Jan / Feb 2013 by jo-ann kalaka-Adams

January/February 2013 • Volume 11 • Issue 1

EDITORIAL The Keyes Award and Edward Lawrence Keyes, MD (1843–1924) Petronic-Rosic

COMMENTARY Paronychia Bonifaz, Paredes, Fierro, López-Lozano, Herrán, and Vázquez-González

What is Woringer–Kolopp Disease? Lee and Cohen

ORIGINAL CONTRIBUTIONS Bioequivalence in Keratolytic Activity of Formulations vs Its Vehicle and Comparator Formulation: Randomized, Double-Blind Clinical Trial Zhai, Zheng, Matravers, Hicks, Wiener, and Maibach

PHOTO CAPSULE Borderline Tuberculoid Evolving Across the Leprosy Spectrum Sehgal and Sharma

NEWSLETTER The Bulletin of the International Association of Ecological Dermatology (Eco-Derm) Serri

CASE STUDIES Hair Extensions: Novel “Source” of a Well-Known Contact Allergen Darlenski, Kazandjieva, and Tsankov

Combining Field Therapies for Actinic Keratoses: Novel Approaches That Intensify Photodynamic Therapy Kaminska and Tsoukas

New Side Effect of TNF-α Inhibitors: Morphea Stewart, Gavino, and Elewski

Perceptions and Practices in Submental Fat Treatment: A Survey of Physicians and Patients Schlessinger, Weiss, Jewell, Narurkar, Weinkle, Gold, and Bazerkanian

REVIEW Cutaneous Viral Diseases in HIV Infection Ivyanskiy and Francis Thomsen

CORE CURRICULUM Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Diagnosis and Treatment Modalities—Part I Sehgal, Srivastava, Aggarwal, and Midha

BOOK REVIEW Pellagra: The Plague that Decimated the Poor of the Southern United States Reviewed by Routh

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CREAM 2% NAFTIN® (Naftifine HCI) Once a day for 2 weeks

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TABLE OF CONTENTS January/February 2013 • Volume 11 • Issue 1

EDITORIAL The Keyes Award and Edward Lawrence Keyes, MD (1843–1924) .................................................................. 10 Vesna Petronic-Rosic, MD, MSc

COMMENTARY Paronychia ................................................................................................................................................... 14 Alexandro Bonifaz, MSc; Vanessa Paredes, MD; Leonel Fierro, MD; Héctor López-Lozano, MD; Perla de la Herrán, MD; Denisse Vázquez-González, MD

What is Woringer–Kolopp Disease? ................................................................................................................ 17 Andrew D. Lee, BA; Philip R. Cohen, MD

ORIGINAL CONTRIBUTIONS Bioequivalence in Keratolytic Activity of Formulations vs Its Vehicle and Comparator Formulation: Randomized, Double-Blind Clinical Trial ......................................................................................................... 21 Hongbo Zhai, MD; Yue Zheng, MD; Peter Matravers, PharmD; Deborah A. Hicks; Sheree Wiener; Howard I. Maibach, MD

Perceptions and Practices in Submental Fat Treatment: A Survey of Physicians and Patients .......................... 27 Joel Schlessinger, MD; Steven R. Weiss, MD; Mark Jewell, MD, PC; Vic Narurkar, MD; Susan Weinkle, MD; Michael H. Gold, MD; Erica Bazerkanian, MBA

REVIEW Cutaneous Viral Diseases in HIV Infection....................................................................................................... 33 Ilya Ivyanskiy, MD; Simon Francis Thomsen, MD, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Diagnosis and Treatment Modalities—Part I ......................................................................................................................... 39 Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Rashmi Midha, MBBS

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Pseudo Positive, Pseudo Positive Negative, Pseudo Positive Positive Negative, and Pseudo Pseudo Positive Positive Negative Positive Margins in Dermatopathology ............................................ 46 Brian Lee, BA; Muriel W. Lambert, PhD; Chinmoy Bhate, MD; Joseph Kamelgard, MD; W. Clark Lambert, MD, PhD

PHOTO CAPSULE Ncoza C. Dlova, MBChB, FRCDerm, Section Editor Borderline Tuberculoid Evolving Across the Leprosy Spectrum ....................................................................... 49 Virendra N. Sehgal, MD; Sonal Sharma, MD

NEWSLETTER The Bulletin of the International Association of Ecological Dermatology (Eco-Derm) ........................................ 50 Riccarda Serri, MD

TABLE OF CONTENTS January/February 2013 • Volume 11 • Issue 1

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

Hair Extensions: Novel “Source” of a Well-Known Contact Allergen ................................................................. 51 Razvigor Darlenski, MD, PhD; Jana Kazandjieva, MD, PhD; Nikolai Tsankov, MD, PhD, MSc

Combining Field Therapies for Actinic Keratoses: Novel Approaches That Intensify Photodynamic Therapy ................................................................................................................................. 54 Edidiong Celestine Ntuen Kaminska, MD, MBS; Maria M. Tsoukas, MD, PhD New Side Effect of TNF-α Inhibitors: Morphea ................................................................................................ 59 Faith A. Stewart, MD; Alde Carlo P. Gavino, MD; Boni E. Elewski, MD

BOOK REVIEW Jennifer L. Parish, MD, Section Editor

Pellagra: The Plague that Decimated the Poor of the Southern United States .................................................. 64 Steffen C: Pellagra: The Plague that Decimated The Poor of the Southern United States Oceanside CA, private printing, 2012; 104 pp, charlessteffen@cox.net

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

Editorial MANAGING EDITOR Dhayanidhi Karunanidhi skinmed@diacritech.com

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.

COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Copyright: ©2013 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760.

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This Little Piggy Had ONMEL

™

(itraconazole) 200-mg tablets

Provide the efﬁcacy of itraconazole in a single, once-daily tablet1 Indications and Usage ONMEL is indicated for the treatment of onychomycosis of the toenail due to Trichophyton rubrum or T. mentagrophytes in non-immunocompromised patients. Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to conﬁrm the diagnosis of onychomycosis. Important Safety Information for ONMEL WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS, AND DRUG INTERACTIONS Do not administer ONMEL for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of ONMEL, discontinue administration. Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide, levacetylmethadol (levomethadyl), felodipine, oral midazolam, nisoldipine, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with ONMEL is contraindicated. ONMEL, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Please see Important Safety Information included in accompanying full Prescribing Information for ONMEL, including BOXED WARNING. For more information, please visit www.ONMEL.com

Reference: 1. ONMEL [package insert]. Greensboro, NC: Merz Pharmaceuticals, LLC; 2012. ONMEL and the ONMEL logo are trademarks of Merz Pharmaceuticals, LLC. © 2013 Merz Pharmaceuticals, LLC. All rights reserved. 5011975 January 2013

ONMEL™ (itraconazole) Initial U.S. Approval: 1992 Brief Summary: For complete details, please see full Prescribing Information. WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS, AND DRUG INTERACTIONS Do not administer ONMEL for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic eﬀects were seen. If signs or symptoms of congestive heart failure occur during administration of ONMEL, discontinue administration. Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide, levacetylmethadol (levomethadyl), felodipine, oral midazolam, nisoldipine, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with ONMEL is contraindicated. ONMEL, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. INDICATIONS AND USAGE ONMEL is indicated for the treatment of onychomycosis of the toenail due to Trichophyton rubrum or T. mentagrophytes in non-immunocompromised patients. Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to conﬁrm the diagnosis of onychomycosis. CONTRAINDICATIONS Congestive Heart Failure: Do not administer ONMEL for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Drug Interactions: Concomitant administration of ONMEL and certain drugs that are metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) or where gastrointestinal absorption is regulated by P-gp may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Co-administration of cisapride, dofetilide, ergot alkaloids such as dihydroergotamine, ergotamine, ergometrine (ergonovine), and methylergometrine (methylergonovine), felodipine, levacetylmethadol (levomethadyl), lovastatin, methadone, oral midazolam, nisoldipine, pimozide, quinidine, simvastatin, and triazolam with ONMEL is contraindicated. Do not administer ONMEL for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

Anaphylaxis and hypersensitivity have been reported with use of itraconazole. ONMEL is contraindicated for patients who have shown hypersensitivity to itraconazole products. WARNINGS AND PRECAUTIONS Congestive Heart Failure, Peripheral Edema, and Pulmonary Edema Cases of CHF, peripheral edema, and pulmonary edema have been reported with itraconazole administration among patients being treated for onychomycosis and/or systemic fungal infections. Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with ONMEL is contraindicated. Cardiac Disease ONMEL should not be administered in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole injection, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of ONMEL therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of ONMEL, discontinue administration. Hepatic Effects Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with hepatotoxicity, treatment should be discontinued immediately and liver function testing performed. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is not recommended. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving ONMEL. Calcium Channel Blockers Calcium channel blockers can have negative inotropic effects which may be additive to

those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of ONMEL and nisoldipine is contraindicated. Neuropathy If neuropathy occurs that may be attributable to ONMEL, the treatment should be discontinued. Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rate observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in clinical practice. Patients in the trial for toenail onychomycosis were treated with a dosing regimen of 200 mg once daily for 12 consecutive weeks. The most commonly reported adverse reaction leading to discontinuation of ONMEL was increased hepatic enzyme (6 subjects, 1.0%), followed by dizziness (3 subjects, 0.5%). No other adverse reaction leading to discontinuation occurred in more than one subject. The adverse reactions reported by at least 1% of ONMEL-treated patients (N=582) and placebo (N=191) during 12 weeks of treatment, respectively, were upper respiratory tract infection (6.0%, 7.3%), bacteriuria (1.4%, 1.6%), urinary tract infection (1.0%, 0.5%), hepatic enzymes increased (2.9%, 0.0%), electrocardiogram abnormal (1.4%, 1.6%), hypoacusis (3.3%, 3.1%), headache (2.2%, 1.6%), dizziness (1.2%, 0.0%), abdominal pain or discomfort (1.7%, 2.6%), diarrhea (1.7%, 3.1%), nausea (1.7%, 1.6%), fatigue (1.5%, 2.6%), sinus bradycardia (1.0%, 0.0%), cough (1.2%, 0.0%), pharyngolaryngeal pain (1.0%, 0.5%), and back pain (1.2%, 2.1%). Post Marketing Experience The following adverse reactions have been identiﬁed during post-approval use of itraconazole (all formulations). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establishing a causal relationship to drug exposure. Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Metabolism and nutritional disorders: Hypertriglyceridemia, hypokalemia Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Eye disorders: Visual disturbances, including vision blurred and diplopia

Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus

Drug plasma concentration increased by itraconazole

Cardiac disorders: Congestive heart failure

Antiarrhythmics: digoxin, dofetilide, quinidine, disopyramide

Respiratory, thoracic and mediastinal disorders: Pulmonary edema Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Musculoskeletal and connective tissue disorders: Myalgia, arthralgia Renal and urinary disorders: Urinary incontinence, pollakiuria Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction General disorders and administration site conditions: Peripheral edema DRUG INTERACTIONS Effects of ONMEL on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are strong inhibitors of the cytochrome P450 3A4 isoenzyme system (CYP3A4). Therefore, concomitant administration of ONMEL and certain drugs metabolized by the cytochrome CYP3A4 may result in increased plasma concentrations of those drugs due to decreased elimination, leading to potentially serious and/or life-threatening adverse events. Itraconazole is also an inhibitor of P-glycoprotein (P-gp) transporter and may result in increased plasma concentrations of drugs whose gastrointestinal absorption is regulated by P-gp. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant ONMEL therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

Anticonvulsants: carbamazepine Anti-HIV Agents: indinavir, ritonavir, saquinavir, maraviroc Antineoplastics: busulfan, docetaxel, vinca alkaloids Antipsychotics: pimozide Benzodiazepines: alprazolam, diazepam, midazolam,2 triazolam Calcium Channel Blockers: dihydropyridines (including nisoldipine and felodipine), verapamil Gastrointestinal Motility Agents: cisapride HMG CoA-Reductase Inhibitors: atorvastatin, cerivastatin, lovastatin, simvastatin Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics: oral hypoglycemics (repaglinide) Opiate Analgesics: fentanyl, levacetylmethadol (levomethadyl), methadone Polyene Antifungals: amphotericin B Other: ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, ﬂuticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide Decrease plasma concentration of itraconazole Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-HIV Agents: nevirapine, efavirenz Antimycobacterials: isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers: antacids, H2-receptor antagonists, proton pump inhibitors Increase plasma concentration of itraconazole Macrolide Antibiotics: clarithromycin, erythromycin Anti-HIV Agents: indinavir, ritonavir 1

This list is not all-inclusive.

For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Selected drugs that are contraindicated for use with itraconazole1 Antipsychotics: pimozide Antiarrhythmics: dofetilide, quinidine Benzodiazepines: oral midazolam2, triazolam

Effects of Other Drugs on ONMEL Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. ONMEL may not be effective in patients concomitantly taking ONMEL and one of these drugs. Therefore, administration of these drugs with ONMEL is not recommended. Inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take ONMEL concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ONMEL. The following are selected drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMEL.1

Calcium Channel Blockers: Nisoldipine, felodipine Ergot Alkaloids: dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine) Gastrointestinal Motility Agents: cisapride HMG CoA-Reductase Inhibitors: lovastatin, simvastatin Opiate Analgesics: levacetylmethadol (levomethadyl), methadone 1

This list is not all-inclusive.

For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Antiarrhythmics The Class IA antiarrhythmic, quinidine and

class III antiarrhythmic, dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide, which could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL and quinidine or dofetilide is contraindicated. The Class IA antiarrhythmic, disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when ONMEL and disopyramide are administered concomitantly. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. Anticonvulsants Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of ONMEL and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of ONMEL and carbamazepine may inhibit the metabolism of carbamazepine. Anti-HIV Agents Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) such as nevirapine and efavirenz are inducers of CYP3A4. Human pharmacokinetic studies have shown that efavirenz, when concomitantly administered with itraconazole, greatly decreased serum concentrations of itraconazole and hydroxyl-itraconazole. Concomitant use of ONMEL and efavirenz is not recommended. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of ONMEL and nevirapine is not recommended. Concomitant administration of ONMEL and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of ONMEL and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when ONMEL and protease inhibitors must be given concomitantly. Concomitant administration of ONMEL and maraviroc has been reported to increase plasma concentration of maraviroc. The dose of maraviroc should be decreased to 150 mg twice daily when given in combination with itraconazole. Antimycobacterials Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents

were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. ONMEL may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of ONMEL could be substantially reduced if given concomitantly with one of these agents and co-administration is not recommended. Antineoplastics ONMEL may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of pimozide with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL and pimozide is contraindicated. Increases in plasma aripiprazole concentrations have been demonstrated in subjects concomitantly receiving ketoconazole, requiring a reduction of the aripiprazole dose. Because of the similarities between ketoconazole and itraconazole, a similar dose reduction for aripiprazole is recommended when patients concomitantly receive itraconazole and aripiprazole. Benzodiazepines Concomitant administration of itraconazole and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of ONMEL and oral midazolam or triazolam is contraindicated. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine, nisoldipine, and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of ONMEL and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of ONMEL and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by co-administration of itraconazole, resulting in approximately 6-fold increase in the AUC and 8-fold increase in the Cmax. The concomitant use of ONMEL and felodipine is contraindicated. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Gastric Acid Suppressors/Neutralizers Reduced plasma concentrations of itraconazole were reported when administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of

itraconazole is impaired when gastric acid production is decreased. ONMEL should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. It is advised that antacids be administered at least 1 hour before or 2 hours after administration of ONMEL. In a clinical study, when itraconazole capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was signiﬁcantly reduced. Gastrointestinal Motility Agents Co-administration of itraconazole with cisapride can elevate plasma cisapride concentrations, which could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL with cisapride is contraindicated. 3-Hydroxy-3-Methyl-Glutaryl CoAReductase Inhibitors Human pharmacokinetic data suggest that itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of ONMEL with 3-Hydroxy-3-Methyl-Glutaryl (HMG) CoA-Reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. Immunosuppressants Concomitant administration of ONMEL and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Similarly, concomitant administration of ONMEL and sirolimus could increase plasma concentrations of sirolimus. Monitoring of blood concentrations of cyclosporine, tacrolimus, or sirolimus are recommended when ONMEL are co-administered with these immunosuppressants and appropriate dosage adjustments should be made. Macrolide Antibiotics Erythromycin and clarithromycin are known inhibitors of CYP3A4 and may increase plasma concentrations of itraconazole. Oral Hypoglycemic Agents Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. A human pharmacokinetic study showed that co-administration with itraconazole and a single dose of repaglinide (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Blood glucose concentrations should be carefully monitored when ONMEL and oral hypoglycemic agents are co-administered.

administration of ONMEL and methadone or levacetylmethadol are contraindicated. Fentanyl plasma concentrations could be increased or prolonged by concomitant use of itraconazole and may cause potentially fatal respiratory depression. In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with itraconazole may increase plasma concentrations of alfentanil. Other t Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with ONMEL is contraindicated. t Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when ONMEL and halofantrine are administered concomitantly. t Human pharmacokinetic data suggest that concomitant administration of itraconazole and buspirone results in significant increases in plasma concentrations of buspirone. t Itraconazole may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone. t Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. t Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with ONMEL. t Co-administration of itraconazole with meloxicam decreased peak plasma concentrations and the exposure of meloxicam by 64% and 37%, respectively. Monitor patients for responses to meloxicam when itraconazole is concomitantly administered and dose adjustment should be considered if warranted. t Co-administration of itraconazole with fexofenadine increased the peak plasma concentration and the total exposure of fexofenadine by approximately 3-fold and augmented its anti-histamine effects.

Polyenes Antifungal Agents Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

t Co-administration of itraconazole with loperamide increased peak plasma concentrations of loperamide by 3-fold and the total exposure by 3.9-fold. In addition, itraconazole is an inhibitor of P-glycoprotein and may inhibit the transport of loperamide out of the brain, leading to elevated concentrations of loperamide in the brain. Patients should be monitored for signs and symptoms of loperamide overdose, such as CNS depression, including drowsiness, dizziness and respiratory depression, and a dose or dosing frequency should be adjusted as necessary.

Opiate Analgesics Levacetylmethadol (levomethadyl) and methadone are known to prolong the QT interval and are metabolized by CYP3A4. Co-administration of methadone or levacetylmethadol with itraconazole could result in serious cardiovascular events. Therefore, concomitant

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic eﬀects. Pregnancy Category C There are no adequate and well-controlled clinical trials in the pregnant women with itraconazole. However, cases of congeni-

tal abnormalities have been reported with itraconazole drug products in post-marketing reports. Therefore, ONMEL should not be administered to pregnant women, women planning pregnancy, or women of child bearing potential unless these onychomycosis patients are using effective contraception measures to prevent pregnancy. Effective contraceptive measures should continue throughout the treatment period and for two months thereafter. ONMEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Itraconazole produced a significant dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dose levels of 40-160 mg/kg/day (2-10 times the maximum recommended human dose [MRHD], based on mg/m2/day comparisons), and in mice at 80 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons). Teratogenic changes in rats included major skeletal defects; encephalocele and/or macroglossia developed in mice. Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of ONMEL therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. Pediatric Use The safety and effectiveness of ONMEL in pediatric patients have not been established. No pharmacokinetic data on ONMEL are available in children. Geriatric Use ONMEL was evaluated in 42 of 593 subjects (7.1%) greater than 65 years of age. Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. Itraconazole should be used with care in elderly patients. Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when ONMEL is administered to patients with renal impairment. Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when ONMEL is administered to patients with hepatic impairment. OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Manufactured by: Sanico N.V. 2300 Turnhout, Belgium Manufactured for Merz Pharmaceuticals, LLC 4215 Tudor Lane Greensboro, NC 27410 SAP item #5011957 Rev date 01/2013

January/February 2013

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 Philadelphia, PA

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

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

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

George M. Martin, MD Kihei, HI

Riccarda Serri, MD Milan, Italy

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

Marc S. Micozzi, MD, PhD Rockport, MA

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

George F. Murphy, MD Boston, MA

Alexander J. Stratigos, MD Athens, Greece

Jack M. Bernstein, MD Dayton, OH

Michael H. Gold, MD Nashville, TN

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

James S. Studdiford III, MD Philadelphia, PA

Sarah Brenner, MD Tel Aviv, Israel Joaquin Calap Calatayud, MD Cadiz, Spain Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Noah Craft, MD, PhD, DTMH Torrance, CA Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI

Orin M. Goldblum, MD Pittsburgh, PA

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

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

Joseph L. Pace, MD, FRCP Naxxar, Malta

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

Art Papier, MD Rochester, NY

Seung-Kyung Hann, MD, PhD Seoul, Korea

Johannes Ring, MD, DPhil Munich, Germany

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

Roy S. Rogers III, MD Rochester, MN

Tanya R. Humphreys, MD Philadelphia, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Livermore, CA

Vincenzo Ruocco, MD Naples, Italy

Jasna Lipozencic, MD, PhD Zagreb, Croatia

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

Robert J. Thomsen, MD Los Alamos, NM Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel

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January/February 2013

Volume 11 • Issue 1

EDITORIAL

The Keyes Award and Edward Lawrence Keyes, MD (1843–1924) Vesna Petronic-Rosic, MD, MSc

he International Academy of Cosmetic Dermatology (IACD) inaugurated the Edward L. Keyes Award for the best Resident Papers at the 8th World Congress in Cancun Mexico, January 31 through February 4, 2012. The award was established in memory of Keyes, who might be considered the first cosmetic dermatologist for developing the cutaneous punch, better known as the Keyes Punch. BACKGROUND Edward Lawrence Keyes (ELK) was born on August 28, 1843, to Erasmus Darwin Keyes and Caroline M. Clarke at the Fort Moultrie Army Base in Charleston, South Carolina. Erasmus Keyes had wide-ranging abilities and character traits. He would later become a decorated Union Army General in the War Between the States, president of a gold mining company, vice president of a savings bank, and vice president of the Vinicultural Society of Napa County, where he built one of the first large wine cellars in California. With his father in the military, ELK spent much of his early life on or near military bases, moving frequently. When Edward was 10 years old, his mother died of puerperal fever after giving birth to his sister Adele. His subsequent childhood years were spent with relatives and in several different preparatory schools. At the age of 16 (September 1859), he matriculated at Yale University. He belonged to the “jolly crowd,” rowed on the freshman crew, and was a member of Kappa Sigma Epsilon, Delta Sigma Phi, and the Scrolling Key Society. He ranked in the first 3rd of his class of 125. In 1863, he “took the war fever,” enlisted, and was appointed as aide de-camp to his father. Before Keyes could take up his post in Virginia, the General was transferred to Wilmington, Delaware. As he awaited further instructions, the war ended, and he was honorably discharged. At the time, Sarah Maria Loughborough, the younger sister of his father’s new wife, paid a visit. Edward began to court her, and in 1870, they married. Their union produced four children.

MEDICAL CAREER Keyes described medicine as his “old and only inclination in life.” He had decided on a career as a physician, when he was 11 years old. Perhaps this inclination was rooted in a strong family tradition of physicians. His paternal grandfather and greatgrandfathers on both sides had been doctors. In August 1863, directly after his discharge from the military, Keyes began medical school at the Medical College of the University of the City of New York. He received his medical degree in 1866 and set out for the Grand Tour of the European clinics, studying syphilis and genitourinary diseases under Velpeau, Nèlaton, and Charcot. Keyes became a prominent urologist and dermatologist. Although he always thought of himself as a general practitioner—at the time, being a generalist was more highly regarded than a specialist—he is considered one of the first teachers of dermatology in the United States and a pioneer in male genitourinary surgery. His book Venereal Diseases was the vade mecum of students and physicians for many years (Figure 1). Keyes was a founder and first president of the American Association of Genitourinary Surgeons. In 1877, he introduced the technique of administering continuous small doses of mercury in treating syphilis, a method that became the standard for more than 20 years. His textbooks and journal contributions gained wide acceptance. DERMATOLOGIC CAREER After returning from Europe in 1867, Keyes entered his first office at 160 East 22nd Street in New York City and began practice as Van Buren’s preceptee. For the first years Keyes barely scraped by because two senior associates, J. W. S. Gooley and George Eliot, picked up most of the work. Keyes mainly saw general medicine charity cases and used his free time for study. He later became a business partner of Dr VanBuren, whom he loved dearly and regarded as his professor and master. Following Van Buren’s death in 1883, Keyes remained in full-time private practice.

From the University of Chicago Prtizker School of Medicine, 5841 South Maryland Avenue, MC 5067, Chicago, IL 60637 Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, Associate Professor and Clinic Director, The University of Chicago, Section of Dermatology, 5841 South Maryland Avenue, MC 5067, Chicago, IL 60637 • E-mail: vprosic@yahoo.com

SKINmed. 2013;11:10–11 (see also pages 51 and 54)

January/February 2013

EDITORIAL society in the world) in 1887. The Keyes’ punch remained in wide use in its original form in the United States until the late 1980s, when disposable punches began to appear. He was a lecturer at the Woman’s Medical College of Stuyvesant in 1868 and became professor of dermatology and genitourinary surgery at Bellevue Hospital Medical College in 1870, where he taught a course on dermatology. Keyes was a founder of the American Dermatological Association in 1876 and was a leader in both dermatology and genito-urinary disease for many years. KEYES, THE MAN Keyes loved to travel, making 30 trans-Atlantic crossings and even received a benediction from Pope Pius X on one trip. An essay, titled The Fear of Death, published in Harpers Monthly in 1909, gained Keyes visibility in the lay press. Keyes used his personal and professional experience to analyze human fear of the end of life, concluding that it is not actually death but pain and suffering to be feared. He reassured the readers that in the final moments, we probably do not feel pain, so there is really nothing to fear. He died quietly on January 24, 1924, aged 80, in his Park Avenue apartment of pneumonia. LEGACY His contribution to medicine and society received due notice, but the IACD has seen fit to renew tribute to this great physician. The winners of the contest, Edidiong C.N. Kaminska, MD, and Razvigor Darlenski, MD, PHD, present their case studies elsewhere in this issue.

Figure 1. Edward L Keyes (1843–1924). Photo courtesy of the New York Academy of Medicine.

REFERENCES

Figure 2. The cutaneous punch pictured in 1887.5

Keyes is best known for the cutaneous punch (Figure 2), which bears his name and is essentially unchanged since he first perfected its use in 1879.5 He developed it to treat a young man with a disfiguring pigmented scar from a fireworks explosion but later applied his method to many other lesions and created a series of punches of different diameters. He presented his work at the New York Dermatological Society (the first dermatology

SKINmed. 2013;11:10–11

Keyes EL. Master surgeons of America: Edward L Keyes. Surg Gyn Obst. 1928;46:728–732.

Parish LC. Biographica dermatologica. Edward L Keyes. Cutis. 1967;3: 394–401.

Keyes EL. Edward Lawrence Keyes. A memoir by his grandson (part I). Urology. 1977;4:484–491.

Smith EB, Vaughan ED, Belt ES, Bloom DA. Edward Lawrence Keyes: a pivotal early specialist in modern genitourinary surgery. Urology. 2003;62:968–972.

Keyes EL. The cutaneous punch. J Cutan Genitourin Dis. 1887;5:98–101.

The Keyes Award and Edward Lawrence Keyes

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COMMENTARY

Paronychia Alexandro Bonifaz, MSc; Vanessa Paredes, MD; Leonel Fierro, MD; Hรฉctor Lรณpez-Lozano, MD; Perla de la Herrรกn, MD; Denisse Vรกzquez-Gonzรกlez, MD

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From the Dermatology Service and Mycology Department, General Hospital of Mexico, Valle, Mรฉxico DF, Mรฉxico Address for Correspondence: Alexandro Bonifaz, MSc, Sรกnchez Azcona 317 int 202, Col. del Valle, CP. 03020, Mรฉxico DF, Mรฉxico t & NBJM B@CPOJGB[!ZBIPP DPN NY

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3PDLXFMM 1( "DVUF BOE DISPOJD QBSPOZDIJB Am Fam Physician. 2001;63: 1113โ 1116.

10 (JBOOJ $ $FSSJ " $SPTUJ $ 6OVTVBM DMJOJDBM GFBUVSFT PG รฅOHFSOBJM JOGFDUJPO CZ 'VTBSJVN PYZTQPSVN Mycoses. o

3JHPQPVMPT % -BSJPT ( (SFHPSJPV 4 "MFWJ[PT " "DVUF BOE DISPOJD paronychia. Am Fam Physician. o

11 #POJGB[ " $SV[ "1 1PODF 3. 0OZDIPNJDPTJT CZ NPMET SFQPSU PG cases. Eur J Dermatol. 2006;17:70โ 72.

%BOJFM $3 %BOJFM .1 %BOJFM $. FU BM $ISPOJD QBSPOZDIJB BOE onycholysis: a thirteen-year experience. Cutis. o

Tosti A, Piraccini BM, Dโ Antuono A, et al. Paronychia associated with antiretroviral therapy. Br J Dermatol o

12 De la Herrรกn P, Lรณpez-Lozano H, Fierro-Arias L, et al. Paroniquia micรณtica por Fusarium solanii: reporte de caso y revisiรณn de la literatura. Dermatologรญa MCQ. o

#PVDIFS ,8 %BWJETPO , .JSBLIVS # FU BM 1BSPOZDIJB JOEVDFE CZ DFUVYJNBC BO BOUJ FQJEFSNBM HSPXUI GBDUPS SFDFQUPS BOUJCPEZ J Am Acad Dermatol o

%PSLP & +BVUPWร + 1JMJQDJOFD & 5Lร DJLPWร - 0DDVSSFODF PG $BOEJEB strains in cases of paronychia. Folia Microbiol (Praha). o

"CBE (PO[ร MF[ + #POJGB[ " 1PODF 3. 0OJDPNJDPTJT QPS $BOEJEB BTPDJBEB DPO EJBCFUFT NFMMJUVT. Dermatologia Rev Mex. o

-JTUFNBOO ) 5SJDIPTQPSPO CFJHFMJJ BT B QBUIPHFO JO QBSPOZDIJB Mykosen. 1985;28:601โ 606.

% "OUPOJP % 3PNBOP ' *BDPOF " FU BM 0OZDIPNZDPTJT DBVTFE CZ Blastoschizomyces capitatus. J Clin Microbiol. 1999;37:2927โ 2930.

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13 8PMMJOB 6 "DVUF QBSPOZDIJB DPNQBSBUJWF USFBUNFOU XJUI UPQJDBM BOUJCJPUJD BMPOF PS JO DPNCJOBUJPO XJUI DPSUJDPTUFSPJE J Eur Acad Dermatol Venereol. o 14 5PTUJ " 1JSBDDJOJ #. (IFUUJ & $PMPNCP .% 5PQJDBM TUFSPJET WFSTVT systemic antifungals in the treatment of chronic paronychia: an open, SBOEPNJ[FE EPVCMF CMJOE BOE EPVCMF EVNNZ TUVEZ J Am Acad Dermatol. o 15 #BSBO 3 $PNNPO TFOTF BEWJDF GPS UIF USFBUNFOU PG TFMFDUFE OBJM disorders. J Eur Acad Dermatol Venereol. 2001;15:97โ 102. 16 %BOJFM $3 %BOJFM .1 %BOJFM + FU BM .BOBHJOH TJNQMF DISPOJD QBSPOZDIJB and onycholysis with ciclopirox 0.77% and an irritant-avoidance regimen. Cutis o

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COMMENTARY

What is Woringer–Kolopp Disease? Andrew D. Lee, BA;1 Philip R. Cohen, MD2–4

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From the University of Texas Medical Branch Medical School, Galveston;1 the University of Houston Health Center, University of Houston, Houston;2 the Department of Dermatology, University of Texas Medical School at Houston, Houston;3 and the Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston,4 TX "EESFTT GPS $PSSFTQPOEFODF 1IJMJQ 3 $PIFO .% 5XJOMFBG $PVSU 4BO %JFHP $" t & NBJM NJUFIFBE!HNBJM DPN

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Figure 1. Distant (A) and closer (B) views of the medial side of the dorsal right foot of a 24-year-old Finish woman who presented with a 10Ă&#x2014;10â&#x20AC;&#x201C;mm, solitary erythematous plaque with central scaling and a raised border. Biopsy results showed a hyperkeratotic and parakeratotic epidermis with acanthosis. An extensive infiltration of atypical lymphocytes in the epidermis was noted as well asÂ an infiltration of abnormal lymphocytes in the papillary dermis. Groups of tumor cells in the epidermis also demonstrated Pautrier microabscess-like configuration. Immunohistochemical studies revealed CD4â&#x20AC;&#x201C;/CD8+ neoplastic T cells. Correlation of the clinical presentation, light microscopy findings, and immunoperoxidase studies established a diagnosis of pagetoid reticulosis, consistent with Woringerâ&#x20AC;&#x201C;Kolopp variant.15

Figure 2. The patient returned to Finland for systemic lymphoma evaluation (which was negative) and for treatment. A decision was made to proceed with surgical excision of the remaining lesion in order to reestablish the diagnosis and to completely remove the residual tumor: distant (A) and closer (B) views. There has been no recurrence during 2 years of follow-up. The patient is regularly evaluated at a cutaneous lymphoma clinic at MD Anderson Cancer Center.

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Table I. Clinical Differential Diagnosis of Woringer– Kolopp Disease

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PATHOGENESIS

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TREATMENTS

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SKINmed. 2013;11:17–20

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January/February 2013

$0..&/5"3:

CONCLUSIONS 8PSJOHFSo,PMPQQ EJTFBTF TIPVME CF UIPVHIU PG BT B EJTUJOD UJWF DMJOJDPQBUIPMPHJD OFPQMBTUJD FOUJUZ *U SFQSFTFOUT B VOJRVF WBSJBOU PG NZDPTJT GVOHPJEFT CFDBVTF PG JUT SFMBUJWFMZ SFMJBCMF DMJOJDBM BOE DPOTJTUFOU IJTUPMPHJDBM mOEJOHT CVU IFUFSPHFOPVT JNNVOPQIFOPUZQJD QSPmMF 8PSJOHFSo,PMPQQ EJTFBTF QSFTFOUT BT B TPMJUBSZ MFTJPO MPDBUFE PO UIF EJTUBM FYUSFNJUJFT BQQFBSJOH BT BO FSZUIFNBUPVT QMBRVF XJUI JOEPMFOU HSPXUI )JTUPMPHJ DBMMZ UIF OFPQMBTUJD DFMMT TIPX NBSLFE FQJEFSNPUSPQJTN XJUI BUZQJDBM MZNQIPDZUFT DPOmOFE UP UIF FQJEFSNJT BOE IBWF WBSJ BCMF JNNVOPQIFOPUZQJD mOEJOHT JODMVEJOH $% $% BOE $% o $% o É¨F QBUIPHFOFTJT JT VODMFBS CVU B OFPQMBTUJD 5 DFMM MJOFBHF IBT CFFO DPOmSNFE -PDBMJ[FE SBEJBUJPO UIFSBQZ JT BO FÄ&#x160;FDUJWF UIFSBQFVUJD NPEBMJUZ BOE QPTTJCMZ UIF USFBUNFOU PG DIPJDF GPS 8PSJOHFSo,PMPQQ EJTFBTF REFERENCES

12 Lu D, Patel KA, Duvic M, Jones D. Clinical and pathological spectrum of CD8positive cutaneous T-cell lymphomas. J Cutan Pathol. 2002;29:465â&#x20AC;&#x201C;472. 13 Palmer RA, Keefe M, Slater D, Whittaker SJ. Case 4: pagetoid reticulosis (Woringer-Kolopp type) or unilesional mycosis fungoides (MF). Clin Exp Dermatol. 2002;27:345â&#x20AC;&#x201C;346. 14 Mourtzinos N, Puri P, Wang G, Liu M. CD4/CD8 double negative pagetoid reticulosis: a case report and literature review. J Cutan Pathol. 2010;37:491â&#x20AC;&#x201C;496. 15 Martin SJ, Cohen PR, Cho-Vega JH, Tschen JA. CD8+ Pagetoid reticulosis presenting as a solitary foot plaque in a young woman. J Clin Aesthet Dermatol. 2010;3:46â&#x20AC;&#x201C;49. 16 Zackheim HS. Is â&#x20AC;&#x153;localized epidermotropic reticulosisâ&#x20AC;? (Woringer-Kolopp disease) benign? J Am Acad Dermatol. 1984;11:276â&#x20AC;&#x201C;283. 17 (PSQFMJPHMV $ 4BSJGBLJPHMV & )BMUBT ) 4QJEFS CJUF JOEVDFE QBHFUPJE reticulosis. J Eur Acad Dermatol Venereol. 2009;23:446â&#x20AC;&#x201C;447. 18 +BDZL 8, (SBZTPO 8 %JOLFM +& 3FRVFOB - 1BHFUPJE SFUJDVMPTJT XJUI $% positivity and cytotoxic/suppressor cells. J Cutan Pathol. 2007;34:644â&#x20AC;&#x201C;647. 19 Howard MS, Smoller BR. Mycosis fungoides: classic disease and variant presentations. Sem Cutan Med Surg. 2000;19:91â&#x20AC;&#x201C;99. 20 Burns MK, Chan LS, Cooper KD. Woringer-Kolopp disease (localized pagetoid reticulosis) or unilesional mycosis fungoides? An analysis of eight cases with benign disease. Arch Dermatol. 1995;131:325â&#x20AC;&#x201C;329.

Willemze R. Cutaneous T-cell lymphoma: epidemiology, etiology and classification. Leuk Lymphoma. 2003;44 suppl 3:S49â&#x20AC;&#x201C;S54.

21 Steffen C. Ketron-Goodman disease, Woringer-Kolopp disease, and pagetoid reticulosis. Am J Dermatopathol. 2005;27:68â&#x20AC;&#x201C;85.

Matsuzaki Y, Kimura K, Nakano H, Hanada K, Sawamura D. Localized pagetoid reticulosis (Woringer-Kolopp disease) in early childhood. J Am Acad Dermatol. 2009;61:120â&#x20AC;&#x201C;123.

22 $FSSPOJ - 'JOL 1VDIFT 3 &M 4IBCSBXJ $BFMFO - FU BM 4PMJUBSZ TLJO lesions with histopathologic features of early mycosis fungoides. Am J Dermatopathol. 2000;22:299â&#x20AC;&#x201C;304.

)BHIJHIJ # 4NPMMFS #3 -F#PJU 1& FU BM 1BHFUPJE SFUJDVMPTJT 8PSJOHFS Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol. 2000;13:502â&#x20AC;&#x201C;510.

23 Suzaki R, Kobayashi K, Ishizaki S, Fujibayashi M, Tanaka M. Dermoscopic features of CD8-positive solitary pagetoid reticulosis on the left leg. Dermatol Res Prac QJJ &QVC +VM

Lichte V, Ghoreschi K, Metzler G, et al. Pagetoid reticulosis (WoringerKolopp disease). J Dtsch Dermatol Ges. 2009;7:353â&#x20AC;&#x201C;354.

24 Carlesimo M, Tammaro A, Cox C, et al. A case of Ketron-Goodman disease. Case Rep Dermatol. 2009;1:39â&#x20AC;&#x201C;43.

Miedler JD, Kristjansson AK, Gould J, Tamburro J, Gilliam AC. Pagetoid reticulosis in a 5-year-old boy. J Am Acad Dermatol. 2008;58: 679â&#x20AC;&#x201C;681.

25 Pagnanelli G, Bianchi L, Cantonetti M, et al. Disseminated pagetoid reticulosis presenting as cytotoxic CD4/CD8 double negative cutaneous T-cell lymphoma. Acta Derm Venereol. 2002;82:314â&#x20AC;&#x201C;316.

Cribier B. History: Frederic Woringer (1903-1964) and Woringer-Kolopp disease. Am J Dermatopathol. 2005;27:534â&#x20AC;&#x201C;545.

Sedghizadeh PP, Allen CM, Kalmar JR, Magro CM. Pagetoid reticulosis: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:318â&#x20AC;&#x201C;323.

26 Nakada T, Sueki H, Iijima M. Disseminated pagetoid reticulosis (Ketron-Goodman disease): six-year follow-up. J Am Acad Dermatol. 2002;47:183â&#x20AC;&#x201C;186.

.BOEPKBOB 3. )FMXJH &# -PDBMJ[FE FQJEFSNPUSPQJD SFUJDVMPTJT (Woringer- Kolopp disease). J Am Acad Dermatol. 1983;8:813â&#x20AC;&#x201C;829.

28 Skiljevic D, Bogdanovic Z, Vesic S, et al. Pagetoid reticulosis of WoringerKolopp. Dermatol Online J. 2008;14:18.

$IP 7FHB +) 5TDIFO + %VWJD . 7FHB ' &BSMZ TUBHF NZDPTJT GVOHPJEFT variants: case-based review. Ann Diagn Pathol. 2010;14:369â&#x20AC;&#x201C;385.

29 Waitzer S, Fisher B. Woringer-Kolopp disease: a form of mycosis fungoides. Int J Dermatol. 1984;23:610â&#x20AC;&#x201C;612.

10 Lee J, Viakhireva N, Cesca C, et al. Clinicopathologic features and treatment outcomes in Woringer-Kolopp disease. J Am Acad Dermatol. 2008;59:706â&#x20AC;&#x201C;712.

30 Grubb B, Henderson DB, Pandya A. Adult T-cell lymphoma/leukemia presenting as pagetoid reticulosis of the palms and soles. J Am Acad Dermatol. 2011;65:1063â&#x20AC;&#x201C;1064.

11 #FSSPFUB - -FXJT +POFT .4 &WBOT "5 *CCPUTPO 4) 8PSJOHFS ,PMPQQ (localized pagetoid reticulosis) treated with topical photodynamic therapy (PDT). Clin Exp Dermatol. 2005;30:446â&#x20AC;&#x201C;447.

31 MĂźhlhoff C, Krenkel B, RĂźbben A, Megahed M. Pagetoid reticulosis in a patient with mycosis fungoides: successful therapy with localized electron beam irradiation. Hautarzt. 2010;61:378â&#x20AC;&#x201C;382.

27 Crowson AN, Magro CM. Woringer-Kolopp disease. A lymphomatoid hypersensitivity reaction. Am J Dermatopathol. 1994;16:542â&#x20AC;&#x201C;548.

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January/February 2013

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ORIGINAL CONTRIBUTION

Bioequivalence in Keratolytic Activity of Formulations vs Its Vehicle and Comparator Formulation: Randomized, Double-Blind Clinical Trial Hongbo Zhai, MD;1 Yue Zheng, MD;1 Peter Matravers, PharmD;2 Deborah A. Hicks;2 Sheree Wiener;2 Howard I. Maibach, MD1 ABSTRACT ɨJT TUVEZ BTTFTTFE UIF CJPFRVJWBMFODF VTJOH LFSBUPMZUJD Fċ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ɨJT FYUFOET QSFWJPVT PCTFSWBUJPOT EJTDFSOJOH CJPFRVJWBMFODF SFTVMUJOH GSPN EJĊFSFOU BDUJWF NBUFSJBMT XJUI WBSZJOH NFDIBOJTN PG BDUJPO BOE QPUFODZ PO UIF TLJO 3FTVMUT TIPXFE OP TJHOJmDBOU EJĊFSFODF CFUXFFO UFTUFE QSPEVDUT ɨF OPWFM GPSNVMBUJPOT XFSF PG FRVBM LFSBUPMZUJD BDUJWJUZ UP UIF iTUBOEBSEw DPNQBSBUPS BOE IFODF CJPFRVJWBMFOU JO LFSBUPMZUJD BDUJWJUZ SKINmed. o

"TJBOT> XJUI B NFBO BHF PG ZFBST XFSF FOSPMMFE 1BUJFOUT XFSF IFBMUIZ XJUI OP PCWJPVT TLJO EJTFBTF PS LOPXO IJTUPSZ PG BUPQJD EFSNBUJUJT ɨF TUVEZ QSPUPDPM BOE JOGPSNFE DPOTFOU GPSNT XFSF SFWJFXFE BOE HJWFO BQQSPWBM CZ UIF "MMFOEBMF JOWFTUJHBUJPOBM SFWJFX CPBSE

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TEST MATERIALS

PATIENTS

TEST SITES

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"MM QBUJFOUT XFSF SFDSVJUFE GSPN UIF 4BO 'SBODJTDP #BZ "SFB ɨF CBDL XBT VTFE BT UIF UFTU TJUF ɨF UFTU TJUFT XFSF EFmOFE XJUI DPNNVOJUZ BOE XFSF TDSFFOFE CZ UIF JOWFTUJHBUPST " UPUBM PG DPEJOH QSPEVDUT " UP ) BOE UIFJS BQQMJDBUJPO QSPDFEVSFT XFSF BEVMU WPMVOUFFST NFO BOE XPNFO < $BVDBTJBOT BOE BT GPMMPXT " -B 1SBJSJF $FMMVMBS .JOVUF 1FFM BQQMZ UP DMFBO From Dermatology Research, San Francisco, CA;1 and Arbonne International Research and Development, Irvine, CA2 Address for Correspondence: Hongbo Zhai, MD, Dermatology Research, 2435 Ocean Avenue, San Francisco, CA 94127 t & NBJM IPOHCP[IBJ!IPUNBJM DPN

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PROTEIN ASSAY

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PROCEDURE

SQUAMOMETRIC ANALYSIS

STUDY DESIGN

ɨF NFUIPE BOE EFUBJMT PG TRVBNPNFUSZ DBO CF GPVOE FMTFXIFSF 5 -10 0OF UBQF EJTD % 4RVBNF NN XBT QMBDFE UP UIF TLJO BU FBDI UFTU TJUF GPMMPXFE CZ UIF BQQMJDBUJPO PG B H QSFTTVSF GPS TFDPOET VTJOH B SPMMFS ɨFSFBGUFS UIF UBQF XBT HFOUMZ SFNPWFE VUJMJ[JOH GPSDFQT BOE FBDI UBQF EJTD XBT TUBJOFE XJUI PS ESPQT PG B TPMVUJPO PG UPMVJEJOF CMVF BOE CBTJD GVDITJO 1PMZDISPNF .VMUJQMF 4UBJO %FMBTDP $PVODJM #MVĊT *" GPS TFDPOET ɨF UBQF EJTDT XFSF SJOTFE XJUI EFJPOJ[FE XBUFS BJS ESJFE PWFSOJHIU BOE NPVOUFE POUP B HMBTT TMJEF ɨF TUBJOFE UBQF EJTDT XFSF FWBMVBUFE CZ NFUIPET DPMPSJNFUSZ BOE NJDSPTDPQZ ɨF DPMPSJNFUSJD FWBMVBUJPOT XFSF QFSGPSNFE VTJOH B .JOPMUB $ISPNB .FUFS $3 .JOPMUB 0TBLB +BQBO 'PS FBDI DPMPSJNFUSJD NFBTVSFNFOU FBDI UBQF EJTD NPVOUFE PO B HMBTT TMJEF XBT QMBDFE POUP B XIJUF SFGFSFODF QMBUF BOE DPMPSJNFUSJD NFBTVSFNFOUT XFSF PCUBJOFE GPS - B BOE C WBMVFT ɨF NFBOT PG UIFTF NFBTVSFNFOUT XFSF PCUBJOFE ɨF DPMPSJNFUSJD JOEFY PG NJMEOFTT $*. XBT UIFO DBMDVMBUFE VTJOH UIF NFBO - B BOE C QBSBNFUFST \$*. - ¦ $ XIFSF $ B 2 C 2 1/2^ ɨF TRVBNPNFUSZ JOEFY UIF DISPNB $ XBT BMTP DBMDVMBUFE

"MM UFTU TJUFT XFSF NBSLFE XJUI B QFO "QQSPYJNBUFMZ - PG FBDI UFTU NBUFSJBM XBT BQQMJFE UP UIF CBDL PG QBUJFOUT PO B QSFNBSLFE UFTU TJUF "GUFS BQQMJDBUJPO QSPDFEVSFT EFTDSJCFE BCPWF GPS EFTJHOBUFE UJNF PG FBDI TBNQMF UIF TJUF XBT SJOTFE XJUI OPSNBM XBUFS &BDI TJUF XBT UIFO DPWFSFE XJUI BO FNQUZ NN QMBTUJD DIBNCFS )JMMUPQ $IBNCFS )JMMUPQ 3FTFBSDI .JBNJWJMMF 0) BOE TFDVSFE XJUI UBQF 4DBOQPS /PSHFTQMBTUFS 0TMP /PSXBZ ɨF PDDMVTJPO TJUF + DPOTJTUFE PG UIF UFTU DIBNCFS XJUI OP UFTU NBUFSJBM XIJDI XBT TFDVSFE JO UIF TBNF NBOOFS BT UIF PUIFS TJUFT ɨF VOUSFBUFE VOPDDMVEFE TLJO TJUF * XBT MFGU PQFO "GUFS IPVST BMM QBUDIFT BOE NBUFSJBMT XFSF SFNPWFE GSPN UFTU TJUFT

TAPE STRIPPING

" QSPQSJFUBSZ BEIFTJWF UBQF % TRVBNF $V%FSN %BMMBT 59 XBT VUJMJ[FE ɨF UBQFT XFSF QMBDFE PO UIF QSFNBSLFE UFTU TJUFT XJUI GPSDFQT VTJOH HMPWFE IBOET " SPMMFS BQQSPYJNBUFMZ H XBT VOJGPSNMZ BQQMJFE UP UIF VQQFS TVSGBDF PG UIF UBQF PWFS JUT FOUJSF BSFB GPS B QFSJPE PG TFDPOET ɨF SPMMFS XBT UIFO SFNPWFE BOE UIF UBQF XBT QFFMFE GSPN UIF TLJO XJUI GPSDFQT #MJOEFE USBJOFE QFSTPOOFM UIFO TDPSFE UIF EJTDT XJUI B NJDSPJO B VOJEJSFDUJPOBM NBOOFS GPS BMM TJUFT 5XFOUZ UBQF TUSJQT XFSF TDPQF BU ¨ NBHOJmDBUJPO BDDPSEJOH UP UIF QPJOU TDBMFT UBLFO GSPN FBDI UFTU TJUF BOE UIF DPOUSPM TJUFT *NNFEJBUFMZ BGUFS EFWJTFE 5BCMF * 10 SKINmed. 2013;11:21–25

#JPFRVJWBMFODF JO ,FSBUPMZUJD "DUJWJUZ PG 'PSNVMBUJPOT

January/February 2013

03*(*/"- $0/53*#65*0/ HSFFO UP QVSF SFE BOE JT LOPXO UP DPSSFMBUF DMPTFMZ XJUI FSZUIFNB RVBOUJmDBUJPO 11 13 ɨF B WBMVF XBT VUJMJ[FE UP EFUFSNJOF FSZUIFNB DIBOHFT QSFUSFBUNFOU BOE QPTUUSFBUNFOU BOE BMTP EVSJOH UBQF TUSJQQJOH BGUFS BOE TUSJQT &BDI NFBTVSFNFOU XBT QFSGPSNFE UISJDF BOE UIF NFBO XBT SFDPSEFE 4UBOEBSE HVJEFMJOFT BOE NFBTVSJOH QSJODJQMFT IBWF CFFO QVCMJTIFE JO EFUBJM 14

Table I. Squamometry Scoring System

SCORE

DESCRIPTION Intercorneocyte cohesion

-BSHF TIFFU

-BSHF DMVTUFST GFX JTPMBUFE DFMMT

4NBMM DMVTUFST NBOZ JTPMBUFE DFMMT

$MVTUFST JO EJTSVQUJPO NPTU DFMMT JTPMBUFE

"MM DFMMT JTPMBUFE NBOZ DBTFT PG MZTJT

ɨF NFBTVSFNFOUT XFSF DPOEVDUFE JO B SPPN XJUI EBJMZ SBOHFT PG SFMBUJWF IVNJEJUZ GSPN BOE UFNQFSBUVSF GSPN ¡$ ¡$ ɨFTF WBMVFT XFSF SFDPSEFE EVSJOH UIF FYQFSJNFOUBM QFSJPE &BDI QBUJFOU SFTUFE BU MFBTU NJOVUFT GPS BDDMJNBUJPO CFGPSF NFBTVSFNFOUT

Amount and distribution of dye found in cells 0

/P TUBJOJOH

4UBJOJOH CFUXFFO DFMMT PS TMJHIU TUBJOJOH JO DFMMT

STATISTICAL ANALYSIS

%BUB XFSF TUPSFE JO .JDSPTPGU &YDFM TIFFUT 4UBUJTUJDBM BOBMZTJT XBT QFSGPSNFE VTJOH B DPNQVUFS QSPHSBN 4JHNB1MPU 4ZTUBU 3 -BSHF BNPVOU PG EZF JO DFMMT CVU VOJGPSN 4PGUXBSF *OD 4BO +PTF $" /PSNBM EJTUSJCVUJPOT XFSF UFTUFE 4 *NQPSUBOU TUBJOJOH JO BMM DFMMT PGUFO XJUI HSBJOT CFGPSF DBMDVMBUJOH DPNQBSJTPOT %JĊFSFODFT BNPOH HSPVQT XFSF BOBMZ[FE VTJOH UIF POF XBZ SFQFBUFE NFBTVSFT BOBMZTJT PG WBSJCLINICAL SCORING BODF *G UIFSF XBT B TJHOJmDBOU EJĊFSFODF BMM QBJSXJTF NVMUJQMF $MJOJDBM BTTFTTNFOU PG UIF UFTU TJUFT XBT QFSGPSNFE CZ JOWFT- DPNQBSJTPO QSPDFEVSFT XFSF GVSUIFS BOBMZ[FE 4UBUJTUJDBM TJHOJmUJHBUPS BDDPSEJOH UP UIF TDBMF TIPXO JO 5BCMF ** ɨF TLJO XBT DBODF XBT BDDFQUFE BU P "OBMZTJT XBT DPOEVDUFE CFGPSF UIF BTTFTTFE QSJPS UP BQQMJDBUJPO PG QBUDIFT IPVS BGUFS UIFJS SFNPWBM DPEF XBT CSPLFO BOE BGUFS BOE UBQF TUSJQT 2

.PEFSBUF TUBJOJOH JO DFMMT

RESULTS

Table II. Visual Assessment Scale

SCALE

CLINICAL SIGNS

CLINICAL SCORING

.BDVMBS FSZUIFNB

&SZUIFNB FEFNB

7FTJDVMBUJPO

6MDFSBUJPO FSPTJPO

"T BTTFTTFE WJTVBMMZ BGUFS IPVS QPTU QBUDI SFNPWBM BOE TUSJQT OFJUIFS UIF CMBOL DPOUSPM VOUSFBUFE TJUF BOE PDDMVTJPO TJUF OPS BMM QSPEVDU UFTUFE TJUFT JOEVDFE FSZUIFNB PS FEFNB JO BOZ PG UIF QBUJFOUT "GUFS TUSJQT IPXFWFS BMM QSPEVDU USFBUFE TJUFT EFNPOTUSBUFE TLJO SFBDUJPOT JO WBSJPVT EFHSFFT UIF QSPEVDU $ TFFNFE UP JOEVDF IJHIFS SFTQPOTF % ' BOE ) XFSF MFTT JSSJUBUJOH IPXFWFS UIFSF XBT OP TUBUJTUJDBM EJĊFSFODF CFUXFFO UIPTF USFBUNFOUT

BIOPHYSICAL MEASUREMENTS Transepidermal water loss: measurement of water barrier. 5SBOTFQJEFSNBM XBUFS MPTT 5&8- EPDVNFOUT JOUFHSJUZ PG 4$ XBUFS CBSSJFS GVODUJPO BOE JT B TFOTJUJWF JOEJDBUPS PG TLJO XBUFS CBSSJFS BMUFSBUJPO 11 5&8- XBT BTTFTTFE CZ B DMPTFE DIBNCFS EFWJDF 7BQPNFUFS 48- %FMmO 5FDIOPMPHJFT -UE ,VPQJP 'JOMBOE 5&8- SFBEJOHT XFSF UBLFO BU CBTFMJOF BMMPXJOH NJOVUFT GPS BDDMJNBUJ[BUJPO BOE UIFO IPVS BGUFS SFNPWBM PG UIF PDDMVTJWF QBUDIFT UP BMMPX GPS PDDMVTJWF TVQFSIZESBUJPO 5&8- XBT BMTP SFDPSEFE BGUFS BOE UBQF TUSJQT BU FBDI UFTU BOE DPOUSPM TJUFT ɨF NFBTVSJOH QSJODJQMF BOE TUBOEBSE HVJEFMJOFT BSF QVCMJTIFE 11 12 ɨF WBMVFT PG 5&8- XFSF FYQSFTTFE BT HSBN QFS TRVBSF NFUFS QFS IPVS

TRANSEPIDERMAL WATER LOSS 5&8- JODSFBTFE BGUFS BOE TUSJQT IPXFWFS UIFSF XBT OP TUBUJTUJDBM EJĊFSFODF CFUXFFO HSPVQT BU FBDI NFBTVSFE UJNF QPJOUT

SKIN COLOR (a* VALUE) ɨF B WBMVFT WBSJFE BU UIF NFBTVSFNFOU UJNF QPJOUT JF IPVS QPTU QBUDI SFNPWBM BU TUSJQT BOE BU UIF FOE PG TUSJQT IPXFWFS UIFSF XBT OP TUBUJTUJDBM EJĊFSFODF CFUXFFO HSPVQT

SQUAMOMETRY

Skin color (a* Value): measurement of skin erythema. EryUIFNB XBT RVBOUJmFE CZ TLJO DPMPS SFnFDUBODF NFBTVSFNFOUT VTJOH B DPMPSJNFUFS $ISPNB .FUFS $3 .JOPMUB 0TBLB +BQBO ɨF B WBMVF SFQSFTFOUT UIF DPMPS TQFDUSVN GSPN UPUBM SKINmed. 2013;11:21–25

Microscopic analysis. %ZF mYBUJPO EJE OPU SFWFBM TJHOJmDBOU EJĊFSFODFT JO UIF DFMM TUBJOJOH CFUXFFO HSPVQT 'JHVSF $PIFTJPO BTTFTTNFOU PG QSPEVDU # BOE % USFBUFE TJUFT TIPXFE B TJHOJmDBOU HSFBUFS MPTT PG DFMM DPIFTJPO P DPNQBSFE XJUI #JPFRVJWBMFODF JO ,FSBUPMZUJD "DUJWJUZ PG 'PSNVMBUJPOT

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Figure 1. Squamometric results (cohesion assessment). *P<.05, compared with I site (ie, normal skin). See text for specific products.

UIF * TJUF JF OPSNBM TLJO ɨFSF XBT OP TJHOJmDBOU EJĊFSFODF JO UIF TRVBNPNFUSZ JOEFY $ PS UIF $*. CFUXFFO HSPVQT EBUB OPU TIPXO 4$ NBTT XBT SFNPWFE BOE UIFSF XBT OP TUBUJTUJDBM EJĊFSFODF PG DVNVMBUJWF NBTT TVN TUSJQT PG 4$ SFNPWFE CZ TFRVFOUJBM UBQF TUSJQQJOH CFUXFFO BOZ HSPVQT DPNQBSFE XJUI FJUIFS PDDMVTJPO DPOUSPM TJUF + PS XJUI OPSNBM TLJO TJUF * DISCUSSION

MPTT PG DFMM DPIFTJPO P DPNQBSFE XJUI UIBU TFFO XJUI UIF * TJUF JF OPSNBM TLJO TVHHFTUJOH UIBU QSPEVDUT # BOE % QPTTFTT TUSPOHFS LFSBUPMZUJD BDUJWJUZ ɨF TRVBNPNFUSZ EBUB IFMQFE UP GVSUIFS FMVDJEBUF UIF NPEF PG BDUJPO PG LFSBUPMZUJD BHFOUT 1SFTVNBCMZ LFSBUPMZUJD USFBUFE TJUFT XPVME EFNPOTUSBUF B NPSF TDBUUFSFE BSSBOHFNFOU PG DPSOFPDZUFT PO UIF UBQF BT DPNQBSFE XJUI WFIJDMF USFBUFE BOE CMBOL DPOUSPM TJUFT XIJDI XPVME EFNPOTUSBUF B NPSF JOUBDU DPSOFPDZUFT TIFFU PO UIF UBQF TVSGBDF 5 ɨJT IBT CFFO QBSUJBMMZ DPOmSNFE ɨF TFOTJUJWJUZ PG UIJT NFUIPE UIFSFGPSF TFFNT JOTVċDJFOU UP EFUFDU B LFSBUPMZUJD FĊFDU BGUFS B TIPSU USFBUNFOU QFSJPE VOEFS PDDMVTJPO "T TIPXO JO B TFQBSBUF TUVEZ VOEFS JO VTF DPOEJUJPOT TRVBNPNFUSZ BMMPXFE EFUFDUJOH BMUFSFE JOUFSDPSOFPDZUF DPIFTJPO POMZ BGUFS B QSPMPOHFE BOE SFQFUJUJWF BQQMJDBUJPO PG XFFLT PS NPSF 15 "EEJUJPOBMMZ OP BEWFSTF FWFOU XBT PCTFSWFE EVSJOH FYQFSJNFOU BOE JU QSFTVNFT UIBU UFTU QSPEVDUT BSF TBGF XJUI TQFDJmD BQQMJDBUJPO QFSJPET

ɨF LFSBUPMZUJD BHFOU FYGPMJBUFT UIF TLJO CZ DBVTJOH UIF DFMMT PG UIF FQJEFSNJT VQQFS MBZFS PG TLJO UP TIFE NPSF FBTJMZ NBLJOH SPPN GPS OFX DFMM HSPXUI 5P JEFOUJGZ UIF LFSBUPMZUJD BDUJWJUZ PG TVDI BO BHFOU JT JNQPSUBOU BOE SFTVMUT NBZ MFBE UP PQUJNBM EFSNBUPMPHJD BOE DPTNFUJD QSPEVDUT "MUIPVHI WBSJPVT NFUIPET IBWF CFFO FNQMPZFE UP BTTFTT UIF LFSBUPMZUJD FĊFDU PG LFSBUPMZUJD BHFOUT UIFZ BSF MJNJUFE BOE OFFE GVSUIFS EFWFMPQNFOU UP BDDVSBUFMZ RVBOUJGZ UIFJS EFSNBUPQIBSNBDPMPHJD BDUJWJUZ 5 ɨF DVSSFOU TUVEZ VTJOH UIF FYQFSJNFOUBM NPEFM UP BTTFTT UIF FċDBDZ PG LFSBUPMZUJD BHFOUT JO CONCLUSIONS IVNBOT JO WJWP BQQFBSFE TFOTJUJWF BDDVSBUF BOE FBTZ UP QFSGPSN ɨJT TUVEZ FYUFOET UIF UFTU NFUIPE GPS EJTDFSOJOH CJPFRVJWBMFODF ɨJT TUVEZ FWBMVBUFE UIF LFSBUPMZUJD BCJMJUZ PG QSPEVDUT XJUI SFTVMUJOH GSPN EJĊFSFOU BDUJWF NBUFSJBMT XJUI WBSZJOH NFDIBOJTN WJTVBM BOE CJPNFUSJD NFUIPET BT XFMM BT QSPUFJO BTTBZ ɨF PG BDUJPO BOE QPUFODZ PO UIF TLJO 3FTVMUT TIPXFE OP TJHOJmDBOU HPBM PG LFSBUPMZUJD BDUJWJUJFT XBT BDIJFWFE CZ BMM QSPEVDUT .PTU EJĊFSFODF XJUI NPTU QBSBNFUFST CFUXFFO UFTUFE QSPEVDUT XIJDI QBSBNFUFST JO UIJT FYQFSJNFOU IPXFWFS EJE OPU HFOFSBUF UIF TVHHFTUT UIBU UIF OPWFM GPSNVMBUJPOT XFSF PG FRVBM LFSBUPMZUJD TUBUJTUJDBM EJĊFSFODF CFUXFFO QSPEVDU HSPVQT 8F TVTQFDU UIBU BDUJWJUZ UP UIF iTUBOEBSEw DPNQBSBUPS QSPEVDU BOE IFODF CJPMPOHFS BQQMJDBUJPO UJNF T PG QSPEVDUT NJHIU HFOFSBUF TJHOJmDBOU FRVJWBMFOU JO LFSBUPMZUJD BDUJWJUZ *O BEEJUJPO GVSUIFS TUVEZ XJUI EJĊFSFODFT CFUXFFO QSPEVDUT IPXFWFS DPIFTJPO EBUB TIPXFE FBDI QSPEVDU BU MPOHFS BQQMJDBUJPO UJNF T NBZ DMBSJGZ EJĊFSFODFT UIBU QSPEVDU # BOE % USFBUFE TJUFT ZJFMEFE B TJHOJmDBOUMZ HSFBUFS CFUXFFO UIPTF QSPEVDUT JG BOZ SKINmed. 2013;11:21–25

#JPFRVJWBMFODF JO ,FSBUPMZUJD "DUJWJUZ PG 'PSNVMBUJPOT

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Disclosures: "MM UFTU GPSNVMBUJPOT JODMVEJOH JUT WFIJDMF BOE DPNQBSBUPS XFSF QSPWJEFE CZ "SCPOOF *OUFSOBUJPOBM 1FUFS .BUSBWFST %FCPSBI " )JDLT BOE 4IFSFF 8JFOFS BSF FNQMPZFFT PG "SCPOOF *OUFSOBUJPOBM É¨JT TUVEZ JT QBSUJBMMZ TVQQPSUFE CZ "SCPOOF *OUFSOBUJPOBM

Bashir SJ, Chew AL, Anigbogu A, et al. Physical and physiological effects of stratum corneum tape stripping. Skin Res Technol. 2001;7:40â&#x20AC;&#x201C;48.

;IBJ ) 'BVU[ 3 'VDIT " FU BM "TTFTTNFOU PG UIF TVCDMJOJDBM JSSJUBUJPO of surfactants: a screening open assay model. Exogenous Dermatol. 2002;1:238â&#x20AC;&#x201C;241.

;IBJ ) 'BVU[ 3 'VDIT " FU BM )VNBO TDBMQ JSSJUBUJPO DPNQBSFE UP UIBU of the arm and back. Contact Dermatitis. 2004;51:196â&#x20AC;&#x201C;200.

REFERENCES

10 1JFSBSE (& 1JFSBSE 'SBODIJNPOU $ 4BJOU -FHFS % ,MJHNBO ". 4RVB NPNFUSZ UIF BTTFTTNFOU PG YFSPTJT CZ DPMPSJNFUSZ PG % 4RVBNF BEIF sive discs. J Soc Cosmet Chem. 1992;47:297â&#x20AC;&#x201C;305.

Fabbrocini G, De Padova MP, Tosti A. Chemical peels: whatâ&#x20AC;&#x2122;s new and what isnâ&#x20AC;&#x2122;t new but still works well. Facial Plast Surg. 2009;25: 329â&#x20AC;&#x201C;336.

#PXF 81 4IBMJUB "3 &GGFDUJWF PWFS UIF DPVOUFS BDOF USFBUNFOUT Semin Cutan Med Surg. 2008;27:170â&#x20AC;&#x201C;176.

Kornhauser A, Wei RR, Yamaguchi Y, et al. The effects of topically applied HMZDPMJD BDJE BOE TBMJDZMJD BDJE PO VMUSBWJPMFU SBEJBUJPO JOEVDFE FSZUIFNB DNA damage and sunburn cell formation in human skin. J Dermatol Sci. 2009;55:10â&#x20AC;&#x201C;17.

11 Wilhelm KP, Surber C, Maibach HI. Quantification of sodium lauryl sul phate dermatitis in man: comparison of four techniques: skin color reflectance, transepidermal water loss, laser Doppler flow measurement and visual scores. Arch Dermatol Res. 1989;281:293â&#x20AC;&#x201C;295. 12 Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for transepidermal XBUFS MPTT 5&8- NFBTVSFNFOU Contact Dermatitis. 1990;22:164â&#x20AC;&#x201C;178.

Bissett DL. Common cosmeceuticals. Clin Dermatol. 2009;27:435â&#x20AC;&#x201C;445.

13 Wilhelm KP, Maibach HI. Skin color reflectance measurement for objec tive quantification of erythema in human beings. J Am Acad Dermatol. 1989;21:1306â&#x20AC;&#x201C;1308.

Bashir SJ, Dreher F, Chew AL, et al. Cutaneous bioassay of salicylic acid as a keratolytic. Int J Pharm. 2005;292:187â&#x20AC;&#x201C;194.

14 Fullerton A, Fischer T, Lahti A, et al. Guidelines for measurement of skin colour and erythema. Contact Dermatitis. 1996;35:1â&#x20AC;&#x201C;10.

Dreher F, Arens A, HostĂ˝nek JJ, et al. Colorimetric method for quantifying IVNBO TUSBUVN DPSOFVN SFNPWFE CZ BEIFTJWF UBQF TUSJQQJOH Acta Derm Venereol. 1998;78:186â&#x20AC;&#x201C;189.

15 1JFSBSE 'SBODIJNPOU $ (PGĂĽO 7 1JFSBSE (& .PEVMBUJPO PG IVNBO TUSB UVN DPSOFVN QSPQFSUJFT CZ TBMJDZMJD BDJE BOE BMM USBOT SFUJOPJD BDJE Skin Pharmacol Appl Skin Physiol. 1998;11:266â&#x20AC;&#x201C;272.

VINTAGE LABEL

$PVSUFTZ PG #VZ&OMBSHF 1IJMBEFMQIJB 1"

SKINmed. 2013;11:21â&#x20AC;&#x201C;25

#JPFRVJWBMFODF JO ,FSBUPMZUJD "DUJWJUZ PG 'PSNVMBUJPOT

University of Athens Medical School, Athens, Greece

WORLD CONGRESS

OF COSMETIC

DERMATOLOGY BY THE INTERNATIONAL ACADEMY OF COSMETIC DERMATOLOGY

ATHENS, GREECE JUNE 27-30, 2013 www.wcocd2013.com info@wcocd2013.com Congress Organising Bureau ERASMUS CONFERENCES TOURS & TRAVEL S.A. E-mail: info@wcocd2013.com Website: www.erasmus.gr

January/February 2013

7PMVNF t *TTVF

ORIGINAL CONTRIBUTION

Perceptions and Practices in Submental Fat Treatment: A Survey of Physicians and Patients Joel Schlessinger, MD;1 Steven R. Weiss, MD;2 Mark Jewell, MD, PC;3 Vic Narurkar, MD;4 Susan Weinkle, MD;5 Michael H. Gold, MD;6 Erica Bazerkanian, MBA7 ABSTRACT -PDBMJ[FE GBDJBM GBU EFQPTJUT BSF DPNNPO BOE USFBUNFOU UP SFTUPSF BOE SFTIBQF UIF MPXFS BTQFDU PG UIF GBDF JT NBJOMZ MJNJUFE UP TVSHJDBM QSPDFEVSFT É¨FSF IBT CFFO B SBQJE HSPXUI JO OPOTVSHJDBM BFTUIFUJD QSPDFEVSFT BOE QIZTJDJBOT BOE QBUJFOUT BSF TFFLJOH MFTT JOWBTJWF OPOTVSHJDBM GBDJBM SFKVWFOBUJPO PQUJPOT 'FX EBUB BSF QVCMJTIFE IPXFWFS PO QIZTJDJBO BOE QBUJFOU QFSDFQUJPOT BOE USFBUNFOU PG TVCNFOUBM GBU É¨JT DPOUSJCVUJPO SFWJFXT EBUB GSPN TVSWFZT PG QIZTJDJBOT EFSNBUPMPHJTUT BOE QMBTUJD TVSHFPOT BOE QBUJFOUT XIP SFDFJWFE OPOTVSHJDBM GBDJBM SFKVWFOBUJPO 0O BWFSBHF QIZTJDJBOT EJTDVTTFE GBU SFEVDUJPO PQUJPOT XJUI PG UIFJS QBUJFOUT PG UIFTF EJTDVTTJPOT JOWPMWFE GBU VOEFS UIF DIJO .PTU QBUJFOUT TVSWFZFE IBE TVCNFOUBM GBU BTTFTTFE CZ B DMJOJDJBO VTJOH B QPJOU SBUJOH TDBMF 4VCNFOUBM GBU XBT PG DPODFSO UP QBUJFOUT TVSWFZFE SFQPSUFE OPUJDJOH FYUSB GBU VOEFS UIFJS DIJO BOE XBOUFE JU SFEVDFE .PTU QBUJFOUT TVSWFZFE XPVME VTF BO FÃªFDUJWF BOE XFMM UPMFSBUFE OPOJOWBTJWF QIBSNBDPMPHJD USFBUNFOU GPS TVCNFOUBM GBU SFEVDUJPO 1BUJFOUT XFSF NPSF MJLFMZ UP XJTI UP SFEVDF UIF GBU CFMPX UIFJS DIJO JG UIFZ IBE IJHIFS DIJO HSBEF TDPSFT CBTFE PO DMJOJDJBO BTTFTTNFOU *OUFSFTUJOH JOTJHIUT BSF QSPWJEFE JOUP UIF QFSDFQUJPOT BOE CFIBWJPS PG QIZTJDJBOT BOE QBUJFOUT XJUI SFHBSE UP TVCNFOUBM GBU SFEVDUJPO SKINmed. o

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From Skin Specialists, PC, Omaha, NE;1 the Dermatology Associates Medical Group, Beverly Hills, CA, and David Geffen School of Medicine, UCLA, Los Angeles, CA;2 Assistant Clinical Professor, Oregon Health Science University, Portland Oregon, Jewell Plastic Surgery Center, Eugene, OR;3 Bay Area Laser Institute, San Francisco, CA;4 Affiliate Clinical Professor of Dermatology, University of Florida, Private Practice, Bradenton, FL;5 Gold Skin Care Center, Tennessee Clinical Research Center, Nashville, TN;6 and KYTHERA Biopharmaceuticals, Inc, Calabasas, CA7 Address for Correspondence: Joel Schlessinger, MD, Skin Specialists, PC, 2806 South 143rd Plaza, Omaha, NE 68144 t & NBJM TLJOEPD!MPWFMZTLJO DPN

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Figure 1. $MJOJDJBO 3FQPSUFE 4VCNFOUBM 'BU 3BUJOH 4DBMF $3 4.'34 JT B QPJOU QIPUPOVNFSJD TDBMF VTFE UP PCKFDUJWFMZ rate the severity of submental fat. It uses text descriptions and representative photographs to classify the convexity of sub mental fat as absent, mild, moderate, severe, or extreme and was used to evaluate patient respondentâ&#x20AC;&#x2122;s severity of chin fat. $3 4.'34 BOE JNBHFT TIPXO IFSF DPVSUFTZ PG ,:5)&3" #JP pharmaceuticals, Inc. Â©2010 KYTHERA Biopharmaceuticals, Inc. All Rights Reserved. Unauthorized duplication and/or VTF PG UIF $MJOJDJBO 3FQPSUFE 4VCNFOUBM 'BU 3BUJOH 4DBMF BOE images is prohibited. 1FSDFQUJPOT BOE 1SBDUJDFT JO 4VCNFOUBM 'BU 5SFBUNFOU

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OPUJDJOH FYUSB GBU VOEFS UIFJS DIJO 'JHVSF C .PTU QBUJFOUT XFSF JO BHSFFNFOU XJUI PS XJUIJO QPJOU PG DMJOJDJBO PHYSICIAN PRACTICE CHARACTERISTICS BTTFTTNFOU PG DIJO GBU PO UIF QPJOU QBUJFOU TDBMF 'JHVSF B É¨F QIZTJDJBOT TVSWFZFE USFBUFE B NFBO PG QBUJFOUT QFS BOE 'JHVSF C NPOUI EFSNBUPMPHJTUT USFBUFE QBUJFOUT BOE QMBTUJD TVSHFPOT USFBUFE QBUJFOUT QFS NPOUI "NPOH DPNNPOMZ QFSGPSNFE .PTU QBUJFOUT BHSFFE TPNFXIBU UP TUSPOHMZ XJUI UIF TUBUFNFOU DPTNFUJD QSPDFEVSFT CPUVMJOVN UPYJO XBT SBOLFE BT UIF NPTU i* XPVME MJLF UP CF BCMF UP TBGFMZ SFEVDF UIF GBU CFMPX NZ DIJO w GSFRVFOU QSPDFEVSF CZ CPUI EFSNBUPMPHJTUT QSPDFEVSFT QFS 0G BMM QBUJFOUT XIP QSPWJEFE B SFTQPOTF O NPOUI BOE QMBTUJD TVSHFPOT QSPDFEVSFT QFS NPOUI GPM- BHSFFE TPNFXIBU UP TUSPOHMZ XJUI UIF TUBUFNFOU NPSFPWFS MPXFE CZ EFSNBM Ã«MMFS USFBUNFOU BOE QSPDFEVSFT QFS QBUJFOUT XFSF NPSF MJLFMZ UP XJTI UP SFEVDF UIF GBU CFMPX UIFJS DIJO JG UIFZ IBE IJHIFS DIJO HSBEF TDPSFT CBTFE PO DMJOJDJBO NPOUI SFTQFDUJWFMZ BTTFTTNFOU PO $3 4.'34 PG QBUJFOUT XJUI B DIJO TDPSF PG XFSF JOUFSFTUFE JO SFEVDJOH TVCNFOUBM GBU DPNQBSFE XJUI PATIENT CHARACTERISTICS "NPOH UIF QBUJFOUT XIP SFQPSUFE UIFJS TFY PG QBUJFOUT XJUI B TDPSF PG XJUI B TDPSF PG XFSF XPNFO É¨F NFBO BHF PG UIF QBUJFOUT XBT ZFBST 0G UIF XJUI B TDPSF PG BOE XJUI B TDPSF PG RESULTS

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Figure 2. Of 372 patients assessed, 80% had some degree PG TVCNFOUBM GBU $MJOJDJBO 3FQPSUFE 4VCNFOUBM 'BU 3BUJOH 4DBMF TDPSF o CBTFE PO DMJOJDJBO BTTFTTNFOU B 1BUJFOU assessment of submental fat. Of 382 patients assessed, 77% SFQPSUFE OPUJDJOH TPNF EFHSFF PG GBU VOEFS UIFJS DIJO C 1FSDFQUJPOT BOE 1SBDUJDFT JO 4VCNFOUBM 'BU 5SFBUNFOU

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PHYSICIAN AND PATIENT PERCEPTIONS TO NEW TREATMENTS .PSF UIBO IBMG PG UIF EFSNBUPMPHJTUT BOE QMBTUJD TVSHFPOT TVSWFZFE XPVME CF MJLFMZ UP USZ BO FÃªFDUJWF BOE B XFMM UPMFSBUFE OPOJOWBTJWF USFBUNFOU GPS TVCNFOUBM GBU SFEVDUJPO %FSNBUPMPHJTUT XPVME CF NPSF MJLFMZ UP USZ USFBUNFOU UIBO QMBTUJD TVSHFPOT XJUI EFSNBUPMPHJTUT MJLFMZ UP USZ B OFX QSPEVDU DPNQBSFE XJUI QMBTUJD TVSHFPOT 4VDI B QSPEVDU XPVME CF UIF QSFGFSSFE USFBUNFOU PQUJPO GPS TVCNFOUBM GBU BOE PS KPXM Figure 4. Localized fat reduction areas and treatments car SFEVDUJPO GPS EFSNBUPMPHJTUT XIP BOUJDJQBUFE USFBUJOH PG SJFE PVU CZ QIZTJDJBOT EFSNBUPMPHJTUT BOE QMBTUJD TVSHFPOT Dermatologists treat more of their fat reduction patients in UIFJS GBU SFEVDUJPO QBUJFOUT XJUI TVDI B QSPEVDU É¨JT OFX QSPEsmall volume areas than plastic surgeons. *Not part of face VDU XPVME CF UIF TFDPOE QSFGFSSFE USFBUNFOU PQUJPO GPS TVCNFOlift procedure. **Includes abdomen, legs/thighs, hips/love UBM GBU BOE PS KPXM SFEVDUJPO GPS QMBTUJD TVSHFPOT XIP XPVME handles, back, buttocks, neck, arms, and face. FYQFDU UP USFBU PG UIFJS QBUJFOUT XJUI TVDI B QSPEVDU -JQPTVDUJPO XPVME SFNBJO UIF QSFGFSSFE USFBUNFOU PQUJPO GPS QMBTUJD CURRENT TREATMENT TVSHFPOT XIP PO BWFSBHF FYQFDU UP USFBU UP PG UIFJS -JQPTVDUJPO XBT UIF NPTU DPNNPO USFBUNFOU QFSGPSNFE CZ MPDBMJ[FE GBU SFEVDUJPO QBUJFOUT XJUI MJQPTVDUJPO QMBTUJD TVSHFPOT GPS BMM MPDBMJ[FE GBU SFEVDUJPO TVCNFOUBM KPXM CBDL PG BSN PUIFS -JQPTVDUJPO XBT VTFE JO PG DBTFT GPS 0G UIF QBUJFOUT XIP QSPWJEFE B SFTQPOTF XPVME TVCNFOUBM BOE PS KPXM GBU SFEVDUJPO PG DBTFT GPS CBDL PG VTF BO FÃªFDUJWF BOE XFMM UPMFSBUFE OPOJOWBTJWF USFBUNFOU GPS UIF BSN GBU SFEVDUJPO BOE PG DBTFT GPS PUIFS MPDBMJ[FE GBU TVCNFOUBM GBU SFEVDUJPO É¨F LFZ BUUSJCVUFT PG B OFX QSPEVDU BSFB SFEVDUJPO 1MBTUJD TVSHFPOT VTFE SBEJPGSFRVFODZ JO GPS TVCNFOUBM GBU SFEVDUJPO XFSF SBOLFE MFBTU JNQPSUBOU BOE BOE MBTFS MJQPTVDUJPO JO BOE PG DBTFT NPTU JNQPSUBOU BT FÃ¯DBDZ OPOJOWBTJWF TJEF GPS TVCNFOUBM KPXM CBDL PG BSN BOE PUIFS MPDBMJ[FE GBU BSFB FÃªFDUT UPUBM UJNF UP TFF SFTVMUT BOE OVNCFS PG SFEVDUJPO SFTQFDUJWFMZ É¨FZ SFGFSSFE BOE PG UIFJS WJTJUT UP UIF QIZTJDJBO 1BUJFOUT SBOLFE MFBTU CBSSJFS SKINmed. 2013;11:27â&#x20AC;&#x201C;31

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Dudelzak J, Hussain M, Goldberg DJ. Laser lipolysis of the arm, with and without suction aspiration: clinical and histologic changes. J Cosmet Laser Ther. 2009;11:70â&#x20AC;&#x201C;73.

American Society for Aesthetic Plastic Surgery. Cosmetic Sur gery National Data Bank: Statistics 2008. New York, NY: ASAPS; 2005.http://media.lasvegassun.com/media/pdfs/blogs/ documents/2009/03/25/2008stats.pdf. Accessed January 11 2010.

Data on file. KYTHERA Biopharmaceuticals Market Research, 2010.

Pitanguy I, Radwanski HN, Machado BHB. Liposuction and ermolipec tomy. In: Shiffman MA, Di Giuseppe A, ed. Liposuction. Heidelberg: 4QSJOHFS 7FSMBH

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ACSICON 2013,

BENGALURU, INDIA

26, 27 & 28th April 2013 ACSICON 2013 - Highlights x x x x x x x x

A â&#x20AC;&#x201C; Z of Procedural Dermatology Unique scientific program with dermato- surgery, aesthetics, cosmetology, and recent advances 10 renowned International faculty More than 100 National faculty 9 parallel HANDS ON / In-theater workshops on 26th and 27th April 2013 All-in-one full day Observational Work Shop on 28th April 2013 Best of Hospitality and Conferencing from TEAM DERMA, Bengaluru, India Best available weather and family holiday at Bengaluru at beautiful and glorious KARNATAKA Organising Committee Congress President Dr Venkataram Mysore N mysorevenkat@hotmail.com

Organizing Chairman Dr S C Rajendran dr_rajendran080@yahoo.co.in

Organizing Secretary Dr Raghunatha Reddy R raghunatha18@yahoo.com

Joint Organizing Secretary & Treasurer Dr Umashankar N usdermavision@gmail.com

Scientific Chairman S Sacchidanand Dr Anil Abraham sacchi1212@gmail.com docanilabe@yahoo.co.in

Scientific Secretary Dr Shashikumar B M shashi_b_m@yahoo.com

Workshop Chairman Workshop Secretary Dr B S Chandrashekar Dr Jagadish P

Co-Ordinators Dr Mukta Sachdev Dr M K Shetty

cutisclinic@gmail.com

mukta.sachdev@gmail.com your_dermatologists@yahoo.com

drjagadish_skin@yahoo.com

Venue: NIMHANS Convention Centre, Hosur Road, Bengaluru - 560 029, India For information log on to www.acsinet.net or write to acsicon2013@gmail.com

January/February 2013

Volume 11 • Issue 1

REVIEW

Cutaneous Viral Diseases in HIV Infection Ilya Ivyanskiy, MD;1,2 Simon Francis Thomsen, MD, PhD2

n Western countries, the life expectancy of human immunodeficiency virus (HIV)-infected patients approaches that of the normal population, which means that with a steady number of incidence cases, more and more die with and not from the disease. This makes the management of complications of HIV infection a major task and signals a need for physicians in general to be familiar with the manifestations associated with long-term infection. Mucocutaneous manifestations in HIV-infected patients occur in almost 90% of all cases during the course of the disease. Viral-induced changes are easily recognizable, very common in HIV, and may be early markers of undiagnosed HIV infection. This review describes diagnostic, differential diagnostic, and treatment aspects of frequent and unusual viral-induced skin manifestations associated with HIV infection.

According to the Joint United Nations Programme on HIV/ AIDS (UNAIDS), about 33.3 million people worldwide are infected with HIV, of whom 22.5 million are inhabitants of sub-Saharan Africa.1 In Western countries, the life expectancy of (HIV)-infected patients, particularly those treated successfully with highly active antiretroviral treatment (HAART), approaches that of the normal population, which means that with a steady number of incidence cases, more and more die with and not from the disease.2 This makes the management of complications of HIV infection a major task and signals a need for physicians in general to be familiar with the manifestations associated with long-term infection.

becomes much more complicated, and many patients develop conditions resistant to traditional approaches. The advent of HAART has dramatically improved quality of life among HIV-infected patients by reducing the burden of opportunistic infections;2 however, HAART also carries the risk of several cutaneous side effects that negatively impact patients’ quality of life, including lipodystrophy, oral mucosal ulceration, and peripheral neuropathy.2 Manifestation of skin disorders, as a rule, is closely connected with CD4 cell count; therefore, among different classification systems for HIV infection, the US Centers for Disease Control and Prevention (CDC) classification system has become one of the most widely used.3 The CDC classification system evaluates the severity of HIV disease by CD4 cell count and by the presence of specific HIV-related conditions. According to the CDC, there are three CD4 cell categories based on the lowest documented CD4 cell count: category 1: ≥500 cells/mL; category 2: 200–499 cells/mL; and category 3: <200 cells/mL. Another well-described classification system is the World Health Organization (WHO) Clinical Staging and Disease Classification System.4 The WHO system does not require a CD4 cell count and classifies HIV disease on the basis of clinical manifestations and comprises four stages (stage 4 being the most advanced).

Mucocutaneous manifestations in HIV-infected patients occur in almost 90% of all cases during the course of the disease.2 Although most of these skin disorders are not pathognomonic for HIV infection, they are markers of the deterioration of immunity and of the presence and severity of the underlying disorder. By these means, they play an invaluable role in the early diagnosis and prevention of severe complications of HIV infection, and moreover, they enable one to monitor the progression of the disease. In HIV infection, skin and mucous diseases undergo significant changes as immunodeficiency progresses in both appearance and severity. Treatment

This review focuses on clinical features and treatment of cutaneous viral diseases of HIV infection. Numerous etiological agents can affect the skin and mucous membranes, but the most frequent are viral infections. Viral-induced changes are easily recognizable and very common in HIV, and thus, all physicians should be able to recognize and treat them. Moreover, they may be early markers of undiagnosed HIV infection. The most common viral skin changes related to HIV are shown in Table 1. ACUTE EXANTHEM OF HIV DISEASE Usually primary HIV is asymptomatic, but in some cases, a flulike syndrome with nonspecific skin lesions in 75% of patients may appear.2 The rash is caused by the release of cytokines and inflammatory mediators as a consequence of widespread infection of cells with HIV. It manifests with maculoerythematous

From the I.M. Sechenov First Moscow State Medical University, Moscow, Russia;1 and the Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark2 Address for Correspondence: Simon Francis Thomsen, MD, PhD, Department of Dermatology, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark • E-mail: sft@city.dk

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January/February 2013

REVIEW

Table 1. Viral Mucocutaneous Diseases of HIV Infection Acute exanthem of HIV disease Herpes zoster Herpes simplex Molluscum contagiosum Human papilloma virus–associated warts Oral hairy leukoplakia (Epstein–Barr virus) Cytomegalovirus Parvovirus B19 Kaposi’s sarcoma (human herpes virus 8) Hepatitis C virus–associated skin changes

lesions on the trunk, roseola-like or morbilliform lesions in the upper body or face, and papulosquamous lesions of the palms and soles. Lesions may resemble an acute drug reaction or syphilis, but other differential diagnoses must be taken into consideration, including erythema multiforme, pityriasis rosea, guttate psoriasis, urticaria, Still’s disease, and exanthems associated with other infections, including Ebstein–Barr virus; cytomegalovirus (CMV); parvovirus B19; human T-lymphotropic virus type 1 and 2; hepatitis virus A, B, and C; gonococcaemia; rheumatic fever; toxoplasmosis; meningococcaemia; and herpes simplex virus (HSV).2 Mucosal involvement has also been described, in which case one must also consider collagen vascular diseases, immuobullous diseases, Behcet’s disease, and Stevens–Johnson syndrome.2 The skin eruption appears between 3 and 6 weeks after exposure with spontaneous resolution after 4 to 8 weeks. HSV INFECTION HSV infection may occur at any stage of HIV infection, and usual sites are in the oral or anogenital region although it may appear anywhere. In children, gingivostomatitis is also common to encounter. Typically, the mouth becomes studded with small vesicles that rapidly break to leave ulcers. Usually it takes 2 to 3 weeks for lesions to resolve entirely. In immunocompromised patients, lesions tend to be more widespread by means of autoinoculation and duration could be significantly prolonged. Presence of lesions for more than 1 month (chronic HSV infection) indicates stage 4 (WHO) HIV infection. As immunodeficiency progresses, HSV may affect the pharynx, esophagus, and skin with hypertrophic, vegetative, or nodular lesions and become resistant to acyclovir. Lesions are extremely painful and deepen into chronic nonhealing ulcers (Figure 1). They can mimic staphylococcal infection when present as scaly, impetiginized lesions. Secondary bacterial infection may complicate the course of the HSV infection, and the lesions may spread universally. Candidal coinfection makes the clinical appearance extremely atypical. Children may also experience poor nutrition and dehydration. SKINmed. 2013;11:33–37

Figure 1. Anal herpes simplex.

An increased HIV-RNA load during HSV infection has been demonstrated in several studies and correlates with a more rapid progression of HIV.5 Moreover, in HIV patients, the risk of recurrence is 3 to 5 times higher compared with immunocompetent individuals, especially when the CD4 count reaches 50 cells/mL.5 HSV may emerge under antiretroviral therapy as a part of immune reconstitution inflammatory syndrome (IRIS) and can be difficult to treat.6 Treatment options for HSV in HIV-infected patients include acyclovir at a dose of 10 to 20 mg/kg 4 times per day in children, 400 mg 3 times per day in adults. Duration of the therapy is 7 to 14 days. Combination of valacyclovir (1 g twice a day) and famciclovir (500 mg twice a day) for 7 days could be an option. If infection is severe, intravenous acyclovir is considered. High doses of acyclovir can cause renal failure, and therefore, liquid support is required. Treatment should be intensive, because HSV accelerates HIV replication.7 In an event of acyclovir-resistant HSV caused by mutant or absent viral thymidine kinase, the drug of choice is foscarnet, which is a direct inhibitor of HSV DNA polymerase. Vidarabine, famciclovir, and valaciclovir are alternative options. Cidofovir, commonly used in CMV infection, can also be prescribed for HSV. HERPES ZOSTER Herpes zoster virus (HZV) infection is a reactivation of latent varicella zoster virus infection. It is one of the commonest cutaneous presentations of IRIS.8 About half of HIV-infected patients have reactivation of preceding chickenpox within 24 months after first eruption.9 Whereas HZV is not a strong indicator for HIV testing in Western countries, it is particularly suggestive of HIV in African patients.10 Presence of HZV infection indicates stage 2 (WHO) of HIV infection, but it may occur at any stage. In spite of the typical clinical presentation, in most cases with painful, vesicular eruptions, appearing in a

Cutaneous Viral Diseases in HIV Infection

January/February 2013

REVIEW 5 mm in diameter. HIV-infected patients are prone to develop extensive endophytic, aggregated, inflamed, and giant lesions of more than 1 cm, disseminating by autoinoculation, sexual contact, or after scratching (Koebner phenomenon). They may emerge on atypical sites such as the face (Figure 3), neck, and scalp and become disfiguring when located on the face. Lesions on the face in adults are very suggestive of HIV infection.2 Differential diagnoses include nevus sebaceous, sebaceous hyperplasia, syringoma, ecthyma, condylomata acuminata, cryptococcosis, histoplasmosis, basal cell carcinoma, and penicillium marneffei cutaneous infection. Often only appropriate antiretroviral treatment of HIV infection itself can prevent frequent recurrences and lessen the severity of the disease.11 Thus, antiretroviral therapy is currently the firstline treatment. Additional temporary options include curettage (particularly for large lesions and leaves no scarring), cryotherapy, electrodessication, topical retinoids, imiquimod, cidofovir, and topical acids.

Figure 2. Herpes zoster.

dermatomal pattern (Figure 2), it is not unusual to observe various lesions such as hemorrhagic, ichyasiform, necrotic, crusted, verrucous, ecthymatous lesions, or hyperkeratotic papules that may cover more than one dermatome and even all the body, resembling chickenpox. Involvement of the eyes, visceral dissemination, encephalitis, meningitis, myelitis, and polyneuritis has also been described, and these manifestations are characteristic for patients with a very low CD4 cell count. Differential diagnoses comprise herpes simplex, ecthyma gangrenosum, disseminated infection with atypical mycobacteria, fungi, and vaccinia. The involvement of sacral nerves results in constipation, urinary retention, and hemorrhagic cystitis.

HUMAN PAPILLOMAVIRUS Human papillomavirus (HPV) is a viral infection that presents as cauliflower warts and frequently occurs in HIV-infected individuals.12 Among different types of HPV, some are associated with malignancy (eg, HPV-16 and HPV-18), whereas others are not (HPV-6 and HPV-11). Patients are at increased risk for

Treatment of HZV with acyclovir should be initiated within 72Â hours. It should be given at a dosage of 20 mg/kg 4 times per day in children, with a maximum dosage of 800 mg 4 times per day. In adults, 800 mg 5 times per day is acceptable, and the duration of therapy is approximately 7 days. In severe cases with central neurological or lung involvement or when vision, sphincteric function, and facial expression are threatened, intravenous introduction at a dosage of 20 mg/kg every 8 hours for 7 days is recommended. Secondary infection requires topical or systemic antibiotics. Pain and post-herpetic neuralgia are managed by analgetics, morphine, carbamazepine, and dosulepin. HZV immunoglobulin has been reported to be effective for prophylaxis of relapses or when acyclovir treatment fails. Vidarabine and recombinant interferon-a are used in cases of acyclovir resistance. MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is a poxvirus infection that is frequently seen in HIV-infected patients.9 Presence of molluscum contagiosum in patients with HIV commonly indicates stage 2 (WHO) in children and a CD4 count <200 cells/mL (stage 4) in adults. Characteristically, moluscum contagiosum presents with umbilicated, dome-shaped, pearly, or flesh-colored papules 2 to SKINmed. 2013;11:33â&#x20AC;&#x201C;37

Figure 3. Molluscum contagiosum. Cutaneous Viral Diseases in HIV Infection

January/February 2013

REVIEW CYTOMEGALOVIRUS Skin manifestations of CMV infection in HIV are relatively rare compared with ocular, gastrointestinal, neurological, or adrenal involvement; but, if involved, the death rate in 6 months is about 85%.13 Reactivation of CMV occurs with a CD4 cell count <50 cells/mL. CMV may present with a wide range of skin lesions, including purpura, papules, nodules, verrucous plaques, painful ulcers, and nodular prurigo-like eruptions. Ulcers in the perineal region are the commonest presentation. Nonetheless, it has been argued whether these lesions result from CMV itself or occur secondary to HSV and other infections. Treatment options include specific antiviral agents (foscarnet, ganciclovir, and cidofovir). Employment of HAART is also of great importance. On the contrary, it may cause the opposite effect with severe cutaneous ulcerative eruption, presumably representing IRIS.

Figure 4. Anal wart.

extensive, numerous, large facial, intraoral, anogenital (Figure 4), and mosaic plantar lesions and can exist simultaneously with other infections such as molluscum contagiosum; moreover, they may develop into intraepithelial carcinoma even though the HPV type is not associated with cancer (HPV-6 and HPV-11).2 The risk of anal cancer is 50 times higher, whereas the risk of penile cancer is 5 times higher in HIV. HPV plays a role in the etiology of Bowen’s disease; erythroplasia of Queyrat; Bowenoid papulosis; and invasive penile, anal, and cervical cancer. Treatment options include cryotherapy, podophylin, imiquimod, cidofovir, laser, and surgery. Combination of cryotherapy or surgery followed by imiquimod has been shown to be very effective in genital warts.10 Treatment by any means should be repeated about 12 times every for 3 weeks to obtain good results. HAART also plays a significant role in wart eradication. It has been reported that once the CD4 cell count has reached 50 cells/mL, it will be highly difficult to eradicate lesions even with appropriate antiretroviral treatment.10

KAPOSI’S SARCOMA Kaposi’s sarcoma (KS) is the most common malignancy observed in patients with HIV.5 It is caused by human herpes virus 8 (KS-associated herpesvirus) and represents a vascular neoplasm, which affects the skin, oral mucosa, respiratory tract, lymph nodes, and other internal organs. Presence of KS indicates stage 4 (WHO) HIV infection. The prevalence of KS in patients with AIDS may be more than 30% in developing countries but is somewhat less, probably below 5%, in patients in Western populations. Cutaneous KS presents as red to brown macules, papules, nodules, or tumors on the skin and mucous membranes, principally on the trunk, legs, face, and oral mucosa (Figure 5). It starts with pink macules, which grow to become disseminated and palpable. Development of KS (Figure 6) is associated with various angiogenic and proinflammatory agents including HIV Tat and LANA-1, expressed in HHV-8-infected cells, which have been

ORAL HAIRY LEUKOPLAKIA Oral hairy leukoplakia (OHL) is caused by Epstein–Barr virus. It is characterized by vertically ribbed, keratinized, small white plaques on the lateral borders of the tongue, but may enlarge, spreading to the adjacent sites of the oral mucosa. Unlike candidiasis, lesions cannot be scraped off. OHL may occur at any stage of HIV infection with a prevalence of about 25%, although it is considered to be typical for stage 3 (WHO) in both children and adults and more frequently in men and in patients with a CD4 cell count <200 cells/mL.5 It has also been correlated with progression from HIV infection to AIDS, as 48% of patients with OHL develop AIDS by 16 months and 83% by 31 months.5 Differential diagnoses include oral candidiasis, lichen planus, and geographic tongue. OHL has been noted to regress with HAART.5 SKINmed. 2013;11:33–37

Figure 5. Hairy leukoplakia. Cutaneous Viral Diseases in HIV Infection

January/February 2013

REVIEW CONCLUSIONS Understanding viral-induced mucocutaneous manifestations in HIV is important to any doctor, not only dermatologists, in order to make the right diagnosis in time to prevent complications including secondary bacterial infection and delay of the course of the underlying disease. Some cutaneous viral infections are potential skin markers only in disseminated or chronic forms (HSV, HZV, HPV, and molluscum contagiosum), whereas others are more likely to be markers of HIV in any form (KS, OHL). ACKNOWLEDGMENT

Figure 6. Kaposi’s sarcoma.

Carsten Sand Petersen, MD, provided the clinical photographs.

found to alter gene expression in the host genes, thereby contributing to the viral oncogenesis.14 Differential diagnoses include dermatofibromas, bacillary angiomatosis (Bartonella infection) bruises, pyogenic granulomas, insect bites, and nevi. Treatment depends on CD4 cell count. If the patient has >400 cells/ mL, management consists of monitoring of CD4 cell count and plasma HIV RNA levels, radiation, and cryotherapy. If the patient has <400 cells/mL, antiretroviral therapy together with systemic administration of interferon-a, liposomal doxorubicin, or paclitaxel should be prescribed. A report from the AIDS Malignancy Consortium suggests that persistent KS despite apparently effective antiretroviral therapy is not a rare, isolated, or recent phenomenon,15 and patients who present with KS despite a high CD4 cell count and a low viral load constitute a particular therapeutic challenge. HEPATITIS C VIRUS Coexistence of HIV and hepatitis C virus (HCV) infection occasionally produces a range of conditions, including lichen planus, xerosis, leukocytoclastic vasculitis, and itch without dermatitis. Xerosis is managed with lubricants and topical steroids. Treatment of vasculitis should be directed against HCV, whereas other agents such as dapsone and colchicine are also useful. Oral steroids are not recommended owing to aggravation of liver disease. Before administration of drugs, a number of other conditions associated with vasculitis have to be excluded, including drug reactions, streptococcal infection, endocarditis, hepatitis A and B virus, collagen vascular disease, cryoglobulinemia, leukaemia, and lymphoma. The itch is likely associated with the central nervous system and often only opioid antagonists (eg, naltrexone) can bring relief. It is advocated that coexisting HIV and HCV infection with dermatological manifestations is managed through a joint effort of several medical specialties including dermatologists, infectious disease specialists, and hepatologists.

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The Joint United Nations Programme on HIV/AIDS. http://www.unaids. org. Accessed December 27, 2012.

Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology. 8th ed. West Sussex, UK: Wiley-Blackwell; 2010.

From the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA. 1993; 269:729–730.

Hare CB. Clinical overview of HIV disease. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco, CA: UCSF Center for HIV Information, 2006.

Rigopoulos D, Paparizos V, Katsambas A. Cutaneous markers of HIV infection. Clin Dermatol. 2004;22:487–498.

Lehloenya R, Meintjes G. Dermatologic manifestations of the immune reconstitution inflammatory syndrome. Dermatol Clin. 2006;24: 549–570.

Schacker T. The role of HSV in the transmission and progression of HIV. Herpes. 2001;8:46–49.

Osei-Sekyere B, Karstaedt AS. Immune reconstitution inflammatory syndrome involving the skin. Clin Exp Dermatol. 2010;35:477–481.

Kovarik CL, Kekitiinwa A, Schwarzwald H. Cutaneous manifestations of HIV infection. In: HIV Curriculum for the Health Professional. 4th ed. Bailor International Pediatric AIDS Initiative, Baylor College of Medicine, Houston, TX, 2010.

10 Colebunders R, Mann JM, Francis H, et al. Herpes zoster in African patients: a clinical predictor of human immunodeficiency virus infection. J Infect Dis. 1988;157:314–318. 11 Maurer TA. Dermatologic manifestations of HIV infection. Top HIV Med. 2005;13:149–154. 12 Johnston J, King CM, Shanks S, et al. Prevalence of plantar verrucae in patients with human immunodeficiency virus infection during the post-highly active antiretroviral therapy era. J Am Podiatr Med Assoc. 2011;101:35–40. 13 Lee JY. Cytomegalovirus infection involving the skin in immunocompromised hosts. A clinicopathologic study. Am J Clin Pathol. 1989;92: 96–100. 14 Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Biberfeld P. KSHV/HHV-8 and HIV infection in Kaposi’s sarcoma development. Infect Agent Cancer. 2007;2:4. 15 Krown SE, Lee JY, Dittmer DP. AIDS malignancy consortium. More on HIV-associated Kaposi’s sarcoma. N Engl J Med. 2008;358:535–536.

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CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Diagnosis and Treatment Modalities—Part I Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Rashmi Midha, MBBS

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ANATOMY

MICROANATOMY OF THE HAIR FOLLICLE

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From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Skin Institute, School of Dermatology, Greater Kailash, New Delhi Address for Correspondence: Virendra N. Sehgal, MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, %FMIJ *OEJB t & NBJM ESTFIHBM!OEG WTOM OFU JO

SKINmed. 2013;11:39–45

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Figure 1. Microanatomy displaying the structure of the hair follicle. SKINmed. 2013;11:39–45

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CLASSIFICATION

GENETICS

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13 5JFEF 4 ,MPFQQFS +& #PEP & FU BM )BJS GPMMJDMF TUFN DFMMT XBMLJOH UIF maze. Eur J Cell Biol. 2007;86:355â&#x20AC;&#x201C;376. 14 Hashimoto K. The structure of human hair. Clin Dermatol. 1988;6:7â&#x20AC;&#x201C;21. 15 .JMOFS : 4VEOJL + 'JMJQQJ . FU BM &YPHFO TIFEEJOH QIBTF PG UIF IBJS growth cycle: characterization of a mouse model. J Invest Dermatol. 2002;119:639â&#x20AC;&#x201C;644. 16 Paus R. Principles of hair cycle control. J Dermatol. 1998;25:793â&#x20AC;&#x201C;802. 17 Rebora A, Guarrere M. Kenogen. A new phase of the hair cycle? Dermatology. 2002;205:108â&#x20AC;&#x201C;110. 18 Venning VA, Dawber RP. Patterned androgenetic alopecia in women. JÂ Am Acad Dermatol. 1988;18:1073â&#x20AC;&#x201C;1077.

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19 Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter and prevalence of female pattern hair loss. Br J Dermatol. 2001;144:297â&#x20AC;&#x201C;304.

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21 Hamilton JB. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat. 1942;71:451â&#x20AC;&#x201C;480.

20 Norwood OT, Lehr B. Female androgenetic alopecia: a separate entity. Dermatol Surg. 2000;26:679â&#x20AC;&#x201C;682.

22 )BNJMUPO +# &GGFDU PG DBTUSBUJPO JO BEPMFTDFOU BOE ZPVOH BEVMU NBMFT upon further changes in the proportions of bare and hairy scalp. J Clin Endocrol Metab. 1960;20:1309â&#x20AC;&#x201C;1318. 23 Oremtreich N. Pathogenesis of alopecia. J Soc Cosmet Chem. 1960;11:479â&#x20AC;&#x201C;499. 24 Inui S, Fukuzato Y, Nakajima T, et al. Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth. FASEB J. 2002;16:1967â&#x20AC;&#x201C;1969.

CONCLUSIONS

25 -FHSP 34 $BSNJOB & 4UBOD[ZL '; FU BM "MUFSOBUJPOT JO BOESPHFO conjugate levels in women and men with alopecia. Fertil Steril. 1994; 62:744â&#x20AC;&#x201C;750.

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26 Miller JA, Darley CR, Karkavitsas K, et al. Low sex hormone binding globulin levels in young women with diffuse hair loss. Br J Dermatol. 1982;106:331â&#x20AC;&#x201C;336.

REFERENCES

27 4BXBZB .& 1SJDF 7) %JGGFSFOU MFWFMT PG alpha-reductase type I and II, aromatase and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol. 1997;109:296â&#x20AC;&#x201C;300.

Cash TF. The psychology of hair loss and its implications for patient care. Clin Dermatol. 2001;19:161â&#x20AC;&#x201C;166.

0MTFO &" 'FNBMF QBUUFSO IBJS MPTT J Am Acad Dermatol. 2001;45: S70â&#x20AC;&#x201C;S80.

-VEXJH & $MBTTJĂĽDBUJPO PG UZQFT PG BOESPHFOFUJD BMPQFDJB DPNNPO baldness) occurring in female sex. Br J Dermatol. 1977;97:247â&#x20AC;&#x201C;254.

Biondo S, Goble D, Sinclair R. Women who present with female pattern hair loss tend to underestimate the severity of their hair loss. Br J Dermatol. 2004;150:750â&#x20AC;&#x201C;752.

de Berker DAR, Messenger AG, Sinclair RD. Disorders of hair. In: Burns T, #SFBUIOBDI 4 $PY / (SJGĂĽUIT $ FET Rookâ&#x20AC;&#x2122;s Textbook of Dermatology. 7th ed. United Kingdom: Blackwell Publishing; 2004:63.1â&#x20AC;&#x201C;63.36.

Suzberger MB, Witten VH, Kopf AW. Diffuse alopecia in women. Its unexplained apparent increase in incidence. Arch Dermatol. 1960; 81:556â&#x20AC;&#x201C;560.

Muller SA. Common baldness. Minn Med. 1974;57:809â&#x20AC;&#x201C;812.

Caserio RJ. Diagnostic techniques for hair disorders. Part I: microscopic examination of the hair shaft. Cutis. 1987;40:265â&#x20AC;&#x201C;270.

Sperling LC. Hair anatomy for the clinician. J Am Acad Dermatol. 1991;25:1â&#x20AC;&#x201C;17.

10 Kligman AM. The human hair cycle. J Invest Dermatol. 1959;33:307â&#x20AC;&#x201C;316. 11 .VSQIZ (' )JTUPMPHZ PG UIF TLJO *O &MEFS %& FE Leverâ&#x20AC;&#x2122;s Histopathology of the Skin. 8th ed. Philadelphia, PA: Lippincott-Raven; 1997:5â&#x20AC;&#x201C;50. 12 Caserio RJ. Diagnostic techniques for hair disorders. Part II: microscopic examination of the hair bulbs, tips, and casts. Cutis. 1987;40: 321â&#x20AC;&#x201C;325.

SKINmed. 2013;11:39â&#x20AC;&#x201C;45

28 Kasick JM, Bergfeld WF, Stick WD, et al. Adrenal androgenic female pattern alopecia sex hormones and the balding. Cleve Clin Q. 1983;50: 111â&#x20AC;&#x201C;122. 29 Georgala G, Papasotiriou V, Stavropoulos P. Serum testosterone and sex hormone globulin levels in women with androgenetic alopecia. Acta Derm Venereol. 1986;66:532â&#x20AC;&#x201C;534. 30 Guerrera M, Rebora A. Anagen hairs may fail to replace telogen hairs in early androgenic female alopecia. Dermatology. 1996;192:28â&#x20AC;&#x201C;31. 31 Adachi K, Takayasu S, TakashimaI, et al. Human hair follicles: metabolism and control mechanisms. J Soc Cosmet Chem. 1970;21: 901â&#x20AC;&#x201C;924. 32 "OEFSTPO 4 #FSNBO %. +FOLJOT &1 FU BM %FMFUJPO PG TUFSPJE alpha reductase-2 gene in male psuedohermaphroditism. Nature. 1991; 354:578â&#x20AC;&#x201C;588. 33 Whiting DA, Waldstreicher J, Sanchez M, et al. Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizonal TFDUJPOT PG TFSJBM TDBMQ CJPQTJFT SFTVMUT PG ĂĽOBTUFSJEF NH USFBUNFOU of men and postmenopausal women. J Invest Dermatol Symp Proc. 1999;4:282â&#x20AC;&#x201C;284. 34 Futterweit W, Dunaif A, Yeh HC, et al. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Am Acad Dermatol. 1988;19:831â&#x20AC;&#x201C;836. 35 Vierhapper H, Maier H, Nowotny P, et al. Production Rates of testosterone and of dihydrotestosterone in female pattern hair loss. Metabolism. 2003;52:927â&#x20AC;&#x201C;929. 36 Lunde O, Magnus P, Sandvick L, et al. Familial clustering in the polycystic ovarian syndrome. Gynecol Obstet Invest. 1989;28:23â&#x20AC;&#x201C;30.

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January/February 2013

$03& $633*$6-6.

37 Kuhn BA. Male pattern alopecia and/or androgenetic hirsutism in GFNBMFT QBSU ***oEFĂĽOJUJPO BOE FUJPMPHZ J Am Med Womenâ&#x20AC;&#x2122;s Assoc. 1972;27:357â&#x20AC;&#x201C;364. 38 Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994;3: 1873â&#x20AC;&#x201C;1876. 39 $POBSE ' 0CSFNVT 6 #PEP & FU BM &TUSPHFOT BOE IVNBO TDBMQ hair growthâ&#x20AC;&#x201C;still more questions than answers. J Invest Dermatol. 2004;122:840â&#x20AC;&#x201C;842.

43 &MMJT +" 4UFCCJOH . )BSSBQ 4# (FOFUJD BOBMZTJT PG NBMF QBUUFSO CBMEOFTT and the 5a reductase genes. J Invest Dermatol. 1998;110:849â&#x20AC;&#x201C;853. 44 $BSFZ ") $IBO ,- 4IPSU ' FU BM &WJEFODF GPS B TJOHMF HFOF FGGFDU causing polycystic ovaries and male pattern baldness. Clin Endocrinol. 1993;38:653â&#x20AC;&#x201C;658. 45 &M 4BNBIZ .) 4IBIFFO ." 4BEEJL %& FU BM &WBMVBUJPO PG BOESPHFO receptor gene as a candidate gene in female androgenetic alopecia. Int J. Dermatol. 2009;48:584â&#x20AC;&#x201C;587. 46 Savin RC. A method forvisually describing and quantitating hair loss in male pattern baldness [abstract]. J Invest Dermatol. 1992;98:604.

40 Thornton MP. The biological actions of estrogens on skin. Exp Dermatol. 2002;11:487â&#x20AC;&#x201C;502.

47 Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci. 1951;53:708â&#x20AC;&#x201C;728.

41 Kuster W, Happle R. The inheritance of common baldness: two B or or not two B? J Am Acad Dermatol. 1984;11:921â&#x20AC;&#x201C;926.

48 Smith MA, Wells RS. Male type alopecia, alopecia areata and normal hair in women: family histories. Arch Dermatol. 1964;89:95â&#x20AC;&#x201C;98.

42 &MMJT +" 4UFCCJOH . )BSSBQ 4# 1PMZNPSQIJTN PG UIF BOESPHFO SFDFQtor gene is associated with male pattern baldness. J Invest Dermatol. 2001;116:452â&#x20AC;&#x201C;455.

49 -FF 84 3P #* )POH 41 FU BM " OFX DMBTTJĂĽDBUJPO PG QBUUFSO IBJS MPTT UIBU JT VOJWFSTBM GPS NFO BOE XPNFO CBTJD BOE TQFDJĂĽD #"41 DMBTTJĂĽDBUJPO J Am Acad Dermatol. 2007;57:37â&#x20AC;&#x201C;46.

SELF-TEST REVIEW QUESTIONS 8 $MBSL -BNCFSU .% 1I% 4FDUJPO &EJUPS Instructions: For each of the following questions, answer as directed at the end of each question (stem). Synonyms for pattern alopecia in women include (Answer as many as apply. All, some, or none of the lettered choices may be appropriate.) a. androgenic alopecia (AGA). b. female pattern alopecia. c. diffuse hormonal alopecia. d. diffuse alopecia in women. e. common baldness in women. f. female pattern baldness (FPB).

In the normal human hair follicle, the Henley layer is a. the innermost layer of the inner root sheath. b. the outermost layer of the inner root sheath. c. the innermost layer of the outer root sheath. d. the outermost layer of the outer root sheath. e. none of these.

The outermost layer of the normal human hair follicle is the a. glossy vitreous layer. b. ĂĽCSPVT SPPU TIFBUI c. outermost layer of the outer root sheath. d. isthmus. e. infundibulum.

SKINmed. 2013;11:39â&#x20AC;&#x201C;45

Most normal scalp hair follicles in women are in which of the following phases? a. Anagen. b. Catagen. c. Telogen. d. &YPHFO e. Kenogen.

Unlike most men, most women with pattern alopecia are (have) a. hyperthyroid. b. cushingoid. c. clinically manifest elevated estrogen levels. d. clinically manifest elevated androgen levels. e. no discernable endocrine anomaly.

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

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January/February 2013

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PERILS OF DERMATOPATHOLOGY

Pseudo Positive, Pseudo Positive Negative, Pseudo Positive Positive Negative, and Pseudo Pseudo Positive Positive Negative Positive Margins in Dermatopathology Brian Lee, BA;1 Muriel W. Lambert, PhD;2 Chinmoy Bhate, MD;3 Joseph Kamelgard, MD;4 W. Clark Lambert, MD, PhD2,3 “Many are called, but few are chosen.”—.BUUIFX

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From the New Jersey Medical School Class of 2013, Newark, NJ;1 the New Jersey Medical School Department of Pathology, Newark, NJ;2 the New Jersey Medical School Department of Dermatology, Newark, NJ;3 the New Jersey Medical School Department of Surgery, Newark, NJ;4 Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building, UMDNJ, 185 South Orange Avenue, Newark, NJ 07103.

SKINmed. 2013;11:46–47

ª 1VMTF .BSLFUJOH $PNNVOJDBUJPOT --$

January/February 2013

1&3*-4 0' %&3."501"5)0-0(:

Figure 1. Margin of squamous cell carcinoma excision showing â&#x20AC;&#x153;pickupâ&#x20AC;? focus of basal cell carcinoma (rapid fixation, x204).

Figure 3. Margin of squamous cell carcinoma excision showing separate large focus of basal cell carcinoma (rapid fixation, x204).

CONCLUSIONS "TTFTTNFOU PG TVSHJDBM NBSHJOT PG FYDJTFE MFTJPOT JO EFSNBUPQBUIPMPHZ JT TPNFUJNFT DIBMMFOHJOH 1 *U JT JNQPSUBOU UP DPOTJEFS BMM PG UIF WBSJPVT XBZT UIBU PTUFOTJCMZ QPTJUJWF NBSHJOT BT XFMM BT UIFJS NJNJDT DBO PDDVS VTJOH FBDI NBSHJO BTTFTTNFOU UFDIOJRVF BOE UP BQQSPBDI FBDI BQQSPQSJBUFMZ 2 4PNF PG UIFTF UFDIOJRVFT JNQPTF TQFDJBM DIBMMFOHFT TVDI BT UIPTF UIBU SFRVJSF BOBMZTJT PG WFSZ OBSSPX TQFDJNFOT 4PNFUJNFT BEEJUJPOBM QSPDFEVSFT TVDI BT DVSFUUBHF 3 NBZ CF VTFGVM JO NBLJOH UIFTF BTTFTTNFOUT *O TPNF DBTFT DFSUBJOUZ JT JNQPTTJCMF BOE JU NBZ CF BQQSPQSJBUF UP BTTVNF B iXPSTU DBTF TDFOBSJP w XJUI NBOBHFNFOU NPEJmFE BDDPSEJOHMZ REFERENCES

Figure 2. Margin of squamous cell carcinoma excision showing separate small focus of excised basal cell carcinoma (rapid fixation, x408).

UIVT HFOFSBUJOH B iQTFVEPQPTJUJWFw NBSHJO CVU OPU CF QBSU PG JU UIVT iOFHBUJWFw NBSHJO UIBU JT OPOFUIFMFTT JO OFFE PG USFBUNFOU HFOFSBUJOH B iQTFVEP QTFVEPQPTJUJWF QPTJUJWF OFHBUJWF QPTJUJWFw NBSHJO

Akcam TM, Gubisch W, Unlu H. Nonmelanoma skin cancer of the head and neck: Surgical treatment. Facial Plast Surg Clin North Am. 2012;20:455â&#x20AC;&#x201C;471.

Weinstein MC, Brodell RT, Bordeaux J, Honda K. The art and science of surgical margins for the dermatopathologist. Am J Dermatopathol. 2012;34:737â&#x20AC;&#x201C;745.

Dika E, Fanti PA, Vaccari S, et al. Basal cell carcinoma margin delineation: is curettage useful? A surgical and histological study. J Dermatolog Treat. 2012 [Epub ahead of print].

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2013;11:46â&#x20AC;&#x201C;47

1TFVEP 1PTJUJWF 1TFVEP 1PTJUJWF /FHBUJWF

2ND ANNUAL CONGRESS

BANGKOK NOVEMBER 6 - 10, 2013

SAVE THE DATE

NOVEMBER 6 - 10, 2013

2013 DASIL CONGRESS The Hilton Millennium Bangkok Hotel

The Dermatologic & Aesthetic Surgery International League For meeting information or to become an industry partner, visit www.theDASIL.org, or contact DASIL headquarters at HQ@theDASIL.org Abstract submissions due by September 1, 2013 and can be submitted to HQ@theDASIL.org

January/February 2013

Volume 11 • Issue 1

PHOTO CAPSULE Ncoza C. Dlova, MBChB, FRCDerm, Section Editor

Borderline Tuberculoid Evolving Across the Leprosy Spectrum Virendra N. Sehgal, MD; Sonal Sharma, MD1

20-year-old man developed increasing pain and progressive impairment of temperature, and touch and weakness of hands for the past 10 months. There were patchy areas of hypopigmentation with red, scaly plaques that were round and/or oval. Their margins were serrated and had satellite lesions (Figure 1a and 1b) that were numerous but countable, with a bilateral distribution. Temperature, touch, and pain

were considerably impaired. Several nerves were enlarged and tender: the supraorbital, greater auricular, and brachial plexus including the radial and the ulnar and their cutaneous branches. The sciatic nerve and its branches, including the lateral popliteal nerves, were involved. A diagnosis was made of borderline tuberculoid leprosy, downgrading per se evolving into borderline borderline, and mid-borderline leprosy. The diagnosis crossed five1 to seven2 groups on the leprosy spectrum, corresponding to the dimorphous groups of Madrid (International)3 classification. The diagnosis was substantiated by histopathology, where hematoxylin and eosin–stained section(s) prepared from the biopsy of a representative lesion showed an unremarkable epidermis. The papillary dermis was relatively free

Figure 2. Section from skin showing unremarkable epidermis. Papillary dermis is relatively free of inflammation with mild perivascular lymphocytic infiltrate. Deeper parts of the dermis show periappendageal and perineural loose epithelioid cell granulomas (hematoxylin and eosin, original magnification ×40). The inset shows a nerve (N) infiltrated by lymphocytes and epithelioid cells (arrow head) (hematoxylin and eosin, original magnification ×400).

Figure 1. Borderline tuberculoid leprosy on the arm (a) and legs (b).

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi; and Department of Pathology, University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara, Delhi1 Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS, Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

SKINmed. 2013;11:49–50

January/February 2013

PHOTO CAPSULE

of inflammation with mild perivascular lymphocytic infiltrate (Figure 2). Deeper aspects of the dermis showed compact, loosely cohesive, periappendageal epithelioid cell granulomas with a few foamy histiocytes. Giant cells were conspicuous by their absence. Perineural and intraneural granulomas were seen in the nerves. No acid-fast bacilli could be demonstrated.

REFERENCES 1

Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis. 1966;34:255–273.

Sehgal VN. A seven group classification for institutional and field work. Lepr Rev. 1989;60:75.

Sehgal VN, Jain MK, Srivastava G. Evolution of classification of leprosy. Int J Dermatol. 1989; 28:161–167.

NEWSLETTER

The Bulletin of the International Association of Ecological Dermatology (Eco-Derm) Riccarda Serri, MD J&J also plans to eliminate phthalates, which have a variety of uses, such as lessening the stiffening effects of hair spray; several fragrance ingredients; triclosan, an antibacterial; and parabens, a preservative.

ECODERMATOLOGY, ROME, 2012 SKINECO organized its first course on Ecodermatology, September 28, 2012, in Rome, Italy, during which time the main goal of the Society was promoted: to have more and more dermatologists well informed and aware of the possible toxicity of all products used on the skin and tissue or used to cleanse the skin. The knowledge of ecodermatological thematics is important for an improved basic preparation on the world in which we live. Dermatologists, when informed of new scientific discoveries, will more readily recognize the “fabrications” promulagated by the “organic” world. ECODERM is then possible through science, knowledge, and rationality. A BIG STEP TOWARD ECOLOGICAL DERMATOLOGY (ECO-DERM) Johnson & Johnson (J&J) released a significant statement in August 2012 saying that it is planning to:

To further this effort, J&J has launched a website: www.safety andcarecommitment.com to keep consumers informed on what it does to ensure that its ingredients are safe and of high quality. SKINECO Ecodermatologists are very pleased that an important pharmaceutical company such as J&J has taken significant measures to eliminate these ingredients from their skin care products. J&J has taken into account recent scientific studies that prove the toxicity and carcinogenic effects of certain ingredients widely used in contemporary skin care products. Use of eco-friendly ingredients that benefit our skin, the human organism, and our planet is to be applauded. TRICLOSAN IN THE NEWS

remove potentially cancer-causing and other dangerous chemicals from nearly all of its adult toiletries and cosmetic products worldwide. During the previous year, the company: pledged to remove “chemicals of concern” from its baby products around the world…. [It] remains on track to have baby products reformulated with safer ingredients by the end of 2013 and it expects to have its adult products reformulated by the end of 2015. Among the ingredients, J&J plans to remove formaldehyde, which “last year was identified by government scientists as a carcinogen” and is released by common preservatives such as quaternium-15, DMDM hydantoin, and 1,4 dioxane, which is:

The recent news that TRICLOSAN introduced in the 1970s and an increasingly popular ingredient in many antibacterial soaps and personal care products was reported in a new study as a substance that can damage both skeletal and heart muscle cells. Researchers affiliated with the University of California, Davis, the University of Colorado, and the Department of Veterans Affairs, Northern California Health Care System published their findings online ahead of print on August 13 in the Proceedings of the National Academy of Sciences (PNAS) (Triclosan impairs excitation–contraction coupling and Ca2+ dynamics in striated muscle PNAS 2012 109 (35) 14158-14163; published ahead of print August 13, 2012, doi:10.1073/pnas.1211314109) The abstract reveals that:

created during a process commonly used to make other ingredients gentler on the skin.

Triclosan (TCS), a high-production–volume chemical used as a bactericide in personal care products, is a priority pollutant of growing concern to human and environmental health.”

President, Skineco, International Association of Ecologic Dermatology, Milan, Italy • www.riccardaserri.it

SKINmed. 2013;11:49–50

The Bulletin of the International Association

January/February 2013

Volume 11 • Issue 1

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

Hair Extensions: Novel “Source” of a Well-Known Contact Allergen Razvigor Darlenski, MD, PhD;1 Jana Kazandjieva, MD, PhD;2 Nikolai Tsankov, MD, PhD, MSc1

31-year-old Caucasian woman presented with complaints of pruritic eruption on the site of attachment of hair extensions (Figure 1). Several days after the initial involvement of the site of integration, the process spread on the flexural aspect of the body and the extremities (Figure 2). On examination, erythematous papules coalescing into plaques and single vesicles were noticed. Excoriations with itching were also observable. The patient had no previous history of skin diseases. Her personal and family histories were positive for allergic rhinitis. The clinical findings corresponded to contact eczema, and adverse allergic reaction to the adhesive material of the hair extension was suspected. Patch testing was performed with European baseline series, adhesive series, and with the adhesive “as is.” Day 2 (Figure 3) and day 3 readings of the patch test revealed positive reaction to paraphenylenediamine. No reaction to the adhesive components or the material itself was observed. The patient dyed her hair many times before; however, no skin reactions were seen until the application of the hair extension. Removal of the hair extensions was advocated as well as complete avoidance of paraphenylenediamine (PPD)-containing products (mostly hair dyes and colorants). In addition, topical symptomatic treatment with mometasone furoate 0.1% scalp solution and cream was administered for a short period, which resulted in complete clearance of the skin and scalp lesions. During the 3-month follow-up, the patient had no further complaints. DISCUSSION Hair extension or integration is a method of adding commercial hair to natural hair when thinning or extensive loss of hair is evident. Different ways of adhesion of the new hair fibers exist, such as sewing, metal and plastic clips, thread, or adhesive. Herein, a case of contact dermatitis after the placement of adhering hair extension is described.

The term scalp dermatitis encompasses a condition with different origins and similar morphologic characteristics as eczema/dermatitis. The most common type of scalp dermatitis is seborrhoeic, with typical predilection sites and intermittent course. Atopic eczema can affect the capillitium especially in children, with a rate of up to 49% of all infants and adolescents.1 Recently, the concept of “sensitive scalp” was introduced in analogy to the sensitive skin syndrome on the face: increased stinging, itching, pricking, or burning sensation on the scalp most often without objective symptoms.2,3 This condition is overlooked by many dermatologists even though the scalp is the most commonly affected site after facial and hand skin.2 Triggering factors include climatic conditions such as cold, heat, dry air, water exposure, hair cosmetics, and emotional stress.4 A schematic overview on the causes for scalp dermatitis is depicted in Figure 4. Contact dermatitis is observed in the scalp although it is not very prevalent. In one study, 22 (4%) of 3684 eczema patients had scalp involvement solely, whereas head and neck involvement was observed in 15%.5 No gender predominance can be outlined in contrast to other skin sites of contact dermatitis. In addition, contact allergy is more common than irritant allergy, contrary to the glabrous skin where irritancy is more often observed. Dermatitis on the scalp was negatively associated with polysensitization (odds ratio, 0.66) primarily in individuals without atopic history.6 A list of the most common contact allergens and irritants is shown in the Table. The majority of contact allergic dermatitis cases affecting the scalp region are caused by PPD, a widely used colorant in hair dyes. It is a lay belief, however, that dermatitis caused by hair dyes constituents is restricted to the scalp. The most common sites of contact allergy to hair dyes is not the scalp but the eyelids, frontal line, neck, and ears (Figure 5).7 The reason for this phenomenon is not quite clear. A possible explanation could be that the allergen penetrates rapidly through the follicles and there is not enough time for the sensitization and elicitation of dermatitis. In our case,

From the Department of Dermatology and Venereology, Tokuda Hospital-Sofia,1 and the Department of Dermatology and Venereology, Faculty of Medicine, Medical University, Sofia, Bulgaria2 Awarded the Edward L Keyes Award, February 1, 2012, Cancun, Mexico Address for Correspondence: Razvigor Darlenski, MD, PhD, Department of Dermatology and Venereology; Tokuda Hospital Sofia, 51B Nikola Vaptzarov Boulevard, 1407 Sofia, Bulgaria • E-mail: darlenski@abv.bg

SKINmed. 2013;11:51–53 (See also page 10)

January/February 2013

CASE STUDY

Figure 1. Erythema and fine scaling at the sites of contact of the hair extension adhesive to the scalp skin.

Figure 2B. Dissemination of the erythematous papulous eruption to the flexural aspects of the patient’s trunk and extremities.

Figure 2A. Dissemination of the erythematous papulous eruption to the flexural aspects of the patient’s trunk and extremities.

dermatitis caused by PPD was observed on the scalp but not on any other common sites. We hypothesize that the adhesive of the hair extensions served as an occlusive agent and a reservoir for the allergen, which facilitated the elicitation of dermatitis reaction on the scalp and enhanced the secondary dissemination of the eruption. This could explain why the patient, who had dyed her hair many times before, developed the reaction only after the application at the site of the extensions. Figure 3. Positive reaction to paraphenylenediamine on day 2 of the patch testing.

CONCLUSIONS We propose a practical algorithm for the diagnostic approach to the patient with scalp dermatitis (Figure 6). Scalp dermatitis is not a uniform disease, and different causes for eczematous SKINmed. 2013;11:51–53

lesions on the scalp exist; therefore, contact allergy should be excluded as an aggravating or causative factor.

Hair Extensions

January/February 2013

CASE STUDY

SCALP DERMATITIS

Atopic

Contact

Seborrhoeic

Irritant

Table. Contact Irritants and Allergens in Contact Dermatitis of the Scalp

Miscellaneous

Sensory

Allergic

(sensitive scalp)

Figure 4. A classification of scalp dermatitis.

IRRITANTS

ALLERGENS

Tar

Paraphenylenediamine

Dithranol (anthralin)

Thioglycolates (permanent wave solutions)

Minoxidil

Persulfates (hair bleaches)

Hair highlighters (hydrogen peroxide, persulfates, and metasilicate)

Nickel (hair clasps and metal accessories)

Detergent surfactants (shampoos and soaps)

Fragrances, preservatives (MDBGN, Kathon CG, parabens), emulsifiers in rinse-off products

Plant extracts (eg, Veratrum lobelianum, false hellebores, or corn lilies)

Quinine (hair loss lotions) Bovine collagen (hair conditioner)

Acknowledgment: The following case presentation was bestowed the Edward Keyes Award during the 8th World Congress of Cosmetic Dermatology by the International Academy of Cosmetic Dermatology, Cancun, Mexico, in 2012. REFERENCES Figure 5. Typical sites of involvement of dermatitis caused by hair dyes.

Is it dermatitis? NO

YES

Objective symptoms

Aggravation by allergens/irritants

YES

Differentials

Sensitive scalp

Diagnosis and treatment

Patch test

Allergen/irritant avoidance

Laboratory evaluation: microbiology, histology, immunology

YES

Personal and/or family history of atopy YES

Shi M, Zhang H, Chen X, et al. Clinical features of atopic dermatitis in a hospital-based setting in China. J Eur Acad Dermatol Venereol. 2011;25:1206–1212.

Misery L, Sibaud V, Ambronati M, et al. Sensitive scalp: does this condition exist? An epidemiological study. Contact Dermatitis. 2008;58: 234–238.

Saint-Martory C, Roguedas-Contios AM, Sibaud V, et al. Sensitive skin is not limited to the face. Br J Dermatol. 2008;158:130–133.

Fluhr JW, Darlenski R, Berardesca E. Ethnic groups and sensitive skin: two examples of special populations in dermatology. Drug Discovery Today: Disease Mechanisms. 2008;5:e249–e263.

Goh CL. Eczema of the face, scalp and neck: an epidemiological comparison by site. J Dermatol. 1989;16:223–226.

Carlsen BC, Andersen KE, Menne T, Johansen JD. Sites of dermatitis in a patch test population: hand dermatitis is associated with polysensitization. Br J Dermatol. 2009;161:808–813.

Davies RF, Johnston GA. New and emerging cosmetic allergens. Clin Dermatol. 2011;29:311–315.

Intermittent course; predilections Seborrhoeic dermatitis

Figure 6. Practical algorithm and diagnostic approach to the patient with scalp dermatitis.

SKINmed. 2013;11:51–53

Hair Extensions

January/February 2013

Volume 11 • Issue 1

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

Combining Field Therapies for Actinic Keratoses: Novel Approaches that Intensify Photodynamic Therapy Edidiong Celestine Ntuen Kaminska, MD, MBS; Maria M. Tsoukas, MD, PhD

Actinic keratosis (AK) is a common dermatologic condition resulting from long-term sun exposure. It is considered a precancerous lesion that may convert into a squamous cell carcinoma, which highlights the importance of prompt identification, early treatment and eradication of AK, and recurrence monitoring. Currently, there are many treatments available for widespread AKs that include a combination of local lesion destruction along with stimulation of an individual’s immune response. Preliminary data from combination therapy studies demonstrate that these may offer improved efficacy, tolerability, and long-term results compared with monotherapy. The authors investigate combination systems aimed at intensifying photodynamic therapy for the treatment of AKs as reported at the 8th World Congress of the International Academy of Cosmetic Dermatology in Cancun, Mexico, and include a comprehensive literature review. Further investigations and data collection are in progress in order to solidify these promising results.

ctinic keratoses (AKs) are considered precancerous skin lesions that are primarily induced by long-term sun exposure and mainly occur in individuals with fair skin. The evolution of AK to squamous cell carcinoma is controversial. Studies estimate a conversion range of 6% to 20% during a 10-year period.1 This highlights the importance of prompt identification and effective treatment for AKs. Various modalities have been employed in AK therapy. These mostly entail a combination of local lesion destruction along with stimulation of an individual’s immune response. Cryotherapy, electrodessication and curettage, laser ablative techniques, and dermabrasion as single therapies are suitable for treating some lesions; however, field therapies such as topical chemotherapy, nonsteroidal anti-inflammatory agents, immunomodulators, chemical peels, lasers, or photodynamic therapy (PDT) are suitable for simultaneously treating multiple clinical and subclinical lesions. Singly, these treatment modalities are effective in treating AKs but may require application during several weeks or multiple sessions. Sequential therapy studies for AKs have been derived from small pilot studies, case series, anecdotal evidence, or individual preference, and no solid data exist demonstrating efficacy

and recurrence rates in the elderly or patients at high risk for nonmelanoma skin cancer. Preliminary data from our institution suggest that sequential topical 5-fluorouracil (5-FU) and 5-aminolevulinic acid (ALA) with PDT (ALA-PDT) can lead to intensified PDT outcomes. Here, we discuss combination systems aimed at intensifying PDT for the treatment of AKs as reported at the 8th World Congress of the International Academy of Cosmetic Dermatology (IACD) in Cancun, Mexico. PHOTODYNAMIC THERAPY PDT is a modality that requires 3 components: a light-sensitizing agent, a light source that emits a specific wavelength that is preferentially absorbed by a photosensitizer, and the presence of oxygen. Exogenous topically applied ALA is highly absorbed by rapidly proliferating cells and utilizes the cell’s heme synthesis pathway to produce protoporphyrin IX (PpIX), which is the photosensitizing agent. These cells become overloaded with PpIX, and exposure to light leads to photoactivation and local phototoxicity that results in cell death (Figure 1). Therefore, PDT causes selective destruction of targeted abnormal premalignant or malignant cells while preserving surrounding normal structures.

From the Section of Dermatology, Department of Medicine, University of Chicago, Prtizker School of Medicine, Chicago, IL Awarded the Edward L Keyes Award, February 1, 2012, Cancun, Mexico Address for Correspondence: Maria M. Tsoukas, MD, PhD, Section of Dermatology, Department of Medicine, University of Chicago, Prtizker School of Medicine, 5841 South Maryland Avenue, Chicago, IL 60637 • E-mail: mtsoukas@medicine.bsd.uchicago.edu

SKINmed. 2013;11:54–58 (See also page 10)

January/February 2013

CASE STUDY

Figure 1. Schematic of photodynamic therapy. Destruction of actinic keratoses by photodynamic therapy requires 3 key components: a photosensitizer, a light source, and tissue oxygen.

POTENTIATING PDT

5-FU AND PDT

The concept of intensifying the effect of PDT has recently been explored. The goals are to facilitate the absorption of topically applied ALA, increase light penetration into the skin, and/or promote the transformation of ALA to PpIX. Trials that have demonstrated increased PDT efficacy while combining different field therapies are briefly outlined in Table I.

5-FU inhibits DNA synthesis by blocking thymidylate synthetase and demonstrates preferential uptake and destruction by rapidly proliferating cells, such as in AKs. Pilot studies have shown the enhancement of PDT with 5-FU.2,3 In our patient population, we have seen complete resolution and decreased facial AKs in patients treated with a single sequential round of 5-FU–ALA PDT

Table I. Combination Field Therapies for AK

REFERENCE TYPE OF STUDY

TREATMENT LOCATION/ PATIENT NO.

METHOD

INCUBATION PERIOD

LIGHT SOURCE

FOLLOW -UP

ADVERSE EFFECTS

OUTCOMES

Galitzer6

Dorsal hands and forearms/10

Tazarotene 0.1% gel, 2 times per d for 1 wk vs control. ALA 20% applied to all sites

1 h ALA under occlusion

Blue light (BLU-U, Dusa Pharmaceuticals), 16 min 40 s, total light dose 10 J/cm2

8 wk

Increased erythema with tazorotenetreated arm 5 min after ALA-PDT

Comparable reduction percentages of AKs in tazorotenepretreated arm and control at 8 wk, although significant difference of tazorotene-treated group from baseline compared with control

Randomized: Conventional PDT vs tazarotene 0.1% gel-PDT

Continued SKINmed. 2013;11:54–58

Combining Field Therapies for Actinic Keratoses

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CASE STUDY

Table I. Combination Field Therapies for AK (Continued)

REFERENCE TYPE OF STUDY

TREATMENT LOCATION/ PATIENT NO.

METHOD

INCUBATION PERIOD

LIGHT SOURCE

FOLLOW -UP

ADVERSE EFFECTS

OUTCOMES

Gilbert2

Case series: 5FU-ALA PDT vs ALAPDT

Face/15

Pretreatment with 5-FU (Efudex, ICN Pharmaceutical, Inc, Costa Mesa, CA) applied daily to face for 5 d, followed by ALA 20% on the 6th day

30–45 min ALA

Single-pass 560-1200 nm IPL (VascuLight or Lumenis One, Lumenis, Israel). Average of 95 pulses in a single treatment. Double pulses 30 J/cm2 at 2.4 and 4.0 ms with 20-ms delay

12 mo

Diffuse erythema and scaling in all patients at 3 or 4 d. Crusting and itching also reported. All patients completed the study.

90% of treated AKs resolved in all but 1 patient who had 50% resolution. Skin texture clinically improveda

Martin3

5FU-ALA PDT/split face/ arms case series

Face and arms/3

Pretreatment with 5-FU cream 0.5% (Carac, Dermic Laboratories, Bridgewater, NJ) applied daily to 1 site for 7 or 10 d. Next 5-ALAa to all sites. Rechallenge to all sites with daily 5-FU cream for 7 d, 3 or 7 mo after ALA-PDT. Then ALA-PDT 7 d afterward

1 h ALA for face, 2 h for arms

Blue light (BLU-U, Dusa Pharmaceuticals), 16 min 40 s

6 mo

Erythema, edema, and crusting of 5-FU pretreated site 3 or 4 d after ALA-PDT treatment. Areas previously treated with ALA-PDT only developed inflammation, irritation, and crusting after 2nd application of 5-FU cream.

No visible AKs and improved skin textureb

Shaffelburg5

Randomized: Conventional PDT vs PDTimiquimod

Face/25

PDT was pretreatment in this study. ALA 20% to the whole face followed by PDT at baseline then repeated 1 mo later. At month 2, imiquimod 5% cream (Aldara) 1 sachet 2 times per d, 2 times per wk for 16 wk to one side of face and vehicle to the other side

1 h ALA

Blue light (BLU-U, Dusa Pharmaceuticals) for 8 min

12 mo

Imiquimodassociated adverse skin reactions included erythema, flaking/scaling/dryness, and scabbing/ crusting

Median AK count reduction 89.9% PDT-imiquimod vs 74.5% conventional PDT

Togsverd et al.8

Randomized: Conventional PDT vs AFXLPDT

Face and scalp/15

Pretreatment with AFXL vs control. All sites then had MAL (Metvix cream 16%; Galderma, La Defense, France) applied, 1-mm thickness

3 h MAL under occlusion

Red light– emitting diode (Aktilite CL128; Galderma), peak emission 632 nm, total light dose 37 cm2 AFXL laser (Lumenis Inc, Santa Clara, CA), 12-mm spot size, 10 mJ/pulse, single pulse, 5% density

3 mo

Pain during illumination, erythema, crusting, and long-term pigmentatry changes greater in AFXL-PDT vs PDT

Complete resolution of AKs with AFXL-PDT vs PDT (88% vs 59%) and improved photo aging with AFXL-PDT

SKINmed. 2013;11:54–58

Combining Field Therapies for Actinic Keratoses

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CASE STUDY

Table I. Combination Field Therapies for AK

REFERENCE TYPE OF STUDY

TREATMENT LOCATION/ PATIENT NO.

METHOD

INCUBATION PERIOD

LIGHT SOURCE

FOLLOW -UP

ADVERSE EFFECTS

OUTCOMES

van der Geer and Krekels7

Dorsal hands/10

Diclofenac 3% gel 2 times per d for 4 wk vs vehiclehyaluronic acid (control). 2 wk after last diclofenac application, all sites had topical ALA appliedb

4-h ALA under occlusion

Red light, 633 nm (Omnilux; Waldmann, Tiel, The Netherlands), 16 min, light fractions of 80 J/cm2

12 mo

One patient pretreated with diclofenac 3% gel developed swollen, red, erosive hand that resolved after 1 wk. Increased pain in diclofenac group although not statistically significant

Total lesion score demonstrated decreased lesions on pretreated hand vs placebo (decrease 12.5 vs 8.8), total thickness score comparable in both groups, and global improvement indices greater in diclofenac group although not statistically significant

Randomized/ Conventional PDT vs diclofenac 3% gel-PDT

Abbreviations: 5-FU, 5-fluorouracil; AFXL, ablative fractional laser resurfacing, AK, actinic keratoses; ALA, aminoleuvulinic acid (ALA 20%, Levulan Kerastick, Dusa Pharmaceuticals, Inc, Wilmington, MA); PDT, photodynamic therapy. aNo objective assessment tool was utilized. bStrength and company not provided.

Figure 2. Sequential topical 5% 5-fluorouracil (5-FU) and 5-aminolevulinic acid photodynamic therapy. Before treatment—extensive actinic keratoses on the forehead and temples (A), after 2 weeks of daily 5-FU (B), and after 9 months of sequential therapy, with no actinic keratoses on the forehead or temples (C).

over a 1-year period (unpublished data, Figure 2). Topical 5% 5-FU cream was applied daily over 7 to 14 days followed by one treatment of ALA-PDT within 1 week after cessation of topical therapy. Because topical 5-FU is broadly affordable for most patients and can lead to more reproducible results when compared with topical immunomodulators,4 it is a logical adjunctive treatment option. The goal of pretreatment with 5-FU is to cause moderate inflammation of AKs and intensify PDT, compared with monotherapy endpoints of topical 5-FU, which eradicate AKs by causing erosions and ulcerations that may potentially decrease compliance and result in poor cosmesis. SKINmed. 2013;11:54–58

IMIQUIMOD AND PDT Imiquimod is a toll-like receptor agonist that acts as an immune system modifier and stimulates apoptosis and disrupts tumor proliferation. Unfortunately, this response is not consistently reproducible per individual case, especially when patients are chronically immunosuppressed. Despite this, it is an effective and safe treatment option for AKs in the elderly and solid organ transplant patients. Sequential use of ALA-PDT and imiquimod has been described for adults with facial AKs. A trial compared ALA-PDT with and without imiquimod 5% cream in 25 patients who were first treated with ALA-PDT at baseline and then again at 1 month.5

Combining Field Therapies for Actinic Keratoses

January/February 2013

CASE STUDY

At month 2, imiquimod 5% cream was applied to half of the face and vehicle to the other half, 2 times per week for 16 weeks. At 1-year follow-up, the reduction in median lesion count was 89.9% in the imiquimod-treated group vs 74.5% in the control group, demonstrating the possible effectiveness of ALA-PDT followed by topical imiquimod.

was a more effective treatment for field decancerization of AKs than conventional PDT. OTHER PDT-INTENSIFYING AGENTS Multiple unpublished modalities to potentiate PDT for AK treatment have been used. Few cases described at the IACD conference included pretreatment with other lasers such as the Thulium or Erbium:Yag, chemical peels, or a mechanical roller pin, which created micropuncture zones in the skin to facilitate ALA absorption.

RETINOIDS AND PDT Topical retinoids can be used alone or in conjunction with PDT to treat AKs. Retinoids normalize the differentiation of dysplastic epithelium in AKs, prevent the formation of UV-induced lesions, and improve the appearance and texture of photodamaged skin. One study in the published literature compared the use of topical tazarotene 0.1% gel twice daily for 1 week before ALA-PDT with ALA-PDT alone (control).6 Ten patients with AKs on the dorsal forearms or hands were treated with combination therapy on one site, while the opposing site was treated with only ALA-PDT. Eight weeks after baseline, a significant difference in the entire treatment area was observed in the tazarotene pretreatment group compared with the control group. It was concluded that pretreatment of AKs on the dorsal hands and forearms with tazarotene gel may enhance the therapeutic effect of ALA-PDT. DICLOFENAC GEL AND PDT Diclofenac 3% gel is a nonsteroidal anti-inflammatory agent that has shown efficacy in treating AKs. It is a potent inhibitor of inducible cyclooxygenase, resulting in a reduction of prostaglandin synthesis and therefore AKs, which have demonstrated raised prostaglandin levels. The efficacy of diclofenac as pretreatment for AKs on the dorsal hands followed by ALA-PDT was evaluated in a study of 10 patients.7 Hands were either pretreated with diclofenac gel or placebo gel, followed by ALA-PDT. At 12-month follow-up, significantly fewer AKs were noted in the diclofenac group.

SIDE EFFECTS For most field therapies combined with PDT, major side effects are increased pain and erythema compared with PDT as monotherapy. Although considerable, these are manageable aspects when comprehensive education, skin cooling during PDT, postoperative instructions, and close clinical follow-up are provided. CONCLUSIONS AK combination therapy with PDT may offer improved efficacy compared with monotherapies. Moreover, these may decrease treatment costs and improve cosmetic outcomes. The ultimate goal is to intensify PDT, possibly by increasing ALA concentration and PpIX production in lesional skin along with enhancing light penetration. Preliminary data on combination modalities are promising in eradicating AKs. Further prospective, randomized controlled trials may substantiate and refine PDTintensifying methods and combination options. REFERENCES 1

Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115:2523–2530.

Gilbert DJ. Treatment of actinic keratoses with sequential combination of 5-fluorouracil and photodynamic therapy. J Drugs Dermatol. 2005; 4:161–163.

Martin G. Prospective, case-based assessment of sequential therapy with topical Fluorouracil cream 0.5% and ALA-PDT for the treatment of actinic keratosis. J Drugs Dermatol. 2011;10:372–378.

Tanghetti E, Werschler P. Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol. 2007;6:144–147.

Shaffelburg M. Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream. J Drugs Dermatol. 2009;8:35–39.

Galitzer BI. Effect of retinoid pretreatment on outcomes of patients treated by photodynamic therapy for actinic keratosis of the hand and forearm. J Drugs Dermatol. 2011;10:1124–1132.

Van der Geer S, Krekels GA. Treatment of actinic keratoses on the dorsum of the hands: ALA-PDT versus diclofenac 3% gel followed by ALA-PDT. A placebo-controlled, double-blind, pilot study. J Dermatolog Treat. 2009;20:259–265.

Togsverd-Bo K, Haak CS, Thaysen-Petersen D, et al. Intensified photodynamic therapy of actinic keratoses with fractional CO2 laser: a randomized clinical trial. Br J Dermatol. 2012;166:1262–1269.

LASERS AND PDT Recently, the efficacy and safety of ablative fractional laser resurfacing (AFXL)–assisted PDT (AFXL-PDT) compared with conventional PDT was reported.8 The premise for this combination was to demonstrate that AFXL augments PDT by facilitating the uptake of methyl aminolevulinate by creating vertical channels in the skin. Fifteen patients with facial and scalp AKs received treatment with either PDT or AFXL-PDT in 2 symmetrical areas. The study results demonstrated that AFXLPDT was significantly more effective than PDT for all AKs (up to 100% vs 79% clearance) at 3-month follow-up. Also, improved photoaging with AFXL-PDT vs PDT-treated skin was noted. Based on these initial findings, it was concluded that AFXL-PDT SKINmed. 2013;11:54–58

Combining Field Therapies for Actinic Keratoses

January/February 2013

Volume 11 • Issue 1

CASE STUDY

New Side Effect of TNF-` Inhibitors: Morphea Faith A. Stewart, MD;1 Alde Carlo P. Gavino, MD;2 Boni E. Elewski, MD1 An otherwise healthy 45-year-old man with a 3-year history of poorly controlled psoriasis (no arthritis) was treated with etanercept 50-mg subcutaneous injections twice weekly for 3 months and then once weekly. Alternative treatment options were either unavailable (long commute for phototherapy) or contraindicated (history of alcohol abuse). The patient initially tolerated etanercept well with significant clinical improvement and had an uneventful course; however, approximately 18 months after initiating therapy, he abruptly developed dusky, indurated, and tender plaques on his abdomen and thighs at the sites of etanercept injections (Figure 1). There was also diffuse woody induration involving his flanks and back where injections had not been performed. His only recent prior exposure to an injectable medication was rabies vaccination in his arm 1 year earlier. The patient denied any systemic symptoms. Upon noting these findings, etanercept was immediately discontinued. Biopsy of an indurated plaque on his right lower abdomen revealed a superficial and deep perivascular lymphoplasmacytic inflammatory infiltrate in a background of thickened and hyalinized collagen fibers with notable loss of perieccrine fat (Figure 2). These features were most consistent with the inflammatory stage of morphea. Further work-up revealed a negative antinuclear antibody, anti–double-stranded DNA, anti-Scl-70, and anti-centromere. Borrelia titers were not obtained. The differential diagnosis included scleredema and scleromyxedema; serum and urine protein electrophoresis were within normal limits. The sites were treated with intralesional corticosteroids. During the next 3 months, there was minimal progression of disease although the plaques of morphea had not yet resolved.

umor necrosis factor α (TNF-α) antagonists have been associated with several adverse cutaneous events including infusion/injection site reactions, psoriasis onset or exacerbation, lupus-like syndromes, infections, and vasculitis.1 To our knowledge, this is the second reported case demonstrating morphea associated with anti-TNF therapy. The first case recently described a 17-year-old woman with Crohn’s disease who developed morphea after 6 injections of adalimumab.2 Her lesions occurred only at injection sites and resolved with topical corticosteroids and Endermologie massage therapy. These two cases suggest that this is likely a real association. The investigator hypothesized that the mechanism leading to sclerosis may be related to inhibition of the antifibrotic effects of TNF-α by the biologic agents. This theory has been supported by in vitro studies demonstrating that TNF-α can prevent the expression of TGF-β receptor proteins and the activation of TFG-β genes.3 This investigator also suggested that immunosuppression from TNF-α antagonism enhances susceptibility to infections that may trigger localized scleroderma.

CONCLUSIONS Of note, our patient was vaccinated for rabies 1 year prior; however, the site of vaccination was distant from where the morpheaform plaques developed. In addition, there are no published reports of morphea associated with the rabies vaccine, although cases of morphea developing at the site of vaccinations including hepatitis B and antitetanus do exist.4,5 Local trauma may also induce morphea; however, our patient developed diffuse induration, which can not be explained by trauma alone. While a direct cause-and-effect relationship can not be conclusively proven, this case, as well as the previous investigators’, warrants further investigation into whether additional instances of morphea associated with anti–TNF-α therapy exist. If so, this may be a new side effect with potential long-term consequences. Disclosures: This manuscript is an original document that is not a duplication of any work another party has ever produced. Any affiliation or financial involvement that we may have with an organization expressing financial interest or conflict with the content of this document has been fully disclosed and we have no financial or other economic interest in this document.

From the Department of Dermatology,1 and the Division of Dermatopathology,2 University of Alabama School of Medicine, Birmingham, AL Address for Correspondence: Boni E. Elewski, MD, Department of Dermatology, University of Alabama School of Medicine, 1530 3rd Avenue South, EFH 414, Birmingham, AL 35294-0009 • E-mail: beelewski@aol.com

SKINmed. 2013;11:59–60

January/February 2013

CASE STUDY REFERENCES

Figure 1. Depressed and indurated plaque on the right thigh (A). Firm erythematous plaque on the abdomen with biopsy site (black arrow) (B).

Borras-Blasco J, Navarro-Ruiz A, Borras C, Castera E. Adverse cutaneous reactions induced by TNF-antagonist therapy. South Med J. 2009;102:1133–1140.

Mattozzi C, Richetta AG, Cantisani C, et al. Morphea, an unusual side effect of anti-TNF-alpha treatment. Eur J Dermatol. 2010;20:400–401.

Yamane K, Ihn H, Asano Y, Jinnin M, Tamaki K. Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGFbeta receptor type II in human dermal fibroblasts. J Immunol. 2003; 171:3855–3862.

Drago F, Rampini P, Lugani C, Rebora A. Generalized morphea after antitetanus vaccination. Clin Exp Dermatol. 1998;23:142.

Schmutz JL, Posth M, Granel F, Trechot P, Barbaud A. Localized scleroderma after hepatitis B vaccination. Presse Med. 2000;29:1046.

A B Figure 2. Squared-off punch biopsy from the right lower part of the abdomen with superficial and deep perivascular inflammation, prominent sclerosis, and loss of hair follicles (A). Higher-power magnification demonstrating thickened and hyalinized collagen with entrapment of adnexae (B). (Hematoxylin-eosin stain original magnifications, ×20 [A] and ×200 [B]).

HISTORY OF DERMATOLOGY SOCIETY

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2013;11:59–60

Morphea

This Little Piggy Had ONMEL

™

(itraconazole) 200-mg tablets

Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus

Drug plasma concentration increased by itraconazole

Cardiac disorders: Congestive heart failure

Antiarrhythmics: digoxin, dofetilide, quinidine, disopyramide

This list is not all-inclusive.

For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Selected drugs that are contraindicated for use with itraconazole1 Antipsychotics: pimozide Antiarrhythmics: dofetilide, quinidine Benzodiazepines: oral midazolam2, triazolam

This list is not all-inclusive.

For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Antiarrhythmics The Class IA antiarrhythmic, quinidine and

January/February 2013

7PMVNF t *TTVF

BOOK REVIEW Jennifer L. Parish MD, Section Editor

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SKINmed. 2013;11:64–64

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At Stiefel, a GSK company, science is at the heart of everything we do. With access to a screening library of more than 2 million compounds,* our researchers are dedicated to pursuing new products that can make a true difference in dermatology. We understand the science of skin health and that when developing innovative dermatologic products, formulation matters. Because we value healthy skin just as much as our patients do. *On ďŹ le with Helium, GSK.

Stiefel, a GSK company Advancing Dermatology and Skin Health for 165 Years

The skin. The largest organ of the human body. Gentle yet strong. It shields and protects us. Our job is to help keep the skin healthy and looking vibrant. We have the science and passion to deliver.

Stiefel, a GSK company Dedicated to Keeping Skin Healthy for 165 Years