 times per day for 5 days. Between washings, one hand was treated with 1.0 mL of the gel, while the other hand was untreated. The final results revealed that the gel-treated hands exhibited significantly lower photographic scores for the major signs of dry and irritated skin, ie, cracking, scaling, and erythema. The gel treatment also helped to maintain normal skin hydration levels, as measured by transepidermal water loss and skin impedance. These authors concluded that an alcohol gel with the appropriate emollients can help eliminate a major deterrent to handwashing among health care personnel by reducing soap-induced irritation.

In an additional study, 50 staff members working full time in a critical care unit followed two randomly assigned hand hygiene regimens for 4 consecutive weeks.10 Participants using a waterless hand rub containing 61% ethanol with emollients showed significant improvements in Hand Skin Assessment scores and in Visual Skin Scaling scores compared with participants who used a 2% chlorhexidine gluconate-containing traditional antiseptic wash. Finally, irritation and dryness of 32 nurses’ hands were evaluated by self-assessment and visual assessment in another prospective randomized trial with a crossover design.11 The ABHR regimen was well tolerated and did not result in skin irritation or dryness. In contrast, skin irritation and dryness increased significantly when nurses washed their hands with the hospital-supplied soap product. CONCLUSIONS The aim of the present report has been to dispel the concern that ABHR damages, dries, and irritates the skin more than handwashing with ordinary soap. Health care workers tend to believe that alcohol is harmful for their skin, mainly due to the stinging and burning sensations caused by ABHRs on intact skin and especially on damaged areas of the skin. All of the publications we cite here support the general consensus that not only are ABHRs better tolerated, less irritating, and less damaging to the skin than handwashing, but they can even reduce the irritation caused by handwashing, probably by eliminating residual detergent remnants. Awareness of these findings might serve the Clear Care is Safer Care campaign. REFERENCES

Two smaller studies, performed by another, this time a noncommercially affiliated, group, had come to similar conclusions.8, 9 In one of them, a detergent, a disinfectant, or alternating disinfectants and detergents were applied twice every 10 minutes for 1 hour to the ventral surfaces of the arms and forearms of 17 volunteers.8 The alcohol-based disinfectant caused less visible skin irritation and less skin-barrier disruption than the detergent. The alternate use of a detergent and a disinfectant caused less irritation than detergent alone, and a possible interaction between the two irritants was not indicated. The other study by the same group and performed on 15 volunteers for 2 days yielded the same results: an alcohol-based disinfectant or the alternate use of a disinfectant and a detergent caused less skin irritation than detergent alone.9 SKINmed. 2011;9:378–380

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Stutz N, Becker D, Jappe U, et al. Nurses’ perceptions of the benefits and adverse effects of hand disinfection: alcohol-based hand rubs vs. hygienic handwashing: a multicentre questionnaire study with additional patch testing by the German Contact Dermatitis Research Group. Br J Dermatol. 2009;160:565–572.

Pittet D, Donaldson L. Clean care is safer care: the first global challenge of the WHO World Alliance for Patient Safety. Am J Infect Control. 2005;33:476–479.

Pittet D, Donaldson L. Clean Care is Safer Care: a worldwide priority. Lancet. 2005;366:1246–1247.

Chamorey E, Marcy PY, Dandine M, et al. A prospective multicenter study evaluating skin tolerance to standard hand hygiene techniques. Am J Infect Control. 2011;39:6–13.

Slotosch CM, Kampf G, Loffler H. Effects of disinfectants and detergents on skin irritation. Contact Dermatitis. 2007;57: 235–241.

Loffler H, Kampf G, Schmermund D, et al. How irritant is alcohol? Br J Dermatol. 2007;157:74–81.

Newman JL, Seitz JC. Intermittent use of an antimicrobial hand gel for reducing soap-induced irritation of health care personnel. Am J Infect Control. 1990;18:194–200.

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Pedersen LK, Held E, Johansen JD, et al. Less skin irritation from alcohol-based disinfectant than from detergent used for hand disinfection. Br J Dermatol. 2005;153: 1142–1146.

Pedersen LK, Held E, Johansen JD, et al. Short-term effects of alcohol-based disinfectant and detergent on skin irritation. Contact Dermatitis. 2005;52:82–87.

10 Larson EL, Aiello AE, Bastyr J, et al. Assessment of two hand hygiene regimens for intensive care unit personnel. Crit Care Med. 2001;29:944–951. 11 Boyce JM, Kelliher S, Vallande N. Skin irritation and dryness associated with two hand-hygiene regimens: soap-and-water hand washing versus hand antisepsis with an alcoholic hand gel. Infect Control Hosp Epidemiol. 2000;21:442–448.

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Tertiary Syphilis. Moulage No 488, made by Lotte Volger in the Dermatology Clinic in Zurich, 1919. Museum of Wax Moulages Zurich, www.moulagen.ch. Courtesy of Michael Geiges, MD

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

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CONCLUSIONS 5P UIF CFTU PG PVS LOPXMFEHF EFSNBUPNBM 13 TFHNFOUBM 13 BOE [PTUFSJGPSN 13 BSF BMM VOSFQPSUFE DMJOJDBM WBSJBOUT PG 13 JO 1VC.FE É¨F DBTF JT QSFTFOUFE IFSF GPS JUT JOUFSFTUJOH GFBUVSF BOE FYUSFNF SBSJUZ JO DMJOJDBM QSBDUJDF Acknowledgement: Dr Steven Emmet, Solan Beach, CA conducted the literature search. REFERENCES

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$IVI "" %JBHOPTUJD DSJUFSJB GPS QJUZSJBTJT SPTFB B QSPTQFDUJWF DBTF DPOUSPM TUVEZ GPS BTTFTTNFOU PG WBMJEJUZ J Eur Acad Dermatol Venereol. o

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November/December 2011

Volume 9 • Issue 6

CASE STUDY

Neutrophilic Dermatosis Caused by Azathioprine Mark C. Valentine, MD;1 John S. Walsh, MD2

An 89-year-old woman came to the office because of a pruritic eruption involving her trunk and limbs, present for a number of years and only partially relieved by topical triamcinolone. She had been evaluated by another dermatologist 9 years previously for an eruption of several months’ duration on the arms, back, and legs. At that time, the eruption consisted of irregularly shaped, red to violaceous papules averaging 5 mm in diameter and was accompanied by lacy white buccal mucosal changes suggestive of lichen planus. Skin biopsy was said to be “quite typical for lichen planus” at that time. She was treated with clobetasol with a fairly good response. Another dermatologist evaluated her itching and diagnosed asteatotic eczema 15 months prior to seeing me. Since that time, she had been applying triamcinolone, but her itching was growing progressively more severe. She had stopped her hydrochlorothiazide 1 week previously in case it was causing her itching. Her medical history was significant for diabetes and hypertension. Her systemic medications were metformin, pioglitazone, lovastatin, atenolol, and hydrochlorothiazide. She had a history of allergies to penicillin, demeclocycline, and chlortetracycline. Her physical findings on initial evaluation consisted of a widespread eruption of excoriated 3- to 6-mm reddish papules on the back, arms, abdomen, and legs, sparing the face and hands. No blisters or lichenoid lesions were noted. Because of the intractable nature of the itching, blood was drawn for epidermal antibody testing, and she was instructed to stay off the hydrochlorothiazide for an additional 2 weeks. Blood testing was positive for elevated levels of immunoglobulin G bullous pemphigoid 180 and 230 antibodies, and there was strongly positive indirect immunofluorescence for immunoglobulin G against monkey esophagus and human split skin substrates, typical for bullous pemphigoid. Skin biopsy was not performed. Because of the appearance and distribution of her skin lesions, it was concluded that she had a nonbullous variant of pemphigoid and that she did not fit the usual description of lichen planus pemphigoides. She was placed on topical clobetasol and prednisone at an initial dosage of 20 mg every other morning. Only when the dose was increased to 30 mg every other day did her eruption resolve, in the ninth week of treatment. By then, she was complaining of severe insomnia and had some facial Cushingoid changes, so she was started on azathioprine 50 mg daily as a steroid-sparing agent. Thiopurine methyltransferase genotyping was normal. She missed her 2-week follow-up visit and went to the emergency department 18 days after starting azathioprine complaining of flank and abdominal pain and some weakness. Workup there, including computed tomography of the abdomen revealed only low-grade fever and hypokalemia. She was discharged and showed up in my office the following day with a new eruption of skin lesions on her hands. She had been off azathioprine for 4 days at that time. Skin findings now consisted of succulent dusky red-violet papules and plaques, some studded with small pustules, limited to the dorsal hands, wrists, and fingers (Figure 1). Skin biopsy showed an epidermis with mild spongiosis and focal overlying neutrophilic scale/crust. In the superficial to mid-dermis there was a dense perivascular and interstitial predominantly neutrophilic inflammatory infiltrate (Figure 2). Occasional eosinophils were observed. Vessels were dilated and lined by prominent endothelial cells. There were extravasated erythrocytes, neutrophilic debris, and prominent papillary dermal edema. Diagnostic findings of a necrotizing vasculitis were not present. There was exocytosis of neutrophils into the overlying epidermis. Results from special stains for bacteria and fungi were negative. It was determined that the biopsy represented a neutrophilic dermatosis such as Sweet syndrome or neutrophilic dermatosis of the dorsal hands. One week after the biopsy was obtained, the new dermatitis improved by 60%, with the patient off azathioprine and taking prednisone 30 mg every other day. The prednisone was reduced to 20 mg every other day, and there was only faint residual erythema on her hands after another 3 weeks. By that time, her original eruption consisted of only a few subtle papules on the torso with minimal itch.

weet syndrome was originally described as “acute febrile neutrophilic dermatosis” in 1964.1 A variant that is limited to the dorsal hands was described in 1995,2 originally termed pustular vasculitis of the hands. The condition

was subsequently described in a number of other patients, and most recent reports have favored the terminology neutrophilic dermatosis of the dorsal hands (NDDH).3 Both the generalized and local forms are reliably responsive to treatment with

From the Department of Medicine, Division of Dermatology, University of Washington, Everett, WA;1 and Dermatopathology Northwest, Bellevue, WA2 Address for Correspondence: Mark C. Valentine, MD, Clinical Professor of Medicine (Derm.), University of Washington, 3327 Colby Avenue, Everett, WA 98201 • E-mail: mark1105@aol.com

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CASE STUDY been under treatment for inflammatory bowel disease (IBD). Confusion may arise in patients with IBD for two reasons. First, spontaneous dermatoses, especially pyoderma gangrenosum and erythema nodosum, but also Sweet syndrome, may occur in patients with IBD, so the eruption may be attributed to the IBD and not to azathioprine. Second, some of the associated systemic symptoms of azathioprine hypersensitivity such as fever, weakness, and diarrhea may easily mislead the clinician to suspect a flare of IBD or infection, rather than azathioprine as the cause. In most reported cases, the skin condition resolved promptly after discontinuation of azathioprine, but the azathioprine dose was actually increased in one case and the rash resolved.8 In some cases, the etiology of the rash was confirmed by recrudescence of neutrophilic dermatosis when the patient was rechallenged with azathioprine.10,11

Figure 1. Multiple lesions of neutrophilic dermatosis on dorsal hand.

Azathioprine is a well-recognized cause of hypersensitivity reactions, ranging from a maculopapular rash to systemic illness with fever, pain, weakness, and sometimes evidence of visceral involvement including hepatitis or pancreatitis.12 These symptoms generally arise in the first 2 to 3 weeks of therapy. A case series from France13 described 5 patients, all with IBD, with erythema nodosum-like and pustular eruptions caused by azathioprine. The authors point out that patients with Crohn’s disease seem to be uniquely susceptible to azathioprine hypersensitivity and cite a report14 that presents evidence associating a specific inosine triphosphate pyrophosphatase gene polymorphism with azathioprine hypersensitivity in this population. The present case differs from most previously reported patients with azathioprine-induced neutrophilic dermatosis because there was no associated IBD and the eruption was localized to the hands. NDDH should be added to the list of potential hypersensitivity reactions to azathioprine.

Figure 2. Inflammatory infiltrate of neutrophils without vasculitis (hematoxylin-eosin, original magnification ×400).

systemic corticosteroids. While most cases of NDDH are of unknown cause, some patients have had associated hematologic disorders, ulcerative colitis, or solid tumors.4 Based on the lack of reports, NDDH caused by drug hypersensitivity seems to be a rare event.

REFERENCES

Generalized Sweet syndrome has a longer list of associated medical conditions5 and may be triggered by hypersensitivity to multiple medications, including some antibiotics.6 Several cases of Sweet syndrome have been reported in patients undergoing treatment with azathioprine, in some instances also accompanied by drug fever.7–11 Researchers reviewed 67 cases of azathioprine hypersensitivity, with 49% of cases exhibiting cutaneous manifestations. The majority of these were consistent with a neutrophilic dermatosis.12 With rare exceptions, these patients have

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Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349–356.

Strutton G, Weedon D, Robertson I. Pustular vasculitis of the hands. J Am Acad Dermatol. 1995;32:192–198.

Walling HW, Snipes CJ, Gerami P, Piette WW. The relationship between neutrophilic dermatosis of the dorsal hands and Sweet syndrome. Arch Dermatol. 2006;142:57–63.

Wang YS, Tan A. Neutrophilic dermatosis of the dorsal hands: an emerging entity. J Eur Acad Dermatol Venereol. 2008;23: 451–452.

Buck T, González LM, Lambert WC, Schwartz RA. Sweet’s syndrome with hematologic disorders: a review and reappraisal. Int J Dermatol. 2008;47:775–782.

Neutrophilic Dermatosis Caused by Azathioprine

November/December 2011

CASE STUDY

Kandula S, Burke WS, Goldfarb JN. Clindamycin-induced Sweet syndrome. J Am Acad Dermatol. 2010;62:898–900.

Paoluzi OA, Crispino P, Amantea A, et al. Diffuse febrile dermatosis in a patient with active ulcerative colitis under treatment with steroids and azathioprine: a case of Sweet’s syndrome. Dig Liver Dis. 2004;36:361–366.

Ali M, Duerkson DR. Ulcerative colitis and Sweet’s syndrome: a case report and review of the literature. Can J Gastroenterol. 2008;22:296–298.

Treton X, Joly F, Alves A, Panis Y, Bouhnik Y. Azathioprineinduced Sweet’s syndrome in Crohn’s disease. Inflamm Bowel Dis. 2008;14:1757–1758.

10 Yiasemides E, Thom G. Azathioprine hypersensitivity presenting as a neutrophilic dermatosis in a man with ulcerative colitis. Australas J Dermatol. 2009;50:48–51.

11 el-Azhary RA, Brunner K, Gibson L. Sweet syndrome as a manifestation of azathioprine hypersensitivity. Mayo Clin Proc. 2008;83:1026–1030. 12 Bidinger J, Sky K, Battafarano D, Henning JS. The cutaneous and Systemic manifestations of azathioprine hypersensitivity syndrome. J Am Acad Dermatol. 2011;65:184–191. 13 de Fonclare AL, Khosrotehrani K, Aractingi S, et al. Erythema nodosum-like eruption as a manifestation of azathioprine hypersensitivity in patients with inflammatory bowel disease. Arch Dermatol. 2007;143:744–748. 14 Marinaki AM, Ansari A, Duley J, et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics. 2004;14:181–187.

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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!

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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

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November/December 2011

Volume 9 • Issue 6

CORRESPONDENCE

Wells on Natural Selection: Right for the Wrong Reason—Described a Giant Congenital Nevus To the Editor: William Charles Wells, MD (1757–1817), rates a footnote in the history of evolutionary thought—he published a theory of natural selection decades before Darwin and Wallace. His theory is based on severely ﬂawed data; thus, Wells may be the patron saint for those who correctly expound grand and correct theories based on bad data. Wells was an American who was educated in South Carolina and Edinburgh and a royalist who left the United States in 1784.1 A recognized scientist, he was awarded the Rumford Medal from the Royal Society for his research on dew. In 1813, Wells presented a paper at the Royal Society on what he thought was a “white English woman with regions of negro skin.”2 Excerpts from his very detailed clinical description include the following: • “lesion observed at her birth.” • “fair female of white race of mankind” except for “the blackness of part of her skin.” • “parts covered by the black skin are, the left shoulder, arm, fore-arm and hand…but are not universally black.” • “The black skin, whenever it is contiguous to the white, terminated very abruptly, so that its boundary may be distinctly traced.” • “Palm of her hand and inside of her ﬁngers are black, whereas these parts in a negro are only a tawny hue.” • Cuticular lines in the black arm appeared everywhere stronger to the sight than similar lines of a black man.”

melanocytic hamartoma and an X-linked genodermatosis with mosaicism. Based on this patient, Wells expounded the hypothesis that the human races are selected by their abilities to survive and propagate in different environments. This patient was briefly mentioned by others after its initial publication, but Wells’ hypothesis was not discussed until Darwin addressed it in the fourth edition of The Origin of the Species.3 Wells’ theory on the origin of races within a species was not truly revolutionary for its time, and this is suggested as the reason why Wells did not enter the evolutionary pantheon.3 In addition, evolution was only one idea within Wells’ varied intellectual career. The case, although dramatic, was not referenced in 18th-century compendiums of rare conditions or dermatology texts (Personal observations). Wells carefully described the lesions and even conducted clinical experiments inspecting the epidermis after blistering. He compared his patient with the skin of two other “Negroes” and was impressed by similarities rather than differences between the patients. Detailed skin microscopic histology, not yet invented, would have identified the lesion but may have prevented Wells from developing his concept of natural selection. Physicians are often presented with the wonders of nature and should be encouraged to use those opportunities for profound thinking. Disclosure: “Negro” and “race” are used in the current manuscript as used in Wells’ publication.2 REFERENCES

• “Nails of her black ﬁngers…darker also than those of a negro’s hand.” • “On the black fore-arm are about a dozen hard substances, the largest the size of a common pea. Some very black… one or two reddish black…readily bled when punctured by a needle.” • “A number of very black hairs…three quarters of an inch long.” With this evidence, I suggest his patient had a giant congenital nevus. The diﬀerential diagnosis could include dermal

390

Green JH. William Charles 1957;179:997–999.

Wells,

1757-1817.

Nature.

Wells WC. “An Account of a Female of the White Race of Mankind, Part of Whose Skin Resembles that of A Negro; with Some Observations on the Causes of the Differences in Colour and Form Between the White and Negro Races of Men,” 1818. http://spot.colorado.edu/~friedmaw/Early_Evolution/Wells. html. Accessed May 27, 2011.

Wells KD. William Charles Wells and the races of man. Isis. 1973;64:215–225. —Lowell A. Goldsmith, MD, MPH, Emeritus Professor of Dermatology, University of North Carolina, Chapel Hill, NC • E-mail: lag1959@gmail.com

November/December 2011

CORRESPONDENCE

Propranolol as a Novel Addition to Anti–Kaposi Sarcoma Armamentarium: A Hypothesis To the Editor: The serendipitous efficacy of propranolol for the treatment of hemangioma was described for the first time in 2008.1 Since then, there have been several studies that highlighted its impressive efficacy.2 In this short paper, the aim is to advise our colleagues about the antiangiogenic effect of propranolol in order to encourage research on the use of this agent in the treatment of Kaposi sarcoma (KS), which is a vascular lesion of low-grade malignant potential.

it could open up a novel therapeutic opportunity for treatment of KS. Our short paper justiﬁes and encourages the conduction of clinical trials on this subject. REFERENCES

Angiogenesis, a process of construction of new blood capillaries, is crucial for tumor progression and metastasis.3 Recent studies have identified a number of molecules and signaling pathways that underlie angiogenesis in KS and clarified the pivotal role of the vascular endothelial growth factor (VEGF) family of proteins and their receptors in tumor development.4,5 Additionally, fibroblast growth factor (FGF-2) plays a pathogenetic role in KS, not only by promoting angiogenesis, but also by conferring a transformed phenotype on KS cells.6 Matrix metalloproteinases (MMPs) are associated with KS tumorigenesis and may contribute to the mechanism of KS invasive growth.7 Notably, MMPs 2 and 9 have been associated with different phases of angiogenesis and can contribute to angiogenesis by disrupting the vessel basement membrane and other extracellular matrix barriers and enabling endothelial cell migration through the surrounding tissues.7 Propranolol is a nonselective b-blocker that interferes with endothelial cells, vascular tone, and angiogenesis and induces apoptosis in proliferating endothelial cells, resulting in tumor regression.8 On the other hand, propranolol causes the blockade of proangiogenic signals by down-regulation of angiogenic factors such as VEGF, FGF-2, MMP-2, and MMP-9 and results in the arrest of growth of hemangiomas.8,9 Taken altogether, given the ability of propranolol to interfere with several essential steps of neovascularization and its decrease of several related molecules and signaling pathways such as VEGF, FGF-2, MMP-2, MMP-9 and induction of apoptosis,

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Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651.

Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as firstline treatment for rapidly proliferating infantile haemangiomas. J Plast Reconstr Aesthet Surg. 2011;64:445–451.

Piyaviriyakul S, Shimizu K, Asakawa T, et al. Anti-angiogenic activity and intracellular distribution of epigallocatechin-3-gallate analogs. Biol Pharm Bull. 2011;34:396–400.

Sakakibara S, Tosato G. Regulation of angiogenesis in malignancies associated with Epstein-Barr virus and Kaposi’s sarcoma-associated herpes virus. Future Microbiol. 2009;4:903– 917

Samaniego F, Young D, Grimes C, et al. Vascular endothelial growth factor and Kaposi’s sarcoma cells in human skin grafts. Cell Growth Differ. 2002;13:387–395.

Cavallaro U, Soria MR, Montesano R. Exogenous fibroblast growth factor-2 induces a transformed phenotype in vascular kaposi’s sarcoma-like cells. Mol Cell Biol Res Commun. 2000;4:203–205.

Bongiorno MR, Doukaki S, Ferro G, Aricò M. Matrix metalloproteinases 2 and 9, and extracellular matrix in Kaposi’s sarcoma. Dermatol Ther. 2010;23(suppl 2):S33–S36.

Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163:269–274.

Zimmermann AP, Wiegand S, Werner JA, Eivazi B. Propranolol therapy for infantile haemangiomas: review of the literature. Int J Pediatr Otorhinolaryngol. 2010;74:338–342. —Amir Feily, MD, Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; Nader Pazyar, MD, Department of Dermatology, Jundishapur University of Medical Sciences, Ahvaz, Iran; Mohammad R. Namazi, MD, Shiraz Skin Research Center, Shiraz University of Medical Sciences, Shiraz, Iran • E-mail: namazi_mr@yahoo.com

November/December 2011

CORRESPONDENCE

Rosette Sign in Dermatoscopy: A Polarized Finding To the Editor: The rosette sign represents a dermatoscopic structure seen exclusively with polarized light examination. It is characterized by the presence of 4 white globules symmetrically arranged, creating a square, with a configuration similar to a 4-leaf clover. It is possible to be located in the center of the follicular openings, and it may correspond histologically to a hyperkeratotic area with orthokeratosis or parakeratosis (flag sign).

with polarized light was performed, and the diagnosis was confirmed by histopathology. We report these findings to demonstrate the rosette sign in different conditions other than those already described, in addition to stimulating practitioners to identify one more interesting dermatoscopic finding. Only with a larger number of cases the confirmation of the importance of this new structure will be possible.

In the literature, there is only one report to date that demonstrates the rosettes in actinic keratosis, lichenoid keratosis, and squamous cell carcinoma over actinic keratosis. We present 4 other dermatoses in which the authors had the opportunity to observe the presence of rosettes: flat seborrheic keratosis (Figure 1), pigmented (Figure 2) and nonpigmented basal cell carcinoma (Figure 3), and melanoma (Figure 4). In all of these lesions, contact dermatoscopy

â&#x20AC;&#x201D;Juliana Marques-da-Costa, MD; Gabriella Campos-do-Carmo, MD; Patricia Ormiga, MD; Cleide Eiko Ishida, MD; Tullia Cuzzi, MD, PhD; Marcia Ramos-e-Silva, MD, PhD, Sector of Dermatology and Post-Graduation Course in Dermatology, University Hospital and SchoolÂ of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil â&#x20AC;˘ E-mail: ramos.e.silva@dermato.med.br

Figure 1. Flat seborrheic keratosis.

Figure 3. Nonpigmented basal cell carcinoma.

Figure 2. Pigmented basal cell carcinoma.

Figure 4. Melanoma.

392

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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

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

Rx Only

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

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

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

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

131B301 Rev 11/09

Now younger eczema patients have something to smile about

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

The power of an ointment with the elegance of a cream Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older. Safety and effectiveness in pediatric patients below 3 months of age have not been established. Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if applied to large surface areas or used under occlusion. Systemic effects of topical corticosteroids may also include manifestations of Cushingâ&#x20AC;&#x2122;s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use if irritation develops. Please see full Prescribing Information on adjacent page. Visit us at www.locoid.com (hydrocortisone butyrate 0.1%) Cream ÂŠ2010 Triax Pharmaceuticals, LLC. All rights reserved. Locoid is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC. LOC-0410-01