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Home , Acne, Hidradenitis suppurativa, Hyaluronic acid, Onychomycosis

HIGHLIGHTS OF A CME/CE CERTIFIED SUPPLEMENT TO

SKIN DISEASE EDUCATION FOUNDATION’S 40th Annual

Hawaii Faculty Joseph F. Fowler, Jr, MD Clinical Professor of University of Louisville Dermatology Louisville, Kentucky Theodore Rosen, MD ™ Professor of Dermatology Seminar Baylor College of Medicine A CONTINUING MEDICAL EDUCATION CONFERENCE Houston, Texas Jeffrey M. Sobell, MD Assistant Professor of Dermatology Tufts University School of Medicine Introduction Director, Treatment Center SkinCare Chestnut Hill, Massachusetts Update on TNF Inhibitors Nowell Solish, MD, FRCP(C) in Dermatology Assistant Professor University of Toronto and Toronto, Ontario, Canada Linda F. Stein Gold, MD Tinea and Director of Dermatology Research Henry Ford Health System : What’s New Detroit, Michigan Christopher B. Zachary, MBBS, FRCP Fillers: What’s Here and What’s Ahead Professor and Chair Department of Dermatology University of California, Irvine The Aging Face: Global Approach Irvine, California With Fillers and Neuromodulators Facial Rejuvenation: 40th Anniversary Review Post-Test and Evaluation Form

Original Release Date: June 2016 • Expiration Date: June 30, 2017 Estimated Time to Complete Activity: Update to 2.33 hours

Jointly provided by

Supported by educational grants from AbbVie Inc., Bayer Healthcare, Merz North America Inc., and Valeant Pharmaceuticals North America LLC A CME/CE CERTIFIED SUPPLEMENT TO HIGHLIGHTS OF DISEASE EDUCATION FOUNDATION’S 40th Annual Hawaii Dermatology Seminar ™ Reprinted from A CONTINUING MEDICAL EDUCATION CONFERENCE Seminars in Cutaneous Medicine and The manuscript was originally published as a supplement to Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 4S, June 2016. It has been reviewed and approved by the faculty as well as the Editors Table of Contents of Seminars in Cutaneous Medicine and Surgery. Introduction...... 5 This continuing medical education Joseph F. Fowler, Jr, MD (CME/CE) supplement was developed Christopher B. Zachary, MBBS, FRCP from faculty presentations at the Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Update on TNF Inhibitors...... 6 Seminar™, February 14-19, 2016. The in Dermatology Guest Editors/Faculty acknowledge the editorial assistance of Global Jeffrey M. Sobell, MD Academy for Medical Education, LLC, and Josh Kilbridge, medical writer, in Facial Dermatitis...... 9 the development of this supplement. The manuscript was reviewed and and Rosacea approved by the Guest Editors as well Joseph F. Fowler, Jr, MD as the Editors of Seminars in Cutaneous Medicine and Surgery for publication as a supplement to the journal. Tinea and Onychomycosis...... 12 This activity was developed under Theodore Rosen, MD the direction of the Faculty/Guest Editors, Global Academy for Medical Education, and Rutgers. The ideas and Acne: What’s New...... 16 opinions expressed in this supplement Theodore Rosen, MD are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Fillers: What’s Here...... 19 Medical Education, Rutgers, or and What’s Ahead the Publisher. Nowell Solish, MD, FRCP(C)

Copyright © 2016 by Global Academy for Medical The Aging Face:...... 22 Education, LLC; Rutgers, The State University of New Jersey; and its Licensors. All rights reserved. No part of this publication may be reproduced or Global Approach transmitted in any form, by any means, without prior written permission of the Publisher. Global With Fillers and Academy for Medical Education, LLC, and Rutgers will not assume responsibility for damages, loss, Neuromodulators or claims of any kind arising from or related to the information contained in this publication, including Nowell Solish, MD, FRCP(C) any claims related to the products, , or services mentioned herein. Facial Rejuvenation:...... 24 40th Anniversary Review Christopher B. Zachary, MBBS, FRCP Post-Test and Evaluation Form...... 27

2 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Original Release Date: June 2016 • Implement updated strategies for managing acne, rosacea, and psoriasis Expiration Date: June 30, 2017 • Discuss the use of biologic agents in the treatment of adult and pediatric psoriasis Estimated Time to Complete Activity: Up to 2.33 hours • Review the status of biosimilars for use in dermatology Participants should read the CE information below, review the activity in its entirety, • Incorporate the recent advances in the treatment of acne vulgaris and complete the online post-test and evaluation. Upon completing this activity as • Discuss the safety, , and dosing of for acne vulgaris designed and achieving a passing score on the post-test, you will be directed to a • Analyze emerging treatments for tinea and onychomycosis Web page that will allow you to receive your certificate of credit via e-mail or you • Identify the considerations in the selection of appropriate filler agents for treating may print it out at that time. different areas of the face • Compare and contrast the efficacy and safety of agents, devices, and techniques The online post-test and evaluation can be accessed at http://tinyurl.com/ currently available in aesthetic and procedural dermatology HDS16Supp. • Determine the appropriate nonsurgical techniques for facial rejuvenation Inquiries may be directed to Global Academy for Medical Education at • Describe the appropriate use of neuromodulators in the treatment of the aging face. [email protected] or (973) 290-8225. Disclosure Declarations Accreditation Statements Individuals in a position to control the content of this educational activity are required Physicians: This activity has been planned and implemented in accordance with to disclose: 1) the existence of any relevant financial relationship with any entity the Essential Areas and Policies of the Accreditation Council for Continuing Medical producing, marketing, re-selling, or distributing health care goods or services consumed Education (ACCME) through the joint providership of Rutgers, The State University by, or used on, patients with the exemption of non-profit or government organizations of New Jersey and Global Academy for Medical Education. Rutgers, The State and non-health care related companies, within the past 12 months; and 2) the identi- University of New Jersey is accredited by the ACCME to provide continuing medical fication of a commercial product/device that is unlabeled for use or an investigational education for physicians. use of a product/device not yet approved. Rutgers, The State University of New Jersey designates this enduring material for Faculty a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the Joseph F. Fowler, Jr, MD, Consultant: Bayer Healthcare, Laboratories, L.P., credit commensurate with the extent of their participation in the activity. GlaxoSmithKline, Johnson & Johnson, Medimetriks Pharmaceuticals, Inc., Ranbaxy Nurses: Rutgers, The State University of New Jersey, Center for Continuing and Outreach Laboratories Ltd., SmartPractice Dermatology/, Valeant Pharmaceuticals Education (CCOE) is an approved provider of continuing nursing education by the North America LLC; Speakers Bureau: Galderma, SmartPractice, Valeant; Grant/ New Jersey State Nurses Association, an accredited approver by the American Nurses Research Support: AbbVie Inc., Allergan, Inc., Amgen Inc., Pharmaceuticals, Credentialing Center’s Commission on Accreditation. Provider Number P173-5/31/16. Inc., Bayer, Celgene Corporation, Centocor, Inc., Chugai Pharma USA, Inc., Dow This activity is awarded 2.33 contact hours. (60 minute CH) Chemical Company, Eli Lilly and Company, Galderma, Genentech, Inc., Innovaderm Research Inc., Janssen Biotech, Inc., Johnson & Johnson, Merck & Co., Inc., Nurses should only claim those contact hours actually spent participating in the activity. Novartis Pharmaceuticals Corporation, Onset Dermatologics, LLC, Pfizer Inc., Target Audience Precision Dermatology, Regeneron Pharmaceuticals, Inc., SmartPractice, Taisho This supplement is intended for dermatologists, family practitioners, internists, Pharmaceutical Co., Ltd., Taro Pharmaceutical Industries Ltd., Valeant nurse practitioners, nurses, assistants, and other clinicians who practice Theodore Rosen, MD, Scientific Advisory Board: Anacor Pharmaceuticals, Inc., Merz medical dermatology or aesthetic medicine. North America Inc., Valeant Educational Needs Jeffrey M. Sobell, MD, Grant/Research Support: Amgen, Celgene, Eli Lilly, Janssen, Research continues to expand our understanding of the pathophysiology and Merck, Novartis; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Janssen; Speakers management of skin diseases and age-related skin damage. Based on this Bureau: AbbVie, Amgen, Celgene, Janssen, Novartis evidence, new pharmacologic agents and medical devices continue to be devel- oped, researched, and approved for use in the . New evidence and Nowell Solish, MD, FRCP(C), Consultant/Grant/Research Support: Allergan, therapies have been developed for acne vulgaris, rosacea, psoriasis, onychomy- Galderma, Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., Valeant cosis/tinea, and facial rejuvenation. Clinicians need to understand the safety and Linda F. Stein Gold, MD, Consultant and Scientific Advisory Board: Anacor, Bayer, efficacy of these new therapies in specific patient types. Eli Lilly, Foamix Pharmaceuticals Inc., Galderma, LEO Pharma Inc., Medimetrix Acne vulgaris affects 40 to 50 million people in the United States, with a prevalence Pharmaceuticals, Inc., Novartis, Pfizer, Taro as high as 85% in teenagers. A wide range of effective treatment strategies are Christopher B. Zachary, MBBS, FRCP, Consultant: Kythera Biopharmaceuticals, Inc., now available to manage acne vulgaris, and new agents continue to be developed, Sciton, Inc., Solta Medical; Scientific Advisory Board: Sciton and ZELTIQ Aesthetics, Inc. offering an enhanced range of options. Psoriasis is an inflammatory skin disease for which a variety of agents, including several (TNF) inhibi- In order to help ensure content objectivity, independence, and fair balance, and to tors, are approved for treatment. Recently, the use of TNF inhibitors for pediatric ensure that the content is aligned with the interest of the public, CCOE has resolved psoriasis has been investigated, and new biosimilar agents are in late stages of all potential and real conflicts of interest through content review by a non-conflicted, development for psoriasis. Clinicians may be reluctant to use TNF inhibitors in chil- qualified reviewer. This activity was peer-reviewed for relevance, accuracy of content, dren with psoriasis and do not yet have clinical experience with biosimilar agents. and balance of presentation by: Jean C. Sines, RN, BSN, Staff Nurse, Department Rosacea is a common chronic affecting the face, affecting approxi- of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. mately 14 million Americans. No cure exists for rosacea, but health care professionals Ms. Sines has no relevant financial relationships to disclose. have several options to treat the symptoms, including new agents to treat facial Field Testers: This activity was pilot-tested for time required by: Physicians: Brian and . The use of these agents requires an understanding of Lee, MD, Sima Patel, DO, and Vijay Vanchinathan, MD. Nurses: Geraldine their safety and use in . Onychomycosis and tinea pedis are Bocchieri, RN, BSN, Kathleen Brown, LPN, and Stacy Johnson, RN. The field testers common fungal affecting the nails and feet, respectively. Newly approved have no relevant financial relationships to disclose. topical agents for onychomycosis and tinea have demonstrated high cure rates in clinical studies. Rutgers, The State University of New Jersey: Tristan Nelsen, MNM, CMP, and Elizabeth Ward, MSJ, have no relevant financial relationships to disclose. Among the most common cosmetic procedures performed in the United States are the use of botulinum toxin A, soft tissue fillers, and treatments. In the Global Academy for Medical Education Staff: Shirley V. Jones, MBA; Sylvia H. last decade, a multitude of new products and devices have been developed for Reitman, MBA, DipEd; and Josh Kilbridge have no relevant financial relationships these indications, including new soft tissue fillers and novel laser technologies. The to disclose. increased availability of options also increases the challenge of selecting the most Off-Label/Investigational Use Disclosure appropriate agent or combination of agents for each patient. This activity discusses the off-label use of the following approved agents: Learning Objectives , cyclosporine ophthalmic emulsion, , , By reading and studying this supplement, participants should be better able to: , , , , methotrexate, • Integrate into daily practice evidence-based recommendations on new and (oral and foam), secukinumab, ustekinumab, and tumor necrosis factor inhibitors emerging therapies for common and uncommon dermatologic diseases as a class.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 3 Guest Editors

Joseph F. Fowler, Jr, MD Clinical Professor of Dermatology University of Louisville Louisville, Kentucky

Theodore Rosen, MD Professor of Dermatology Baylor College of Medicine Houston, Texas

Jeffrey M. Sobell, MD Assistant Professor of Dermatology Tufts University School of Medicine Director, Psoriasis Treatment Center SkinCare Physicians Chestnut Hill, Massachusetts

Nowell Solish, MD, FRCP(C) Assistant Professor University of Toronto Toronto, Ontario, Canada

Linda F. Stein Gold, MD Director of Dermatology Research Henry Ford Health System Detroit, Michigan

Christopher B. Zachary, MBBS, FRCP Professor and Chair Department of Dermatology University of California, Irvine Irvine, California

4 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Guest Editors Introduction

ermatology is a diverse and expanding field, and new research continues to improve our understanding of the mechanisms of disease and opportunities for therapeutic intervention. This expanding knowledge base also creates a broad range of educational Dneeds for practicing clinicians. Skin Disease Education Foundation’s 40th Hawaii Dermatology Seminar offers updates from experts that cover advances in both medical and aesthetic dermatology. The articles in this educational supplement summarize the highlights of clinical sessions presented during the CME/CE conference by leading experts in the field of dermatology. Tumor necrosis factor (TNF) inhibitors play a critical role in the treatment of psoriasis and continue to be evaluated for new indica- tions. This supplement includes a discussion of TNF inhibitors for use in new indications—such as pediatric psoriasis and suppurativa—as well as the impending introduction of biosimilars in the United States. Although the pathophysiology of rosacea is not well understood, chronic inflammation and vascular changes are believed to be central to the disease process. And new evidence implicates a family of called . New therapies targeting the inflammatory, erythematous, and/or antimicrobial components of the disease are now available or in development. This CME/CE supplement summarizes the latest evidence for these therapies and disease mechanisms. Our faculty discusses the evolving management of toenail onychomycosis and tinea pedis, including two new topical therapies recently approved by the US Food and Administration. The faculty summarizes the evidence supporting these therapies, as well as data describing the benefits of early intervention and how to manage recurrence of these infections. Acne is an extremely common condition in dermatologic practice. Our faculty reviews recent studies addressing key considerations in the use of antibiotics, topical treatments approved and in development, and novel agents that target sebum production. The faculty also discusses several approaches to aesthetic medicine, including the use of fillers and other technologies to treat the aging face. This educational supplement reviews multiple new and emerging soft tissue augmentation products and techniques for facial rejuvenation. The wide range of dermatology treatments and new therapies for skin conditions challenge the busy clinician to remain abreast of the latest information. We hope that you can apply these updates from our seminar to your clinical practice.

Joseph F. Fowler, Jr, MD, Chair Clinical Professor of Dermatology University of Louisville Louisville, Kentucky Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey, and Global Academy for Medical Christopher B. Zachary, MBBS, FRCP, Chair Education, LLC, with Skin Disease Education Foundation (SDEF) Professor and Chair and is supported by educational grants from AbbVie Inc., Bayer Department of Dermatology Healthcare, Merz North America Inc., and Valeant Pharmaceuticals University of California, Irvine North America LLC. Irvine, California Dr Fowler and Dr Zachary have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Joseph F. Fowler, Jr, MD, Consultant: Bayer, Galderma Laboratories, L.P., GlaxoSmithKline, Johnson & Johnson, Medimetriks Pharmaceuticals, Inc., Ranbaxy Laboratories Ltd., SmartPractice Dermatology/Allergy, Valeant; Speakers Bureau: Galderma, SmartPractice, Valeant; Grant/ Research Support: AbbVie, Allergan, Inc., Amgen Inc., Anacor Pharmaceuticals, Inc., Bayer, Celgene Corporation, Centocor, Inc., Chugai Pharma USA, Inc., Dow Chemical Company, Eli Lilly and Company, Galderma, Genentech, Inc., Innovaderm Research Inc., Janssen Biotech, Inc., Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Onset Dermatologics, LLC, Pfizer Inc., Precision Dermatology, Regeneron Pharmaceuticals, Inc., SmartPractice, Taisho Pharmaceutical Co., Ltd., Taro Pharmaceutical Industries Ltd., Valeant. Christopher B. Zachary, MBBS, FRCP, Consultant: Kythera Biopharmaceuticals, Inc., Sciton, Inc., Solta Medical; Scientific Advisory Board: Sciton and ZELTIQ Aesthetics, Inc. Address reprint requests to: Christopher B. Zachary, MBBS, FRCP, Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697, [email protected]

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 5 Update on TNF Inhibitors in Dermatology Jeffrey M. Sobell, MD*

90% improvement (PASI 90) (compared to 11% and 7% with Abstract placebo, respectively; P<0.0001, both comparisons). Tolerability Emerging data describe new potential indications for tumor of the study drug was good, although there was an increase in necrosis factor (TNF) inhibitors in dermatology, including infections (47.2%, etanercept vs 31.4%, placebo). No serious pediatric psoriasis and . New biosimilar TNF agents are in late stages of development and infections were reported at week 12. A 5-year extension study may be available in the United States in the near future. demonstrated stable response rates over long-term use, with PASI Biosimilar agents are similar but not identical to available TNF 75 rates approximately 60% and PASI 90 rates approximately inhibitors, and approval requires extensive analytic, toxicity, 30%.3 Safety results were also stable over time, with no incidence pharmacokinetic, pharmacodynamic, and clinical testing. of malignancy or opportunistic infections and only one serious Semin Cutan Med Surg 35(supp6):S104-S106 related to the study drug during the 5-year period. © 2016 published by Frontline Medical Communications Adalimumab has also been evaluated in a phase III trial for Keywords pediatric psoriasis.4 This active-control study randomized 114 Biosimilars; hidradenitis suppurativa; pediatric psoriasis; psoriasis; children aged 4 to 17 years with moderate to severe psoriasis to TNF inhibitors treatment with adalimumab (0.8 mg/kg biweekly or 0.4 mg/kg biweekly, maximum dose 40 mg biweekly) or methotrexate (0.1- umor necrosis factor (TNF) inhibitors have been approved 0.4 mg/kg weekly). After the initial 16-week treatment period, for the treatment of adult patients with psoriasis for a dozen all PASI 75–achieving subjects discontinued study drugs and Tyears, starting with etanercept and followed by were retreated with adalimumab for 16 weeks if their psoriasis and adalimumab. Current evidence also suggests that TNF recurred. Subjects were then followed for 1 year of open-label inhibitors can be safe and effective for pediatric patients, and therapy. Of note, 14.9% of subjects were overweight and 21.1% new biosimilars are also in late stages of development. Finally, were obese. After the initial 16-week treatment period, 57.9% the TNF inhibitor adalimumab was recently approved for a new of subjects in the adalimumab 0.8 mg/kg group achieved PASI dermatologic indication, hidradenitis suppurativa. 75, compared to 32.5% of the methotrexate group (P=0.027 vs methotrexate). The study drugs were well tolerated, with only one Pediatric Psoriasis serious infection reported. Of subjects whose disease recurred Psoriasis is relatively common in the pediatric population. For following treatment discontinuation, PASI 75 recapture rates after example, approximately 40% of adults with psoriasis report 16 weeks of retreatment were 54.5% (adalimumab 0.4 mg/kg) onset during childhood.1 The use of etanercept for pediatric to 78.9% (adalimumab 0.8 mg/kg).5 psoriasis was initially evaluated in a phase III trial (n=211) that included a 12-week double-blind treatment period, followed by New Biologics for Adults With Psoriasis 24 weeks of open-label treatment and a 12-week double-blind Certolizumab pegol is a humanized antigen-binding fragment withdrawal period.2 Enrolled subjects were aged 4 to 17 years and (Fab′) of a monoclonal antibody to TNF-α, conjugated to poly- had moderate to severe psoriasis. Etanercept dosing was weight ethylene glycol. This approach stabilizes and extends the half-life based (0.8 mg/kg once weekly). At week 12, among subjects of the molecule. In a phase II study, 176 subjects with moderate treated with etanercept, 57% had at least 75% improvement on to severe psoriasis were randomized to certolizumab pegol (200 or the Psoriasis Area Severity Index (PASI 75), and 27% had at least 400 mg biweekly) or placebo for a total of 12 weeks.6 At study end, 75% to 83% of the certolizumab groups achieved PASI 75, compared * Assistant Professor of Dermatology, Tufts University School of to 7% of the placebo group (P<0.001, both comparisons). Safety Medicine; Director, Psoriasis Treatment Center, SkinCare Physicians, Chestnut Hill, Massachusetts outcomes were consistent with previous studies in other indications. Large phase III trials are currently under way to demonstrate the Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey, and Global Academy for Medical efficacy of certolizumab pegol in adults with psoriasis. The agent is Education, LLC, with Skin Disease Education Foundation (SDEF) approved by the US Food and Drug Administration (FDA) for use and is supported by educational grants from AbbVie Inc., Bayer in psoriatic but not for psoriasis. Healthcare, Merz North America Inc., and Valeant Pharmaceuticals North America LLC. Biosimilars Dr Sobell has received an honorarium for his participation in this activity. Biosimilars are biologic agents currently in development for a He acknowledges the editorial assistance of Josh Kilbridge, medical writer, variety of indications. Biosimilars are similar, but not identical, and Global Academy for Medical Education in the development of this continuing medical education journal article. versions of currently approved biologic drugs. They have iden- Jeffrey M. Sobell, MD: Grant/Research Support: Amgen Inc., Celgene tical amino sequences to the original biologic but differ in Corporation, Eli Lilly and Company, Janssen Biotech, Inc., Merck & Co., post-translational modifications and production processes.7 The Inc., Novartis Pharmaceuticals Corporation; Consultant: AbbVie, Amgen, FDA requires that these biologic agents have no clinically mean- Celgene, Eli Lilly, Janssen; Speakers Bureau: AbbVie, Amgen, Celgene, ingful differences in terms of safety, purity, and potency from Janssen, Novartis. the approved agent they emulate. Currently, biosimilars in devel- Address reprint requests to: Jeffrey M. Sobell, MD, Tufts University School of Medicine, 145 Harrison Ave, Boston, MA 02111, opment for psoriasis include agents biosimilar to etanercept, [email protected] infliximab, and adalimumab.

6 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar To demonstrate biosimilarity, companies must complete exten- Immunogenicity is an important consideration with all sive analytic testing, toxicity studies in animals, pharmacokinetic biologic agents, including biosimilars. Adalimumab, as well as and pharmacodynamic studies in humans, and clinical trials other TNF inhibitors, has been associated with the develop- to evaluate efficacy, safety, and immunogenicity. Examples in ment of neutralizing anti-drug antibodies, which may impact development for psoriasis include GP2015 (etanercept), CT-P13 efficacy in clinical practice. The immunogenicity of ABP 501 (infliximab), and ABP 501 (adalimumab). Preclinical studies was evaluated in the phase III trial and found to be similar illustrate the high degree of similarity between GP2015 and etan- to adalimumab. Through week 16, the proportion of subjects ercept originator (Table).8 A phase III trial with GP2015 has been developing anti-drug antibodies was 55.2% with ABP 501 and completed, but results have not been reported. 63.6% with adalimumab originator.11 CT-P13, a biosimilar to infliximab, has been evaluated in two The availability of biosimilars in the United States awaits expi- randomized studies—one in and one ration of patent protection for individual agents. Once they do in .9 The agent is approved in Europe and become available, clinicians will face many questions, including Canada, and most recently in the United States. One interesting which patients to prescribe them for (eg, new patients, switching aspect of biosimilar development is extrapolation of indica- patients from their current drug) and whether the biosimilars are clinically interchangeable with existing TNF inhibitors. tions, by which biosimilars, when approved, may receive the same indications as the original biologic. This extrapolation is Hidradenitis Suppurativa just one of several controversies regarding biosimilar develop- Hidradenitis suppurativa (HS) is a relatively rare chronic ment and approval. skin disease characterized by painful, recurrent inflamma- ABP 501 is a biosimilar to adalimumab. In preclinical testing, tory affecting areas of the body containing ABP 501 demonstrated nearly identical pharmacokinetics to glands.12,13 The disease has a prevalence of approximately 1% in adalimumab originator in healthy subjects,10 and a multicenter the general population, with a mean onset at age 22 years and a phase III trial demonstrated equivalent clinical efficacy and safety 3:1 female to male predominance. Unfortunately, the mean delay to adalimumab over 16 weeks.11 before accurate diagnosis is 12 years, highlighting the risk for misdiagnosis and inappropriate treatment.13-16 Risk factors associated with HS include (odds ratio TABLE Biosimilars: Extensive Testing at [OR], 12.55) and (OR, 4.42), although no causal relation- Preclinical Level ship to HS has been demonstrated. Known causal risk factors include mechanical triggers (eg, friction), certain (eg, ), and, possibly, hormonal factors, although data Biosimilars must match originators across multiple describing the influence of on HS are conflicting.13,17-19 quality attributes The diagnosis of HS is clinical and requires 3 criteria: typical lesions (deep-seated nodules, abscesses, and/or ), For monoclonal antibodies, typically >40 different typical anatomic location (axillae and inguinocrural regions), methodologies are applied, analyzing more than and relapses.20 Severity is graded using the Hurley stages 100 different quality attributes (Figure).18,21 HS can have a tremendous impact on patients’ quality of Primary structures Higher-order structures life, especially in more severe disease, and is often associated • LC-MS intact mass • NMR with important comorbidities such as and meta- LC-MS subunits CD spectroscopy bolic syndrome.22-24 Because levels, including TNF-α, • • 25 Peptide mapping FT-IR are elevated in the lesions of HS, researchers evaluated the • • 26 X-ray safety and efficacy of the TNF inhibitor adalimumab. In the • PIONEER I and II trials, subjects with moderate to severe HS were randomized to adalimumab (160 mg at week 0, 80 mg at Impurities Post-translational modification week 2, and 40 mg weekly thereafter) or placebo. After 12 weeks, • CEX, c/EF acidic/basic • NP-HPLC-(MS) N-glycans adalimumab was associated with significantly greater HS clin- variants LC glycation • AEX N-glycans ical response compared to placebo (PIONEER I: 41.8% vs 26%, Peptide mapping MALDI-TOF N-glycans P<0.01; PIONEER II: 58.9% vs 27.6%, P<0.001). Improvements • deamination, • 26 HPAEC-PAD N-glycans were sustained for up to 72 weeks of follow-up. Adalimumab oxidation, mutation, • was associated with a similar, low incidence of serious side effects MALDI-TOF O-glycans glycation • as placebo. Based on these studies, adalimumab is the first medi- • SEC/FFF/AUC • HPAEC-PAD sialic cation specifically approved by the FDA for the treatment of HS. aggregation • RP-HPLC sialic acids In summary, TNF inhibitors have demonstrated efficacy in psoriasis, and TNF inhibitors used for other indications are under investigation for use in psoriasis. Biosimilar agents, which are Biological activity Combination of attributes similar to but not identical to available TNF inhibitors, may also Binding assay MVDA, mathematical soon be available, depending on duration of patent protection • • algorithms • ADCC assay and other factors. Finally, HS is a rare but serious skin condi- • CDC assay tion that significantly affects patients’ quality of life and normal function. Based on strong phase III data, adalimumab is now Source: Da Silva A, et al. EADV 2013: P0304. indicated for the treatment of patients with HS.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 7 I . II. III.

Single or multiple abscesses without One or more widely separated recurrent Multiple interconnected tracts and cicatrization and sinus tracts abscesses, with tract formation and abscesses throughout an entire area

FIGURE Staging of Hidradenitis Suppurativa Using the Hurley Stages.18,21 Source: Photos courtesy of Robert G. Micheletti, MD.

References 1. Lewkowicz D, Gottlieb AB. Pediatric psoriasis and . Dermatol 16. Palmer RA, Keefe M. Early-onset hidradenitis suppurativa. Clin Exp Dermatol. Ther. 2004;17:364-375. 2001;26:501-503. 2. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and 17. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associ- adolescents with plaque psoriasis. N Engl J Med. 2008;358:241-251. ated with hidradenitis suppurativa: Results from two case-control studies. J Am 3. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etan- Acad Dermatol. 2008;59:596-601. ercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 18. Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: A comprehensive 2016;74:280-287.e3. review. J Am Acad Dermatol. 2009;60:539-561. 4. Papp KA, Thaci D, Marcoux D, Weibel L, Unnebrink K, Williams DA. Efficacy 19. Yazdanyar S, Jemec GB. Hidradenitis suppurativa: A review of cause and treat- and safety of adalimumab versus methotrexate treatment in pediatric patients ment. Curr Opin Infect Dis. 2011;24:118-123. with severe chronic plaque psoriasis: Results from the 16-week randomized, 20. Poli F, Jemec GBE, Revuz J. Clinical presentation. In: Jemec GBE, Revus J, Leyden double-blind period of a phase 3 study. Presented at: 23rd World Congress of JJ, eds. Hidradenitis Suppurativa. Heidelberg, Germany: Springer; 2006:11-24. Dermatology; June 8-13, 2015; Vancouver, Canada. 21. Ducroux E, Ocampo MA, Kanitakis J, et al. Hidradenitis suppurativa after renal 5. Philipp S, Ghislain PD, Landells I, Unnebrink K, Williams DA. Efficacy, safety transplantation: Complete remission after switching from oral cyclosporine to oral of adalimumab vs methotrexate in pediatric patients with severe placque psoriasis: . J Am Acad Dermatol. 2014;71:e210-e211. Results from the treatment withdrawal and double-blind retreatment periods of a 22. Matusiak Ł, Bieniek A, Szepietowski JC. Hidradenitis suppurativa mark- phase 3 study. Presented at: 23rd World Congress of Dermatology; June 8-13, 2015; edly decreases quality of life and professional activity. J Am Acad Dermatol. Vancouver, Canada. 2010;62:706-708.e1. 6. Reich K, Ortonne JP, Gottlieb AB, et al. Successful treatment of moderate to 23. Matusiak Ł, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis severe plaque psoriasis with the PEGylated Fab′ certolizumab pegol: Results of a suppurativa. Acta Derm Venereol. 2010;90:264-268. phase II randomized, placebo-controlled trial with a re-treatment extension. Br J 24. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of Dermatol. 2012;167:180-190. metabolic syndrome in patients with acne inversa. PLoS One. 2012;7:e31810. 7. McCamish M, Woollett G. The state of the art in the development of biosimilars. 25. van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Clin Pharmacol Ther. 2012;91:405-417. Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 8. Da Silva A, Kronthaler U, Fritsch C, et al. Target-directed development of in hidradenitis suppurativa skin: A rationale for targeting TNF-α and IL-1β. Br J a proposed etanercept biosimilar, GP2015: Comparability of an in vitro target Dermatol. 2011;164:1292-1298. binding and neutraliazation, and in vivo efficacy and pharmacokinetics with the 26. Kimball A, Jemec G, Armstrong A, Forman SB, Gu Y, Williams DA. Evaluating reference product etanercept at the pre-clinical level. Presented at 22nd Congress optimal medium-term dosing strategy for adalimumab in patients with moderate- of the European Association of Dermatology and Venereology; October 2-6, 2013; to-severe hidradenitis suppurativa based on analysis of integrated results from the Istanbul, Turkey, P0304. PIONEER I and II phase 3, randomized, placebo-controlled trials. Presented at: 9. McKeage K. A review of CT-P13: An infliximab biosimilar. BioDrugs. 73rd Annual Meeting of the American Academy of Dermatology; March 20-24, 2014;28:313-321. 2015; San Francisco, CA. 10. Kaur P, Chow V, Zhang N, Moxness M, Markus R. A randomized, single-blind, single-dose, three-arm, parallel group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab: Results of a compar- ison with adalimumab. Presented at: Annual European Congress of Rheumatology; June 11-14, 2014; Paris, France. 11. Amgen. Amgen presents detailed results from phase 3 study demonstrating clinical equivalence of biosimilar candidate ABP 501 with adalimumab [press release]. November 9, 2015. Thousand Oaks, CA: Amgen; 2015. 12. van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: Viewpoint on clinical phenotyping, pathogenesis and novel treatments. Exp Dermatol. 2012;21:735-739. 13. Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012; 366:158-164. 14. von der Werth JM, Williams HC. The natural history of hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2000;14:389-392. 15. Cosmatos I, Matcho A, Weinstein R, Montgomery MO, Stang P. Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2013;68:412-419.

8 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Facial Dermatitis and Rosacea Joseph F. Fowler, Jr, MD*

Treating Erythema Abstract A new topical agent approved for the treatment of erythema in Rosacea is a chronic skin disorder associated with , rosacea is , a selective α2 receptor agonist. The α2 erythema, dryness, burning and stinging, and inflammatory receptors are the predominant mechanism for vasoconstriction and pustules. New treatments available or in development target the inflammatory and erythematous in the cutaneous vasculature, in contrast to α1 receptors, which components of the disease. These agents include the selective mediate vasoconstriction in the large, central vessels. Brimonidine 3 α2 receptor agonist brimonidine, the topical agents ivermectin is 1,000-fold more selective for α2 receptors than α1 receptors. cream 1% and foam 15%, and use of - Promoting vasoconstriction addresses the neurovascular compo- type antibiotics, which affect the pathway. nent of rosacea and alleviates flushing and redness. In initial Semin Cutan Med Surg 35(supp6):S107-S109 © 2016 published by Frontline Medical Communications clinical trials, brimonidine produced significantly greater reduc- tions in erythema compared to vehicle (P<0.001), with similar, Keywords low rates of adverse events.4 The onset of action of brimonidine Azelaic acid; brimonidine; cathelicidin; ivermectin; rosacea is rapid in many patients; response is noted within 30 minutes of application in a substantial proportion of patients.5 osacea is a common, chronic skin disorder associated Concern about a potential rebound effect following admin- 6 with manifestations such as flushing, erythema, dryness, istration of brimonidine prompted evaluation of burning and stinging, and inflammatory papules and data to detect worsening of erythema.7 Overall, mean changes in R 1 pustules. Although the pathophysiology of rosacea is not well erythema scores were reduced compared to vehicle at weeks 6 and understood, chronic inflammation and vascular changes are 8 of treatment, although a few subjects in the active treatment believed to be central to the disease process.2 Evidence also group showed worsening in scores during the follow-up period suggests that a family of antimicrobial peptides called cathelici- relative to baseline (1.6%-4.7% of brimonidine subjects across scales and time points). A 1-year, open-label safety trial evalu- dins contributes to the pathogenesis of rosacea. New therapies ated approximately 345 subject-years of exposure to brimonidine provide additional options for the treatment of patients with tartrate 0.5%.8 The incidence of adverse events related to study these inflammatory conditions. These treatments target the drug decreased over the course of the study, and no tachyphylaxis inflammatory, erythematous, and/or antimicrobial components was observed. The authors concluded that the agent was safe and of the disease. provided consistent efficacy over long-term use. However, several post-marketing case reports described a rebound of erythema or * Clinical Professor of Dermatology, University of Louisville, Louisville, allergic associated with brimonidine use.6,9,10 Kentucky In these cases, patients initially responded to brimonidine with Publication of this CME/CE article was jointly provided by Rutgers, reductions in erythema, followed by an increase in erythema. The State University of New Jersey, and Global Academy for Medical Education, LLC, with Skin Disease Education Foundation (SDEF) The take-home message from these studies and case reports and is supported by educational grants from AbbVie Inc., Bayer is that treatment with brimonidine is safe in the majority of Healthcare, Merz North America Inc., and Valeant Pharmaceuticals patients and will not lead to a worsening of rosacea over time. North America LLC. But a minority of patients may have increased redness a day after Dr Fowler has received an honorarium for his participation in this activity. treatment. This effect may be transient, lasting a day or two, and He acknowledges the editorial assistance of Josh Kilbridge, medical writer, patients can keep using the drug to treat erythema. Alternatively, and Global Academy for Medical Education in the development of this the drug can be discontinued for a few days and reintroduced to continuing medical education journal article. determine if the patient is experiencing allergic contact dermatitis. Joseph F. Fowler, Jr, MD, Consultant: Bayer Healthcare, Galderma Other topical agents in development for the treatment of facial Laboratories, L.P., GlaxoSmithKline, Johnson & Johnson, Medimetriks Pharmaceuticals, Inc., Ranbaxy Laboratories Ltd., SmartPractice erythema include and low-molecular-weight Dermatology/Allergy, Valeant; Speakers Bureau: Galderma, . Neither agent has yet been approved for the SmartPractice, Valeant; Grant/Research Support: AbbVie, Allergan, Inc., treatment of rosacea. Amgen Inc., Anacor Pharmaceuticals, Inc., Bayer, Celgene Corporation, Centocor, Inc., Chugai Pharma USA, Inc., Dow Chemical Company, Eli Treating Inflammation Lilly and Company, Galderma, Genentech, Inc., Innovaderm Research One limitation of brimonidine is that it does not treat the inflam- Inc., Janssen Biotech, Inc., Johnson & Johnson, Merck & Co., Inc., matory component of rosacea, for which an additional Novartis Pharmaceuticals Corporation, Onset Dermatologics, LLC, Pfizer Inc., Precision Dermatology, Regeneron Pharmaceuticals, Inc., will be required. Two new topical agents are now available for the SmartPractice, Taisho Pharmaceutical Co., Ltd., Taro Pharmaceutical treatment of inflammatory components of rosacea: ivermectin Industries Ltd.,Valeant. cream 1% and azelaic acid foam 15%. Address reprint requests to: Joseph F. Fowler, Jr., MD, 3100 Boxhill Lane, Ivermectin has been used to eradicate parasites in humans and Louisville, KY, 40222; 502-583-7546 [email protected] animals, and its mechanism of action in rosacea might include

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 9 The Cathelicidin Pathway licidin Prec Mounting evidence suggests that a family of antimicrobial he ur peptides produced in the skin called cathelicidins may be impor- at so C r tant in the pathogenesis of rosacea. These peptides are important Normal Rosacea in the normal immune defense against and some viruses, and also act as inflammatory mediators.19,20 Increased levels of Normal cathelicidins promote tissue responses that resemble the histo- KLK5*-mediated KLK5* processing pathologic features of rosacea, including increased leukocyte infiltration and . It may be that cathelicidin peptides are overexpressed in rosacea, as illustrated in the Figure.19,20 LL-37 LL-37 and variant peptides Initial studies examined the effect of tetracycline-type antibi-

E otics on the cathelicidin pathway, and findings suggested an effect

f 21 f mediated by inhibition of matrix metalloproteinases. This inhib- e

c n itory effect appears to be strongest with doxycycline compared t o 22 i i to minocycline or tetracycline. Importantly, clinical studies of v • Angiogenic Pro-inflammatory t e activities a doxycycline in rosacea have demonstrated similar reductions in • Bactericidal in (chemotatic and m inflammatory lesions with antimicrobial (100 mg) and subanti- Chemotactic angiogenic) n • m a a microbial (40 mg) doses, meaning that use of this at te fl low doses can be effective without increasing risk for selection of i in m ic resistant bacteria.23 mu on nity Chr in Rosacea Corticosteroids are highly potent agents with a myriad of poten- FIGURE tial side effects. Side effects of topical corticosteroids include Pathways of Cathelicidin-Mediated Inflammation in atrophy and telangiectasia, which may be confused with the 19,20 Normal Skin and Rosacea. underlying disease and can be irreversible. Because of these side *KLK5 is also known as SCTE (stratum corneum tryptic ). effects, use of corticosteroids for rosacea and other facial inflam- matory conditions should be limited to the shortest possible activity against the mite, which some investigators duration and lowest effective dose. Nevertheless, some patients believe contributes to rosacea.11 However, ivermectin also has may be using topical corticosteroids for chronic disease manage- anti-inflammatory properties. The agent decreases both cellular ment. Discontinuing corticosteroids in these patients can be a and humoral immune responses, including regulation of pro- challenge, as symptoms may flare when patients stop applying the inflammatory .12-14 In a pair of 12-week, phase III trials, agent. Some patients may be able to tolerate the burning and other daily use of ivermectin 1% cream was associated with signifi- symptoms, but most will require some kind of additional agent cantly greater reductions in inflammatory lesions compared to to facilitate discontinuation. For example, topical calcineurin vehicle, starting at week 2 (P<0.05) and continuing through week inhibitors may be used while the is tapered and 12 (P<0.001).15 At 12 weeks, a greater proportion of patients eventually discontinued. Prescription moisturizers may also help achieved treatment success (clear or almost clear) in the iver- minimize symptoms. Finally, low-dose doxycycline (ie, 40 mg) mectin group (38.4%-40.1% vs 11.6%-18.8%; P<0.001, both may be considered for its anti-inflammatory effects. comparisons). Safety outcomes were comparable between groups. In summary, the treatment of rosacea may include agents Extension studies demonstrated maintained efficacy and targeting erythema, inflammation, and the cathelicidin pathway. safety over long-term treatment; at 40 weeks, approximately 70% Brimonidine is approved for the treatment of erythema in rosacea 16 of subjects treated with ivermectin were clear or almost clear. and is safe and effective in most patients, although some may Ivermectin also appears to outperform the established agent, develop a rebound of redness following treatment. New anti- , for the treatment of rosacea. A phase III study inflammatory agents available for rosacea include ivermectin and randomized 962 subjects with papulopustular rosacea to iver- azelaic acid, both of which have demonstrated efficacy in clinical 17 mectin 1% cream every day or metronidazole 0.75% cream. At trials. Finally, agents targeting the cathelicidin pathway, such as 16 weeks, ivermectin produced greater reductions in inflammatory tetracycline-family antibiotics, have also demonstrated efficacy lesions (83.9% vs 73.7%; P<0.001) and a higher rate of treatment in rosacea. success (84.9% vs 75.4%; P<0.001) compared with metronidazole. Tolerability was similar between groups, with better local toler- References ability for ivermectin. 1. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: A Azelaic acid foam 15% was evaluated in two parallel phase III chronic vascular and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20:623-629. studies in 961 subjects with moderate to severe papulopustular 2. Del Rosso JQ. Advances in understanding and managing rosacea: Part 1: rosacea.18 At 16 weeks, the success rate (clear or almost clear) Connecting the dots between pathophysiological mechanisms and common clinical was significantly greater with azelaic acid compared to vehicle features of rosacea with emphasis on vascular changes and facial erythema. J Clin (30.8% vs 23.8%; P=0.025). Decreases in mean inflammatory Aesthet Dermatol. 2012;5:16-25. 3. Piwnica D, Rosignoli C, de Ménonville ST, et al. Vasoconstriction and anti-inflammatory lesion counts were also greater with azelaic acid foam compared properties of the selective α-adrenergic receptor agonist brimonidine. J Dermatol to vehicle (−13.5 vs −9.5; P<0.001). Azelaic acid was associated Sci. 2014;75:49-54. with numerically higher rates of local adverse effects (eg, applica- 4. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: Results tion-site , 4.5%), but tolerability was not statistically different of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. between groups. 2012;166:633-641.

10 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar 5. Jackson JM, Fowler J, Moore A, et al. Improvement in facial erythema within 30 minutes of initial application of brimonidine tartrate in patients with rosacea. J Drugs Dermatol. 2014;13:699-704. 6. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to significant rebound erythema. J Am Acad Dermatol. May 2014;70:e109-e110. 7. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728. 8. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once- daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: Results of a 1-year open-label study. J Drugs Dermatol. 2014;13:56-61. 9. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70:e37-e38. 10. Swanson LA, Warshaw EM. Allergic contact dermatitis to topical brimonidine tartrate gel 0.33% for treatment of rosacea. J Am Acad Dermatol. 2014;71:832-833. 11. Dourmishev AL, Dourmishev LA, Schwartz RA. Ivermectin: Pharmacology and application in dermatology. Int J Dermatol. 2005;44:981-988. 12. Labro MT. Anti-inflammatory activity of macrolides: A new therapeutic potential? J Antimicrob Chemother. 1998;41(suppl B):37-46. 13. Stankiewicz M, Cabaj W, Jonas WE, Moore LG, Millar K, Ng Chie W. Influence of ivermectin on cellular and humoral immune responses of lambs. Vet Immunol Immunopathol. 1995;44:347-358. 14. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downreg- ulating the nuclear transcription factor kappa-B and mitogen-activated activation pathway. Fundam Clin Pharmacol. 2009;23:449-455. 15. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: Results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323. 16. Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: Results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13:1380-1386. 17. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: A randomized, investigator-blinded trial. Br J Dermatol. 2015;172:1103-1110. 18. Draelos ZD, Elewski BE, Harper JC, et al. A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid foam 15% in the treatment of papulopus- tular rosacea. Cutis. 2015;96:54-61. 19. Bevins CL, Liu FT. Rosacea: Skin innate immunity gone awry? Nat Med. 2007; 13:904-906. 20. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat Med. 2007;13:975-980. 21. Kanada KN, Nakatsuji T, Huang EY, Gallo RL. Inhibition of cathelicidin processing as therapy for rosacea. Presented at: 71st Annual Meeting of the Society for Investigative Dermatology; May 4-7, 2011; Phoenix, AZ. 22. Ryan ME, Usman A, Ramamurthy NS, Golub LM, Greenwald RA. Excessive activity in : Inhibition by tetracycline analogues with zinc reactivity. Curr Med Chem. 2001;8:305-316. 23. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 11 Tinea and Onychomycosis Theodore Rosen, MD*

demonstrated strong sensitivity (83%), specificity (84%), and Abstract positive (71%) and negative (91%) predictive values.3-5 However, Onychomycosis and tinea pedis are common fungal PCR cannot differentiate viable from nonviable fungi; in other infections affecting the nails and feet, respectively. Two words, PCR is a sensitive method for diagnosis but a poor method newly approved topical agents for onychomycosis are to confirm cure. Following treatment, only culture can confirm and , both of which have demonstrated respectable cure rates in clinical studies. For the absence of viable fungi. tinea pedis, naftifine 2% and luliconazole 1% are new agents, Treatment of Onychomycosis both administered for relatively short courses, that may foster greater adherence Treatments for onychomycosis include topical and oral medi- Semin Cutan Med Surg 35(supp6):S110-S113 cations, as well as nonpharmacologic approaches. Available © 2016 published by Frontline Medical Communications approved topical agents include , efinaconazole, and Keywords tavaborole. New options are now available for the treatment of Efinaconazole; luliconazole; naftifine; onychomycosis; onychomycosis. tavaborole; tinea pedis Outcomes typically reported by studies of treatment include mycological cure (negative culture and KOH), complete cure (absence of clinical sign plus mycological cure), and “almost nychomycosis is a common fungal infection affecting complete cure,” in which there remains ≤5% to 10% residual the nails. In the general population, the prevalence of abnormality.6,7 Reported rates of complete cure often appear to onychomycosis is low—about 4% in one systematic be relatively low because of the need for absence of clinical signs. O 1 review —but the prevalence is much higher in certain popula- For this reason, many studies (and product labels) cite the second tions, such as elderly patients (16%), those with diabetes (14%), outcome of almost complete cure. Furthermore, microscopic psoriasis (16%), or human immunodeficiency virus (11%), or analysis may conflict with clinical findings or culture results. This those receiving dialysis (14%) or renal transplant (7%). It is espe- relationship was demonstrated by a review of seven international cially important in immunosuppressed or immunocompromised trials, in which 78.7% of 2,360 culture-negative samples remained patients, who may harbor unusual fungal species (eg, saprophytes positive by KOH analysis.8 Morphologic analysis of these samples rather than ). Onychomycosis may be considered a identified hyphal breakage or distortion in a majority of the cosmetic problem by many clinicians, but the condition can lead samples, suggesting that the fungi were nonviable. to pedal pain and breaks in the skin that both facilitate lower Older agents approved for onychomycosis include the oral extremity and allow for exposure of the bloodstream to agents and itraconazole and the topical agent infectious fungal agents. ciclopirox. Two new topical agents have been approved for The diagnosis of onychomycosis is typically performed through onychomycosis: efinaconazole and tavaborole. Efinaconazole is with potassium hydroxide (KOH) preparation, histo- an azole-class drug that interferes with ergosterol biosynthesis pathologic analysis with periodic acid–Schiff (PAS) staining, and/ by blocking lanosterol demethylase. Tavaborole is a boron- or fungal culture.2 The PAS technique is generally considered the containing compound with a novel mechanism of action. The most sensitive of these tests (88%-93% sensitivity in one study).2 agent interferes with protein synthesis by blocking the formation However, the most sensitive test for diagnosis of onychomycosis of leucine transfer RNA.9 In vitro analysis of these compounds is polymerase chain reaction (PCR), and commercial PCR kits demonstrates a wide range of minimum inhibitory concentrations are available for this purpose in some industrialized countries. (MICs) for different organisms (Table 1).10 Of course, it should be PCR can be adjusted to identify specific fungal species and has noted that in vitro fungal susceptibilities do not always correlate with in vivo efficacy. * Professor of Dermatology, Baylor College of Medicine, Houston, Texas Of note, efinaconazole has excellent in vitro activity against both Publication of this CME/CE article was jointly provided by Rutgers, dermatophytes (the most common organisms in onychomycosis) The State University of New Jersey, and Global Academy for Medical and some saprophytes. The MICs for tavaborole are higher overall, Education, LLC, with Skin Disease Education Foundation (SDEF) but it must be kept in mind that in vitro susceptibility does not reli- and is supported by educational grants from AbbVie Inc., Bayer Healthcare, Merz North America Inc., and Valeant Pharmaceuticals ably predict clinical effect, and tavaborole demonstrates sufficient North America LLC. MIC for clinical efficacy. Furthermore, reliable standards for MIC Dr Rosen has received an honorarium for his participation in this activity. for dermatophytes have not yet been firmly established.9 He acknowledges the editorial assistance of Josh Kilbridge, medical writer, Cure rates as reported in product labels and key clinical trials and Global Academy for Medical Education in the development of this 11-20 continuing medical education journal article. are illustrated in Table 2. These data must be interpreted with caution, as they do not represent head-to-head trials, and Theodore Rosen, MD: Scientific Advisory Board: Anacor Pharmaceuticals, Inc., Merz, Valeant. differences in trial designs (eg, subject demographics, degree of Address reprint requests to: Theodore Rosen, MD, 1977 Butler Blvd, nail involvement, allowable trimming practices) may also influ- Suite E6.200, Houston, TX 77030; [email protected] ence outcomes.

12 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Both of the new topical agents have good penetration (including This finding is logical, as fungi on the skin of the foot can easily through nail polish) and are formulated to promote spreading colonize the nails, even following treatment for onychomycosis. into lateral nail folds and under the nail bed. Both are also Thus, eradication of a fungal reservoir on the pedal skin should well tolerated.16-20 Limitations of available data for these agents promote better results when treating affected nails. include treatment duration, degree of nail involvement, amount of subungual debris, and nail thickness. The pivotal studies for Other Agents and Therapies for Onychomycosis these agents lasted 48 weeks, and long-term treatment may be Additional approaches to the treatment of onychomycosis include required to achieve reported results. Older patients may require , , electrically generated plasma, nail even longer duration of therapy, as nail growth slows with age, drilling, and posaconazole. The mechanism of action of laser possibly requiring 12 to 18 months for the toenail to grow out. therapy remains unknown, but studies have demonstrated suffi- Also, nails in these studies had 20% to 60% involvement and did cient effectiveness to support the approval of several devices.23 not extend to the matrix; cure rates and/or treatment duration However, the improvements demonstrated to date are modest and may differ in nails with greater involvement. Finally, patients may not be durable. Accordingly, lasers are currently approved with large amounts of subungual debris or thick nails were not only for temporary cosmetic improvement of onychomycosis.23 included in these studies.16-20 Other physical modalities remain investigational. Early Intervention Posaconazole is an azole antifungal indicated for the prophy- Recent studies suggest advantages to early intervention. laxis of invasive and infections in severely Efinaconazole, for example, was more effective when used to treat immunocompromised patients and for oropharyngeal candi- 24 early disease (<1 year duration) compared with longer durations diasis. The agent has high potency and a broad spectrum of of disease (1-5 years or >5 years).21 Many dermatologists may coverage. In a phase II trial, subjects treated with posaconazole delay treatment of onychomycosis in patients with more serious demonstrated significantly greater rates of complete cure at comorbid conditions that require attention, but these data suggest 48 weeks compared to subjects treated with placebo and at least that delaying therapy will ultimately make the condition even comparable to those treated with terbinafine.25 These results harder to treat. Finally, a post hoc analysis of two efinaconazole illustrate the utility of posaconazole for immunocompromised studies demonstrated that treatment of concomitant tinea pedis patients with onychomycosis and for patients infected with significantly increased complete cure rates for onychomycosis.22 unusual organisms.

TABLE 1 Minimum Inhibitory Concentrations (μg/mL) of Topical Agents Used for the Treatment of Onychomycosis

Dermatophytes

Trichophyton rubrum 1–8 0.03–1 0.004–0.015 0.001–0.015 mentagrophytes 2–8 0.03–0.5 0.004–0.06 0.001–0.03 2–4 ≤0.5 0.25 0.016 floccosum ≤0.5 0.25–0.5 0.13–0.25 ≤0.002–0.0078 2 1 — — 2 0.25–0.5 >4 0.13–0.25 2 0.25–0.5 0.063–0.13 0.0039–0.016

Nondermatophyte

Aspergillus fumigatus 0.25 0.25–0.50 >4 0.031–0.5 solani ≤0.5 ≥4 >4 0.5 Ciclopirox Tavaborole

Yeasts Efinaconazole

Candida albicans 1.0 0.06–0.5 ≤0.03–8 <0.0005–>0.25 ≤0.5 0.13–0.5 2–>8 0.0039–0.13 1 0.13–0.25 0.13–0.5 0.0078–0.063 ≤0.5 0.13–0.5 0.13–4 <0.002–0.016 Candida tropicalis ≤0.5 ≤0.5 ≤0.016–>8 0.0078–0.063 0.25 ≤0.031 ≤0.016–0.13 0.002–0.0039 furfur 1 ≤0.5 — — Malassezia pachydermatis 1 ≤0.5 — — Malassezia sympodialis 1 ≤0.5 — —

Source: Adapted from Gupta AK, Daigle D.10

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 13 Recurrence Following Treatment In summary, effective new agents are available for onycho- Even following mycological cure, onychomycosis may recur. and tinea pedis, but complete elimination of fungal Recurrence rates vary substantially between studies and agents. infections is challenging, and recurrence often follows mycolog- For example, reported recurrence rates following mycological ical cure. When managing patients with onychomycosis or tinea cure with terbinafine range from 6% to 23%, and 24% to 100% pedis, clinicians must be sure to identify and treat both conditions following cure with itraconazole.26-30 Tips to limit risk for recur- to reduce the risk for recurrence following treatment of one but rence include sanitizing footwear, washing feet and changing not the other condition. socks frequently, using medicated powders in shoes and socks, and avoiding walking barefoot in public areas such as hotel References 1. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail rooms or locker rooms.31-33 onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015;29:1039-1044. Tinea Pedis 2. Jung MY, Shim JH, Lee JH, et al. Comparison of diagnostic methods for Tinea pedis and onychomycosis commonly co-occur, and the onychomycosis, and proposal of a diagnostic algorithm. Clin Exp Dermatol. 2015;40:479-484. presence of tinea pedis may increase the risk for onychomycosis, 3. Spesso MF, Nuncira CT, Burstein VL, Masih DT, Dib MD, Chiapello LS. even after effective treatment. More than a dozen topical agents Microsatellite-primed PCR and random primer amplification polymorphic DNA are available for the treatment of tinea pedis (Table 3). The newest for the identification and of dermatophytes.Eur J Clin Microbiol Infect Dis. 2013;32:1009-1015. agents are naftifine 2% and luliconazole 1%, both of which are 4. Kondori N, Tehrani PA, Strömbeck L, Faergemann J. Comparison of dermato- administered every day for 2 weeks, a relatively short course of phyte PCR kit with conventional methods for detection of dermatophytes in skin treatment that may foster greater adherence. specimens. Mycopathologia. 2013;176:237-241. 5. Garg J, Tilak R, Garg A, Prakash P, Gulati AK, Nath G. Rapid detection of Cure rates with these agents are similar: high mycological dermatophytes from skin and . BMC Res Notes. 2009;2:60. cure rates (72%, naftifine; 78%, luliconazole), lower complete 6. Gupta AK, Studholme C. How do we measure efficacy of therapy in onycho- cure rates (25%, naftifine; 21%, luliconazole), and modest rates mycosis: Patient, physician, and regulatory perspectives. J Dermatolog Treat. 2016:1-7. of “effective treatment,” defined as elimination of itching (60%, 7. Scher RK, Tavakkol A, Sigurgeirsson B, et al. Onychomycosis: Diagnosis and naftifine; 43%, luliconazole).34,35 definition of cure.J Am Acad Dermatol. 2007;56(6):939-944.

TABLE 2 Reported Rates of Complete, Almost Complete, and Mycological Cure for Available Agents for the Treatment of Onychomycosis11-20

Agent Complete Cure Almost Complete Cure Mycological Cure

Ciclopirox 8% 7% 9.3% 33% Efinaconazole 10% 16.5% 24.9% 54.3% Itraconazole 14% 35% 54% Tavaborole 5% 7.8% 16.6% 54.3% Terbinafine 38% 59% 70%

TABLE 3 Agents Available for the Treatment of Tinea Pedis

Agent Formulation(s) Mycological Cure

Naftifine 2% Cream, gel Once a day × 2 weeks Luliconazole 1% Cream Once a day × 2 weeks Once a day × 1–4 weeks (gel) Terbinafine 1% Cream, gel, spray Twice a day × 1–4 weeks (cream, spray) Butenafine 1% Cream Once a day × 4 weeks Oxiconazole 1% Cream, Once/twice a day × 4 weeks Once a day × 4 weeks (cream) Naftifine 1% Cream, gel Twice a day × 4 weeks (gel) Econazole 1% Cream, foam Once a day × 4 weeks Tolnaftate 1% Cream, gel, powder, spray Twice a day × 2–6 weeks Sertaconazole 2% Cream Twice a day × 4 weeks Ciclopirox 0.77% Cream, gel, lotion, powder, solution, suspension Twice a day × 4 weeks 2% Cream, gel, liquid spray, powder, solution Twice a day × 4 weeks 2% Cream, lotion, solution Twice a day × 4–8 weeks Ketoconazole 2% Cream,gel Once a day × 6 weeks

14 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar 8. Ghannoum M, Isham N, Catalano V. A second look at efficacy criteria for onycho- mycosis: Clinical and mycological cure. Br J Dermatol. 2014;170:182-187. 9. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728. 10. Gupta AK, Daigle D. Potential role of tavaborole for the treatment of onychomy- cosis. Future Microbiol. 2014;9:1243-1250. 11. Penlac [prescribing information]. Bridgewater, NJ: Dermik Laboratories; 2006. 12. Jublia [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2016. 13. Sporanox [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014. 14. Kerydin [prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; 2014. 15. Lamisil [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. 16. Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinacon- azole 10% solution for treatment of mild to moderate onychomycosis: A pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014;13:815-820. 17. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608. 18. Del Rosso JQ, Plattner JJ. From the test tube to the treatment room: Fundamentals of boron-containing compounds and their relevance to dermatology. J Clin Aesthet Dermatol. 2014;7:13-21. 19. Gupta AK, Daigle D, Abramovits W. Tavaborole 5% solution for onychomycosis. Skinmed. 2015;13:55-58. 20. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73:62-69. 21. Rich P. Efinaconazole topical solution, 10%: The benefits of treating onychomy- cosis early. J Drugs Dermatol. 2015;14:58-62. 22. Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea pedis. J Drugs Dermatol. 2015;14:492-494. 23. Liddell LT, Rosen T. Laser therapy for onychomycosis: Fact or fiction?J Fungi. 2015;1:44-54. 24. Noxafil [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; 2015. 25. Elewski B, Pollak R, Ashton S, Rich P, Schlessinger J, Tavakkol A. A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onycho- mycosis. Br J Dermatol. 2012;166:389-398. 26. Brautigam M, Weidinger G, Nolting S. Successful treatment of toenail mycosis with terbinafine and itraconazole gives long term benefits.BMJ. 1998;317:1084. 27. Tosti A, Piraccini BM, Stinchi C, Colombo MD. Relapses of onychomycosis after successful treatment with systemic : A three-year follow-up. Dermatology. 1998;197:162-166. 28. De Cuyper C, Hindryckx PH. Long-term outcomes in the treatment of toenail onychomycosis. Br J Dermatol. 1999;141(suppl 56):15-20. 29. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol. 2010;62:411-414. 30. Sigurgeirsson B, Olafsson JH, Steinsson JB, Paul C, Billstein S, Evans EG. Long- term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: A 5-year blinded prospective follow-up study. Arch Dermatol. 2002;138:353-357. 31. Gupta AK, Brintnell W. Ozone gas effectively kills laboratory strains of and Trichophyton mentagrophytes using an in vitro test system. J Dermatolog Treat. 2014;25:251-255. 32. Gupta AK, Brintnell WC. Sanitization of contaminated footwear from onychomy- cosis patients using ozone gas: A novel adjunct therapy for treating onychomycosis and tinea pedis? J Cutan Med Surg. 2013;17:243-249. 33. Rosen T. Concepts in onychomycosis treatment and recurrence prevention: An update. Semin Cutan Med Surg. 2016;35(3 suppl 3):S56-S59. 34. Jones TM, Jarratt MT, Mendez-Moguel I, et al. A randomized, multicenter, double-blind, vehicle-controlled study evaluating the efficacy and safety of lulicon- azole cream 1% once daily for 7 days in patients aged ≥12 years with . J Drugs Dermatol. 2014;13:32-38. 35. Parish LC, Parish JL, Routh HB, et al. A double-blind, randomized, vehicle- controlled study evaluating the efficacy and safety of naftifine 2% cream in tinea cruris. J Drugs Dermatol. 2011;10:1142-1147.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 15 Acne: What’s New Linda F. Stein Gold, MD*

A similar 12-week dose-ranging study of doxycycline (0.6, 1, Abstract 2, or 2.4 mg/kg/day) found that only the highest dose (2.4 mg/ Acne vulgaris is one of the most prevalent skin conditions. kg/day, equivalent to approximately 160 mg/day) was statistically Antibiotics, when considered, are most effective in combi- superior to placebo for improving acne.4 However, conflicting nation with other therapies, and limited evidence suggests results were found in 2 studies looking at lower doses of doxycy- that submicrobial doses of antibiotics may improve acne without increasing the risk for antibiotic resistance. A small cline (ie, below antimicrobial doses), which both suggest potential but significant risk for inflammatory bowel disease has also efficacy for acne. A small randomized study of adults with been identified in children treated with multiple courses of moderate acne (N=51) compared low-dose doxycycline (20 mg antibiotics. New topical agents are expanding therapeutic twice daily) to placebo for 6 months.5 At study end, the doxycy- options for acne. Semin Cutan Med Surg 35(supp6):S114-S116 cline group showed significantly greater reductions in the number © 2016 published by Frontline Medical Communications of comedones and inflammatory and non-inflammatory lesions compared to placebo. Treatment with low-dose doxycycline had Keywords no detectable antimicrobial effect on the cultivable skin flora and Acne vulgaris; antibiotics; inflammatory bowel disease; topical therapy did not increase resistance to antibiotics. A recent, larger study of subjects with moderate to severe acne (N=662) compared subantimicrobial (40 mg, modified- cne vulgaris affects a majority of young people worldwide release) and routine (100 mg) doses of doxycycline to placebo for and is one of the most prevalent skin conditions in the 16 weeks.6 The subantimicrobial dose of modified-release doxy- general population.1 A common approach to the treatment A cycline was associated with statistically greater reduction in the of moderate to severe acne is the use of antibiotics to target both acnes and inflammation. However, the poten- mean number of inflammatory lesions compared to placebo tial for antibiotic resistance is a serious consideration. According (16.1 vs 12.6; P=0.006) and compared to doxycycline 100 mg to the Centers for Disease Control and Prevention (CDC), at least (16.1 vs 12.9; P=0.024). Other outcomes were equivalent between 2 million Americans become infected with resistant bacteria each doxycycline groups (and superior to placebo), such as percent year, and 23,000 die as a result of these infections.2 What does the reduction of total lesions and Investigator Global Assessment potential for antibiotic resistance mean for the treatment of acne? (IGA) success rate. These findings suggest that subantimicrobial Factors that affect the risk for the development of antibiotic doses of doxycycline are at least as effective as include the dose and duration of antibiotic treatment. doses for the treatment of acne. Indeed, it may be that targeting Finding the most effective dose, frequency, and duration of admin- P. acnes is not essential; rather, the anti-inflammatory effects of istration for the treatment of acne could limit the risk for ineffective antibiotics may account for their efficacy in acne. dosing or approaches that may increase the risk for the develop- ment of resistance. For example, a 12-week dose-ranging study of Are Antibiotics Even Necessary? extended-release minocycline in subjects with moderate to severe Another question is whether oral antibiotics are even necessary acne (N=233) found no difference in efficacy between doses of 1, for the successful treatment of acne. For example, a random- 2, or 3 mg once daily, although higher doses were associated with a ized study compared oral doxycycline (100 mg once daily) with higher incidence of adverse events.3 This study clearly suggests no or without topical 0.1%/ 2.5%.7 advantage to higher doses of minocycline for the treatment of acne. Although the doxycycline monotherapy group showed improve- ment in IGA scores by 8-12 weeks, the combination group had * Director of Dermatology Research, Henry Ford Health System, significantly greater improvements at these time points. As illus- Detroit, Michigan trated in the Figure, only 8% of subjects taking oral doxycycline Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey, and Global Academy for Medical monotherapy were clear or almost clear of acne by week 12, Education, LLC, with Skin Disease Education Foundation (SDEF) whereas adding a potent topical agent quadrupled the proportion and is supported by educational grants from AbbVie Inc., Bayer of subjects achieving this target. Based on such data, it appears Healthcare, Merz North America Inc., and Valeant Pharmaceuticals North America LLC. that oral antibiotics contribute to therapeutic effect but have Dr Stein Gold has received an honorarium for her participation in this limited utility as monotherapy. activity. She acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the The Risks of Tapering Antibiotics development of this continuing medical education journal article. Tapering of antibiotics used for the treatment of acne has been Linda F. Stein Gold, MD: Consultant and Scientific Advisory Board: routinely used in clinical practice. However, evidence indicates Anacor Pharmaceuticals, Inc., Bayer, Eli Lilly and Company, Foamix that there is no need to taper antibiotics. Studies of combina- Pharmaceuticals Inc., Galderma Laboratories, L.P., LEO Pharma Inc., Medimetrix Pharmaceuticals, Inc., Novartis Pharmaceuticals tion therapy with oral antibiotics and topical agents show that Corporation, Pfizer Inc., Taro Pharmaceutical Industries Ltd. efficacy is maintained in a significant number of patients when Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood the antibiotic is discontinued after 3 months, while the topical Drive, Bloomfield Hills, MI 48302; [email protected]. agent is continued.8,9

16 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar In fact, this practice may increase risk for the development of 12-week study.15 Approximately half the subjects enrolled in resistance. The reason has to do with minimum antimicrobial this trial had severe acne, a substantially larger proportion than serum drug levels and bacterial selection pressures. If antibi- any other topical acne trial. Overall, 33.5% of subjects treated otic serum levels exceed this minimum antimicrobial threshold with the high-dose adapalene formulation achieved IGA success and then drop below the threshold, there is an increased risk (ie, clear or almost clear), compared to 11.5% of the vehicle group that only the weaker bacteria will be killed, leaving more robust (P<0.001). Among patients with severe acne, IGA success was bacteria unaffected. This association also underlies the risks of achieved by 31.2% of the high-dose adapalene group, compared poor adherence to antibiotic therapy, potentially leading to the to 21% of the regular-dose adapalene group and 13.3% of the selection of more resistant bacteria. For the same reason, clini- vehicle group. Only the high-dose group was statistically supe- cians should use caution when selecting subantimicrobial doses rior to vehicle in patients with severe acne (P=0.029). Tolerability of antibiotics for the treatment of acne. As demonstrated in a was not significantly different between the adapalene groups, and pharmacokinetic study, doxycycline dosed at 20 mg twice daily local irritation generally faded after the first 2 weeks of treatment. does not exceed the minimum antimicrobial level, but a 50-mg A new formulation of containing 7.5% active drug dose exceeds the threshold for a few hours per day, theoretically was recently approved by the US Food and Drug Administration increasing risk for the selection of resistance.5 for once-daily use (compared with 5% dapsone, which is applied twice daily). A recent study randomized 2,102 patients with Antibiotics and Inflammatory Bowel Disease: moderate acne to once-daily dapsone gel 7.5% or vehicle for How Great Is the Risk? 12 weeks.16 At weeks 8 and 12, significantly more subjects treated In 2010, a report was published on a retrospective study of 94,487 with dapsone gel achieved treatment success compared to vehicle patients with acne who were treated with tetracycline-type antibi- (P<0.05 and P<0.001, weeks 8 and 12, respectively). otics.10 Patients were treated with antibiotics for at least 1 month A recently approved combination topical gel consists of and followed for at least 1 year. Overall, the hazard ratio (HR) for 1.2% plus benzoyl peroxide 3.75%. In a 12-week developing inflammatory bowel disease (IBD) was 1.39 (95% CI, trial (N=498), once-daily application of this agent produced 1.02-1.90) for patients with any exposure to a tetracycline anti- significantly greater reductions in comedonal and inflammatory biotic. Risk for IBD was greatest for developing Crohn’s disease lesions compared to vehicle (P<0.001, all comparisons). Also, among patients treated with doxycycline (HR, 2.25; 95% CI, 1.27- statistically more patients achieved a two-grade improvement in 17 4.00). A second study used a nested case-control design, matching investigator’s global improvement compared to vehicle. 2,234 patients with IBD to 22,346 controls.11 Information on Topical Agents to Reduce Sebum Production? antibiotic use was extracted from a comprehensive prescription Until recently, no topical agent has demonstrated the ability to database. The use of more than 3 courses of antibiotics was asso- reduce sebum production, which contributes to the pathophys- ciated with an odds ratio (OR) for IBD of 1.5 (95% CI, 1.3-1.8). iology of acne. Currently, three topical agents in development Dose-response relationships were identified between antibiotic have shown the ability to affect sebum production. The first is use and risk for both ulcerative colitis and Crohn’s disease. SB204, a topical agent that releases . Nitric oxide has More recently, a meta-analysis of 11 observational studies both antimicrobial and anti-inflammatory activities and may (N=7208 with IBD) found a significant relationship between anti- also reduce sebum production.18,19 In a phase IIa trial, 2 doses biotic exposure and Crohn’s disease (OR, 1.74; 95% CI, 1.35-1.94) of SB204 (1% and 4%) were compared to vehicle in 153 subjects but not ulcerative colitis.12 Children with antibiotic exposure had with acne.20 At 4 weeks, the 4% dose of SB204 demonstrated a the greatest increase in risk for Crohn’s disease (OR, 2.75; 95% statistically significant reduction in both non-inflammatory and CI, 1.72-4.38). The risk for IBD in children was further evalu- inflammatory lesions compared to vehicle. ated in a retrospective cohort study from 464 ambulatory care centers in the , including 1,072,426 patients.13 40 In this study, the risk for IBD with antibiotic use decreased with Adap-BPO + doxycycline (n=232) 32% older age at time of exposure. Antibiotic use before 1 year of Vehicle + doxycycline (n=227) age had the greatest risk (HR, 5.51; 95% CI, 1.66-18.28). The *P<0.001 risk decreased with age (HR, 1.57 by age 15). Furthermore, each course of antibiotics increased the hazard of IBD by 6%. Although the absolute risk for IBD likely remains small, these data suggest caution when considering antibiotic treatment of 20 children with acne. 10%

Topical Agents Percentage 8% Several topical formulations of antibiotics are currently avail- able and used in some patients with acne (eg, , 3% clindamycin). New topical antibiotic formulations in development have demonstrated promise, including minocycline foam and gel. 10 A 12-week study of once-daily minocycline foam demonstrated a Baseline 4 Weeks 8 Weeks 12 Weeks dose-response relationship, with 4% minocycline achieving statis- tical superiority to vehicle for reducing acne lesions and achieving FIGURE an IGA score <2.14 Percentage of Patients Achieving Treatment Success New fixed-combination topical agents have been approved for (Clear or Almost Clear) on Investigator Global use in acne. One contains a higher dose of adapalene (0.3%), Assessment With Oral Doxycycline Compared With combined with benzoyl peroxide 2.5%. This combination Oral Doxycycline Plus Adapalene/Benzoyl Peroxide was compared to vehicle and the regular-strength combina- BPO=benzoyl peroxide. tion (adapalene 0.1%/benzoyl peroxide 2.5%) in a randomized, Source: Stein Gold L, Cruz A, Eichenfield L, et al.7

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 17 A second drug that may decrease sebum production is DRM01. 16. Stein Gold L, et al. Efficacy and safety of once-daily dapsone gel 7.5% for treatment of adolescents and adults with acne vulgaris: First of two identically This agent targets acetyl coenzyme-A carboxylase (ACC), which designed, large, multicenter, randomized, placebo-controlled trials. Presented at: is a key regulator of sebum production. A phase IIa trial random- Winter Clinical Dermatology Conference; January 15-20, 2016; Kaua’i, HI. ized 108 subjects to DRM01 7.5% twice daily or to vehicle for 17. Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed combi- 12 weeks.21 Statistical improvement in all efficacy parameters was nation of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris. J Drugs Dermatol. demonstrated with DRM01, including significantly greater reduc- 2014;13:1083-1089. tions in inflammatory and non-inflammatory lesions compared to 18. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles placebo (P=0.0005 and 0.0025, respectively). prevent Propionibacterium acnes induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. The third topical agent is a potent called CB-03-01 J Invest Dermatol. 2015;135:2723-2731. 22 (cortexolone 17α-propionate 1%). Initial study compared this 19. Niedbala W, Alves-Filho JC, Fukada SY, et al. Regulation of type 17 helper agent to 0.05% and vehicle in 77 men with facial acne.23 T-cell function by nitric oxide during inflammation.Proc Natl Acad Sci U S A. After 8 weeks, CB-03-01 produced significantly greater reductions 2011;108:9220-9225. 20. Rico J, et al. Data on file. Novan, Inc. www.novantherapeutics.com. Accessed in total and inflammatory lesion counts compared to vehicle, and April 13, 2016. at least comparable efficacy to tretinoin. 21. Bissonnette R, et al. Early onset of action in a randomized, vehicle-controlled phase 2a study of DRM01, a novel topical sebum inhibitor, in subjects with acne Summary vulgaris. Presented at: 24th European Academy of Dermatology and Venereology Congress. October 7-11, 2015; Copenhagen, Denmark. The treatment of acne continues to advance, with new agents 22. Celasco G, Moro L, Bozzella R, et al. Biological profile of cortexolone and combinations of agents in development and approved for 17α-propionate (CB-03-01), a new topical and peripherally selective clinical use. Emerging data also suggest limiting the use of oral antagonist. Arzneimittelforschung. 2004;54:881-886. antibiotics in patients with acne—in particular, minimizing 23. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of exposure of children to oral antibiotics. Finally, new topical acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and agents that reduce sebum production offer possible novel thera- tretinoin 0.05% cream. Br J Dermatol. 2011;165:177-183. peutic approaches for our acne patients. References 1. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol. 2013;168: 474-485. 2. Centers for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance. 2016; http://www.cdc.gov/drugresistance/. Updated April 19, 2016. Accessed May 18, 2016. 3. Stewart DM, Torok HM, Weiss JS, Plott RT; Solodyn Phase 2 Study Group. Dose- ranging efficacy of new once-daily extended-release minocycline for acne vulgaris. Cutis. 2006;78(4 suppl):11-20. 4. Leyden JJ, Bruce S, Lee CS, et al. A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxy- cycline calcium. J Drugs Dermatol. 2013;12:658-663. 5. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycy- cline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464. 6. Moore A, Ling M, Bucko A, Manna V, Rueda MJ. Efficacy and safety of suban- timicrobial dose, modified-release doxycycline 40 mg versus doxycycline 100 mg versus placebo for the treatment of inflammatory lesions in moderate and severe acne: A randomized, double-blinded, controlled study. J Drugs Dermatol. 2015;14:581-586. 7. Stein Gold L, Cruz A, Eichenfield L, et al. Effective and safe combination therapy for severe acne vulgaris: A randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycy- cline hyclate 100 mg. Cutis. 2010;85:94-104. 8. Tan J, Stein Gold L, Schlessinger J, et al. Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris. J Drugs Dermatol. 2012;11:174-180. 9. Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of and minocycline maintenance therapies in acne vulgaris: A multicenter, double-blind, randomized, parallel-group study. Arch Dermatol. 2006;142:605-612. 10. Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010;105:2610-2616. 11. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011;106:2133-2142. 12. Ungaro R, Bernstein CN, Gearry R, et al. Antibiotics associated with increased risk of new-onset Crohn’s disease but not ulcerative colitis: A meta-analysis. Am J Gastroenterol. 2014;109:1728-1738. 13. Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE. Antibiotic exposure and IBD development among children: A population-based cohort study. Pediatrics. 2012;130:e794-e803. 14. Stein Gold L, Shemer A, Sprecher E, Shiri Y. A phase 2 randomized trial of a new minocycline foam for the treatment of moderate-to-severe acne vulgaris. Presented at: 39th Annual Hawaii Dermatology Seminar; March 1-6, 2015; Kaua’i, HI. 15. Weiss J, Stein Gold L, Leoni M, Rueda MJ, Liu H, Tanghetti E. Customized single-agent therapy management of severe inflammatory acne: A randomized, double-blind, parallel-group, controlled study of a new treatment—Adapalene 0.3%-benzoyl peroxide 2.5% gel. J Drugs Dermatol. 2015;14:1427-1435.

18 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Fillers: What’s Here and What’s Ahead Nowell Solish, MD, FRCP(C)*

high- and low-molecular-weight HA designed to improve dura- Abstract bility and reduce swelling of the gel. Products within this family Soft tissue augmentation products (or fillers) are used for are tailored to provide different degrees of lift and spreadability. the correction of age-related changes in areas of the face. The main differences between Hylacross and Vycross products The most common filler material is hyaluronic acid, which is synthetically cross-linked. These materials are generally safe, are the length and molecular weight of the HA chains and extent but some side effects do occur. New fillers are expected to be of cross-linking: Hylacross consists of cross-linked, long-chain, approved in the United States in the near future. mostly high-molecular-weight HA; Vycross is a proprietary Semin Cutan Med Surg 35(supp6):S117-119 mixture of low- and high-molecular-weight, short- and long- © 2016 published by Frontline Medical Communications chain HA that is highly crosslinked.3 The same method of Keywords cross-linking is used in both products (1,4-butanediol diglycidyl Delayed nodules; fillers; hyaluronic acid; NASHA; soft tissue ether, or BDDE). The low-molecular-weight HA and high degree augmentation of cross-linking in the Vycross products leaves less space for water retention and swelling and provides good durability.3-5 The physiochemical properties of this family of products are ew soft tissue augmentation products (also called fillers) illustrated in the Table.4-8 Overall, the Vycross products absorb have become available in recent years, and others are in late less water than Hylacross products, meaning that the final volume stages of development. Fillers are used for the correction N will be similar to the injected volume. of age-related changes in areas of the face, such as the nasolabial folds, vertical lip lines, marionette lines around the mouth, and In preclinical studies, the Vycross products demonstrated a the thinning lip.1 These products are injected into these regions to balance between cohesivity and G′, high initial moldability, and 3,9 address the loss of subcutaneous volume that accompanies aging, good integration into host tissue. Integration is believed to thereby improving cosmesis and self-image. contribute to the natural appearance of the product with move- The most common material used for fillers is hyaluronic acid ments of the face. Vycross Voluma, which is approved for use (HA).2 How the HA is produced affects its physiochemical in the United States, demonstrated durability up to 24 months in properties and clinical application. These properties include trials, although clinical experience suggests longevity closer to 4,10 concentration, molecular weight, extent and method of cross- 1 year, after which reinjection may be considered. This filler is linking, and particle size. The related clinical performance very thick and provides volume and lift. characteristics include durability, stiffness (called G′), spread- Adverse events do occur with Vycross products, although they ability, volumization, and cohesivity. are rare. One adverse event that may be specific to these prod- For example, the Hylacross products are cross-linked, ucts is the development of delayed nodules. In a retrospective smooth with high HA concentration and high cohesivity. chart review study (N=2,342), aesthetic results lasted at least The high HA concentration provides durability, whereas the 12 months, and side effects were mostly transient and mild. high cohesivity provides lift. However, clinicians needed addi- However, 21 patients (<0.5%) developed delayed, non-tender tional products with different characteristics, such as products nodules.11 The nodules were successfully managed with conser- that can have a high lifting capacity or the opposite products vative measures. In clinical practice, nodules typically develop that are spreadable and have a very low lifting capacity.3 The within 4 to 6 months. newer Vycross family of products uses a mixture of cross-linked A proposed algorithm for the management of nodules is shown in the Figure. If infected, the nodules can be drained and then managed with antibiotics. For non-infected nodules, of * Assistant Professor, University of Toronto, Toronto, Ontario, Canada may help remove some of the HA and reduce the Publication of this CME/CE article was jointly provided by Rutgers, . Intralesional may also reduce nodules. The State University of New Jersey, and Global Academy for Medical Education, LLC, with Skin Disease Education Foundation (SDEF) Volbella has a very fine consistency and flows quickly during and is supported by educational grants from AbbVie Inc., Bayer injection. Its main uses are for lip hydration and perioral lines, Healthcare, Merz North America Inc., and Valeant Pharmaceuticals North America LLC. not for volume per se. Each injection lasts approximately 9 to 12 months.5 In one clinical study, 48.3% of subjects main- Dr Solish has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, tained ≥1-point improvement in the Lip Fullness Scale (LFS) at and Global Academy for Medical Education in the development of this 12 months, compared to 98.3% at 1 month. Clinical experience continuing medical education journal article. suggests that Volbella should be injected underneath the Nowell Solish, MD, FRCP(C): Consultant/Grant/Research Support: Allergan, in small amounts and then blended by hand to reduce fine lines. Inc., Galderma Laboratories, L.P., Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., Valeant. The characteristics of Volift place it between Voluma and Address reprint requests to: Nowell Solish, MD, 66 Avenue Road, Suite 1, Volbella. The product is best suited for marionette lines, smile Toronto, Ontario M5R3N8; [email protected] lines, and other mild to moderate lines around the face.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 19 Fluctuant?

Yes No; Red?

Puncture, drain, culture; Initiate antibiotics

Yes No; “Cold nodules” can be observed and may resolve Resolved If not resolved after 1 mo, on their own; if problematic +/– for culture/histo consider treatment below

As per clinical judgment, weekly to bi-weekly: +/– intralesional hyaluronidase* +/– Steroids (intralesional or short oral course)† +/– Continue or initiate antibiotics‡ THEN +/– Biopsy for culture/histo if non-resolving (rare)

FIGURE Delayed HA Nodule Treatment Algorithm *Intralesional hyaluronidase: standard start of 150 U/mL, inject 0.1-0.3/cm2 (consider starting 50-150 U/mL for non-Vycross, inject 0.1-0.3/cm2); †Intralesional steroids: TAC 2.5-5 mg/mL (up to 10, or even 20 mg/mL, for unresponsive), inject 0.1 mL/cm2; ‡Consider anti-inflammatory antibiotics. Note: Very early nodule appearance is not rare and will resolve in 1-2 weeks with watchful waiting and massage.

Non-Animal Stabilized HA (NASHA) defined as at least a one-grade increase from baseline in the Traditional cross-linking involves treating natural HA with a Medicis Lip Fullness Scale (MLFS). At 8 weeks in the intent-to- reagent (often BDDE) to generate a synthetically cross-linked treat population, 76.1% to 80.2% of treated subjects demonstrated gel. Non-animal stabilized HA (NASHA) is generated by response on the MLFS, compared to 11.6% to 18.4% of untreated subjects (P<0.001, all comparisons). Significant improvements preserving the naturally occurring HA network, in which the in perioral rhytides were noted at weeks 12 (37.1% vs 20%) and HA chains are entangled, and contains minimal synthetic cross- 16 (35.4% vs 17.5%) with NASHA compared to no treatment 12,13 links. NASHA products demonstrate greater resistance to (P<0.05, both comparisons). 13 deformation than other HA products. The size of the parti- The NASHA product tested in the study described above is cles of NASHA can be selected using screens of different sizes, branded Restylane Silk in the United States.15 Overall, this creating a range of products from small to large particle size. product is a smooth, fast-flowing filler that can be used to improve A recent study randomized 220 subjects to no treatment or the definition of lips but does not provide much volume. It also treatment with a small-particle NASHA plus lidocaine for lip provides hydration of the lip, giving the patient the appearance of augmentation and perioral rhytides.14 Treatment success was wearing lip gloss. It is not very hygroscopic.

TABLE 1 Characteristics of Vycross Family of Products4-8

Volbella* Volift* Voluma

Indication Lips Nasolabial folds Cheek and chin area

Implantation depth Lip mucosa Deep dermis Deep dermis

Total HA concentration 15 mg/mL 17.5 mg/mL 20 mg/mL

Formulation Smooth viscous gel Smooth viscous gel Smooth viscous gel

Gel hardness/viscosity 271 Pa 340 Pa 398 Pa (G′ @ 5 Hz)†

Cohesivity 19 gmf 30 gmf 40 gmf

Duration Up to 12 months Up to 12 months Up to 24 months

Lidocaine 0.3% 0.3% 0.3%

Needle gauge and length 30G ½ in 30G ½ in 27G ½ in

Shelf life 2 years 2 years 2 years

*Not yet approved by US Food and Drug Administration. †Approximate values.

20 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Another NASHA (to be branded Emervel in the United States when approved) consists of biosynthetic HA and the cross-linking agent BDDE. The HA in this product line is similar to other NASHA products, but the amount of cross-linking is increased and the particle size is varied. Previous products have been designed with a focus on either calibration (creating homoge- neous particle sizes) or cross-linking and HA concentration. This new product class combines these approaches for the first time to create products with a range of cross-linking and particle sizes. A lower degree of cross-linking creates a softer gel, and vice versa, meaning that this range of products provides different levels of resistance to deformation. The least cross-linked product would be best for very fine lines, whereas the more cross-linked products provide volume. Similarly, smaller gel particles provide less lifting capacity, which is required for finer lines and more superficial injections; larger gel particles have greater lifting capacity, which is required for more severe lines and deeper injections. In summary, fillers are used to address loss of tissue volume associated with aging. Most products are composed of HA, which is processed in different ways to produce different clinical characteristics. For example, NASHA products can resist defor- mation better than other HA products. New HA-based fillers are expected to be approved in the United States in the near future. References 1. Gold MH. Use of hyaluronic acid fillers for the treatment of the aging face.Clin Interv Aging. 2007;2:369-376. 2. Pierre S, Liew S, Bernardin A. Basics of dermal filler rheology.Dermatol Surg. 2015;41(suppl 1):S120-S126. 3. Bernardin A, et al. Presented at: Anti-Aging Medicine European Congress; October 11-12, 2013; Paris, France. 4. Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume deficit: 2-year results from a pivotal single-blind randomized controlled study. Dermatol Surg. 2013;39:1602-1612. 5. Eccleston D, Murphy DK. Juvederm® Volbella™ in the perioral area: A 12-month prospective, multicenter, open-label study. Clin Cosmet Investig Dermatol. 2012;5:167-172. 6. Juvéderm Voluma XC [product information]. Irvine, CA: Allergan, Inc.; 2014. 7. Raspaldo H. Volumizing effect of a new hyaluronic acid sub-dermal facial filler: A retrospective analysis based on 102 cases. J Cosmet Laser Ther. 2008;10:134-142. 8. Borrell M, Leslie DB, Tezel A. Lift capabilities of hyaluronic acid fillers.J Cosmet Laser Ther. 2011;13:21-27. 9. Narukar V, Shumate GT, Van Epps D, Messina DJ, Paliwal S. Volumizing and moldability characteristics of crosslinked hyaluronic acid fillers. Presented at: 2013 American Society for Dermatologic Surgery Annual Meeting; October 3-6, 2013; Chicago, IL. 10. Callan P, Goodman GJ, Carlisle I, et al. Efficacy and safety of a hyaluronic acid filler in subjects treated for correction of midface volume deficiency: A 24 month study. Clin Cosmet Investig Dermatol. 2013;6:81-89. 11. Humphrey S, Carruthers J, Carruthers A. Clinical experience with 11,460 mL of a 20-mg/mL, smooth, highly cohesive, viscous hyaluronic acid filler.Dermatol Surg. 2015;41:1060-1067. 12. Edsman K, Nord LI, Ohrlund A, Lärkner H, Kenne AH. Gel properties of hyal- uronic acid dermal fillers.Dermatol Surg. 2012;38:1170-1179. 13. Edsman K, Ohrlund A, Sturesson C, Nord LI, Kenne AH, Nasstrom J. The differ- ence between stabilization and crosslinking. Presented at: 8th Anti-Aging Medicine World Congress; April 8-10, 2010; Monte Carlo, Monaco. 14. Beer K, Glogau RG, Dover JS, et al. A randomized, evaluator-blinded, controlled study of effectiveness and safety of small particle hyaluronic acid plus lidocaine for and perioral rhytides. Dermatol Surg. 2015;41(suppl 1): S127-S136. 15. Restylane Silk [product information]. Bridgewater, NJ: Medicis – A Division of Valeant Pharmaceuticals North American LLC; 2014.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 21 The Aging Face: Global Approach With Fillers and Neuromodulators Nowell Solish, MD, FRCP(C)*

youthful appearance. The facial evaluation, therefore, should Abstract focus on areas of volume loss and opportunities to use neuro- The goal of treating the aging face is to restore facial modulators (eg, botulinum toxin A) and the use of fillers. balance and modify shadows. A facial evaluation should focus on areas of volume loss and opportunities to use Neuromodulators and the Aging Face neuromodulators (eg, botulinum toxin A) and the use of Injections of neuromodulators relax specific muscle groups and fillers. A thorough understanding of facial , including can reduce and improve cosmesis. There are several muscles, nerves, , and pads, is essential for effective and safe treatment. common facial targets for neuromodulators. The forehead is Semin Cutan Med Surg 35(supp6):S120-S121 a complex region with corrugator muscles that adjust brow © 2016 published by Frontline Medical Communications height and volume. The pattern of movement of these muscles Keywords varies by individual, and several patterns have been described Aging face; botulinum toxin A; fillers; neuromodulators (Figure 1). The most common is the V pattern, which can be addressed with neuromodulator injections in the procerus medial corrugators and lateral corrugators. The inverted omega s we age, bone and fat volume in the face and neck natu- pattern involves medial contraction of the corrugators and often rally decrease. Furthermore, rotational descent of the face includes the nasalis muscles. Neuromodulator injections should Aoccurs with aging, contributing to a lengthening of the be focused centrally. The omega pattern involves the frontalis face and the creation of lines, folds, and shadows. Youthful faces and procerus muscles, and injections focus on the central areas. often have a heart-shaped pattern, but with age the face becomes The U-shaped pattern typically responds well to treatment and more oval (elongated) or square (broadened, bottom heavy). For may need less neuromodulator. Finally, the converging arrow example, a baby’s face has a shape similar to an inflated beach patterns typically involve deep central lines on the forehead. ball, round and unlined. But the muscular atrophy, photodamage, When treated with neuromodulators, this pattern often shows and fat atrophy that occur with aging lead to an appearance more the greatest improvements. like a wrinkled, deflated beach ball. Other facial sites for neuromodulators include the masseter In the midface, aging often increases fat in the lower areas muscles. Hypertrophy of the masseters may occur even in young and decreases volume in upper areas. The bone also resorbs and patients, contributing to a bottom-heavy facial appearance. remodels. Resorption is common in the frontal bone, contributing to a convexity of the bone and ptosis of the brow. Resorption of Injection of these muscles can ameliorate this hypertrophy. the zygomatic angle makes the angle more acute, and the malar Fillers and the Aging Face fat pad sags medially and creates or worsens the nasolabial fold. Neuromodulators can improve cosmesis of the forehead by Other changes that contribute to the appearance of aging include relaxing muscles that contribute to folds and wrinkles. But periorbital hollowing, marionette lines, submalar hollowing, and volume loss can also contribute to poor cosmesis. For example, an periocular rhytidosis. arched eyebrow is generally considered more youthful and attrac- The goal of treating the aging face is to restore facial balance tive; fillers can be used in the forehead to achieve this arched or and modify shadows. For example, the infraorbital fat pad tends rounded appearance. The safest zone for the injection of fillers in to protrude as people age. Part of the cosmetic problem caused the forehead is in the mid-forehead at the level of the periosteum, by this change is the shadow that the pad creates; filling below which can help avoid an intra-arterial injection. A typical volume the protruding pad can reduce this shadow and create a more for this application is 0.1 to 0.2 mL of filler per site, with 3 or 4 injections per side, followed by blending by hand to achieve the * Assistant Professor, University of Toronto, Toronto, Ontario, Canada desired look. Blending is easy in this region because the filler is Publication of this CME/CE article was jointly provided by Rutgers, injected on the periosteum. The State University of New Jersey, and Global Academy for Medical Education, LLC, with Skin Disease Education Foundation (SDEF) Fillers can also be used to increase brow height. Caution should and is supported by educational grants from AbbVie Inc., Bayer be exercised when injecting filler into the brow, and a cannula may Healthcare, Merz North America Inc., and Valeant Pharmaceuticals North America LLC. be safer than a needle. The general approach involves injecting at the lower margin of the brow from the peak of the brow and Dr Solish has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, continuing laterally. The temples are another site that may benefit and Global Academy for Medical Education in the development of this from application of fillers. Injection should be performed 1 cm continuing medical education journal article. above the orbital rim and 1 cm medial to the temporal fusion Nowell Solish, MD, FRCP(C): Consultant/Grant/Research Support: Allergan, plane, with a finger pressed behind the needle to prevent the filler Inc., Galderma Laboratories, L.P., Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., Valeant. from flowing into the hairline. Up to 1 mL of filler per side may Address reprint requests to: Nowell Solish, MD, 66 Avenue Road, Suite 1, be needed to eliminate shadows. Injecting filler in this spot is Toronto, Ontario M5R3N8; [email protected] generally quite safe.

22 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar 3 4 1 2

FIGURE 2 Two Techniques for Submalar Injection of Filler Technique 1 (top panels) uses deep subcutaneous injections in a grid pattern. Technique 2 (bottom panels) uses one injection site (1), with medial or lateral entry, in a fanning motion (triangle and arrows).

crease, which occurs as fat in the cheek begins to sag. It is impor- tant not to add filler below the malar crease, as this may produce an unnatural appearance. Injections of filler from the bottom of the malar crease upward and in the anteromedial and lateral cheek can ameliorate this crease, as well as the nasolabial fold. Using this approach, injections in the nasolabial fold may not be necessary. The medial and lateral lid-cheek junction will also be addressed when the midface is corrected. Filler can be added to the medial and lateral tear trough by injecting one or two small boluses (approximately 0.1 mL) near the periosteum and massaging the gel up to the medial canthus. Both medial and lateral tear troughs must be addressed. Lateral scleral show of the eye (analogous to a downturned corner of the mouth) can be lifted with filler. This technique should only be attempted by clinicians with extensive experience injecting filler. To treat lateral scleral show, a small amount of filler can be FIGURE 1 injected below the lateral canthus to provide lift. Patterns of Corrugator Movement and Sites for The submalar area can be injected with small amounts of filler Neuromodulator Injection (approximately 0.05-0.1 mL per injection) in a grid pattern in the From top: V pattern, inverted omega, omega pattern, U pattern, subcutaneous plane (Figure 2). and converging arrows. Sites for injection of neuromodulator are Finally, in the lower face, areas for fillers include the mario- noted in red dots below each pair of images. nette lines, chin apex, and the pre- and post-jowl sulci. However, some patients who complain about jowls actually have protru- A youthful orbit is characterized by a long, flat, and full , sion of the submandibular gland. This protrusion can usually with the upper lid concealed by skin. The bony orbit is not visible. be managed with application of neuromodulator (eg, 5-8 units With aging, the orbit loses volume and becomes more skeleton- botulinum toxin A on each side), often with rapid resolution. ized. The typical finding with age is called the A-frame deformity. In summary, use of fillers and neuromodulators is an effective Fillers can be used to replace this volume loss, although injecting strategy for the treatment of age-related facial changes. A thor- in this area requires advanced technique, and use of a cannula is recommended. Small volumes of filler (eg, approximately 0.1 mL) ough understanding of facial anatomy, including muscles, nerves, are usually sufficient to rectify A-frame deformities. bone, and fat pads, is essential for effective and safe treatment. The midface is one of the most important areas to address in Reference aging. The focus should be on the cheek, lower lid, and submalar Shaw RB Jr, Kahn DM. Aging of the midface bony elements: A three-dimensional area. A common finding that occurs with aging is the malar computed tomographic study. Plast Reconstr Surg. 2007;119:675-681.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 23 Facial Rejuvenation: 40th Anniversary Review Christopher B. Zachary, MBBS, FRCP*

Fractionated Non-Ablative and Ablative Lasers Abstract Scars, facial photodamage, and normal have all been For decades, devices and peels have been used for facial well treated in the past with chemical peels, , and rejuvenation and the treatment of skin damage. In recent years, new laser systems have been developed, including traditional laser resurfacing techniques. Various non-ablative fractionated ablative and non-ablative lasers which, heating technologies such as the CoolTouch® (1320 nm) laser were while not as effective as the traditional laser resurfacing, developed in the hope that this would improve acne scarring, skin can provide nice results with reduced side effects. While tightness, and aging changes, but early results were mixed.1 Rox fractionated hybrid systems, picosecond lasers, and daylight photodynamic therapy have all been rolled out for clinicians Anderson and Dieter Manstein first considered the concept of to assess their efficacy, future technology, including TRASER fractionation as a method to create universal benefit by inducing (total reflection amplification of spontaneous emission of myriad tiny areas of , much akin to the lawn aerator benefit radiation) technology, should be just around the corner. for a lawn. The first device manufactured by Reliant delivered These technologies offer new potential applications, efficacy, 1,2 and recovery periods. multiple microbeams using a computer-controlled scanner. Semin Cutan Med Surg 35(supp6):S122-S124 These are characterized by having normal unaffected © 2016 published by Frontline Medical Communications and dermis between the areas of laser-treated skin, preserving a Keywords reservoir of healthy cells that expedite healing.3 Subsequently, Ablative lasers; daylight photodynamic therapy; facial Reliant developed an ablative device with similar characteristics, rejuvenation; fractionated lasers; picosecond lasers, TRASER though instead of inducing a thermal injury, this device vaporized the tissue, leaving relatively deep but narrow channels into the dermis. Although the original fractionated devices induced inju- aser skin resurfacing remains a major therapeutic tool for ries of 150 µm or less, many useful devices create of up to facial rejuvenation and the treatment of acne scars and 400-500 µm, which are still small enough to allow the intervening other skin damage. The technologies work by altering the skin cells to promote healing. L Among the advantages of fractionated laser treatment is a epidermis and dermis, either by full field treatment or fraction- reduced incidence of side effects of the traditional devices. This ated delivery of coagulative or ablative injury, thereby inducing includes an absence of delayed onset loss of pigmentation, which regrowth of new epidermis and growth of new and occurred in about 25% of CO2 laser resurfacing patients, a reduced elastin in the dermis. The first lasers introduced to dermatology amount of persistent erythema, and other side effects such as were ablative lasers, such as the CO2 and erbium:YAG (yttrium- scarring and infection. Another advantage is the ability to treat aluminum-garnet) lasers, both of which target water. Although nonfacial areas, such as the neck or chest, which are challenging traditional laser resurfacing techniques are still considered to treat with traditional lasers. Healing following treatment with the gold standard by many dermatologists, a variety of new an ablative fractionated device is relatively fast; induced defi- laser systems have become available, with each device inducing cits generally close within 24-48 hours (Figure 1).4 Importantly, different patterns of focal injury and subsequent outcomes. patients typically do not report pain following treatment with fractionated ablative devices, in contrast to the traditional CO2 or erbium:YAG ablative lasers. Although fractionated lasers induce * Professor and Chair, Department of Dermatology, University of low-density injuries to the skin (for example, 5% of the target California, Irvine, Irvine, California area), the entire target area will respond uniformly with forma- Publication of this CME/CE article was jointly provided by Rutgers, tion of new epidermis. The State University of New Jersey, and Global Academy for Medical As with any device, the laser surgeon must consider laser tissue Education, LLC, with Skin Disease Education Foundation (SDEF) and is supported by educational grants from AbbVie Inc., Bayer interactions. For those who have darker skin types, or in areas Healthcare, Merz North America Inc., and Valeant Pharmaceuticals that are underprivileged with regard to numbers of adnexal North America LLC. glands such as the neck and chest, the fractional density should Dr Zachary has received an honorarium for his participation in this be reduced to prevent post-inflammatory and activity. He acknowledges the editorial assistance of Josh Kilbridge, medical the potential for scarring, respectively. The relationship between writer, and Global Academy for Medical Education in the development of more aggressive treatment, including higher density, and better this continuing medical education journal article. outcomes may not be supported for all applications, particularly Christopher B. Zachary, MBBS, FRCP: Consultant: Kythera with acne scarring. Repeated and immediate scanning of the same Biopharmaceuticals, Inc., Sciton, Inc., Solta Medical; Scientific Advisory Board: Sciton and ZELTIQ Aesthetics, Inc. region of skin may result in bulk heating of the skin with loss of selectivity, possibly leading to scarring. Once an area has been Address reprint requests to: Christopher B. Zachary, MBBS, FRCP, Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697; scanned with the device, it is important to move to a different area [email protected]. to allow the skin to cool before rescanning (if necessary).

24 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar 48 HOURS 7 DAYS 1 MONTH 3 MONTHS

FIGURE 1 Chronology of Healing After Use of Fractionated Ablative Laser All data points shown above were recorded at 20 mJ treatments. Source: Used with permission.4

Wavelength and Absorption Total Reflection Amplification of Spontaneous The wavelength generated by the laser determines its absorption Emission of Radiation by skin structures and therefore its clinical effect. The thulium A new, non-laser, non– (IPL) technology, fiber laser with a 1927 nm wavelength, for example, has roughly called TRASER (total reflection amplification of spontaneous 10 times the absorption in skin compared to erbium fiber 1550 nm emission of radiation), has been developed that can target blood wavelength lasers. The thulium 1927 nm laser has very little dose- vessels and hair follicles. The TRASER device is capable of very response in terms of lesion depth with increasing pulse energy; high power output, variable wavelengths, and pulse durations this contrasts with the erbium 1550 nm laser, which demonstrates from 0.45 to more than 100 msec. Photons generated by two a robust dose-response relationship. Clinically, this difference flash lamps are absorbed by a dye, which then produces photons translates into more superficial tissue heating, similar to a very of a specific wavelength based on the characteristic of the dye. Changing the dye and its concentration will change the wave- superficial high energy, short pulsed CO2 laser, though without the epidermal vaporization and with the absence of bleeding or length output. It can emulate a potassium-titanyl-phosphate fluid loss, and with less need for care. (KTP) laser, pulsed dye laser, and a ruby laser. As such, the device could be used to treat port-wine stain in one Hybrid Lasers patient, then (once the dye is switched) hair removal in the next. Hybrid laser systems combine ablative and non-ablative wave- lengths in one device. For example, a new device manufactured Daylight Photodynamic Therapy Dermatologists are familiar with conventional photodynamic by Sciton combines 2940 nm and 1470 nm wavelengths, each of therapy (cPDT). Daylight PDT (dPDT) is a novel approach that which can be adjusted for coverage and depth of penetration. The delivers continuous low-level activation of protoporphyrin IX 2940 nm wavelength removes superficial epidermis and can allow (PpIX) for the treatment of photoaged skin and actinic keratoses. the 1470 nm to immediately and sequentially treat the underlying cPDT uses artificial light sources, but dPDT has been demon- dermal tissue. These wavelengths target epidermal and dermal strated to have at least comparable results.6 The technique involves pigmented lesions, dermal elastosis, fine lines, texture, and pore degreasing the face, gentle curettage of any thicker lesions, and size. Although treatment with this system produces less pain than application of for 60 minutes. A chemical some other fractionated devices, patients should be warned that is applied 30 minutes into this incubation. Then the the treated area may look worse for 2-3 days after treatment, skin is exposed to shaded daylight for 2-2.5 hours, after which before the skin regenerates. the patient should remain indoors for 48 hours. The technique may also be used for treatment of other skin conditions, such as Picosecond Lasers acne. In one trial, PDT produced at least moderate improvement Picosecond lasers, which use pulse durations in the picosecond in acne in a greater proportion of subjects than intense pulsed range, may produce superior results to nanosecond lasers for or blue-red light-emitting diode therapy.7 Our results certain applications, such as tattoo removal. For example, a small of dPDT in recalcitrant acne have been quite impressive, with study of patients with multicolor tattoos reported at least 75% almost compete clearing after 4-5 treatments. clearance of blue and green pigments after one or two treatments In summary, lasers have long been used in dermatology prac- with a picosecond 755 nm alexandrite laser, including tattoos that tices. New types of lasers have been developed that differ in the resisted previous treatments.5 Other potential applications for type of injury produced in the skin and therefore the potential picosecond lasers include pigmented lesions, nevi, and . application, efficacy, and recovery of patients.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 25 References

1. Omi T, Numano K. The role of the CO2 laser and fractional CO2 laser in derma- tology. Laser Ther. 2014;23:49-60. 2. Manstein D, Herron GS, Sink RK, Tanner H, Anderson RR. Fractional photo- thermolysis: A new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med. 2004;34:426-438. 3. Hession MT, Graber EM. Atrophic acne scarring: A review of treatment options. J Clin Aesthet Dermatol. 2015;8:50-58. 4. Hantash BM, Bedi VP, Chan KF, Zachary CB. Ex vivo histological charac- terization of a novel ablative fractional resurfacing device. Lasers Surg Med. 2007;39:87-95. 5. Brauer JA, Reddy KK, Anolik R, et al. Successful and rapid treatment of blue and green tattoo pigment with a novel picosecond laser. Arch Dermatol. 2012;148:820-823. 6. Wiegell SR, Haedersdal M, Philipsen PA, Eriksen P, Enk CD, Wulf HC. Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study. Br J Dermatol. 2008;158:740-746. 7. Liu LH, Fan X, An YX, Zhang J, Wang CM, Yang RY. Randomized trial of three phototherapy methods for the treatment of acne vulgaris in Chinese patients. Photodermatol Photoimmunol Photomed. 2014;30:246-253.

24 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Post-Test Original Release Date: June 2016 Expiration Date: June 30, 2017 • Estimated Time to Complete Activity: Up to 2.33 hours To get instant CME/CE credits online, go to http://tinyurl.com/HDS16Supp. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it at that time. If you have any questions or difficulties, please contact the Global Academy for Medical Education office at [email protected].

Questions: For each question or incomplete statement, choose the answer or completion that is correct. Circle the most appropriate response.

1. In the registration clinical trial, the mycological 6. Which of the following agents is FDA-approved for cure rate of efinaconazole 10% for treatment of the treatment of facial erythema associated with onychomycosis was approximately what? rosacea? A. 30% A. Brimonidine B. 50% B. Oxymetazoline C. 70% C. Ivermectin cream D. 90% D. Low-molecular-weight hyaluronic acid

2. Which of the following describes the mechanism of 7. A phase III trial comparing ivermectin cream to action of tavaborole? metronidazole cream for the treatment of rosacea reported all of the following results, EXCEPT: A. Blocks lanosterol demethylase A. Similar overall tolerability between groups B. Inhibits pro-inflammatory cytokines B. Better local tolerability with metronidazole cream C. Blocks formation of leucine transfer RNA C. Significantly higher rate of treatment success with D. Inhibits function of fungal DNA topoisomerase ivermectin 3. Observational studies have identified increased D. Significantly greater reductions in inflammatory risk for inflammatory bowel disease associated with lesions with ivermectin antibiotic use in children. In which patient group 8. Advantages of fractionated lasers compared to was this risk greatest? non-fractionated lasers for facial rejuvenation A. Children younger than 1 year include all of the following, EXCEPT: B. Adolescents aged 10-16 years A. Reduced post-procedural pain C. Children with very severe acne B. Faster post-procedural healing D. Patients with pre-existing bowel symptoms C. Reduced incidence of loss of pigmentation D. Production of high-density injury to the target area 4. When considering the use of fillers for soft tissue augmentation, a filler with which of the following 9. After 12 weeks of treatment with etanercept characteristics would be appropriate for very in a phase III trial for pediatric psoriasis, what fine lines? proportion of patients achieved PASI 75? A. Larger-sized gel particles A. 25% B. Greater resistance to deformation B. 39% C. Lower degree of cross-linking C. 57% D. High molecular weight and concentration of D. 78% hyaluronic acid 10. To support approval of a biosimilar agent, the FDA 5. The use of a cannula is recommended when requires all of the following, EXCEPT: applying soft tissue filler to which of the following A. Toxicity studies in animals facial regions? B. Identical amino acid sequence to original biologic A. Chin apex C. Pharmacokinetic and pharmacodynamic studies B. Malar crease in humans C. Nasolabial fold D. Clinical trials to demonstrate safety and efficacy for D. A-frame deformity of the orbit each indication of the original biologic

Rutgers, The State University of New Jersey, thanks you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patient care.

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 25 Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Evaluation Form Original Release Date: June 2016 • Expiration Date: June 30, 2017 • Estimated Time to Complete Activity: Up to 2.33 hours To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few moments to complete this evaluation form. Your response will help ensure that future programs are informative and meet the educational needs of all participants. CME/CE credit letters and long-term credit retention information will only be issued upon completion of the post-test and evaluation online at: http://tinyurl.com/HDS16Supp.

Please indicate your profession/background: (check one) MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator Student Other; specify ______

LEARNING OBJECTIVES: Having completed this activity, you are better able to: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

Integrate into daily practice evidence-based recommendations on new and emerging 5 4 3 2 1 therapies for common and uncommon dermatologic diseases. Implement updated strategies for managing acne, rosacea, and psoriasis. 5 4 3 2 1 Discuss the use of biologic agents in the treatment of adult and pediatric psoriasis. 5 4 3 2 1 Review the status of biosimilars for use in dermatology. 5 4 3 2 1 Incorporate the recent advances in the treatment of acne vulgaris. 5 4 3 2 1 Discuss the safety, efficacy, and dosing of antibiotics for acne vulgaris 5 4 3 2 1 Analyze emerging treatments for tinea and onychomycosis. 5 4 3 2 1

Identify the considerations in the selection of appropriate filler agents for treating different areas 5 4 3 2 1 of the face.

Compare and contrast the efficacy and safety of agents, devices, and techniques currently 5 4 3 2 1 available in aesthetic and procedural dermatology. Determine the appropriate nonsurgical techniques for facial rejuvenation. 5 4 3 2 1 Describe the appropriate use of neuromodulators in the treatment of the aging face. 5 4 3 2 1 If you do not feel confident that you can achieve the above objectives to some If you anticipate changing one or more aspects of your practice/professional extent, please describe why not. responsibilities as a result of your participation in this activity, please briefly ______describe how you plan to do so. ______Based on the content of this activity, what will you do differently in the care of ______your patients/regarding your professional responsibilities? (check one) If you plan to change your practice/professional responsibilities, may we Implement a change in my practice/workplace. contact you in 2 months to see how you are progressing? Seek additional information on this topic. Yes No I don’t plan to make a change. Implement a change in my practice/workplace and seek additional information on this topic. If you are not able to effectively implement what you learned in this activity, Do nothing differently. Current practice/job responsibilities reflect activity please tell us what the system barriers are (eg, institutional systems, lack of recommendations. resources, etc). Do nothing differently. Content was not convincing. ______Do nothing differently. System barriers prevent me from changing my ______practice/workplace. ______

OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree This education increased my understanding of the subject. 5 4 3 2 1 This education will influence how I do my job. 5 4 3 2 1 This education will help me improve my job performance. 5 4 3 2 1 This education will help me collaborate with other healthcare professionals. 5 4 3 2 1 This education addressed issues in cultural competency 5 4 3 2 1 This education was educationally sound and scientifically balanced. 5 4 3 2 1 This education was free of commercial bias or influence This education met my expectations. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Joseph F. Fowler, Jr, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Theodore Rosen, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Jeffrey M. Sobell, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Nowell Solish, MD, FRCP(C) Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Linda F. Stein Gold, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Christopher B. Zachary, MBBS, FRCP Author was organized in the written materials. 5 4 3 2 1

What issue(s) are you experiencing in your practice/regarding your Please provide additional comments pertaining to this activity and any professional responsibilities that could be addressed in future programming? suggestions for improvement. ______

Rutgers, The State University of New Jersey, thanks you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patient care. © 2016 Global Academy for Medical Education, LLC. All Rights Reserved.