Mar / April 2013 by jo-ann kalaka-Adams

March/April 2013 • Volume 11 • Issue 2 EDITORIAL Pyogenic Granuloma: An Enigma Within a Paradox or a Solution in Search of a Problem

new to the clinic Absorica (Isotretinoin): A New Form Scheinfeld

Yazdanian, Parish, Lambert, and Lambert

COMMENTARY Muckle-Wells Syndrome: Individualized, Reflare-Guided Dosing of the Orphan Drug Canakinumab Mueller, Itin, and Haeusermann

ORIGINAL CONTRIBUTIONS Assessment of the Antidandruff Activity of a New Shampoo: A Randomized, Double-Blind, Controlled Study by Clinical and Instrumental Evaluations

CASE STUDIES Treatment of Necrobiotic Xanthogranuloma With 2-Chlorodeoxyadenosine Sutton, Sutton, and Sutton

Phacomatosis Pigmentokeratotica—A Patient With Hypophosphatemic Rickets

de Morais, Costa, Shinzato, de Castro Wiziack, and Hans-Filho

Sparavigna, Setaro, Caserini, and Bulgheroni

Persistent Serpentine Supravenous Hyperpigmentation— A Possible Cutaneous Manifestation of HIV Infection or a Normal Racial Variant: A Report of 3 Cases O’Malley, Lieb, Weiser, and Grossman

CORE CURRICULUM Lichen Planus Pigmentosus

Sehgal, Verma, Bhattacharya, Sharma, and Rasool

DEPARTMENTS New therapy update ONMEL (Itraconazole) 200-mg Tablet Gupta, Paquet, and Abramovits

PICATO (Ingenol Mebutate 0.015% and 0.05% Gels): A Novel Treatment for Actinic Keratosis Abramovits, Oquendo, Vincent, and Gupta

Lebanese Dermatological Society

Twice as Strong Half as Long

More than

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Topical Antifungal Brand Prescribed by Dermatologists 1 and Podiatrists

of patients were able to adhere to the full course of treatment2,3

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

Indication NAFTIN® (naftifine hydrochloride) Cream 2% is an allylamine antifungal indicated for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum in adult patients ≥18 years of age. Important Safety Information In clinical trials with NAFTIN® Cream 2%, the most common adverse reaction (≥1%) was pruritus. Please see brief Prescribing Information on adjacent page.

www.NAFTIN.com

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TABLE OF CONTENTS March/April 2013 • Volume 11 • Issue 2

EDITORIAL

Pyogenic Granuloma: An Enigma Within a Paradox or a Solution in Search of a Problem............................. 74

Shideh Yazdanian, MD; Lawrence Charles Parish, MD, MD (Hon); Peter C. Lambert, BA, MA; W. Clark Lambert, MD, PhD

COMMENTARy

Muckle-Wells Syndrome: Individualized, Reflare-Guided Dosing of the Orphan Drug Canakinumab............. 80

Simon M. Mueller, MD; Peter Itin, MD; Peter Haeusermann, MD

ORIGINAL CONTRIBUTIONs

Assessment of the Antidandruff Activity of a New Shampoo: A Randomized, Double-Blind, Controlled Study by Clinical and Instrumental Evaluations........................................................................... 85

Adele Sparavigna, MD; Michele Setaro, Eng; Maurizio Caserini, MD; Anna Bulgheroni, MSc

Persistent Serpentine Supravenous Hyperpigmentation—A Possible Cutaneous Manifestation of HIV Infection or a Normal Racial Variant: A Report of 3 Cases..................................................................... 93

John T. O’Malley, MD, PhD; Jocelyn L. Lieb, MD; Jessica A. Weiser, MD; Marc E. Grossman, MD

core curriculum Virenda N. Sehgal, MD, Section Editor

Lichen Planus Pigmentosus......................................................................................................................... 96

Virendra N. Sehgal, MD; Prashant Verma, MD; Sambit N. Bhattacharya, MD; Sonal Sharma, MD; Farhan Rasool, MD

Departments New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

ONMEL (Itraconazole) 200-mg Tablet......................................................................................................... 105

Aditya K. Gupta, MD, PhD; Maryse Paquet, PhD; William Abramovits, MD

PICATO (Ingenol Mebutate 0.015% and 0.05% Gels): A Novel Treatment for Actinic Keratosis.................. 111

William Abramovits, MD; Marcial Oquendo, MD; Kimberly D. Vincent, MD; Aditya K. Gupta, MD, PhD

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

Absorica (Isotretinoin): A New Form....................................................................................................... 117

Noah Scheinfeld, MD, JD

TABLE OF CONTENTS March/April 2013 • Volume 11 • Issue 2

case studies Vesna Petronic-Rosic, MD, MSc, Section Editor

Treatment of Necrobiotic Xanthogranuloma With 2-Chlorodeoxyadenosine................................................ 121

Leigh Sutton, MD; Stephanie Sutton, BA; Margaret Sutton, MD

Phacomatosis Pigmentokeratotica—A Patient With Hypophosphatemic Rickets......................................... 125

Orlando Oliveira de Morais, MD; Lidiane Oliveira Costa, MD; Dayane Higa Shinzato, MD; Nayara de Castro Wiziack, MD; Günter Hans-Filho, MD, PhD

Editorial

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. 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.

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Composition Paul Bennett paul@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Associate Publisher James R. Adams jadams@skinmedjournal.com

Corporate President Arthur Kalaka akalaka@skinmedjournal.com

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.

Chief Executive Officer Jo-Ann Kalaka-Adams jadams@skinmedjournal.com

General Counsel Marianne Mckenzie mmckenzie@skinmedjournal.com Pulse Marketing & Communications, LLC 4 Peninsula Avenue • Suite 401 • Sea Bright, NJ 07760 Tel (732) 747-6525 • Fax (732) 747-7010

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

Lebanese Dermatological Society

This Little Piggy Had ONMEL

â&#x201E;˘

(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. ÂŠ 2013 Merz Pharmaceuticals, LLC. All rights reserved. 5011975 January 2013

ONMELâ&#x201E;˘ (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. 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

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 This list is not all-inclusive.

1 2

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 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 This list is not all-inclusive.

1 2

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 • 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. • Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when ONMEL and halofantrine are administered concomitantly. • Human pharmacokinetic data suggest that concomitant administration of itraconazole and buspirone results in significant increases in plasma concentrations of buspirone. • Itraconazole may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone. • Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. • Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with ONMEL. • 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. • 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.

• 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

March/April 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 Aditya K. Gupta, MD, PhD, FRCP(C) London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK Tanya R. Humphreys, MD Philadelphia, PA

Joseph L. Pace, MD, FRCP Naxxar, Malta Art Papier, MD Rochester, NY Johannes Ring, MD, DPhil Munich, Germany Roy S. Rogers III, MD Rochester, MN 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 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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March/April 2013

Volume 11 • Issue 2

EDITORIAL

Pyogenic Granuloma: An Enigma Within a Paradox or a Solution in Search of a Problem Shideh Yazdanian, MD;1 Lawrence Charles Parish, MD, MD (Hon);2 Peter C. Lambert, BA, MA;3 W. Clark Lambert, MD, PhD4

yogenic granuloma (PG) presents as an elevated lesion that is associated with easy bleeding. While it may cause concern on the part of the patient, because it bleeds easily when traumatized and is elevated, the clinician usually recognizes this innocuous lesion on inspection. The question arises: How did this benign tumor attract such a formidable name? Background Like the Holy Roman Empire, which was not holy, not Roman, and not an empire, PG is currently believed to be neither pyogenic nor a granuloma. PG was initially described in France in the 1880s, when it was thought to resemble the tumor often created in horses following castration. This was an era when germs of all types were being assigned to various disease causations. Even acne had its own bacterium. PG was attributed to Botrymycetes species and given a new name: botymycosis.

The germ theory did not set well with some clinicians, however, and Milton B. Hatrzell, who would become the second professor of dermatology at the University of Pennsylvania, published a study in 1904 concluding that there was no infectious origin. He proposed the current name pyogenic granuloma.1 The cause, perhaps trauma, would remain elusive, but the name pyogenic granuloma would continue. From the discussion of this paper, presented at the 1904 American Dermatological Association Meeting, PG had previously been ignored or gone unnoticed. A later definitive paper by Henry Michelson of the University of Minnesota would trace the background of PG through 1925.2 Over the years, various observations have been made. Perhaps the most curious invokes hypertension as a contributing factor.3 This is an interesting theory based on the prominent vascular component of the tumor, especially in its later stages, but it

does not seem to be borne out. Some 90 years later, a study was performed in September 2012, which demonstrated that just 3 among 190,000 people with hypertension also had PG.4 Clinical Findings Initially, PG evolves rapidly over a few weeks and then abruptly stops growing; however, spontaneous disappearance is uncommon. PG is not painful, with the main complaint being frequent bleeding. The characteristic lesion is a red to purplish tumor, often on the hands or scalp, but no location seems immune (Figure 1, Figure 2, and Figure 3). It can develop in the mouth, particularly on the gingivae5 and tongue, and sometimes on the genitalia. The conjunctivae, as well as the nasal or sinus passages,6 may give rise to this lesion. PG not uncommonly develops under or near the nail.7 PG has even been documented in internal organs, including the urinary bladder, gastrointestinal tract, trachea, and central nervous system (Figure 1, Figure 2, and Figure 3). PG may be subcutaneous8 or even intravascular.9 It is often solitary but multiple tumors and satellite lesions have been known to occur, sometimes following a drug reaction and/or excision, but why this is so is unclear.10 There is no sex difference, but it has a propensity for children and young adults. A variant occurs in the second and third trimester of pregnancy and is also known as granuloma gravidarum, with an incidence in up to 5% of pregnancies.11 When typical, especially when accompanied by a history of recent penetrating injury at the same site and easy bleeding with or without irritation, it is rarely mistaken for any other lesion. A tabulation of possible differential diagnoses is found in the Table. When hemorrhage is present, however, particularly in a subungual or periungual location, melanoma may be an important differential consideration.

From the Department of Dermatology, Imam University Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran;1 the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;2 St. Georges University School of Medicine, St. Georges, Grenada, W.I.;3 and the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ4 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2013;11:74–77

March/April 2013

EDITORIAL

Figure 1. Clinical manifestation of pyogenic granuloma showing the characteristic red, elevated lesion on the hand.

Figure 3. Clinical manifestation of pyogenic granuloma showing the characteristic red, elevated lesion on the face.

Table. Differential Diagnosis of Pyogenic Granuloma (PG) Red and vascular skin lesions that resemble PG Cherry hemangioma Kaposi sarcoma Bacillary angiomatosis Angiolymphoid hyperplasia with eosinophilia Spitz nevus Venous lakes Granuloma gluteale infantum Infantile hemangioma Skin lesions that resemble PG on the extremities Glomus tumor Acquired digital fibrokeratoma Giant cell tumor of the tendon sheath

Figure 2. Clinical manifestation of pyogenic granuloma showing the characteristic red, elevated lesion on the ear.

Skin lesions that resemble ulcerated PG Atypical fibroxanthoma Squamous cell carcinoma Basal cell carcinoma

Dermatoscopy has been used in diagnosing PG. Unfortunately, as PG progresses, PG becomes indistinguishable from melanoma on dermatoscopy.12

Malignant skin lesions that rarely resemble PG Malignant melanoma Metastatic carcinoma of the skin

Histopathology A diagnostic biopsy is rarely needed. The characteristic histologic picture of an early lesion is an exophytic process consisting of granulation tissue (Figure 4) that gives rise over a few weeks to a lobular proliferation of small blood vessels, which erupt through the epidermis to produce a globular pedunculated tumor (Figure SKINmed. 2013;11:74â&#x20AC;&#x201C;77

Oral lesions that resemble mucosal PG Epulis Metastatic neoplasms to the oral cavity

Pyogenic Granuloma

March/April 2013

EDITORIAL

Figure 5. Pyogenic granuloma: Later lesion with fibrous septae beginning to form between tufts of small blood vessels (hematoxylin and eosin stain, original magnification ×121).

Figure 4. Pyogenic granuloma: Early lesion with granulation tissue and a collaret around the lesion. An ulcerated surface with neutrophilic infiltrate (hematoxylin and eosin stain, original magnification ×121).

5). The epidermis forms a collaret at the base. Early, there is a myxoid stroma, which gives rise to a fine fibrous stroma later. Fibrous septae appear between tufts of small blood vessels (Figure 5). In regressing lesions, there may be extensive fibrosis. At the base, a large “central vein” appears later. A variable feature, particularly likely early, is ulceration, with a prominent neutrophilic infiltrate (Figure 4). Perhaps the early lesion grows too rapidly for the epidermis to keep up with it; alternatively, it is friable and therefore easily develops ulceration secondary to mild trauma. Whatever the cause, ulceration with superficial pus formation is not uncommon in PG and may have been responsible for the notion that the whole lesion is secondary to the pus formation, and not the other way around. This is consistent with the theory, held by many 19th-century physicians, that pus is beneficial, perhaps even essential, for wound healing. This is reinforced by the observation that patients in whom pus did not develop in a surgical wound often did not fare well. Today it is believed that such patients are simply too sick to mount a neutrophilic response, but this is less clear. The presence of pus in PGs was also thought to reinforce this theory, since it seemed to give rise to granulation tissue. A possible third source of this belief, observed by one of the authors (WCL) in a diagnostic microbiology laboratory, is the fact that cultures of Staphylococcus aureus grown on agar plates exude a smell that seems extremely healthful, reminiscent of freshly baked bread. In normal wound healing, granulation tissue extends from both sides of the wound, meets in the middle, and then gives to further stages, such as fibrosis. We suspect that the etiopathogenesis SKINmed. 2013;11:74–77

of PG on skin may be that granulation tissue forms but does not meet its counterpart, and so gives rise to a PG. This may explain why PG tends to form in periungual tissue, where the skin surfaces rarely form a plane, and why young individuals and pregnant women, in whom wound healing proceeds more rapidly, are prone to develop PG. The etiopathogenesis of PG in oral tissue may be more complex, and may be related to the interesting fact that scar tissue either does not form or forms very slowly in oral mucosal tissue. At no point does a PG form a granuloma, defined as a lesion in which epithelioid cells consisting of terminally developed macrophages are present. Thus, a PG, despite its name, does not appear to be either pyogenic or a granuloma. More recently, however, certain proliferative lesions containing prominent vessels have been found to be associated with bacterial infections, one of which is bacillary angiomatosis,13 which commonly arises in immunocompromised patients, particularly those with acquired immunodeficiency syndrome.14 Such lesions are best managed with medical rather than surgical care. Treatment Removal of the PG allays the anxiety of the patient, parent, or spouse who may be imagining all sorts of awful states. Intervention can include anything from curettage to excision and from cryosurgery to laser surgery. Untreated PG slowly regresses, eventually becoming atrophic and fibromatous. Recurrences, sometimes even with satellite lesions, are not uncommon, but reassurance of the benign nature of PG is helpful.

Pyogenic Granuloma

March/April 2013

Editorial

Speculation A PG is comprised of rapidly growing, primitive tissues and is likely to contain a variety of relatively uncommitted stem cells. Indeed, particularly in lesions showing a myxoid stroma, extramedullary hematopoiesis has been documented.15 This raises the question: Could a PG be used as a source tissue for stem cells? Such cells could then be cultured ex vivo and returned to the host to serve a variety of purposes. Culture of stem cells is particularly challenging in the early stages, when development in a PG would most readily substitute for it. As far as we are aware no one has deliberately induced a PG in humans or even in animals, but since it appears to be induced by mild trauma, and to have already been induced inadvertently as a complication of castration in horses,1 this would appear to be feasible. Conclusions Who would have thought that PG could have a systemic association or that this benign tumor started off as a bacterial infection? Or that a lesion that seems to have misled physicians in the 19th century could possibly prove to be so helpful in advancing medicine in the 21st? References

5 Kamal R, Dahiya P, Puri A. Oral pyogenic granuloma: Various concepts of etiopathogenesis. J Oral Maxillofac Pathol. 2012;16:79–82. 6 Smith SC, Patel RM, Lucas DR, McHugh JB. Sinonasal lobular capillary hemangioma: A clinicopathologic study of 34 cases characterizing potential for local recurrence. Head Neck Pathol. 2012 Nov 27 [Epub ahead of print]. 7 Piraccini BM, Bellavista S, Misciali C, et al. Periungual and subungual pyodgenic granuloma. Br J Dermatol. 2010;163:941–953. 8 Fortna RR, Junkins-Hopkins JM. A case of lobular capillary hemangioma (pyogenic granuloma) of the subcutaneous tissue, and a review of the literature. Am J Dermatopathol. 2007;29:408–411. 9 Maher A. Intravenous lobular capillary hemangioma. Ann Vasc Surg. 2010;24:951. 10 Palmero ML, Pope E. Eruptive pyogenic granulomas developing after drug hypersensitivity reaction. J Am Acad Dermatol. 2009;60:855–857. 11 Sills ES, Zegarelli DJ, Hoschander MM, Strider WE. Clinical diagnosis and management of hormonally responsive oral pregnancy tumor (pyogenic granuloma). J Reprod Med. 1996;41:467–470. 12 Zaballos P, Rodero J, Serrano P, et al. Pyogenic granuloma clinically and dermoscopically mimicking pigmented melanoma. Dermatol Online J. 2009;15:10. 13 Al-Thunayan A, Al-Rehaili M, Al-Meshal O, Al-Qattan MM. Bacillary angiomatosis presenting as a pyogenic granuloma of the hand in an otherwise apparently healthy patient. Ann Plast Surg. 2012 Oct 3 [Epub ahead of print].

1 Wile UJ. Granuloma pyogenicum. J Cut Dis incl Syph. 1910;26:663–669. 2 Michelson, HE. Granuloma pyogenicum; a clinical and histologic review of 29 cases. Arch Dermatol Syphilol. 1925;12:492–505. 3 Montgomery DW, Culver GD. Granuloma pyogenicum and high blood pressure. J Cut Dis incl Syph. 1917;35:338– 343. 4 h t t p : / / w w w. e h e a l t h m e. c o m / c s / h y p e r t e n s i o n / pyogenic+granuloma. Accessed October 1, 2012.

14 Schwartz RA, Nychay SG, Janniger CK, Lambert WC. Bacillary angiomatosis: presentation of six patients, some with unusual features. Br J Dermatol. 1997;136:60–65. 15 Vega Harring SM, Niyaz M, Okada S, Kudo M. Extramedullary hematopoiesis in a pyogenic granuloma: A case report and review. J Cutan Pathol. 2004;31:555–557.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2013;11:74–77

Pyogenic Granuloma

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PLAQUE PSORIASIS OF THE SCALP AND BODY IN PATIENTS 18 YEARS AND OLDER

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Important Safety Information for SORILUX Foam SORILUX Foam should not be used by patients with known hypercalcemia The propellant in SORILUX Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application Transient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored Instruct the patient to avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning booths and sun lamps. Physicians may wish to limit or avoid use of phototherapy in patients who use SORILUX Foam

Please see Brief Summary of Prescribing Information on the next page.

Adverse reactions reported in ≥1% of subjects treated with SORILUX Foam and at a higher incidence than subjects treated with vehicle were application site erythema (2%) and application site pain (3%). The incidence of these adverse reactions was similar between the body and scalp SORILUX Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SORILUX Foam is administered to a nursing woman Safety and effectiveness of SORILUX Foam in pediatric patients less than 18 years of age have not been established SORILUX Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis SORILUX Foam is not for oral, ophthalmic, or intravaginal use

Reference: 1. Data on file, Stiefel Laboratories, Inc. SORILUX is a trademark and VersaFoam is a registered trademark of Stiefel Laboratories, Inc. ©2013 Stiefel Laboratories, Inc. All rights reserved. Printed in USA. SLX127R0 April 2013

SORILUX

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BRIEF SUMMARY Mothers (calcipotriene) Foam, 0.005% Nursing It is not known whether calcipotriene is excreted in human milk. Because

The following is a brief summary only; see full prescribing information for complete product information.

INDICATIONS AND USAGE

SORILUX Foam is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 18 years and older.

CONTRAINDICATIONS

many drugs are excreted in human milk, caution should be exercised when SORILUX Foam is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of SORILUX Foam in pediatric patients less than 18 years of age have not been established.

Geriatric Use

WARNINGS AND PRECAUTIONS

Clinical trials of SORILUX Foam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Flammability

Unevaluated Uses

SORILUX Foam should not be used by patients with known hypercalcemia.

The propellant in SORILUX Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.

Effects on Calcium Metabolism

Transient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.

Risk of Ultraviolet Light Exposure

Instruct the patient to avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning booths and sun lamps. Physicians may wish to limit or avoid use of phototherapy in patients who use SORILUX Foam. [See Nonclinical Toxicology (13.1).]

ADVERSE REACTIONS Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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. SORILUX Foam was studied in four vehicle-controlled trials. A total of 1094 subjects with plaque psoriasis, including 654 exposed to SORILUX Foam, were treated twice daily for 8 weeks. Adverse reactions reported in ≥1% of subjects treated with SORILUX Foam and at a higher incidence than subjects treated with vehicle were application site erythema (2%) and application site pain (3%). The incidence of these adverse reactions was similar between the body and scalp.

DRUG INTERACTIONS

No drug interaction studies were conducted with SORILUX Foam.

USE IN SPECIFIC POPULATIONS Pregnancy

Teratogenic Effects, Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. Therefore, SORILUX Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 mcg/kg/day (132 mcg/m2/day). Rabbits administered 36 mcg/kg/day (396 mcg/m2/day) resulted in fetuses with a significant increase in the incidences of incomplete ossification of pubic bones and forelimb phalanges. In a rat study, doses of 54 mcg/kg/day (318 mcg/m2/day) resulted in a significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to calcipotriene’s effect upon calcium metabolism. The maternal and fetal no-effect exposures in the rat (43.2 mcg/m2/day) and rabbit (17.6 mcg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 mcg/m2/day) from dermal application.

SORILUX Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis.

OVERDOSAGE

Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with use of topical calcipotriene. [See Warnings and Precautions (5.2).]

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis Calcipotriene topically administered to mice for up to 24 months at dose levels of 3, 10, or 30 mcg /kg/day (corresponding to 9, 30, or 90 mcg /m2/day) showed no significant changes in tumor incidence when compared to controls. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. [See Warnings and Precautions (5.3).]

Mutagenesis The genotoxic potential of calcipotriene was evaluated in an Ames assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, and a mouse micronucleus assay. All assay results were negative. Impairment of Fertility Studies in rats at doses up to 54 mcg /kg/day (318 mcg /m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.

PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling (Patient Information) in full Prescribing Information. Inform the patient to adhere to the following instructions: • Avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. • Avoid contact with the face and eyes. If SORILUX Foam gets on the face or in or near their eyes, rinse thoroughly with water. • Apply SORILUX Foam to the scalp when the hair is dry. • Talk to your doctor if your skin does not improve after treatment with SORILUX Foam for 8 weeks. • Wash your hands after applying SORILUX Foam unless your hands are the affected site. • Avoid fire, flame, and smoking during and immediately following application since SORILUX Foam is flammable. • Do not place SORILUX Foam in the refrigerator or freezer. SOR:5BRS

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Volume 11 • Issue 2

COMMENTARY

Muckle-Wells Syndrome: Individualized, ReflareGuided Dosing of the Orphan Drug Canakinumab Simon M. Mueller, MD; Peter Itin, MD; Peter Haeusermann, MD

uckle-Wells syndrome (MWS) belongs to the cryopyrin-associated periodic fever syndromes (CAPS). These are rare inherited clinically overlapping diseases caused by mutations in the NLRP3 gene on chromosome 1q44 encoding a protein called cryopyrin (also known as NALP3). In addition to MWS, CAPS also include the milder familial cold autoinflammatory syndrome (FCAS) and the more severe neonatal-onset multisystem inflammatory disorder (NOMID).1 Cryopyrin belongs to a family of nucleotide oligomerization domain (NOD)-like receptors (NLRs) and is part of the multiprotein inflammasome complex in monocytes and macrophages. This danger-sensing complex is a crucial component of innate immunity.2 Normally, the NLRP3-inflammasome is activated by various infectious and noninfectious stimuli (eg, bacterial lipopolysaccharides, toxins, viral RNA, and urate crystals) and this activation results in caspase-1–mediated interleukin (IL) 1b secretion and, hence, the promotion of an inflammatory response to the stimulus. The proinflammatory bioactivity of IL1b includes IL-6–dependent elevation of acute-phase proteins, activation of cyclooxygenase 2, and mobilization of neutrophils and platelets from the bone marrow. The altered gene product (cryopyrin) in CAPS leads to a permanent overproduction of IL-1b independent of danger signals resulting in persistent inflammation.

In 1962, MWS was first described in an affected family as a hereditary syndrome with episodic fever, daily urticarial rash, malaise, arthralgias, conjunctivitis, and progressive sensorineural hearing loss.3 In 25% to 30% of patients, secondary (AA) amyloidosis occurs, potentially leading to renal failure4-6 and rarely to gastrointestinal involvement, hepatosplenomegaly, or neuropathy. Patients with MWS often also present with neurologic manifestations including symptoms such as headache (92%), features of migraine, myalgias (69%), papilledema (46%), and optic disc pallor (15%).7 Periodic symptoms appear synchronized or shifted and are usually accompanied by elevated acute-phase proteins such as C-reactive protein (CRP) and serum amyloid-A protein (SAA) leading to AA amy-

loid fibrils by proteolytical cleavage.5,8 Diagnosis is often delayed for years to decades, and many cases are misdiagnosed as chronic idiopathic urticarial. Before the development of an IL-1–blocking treatment a decade ago, no effective therapy could be offered to patients with CAPS. Rapid and Complete Remission of Symptoms and Signs With IL-1b Blockade Investigations have shown that CAPS are completely mediated by IL-1b and that blockade of IL-1b results in complete resolution of systemic symptoms in affected CAPS patients.9,10 Based on the promising efficacy and safety data, canakinumab,9,10 a long-acting human anti–IL-1b monoclonal antibody, was approved by the Food and Drug Administration (FDA) for the treatment of MWS and FCAS in 2009. This drug was granted orphan drug (OD) status, but its promising off-label use for the treatment of Schnitzler syndrome,11 adult-onset Still’s disease,12 systemic juvenile arthritis,13 and gouty arthritis14 has been reported. Furthermore, IL-1 blockade might be an interesting treatment option for many acute neutrophilic dermatoses.15,16 Endogenous human IL-1b cannot bind to its receptor on the surface of target cells and, hence, is functionally neutralized in its downstream pro-inflammatory bioactivity. In patients with CAPS, canakinumab reduces the production rates of IL-1b to physiological levels.9,10 The market approval of canakinumab was mainly based on the pivotal 3-part study10 that compared a placebo group with patients treated with 150 mg canakinumab (or weight-adjusted with 2 mg/ kg between 15–40 kg body weight) every 8 weeks and revealed a rapid complete clinical remission with normalization of CRP and SAA10 accompanied by substantial improvement of health-related quality of life.17 No life-threatening adverse events associated with canakinumab and no clear pattern of side effects other than an increase in infections were observed. Adverse events were mostly mild (eg, nasopharyngitis, gastroenteritis, urinary tract infections, viral

From the Department of Dermatology, University Hospital Basel, Switzerland Address for Correspondence: Simon M. Mueller, MD, Petersgraben 4, 4031 Basel, Switzerland • E-mail: muellersim@uhbs.ch

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infections, joint sprain, headache, and vertigo, among others) and in only one case serious (recurrent antibiotic-resistant lower urinary tract infections and sepsis). Mild injection site reactions affected <10% of patients.10 A 2-year follow-up open-label study confirmed sustained disease control in children and adults across all CAPS phenotypes (n=166) treated with subcutaneous canakinumab 150 mg every 8 weeks, but upward adjustments of dose or frequency were needed in nearly 25% of the patients (mostly children and patients with severe CAPS) to achieve complete response.18 Serious adverse events were reported in 11% of patients, mainly infections responsive to standard treatments, but the majority of the patients tolerated this treatment well. We conclude that canakinumab in CAPS patients is a highly effective drug with a good safety and tolerability profile in CAPS patients. So far, so good? From the medical point of view, “yes,” from the economic perspective, “no.” The officially recommended dosing schedule of subcutaneous canakinumab 150 mg every 8 weeks that was established by the manufacturer Novartis Pharmaceuticals according to a flare probability model costs $90,000 to $100,000 per patient-year (price of the drug, treatment costs, and upward adjustments of dose not included). Remarkably, the data of only 4 patients were used to predict the model.9,10 The Orphan Act: A Double-Edged Sword? Defined by the Rare Disease Act in 2002, a rare or orphan disease affects fewer than 200,000 individuals in the United States. In order to make the small market of ODs attractive for pharmaceutical companies, the Orphan Drug Act (ODA) was approved by Congress and signed into law by President Reagan in 1983. The ODA offers incentives to develop ODs, including federal tax credits, a 7-year monopoly on sales of a particular drug, exclusive market rights for the drug if a different use is approved by the FDA, and waivers of drug approval/annual fees. From a scientific view and for patients, the ODA is a success story. It encourages the development of novel drugs and pharmaceutical technologies, leads to identification of new diseases, and increases the annual flow of clinical trials.19 Since the introduction of the ODA, more than 360 ODs have been approved for the US market.20 In contrast to these positive aspects, the astronomical prices of the ODs (eg, imiglucerase for the treatment of Gaucher disease costs up to $400,000 per year for an adult patient21) remain an important issue. They may be partly explained by the development/production costs and the small market, but they may also reflect unintended consequences of the ODA (eg, little competition, off-label use for non-orphan or non–FDASKINmed. 2013;11:80–83

approved indications,22 missing price regulations if a drug provided a rapid return of investment). ODs can bring in significant revenue for pharmaceutical companies: a quarter of products that reached blockbuster status in 2006 had at least one orphan drug designation.23,24 The trend of OD approvals by the FDA is emerging and more than 1100 new orphan treatments are in research.25 More than 7000 different orphan diseases have been identified and new ones are regularly published.26 Thus, not only are the number of ODs increasing, but also the number of orphan diseases, leading to the development of even more ODs (given the market conditions stay that incentive). Providing all eligible patients with ODs at the present price policy will inevitably be prohibitive in the future and, hence, ethical issues (eg, patient selection, individual/private vs collective/public health benefit) will be amplified. It is clear that international health authorities with regulatory powers are needed to address profitable, excessively priced ODs. In Japan, Canada, and the European Union, such endeavors are being made.27 An overview on that topic with concrete proposals of reforms has been published.27 In this context, we would like to give you an example of how to contribute in clinical practice to a substantial cost reduction of canakinumab. Experience From Clinical Practice: Tailoring Canakinumab by a ReflareGuided Cost-Saving Schedule In 2011 we reported on 2 paternal half-siblings (aged 40 and 51 years) with recently diagnosed MWS based on identical NLRP-3 mutations (R260W).28 Since infancy, both had almost daily experienced urticaria-like eruptions––pronounced in the evening, accompanied by periodic fever and arthralgias and since adolescence from a progressive sensineural hearing loss. Evidence of secondary amyloidosis could not be found. Treated first with anakinra, an IL-1 receptor antagonist, both patients were immediately asymptomatic for the first time in their lives. Due to severe injection site reaction in 1 patient, the off-label use (anakinra is approved for rheumatoid arthritis), they were switched to canakinumab. Treated with subcutaneous canakinumab 150 mg, both patients showed a sustained long-term treatment effect extending 8 weeks (105–217 days). From a cost-efficiency perspective, we considered it reasonable to watchfully wait for clinical signs of reflare before redosing in both cases (instead of redosing every 8 weeks according to the recommended schedule). The clinical relapses were mostly accompanied by slight elevation in white blood cell counts and CRP; however, no clear indicator function of CRP as a surrogate marker for subclinical reflare was identified. For technical reasons, we were not able to analyze SAA. In a pivotal study investigating canakinumab in CAPS patients,10 the median time to reflare (in part 2) was 100 days after the last dose of 150 mg of canakinumab. A total of 19%

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of patients in the placebo group were even flare-free after 224 days (end of part 2). Novartis Pharmaceuticals kindly performed and sponsored serum level testing of canakinumab in both our cases at week 45. The results were in good accordance with the proposed minimum flare-free canakinumab level, which is considered 1 µg/ mL, indicating that this measurement could be helpful in detecting preclinical reflare. Canakinumab, when given as recommended, will generate costs of approximately $100,000 per patient-year. Because of our modified “reflare-guided” administrations of canakinumab, costs could be reduced by about 50% in both patients during the observation period of 2 years. When considering the need for lifelong therapy of CAPS patients, reflare-guided drug schedules could substantially save cost and might have a relevant impact on optimizing cost-effectiveness for the treatment of CAPS. We assume that our modified administration scheme is also rational to prevent amyloidosis, as we hypothesize that amyloidosis is mainly triggered by clinical disease with marked inflammation and persistently high SAA serum levels.6,29 With respect to our patients, who needed an upward adjustment dose,12 we are fully aware that this strategy might not be reasonable for all cases; however, under certain conditions (no V198M or Q307K mutation variant,18 stable disease without signs of amyloidosis), a deviation of the recommended dosing schedule might help to substantially reduce costs without implication on safety and efficacy. Prompt redosing of canakinumab upon first signs of reflare is a prerequisite of this changed schedule. Since AA amyloidosis cannot occur in the absence of an SAA response,29 serial measurements of SAA serum level might help to prevent amyloidosis. Until recently, SAA seemed to be the only sensitive marker for disease activity that indicates preclinical reflare; however, MRP8 and MRP14 (calprotectin), two phagocyte-specific molecules myeloid-related proteins have lately been introduced as novel sensitive biomarkers for monitoring disease activity, status of inflammation, and response to IL-1 blockade in patients with CAPS.30 Conclusions MWS is an example of a well-defined orphan disease that dramatically responds to “its OD” canakinumab, meaning a new life for most patients. Considering the excessive price of this exemplary OD, ethical and financial concerns are closely linked to that “new life.” These concerns related to the ODs in general have to be primarily addressed by health authorities with regulatory powers, but, based on our limited experience, we believe that individually tailored treatment schedules might help reduce the costs associated with these drugs.

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References 1 Farasat S, Aksentijevich I, Toro JR. Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol. 2008;144:392–402. 2 Petrilli V, Dostert C, Muruve DA, et al. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. 2007;19:615–622. 3 Muckle TJ, Wells M. Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med. 1962;31:235–248. 4 Toker O, Hashkes PJ. Critical appraisal of canakinumab in the treatment of adults and children with cryopyrin-associated periodic syndrome (CAPS). Biologics. 2010;4:131– 138. 5 Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004;50:607–612. 6 Lachmann HJ, Goodman HJ, Gilbertson HJ et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–2371. 7 Kitley JL, Lachmann HJ, Pinto A, et al. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010;74:1267–1270. 8 van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med. 2005;5:87–98. 9 Lachmann HJ, Lowe P, Felix SD, et al. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009;206:1029–1036. 10 Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–2425. 11 De Koning HD, Schalkwijk J, van der Meer JW. Successful canakinumab treatment identifies IL-1b as a pivotal mediator in Schnitzler syndrome. J Allergy Clin Immunol. 2011;128:1352–1354. 12 Gampietro C, Fautrel B. Anti-interleukin-1 agents in adult onset Still’s disease. Int J Inflam. 2012;2012:317820. 13 Ruperto N, Quartier P, Wulffraat N. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64:557–567. 14 Schlesinger N, Alten RE, Bardin T. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis. 2012;71:1839–1848. 15 Lipsker D, Lachmann H. IL-1 Inhibition in cryopyrin-associated periodic syndrome and beyond: a million dollar question about the injection schedule of biotherapies. Dermatology. 2011;223:119–121.

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16 Menu P, Vince JE. The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol. 2011;166:1–15. 17 Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB. Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a doubleblind placebo-controlled randomized withdrawal study. Arthritis Res Ther. 2011;13:R202.

cessed June 18, 2012. 24 Blockbuster Drugs 2006. 2006 Sales of 114 Blockbuster Drugs. R&D Pipeline News. La Merie Business Intelligence 2007. http://www.pipelinereview.com/index. php/2007072313312/Press-Room. Accessed June 18, 2012. 25 Cote T, Kelkar A, Xu K, et al. orphan products: an emerging trend in drug approvals. Nat Rev Drug Discov. 2010;9:84.

18 Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70:2095–2102.

26 Orphanet, “about rare diseases.” http://www.orpha.net/ consor/cgibin/Education_AboutRareDiseases.php?lng=EN. Accessed June 18, 2012.

19 Yin W. Market incentives and pharmaceutical innovation. J Health Econ. 2008;27:1060–1077.

28 Mueller SM, Itin P, Haeusermann P. Muckle Wells syndrome effectively treated with canakinumab: is the recommended dosing schedule mandatory? Dermatology. 2011;223:113– 118.

20 Michel M, Toumi M. Access to orphan drugs in Europe: current and future issues. Expert Rev Pharmacoecon Outcomes Res. 2012;12:23–29. 21 Haffner M, Torrent-Farnell J, Maher PD. Does orphan drug legislation really answer the needs of patients? Lancet. 2008;371:2041–2044. 22 Kesselheim A, Myers J, Solomon D. The prevalence and cost of unapproved uses of top selling orphan drugs. PLoS One. 2012;7:e31894. 23 Borda C. 25 years of the Orphan Drug Act. Pharma Voice, 2008. http://www.pharmavoice.com/archives/article. Ac-

27 Wellmann-Labadie O, Zhou Y. The US orphan drug act: rare disease research stimulator or commercial opportunity? Health Policy. 2010;95:216-228.

29 Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358:24-29. 30 Wittkowski H, Kuemmerle-Deschner JB, Austermann J. MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes. Ann Rheum Dis. 2011;70:2075– 2081.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 119) SKINmed. 2013;11:80–83

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Volume 11 • Issue 2

ORIGINAL CONTRIBUTION

Assessment of the Antidandruff Activity of a New Shampoo: A Randomized, Double-Blind, Controlled Study by Clinical and Instrumental Evaluations Adele Sparavigna, MD;1 Michele Setaro, Eng;2 Maurizio Caserini, MD;3 Anna Bulgheroni, MSc3 Abstract The aim of this randomized, double-blind, controlled study was to evaluate the antidandruff activity exerted by a new shampoo on patients affected by dandruff and/or mild seborrheic dermatitis by means of both D-squame technique coupled with image analysis and clinical assessments. Thirty-four patients were enrolled and 1:1 randomly assigned to either a test shampoo or a comparative shampoo group. Treatment schedule was twice a week for 4 weeks. The D-squame technique was shown to be able to objectively record variations in scalp desquamation both between test and comparative groups and within the same group over time. The results obtained with this instrumental approach showed a statistically significant reduction by 52% vs baseline after 2 weeks of treatment. There was an even greater reduction after 4 weeks (–66%). This reduction was statistically significant compared with the comparative group at the same time points. The analysis of all the other parameters (except Wood’s lamp) confirmed the superiority of the test vs the comparative shampoo. The test shampoo proved to be safe, well tolerated, and accepted by the patients for cosmetic acceptability and efficacy. The study confirmed the antidandruff efficacy of the test shampoo and its superiority vs the comparative shampoo. (SKINmed. 2013;11:85–91)

andruff (Pityriasis capitis) consists of the desquamation of small flakes from otherwise normal scalp. The scales may be dry (Pityriasis simplex) or trapped in a film of sebum (Pityriasis steatoides).1 About half of the postpubertal population, irrespective of ethnicity and sex, experiences dandruff. Dandruff scales are composed of clusters of corneocytes that have retained a high degree of cohesion and become detached from the surface of the stratum corneum. Both size and abundance of the scales are heterogeneous from one site of the scalp to another and over time. Dandruff represents mainly an aesthetic disturbance, often associated with itching. In any given dandruff-prone patient, the condition may have seasonal fluctuation, with worsening noticed more often during the winter.2 When dandruff and seborrhea coexist (Pityriasis steatoides), there is an increased susceptibility to seborrheic dermatitis. In the mild form of seborrheic dermatitis, slight erythema of the scalp may occur. Dandruff and mild seborrheic dermatitis may overlap, with skin desquamation, Wood’s lamp fluorescence testing, and scalp erythema being differently represented over time in the same patient.

Wide variations in outcome methodology make the interpretation of patient outcomes confusing, and the comparison of results obtained from different studies impossible. Image analysis of skin scaling using D-squame samplers has been previously proposed as an objective technique to evaluate the severity of scaling disorders.3 The aim of this controlled study was to evaluate the activity of a new shampoo on patients affected by dandruff and/ or mild seborrheic dermatitis by means of D-squame technique, coupled with image analysis (antidandruff efficacy) and clinical assessment of erythema (soothing activity). The study also aimed at assessing the safety profile of the treatment. Methods

Study Design A 4-week, randomized, double-blind, comparative controlled study was conducted in patients of both sexes who experienced dandruff and/or mild seborrheic dermatitis (dandruff). Informed consent was obtained. Patients with dermatological

From the Clinical Research and Bioengineering Institute, Monza, Italy;1 the Tecnolab del Lago Maggiore S.r.l., Verbania Fondotoce, Italy;2 and the Scientific Department, Polichem SA, Lugano, Switzerland3 Address for Correspondence: Anna Bulgheroni, MSc, Polichem SA, via Senago 42D, 6912 Lugano-Pazzallo, Switzerland • E-mail: anna.bulgheroni@polichem.com

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ORIGINAL CONTRIBUTION

diseases, other than seborrheic dermatitis, with lesions, scars, or malformations on the scalp were excluded.

ated a few numbers representing the quantitative and qualitative properties of the sample.4

A total of 34 patients with dandruff and/or mild seborrheic dermatitis were enrolled in this blinded study, in equal proportion, to either the test shampoo group or to the comparative shampoo group according to an encoded randomization list.

The skin desquamation index, calculated as the disk area occupied with corneocytes and the individual thickness of the scales, was measured instrumentally using a method recommended and described by the European Group on Efficacy Measurement of Cosmetics and Other Topical Products (EEMCO) for the study of dry skin and scaling.5 Scales, collected on D-squame, were computer analyzed in terms of number and characteristics in order to evaluate the morphometric and structural aspects of desquamation and the process of keratinocyte cohesion (total area, major axis, minor axis).

Each patient was asked to use the test or the comparative formulation twice a week (at least 3 days between two applications) for 4 weeks, instead of their usual shampoo. Three visits were performed during the trial: at enrollment (T0), after 2 weeks of treatment (T2), and at the end of the 4-week treatment period (T4). At each visit, scalp desquamation, erythema, and skin desquamation were evaluated using clinical and instrumental tools, as described below, in order to determine the soothing and antidandruff efficacy of the shampoo under investigation compared with the reference shampoo.

Qualitative composition of test and comparative shampoos

Scalp Desquamation by Wood’s Lamp To clinically evaluate the scalp desquamation, a previously described Wood’s lamp procedure6 was used. Scalp desquamation spots were detected and scored on the basis of the intensity of the fluorescent light emitted at the level of the hair insertion line as follows: 0=absent; 1=mild; 2=moderate; 3=severe.

The test shampoo (Lygal Duo, Taurus Pharma, Germany) was comprised of aqua, sodium lauryl sulfate, lauryl-2, PEG-10 olive glycerides, denatured alchohol, sodium chloride, piroctone olamine, PEG-7 glyceryl cocoate, climbazole, potassium, undecylenoyl hydrolized soy protein, panthenol, citric acid, and perfume. The comparative shampoo was comprised of aqua, sodium lauryl sulfate, lauryl-2, PEG-10 olive glycerides, denatured alchohol, sodium chloride, PEG-7 glyceryl cocoate, potassium undecylenoyl hydrolized soy protein, panthenol, citric acid, and perfume. Antidandruff ingredients were piroctone olamine and climbazole. The comparative shampoo did not contain those two ingredients.

Scalp Erythema The severity of erythema was quantified by visual evaluation of the following score: 0=absence; 1=very slight erythema (barely perceptible); 2=well-defined erythema; 3=moderate to severe erythema; 4=severe erythema.

Self-Evaluation Questionnaire At the end of the treatment period, all patients were asked to complete a questionnaire in order to collect subjective judgments related to efficacy and cosmetic acceptability. Each patient was invited to score as negative, poor, good, or positive the following parameters: • efficacy parameters: dandruff reduction, cleansing efficacy, itching reduction (if present at baseline), reduction of scalp redness, increase in bright hair, increase in hair mass;

Clinical and instrumental assessments Scalp Desquamation by D-squame D-squame, a circular, transparent, adhesive support, was used to collect the stratum corneum scales following application with a slight and constant pressure on the scalp surface. The disk was then placed against a black background to provide the maximum of contrast for evaluating the desquamation patterns. The clinical score for skin desquamation was assigned according to the visual evaluation of dryness grade with respect to a photographic reference scale as follows: 0=very hydrated; 1=hydrated; 2=normal; 3=slightly dry; 4=dry; 5=very dry. The disks were then illuminated and viewed by a CCD video camera attached to a stereomicroscope. The video image of the sample was captured in a personal computer and then processed with the aid of an image analysis program. Within seconds, the computer generSKINmed. 2013;11:85–91

• cosmetic acceptability parameters: smell (before application), easy to rinse, presence of shampoo residuals on hair after wash, smell (after wash), easy to comb.

Safety Evaluation Any adverse events and serious adverse events, as well as severity and relationship to the study product, were recorded during the whole study period.

Statistical Analysis

The statistical analysis was performed on the per protocol population, defined as all patients who completed the study as protocol-directed. Semiquantitative clinical data were processed by Assessment of the Antidandruff Activity of a New Shampoo

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nonparametric tests (Wilcoxon test and Friedman test), while continuous variables were processed by parametric tests (analysis of variance, Dunnett test, and Student t test).

Results

2.8

1 T0

T4 Comparative shampoo

Figure 1. Time course of the skin desquamation: visual score of scalp dryness (0=absent; 1=mild; 2=moderate; 3=severe). *P<0.05 T2 and T4 vs T0. $P<.05 test shampoo vs comparative shampoo at the same time points.

% of subjects (variation vs baseline)

Efficacy evaluation

3.9

Test shampoo

The study was conducted on 34 healthy volunteers, 11 men and 23 women, affected by dandruff and/or mild seborrheic dermatitis. The mean age of the population was 43 years, ranging from 18 to 65 years. One patient dropout in the test shampoo group was lost to follow-up and not related to the use of the investigational product. The enrolled patients were randomly distributed in the two groups as follow: 17 patients (6 men and 11 women) with a mean age of 38.7 years (range, 18 to 60 years) in the test shampoo group and 17 patients (5 men and 12 women) with a mean age of 47.1 years (range, 21 to 65 years) in the comparative shampoo group.

3.9

Study Population

100 12

90 70

40 30 20

38 13

10 6

Test shampoo

Dryness grade of scalp desquamation was evaluated according to the photographic reference scale scored at baseline 3.9+0.81 (mean score+standard deviation) in the test shampoo group and 3.8+0.88 in the comparative shampoo group. After 2 weeks of treatment, the test shampoo was able to significantly reduce skin scalp desquamation to 3.0+0.89, the difference being significant compared with baseline (Dunnett test, P<.05) and compared with the comparative shampoo (mean score 3.9+1.05; Wilcoxon test, P<.05). This trend even improved by the end of the treatment period (test shampoo mean score, 2.8+0.54; Dunnett test, P<.05 vs T0; Wilcoxon test P<.05 vs comparative shampoo mean score 3.9+0.86); no significant change was observed with the comparative shampoo (Figure 1). Patients with improvement of at least 1 grade compared with T0 were 56% at T2 and 81% at T4 for the test product, while in the comparative shampoo group, this improvement was observed in only 12% of the patients at T2 and in 18% at T4 (Figure 2). Results obtained from the morphometric and structural examination of D-squame samples showed that the test shampoo was able to significantly reduce all the assessed parameters. Mean+standard deviation and statistical analysis are reported in Table I.

Scalp Desquamation by D-squame Technique

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3.9 3.8

The activity of test shampoo was expressed both in terms of absolute and relative values with respect to comparative shampoo. The statistical analysis of the test product was performed comparing T2 and T4 vs baseline and vs reference.

Visual score (mean values)

worsening

Comparative shampoo no change

better

Figure 2. Skin desquamation percentage variation in comparison to the comparative shampoo: visual score of scalp dryness.

A significant reduction in the desquamation index was obtained after 2 weeks of treatment and further improved by the end of the treatment period. This reduction was also statistically significant in comparison to the comparative group at the same time points. Similarly, a statistically significant reduction in the number of scales was observed in the test group after 2 weeks of treatment with respect to baseline and to the comparative group and further improved by the end of the treatment period.

In the comparative shampoo group, a statistically significant increase in the number of scales, indicative of a worsening condition, was observed both at T2 and T4. The total area covered by scales was significantly reduced in the test group compared with Assessment of the Antidandruff Activity of a New Shampoo

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Table I. D-squame Instrumental Measurements and Statistical Analysis

Mean+Standard Deviation Test

Comparative

P<.05

8846+6445

6414+3764

vs T0a

7686+4927a

11573+4799a

vs comparative

7093+4872a

11519+4356a

175,850+34,704a

176,118+21,133

vs T0a

87,075+70,647a

163,546+53,534

vs comparative

57,618+56,490a

154,884+59,523

14.14+4.69

16.06+4.60

vs T0a

9.13+2.26

10.32+2.86

vs comparative

7.49+2.30a

10.40+1.5

5.94+2.02

6.78+1.97

vs T0a

3.74+1.02a

4.31+1.2

vs comparative

3.01+0.96a

4.32+0.67

1.86+0.54

2.07+0.61

vs T0a

1.40+0.12a

1.42+0.38

vs comparative

1.26+0.12a

1.46+0.10

0.32+0.04

0.32+0.05

vs T0a

0.15+0.13a

0.30+0.08

vs comparative

0.11+0.12a

0.29+0.11

Scales (No.)

Total area (pixel2)

Perimeter (pixel)

Major axis (pixel)

Minor axis (pixel)

Desquamation index

Abbreviations: T0, at enrollment; T2, after 2 weeks of treatment; T4, at the end of the 4-week treatment period. P<.05 vs T0; P<.05 vs comparative shampoo.

baseline after 2 weeks of treatment and with respect to the comparative shampoo at the same time point. This reduction was also clearly visible by scalp observation (Figure 3). A statistically significant reduction compared with baseline in the scale mean perimeter and major and minor axis was observed

in the test group at the end of the treatment period (T4); moreover, this activity was statistically significant in comparison to the comparative shampoo. Percentage variations with respect to baseline of both test and comparative shampoos are reported in Figure 4.

SKINmed. 2013;11:85â&#x20AC;&#x201C;91

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ORIGINAL CONTRIBUTION

Figure 3. Volunteers treated with the test shampoo at baseline and after 2- and 4-week treatment

Scalp Desquamation by Wood’s Lamp

Scalp Erythema

The clinical examination of the scalp desquamation by Wood’s lamp did not show any statistically significant variation of the scalp desquamation visual score with test shampoo compared with baseline conditions and comparative shampoo (Table II). The percentage of patients who showed an improvement with test shampoo at the end of the study was higher than that observed with the comparative shampoo (50% and 29%, respectively). None of the patients enrolled in the study experienced a worsening of scalp desquamation (Figure 5).

A slight reduction of the baseline erythema visual score, more marked for the test shampoo (38% improvement with the test and 24% with the comparative shampoo), was observed after 2 weeks of treatment (Table II), but the observed difference was not statistically significant.

SKINmed. 2013;11:85–91

Self-Evaluation Questionnaire More than 50% of the patients treated with the test shampoo judged the efficacy parameters as good or very good, even Assessment of the Antidandruff Activity of a New Shampoo

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ORIGINAL CONTRIBUTION

100

test shampoo T2 test shampoo T4 comparative shampoo T2 comparative shampoo T4

40 20 0 –20 –40 –60 –80 –100

desquamation scale number index

total area

perimeter mean

major axis mean

minor axis mean

Figure 4. Skin desquamation instrumental evaluation through morphometric and structural parameter: percentage variations vs baseline.

The cosmetic acceptability resulted in good or very good responses for both the test shampoo and comparative shampoo and for all considered items (Figure 8; comparative shampoo data not shown). According to the investigator’s judgment, the treatment tolerance was optimal for both the test shampoo and comparative shampoo. No adverse events related to the study product occurred during the entire study period.

Table II. Visual Score Summary Table T0

Test shampoo

2.06+0.85

1.88+0.81

1.56+0.73

Comparative shampoo

2.18+0.73

2.05+0.75

1.82+0.33

Test shampoo

1.3+1.18

0.9+1.03

0.9+0.89

Comparative shampoo

1.3+1.11

1.1+0.90

1.0+0.79

Scalp desquamation visual score

Scalp erythema visual score

Values are expressed as mean±standard deviation.

100

100 12

80 70 60 50 40

40 30

0 T2

Test shampoo

Comparative shampoo

no change

10 T2

% of subjects

90 % of subjects

% variation vs baseline

though no statistically significant differences were observed. The judgment was, in general, better than that registered in the comparative shampoo group (Figure 6). These data were confirmed by the investigator who judged very considerable and clinically relevant the global study product activity (excellent in 75% of the cases, good in 19%, and medium in 6%), also compared with comparative shampoo (excellent and good in 0% of the cases, medium in 18%, poor in 59%, and bad in 23%) (Figure 7).

Overall

Dandruff

positive negative

Test shampoo

Itching

Overall

Dandruff

Itching

Comparative shampoo

better

Figure 5. Clinical evaluation of the scalp desquamation by Wood’s lamp procedure.

SKINmed. 2013;11:85–91

Figure 6. Self-evaluation questionnaire related to efficacy.

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100

50 40 30 20

31.3

43.8

60 50

25 31.3

62.5

poor Test shampoo

medium

good

excellent

6.2

12.5

18.8 6.2

6.2

Figure 8. Self-evaluation questionnaire related to cosmetic acceptability of test shampoo. A=smell (before application); B=hair easy to rinse; C=presence of shampoo residuals on hair after wash; D=smell (after wash); E=hair easy to comb.

Figure 7. Investigator’s judgment related to efficacy.

Disclosure: This study was supported by Polichem SA, Lugano, Switzerland. Anna Bulgheroni and Maurizio Caserini are employees of Polichem SA.

Discussion The importance of developing a tool able to objectively evaluate the severity of scaling disorders has been previously addressed.3 To objectively analyze the desquamating portion of the horny layer, a new image analysis technique has been developed. The method proved to be reproducible and well correlated with clinical observations.5,7 In this study, this technique has been used to monitor dandruff improvement following 4 weeks of treatment with a new shampoo provided with antidandruff activity. The D-squame technique was shown to be able to record variations in the parameters under evaluation both between the test and the comparative groups and within the same group over time. The instrumental monitoring of D-squame samples was also shown to be sensitive enough in recording slight variations over time and differences between treatments. The results obtained in this study demonstrate that this test shampoo is safe and well tolerated and reduces scalp desquamation in patients with dandruff, indicative of effective antidandruff activity. In addition, the efficacy and cosmetic acceptability of the test shampoo was judged by more than 50% of the patients as good or very good for all considered parameters, suggesting potential improved compliance and, hence, a higher treatment success.

References 1 Ebling FJ, Dauber R, Rook A. Pityriasis capitis. In: Text Book of Dermatology. Rook A, Wilkinson DS, Ebling FJ, Champion RH, Burton JL, eds. Oxford, England: Blackwell Scientific Publications; 1986. 2 Piérard-Franchimont C, Xhauflaire-Uhoda E, Piérard GE. Revisiting dandruff. Int J Cosmet Sci. 2006;28:311–318. 3 Black D, Boyer J, Lagarde JM. Image analysis of skin scaling using D-squame samplers: comparison with clinical scoring and use for assessing moisturizer efficacy. Int J Cosmet Sci. 2006;28:35–44. 4 Schartz H, Altmeyer PJ, Kligman AM. Dry skin and scaling evaluated by D-squames and image analysis. In: Handbook on Non-Invasive Methods and Skin. Serup J, Jemec G, eds. Boca Raton, FL: CRC Press; 1995:153– 157. 5 El Gammal C, Pagnoni A, Kligman AM, El Gammal S. A model to assess the efficacy of moisturizers, the quantification of soap-induced xerosis by image analysis of adhesive-coated discs (D-Squames). Clin Exp Dermatol. 1996;21:338–343. 6 Gupta LK, Singhi MK. Wood’s lamp. Indian J Dermatol, Venerol Leprol. 2004;70:131–135. 7 Wilhelm KP, Kaspar K, Schumann F, Articus K. Development and validation of a semiautomatic image analysis system for measuring skin desquamation with DSquames. Skin Res Technol. 2002;8:98–105.

Conclusions On the basis of these considerations, this antidandruff shampoo deserves to be acknowledged as a valid treatment alternative. SKINmed. 2013;11:85–91

12.5

Comparative shampoo

Negative

43.8 31.2

Good Poor

31.2

20 bad

Very Good 50

10 0

31.3

% of subjects

Assessment of the Antidandruff Activity of a New Shampoo

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March/April 2013

Volume 11 • Issue 2

ORIGINAL CONTRIBUTION

Persistent Serpentine Supravenous Hyperpigmentation—A Possible Cutaneous Manifestation of HIV Infection or a Normal Racial Variant: A Report of 3 Cases John T. O’Malley, MD, PhD; Jocelyn L. Lieb, MD; Jessica A. Weiser, MD; Marc E. Grossman, MD Abstract Persistent serpentine supravenous hyperpigmentation (PSSH) describes a hyperpigmentation of the skin overlying peripheral veins. This cutaneous finding is typically seen in association with systemic chemotherapy or collagen vascular diseases such as progressive systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Three dark-skinned patients with idiopathic serpentine supravenous hyperpigmentation (ISSH) without collagen vascular disease or prior intravenous cytotoxic treatments were reported. All 3 patients were dark-skinned men with symmetric, uniform hyperpigmentation of the supravenous network of the bilateral lower extremities that had been present for years. The serpentine supravenous hyperpigmentation on the lower extremities was uniform in width and color, which contrasts with the darker discoloration near the site of infusion seen with PSSH associated with chemotherapy. Interestingly, 2 of the patients had advanced human immunodeficiency virus (HIV) disease in association with their ISSH while the HIV status of the third patient was unknown. Thus, we contend that ISSH be considered a normal racial variant or a possible cutaneous manifestation of HIV disease. (SKINmed. 2013;11:93–94)

ersistent serpentine supravenous hyperpigmentation (PSSH) refers to the discoloration of the skin overlying peripheral veins in association with chemotherapy.1 This hyperpigmentation may fade over a period of weeks to months after drug discontinuation. In addition, there have been rare reports of this unusual pattern of hyperpigmentation in progressive systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, suggesting that collagen vascular diseases can also be associated with PSSH.2,3

a history of malignancy, prior cytotoxic drug administration, intravenous drug use, or rheumatologic conditions (ANA negative, RF negative, complement levels normal). Reportedly, the hyperpigmentation was present for years and the patient was unable to identify an inciting event prior to its development. Case 2

We report PSSH as either a normal racial variant or a possible cutaneous manifestation of human immunodeficiency virus (HIV) disease in 3 dark-skinned patients without collagen vascular disease or prior intravenous cytotoxic treatments.

A 48-year-old man from the Dominican Republic with asthma was seen in the dermatology clinic for a papular, pruritic eruption clinically and histologically consistent with lichen planus. He was noted to have symmetric SSH on his lower extremities. The patient denied a history of malignancy, prior cytotoxic drug administration, intravenous drug use, or rheumatologic conditions (ANA negative, DNA antibody negative, RF negative, normal complement levels). The HIV status of the patient was unknown, and the patient has since been lost to follow-up.

Case 1 A 55-year-old man from the Dominican Republic with newly diagnosed advanced HIV disease (CD4=3, viral load=366,000), Pneumocystis jiroveci pneumonia, and Kaposi’s sarcoma was found to have bilateral serpentine supravenous hyperpigmentation (SSH) on his lower extremities (Figure). The patient denied

Case 3 A 39-year-old African American man from New York City with HIV (CD4=3, viral load=58,763) and complaints of cough, fe-

From the Department of Dermatology, Columbia University Medical Center, New York, NY Address for Correspondence: John T. O’Malley, MD, PhD, 161 Fort Washington Avenue, 12th Floor, New York, NY 10032 • E-mail: jo2355@columbia.edu

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ORIGINAL CONTRIBUTION tomatic idiopathic serpentine supravenous hyperpigmentation (ISSH). All 3 patients were dark-skinned men with symmetric, uniform hyperpigmentation of the supravenous network of the bilateral lower extremities that had been present for years. The SSH on the lower extremities was uniform in width and color. There were no track marks or scars suggestive of drug abuse. This uniform width and color contrasts with previous reports of cytotoxic medication–induced SSH in which the hyperpigmentation was limited to the veins of the arms and forearms, with maximal pigmentation near the site of intravenous drug administration.4 Upon reviewing the patients’ medication home and hospital medication lists, none of the medications taken by these patients before or after the finding of PSSH were associated with hyperpigmentation. Conclusions Our cohort of patients displayed long-term and uniform supravenous hyperpigmentation of the lower extremities in the absence of any known cytotoxic drug ingestion. Interestingly, 2 of the 3 patients were noted to be HIV positive and the third patient’s HIV status was unknown. Therefore, we propose that ISSH, when recognized in dark-skinned individuals, warrants HIV testing in addition to a thorough medication history and work-up for rheumatologic disease. If the workup is negative, we contend that ISSH can also be considered a normal racial variant. Disclosures: All authors were responsible for the compilation of data and drafting of the manuscript. The authors have no conflicts of interest or financial disclosures to declare.

Figure 1. A linear hyperpigmented patch overlying a superficial vein along the medial right lower leg.

References

ver, and pleuritic chest pain was found to have Candida pneumonia. After being consulted for an anal condyloma and ulcerated herpes simplex virus 2 in his gluteal fold, the patient was also found to have SSH on his arms and legs. Although this patient reported a history of crack/cocaine use, he denied intravenous drug use, malignancy, prior cytotoxic drug administration, or symptoms suggestive of rheumatologic conditions. Comments The 3 hospitalized patients without rheumatologic disease or cytotoxic treatment were incidentally noted to have asymp-

SKINmed. 2013;11:93–94

1 Marcoux D, Anex R, Russo P. Persistent serpentine supravenous hyperpigmented eruption as an adverse reaction to chemotherapy combining actinomycin and vincristine. J Am Acad Dermatol. 2000;43:540–546. 2 Jawitz JC, Albert MK, Nigra TP, Bunning RD. A new skin manifestation of progressive systemic sclerosis. J Am Acad Dermatol. 1984;11(2 pt 1):265–268. 3 Werth VP, Schumacher HR, Jr, Von Feldt JM. Linear hyperpigmentation overlying veins in association with collagen vascular disease. J Am Acad Dermatol. 1993;29:1039– 1040. 4 Aydogan I, Kavak A, Parlak AH, et al. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol. 2005;19:345–347.

Persistent Serpentine Supravenous Hyperpigmentation

2013

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Ellen Gendler, MD Vivian Bucay, MD Pamela Basuk, MD Roslyn Rivkah Isseroff, MD Julie Woodward, MD Marc Darst, MD Candace Spann, MD Allan Wirtzer, MD Adam Rotunda, MD

Proposed Lecture Topics Murad Alam, MD Emily Altman, MD Mimi Cummings, MD Rhett Drugge, MD Carl Thornfeldt, MD Barry Lycka, MD Haines Ely, MD S. Manjula Jegasothy, MD Cory Maas, MD

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March/April 2013

Volume 11 • Issue 2

Core curriculum Virendra N. Sehgal, MD, Section Editor

Lichen Planus Pigmentosus Virendra N. Sehgal, MD; Prashant Verma, MD; Sambit N. Bhattacharya, MD; Sonal Sharma, MD; Farhan Rasool, MD

Lichen planus pigmentosus, a variant of lichen planus, is a disorder with conflicting taxonomy. Its worldwide recognition is still not fully understood because of insufficient contemporary evidence of the disease in the literature. The authors review the historical background, etiopathogenesis, clinical connotation, atypical variants, and histopathology to highlight its diversity.

ichen planus pigmentosus (LPP) is condition that has been documented by infrequent reports in the literature.1–14 A search of PubMed resulted in 44 references available to date, the critical analysis of which provides adequate material to enrich the contents of this core curriculum. Historical Background

The tell tale signs of LPP are evident from Gougerot’s work15,16 published in the year 1935, when he termed the entity “Lichen atypiques ou invisibles pigmentogenes.” Since then, the term has been associated with numerous semantics/synonyms. Precisely, the acknowledgment for the first description of the entity is credited to Desai,17 who carefully evaluated the clinical presentation of generalized mottled pigmentation of bluish black or grey color, unusually accompanied by lesions of typical lichen planus: the Lichen Planus Pigmentosus sine Lichen. In addition, Pinkus18 focused attention to the entity Lichen plan pigmente or lichen invisible pigmentonene, which was already well-recognized. Lichen pigmentosus and Lichen invisible pigmentogeno were the other nomenclature assigned to the entity with identical morphological description in Japan and Italy, respectively, in the 1950s. Finally, the first larger clinico-histopathological representation was documented by Bhutani19 in 1974, who coined it Lichen planus pigmentosus, the currently recognized entity. Etiopathogenesis The pathogenesis of LPP is still unclear. Several factors, including mustard oil19,20 and hepatitis C virus infection21 have been

incriminated. Allyl-thiocynate, an essential ingredient in mustard oil, may stimulate photosensitization.20 A correlation of immunopathogensis between lichen planus and LPP, based on direct immunofluorescence studies, has been speculated, and should be looked into in the future.20 LPP has been reported to flare immediately after the relapse of nephrotic syndrome, which substantiates the possibility of common immunological abnormalities, based on an altered cell-mediated immune response.22 LPP has also been observed as a paraneoplastic phenomen.23 Gold has also been incriminated.2 The short duration of the inflammatory process in LPP likely leads to a quick transformation into a long noninflammatory regressive phase with incontinence of the pigment. These specific morphogenetic dynamics are possibly why LPP presents as brown, nonpruritic, small inflammatory macules.24 Histopathology The histopathological changes associated with LPP consist of mild, band-like lymphocytic infiltrate with vacuolar degeneration of the basal layer in the epidermis (Figure 1, Figure 2, and Figure 3). There is usually prominent melanin incontinence in the upper dermis with apoptosis or necrosis of keratinocytes (Figure 4). Older lesions typically show predominance of melanin incontinence and less prominent epithelial changes (Figure 5a and 5b). LPP is an entity identified by clinical overtones; however, it needs to be confirmed by microscopic pathology. The latter is required to be consolidated from the reports on clinicopatho-

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

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core curriculum

Figure 1. Scanner view of skin biopsy showing thinned-out epidermis with flattening of rete-ridges, and band-like infiltrate (hematoxylin and eosin stain ×40).

Figure 3. Low-power view showing thinned-out atrophic epidermis with scant inflammation and pigment incontinence (hematoxylin and eosin stain ×100).

Figure 2. Scanner view of skin biopsy showing thinned-out epidermis with flattening of rete-ridges, and band-like infiltrate (hematoxylin and eosin stain ×40).

Figure 4. Low-power view showing thinned-out atrophic epidermis with scant inflammation and pigment incontinence (hematoxylin and eosin stain ×100).

logical studies.19–21,25 The disease is borne by both the epidermis and the dermis. The changes in the former are apparent in the form of variable mild and patchy to extensive and liquefactive basal cell degeneration and presence of abundant melanin pigment in the basal and malphigian layer. In addition, moderate hyperkeratosis and hypergranulosis may also be an accompaniment. The dermal changes are variable and comprised primarily of lymphohistiocytic infiltrate, the configuration of which may SKINmed. 2013;11:96–103

either be band-like or perivascular. Melanophages in the subepidermal zone, indicative of melanin incontinence, may be a prominent feature. Colloid bodies may also be a part of the infiltrate. Moreover, the histopathologic features in patients with or without concomitant lichen planus are similar. In addition, increased number of melanophages and free melanin granules in the lamina propria are the features in the mucosal lesions. Lichen Planus Pigmentosus

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Figure 5a. Vacuolar degeneration of basal cell layer, increased melanin in lower layers, and patchy lymphohistiocytic infiltrate, containing melanophages (hematoxylin and eosin stain ×400).

Figure 5b. Atrophic epidermis with increased melanin and vacuolization of basal layer, with mild lichenoid lymphocytic infiltrate and pigment incontinence (hematoxylin and eosin stain ×400).

Immunofluorescence Immunofluorescence is another viable supplement to the microscopic pathology. The outcome of this is envisaged by the presence of IgM and IgG, and complement containing colloid bodies in the dermis, similar to that found in lichen planus, although the expression is weaker in the former. It may have predominant CD8+ lymphocytes.20,21,26 In addition, CD1a expression has been demonstrated in the epidermis and upper dermis.27 Immunofluorescence in erythema dyschromicum perstans differs from lichen planus by the absence of nuclear affinity of immunoglobulins and by the presence of positive extranuclear staining of basal cells. Presence of fluorescent bodies arranged in clusters in the upper dermis, IgG and IgA in the nuclei of epidermal cells, complement component 3 (C3), and fibrinogen in perifollicular blood vessels has been reported.26

grey and brown. The face and neck are the most often involved and the pre-auricular areas and temples are the initial sites of affliction. The upper limbs, trunk, and lower limbs are the other commonly affected areas. Extension of the lesions conforming to diffuse or reticulate pigmentation below the knees and onto the scalp is rare.19 Flexural areas, namely the axillae, inframammary folds, and the groin, are less often affected. The pigmentation is symmetrical, and its pattern is most often diffuse (Figure 7) followed by reticular (Figure 8), blotchy, and perifollicular, depicting a spectrum.20,21 Perifollicular pigmentation is yet another pattern,19 seen in 5% to 25%20,21 of cases. The palms, soles, and nails are spared. Oral mucosa is seldom affected and characterized by diffuse or specked, bluish black pigmentation over the buccal mucosae of both sides and along the lateral borders of the tongue. Atypical Variants of LPP

Clinical Connotation

Linear/Blaschoid LPP

LLP is most often seen in the 3rd to 5th decades of life. Men and women are equally affected. Skin phototype IV has been found to be susceptible.21 The lesions are insidious in onset and are either asymptomatic or slightly itchy. The lesions are usually multifocal, and start as small, discrete, ill-defined, and oval to round macules (Figure 6), which subsequently coalesce to form confluent sheets of pigmentation. Irregular margins, merging imperceptibly with the surrounding normal skin, are cardinal.19 Homogenous colors are seen, varying from slate-blue to steelSKINmed. 2013;11:96–103

Linear/Blaschoid LPP is a chronic pigmentary disorder that shows diffuse and/or reticulated hyperpigmented, dark brown macules with a linear distribution related to Blaschko’s lines (Figure 9), especially the sun-exposed areas such as the face, neck, and chin. It is different from classical lichen planus because LPP has a longer clinical course. The histopathology of the lesion shows an atrophic epidermis, the presence of melanophages, and a vacuolar alteration of the basal cell layer with a sparse lymphoLichen Planus Pigmentosus

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core curriculum

Figure 6. Ill-defined round to oval macule of lichen planus pigmentosus.

Figure 8. Reticulate pattern of lichen planus pigmentosus.

Figure 7. Diffuse pattern of lichen planus pigmentosus.

Figure 9. Pigmented macules along the lines of Blaschko associated with lichen planus pigmentosus.

histiocytic lichenoid infiltration. There are only 3 cases of linear LPP along the lines of Blaschko reported from Korea.28 The linearity of the lesions is representative of Blaschkoâ&#x20AC;&#x2122;s lines, which suggests its origin during embryogenesis.29

characterized by idiopathic, eruptive, hyperpigmented macules, irrespective of the presence or absence of interface dermatitis33 on histopathological examination. Lichen striatus can be differentiated clinically by the presence of inflammatory papules or a scaly eruption, which may last for 4 months to 4 years. Histopathologically, it is characterized by a perivascular and periadnexal inflammatory cell infiltration.34

Zosteriform/Linear Pattern LPP Zosteriform, or linear pattern, LPP is yet another clinical manifestation of LPP30 (Figure 10), which is depicted in the Table. There are several clinical conditions that may simulate this particular expression of LPP. Multiple linear erythema dyschromicum perstans (ashy dermatosis) in the line of Blaschko32 is SKINmed. 2013;11:96â&#x20AC;&#x201C;103

Linear and whorled nevoid hypermelanosis usually presents within a few weeks of birth and may be associated with congenital anomalies. Its diagnosis is supplemented by basal pigmen-

Lichen Planus Pigmentosus

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core curriculum tation without pigment incontinence.35 Progressive zosteriform and cribriform hyperpigmentation starts after birth with gradual extension, characterized by uniformly tan cribriform pigmented macules displayed in a zosteriform distribution. Histopathologically, there is a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells. There is a lack of other associated cutaneous and/or internal abnormalities.36 Incontinentia pigmenti is most often seen in women and infants, born with streaky, blistering areas that heal leaving behind rough bumps and darkened skin. The discolored skin develops within the first 2 weeks. The discoloration is because of gradual build-up of melanin. Several years later, the skin returns to normal and may be punctuated by hypopigmentation. It may also be associated with anomalies of the central nervous system.

Figure 10. Zosteriform pattern of lichen planus pigmentosus.

Table. Clinical Features of Linear Lichen Panus Pigmentosus Author

Age/Sex

Duration

Location

Pruritus

Histopathology

Treatment and Outcome

Jong Keun Seo12

60 y/man

8 mo

Chin and neck

Absent

Skin biopsy showed epidermal thinning, basal cell degeneration, some dyskeratotic cells with pigment incontinence, and a lymphohistiocytic infiltration in the dermis

Both systemic and topical steroids without any improvement

Vachiramon V13

33 y/man

Both arms and forearms

–

Compact orthokeratosis, epidermal atrophy and focal hypergranulosis with vacuolar alteration of the basal cell layer and band-like infiltration of lymphocytes and melanophages with incontinence of pigment

Improvement seen with sun avoidance and treatment of hepatitis C virus infection with a combination of interferon and ribavirin

Hong S31

23 y/woman

Left leg

Absent

Atrophic epidermis, basal hydropic degeneration with sparse perivascular lymphohistiocytic infiltrates, and numerous melanophages

–

Hong S31

16 y/woman

Left arm

Absent

Orthokeratosis, focal basal liquefaction, a sparse perivascular inflammatory infiltrate, and pigmentary incontinence

–

SKINmed. 2013;11:96–103

100

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LPP-inversus LPP-inversus is a rare variant of LPP, characterized by the exclusive affliction of the axilla, infra-mammary, groin, popliteal, antecubital fossa, and the flexures,37 with patients aged 27 to 71 years being the most vulnerable group. The lesions are usually asymptomatic or slightly pruritic.38–43 Differential Diagnosis

Pigmented Cosmetic Dermatitis Riehl’s melanosis, melanosis feminae faciei, chloasma cosmetia, inflammatory chloasma, and cosmetic dermatitis with secondary hyperpigmentation are synonyms, associated with pigmented cosmetic dermatitis, usually following an allergic response to cosmetics and mineral oil. Bizarre-shaped, reticular, patchy, irregular or diffuse hyperpigmentation with hues varying from black to yellowish are its morphological characteristics. The face and neck are the sites of its predilection. The lesions may extend to involve the arms and shoulders. Atrophy of the epidermis, spongiosis, presence of basal liquefaction, coat sleeve–like mononuclear cell infiltration of patchy or disperse arrangements, colloid bodies, and marked melanin incontinence are its cardinal histopathological features; however, hypergranulosis and band-like infiltrate beneath the epidermis are conspicuous by their absence.44,45

Erythema Dyschromicum Perstans/Ashy Dermatosis and Dermatosis Cenicienta Erythema dyschromicum perstans/ashy dermatosis and dermatosis cenicienta46–48 are characterized clinically by an extensive and asymptomatic eruption of blue-gray macules. The macules have elevated, erythematous borders. With time, these macules assume their blue-gray color, lose their erythematous borders, and coalesce, forming patches that affect large areas of skin. Histologically, early lesions may resemble a mild lichenoid dermatitis/interface dermatosis, while pigment incontinence is the prominent feature in the later stages.

Postinflammatory Hyperpigmentation The distribution of the lesions associated with postinflammatory hyperpigmentation ncorresponds to the primary dermatoses. Histopathologically, while prominent melanin incontinence may be the only feature in older lesions of LPP, the pigment usually extends deeper into the dermis, compared with postinflammatory pigmentation.

Fixed-Drug Eruption Fixed-drug eruptions are characterized by a peculiar sudden onset of round and/or oval, edematous, dusky red macules/plaques SKINmed. 2013;11:96–103

on the skin and/or mucous membranes, accompanied by burning and/or itching, in the context of a history of offending drug intake. Histopathologically, intense hydropic degeneration of the basal cell layer and pigmentary incontinence are characteristic features. Individual eosinophilic dyskeratotic cells in the upper epidermis, the presence of subepidermal bullae containing remnants of necrotic basal cells, marked edema, vascular dilatation, and a perivascular inflammatory infiltrate composed of lymphocytes, neutrophils, histiocytes, and mast cells may be conspicuous features in the upper dermis and help distinguish fixed-drug eruptions from LPP.49

Idiopathic Eruptive Macular Pigmentation Idiopathic eruptive macular pigmentation is characterized by an eruption of brownish, nonconfluent, asymptomatic macules involving the trunk, neck, and proximal extremities in children or adolescents; absence of a preceding inflammatory process; no previous drug exposure; basal cell layer hyperpigmentation of the epidermis; and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate.50 Spontaneous regression of the lesions over a period of a few months or years is the usual outcome.

Urticaria Pigmentosa Urticaria pigmentosa is characterized by a few to thousands of yellow-tan to red-colored macules and papules symmetrically distributed over the trunk and extremities. Darier’s sign and typical histopathology are diagnostic. Controversies There are a number of closely related or possibly even the same pigmentary disorders that have been described under different entities from all over the world. The unusual pigmentation disorder, LPP, was reported from India in 1974 and a few discrepancies in the reports were apparent. Of the 40 studied cases, 11 (27%) were lichen planus, of which 2 were that of bullous lichen planus, and the latter were not confirmed by direct immunofluorescence. In addition, 4 patients had skin-colored, shiny, pinhead-sized, grouped papules, occupying the extensor aspect of the arms and exposed parts of the back, conforming to the description of polymorphous light eruption and not to LPP. The remaining 73% of cases, however, did not have any associated lesions of classical lichen planus. The later could have been of identical morphology but different pigmentation disorders. Furthermore, patch and photopatch tests, an essential ingredient of diagnosis, were undertaken in only 15 of the 40 participants, in whom there was a history of photosensitivity. The patch test results were reported to be negative in all patients, as none of the

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cases showed a vesicular or any infiltration/erythematous papules response. A similar incongruity was the major pitfall of the other studies.20,21 It is, therefore, imperative to perform patch testing on patients with this kind of presentation to rule out pigmented contact dermatitis before labelling it as LPP.51 Ever since its advent in dermatology, ashy dermatosis has compounded the controversy by adding new dimensions. This is because of its varied morphology simulating several pigmentation disorders, including LPP. The attempt to solve this dilemma has been made by proposing a simplified clinical classification,48 which envisages 3 components, namely (1) ashy dermatosis, (2) erythema dyschromicum perstans (vide supra), and (3) simulators such as lichen planus and its variants LPP and actinic lichen planus, postinflammatory hyperpigmentation such as pityriasis rosea and erythema multiforme, drug-induced melanodermas, mastocytosis, and others. Treatment LPP is a chronic, recalcitrant entity. More often than not the lesions persist together for years. The contemporary treatment modalities are largely ineffective; moreover, they lack quality evidence. Vitamin A,49 both local and systemic corticosteroids,49 have been shown to hasten the clearance of the lesions. Tacrolimus (FK-506 or Fujimycin), a topical immunomodulator, has been recommended for use. A recent uncontrolled study has been shown to induce the clearance of lesions after a period of 4 months.21 In the authors’ experience, a synergistic combination of diamino-phenyl-sulfone (dapsone) and oral immunomodulator and topical tacrolimus along with photoprotection has been found to be effective in controlling the progression of LPP. References 1 Laskaris GC, Papavasiliou SS, Bovopoulou OD, et al. Lichen planus pigmentosus of the oral mucosa: a rare clinical variety. Dermatologica. 1981;162:61–63. 2 Ingber A, Weissmann-Katzenelson V, David M, et al. Lichen planus and lichen planus pigmentosus following gold therapy--case reports and review of the literature. Z Hautkr. 1986;61:315–319. 3 Kim KJ, Bae GY, Choi JH, et al. A case of localized lichen planus pigmentosus on the thigh. J Dermatol. 2002;29:242–243. 4 Muñoz-Pérez MA, Camacho F. Pigmented and reticulated plaques of folds. A case of lichen planus pigmentosus-inversus? Eur J Dermatol. 2002;12:282. 5 Akagi A, Ohnishi Y, Tajima S, et al. Linear hyperpigmentation with extensive epidermal apoptosis: a variant of linear lichen planus pigmentosus? J Am Acad Dermatol. 2004;50:S78–S80.

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6 Namazi MR. Lichen planus pigmentosus presenting as diffuse facial melanosis. J Drugs Dermatol. 2004;3:436– 437. 7 Kim BS, Aum JA, Kim HS, et al. Coexistence of classic lichen planus and lichen planus pigmentosus-inversus: resistant to both tacrolimus and clobetasol propionate ointments. J Eur Acad Dermatol Venereol. 2008;22:106– 107. 8 Ghoul-Mazgar S, Hentati-Aloulou H, Abidi H, et al. Apoptosis and proliferation in oral lichen planus pigmentosus. J Eur Acad Dermatol Venereol. 2009;23:836–837. 9 Ozden MG, Yildiz L, Aydin F, et al. Lichen planus pigmentosus presenting as generalized reticulate pigmentation with scalp involvement. Clin Exp Dermatol. 2009;34:636– 637. 10 Bennàssar A, Mas A, Julià M, et al. Annular plaques in the skin folds: 4 cases of lichen planus pigmentosus-inversus. Actas Dermosifiliogr. 2009;100:602–605. 11 Bickle K, Smithberger E, Lien MH, et al. Unilateral lichen planus pigmentosus mimicking acral lentiginous melanoma. J Drugs Dermatol. 2010;9:841–843. 12 Seo JK, Lee HJ, Lee D, et al. A case of linear lichen planus pigmentosus. Ann Dermatol. 2010;22:323– 355. 13 Vachiramon V, Suchonwanit P, Thadanipon K. Bilateral linear lichen planus pigmentosus associated with hepatitis C virus infection. Case Rep Dermatol. 2010;2:169– 172. 14 Zhang RZ, Zhu WY. Lichen planus pigmentosus over superficial leg veins. J Dtsch Dermatol Ges. 2011;9:540– 541. 15 Gougerot MH. Lichen atypiques ou invisibles pigmentogenes reveles par des pigmentations. Bull Soc Fr Dermatol Syphiligr. 1935;42:792–794. 16 Gougerot MH. Lichen atypiques ou invisibles pigmentogenes. Bull Soc Fr Dermatol Syphiligr. 1935;42:894–898. 17 Desai SC, Marquis L. Lichen planus: clinical study of 67 cases with results of penicillin therapy. Indian J Dermatol Venereol. 1956;22:31–48 18 Pinkus H.Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans. Arch Dermatol. 1973;107:840–846. 19 Bhutani LK, Bedi TR, Pandhi RK, et al. Lichen planus pigmentosus. Dermatologica. 1974;149:43–50. 20 Kanwar AJ, Dogra S, Handa S, et al. A study of 124 Indian patients with lichen planus pigmentosus. Clin Exp Dermatol. 2003;28:481–485. 21 Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of lichen planus pigmentosus and its response to tacrolimus ointment: an open label, non-randomized, prospective study. J Eur Acad Dermatol Venereol. 2010;24:535–540. 22 Mancuso G, Berdondini RM. Coexistence of lichen planus pigmentosus and minimal change nephrotic syndrome. Eur J Dermatol. 2009;19:389–390.

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23 Sassolas B, Zagnoli A, Leroy JP, et al. Lichen planus pigmentosus associated with acrokeratosis of Bazex. Clin Exp Dermatol. 1994;19:70–73. 24 Pock L, Jelínková L, Drlík L, et al. Lichen planus pigmentosus-inversus. J Eur Acad Dermatol Venereol. 2001;15:452–454. 25 Vega ME, Waxtein L, Arenas R, et al. Ashy dermatosis and lichen planus pigmentosus: a clinicopathologic study of 31 cases. Int J Dermatol. 1992;31:90–94. 26 Parodi G, Parodi A, Guarrera M, et al. Lichen pigmentosus with scarring alopecia and circulating antinuclear antibodies. Int J Dermatol. 1990;29:227–228. 27 Kashima A, Tajiri A, Yamashita A, et al. Two Japanese cases of lichen planus pigmentosus-inversus. Int J Dermatol. 2007;46:740–742. 28 Akarsu S, Ilknur T, Ozer E, et al. Lichen planus pigmentosus distributed along the lines of Blaschko. Int J Dermatol. 2013;52:253–254. 29 Park HJ, Lee YS. A case of multiple linear lichen planus along the lines of Blaschko. Korean J Dermatol. 2006;44:627–629. 30 Cho S, Whang KK. Lichen planus pigmentosus presenting in zosteriform pattern. J Dermatol. 1997;24:193– 197. 31 Hong S, Shin JH, Kang HY. Two cases of lichen planus pigmentosus presenting with a linear pattern. J Korean Med Sci. 2004;19:152–154. 32 Yokozeki H, Ueno M, Komori K, Nishioka K. Multiple linear erythema dyschromicum perstans (ashy dermatosis) in the lines of Blaschko. Dermatology. 2005;210:356– 357. 33 Sehgal VN, Srivastava G, Sharma S, et al. Lichenoid tissue reaction/interface dermatitis: Recognition, classification, etiology, and clinicopathological overtones. Indian J Dermatol Venereol Leprol. 2011;77:418–430.

mentosus-inversus. 2001;15:452–454.

J Eur Acad Dermatol Venereol.

38 Kim BS, Aum JA, Kim HS, et al. Coexistence of classic lichen planus and lichen planus pigmentosus-inversus: resistant to both tacrolimus and clobetasol propionate ointments. J Eur Acad Dermatol Venereol. 2008;22:106– 107. 39 Kashima A, Tajiri A, Yamashita A, et al. Two Japanese cases of lichen planus pigmentosus-inversus. Int J Dermatol. 2007;46:740–742. 40 Muñoz-Pérez MA, Camacho F. Pigmented and reticulated plaques of folds. A case of lichen planus pigmentosus-inversus? Eur J Dermatol. 2002;12:282. 41 Bennàssar A, Mas A, Julià M, et al. Annular plaques in the skin folds: 4 cases of lichen planus pigmentosus-inversus. Actas Dermosifiliogr. 2009;100:602–605. 42 Kim BS, Park KD, Chi SG, et al. Two cases of lichen planus pigmentosus-inversus arising from long-standing lichen planus-inversus. Ann Dermatol. 2008;20:254–256. 43 Pock L, Jelínková L, Drlík L, et al. Lichen planus pigmentosus-inversus. J Eur Acad Dermatol Venereol. 2001;15:452–454. 44 Nakayama H, Harada R, Toda M. Pigmented cosmetic dermatitis. Int J Dermatol. 1976;15:673–675. 45 Nakayama H, Matsuo S, Hayakawa K, et al. Pigmented cosmetic dermatitis. Int J Dermatol. 1984;23:299–305. 46 Ramirez CO. Dermatosis Cenicienta. Dermatologia Rev Mex. 1963;7:232–244. 47 Vega ME, Waxtein L, Arenas R, et al. Ashy dermatosis versus lichen planus pigmentosus: a controversial matter. Int J Dermatol. 1992;31:87–88. 48 Zaynoun S, Rubeiz N, Kibbi AG. Ashy dermatoses--a critical review of the literature and a proposed simplified clinical classification. Int J Dermatol. 2008;47:542–544.

34 Müller CS, Schmaltz R, Vogt T, et al. Lichen striatus and blaschkitis: reappraisal of the concept of blaschkolinear dermatoses. Br J Dermatol. 2011;164:257–262.

49 Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006;45:897–908.

35 Di Lernia V. Linear and whorled hypermelanosis. Pediatr Dermatol. 2007;24:205–210.

50 De Galdeano CS, Leaute-Labreze C, Bioulac-Sage P, et al. Idiopathic eruptive macular pigmentation: report of five patients. Pediatr Dermatol. 1996;13:274–277.

36 Rower JM, Carr RD, Lowney ED.Progressive cribriform and zosteriform hyperpigmentation. Arch Dermatol. 1978;114:98–99. 37 Pock L, Jelínková L, Drlík L, et al. Lichen planus pig-

51 Bhutani LK, George M, Bhate SM. Vitamin A in the treatment of lichen planus pigmentosus. Br J Dermatol. 1979;100:473–474.

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University of Athens Medical School, Athens, Greece

WORLD CONGRESS

OF COS COSMETIC

DERMATOLOGY DERMA ATO AT TOLOGY L 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

March/April 2013

Volume 11 • Issue 2

New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

ONMEL (Itraconazole) 200-mg Tablet Aditya K. Gupta, MD, PhD;1,2 Maryse Paquet, PhD;2 William Abramovits, MD3

nychomycosis is a fungal infection of the nails, with toenails being affected much more frequently than fingernails.1 Onychomycosis is caused predominantly by dermatophyte fungi of the genus Trichophyton, but the condition can also be caused by Candida species and nondermatophyte molds.2 Several treatments are currently available for the treatment of onychomycosis, but the gold standard treatment for onychomycosis is still systemic antifungal therapy, especially when the disease is severe with lunula involvement.3,4 One of the main oral treatments, itraconazole, has been shown to be both effective and safe for the treatment of onychomycosis. Itraconazole is a triazole that inhibits the enzyme lanosterol-14ademethylase involved in the biosynthetic pathway of ergosterol. This inhibition results in depletion of ergosterol and fungistatic activity.5 For onychomycosis treatment in nonimmunocompromised patients, a pulse itraconazole regimen for fingernails (200 mg twice daily for 1 week per month for 2 months) and a continuous itraconazole regimen (200 mg daily for 12 weeks) for toenails are approved by the Food and Drug Administration (FDA) for 100-mg capsules.6 A new formulation in a 200-mg tablet is now also approved by the FDA for the treatment of toenail onychomycosis in nonimmunocompromised patients with a similar continuous regimen of 200 mg daily for 12 weeks.7

The use of melt-extrusion technology enables the packaging of 200 mg of itraconazole in a single tablet. This new formulation is associated with modified itraconazole pharmacokinetics; indeed, half-lives of 37±10 (standard deviation) and 20±7 hours have been reported for itraconazole and its active metabolite hydroxyl-itraconazole for the tablet formulation7 compared with 21±5 and 12±3 hours for the capsules.6 Taking itraconazole capsules with a meal results in better bioavailability compared with a fasting state, with the tablet being bioequivalent to the capsule.6,7 This bioequivalence between the two itraconazole formulations

has been confirmed by a phase III clinical trial comparing their efficacy and safety with a total of 1381 participants.7–9 Clinical studies One multicenter phase III randomized, evaluator-blind, parallelgroup study compared itraconazole tablets, itraconazole capsules, and placebo tablets for the treatment of dermatophyte toenail onychomycosis.8 Men and women, aged between 16 to 75 years with a clinical diagnosis of onychomycosis of at least one great toenail, were eligible if 25% to 75% of the most severely affected great toenail (target toenail) were involved and if they had at least 2 mm of unaffected target toenail. The diagnosis had to be confirmed by direct potassium hydroxide (KOH) microscopy and a positive culture for dermatophytes. Participants were excluded if the onychomycosis was caused by Candida spp. only or they had participated in a clinical trial for systemic treatment of toenail onychomycosis within 24 weeks prior to the first visit. They were also excluded if they used the following treatments prior to the first visit: systemic antifungals within 12 weeks, topical antifungal nail lacquer within 30 days, and any other topical treatments for onychomycosis within 7 days. Participants with evidence or history of ventricular dysfunction such as congestive heart failure, known liver disease or a history of liver toxicity with other drugs, or using systemic immunosuppressants were excluded from this study. Participants were randomized to 1 of the 3 treatment arms in a 3:3:1 ratio7,8: (1) 593 participants were treated with one 200-mg itraconazole tablet once daily, (2) 590 participants were treated with two 100-mg itraconazole capsules once daily, and (3) 198 participants received a placebo tablet once daily (Table I). The participants were instructed to take 1 tablet or 2 capsules after a full meal every day for 12 weeks. The compliance with the dosing regimen was slightly higher (4%) with the itraconazole tablet compared with the itraconazole capsules (Table I).

From the Division of Dermatology, Department of Medicine, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada;1 Mediprobe Research, London, Ontario, Canada;2 and the Department of Medicine, Baylor University Medical Center; Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School; Dermatology Treatment and Research Center, Dallas, TX3 Address for Correspondence: William Abramovits, MD, Dermatology Treatment & Research Center, 5310 Harvest Hill Rd, #160, Dallas, TX 75230 • E-mail: dra@dermcenter.us

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Table I. Number of Participants and Their Compliance Treatment Groups

Itraconazole Tablets

Itraconazole Capsules

Placebo Tablets

Randomized, No.

593

590

198

517 (87.2)

496 (84.1)

156 (78.8%)

93.0%

89.0

90.1

Treatment Groups

Itraconazole Tablets

Itraconazole Capsules

Placebo Tablets

Complete cure, %7–10

22.3

21.7

1 (P<.001)a

Mycological cure, %7,10

33.7

29.3 (P<.001)

Completed, No. (%) Compliance, %

8,9

Table II. Efficacy Outcomes at Week 52

Clinical cure, %

7,10

Clinical improvement, %

8,9

3 b

2.0 (P<.001)a

Cochran-Mantel-Haenszel test compared with itraconazole tablet. Wald’s confidence limits compared with itraconazole tablet.

The baseline characteristics of the participants were similar in the 3 treatment groups.8 The mean age of the participants was 47.4+12.13 (standard deviation) years and 74.9% were women. Most of the participants were American (88.8%) and Caucasian (85.0%). The percentages of participants who completed the study were 3.1% and 8.4% higher in the itraconazole tablet group compared with the itraconazole capsules and placebo tablets groups, respectively (Table I).

Clinical improvement was also assessed at week 52 and analyzed based on the intention-to-treat population. In terms of clinical improvement rates, itraconazole tablets were noninferior to itraconazole capsules and showed a significant difference of +4.4% (Table II). The itraconazole tablet was also significantly more effective than placebo.

Efficacy

The safety profile of the participants treated with itraconazole tablets was generally comparable with that of the participants treated with itraconazole capsules.7,9,10 A larger percentage of participants did not complete the study because of adverse events in the itraconazole capsules group (31 of 590 [5.3%]) compared with the itraconazole tablets (21 of 593 [3.5%]) and placebo tablets (8 of 198 [4.0%]) groups.8 The only adverse event reported was hearing loss. No difference in hearing lost was noted during the treatment period. In contrast, in the follow-up period, a higher number of participants in the itraconazole capsules group (36 of 515 [6.99%]) experienced hearing loss compared with the itraconazole tablets (19 of 535 [3.55%]) and placebo tablets (8 of 168 [4.76%]) groups.

The primary outcome of complete cure was defined as no evidence of onychomycosis and normal nail unit without subungual hyperkeratosis or onycholysis (clinical cure) and negative KOH microscopy and culture for dermatophyte (mycological cure) of the target toenail.9 The complete cure was assessed at week 52 and analyzed in the intention-to-treat population. As shown in Table II, the complete cure rates were similar (approximately 22%) between the groups treated with itraconazole, which was significantly more effective than placebo tablets. Individual rates for mycological cure and clinical cure have also been reported post-hoc (Table II).7,10 The type of analysis used (per protocol or intention-to-treat) and the results of statistical analyses were not specified, however. The cure rates suggest a possible superiority of the itraconazole tablet to achieve mycological cure. The secondary outcome of this study was clinical improvement, which was defined as mycological cure with no or minimal evidence of onychomycosis (<10% dystrophy and/or discoloration with minimal subungual hyperkeratosis and/or onycholysis).8 SKINmed. 2013;11:105–107

Safety

Indications and Administration Itraconazole 200-mg tablets are approved for the treatment of toenail onychomycosis caused by dermatophytes in nonimmunocompromised adults.7 The recommended dosing regimen is once daily after a full meal for 12 weeks. As for all itraconazole formulations, the prescription of itraconazole is contraindicated

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in patients with evidence or history of ventricular dysfunction such as congestive heart failure, in pregnant or breastfeeding women, and in patients with known hypersensitivity to itraconazole products. Co-administration of itraconazole with 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 is also contraindicated. For a complete list of drug interactions, the reader is referred to the product monograph.7

5 Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993;28:S28–S34.

As previously mentioned, itraconazole absorption is influenced by food intake. The absorption of itraconazole is increased with meals for tablets and capsules6,7 but not for the oral solution11; however, not all meals have the same effect. For example, bread meals increase itraconazole bioavailability compared with fasted state, whereas rice meals have the opposite effect.12 Acidic beverages such as vitamin C beverages13 and cola soft drinks13–15 generally increase itraconazole absorption from the capsule formulation. A decrease in bioavailability, however, was observed with orange juice16 and with a single dose of grapefruit juice.17 Repeated consumption of grapefruit juice with itraconazole oral solution increased its bioavailability in healthy women but not men.16,18,19

9 Scher RK, Kempers S, Bissonnette R, Quiring J, Bulger L. A novel itraconazole tablet for the treatment of onychomycosis. http://www.aad.org/Posters/Documents/ AM2010/Poster/2414/2414.pdf. Accessed February 4, 2013.

Conclusions When administered in a continuous 12-week regimen, ONMEL itraconazole tablets (Merz Pharmaceuticals, LLC, Greensboro, NC) have been shown to be equivalent to Sporanox itraconazole capsules (Janssen Pharmaceuticals Inc, Titusville, NJ) in terms of efficacy and safety for the treatment of toenail onychomycosis. As a result of the longer half-life observed for the tablet, it would be interesting to compare the two formulations in a randomized clinical trial using a pulse regimen. In clinical practice, patients may find it easier to take one 200-mg tablet as opposed to two 100-mg capsules. References 1 Roberts DT. Onychomycosis: current treatment and future challenges. Br J Dermatol. 1999;141:1–4. 2 Seebacher C, Bouchara JP, Mignon B. Updates on the epidemiology of dermatophyte infections. Mycopathologia. 2008;166:335–352. 3 Shemer A. Update: medical treatment of onychomycosis. Dermatol Ther. 2012;25:582–593. 4 Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother. 2012;13:1131– 1142.

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6 Ortho-McNeil-Janssen Pharmaceuticals. Sporanox capsules (Itraconazole) label information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083 s048s049s050lbl.pdf. Accessed February 4, 2013. 7 Merz Pharmaceuticals. ONMEL tablets (Itraconazole) (on file). 8 Stiefel Laboratories. Itraconazole tablets vs. itraconazole capsules vs. placebo in onychomycosis of the toenail. http://clinicaltrials.gov/ct2/show/NCT00356915 ?term=NCT00356915&rank=1. Accessed February 4, 2013.

10 Merz Pharmaceuticals. ONMEL promotional document. 2013 (on file). 11 Barone JA, Moskovitz BL, Guarnieri J, et al. Food Interaction and Steady-State Pharmacokinetics of Itraconazole Oral Solution in Healthy Volunteers. J Human Pharmacol Drug Ther. 1998;18:295–301. 12 Yun H, Baek MS, Park IS, et al. Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers. Eur J Clin Pharmacol. 2006;62:1033–1039. 13 Bae SK, Park S-J, Shim E-J, et al. Increased oral bioavailability of itraconazole and its active metabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants. J Clin Pharmacol. 2011;51:444–451. 14 Jaruratanasirikul S, Kleepkaew A. Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin Pharmacol. 1997;52:235–237. 15 Lange D, Pavao JH, Wu J, et al. Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol. 1997;37:535–540. 16 Kawakami M, Suzuki K, Ishizuka T, et al. Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects. Int J Clin Pharmacol Ther. 1998;36:306–308. 17 Penzak SR, Gubbins PO, Gurley BJ, et al. Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers. Ther Drug Monit. 1999;21:304–309. 18 Gubbins PO, McConnell SA, Gurley BJ, et al. Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers. Pharmacotherapy. 2004;24:460–467. 19 Gubbins PO, Gurley BJ, Williams DK, et al. Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice. Eur J Clin Pharmacol. 2008;64:293–301.

ONMEL (Itraconazole) 200-mg Tablet

This Little Piggy Had ONMEL

â&#x201E;˘

(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

1 2

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

1 2

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

Antiarrhythmics The Class IA antiarrhythmic, quinidine and

March/April 2013

Volume 11 • Issue 2

New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

PICATO (Ingenol Mebutate 0.015% and 0.05% Gels): A Novel Treatment for Actinic Keratosis William Abramovits, MD;1,2,3 Marcial Oquendo, MD;3 Kimberly D. Vincent, MD;4 Aditya K. Gupta, MD, PhD5

ctinic keratoses (AKs) are pre-malignant skin lesions typically caused by UV radiation that may progress to squamous cell carcinoma (SCC). Treatment of AKs traditionally includes two types of options: (1) localized destructive (via cryosurgery, curettage and electrodessication, photodynamic therapy, lasers, and excision), and (2) field therapy (intended to eradicate lesions that are clinically visible and/or palpable or subclinical), generally via applications of 5-fluorouracil, imiquimod, and diclofenac formulations for topical use. Field therapy currently requires weeks or months of treatment. A novel medication recently approved by the US Food and Drug Administration (FDA) has been shown to topically treat AKs in 2 or 3 days with purported safety and efficacy rates similar to conventional therapy.1-3 Ingenol mebutate is a hydrophobic diterpene ester isolated from the plant Euphorbia peplus; however, its mechanism of action (MOA) is poorly understood. MOA studies show plasmatic and mitochondrial membrane disruption followed by cell death by primary necrosis within 1 hour; it also modulates proliferation, neutrophilic infiltration, and apoptosis through activation of the protein kinase C pathways. In 4 multicenter, double-blind, randomized, vehicle-controlled clinical trials, 1005 adult patients with AKs treated with ingenol mebutate 0.015% and 0.05% gel demonstrated higher complete and partial clearance rates at day 57 compared with rates seen with placebo. Overall, treated patients showed a median reduction of 79% from baseline in the number of AKs vs 0% for placebo. Comparisons between field therapies for AKs are difficult to perform because the designs of the available studies are quite different, and no head-to-head studies including ingenol mebutate

gels have been done. An advantage of ingenol mebutate 0.015% and 0.05% resides in high compliance as the full course of therapy consists of 2 or 3 sequential daily applications vs weeks of daily applications for the currently available products, for which patients are likely to interrupt or discontinue treatment because of adverse events, reducing the likelihood that a full course of therapy will be completed. AKs are pre-malignant skin lesions (early evolving, in situ SCCs) typically caused by UV radiation. AKs affect more than 58 million Americans. Treatment of AKs is necessary because approximately 65% of all cases of SCCs arise in lesions previously diagnosed as AKs. SCCs result in approximately 2500 deaths a year. In patients with a history of ≥2 skin cancers, 36% of basal cell carcinomas arise in lesions previously misdiagnosed as AKs.1 Description Ingenol mebutate (ingenol-3-angelate) is a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Euphorbiaceae are distributed worldwide and produce an irritant sap. The use of this plant for medicinal purposes has a long history across multiple continents, with documented successful use on biopsy-proven basal cell carcinoma. The process of extraction, purification, and crystallization takes approximately 5 months from dried plant to active pharmaceutical ingredient.2,3 Ingenol mebutate (PICATO) is manufactured and marketed by LEO Pharma, Inc, in Parsippany, NJ. In January 2012, the FDA granted approval for its use in topical treatment of AKs. Approval is based on data from 4 phase III studies in more than 1000 participants showing that once-daily application for 2 or 3 consecutive days is significantly more effective than placebo at clearing AKs.4,5

From the Department of Medicine, Baylor University Medical Center;1 the Departments of Dermatology & Family Practice, University of Texas Southwestern Medical School,2 Dallas, TX; Dermatology Treatment & Research Center, Dallas, TX;3 Belle Meade Dermatology, Nashville, TN;4 and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada5 Address for Correspondence: William Abramovits, MD, Dermatology Treatment & Research Center, 5310 Harvest Hill Rd, #160, Dallas, TX 75230 • E-mail: dra@dermcenter.us

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Table I. Participants Achieving Complete and Partial Clearance at Day 57 in Each Trial Study 1 Face and Scalp

Study 2 Face and Scalp

Study 3 Trunk and Extremities

Study 4 Trunk and Extremities

Ingenol mebutate gel, 0.015% (n=135)

Vehicle (n=134 )

Ingenol mebutate gel, 0.015% (n=142)

Vehicle (n=136)

Ingenol mebutate gel, 0.05% (n=126 )

Vehicle (n=129 )

Ingenol mebutate gel, 0.05% (n=100)

Vehicle (n=103)

Complete clearance rate

50 (37)

3 (2)

67 (47)

7 (5)

35 (28)

6 (5)

42 (42)

5 (5)

Partial clearance rate (≥75%)

81 (60)

9 (7)

96 (68)

11 (8)

56 (44)

9 (7)

55 (55)

7 (7)

Values are expressed as number (percentage).

Mechanism of Action The mechanism of action of ingenol mebutate is poorly understood. In vitro and in vivo studies in mice showed that it causes plasma membrane disruption and rapid loss of the mitochondrial membrane potential and subsequent mitochondrial swelling, followed by cell death by primary necrosis within 1 hour. Ingenol mebutate has been shown to be a potent activator of classic and novel protein kinase C (PKC) isoenzymes, which play an important role in modulating proliferation, neutrophilic infiltration, and apoptosis in several cellular models either directly or via interaction with other signaling pathways.6-8 In preclinical studies, high concentrations of the drug exerted a direct cytotoxic effect on tumor cells that was mostly confined to the epidermis, whereas concentrations 100-fold lower leading to PKC activation was found mostly in the dermis. Both concentrations lead to a field-wide inflammatory response with subsequent cell death.9,10 P-glycoprotein–mediated absorptive drug transport seems to be responsible for subepidermal tumor cell effect.11 Ingenol mebutate increases cytosolic calcium levels via intracellular stores, which are more present in proliferating keratinocytes and SCC cells than in differentiated epidermis cells.12 Tumor necrosis factor a was also found in higher concentration in treated normal keratinocytes and endothelial cells when compared with treated cancer cells, which may contribute to the selectiveness of the field therapy.9,10,13 Infiltration with neutrophils, mediated by a PKC-dependent production of interleukin 8 and adhesion molecules activation, may explain the prevention of relapse of a treated lesion via antibody-dependent cellular cytotoxicity mediation against residual SKINmed. 2013;11:111–115

tumor cells.2 Removal of p53-mutated cells by ingenol mebutate in the treated field prevented the development of dysplastic epidermal cells in continuous UV light–exposed mice.14 Clinical Pharmacology There is scant pharmacokinetic information for ingenol mebutate. Absorption studies showed that blood levels of drug and metabolites were below the lower limit of quantification (0.1 ng/ mL) after 1 g of topical applications. Although metabolized in hepatocytes, no inhibition or induction of human cytochrome P450 enzymes was demonstrated.5 Clinical Trials In 4 multicenter, double-blind, randomized, vehicle-controlled, clinical trials, 1005 adult participants with AKs were divided into 1 of 2 trials for face and scalp (study 1 and study 2) or 1 of 2 trials for trunk and extremities (study 3 and study 4). The studies enrolled participants with 4 to 8 clinically typical, visible, discrete AK lesions within a 25 cm2 contiguous treatment area. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 94% of patients had Fitzpatrick skin type I, II, or III, and those in the drug-treated groups were all Caucasian.5,15 A total of 547 adult participants with AKs on the face or scalp were randomized (approximately 1:1) to treatment with either ingenol mebutate gel 0.015% or vehicle gel for 3 consecutive days, followed by an 8-week follow-up period. A total of 536 participants (98%) completed these studies. Study participants ranged from 34 to 89 years (mean age, 64 years) and approximately 85% were men.

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A total of 458 adult participants with AK on the trunk or extremities were randomized to treatment with either ingenol mebutate gel 0.05% or vehicle gel for 2 consecutive days, followed by an 8-week follow-up period. A total of 447 participants (98%) completed these studies. Study participants ranged from 34 to 89 years (mean age, 66 years) and approximately 62% were men.

Efficacy

Table II. Participants Achieving Complete Clearance at Day 57 by Anatomical Location (Combined Trials) Ingenol Mebutate (n=135)

Vehicle (n=134)

Scalpa

13/57 (23)

1/50 (2)

Facea

104/220 (47)

9/220 (4)

Armb

49/143 (34)

7/149 (5)

Back of handb

10/53 (19)

0/56 (0)

Chest

11/14 (79)

2/11 (18)

7/16 (44)

2/16 (13)

Other

Complete clearance, the primary outcome, was assessed at 57 days and local reactions were quantitatively measured. Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible AK lesions in the treated area. Partial clearance rate was defined as the proportion of patients with â&#x2030;Ľ75% reduction in the number of AK lesions present at baseline in the selected treatment area. An additional secondary endpoint, which was not prespecified in the protocol, was the percentage change from baseline in the total number of AKs.

In the combined analysis, ingenol mebutate 0.015% gel demonstrated higher complete clearance rate at day 57 than placebo in both trials involving the face and scalp (42.2% vs 3.7%, P<.001), as did the 0.05% gel used in both trials involving the trunk and extremities (34.1% vs 4.7%, P<.001). Partial clearance rate was higher in the ingenol mebutate group for both trials involving the face and scalp (63.9% vs 7.4%, P<.001), as well as those in the trunk and extremities (49.1% vs 6.9%, P<.001) (Table I). Overall, treated participants showed a median reduction of 79% from baseline in the number of AKs vs 0% for placebo, as well as a higher complete clearance rate on all the tested anatomical areas when compared with placebo5,15 (Table II).

Values are expressed as number (percentage). a Study 1 + study 2. b Study 3 + study 4. c Other includes shoulder, back, and leg.

A total of 146 participants who received ingenol mebutate and whose lesions completely cleared at day 57 were included in an

Table III. Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area During the 57-Day Post-Treatment Period (Combined Trials)5 Any Grade >Baseline Face and Scalp

Grade 4 Face and Scalp

Any Grade >Baseline Trunk and Extremities

Grade 4 Trunk and Extremities

Ingenol mebutate gel, 0.015% (n=274)

Vehicle (n=271)

Ingenol mebutate gel, 0.015% (n=274)

Vehicle (n=271)

Ingenol mebutate gel, 0.05% (n=225)

Vehicle (n=232)

Ingenol mebutate gel, 0.05% (n=225)

Vehicle (n=232)

Erythema

258 (94)

69 (25)

66 (24)

0 (0)

207 (92)

43 (19)

34 (15)

0 (0)

Flaking/ scaling

233 (85)

67 (25)

25 (9)

0 (0)

203 (90)

44 (19)

18 (8)

0 (0)

Crusting

220 (80)

46 (17)

16 (6)

0 (0)

167 (74)

23 (10)

8 (4)

0 (0)

Swelling

217 (79)

11 (4)

14 (5)

0 (0)

143 (64)

13 (6)

7 (3)

0 (0)

Vesiculation/ pustulation

154 (56)

1 (0)

15 (5)

0 (0)

98 (44)

2 (1)

3 (1)

0 (0)

Erosion/ ulceration

87 (32)

3 (1)

1 (0)

0 (0)

58 (26)

6 (3)

2 (1)

0 (0)

Values are expressed as number (percentage). a Mild (grade 1), moderate (grade 2 or 3), or severe (grade 4). SKINmed. 2013;11:111â&#x20AC;&#x201C;115

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observational follow-up trial; 12 months later, a mean of 86% of the number of lesions in the treatment area at baseline were still clear. Approximately half of the patients developed or had recurrence of ≥1 lesions in the treated field.15 Adverse Reactions Local skin reactions, including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration were assessed within the selected treatment area and graded by the investigator on a scale of 0 to 4. A grade of 0 represented no reaction present in the treated area, and a grade of 4 indicated a marked and severe skin reaction that extended beyond the treated area (Table III).5 There was minimal change in pigmentation and minimal scarring in all study groups. The most common adverse events that occurred in the ingenol mebutate treatment group were pruritus, pain, and irritation at the application site. No serious adverse events related to the study treatment occurred. (Table IV).5 Local skin reactions typically occurred within 1 day of treatment initiation, peaked in intensity up to 1 week following completion of treatment, and resolved within 2 to 4 weeks depending on the treated area.5,15 Safety Ingenol mebutate is a pregnancy category C medication, meaning that there are no adequate or well-controlled studies in pregnant women. In experiments with pregnant female rabbits, increased incidence of fetal visceral and skeletal variations was noted after intravenous doses of 1, 2, and 4 μg/kg/day; however, the clinical relevance of these findings is unclear since systemic exposure was undetectable in human trial patients. The safety

and effectiveness rates in patients younger than 18 years have not been established. Of the 1165 participants treated in the clinical trials, 56% were 65 years and older and 21% were 75 years and older; no overall differences in safety or effectiveness were observed between these groups of participants.5 Discussion The FDA has changed its demands on pharmaceutical companies attempting to obtain approval for their products intended for the treatment of AKs. This makes comparing the benefits of these two ingenol mebutate gels with products previously approved for a similar indication, in a manner that the latter could serve as historical controls, not possible. To assume that ingenol mebutate is better or worse at treating AKs without appropriately designed head-to-head studies is impractical; however, we render our opinion for the reader to take with reservation. In the ingenol mebutate studies, the definition of clearance was determined by the ability of the gels to eradicate each and every of the 4 to 8 thin AKs present on a 25-cm2 area (roughly the size of a dollar bill cut in half ). This design impedes comparisons with most other therapeutic options, particularly with cryosurgery and photodynamic therapy, which do not intend to address field effects. Based on our clinical trial experience, even comparisons with other field therapies are difficult to assess as the designs for such studies are sufficiently different. For example, some studies, like the ones for the ingenol mebutate gels, allowed for the inclusion of macular AKs only, and their results do allow us to interpret how effective and safe field therapy treatments of thin or macular AK products may be. If there is a fairly clear advantage in the use of this product, it resides on the issue of compliance, as the full course of therapy

Table IV. Adverse Reactions Occurring in ≥2% of Participants Treated With Ingenol Mebutate Gel and at Higher Frequency Than Vehicle (Combined Trials)5 Face/Scalp

Trunk/Extremities

Adverse Reactions

Ingenol mebutate gel, 0.015% (n=274)

Vehicle (n=271)

Ingenol mebutate gel, 0.05% (n=225)

Vehicle (n=232)

Application site pain

42 (15)

1 (0)

18 (8)

0 (0)

Application site pruritus

22 (8)

3 (1)

8 (4)

1 (0)

Application site infection

7 (3)

0 (0)

4 (2)

2 (1)

Periorbital edema

7 (3)

0 (0)

5 (2)

0 (0)

Headache

6 (2)

3 (1)

Values are expressed as number (percentage). Abbreviation: NA, not applicable. SKINmed. 2013;11:111–115

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consists of 2 or 3 daily applications (done sequentially), compared with weeks of daily applications with currently available products that are likely to be interrupted or discontinued because of adverse events. The safety profile shown in the ingenol mebutate gels studies suggest that there is reduced risk that a potential adverse reaction would be severe enough to interrupt therapy. In other words, compliance with the brief full course is unlikely to be compromised. Furthermore, the implied convenience of a short treatment course with more tolerable side effects vs previous field therapies with potential for severe adverse events makes repeat courses, if needed, more likely to be accepted.

5 LEO PHARMA Inc. Picato® [Package Insert]. Parsippany, NJ 07054, USA. 2012.

Regarding the limitation in area (5x5 cm) that can be treated with each unit dose, the favorable safety profile suggests that an area twice as large, and possibly larger, could be comfortably treated. A multicenter, open-label, dose-area escalation study performed in 64 patients on the upper extremities, showed that 0.05% ingenol mebutate gel was well tolerated when applied to treatment areas up to 100 cm2 for 2 days in the majority of patients.16

9 Zibert JR BM, Grue-Soerensen G, Møller K, Stahlhut M, Eriksson AH, et al. Ingenol Mebutate Penetrates Reconstructed Human Skin In A Gradient Dependent Manner And Clears Subclinical Skin Cancer. J Am Acad Dermatol. 2012; 66(4, Suppl 1): AB152.

We foresee that this product will likely be used in combinations, even if done sequentially, with localized lesion destructive therapies (such as cryosurgery, reducing its intended depth and duration). A clinical trial using sequential cryotherapy and field treatment with ingenol mebutate is currently ongoing.17 It is also possible that such therapies could be reduced in number by the concomitant use of ingenol mebutate gels. Conclusions This is an entirely new class of product with long-term benefits and risks that are not yet fully known, but in view of the limitations of currently available field therapies, we feel that these ingenol mebutate gels deserve consideration. References 1 Skin Cancer Foundation. Skin Cancer Information. http://www.skincancer.org/.

6 Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. Apr 15 2004;64(8):2833-9. 7 Serova M, Ghoul A, Benhadji KA, et al. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther. Apr 2008;7(4):915-22. 8 Tomas D. [Apoptosis, UV-radiation, precancerosis and skin tumors]. Acta Med Croatica. Oct 2009;63 Suppl 2:53-8.

10 Challacombe JM SA, Parsons PG, Jones B, Hampson P, Kavanagh D, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006;177(11):8123-32. 11 Li L SS, Lee A, Garfield SH, Maloney DJ, Ambudkar SV, et al. Cancer Res 477. 2010;70:4509-19. 12 Stahlhut M LJ, Bertelsen M, Worm J, Hampson P, Chahal H, Zibert J. Ingenol mebutate initiates multiple specific cell death pathways in human cancer cells. J Am Acad Dermatol. 2012;66(4, Suppl 1): AB152. 13 Fecker LF SE, Braun FK, Rodust PM, Schwarz C, Kohler A, et al. Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac/hyaluronic acid correlates with downregulation of c-FLIP. J Invest Dermatol. 2010;130(8):2098-109. 14 Cozzi SJ OS, James C, Rebel HG, de Gruijl FR, Ferguson B, et al. Ingenol mebutate field-directed treatment of UVB-damaged skin reduces lesion formation and removes mutant p53 patches. J Invest Dermatol. 2011;doi:10.1038/jid.2011.418. 15 Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. Mar 15 2012;366(11):1010-9.

3 Weedon D, Chick J. Home treatment of basal cell carcinoma. Med J Aust. Jun 12 1976;1(24):928.

16 Schmieder G. Multicenter, open-label, dose-area escalation, cohort study to evaluate the safety and tolerability of PEP005 (ingenol mebutate) gel 0.05% applied for two consecutive days to treatment area(s) of up to a total of 100cm2 in patients with actinic keratoses. Poster 2010 Annual AAD Meeting. 2010.

4 LEO Pharma announces that Picato® (ingenol mebutate) gel has been approved by US FDA for once-daily, 2 or 3 day treatment of actinic keratoses. 2012. http://www. leo-pharma.us/Home/News.aspx.

17 LEO Pharma. A Sequential Treatment Regimen of Cryotherapy and Picato® for the Treatment of Actinic Keratosis on the Face and Scalp. 2012. http://clinicaltrials. gov/ct2/show/study/NCT01541553.

2 Fallen RS, Gooderham M. Ingenol mebutate: an introduction. Skin Therapy Lett. Feb 2012;17(2):1-3.

SKINmed. 2013;11:111–115

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March/April 2013

Volume 11 • Issue 2

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

Absorica (Isotretinoin): A New Form Noah Scheinfeld, MD, JD

bsorica (Cipher/Ranbaxy Laboratories Inc, Jacksonville, FL) is a recently released form of isotretinoin, which differs from generic isotretinoin in that it can be taken without food. The brand Accutane first became available in the United States in 1982, but it is no longer marketed. Accutane continues to be marketed abroad under the name Roaccutane (Hoffman-La Roche, Nutley, NJ). Because of its high lipophilicity, oral absorption of isotretinoin, like griseofulvin, is enhanced when given with a high-fat meal, but unlike acitretin and etretinate, isotretinoin is not stored in the adipose tissue, having a much shorter half-life than other retinoids. The main advantage of Absorica, however, is its administration with or without food. With food, Absorica has even higher serum concentrations than when it is taken without food.1 All oral retinoid levels are affected by alcohol intake, which should be avoided. Absorica, which comes in 10-, 20-, 30-, and 40-mg tablets, is recommended to be taken with 8 to 12 ounces of water to decrease the risk of esophageal irritation such as generic isotretinoin. A dosage of 30 mg of Absorica taken twice a day has a wholesale price of $1416.82 a month, more than twice the cost of any other generic forms of isotretinoin.2 Effectiveness The efficacy of Absorica without taking food is clinically equivalent to Accutane taken with fatty food. In clinical studies, Absorica cleared nodular lesions (average 15.68) as compared with Accutane (average 15.62) at a similar rate. Interestingly, the number of patients who achieved a 90% clearance was 75% with Accutane and only 70% with Absorica, although differences did not rise to the level of statistical significance. The pharmacokinetics of Absorica differ from that of isotretinoin. The area under the curve (AUC) differs for Absorica and isotretinoin. The AUC of Absorica is approximately 83% greater than that of Accutane,

but somehow this does not make Absorica more effective. The therapeutic impact of a greater AUC value is not clear. A good example of this is cefdinir whose AUC is much greater than cephalexin, but both medications are similar in clinical affect at the recommended doses. Data suggest that fatty food should accompany all oral retinoid intake. Generic isotretinoins and Absorica are not identical to Accutane (branded medications’ formulations that often trump generics’ forumations). Some have suggested that when using generic isotretinoin, patients are underdosed, because the generics are not as bioactive or effective as the brand.3 Indications Absorica, like generic isotretinoin,4 is a synthetic retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years and older. The recommended dosage of Absorica is 0.5 to 1 mg/kg/d given in two divided doses without regards to meals for 15 to 20 weeks. Interestingly, in the original isotretinoin studies, dosing ranged from 0.5 to 2 mg/d for 20 weeks. Once-daily dosing is not recommended (Michael Fisher, MD, oral communication; dosed Accutane once-a-day with no apparent difference in clinical effectiveness). In women of childbearing age, 2 pregnancy tests prior to prescribing, each month during therapy, at the end of therapy, and 1 month after discontinuation are required, as well as two forms of birth control. Prior to prescribing Absorica, fasting lipid profile and liver function tests should be performed, according to the package insert. Absorica is not interchangeable with other isotretinoins, therefore a pharmacists should not substitute with a generic isotretinoin. Warnings Warning and precautions listed for Absorica1 are the same as for generic isotretinoin4 but appear to be more stringent. In fact, the May 2012 package insert for generic isotretinoin and Absorica are virtually identical, save for food intake and noninterchangeability.

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Assistant Clinical Professor of Dermatology at Weil Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: NSS32@columbia.edu

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The package insert of Absorica includes: (1) embryofetal toxicity, (2) iPLEDGE participation, (3) the need for acceptable contraception (micro-dosed progesterone preparations (“minipills” that do not contain an estrogen are an inadequate method of contraception during Absorica therapy), (4) psychiatric disorders (eg, psychosis, depression), (5) pseudotumor cerebri, (6) serious skin reactions, (7) pancreatitis, (8) lipid abnormalities, (9) hearing impairment (if the patient experiences tinnitus or hearing impairment, discontinue Absorica), (10) hepatotoxicity (rare, data scant), (11) risk for inflammatory bowel disease (questionable as studies gainsay association), (12) other gastrointestinal problems (if patient experiences abdominal pain, rectal bleeding, or severe diarrhea, stop Absorica), (12) musculoskeletal pathology (the insert notes that back pain apparently occurs in 13.5% of adolescents using isotretinoin (79 of 358) of 22% pediatric patients experienced arthralgias (7.6% severe), (13) ocular abnormalities (eg, hordeolum, night vision changes), (14) hypersensitivity, and (15) the need for laboratory monitoring for adverse reactions. Few patients have encountered severe side effects but the insert includes every Food and Drug Administration–reported side effect.1,4 Like isotretinoin, Absorica can induce mucocutaneous and xerotic conditions such as dry skin, dry eyes (contact lenses intolerance), epistaxis, nasopharyngitis, cheilitis, alopecia, eczema, upper respiratory tract infection, eczema herpticum, skin fragility, and photosensitivity. In addition, Absorica should not be taken with vitamin A (as their side effects are redundant and additive); (2) tetracyclines (as both cause pseudotumor cerebri); (3) phenytoin (drug interactions);5 (4) St. John’s wort (as it might effect OCPs); (5) systemic corticosteroids (as both cause osteoporosis); and (6) norethindrone/ethinyl estradiol (changes efficacy). Interestingly, isotretinoin can ameliorate the gingival hypertrophy associated with phenytoin.6 As with generic isotretinoin, sexually active men should be counseled about the risks of Absorica, because remote sperm side effects have been known to cause birth defects. In addition, because many drugs are present in human milk, nursing mothers who take isotretinoin should either discontinue nursing or not use the drug. Retinoids have been known to affect bones. Hyperostosis does not seem to be an issue with one course of isotretinoin of any type. Premature epiphyseal closure can occur with any type of isotretinoin. In a 20-week clinical trial that included 289 adolescents taking Absorica vs a generic product of Accutane with hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were deemed clinically sig-

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nificant. The original pivotal clinical trial for Accutane found that 75% of patients were cured taking a full dose for 5 months.8 Laboratory Monitoring and Alcohol Use According to the package insert, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, blood cholesterol, low-density lipoprotein, and blood alkaline phosphatase, and blood bilirubin levels increased; white blood cell count decreased; and creatine phosphokinase, glucose, lipids (triglycerides in particular), and complete blood cell count levels (because of rare anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis) could be altered while taking Absorica. The lipid monitoring warning state: “pretreatment and followup blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Absorica is established.”1 Elevated sedimentation rates, increased platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic, and gross hematuria have been noted. Creatine phosphokinase can also be elevated with Absorica, along with muscle pain. This laboratory information suggests that testing these values is advisable when an index for clinical suspicion exists as they may be altered when using Absorica. The key values to monitor patients taking isotretinoin are b human chorionic gonadotropin in women, triglycerides in all patients, and LFTs where clinically appropriate. Retreatment In the original Accutane studies, 25% of patients, while not considered clinical failures, required retreatment with Accutane. A similar need for retreatment was found in studies for Absorica. The package insert explicates how to proceed if further treatment is desired to fully clear acne. After a period of 2 months or more after Absorica therapy, and if warranted by persistent or recurring severe nodular acne, a second course of Absorica therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Absorica, even in low doses, has not been studied and is not recommended. Outside of the United States, isotretinoin is commonly given at doses as low as 0.25 to 0.4 mg/kg for longer periods.9 To insulate Absorica from product liability law suits,10 which means reiterating the warning contained in the package insert for Absorica, states that it should be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Absorica on bone loss is unknown.

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Conclusions Selecting Absorica over other marketed forms of isotretinoin should increase patient compliance by removing from the equation the need to take food with administration. Unfortunately, Absorica is priced twice as much as the current generics, but administration without the need for food is a definite advantage and enhances compliance. References 1 Absorica (isotretinoin capsules) [package insert]. Jacksonville, FL: Ranbaxy Laboratories Inc; 2012 2 Absorica for acne. Med Letter Drugs Therapeut. 2013;21:8. 3 Mutizwa MM, Sheinbein DM. Are we underdosing acne patients with generic isotretinoin? Dermatol Online J. 2013;15:1912. 4 Amnesteem (isotretinoin capsules USP) [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc; 2012. Available at https://www.ipledgeprogram.com/Documents/Mylan%20Amnesteem%20Package%20InsertI.pdf.

6 Fex G, Larsson K, Andersson A, Berggren-Söderlund M. Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity. Arch Toxicol. 1995;69:572–574. 7 Norris JF, Cunliffe WJ. Phenytoin-induced gum hypertrophy improved by isotretinoin. Int J Dermatol. 1987;26:602–603. 8 Shalita AR, Cunningham WJ, Leyden JJ, Pochi PE, Strauss JS. Isotretinoin treatment of acne and related disorders: an update. J Am Acad Dermatol. 1983;9:629– 638. 9 Lee JW, Yoo KH, Park KY, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol. 2011;164:1369– 1375. 10 Pliva v. Mensing, 131 S. Ct, 2567, 2011 WL 2472780 (U.S.).

Historical Diagnosis and treatment: eczema varicosum (continued from page 83)

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Volume 11 • Issue 2

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

Treatment of Necrobiotic Xanthogranuloma With 2-Chlorodeoxyadenosine Leigh Sutton, MD;1 Stephanie Sutton, BA;1 Margaret Sutton, MD2

A 71-year-old man presented with ulcerating yellow-red plaques of the back, chest, face, and extremities (Figure 1). He had a 10-year history of these lesions. The initial plaque appeared on the back followed by rapid progression of multiple similar lesions involving the face, chest, abdomen, and extremities. The plaques on his face were predominately in the periorbital and eyelid regions. Skin biopsy revealed an ulcerated epidermis. Dense sheets of foamy histiocytes were present in the dermis and contained foci of necrobiosis. Numerous Touton giant cells were present and cholesterol clefts were prominent. Special stains for organisms were negative. On further laboratory evaluation, serum protein electrophoresis revealed a monoclonal spike of 0.5 g/dL IgG lambda. Results from bone marrow biopsy were negative. Other significant laboratory findings included an elevated sedimentation rate and low serum complement. Clinical findings, histopathology, and laboratory evaluations were consistent with the diagnosis of necrobiotic xanthogranuloma (NXG).

he treatment course for this individual has been fraught with many disappointments. Prior to presentation, the patient had been treated with melphalan, which was discontinued after 3 months due to no improvement of his NXG. Next, doxorubicin was attempted for 6 months, again with no improvement observed. One year after his failed trial with doxorubicin, he agreed to treatment with total skin electron beam radiation therapy, receiving a total dose of 3000 cGy. During this treatment, the plaques improved but did not resolve. Within a few months after completion of radiation therapy, the plaques began to reactivate. In the years following his radiation treatment, other medication therapies had been attempted. These therapies included 4 cycles of infliximab, then dapsone, followed by pentoxyfiline. None of the previously listed therapies were successful. Next, combined use of prednisone and chlorambucil was introduced but felt to be no more beneficial than prednisone alone. Initial prednisone dose was 70 mg daily, tapered to 30 mg daily. It became necessary to discontinue prednisone when the patient’s blood sugar values became persistently elevated and the plaques were no longer responsive. Consultation from hematology-oncology resulted in the suggestion of 2-chlorodeoxyadenosine (2-CDA) treatment. The pa-

Figure 1. Plaques of necrobiotic xanthogranuloma at initial diagnosis 10 years prior to presentation.

From the University of Nebraska Medical Center, Omaha, NE;1 and Sutton Ryan Dermatology, Lincoln, NE2 Address for Correspondence: Leigh Sutton, MD, University of Nebraska Medical Center, 2212 South 64th Plaza #401, Omaha, NE 68106 • E-mail: leighmsutton@gmail.com

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CASE STUDY NXG is significant on a systemic level because of its strong association with paraproteinemia, including multiple myeloma.1–9 Paraproteinemia has been reported to occur in 72% to 90% of NXG cases.6 Most frequently, IgG k gammopathy is noted.3,7 Bone marrow biopsies range from normal to disclosing hematologic malignancies including multiple myeloma and lymphoproliferative disorders.1,6 The onset of hematologic malignancy may precede or supersede the onset of NXG by a number of years. As a result, continual testing for paraproteinemia is recommended.3,6,8 This patient demonstrated IgG lambda gammopathy and has not demonstrated malignancy thus far. Other laboratory abnormalities frequently observed in NXG include elevated estimated sedimentation rate, leukopenia, decreased C4, and dyslipidemia.1,6,9

Figure 2. Histopathology: routine hematoxylin and eosin stain (original magnification ×200) demonstrating Touton-type multinucleated giant cells and xanthomatized histiocytes.

The periorbital region, especially the eyelids, is involved in 65% to 85% of NXG cases.2-4 Reported ophthalmologic complications include scleritis, episcleritis, keratitis, ulcerative keratitis, ptosis,3 perforation, and blindness.3,5 In addition, lesions involving the oral mucosa and internal viscera have been documented.2,6 The most frequent extracutaneous site reported is the respiratory tract (larynx and lung), while the heart follows in frequency.6

tient consented and underwent 2-CDA therapy with 5 mg/m2 IV for days 1, 2, 3, 4, and 5 of a 28-day cycle. His response was favorable with ulcerations healing and plaques showing regression; however, after 4 cycles, the patient developed significant pancytopenia requiring multiple blood transfusions and 2-CDA therapy was discontinued. Despite discontinuation of therapy, the patient’s pancytopenia has been slow to recover. One year after discontinuation of therapy, the patient’s plaques began to reactivate. In addition, his eyelids are demonstrating cicatricial retraction not allowing lid closure and resulting in a nonhealing corneal ulcer. He is not currently on any treatment for his NXG. As of this date, no hematologic or internal malignancy has been identified. Comment NXG is a rare histiocytic disorder that is frequently characterized as paraneoplastic because of its strong association with paraproteinemia. Kossard and Winkelman initially described NXG in 1980 in an 8-patient case series.1 NXG lesions typically begin as yellow-red papules that enlarge into sharply demarcated plaques.2,3 The plaques may develop a central ulceration with necrosis. NXG is unremitting and the resultant lesions often enlarge and increase in number. NXG most frequently presents in the sixth decade of life and the prognosis is strongly associated with an underlying systemic disorder.2–5 SKINmed. 2013;11:121–123

NXG has characteristic dermatopathologic features. In 1980 a dermal and subcutaneous granulomatous process with necrobiosis was identified.6 In addition to histiocytes within the granulomas, Touton giant cells, foam cells, and inflammatory cells were noted.3,4 When considering the diagnosis of NXG, Touton giant cells and foreign body giant cells should be identified. Other distinguishing features include lymphoid nodules and cholesterol clefts.3,4 Although histopathologically similar to necrobiosis lipoidica diabeticorum (NLD), NXG can be distinguished by a few key features. Unlike NLD, lipid deposition is scarce and foreign body giant cells are prominent in NXG. Cholesterol clefts and lymphoid nodules are more frequent in NXG.3,9 As demonstrated by this case, the treatment of NXG is difficult at best. Lesions can regress with treatment but then reappear and become resistant to therapy. Multiple treatments have been attempted with varying success. One review indicated that corticosteroids and chlorambucil have been effective.3 Variable success has been documented with melphalan, radiation therapy, lenalidomide, plasmapheresis, corticosteroids alone, and antimicrobials in patients with NGX.6,7,8 Other treatments such as methotrexate, Yag laser, and psoralen–UV-A have not demonstrated improvement.6 The use of 2-CDA for the treatment of NXG has been previously reported.5 In this case, improvement of plaques with 2-CDA and hyperbaric oxygen therapy was noted. Periorbital lesions have been excised with documentation of reoccurrence in some cases.3

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Conclusions This case highlights NXG as a rare paraneoplastic condition that is frequently refractory to treatment. This patient demonstrated some success with 2-CDA, but was unable to continue therapy because of pancytopenia.

3 Wood AJ, Wagner VU, Abbott JJ, et al. Necrobiotic xanthogranuloma. Arch Dermatol. 2009;145:279–284. 4 Newman B, Hu W, Nigro K, et al. Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol 2007;56:302–316.

Disclosures: The authors have no financial interest in any products listed in the manuscript.

5 Reddy VC, Salomao DR, Garrity JA, et al. Periorbital and ocular necrobiotic xanthogranuloma leading to perforation. Arch Ophthalmol. 2010;128:1493– 1494.

References

6 Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol. 2009;49:1–10.

1 Kossard S, Winkelman RK. Necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol. 1980;3:257– 270. 2 Gelmetti C, Caputo R. Non-Langerhans cell histiocytosis. In: Wolff K, Goldsmith LA, Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2008. http://www.accessmedicine.com.library1. Accessed February 28, 2011.

7 Silapunt S, Chon SY. Generalized necrobiotic xanthgranuloma successfully treated with lenalidomide. J Drugs Dermatol. 2010;9:273–276. 8 Guo J, Wang J. Adult orbital xanthogranulomatous disease. Arch Pathol Lab Med. 2009;133:1994–1997. 9 Finan MC, Winkelman RK. Histiopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol. 1986;14:92–99.

Wax Moulage

Lupus erythematodes. Moulage No. 946, made by Lotte Volger in 1940 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2013;11:121–123

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2ND ANNUAL CONGRESS

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2013 DASIL CONGRESS The Hilton Millennium Bangkok Hotel

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March/April 2013

Volume 11 • Issue 2

CASE STUDY

Phacomatosis Pigmentokeratotica—A Patient With Hypophosphatemic Rickets Orlando Oliveira de Morais, MD; Lidiane Oliveira Costa, MD; Dayane Higa Shinzato, MD; Nayara de Castro Wiziack, MD; Günter Hans-Filho, MD, PhD

The epidermal naevus syndrome (ENS) is a sporadic condition characterized by congenital epidermal naevi associated with anomalies in other organ systems, most commonly the central nervous system and skeleton. We report a case of ENS presenting hypophosphataemic rickets resistant to traditional therapeutic agents.

9-year-old girl with a clinical history since birth of yellow-brown verrucous plaques over the left temporoparietal area, ears, face, neck, chest, back, buttocks, and right upper and left lower limbs presented for dermatologic evaluation (Figure 1). The lesions followed Blaschko’s lines and no hair growth was evident on the affected areas of the scalp (Figure 1 and Figure 2). Indeed, café au lait macules superimposed by multiple dark brown to black papules arranged in a checkerboard pattern were found adjacent to or on the verrucous lesions previously described (Figure 3). Dark brown–pigmented spots on sclera of both eyes were also noted (Figure 1). Skin biopsy of the scalp characterized the verrucous plaques as sebaceous nevi, occasionally associated with pilomatrixoma. In addition, spilus nevus was shown in the biopsy of a black speckled lesion of the right upper limb. No angiomatous lesions were noted during clinical or histological skin evaluation. At the age of 21 months, the patient developed discrepancies in lower limbs length and alignment, pain, and walking impairment, ultimately leading to the diagnosis of rickets. Radiological evaluation showed decreased bone mineral density, cortical fractures, kyphoscoliosis, shortening of the right tibia, and genu valgum of the left and right lower extremities. Results from laboratory tests demonstrated normal serum calcium and parathyroid hormone levels, decreased serum phosphorus, elevated serum alkaline phosphatase (1630 U/L; normal, 175–420 U/L), and elevated serum osteocalcin (58 ng/mL; normal, 10–25 ng/mL). Neither ophthalmologic nor neurological disabilities were revealed by clinical or radiologic examinations. The initial

treatment proposed was an oral reposition of calcitriol (0.75 mg/d) and phosphorus (2.5 g/d), although this therapy did not noticeably improve clinical parameters. The patient’s family had an unremarkable medical background. Based on clinical and examination findings the diagnosis of an epidermal nevus syndrome complicated with resistant hypophosphatemic rickets was proposed, being the phacomatosis pigmentokeratotica (PPK) epidermal nevus syndrome (ENS) phenotype correspondent to the clinical picture. Surgical removal of sebaceous nevi was not performed because of its wide dimensions and disagreement of the patient’s family. Discussion ENS is an uncommon dermatological condition characterized by congenital epidermal nevus associated with a variety of anomalies that commonly affect the central nervous system and skeleton, and less often, the ocular, cardiac, genitourinary, and endocrine systems.1-3 As proposed by some researchers,1 we agree that patients with ENS should be further classified into one of the defined disease phenotypes (eg, proteus syndrome, Schimmelpenning syndrome, nevus comedonicus syndrome, pigmented hairy epidermal nevus syndrome, congenital hemidysplasia with ichthyosiform erythroderma and limb defects [CHILD] syndrome, phacomatosis pigmentokeratotica). While these phenotypes share the common features of mosaicism, they differ in their genetic origins and prognosis.1 PPK is a rare organoid nevus syndrome of still unknown molecular basis. It is characterized by a concomitant occurrence of ne-

From the Department of Dermatology, Faculty of Medicine, Universidade Federal de Mato Grosso do Sul, Brazil Address for Correspondence: Orlando Oliveira de Morais, MD, Rua Utiariti, 197, Vila Rica, Campo Grande, Mato Grosso do Sul, Brasil 79022-240 • E-mail: orlando.unb@gmail.com

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Figure 2. Anterior cervical region and chest showing sebaceous nevi along with Blaschko’s lines. Speckled lentiginous nevi are arranged in a checkerboard pattern. Postural deviation secondary to scoliosis is noted.

Figure 1. Sebaceous nevi are seen over the left temporoparietal area, face, ear and neck. Lesions show overlap with multiple dark speckled lesions. A dark brown pigmented spot is seen on sclera.

vus sebaceous and speckled lentiginous nevus of the papular type (papular spilus nevus), associated with extracutaneous anomalies.4 The disease has been proposed by some authors to represent an example of didymosis (twin spotting), with one half of the didymosis defined as Schimmelpenning syndrome, and the other half delineated as papular nevus spilus syndrome.2,4,5 Didymosis is defined as paired patches of mutant tissue that differ genetically from each other and from the phenotypically normal heterozygous background tissue.2,5 To explain that, in an embryo heterozygous for two different recessive mutations localized on the same chromosome, an event of somatic crossing-over would give rise to two homozygous daughter cells representing stem cells of the two types of nevi and of the extracutaneous defects distributed in a mosaic pattern.2,5 Apparently, either component of PPK is caused by a lethal mutation surviving by mosaicism, since all the cases observed to date have been sporadic.1,2 SKINmed. 2013;11:125–128

The sebaceous nevi in PPK are often extensive and characteristically follow Blaschko’s lines. The speckled lentiginous nevus may present morphological changes during a patient’s growth, which are important to the diagnosis. Whereas only café au lait macules may be present in infancy, the characteristic papular and macular speckles can only appear later in life.2,6 During follow-up, our patient showed an increase in the number of speckled lesions, although no other cutaneous abnormalities such as linear connective tissue nevus or angioma were found, as previously reported by contemporary authors.2,7 Hyperhidrosis also belongs to the spectrum of speckled lentiginous nevus syndrome and may occur in some cases in a segmental pattern.2 Benign and malignant tumors may arise from epidermal nevus in PPK, influencing the patient’s prognosis. The frequency of basal cell carcinoma in PPK sebaceous nevus seems to be higher than

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CASE STUDY thy.1,2 Our patient did not present with cranial defects or central nervous system damages such as mental deďŹ ciency, seizures, or hemiparesis; however, she presented many skeletal abnormalities consistent with the Schimmelpenning syndrome component of PPK, eg, kyphoscoliosis, limb deformities, and hypophosphatemic rickets. A case series study found hemiatrophy as the most consistent extracutaneous anomaly of PPK2; otherwise, the patients are prone to develop hypophosphatemic rickets.1 The treatment of hypophosphatemic rickets includes phosphorus and calcitriol supplementation. It aims to improve the clinical symptoms of bone pain as well as normalize serum phosphorus and improve bone mineralization. Early recognition and appropriate treatment can prevent, or at least alleviate, growth retardation and bone deformities.

Figure 3. Sebaceous nevi on the back following Blaschkoâ&#x20AC;&#x2122;s lines and adjacent to speckled lentiginous nevus on left scapular and left lumbar regions.

is usually observed in patients with Schimmelpenning syndrome. It occurs in 6.5% to 22% of patients and is followed in terms of frequency by squamous cell carcinoma.1,8,9 Among benign lesions, the syringocystadenoma develops in approximately 10% to 20% of patients with sebaceous nevus, being rarer than other tumors such as hidradenoma and keratoacanthoma.10 Although the specked lesions of spilus nevus could undergo malignant transformation, they have been scarcely reported.9 Histologic evaluation of our case did not show any sign of malignant transformation. The wide number of extracutaneous anomalies in phacomatosis pigmentokeratotica can be didactically separated between those originally associated with Schimmelpenning syndrome, most commonly neurological or skeletal, and those related to the speckled lentiginous nevus syndrome, found in a lesser frequency, such as muscular weakness, dysesthesia, and sensory or motor neuropaSKINmed. 2013;11:125â&#x20AC;&#x201C;128

The pathogenic mechanism associated with the onset of hypophosphatemic rickets in patients with ENS remains unknown. It is generally accepted that this condition is a variant of tumor-induced rickets because the excision of bone and soft tissue mesenchymal tumors associated with hypophosphatemic rickets usually causes remission of the skeletal disease.11,12 Researchers postulated in 1977 that it was caused by a phosphaturic substance produced by cutaneous lesions, following the observation that rickets improved in a 12-year-old boy with surgical removal of fibroangiomas on the face and left lower limb.13 Other authors have also incriminated angiomas found within the sebaceous nevi or the bones of patients with ENS as the probable secretors of an endocrine factor causative of the rickets.11,12 Other researchers showed that hemangioma cells obtained from a patient with oncogenic rickets, when cultured in vitro, were able to produce a factor with inorganic phosphate transport inhibitory activity.12 Somehow, these data limit the indication of surgical intervention in cases of hypophosphatemic rickets to only those patients who have angiomas, as suggested by some authors.1 Doctors should be aware, however, that not all of these patients will respond to surgical excision,14 whereas some patients without angiomatous lesions will benefit from surgical intervention.15 Conclusions Since each type of ENS presents a particular pattern of cutaneous and systemic involvement that determines differences in follow-up and prognosis, we strongly suggest the classification of patients into one of the defined ENS phenotypes. Furthermore, detailed follow-up is advisable for early detection of any malignant transformation of nevus components in PPK, as well as the occurrence of eventual visceral tumors as rhabdomyosarcoma or pheochromocytoma. Patients with resistant hypophosphatemic rickets must undergo a detailed screening for angiomatous lesions, mainly on the skin and skeleton, since these patients could have improvement of rickets following surgical treatment. Neverthe-

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less, we consider that multidisciplinary support, preferably in tertiary care centers, is essential to the management of PPK patients because of the wide range of organic complications. Disclosures: None of the authors received financial support to develop this work. All the authors declare not to have conflict of interests. References

mentokeratotica: a follow-up report documenting additional cutaneous and extracutaneous anomalies. Pediatr Dermatol. 2008;25:76–80. 8 Vujevich JJ, Mancini AJ. The epidermal nevus syndromes: multisystem disorders. J Am Acad Dermatol. 2004;50:957–961. 9 Martinez-Menchon T, Mahiques Santos L, Vilata Corell JJ, et al. Phacomatosis pigmentokeratotica: a 20-year follow-up with malignant degeneration of both nevus components. Pediatr Dermatol. 2005;22:44–47.

1 Happle R. The group of epidermal nevus syndromes Part I. Well defined phenotypes. J Am Acad Dermatol. 2010;63:1–22.

10 Jones E, Heyl T. Naevus sebaceus: a report of 140 cases with special regard to the development of secondary malignant tumours. Br J Dermatol. 1970;82:99–117.

2 Tadini G, Restano L, Gonzáles-Pérez R, et al. Phacomatosis pigmentokeratotica: report of new cases and further delineation of the syndrome. Arch Dermatol. 1998;134:333–337.

11 Cai Q, Hodgson SF, Kao PC, et al. Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med. 1994;330:1645–1649.

3 Sanmaneechai O, Wisuthsarewong W, Sawathiparnich P. Epidermal nevus syndrome presenting as hypophosphatemic rickets. A case report of an uncommon association. The Endocrinologist. 2006;16:145–149. 4 Happle R. Speckled lentiginous nevus syndrome: delineation of a new distinct neurocutaneous phenotype. Eur J Dermatol. 2002;12:133–135. 5 Boente MC, Pizzi de Parra N, Larralde de Luna M, et al. Phacomatosis pigmentokeratotica: another epidermal nevus syndrome and a distinctive type of twin spotting. Eur J Dermatol. 2000;10:190–194. 6 Wu CY, Chang WY, Wu CS, Chen GS. Phacomatosis pigmentokeratotica: a 4-month-old infant with rare melanocytic-epidermal twin nevus syndrome—case report. Dermatologica Sinica. 2007;25:256–260. 7 Boente Mdel C, Asial RA, Happle R. Phacomatosis pig-

12 Stosiek N, Hornstein OP, Hiller D, et al. Extensive linear epidermal nevus associated with hemangiomas of bones and vitamin D–resistant rickets. Dermatology. 1994;189:278–282. 13 Aschinberg LC, Solomon LM, Zeis PM, et al. Vitamin Dresistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J Pediatr. 1977;91:56–60. 14 Olivares JL, Ramos FJ, Carapeto FJ, et al. Epidermal naevus syndrome and hypophosphataemic rickets: description of a patient with central nervous system anomalies and review of the literature. Eur J Pediatr. 1999;158:103–107. 15 Ivker R, Resnick SD, Skidmore RA. Hypophosphatemic vitamin D-resistant rickets, precocious puberty, and the epidermal nevus syndrome. Arch Dermatol. 1997;133:1557–1561.

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SORILUX

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BRIEF SUMMARY Mothers (calcipotriene) Foam, 0.005% Nursing It is not known whether calcipotriene is excreted in human milk. Because

The following is a brief summary only; see full prescribing information for complete product information.

INDICATIONS AND USAGE

SORILUX Foam is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 18 years and older.

CONTRAINDICATIONS

many drugs are excreted in human milk, caution should be exercised when SORILUX Foam is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of SORILUX Foam in pediatric patients less than 18 years of age have not been established.

Geriatric Use

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Unevaluated Uses

SORILUX Foam should not be used by patients with known hypercalcemia.

The propellant in SORILUX Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.

Effects on Calcium Metabolism

Risk of Ultraviolet Light Exposure

ADVERSE REACTIONS Clinical Trials Experience

DRUG INTERACTIONS

No drug interaction studies were conducted with SORILUX Foam.

USE IN SPECIFIC POPULATIONS Pregnancy

SORILUX Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis.

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NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility

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PLAQUE PSORIASIS OF THE SCALP AND BODY IN PATIENTS 18 YEARS AND OLDER

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