Highlights of Skin Disease Education Foundation’s 40th ... · Onychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Newly approved

EDITORS Kenneth A. Arndt, MDPhilip E. LeBoit, MDBruce U. Wintroub, MD

SUPPLEMENT 6

VOL. 35, NO. 6S

JUNE 2016

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii

Dermatology Seminar

GUEST EDITORS

Joseph F. Fowler, Jr, MDChristopher B. Zachary, MBBS, FRCP

Theodore Rosen, MDJeffrey M. Sobell, MD

Nowell Solish, MD, FRCP(C) Linda F. Stein Gold, MD

Introduction S103

Update on TNF Inhibitors in Dermatology S104

Facial Dermatitis and Rosacea S107

Tinea and Onychomycosis S110

Acne: What’s New S114

Fillers: What’s Here and What’s Ahead S117

The Aging Face: Global Approach With S120 Fillers and Neuromodulators

Facial Rejuvenation: 40th Anniversary Review S122

Post-Test and Evaluation Form S125

A CME/CE CERTIFIED SUPPLEMENT TO

Jointly provided by Supported by educational grants from AbbVie Inc., Bayer Healthcare, Merz Pharma North America Inc.,

and Valeant Pharmaceuticals North America LLC

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology SeminarOriginal Release Date: June 2016 • Expiration Date: June 30, 2017 Estimated Time to Complete Activity: Up to 2.33 hoursParticipants should read the CE information below, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test, 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 out at that time.The online post-test and evaluation can be accessed at http://tinyurl.com/HDS16Supp.Inquiries may be directed to Global Academy for Medical Education at [email protected] or (973) 290-8225.

Accreditation StatementsPhysicians: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Rutgers, The State University of New Jersey and Global Academy for Medical Education. Rutgers, The State University of New Jersey is accredited by the ACCME to provide continuing medical education for physicians. Rutgers, The State University of New Jersey designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses: Rutgers, The State University of New Jersey, Center for Continuing and Outreach Education (CCOE) is an approved provider of continuing nursing education by the New Jersey State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Provider Number P173-5/31/16. This activity is awarded 2.33 contact hours. (60 minute CH) Nurses should only claim those contact hours actually spent participating in the activity.

Target AudienceThis supplement is intended for dermatologists, family practitioners, internists, nurse practitioners, nurses, physician assistants, and other clinicians who practice medical dermatology or aesthetic medicine.

Educational NeedsResearch continues to expand our understanding of the pathophysiology and management of skin diseases and age-related skin damage. Based on this evidence, new pharmacologic agents and medical devices continue to be developed, researched, and approved for use in the United States. New evidence and therapies have been developed for acne vulgaris, rosacea, psoriasis, onychomycosis/tinea, and facial rejuvenation. Clinicians need to understand the safety and efficacy of these new therapies in specific patient types. Acne vulgaris affects 40 to 50 million people in the United States, with a prevalence as high as 85% in teenagers. A wide range of effective treatment strategies are now available to manage acne vulgaris, and new agents continue to be developed, offering an enhanced range of options. Psoriasis is an inflammatory skin disease for which a variety of agents, including several tumor necrosis factor (TNF) inhibitors, are approved for treatment. Recently, the use of TNF inhibitors for pediatric psoriasis has been investigated, and new biosimilar agents are in late stages of development for psoriasis. Clinicians may be reluctant to use TNF inhibitors in children with psoriasis and do not yet have clinical experience with biosimilar agents. Rosacea is a common chronic skin condition affecting the face, affecting approximately 14 million Americans. No cure exists for rosacea, but health care professionals have several options to treat the symptoms, including new agents to treat facial erythema and inflammation. The use of these agents requires an understanding of their safety and use in combination therapy. Onychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Newly approved topical agents for onychomycosis and tinea have demonstrated high cure rates in clinical studies. Among the most common cosmetic procedures performed in the United States are the use of botulinum toxin A, soft tissue fillers, and laser treatments. In the last decade, a multitude of new products and devices have been developed for these indications, including new soft tissue fillers and novel laser technologies. The increased availability of options also increases the challenge of selecting the most appropriate agent or combination of agents for each patient.

Learning ObjectivesBy reading and studying this supplement, participants should be better able to:• Integrate into daily practice evidence-based recommendations on new and emerging

therapies for common and uncommon dermatologic diseases• Implement updated strategies for managing acne, rosacea, and psoriasis

• Discuss the use of biologic agents in the treatment of adult and pediatric psoriasis • Review the status of biosimilars for use in dermatology • Incorporate the recent advances in the treatment of acne vulgaris• Discuss the safety, efficacy, and dosing of antibiotics for acne vulgaris • Analyze emerging treatments for tinea and onychomycosis• Identify the considerations in the selection of appropriate filler agents for treating

different areas of the face• Compare and contrast the efficacy and safety of agents, devices, and techniques

currently available in aesthetic and procedural dermatology• Determine the appropriate nonsurgical techniques for facial rejuvenation• Describe the appropriate use of neuromodulators in the treatment of the aging face. Disclosure DeclarationsIndividuals in a position to control the content of this educational activity are required to disclose: 1) the existence of any relevant financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients with the exemption of non-profit or government organizations and non-health care related companies, within the past 12 months; and 2) the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

Faculty Joseph F. Fowler, Jr, MD, Consultant: Bayer Healthcare, Galderma Laboratories, L.P., GlaxoSmithKline, Johnson & Johnson, Medimetriks Pharmaceuticals, Inc., Ranbaxy Laboratories Ltd., SmartPractice Dermatology/Allergy, Valeant Pharmaceuticals North America LLC; Speakers Bureau: Galderma, SmartPractice, Valeant; Grant/Research Support: AbbVie Inc., 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., ValeantTheodore Rosen, MD, Scientific Advisory Board: Anacor Pharmaceuticals, Inc., Merz Pharma North America Inc., ValeantJeffrey M. Sobell, MD, Grant/Research Support: Amgen, Celgene, Eli Lilly, Janssen, Merck, Novartis; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Janssen; Speakers Bureau: AbbVie, Amgen, Celgene, Janssen, NovartisNowell Solish, MD, FRCP(C), Consultant/Grant/Research Support: Allergan, Galderma, Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., ValeantLinda F. Stein Gold, MD, Consultant and Scientific Advisory Board: Anacor, Bayer, Eli Lilly, Foamix Pharmaceuticals Inc., Galderma, LEO Pharma Inc., Medimetrix Pharmaceuticals, Inc., Novartis, Pfizer, TaroChristopher B. Zachary, MBBS, FRCP, Consultant: Kythera Biopharmaceuticals, Inc., Sciton, Inc., Solta Medical; Scientific Advisory Board: Sciton and ZELTIQ Aesthetics, Inc.In order to help ensure content objectivity, independence, and fair balance, and to ensure that the content is aligned with the interest of the public, CCOE has resolved all potential and real conflicts of interest through content review by a non-conflicted, qualified reviewer. This activity was peer-reviewed for relevance, accuracy of content, and balance of presentation by: Jean C. Sines, RN, BSN, Staff Nurse, Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. Ms. Sines has no relevant financial relationships to disclose. Field Testers: This activity was pilot-tested for time required by: Physicians: Brian Lee, MD, Sima Patel, DO, and Vijay Vanchinathan, MD. Nurses: Geraldine Bocchieri, RN, BSN, Kathleen Brown, LPN, and Stacy Johnson, RN. The field testers have no relevant financial relationships to disclose.

Rutgers, The State University of New Jersey: Tristan Nelsen, MNM, CMP, and Elizabeth Ward, MSJ, have no relevant financial relationships to disclose.

Global Academy for Medical Education Staff: Shirley V. Jones, MBA; Sylvia H. Reitman, MBA, DipEd; and Josh Kilbridge have no relevant financial relationships to disclose.

Off-Label/Investigational Use DisclosureThis activity discusses the off-label use of the following approved agents: adalimumab, cyclosporine ophthalmic emulsion, doxycycline, etanercept, fluconazole, isotretinoin, itraconazole, ketoconazole, methotrexate, minocycline (oral and foam), secukinumab, ustekinumab, and tumor necrosis factor inhibitors as a class.

This continuing medical education (CME/CE) supplement was developed from faculty presentations at the Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar™, February 14-19, 2016. The Guest Editors/Faculty acknowledge the editorial assistance of Global Academy for Medical Education, LLC, and Josh Kilbridge, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery for publication as a supplement to the journal. This activity was developed under the direction of the Faculty/Guest Editors, Global Academy for Medical Education, and Rutgers. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, Rutgers, or the Publisher.

Kenneth A. Arndt, MDClinical Professor of Dermatology, Emeritus Harvard Medical School Adjunct Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Adjunct Professor of Dermatology Brown Medical School Providence, Rhode Island

EDITORS

Philip E. LeBoit, MDProfessor of Clinical Dermatology University of California, San Francisco San Francisco, California

Bruce U. Wintroub, MDAssociate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California

STATEMENT OF PURPOSESeminars in Cutaneous Medicine and Surgery presents well-rounded and authoritative discussions of important clinical areas, especially those undergoing rapid change in the specialty. Each issue, under the direction of the Editors and Guest Editors selected because of their expertise in the subject area, includes the most current information on the diagnosis and management of specific disorders of the skin, as well as the application of the latest scientific findings to patient care.

Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is published quarterly by Frontline Medical Communications Inc., 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue are March, June, September, and December. Periodicals postage paid at Parsippany, NJ, and additional mailing offices.

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The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily reflect those of the Editors or Publisher. Publication of an advertisement or other product mention in Seminars in Cutaneous Medicine and Surgery should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the products mentioned. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient.

Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/MEDLINE.

Theodore Rosen, MDProfessor of DermatologyBaylor College of MedicineHouston, Texas

GUEST EDITORS

June 2016, Vol. 35, No. 6S

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar

TABLE OF CONTENTS

S103 Introduction Joseph F. Fowler, Jr, MD Christopher B. Zachary, MBBS, FRCP

S104 Update on TNF Inhibitors in Dermatology

Jeffrey M. Sobell, MD

S107 Facial Dermatitis and Rosacea Joseph F. Fowler, Jr, MD

S110 Tinea and Onychomycosis Theodore Rosen, MD

S114 Acne: What’s New Linda F. Stein Gold, MD

S117 Fillers: What’s Here and What’s Ahead

Nowell Solish, MD, FRCP(C)

S120 The Aging Face: Global Approach With Fillers and Neuromodulators


S122 Facial Rejuvenation: 40th Anniversary Review

Christopher B. Zachary, MBBS, FRCP

S125 Post-Test and Evaluation Form

Jeffrey M. Sobell, MDAssistant Professor of DermatologyTufts University School of MedicineDirector, Psoriasis Treatment Center SkinCare Physicians Chestnut Hill, Massachusetts

Joseph F. Fowler, Jr, MDClinical Professor of DermatologyUniversity of LouisvilleLouisville, Kentucky

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

Christopher B. Zachary, MBBS, FRCPProfessor and ChairDepartment of DermatologyUniversity of California, IrvineIrvine, California

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

Vol. 35, No. 6S, June 2016, Seminars in Cutaneous Medicine and Surgery S103

Vol. 35, No. 6S, June 2016

INTRODUCTION

Dermatology 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 needs 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 hidradenitis 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 antimicrobial peptides called cathelicidins. 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 Drug 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.

1085-5629/13/$-see front matter © 2016 Frontline Medical Communications doi:10.12788/j.sder.2016.032

Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey, and Global Academy for Medical Education, LLC, with Skin Disease Education Foundation (SDEF) and is supported by educational grants from AbbVie Inc., Bayer Healthcare, Merz Pharma North America Inc., and Valeant Pharmaceuticals North America LLC.

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]

Joseph F. Fowler, Jr, MDClinical Professor of Dermatology

University of LouisvilleLouisville, Kentucky

Skin Disease Education Foundation Director Medical Dermatology

Christopher B. Zachary, MBBS, FRCPProfessor and Chair

Department of DermatologyUniversity of California, Irvine

Irvine, California

Tumor necrosis factor (TNF) inhibitors have been approved for the treatment of adult patients with psoriasis for a dozen years, starting with etanercept and followed by infliximab

and adalimumab. Current evidence also suggests that TNF inhibitors can be safe and effective for pediatric patients, and new biosimilars are also in late stages of development. Finally, the TNF inhibitor adalimumab was recently approved for a new dermatologic indication, hidradenitis suppurativa.

Pediatric Psoriasis Psoriasis is relatively common in the pediatric population. For example, approximately 40% of adults with psoriasis report onset during childhood.1 The use of etanercept for pediatric psoriasis was initially evaluated in a phase III trial (n=211) that included a 12-week double-blind treatment period, followed by 24 weeks of open-label treatment and a 12-week double-blind withdrawal period.2 Enrolled subjects were aged 4 to 17 years and had moderate to severe psoriasis. Etanercept dosing was weight based (0.8 mg/kg once weekly). At week 12, among subjects treated with etanercept, 57% had at least 75% improvement on the Psoriasis Area Severity Index (PASI 75), and 27% had at least

90% improvement (PASI 90) (compared to 11% and 7% with placebo, respectively; P<0.0001, both comparisons). Tolerability of the study drug was good, although there was an increase in infections (47.2%, etanercept vs 31.4%, placebo). No serious infections were reported at week 12. A 5-year extension study demonstrated stable response rates over long-term use, with PASI 75 rates approximately 60% and PASI 90 rates approximately 30%.3 Safety results were also stable over time, with no incidence of malignancy or opportunistic infections and only one serious infection related to the study drug during the 5-year period.

Adalimumab has also been evaluated in a phase III trial for pediatric psoriasis.4 This active-control study randomized 114 children aged 4 to 17 years with moderate to severe psoriasis to treatment with adalimumab (0.8 mg/kg biweekly or 0.4 mg/kg biweekly, maximum dose 40 mg biweekly) or methotrexate (0.1-0.4 mg/kg weekly). After the initial 16-week treatment period, all PASI 75–achieving subjects discontinued study drugs and were retreated with adalimumab for 16 weeks if their psoriasis recurred. Subjects were then followed for 1 year of open-label therapy. Of note, 14.9% of subjects were overweight and 21.1% were obese. After the initial 16-week treatment period, 57.9% of subjects in the adalimumab 0.8 mg/kg group achieved PASI 75, compared to 32.5% of the methotrexate group (P=0.027 vs methotrexate). The study drugs were well tolerated, with only one serious infection reported. Of subjects whose disease recurred following treatment discontinuation, PASI 75 recapture rates after 16 weeks of retreatment were 54.5% (adalimumab 0.4 mg/kg) to 78.9% (adalimumab 0.8 mg/kg).5

New Biologics for Adults With Psoriasis Certolizumab pegol is a humanized antigen-binding fragment (Fab′) of a monoclonal antibody to TNF-α, conjugated to poly-ethylene glycol. This approach stabilizes and extends the half-life of the molecule. In a phase II study, 176 subjects with moderate to severe psoriasis were randomized to certolizumab pegol (200 or 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 to 7% of the placebo group (P<0.001, both comparisons). Safety outcomes were consistent with previous studies in other indications. Large phase III trials are currently under way to demonstrate the efficacy of certolizumab pegol in adults with psoriasis. The agent is approved by the US Food and Drug Administration (FDA) for use in psoriatic arthritis but not for psoriasis.

Biosimilars Biosimilars are biologic agents currently in development for a variety of indications. Biosimilars are similar, but not identical, versions of currently approved biologic drugs. They have iden-tical amino acid sequences to the original biologic but differ in post-translational modifications and production processes.7 The FDA requires that these biologic agents have no clinically mean-ingful differences in terms of safety, purity, and potency from the approved agent they emulate. Currently, biosimilars in devel-opment for psoriasis include agents biosimilar to etanercept, infliximab, and adalimumab.

n AbstractEmerging data describe new potential indications for tumor necrosis factor (TNF) inhibitors in dermatology, including pediatric psoriasis and hidradenitis suppurativa. New biosimilar TNF agents are in late stages of development and may be available in the United States in the near future. Biosimilar agents are similar but not identical to available TNF inhibitors, and approval requires extensive analytic, toxicity, pharmacokinetic, pharmacodynamic, and clinical testing.Semin Cutan Med Surg 35(supp6):S104-S106 © 2016 published by Frontline Medical Communications

n Keywords Biosimilars; hidradenitis suppurativa; pediatric psoriasis; psoriasis; TNF inhibitors

Update on TNF Inhibitors in Dermatology Jeffrey M. Sobell, MD*

* Assistant Professor of Dermatology, Tufts University School of Medicine; Director, Psoriasis Treatment Center, SkinCare Physicians, Chestnut Hill, Massachusetts


Dr Sobell has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Jeffrey M. Sobell, MD: Grant/Research Support: Amgen Inc., Celgene Corporation, Eli Lilly and Company, Janssen Biotech, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Janssen; Speakers Bureau: AbbVie, Amgen, Celgene, Janssen, Novartis.

Address reprint requests to: Jeffrey M. Sobell, MD, Tufts University School of Medicine, 145 Harrison Ave, Boston, MA 02111, [email protected]

S104 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 6S, June 2016© 2016 Frontline Medical Communications 1085-5629/13/$-see front matter

doi:10.12788/j.sder.2016.033

To demonstrate biosimilarity, companies must complete exten-sive analytic testing, toxicity studies in animals, pharmacokinetic and pharmacodynamic studies in humans, and clinical trials to evaluate efficacy, safety, and immunogenicity. Examples in development for psoriasis include GP2015 (etanercept), CT-P13 (infliximab), and ABP 501 (adalimumab). Preclinical studies illustrate the high degree of similarity between GP2015 and etan-ercept originator (Table).8 A phase III trial with GP2015 has been completed, but results have not been reported.

CT-P13, a biosimilar to infliximab, has been evaluated in two randomized studies—one in ankylosing spondylitis and one in rheumatoid arthritis.9 The agent is approved in Europe and Canada, and most recently in the United States. One interesting aspect of biosimilar development is extrapolation of indica-tions, by which biosimilars, when approved, may receive the same indications as the original biologic. This extrapolation is just one of several controversies regarding biosimilar develop-ment and approval.

ABP 501 is a biosimilar to adalimumab. In preclinical testing, ABP 501 demonstrated nearly identical pharmacokinetics to adalimumab originator in healthy subjects,10 and a multicenter phase III trial demonstrated equivalent clinical efficacy and safety to adalimumab over 16 weeks.11

Immunogenicity is an important consideration with all biologic agents, including biosimilars. Adalimumab, as well as other TNF inhibitors, has been associated with the develop-ment of neutralizing anti-drug antibodies, which may impact efficacy in clinical practice. The immunogenicity of ABP 501 was evaluated in the phase III trial and found to be similar to adalimumab. Through week 16, the proportion of subjects developing anti-drug antibodies was 55.2% with ABP 501 and 63.6% with adalimumab originator.11

The availability of biosimilars in the United States awaits expi-ration of patent protection for individual agents. Once they do become available, clinicians will face many questions, including which patients to prescribe them for (eg, new patients, switching patients from their current drug) and whether the biosimilars are clinically interchangeable with existing TNF inhibitors.

Hidradenitis SuppurativaHidradenitis suppurativa (HS) is a relatively rare chronic skin disease characterized by painful, recurrent inflamma-tory abscesses affecting areas of the body containing apocrine glands.12,13 The disease has a prevalence of approximately 1% in the general population, with a mean onset at age 22 years and a 3:1 female to male predominance. Unfortunately, the mean delay before accurate diagnosis is 12 years, highlighting the risk for misdiagnosis and inappropriate treatment.13-16

Risk factors associated with HS include smoking (odds ratio [OR], 12.55) and obesity (OR, 4.42), although no causal relation-ship to HS has been demonstrated. Known causal risk factors include mechanical triggers (eg, friction), certain medications (eg, lithium), and, possibly, hormonal factors, although data describing the influence of hormones on HS are conflicting.13,17-19 The diagnosis of HS is clinical and requires 3 criteria: typical lesions (deep-seated nodules, abscesses, and/or fibrosis), typical anatomic location (axillae and inguinocrural regions), and relapses.20 Severity is graded using the Hurley stages (Figure).18,21

HS can have a tremendous impact on patients’ quality of life, especially in more severe disease, and is often associated with important comorbidities such as depression and meta-bolic syndrome.22-24 Because cytokine levels, including TNF-α, are elevated in the lesions of HS,25 researchers evaluated the safety and efficacy of the TNF inhibitor adalimumab.26 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 week 2, and 40 mg weekly thereafter) or placebo. After 12 weeks, adalimumab was associated with significantly greater HS clin-ical response compared to placebo (PIONEER I: 41.8% vs 26%, P<0.01; PIONEER II: 58.9% vs 27.6%, P<0.001). Improvements were sustained for up to 72 weeks of follow-up.26 Adalimumab was associated with a similar, low incidence of serious side effects as placebo. Based on these studies, adalimumab is the first medi-cation specifically approved by the FDA for the treatment of HS.

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 similar to but not identical to available TNF inhibitors, may also soon be available, depending on duration of patent protec-tion and other factors. Finally, HS is a rare but serious skin condition that significantly affects patients’ quality of life and normal function. Based on strong phase III data, adalimumab is now indicated for the treatment of patients with HS.


Jeffrey M. Sobell, MD

n TABLE Biosimilars: Extensive Testing at Preclinical Level

Biosimilars must match originators across multiple quality attributes

For monoclonal antibodies, typically >40 different methodologies are applied, analyzing more than 100 different quality attributes

Primary structures

• LC-MS intact mass

• LC-MS subunits

• Peptide mapping

Higher-order structures

• NMR

• CD spectroscopy

• FT-IR

• X-ray

Impurities

• CEX, c/EF acidic/basic variants LC glycation

• Peptide mapping deamination, oxidation, mutation, glycation

• SEC/FFF/AUC aggregation

Post-translational modification

• NP-HPLC-(MS) N-glycans

• AEX N-glycans

• MALDI-TOF N-glycans

• HPAEC-PAD N-glycans

• MALDI-TOF O-glycans

• HPAEC-PAD sialic acids

• RP-HPLC sialic acids

Biological activity

• Binding assay

• ADCC assay

• CDC assay

Combination of attributes

• MVDA, mathematical algorithms

Source: Da Silva A, et al. EADV 2013: P0304. Key?

References1. Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis. Dermatol

Ther. 2004;17:364-375.2. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and

adolescents with plaque psoriasis. N Engl J Med. 2008;358:241-251.3. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etan-

ercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74:280-287.e3.

4. Papp KA, Thaci D, Marcoux D, Weibel L, Unnebrink K, Williams DA. Efficacy and safety of adalimumab versus methotrexate treatment in pediatric patients with severe chronic plaque psoriasis: Results from the 16-week randomized, double-blind period of a phase 3 study. Presented at: 23rd World Congress of Dermatology; June 8-13, 2015; Vancouver, Canada.

5. Philipp S, Ghislain PD, Landells I, Unnebrink K, Williams DA. Efficacy, safety of adalimumab vs methotrexate in pediatric patients with severe placque psoriasis: Results from the treatment withdrawal and double-blind retreatment periods of a phase 3 study. Presented at: 23rd World Congress of Dermatology; June 8-13, 2015; Vancouver, Canada.

6. Reich K, Ortonne JP, Gottlieb AB, et al. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab′ certolizumab pegol: Results of a phase II randomized, placebo-controlled trial with a re-treatment extension. Br J Dermatol. 2012;167:180-190.

7. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91:405-417.

8. Da Silva A, Kronthaler U, Fritsch C, et al. Target-directed development of a proposed etanercept biosimilar, GP2015: Comparability of an in vitro target binding and neutraliazation, and in vivo efficacy and pharmacokinetics with the reference product etanercept at the pre-clinical level. Presented at 22nd Congress of the European Association of Dermatology and Venereology; October 2-6, 2013; Istanbul, Turkey, P0304.

9. McKeage K. A review of CT-P13: An infliximab biosimilar. BioDrugs. 2014;28:313-321.

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.

16. Palmer RA, Keefe M. Early-onset hidradenitis suppurativa. Clin Exp Dermatol. 2001;26:501-503.

17. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associ-ated with hidradenitis suppurativa: Results from two case-control studies. J Am Acad Dermatol. 2008;59:596-601.

18. Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: A comprehensive review. J Am Acad Dermatol. 2009;60:539-561.

19. Yazdanyar S, Jemec GB. Hidradenitis suppurativa: A review of cause and treat-ment. Curr Opin Infect Dis. 2011;24:118-123.

20. Poli F, Jemec GBE, Revuz J. Clinical presentation. In: Jemec GBE, Revus J, Leyden JJ, eds. Hidradenitis Suppurativa. Heidelberg, Germany: Springer; 2006:11-24.

21. Ducroux E, Ocampo MA, Kanitakis J, et al. Hidradenitis suppurativa after renal transplantation: Complete remission after switching from oral cyclosporine to oral tacrolimus. J Am Acad Dermatol. 2014;71:e210-e211.

22. Matusiak Ł, Bieniek A, Szepietowski JC. Hidradenitis suppurativa mark-edly decreases quality of life and professional activity. J Am Acad Dermatol. 2010;62:706-708.e1.

23. Matusiak Ł, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol. 2010;90:264-268.

24. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7:e31810.

25. van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: A rationale for targeting TNF-α and IL-1β. Br J Dermatol. 2011;164:1292-1298.

26. Kimball A, Jemec G, Armstrong A, Forman SB, Gu Y, Williams DA. Evaluating optimal medium-term dosing strategy for adalimumab in patients with moderate-to-severe hidradenitis suppurativa based on analysis of integrated results from the PIONEER I and II phase 3, randomized, placebo-controlled trials. Presented at: 73rd Annual Meeting of the American Academy of Dermatology; March 20-24, 2015; San Francisco, CA.

S106 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 6S, June 2016

n n n Update on TNF Inhibitors in Dermatology

■ FIGURE Staging of Hidradenitis Suppurativa Using the Hurley Stages.18,21

Source: Photos courtesy of Robert G. Micheletti, MD.

Single or multiple abscesses without cicatrization and sinus tracts

One or more widely separated recurrent abscesses, with tract formation and scars

Multiple interconnected tracts and abscesses throughout an entire area

I. II. III.

1085-5629/13/$-see front matter © 2016 Frontline Medical Communications doi:10.12788/j.sder.2016.034

Rosacea is a common, chronic skin disorder associated with manifestations such as flushing, erythema, dryness, burning and stinging, and inflammatory papules and

pustules.1 Although the pathophysiology of rosacea is not well understood, chronic inflammation and vascular changes are believed to be central to the disease process.2 Evidence also suggests that a family of antimicrobial peptides called cathelici-dins contributes to the pathogenesis of rosacea. New therapies provide additional options for the treatment of patients with these inflammatory conditions. These treatments target the inflammatory, erythematous, and/or antimicrobial components of the disease.

Treating Erythema A new topical agent approved for the treatment of erythema in rosacea is brimonidine, a selective α2 receptor agonist. The α2 receptors are the predominant mechanism for vasoconstriction in the cutaneous vasculature, in contrast to α1 receptors, which mediate vasoconstriction in the large, central vessels. Brimonidine is 1,000-fold more selective for α2 receptors than α1 receptors.3 Promoting vasoconstriction addresses the neurovascular compo-nent of rosacea and alleviates flushing and redness. In initial clinical trials, brimonidine produced significantly greater reduc-tions in erythema compared to vehicle (P<0.001), with similar, low rates of adverse events.4 The onset of action of brimonidine is rapid in many patients; response is noted within 30 minutes of application in a substantial proportion of patients.5

Concern about a potential rebound effect following admin-istration of brimonidine6 prompted evaluation of clinical trial data to detect worsening of erythema.7 Overall, mean changes in erythema scores were reduced compared to vehicle at weeks 6 and 8 of treatment, although a few subjects in the active treatment group showed worsening in scores during the follow-up period relative to baseline (1.6%-4.7% of brimonidine subjects across scales and time points). A 1-year, open-label safety trial evalu-ated approximately 345 subject-years of exposure to brimonidine tartrate gel 0.5%.8 The incidence of adverse events related to study drug decreased over the course of the study, and no tachyphylaxis was observed. The authors concluded that the agent was safe and provided consistent efficacy over long-term use. However, several post-marketing case reports described a rebound of erythema or allergic contact dermatitis associated with brimonidine use.6,9,10 In these cases, patients initially responded to brimonidine with reductions in erythema, followed by an increase in erythema.

The take-home message from these studies and case reports is that treatment with brimonidine is safe in the majority of patients and will not lead to a worsening of rosacea over time. But a minority of patients may have increased redness a day after treatment. This effect may be transient, lasting a day or two, and patients can keep using the drug to treat erythema. Alternatively, the drug can be discontinued for a few days and reintroduced to determine if the patient is experiencing allergic contact dermatitis.

Other topical agents in development for the treatment of facial erythema include oxymetazoline and low-molecular-weight hyaluronic acid. Neither agent has yet been approved for the treatment of rosacea.

Treating Inflammation One limitation of brimonidine is that it does not treat the inflam-matory component of rosacea, for which an additional medication will be required. Two new topical agents are now available for the treatment of inflammatory components of rosacea: ivermectin cream 1% and azelaic acid foam 15%.

Ivermectin has been used to eradicate parasites in humans and animals, and its mechanism of action in rosacea might include

n AbstractRosacea is a chronic skin disorder associated with flushing, erythema, dryness, burning and stinging, and inflammatory papules and pustules. New treatments available or in development target the inflammatory and erythematous components of the disease. These agents include the selective α2 receptor agonist brimonidine, the topical agents ivermectin cream 1% and azelaic acid foam 15%, and use of tetracycline-type antibiotics, which affect the cathelicidin pathway. Semin Cutan Med Surg 35(supp6):S107-S109 © 2016 published by Frontline Medical Communications

n Keywords Azelaic acid; brimonidine; cathelicidin; ivermectin; rosacea

Facial Dermatitis and RosaceaJoseph F. Fowler, Jr, MD*

* Clinical Professor of Dermatology, University of Louisville, Louisville, Kentucky


Dr Fowler has received an honorarium for his participation in this activity. He acknowledges 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 Healthcare, 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.

Address reprint requests to: Joseph F. Fowler, Jr., MD, 3100 Boxhill Lane, Louisville, KY, 40222; 502-583-7546 [email protected]


activity against the Demodex mite, which some investigators believe contributes to rosacea.11 However, ivermectin also has anti-inflammatory properties. The agent decreases both cellular and humoral immune responses, including regulation of pro-inflammatory cytokines.12-14 In a pair of 12-week, phase III trials, daily use of ivermectin 1% cream was associated with signifi-cantly greater reductions in inflammatory lesions compared to vehicle, starting at week 2 (P<0.05) and continuing through week 12 (P<0.001).15 At 12 weeks, a greater proportion of patients achieved treatment success (clear or almost clear) in the iver-mectin group (38.4%-40.1% vs 11.6%-18.8%; P<0.001, both comparisons). Safety outcomes were comparable between groups.

Extension studies demonstrated maintained efficacy and safety over long-term treatment; at 40 weeks, approximately 70% of subjects treated with ivermectin were clear or almost clear.16 Ivermectin also appears to outperform the established agent, metronidazole, for the treatment of rosacea. A phase III study randomized 962 subjects with papulopustular rosacea to iver-mectin 1% cream every day or metronidazole 0.75% cream.17 At 16 weeks, ivermectin produced greater reductions in inflammatory lesions (83.9% vs 73.7%; P<0.001) and a higher rate of treatment success (84.9% vs 75.4%; P<0.001) compared with metronidazole. Tolerability was similar between groups, with better local toler-ability for ivermectin.

Azelaic acid foam 15% was evaluated in two parallel phase III studies in 961 subjects with moderate to severe papulopustular rosacea.18 At 16 weeks, the success rate (clear or almost clear) was significantly greater with azelaic acid compared to vehicle (30.8% vs 23.8%; P=0.025). Decreases in mean inflammatory lesion counts were also greater with azelaic acid foam compared to vehicle (−13.5 vs −9.5; P<0.001). Azelaic acid was associated with numerically higher rates of local adverse effects (eg, applica-tion-site pain, 4.5%), but tolerability was not statistically different between groups.

The Cathelicidin PathwayMounting evidence suggests that a family of antimicrobial peptides produced in the skin called cathelicidins may be impor-tant in the pathogenesis of rosacea. These peptides are important in the normal immune defense against bacteria and some viruses, and also act as inflammatory mediators.19,20 Increased levels of cathelicidins promote tissue responses that resemble the histo-pathologic features of rosacea, including increased leukocyte infiltration and angiogenesis. It may be that cathelicidin peptides are overexpressed in rosacea, as illustrated in the Figure.19,20

Initial studies examined the effect of tetracycline-type antibi-otics on the cathelicidin pathway, and findings suggested an effect mediated by inhibition of matrix metalloproteinases.21 This inhib-itory effect appears to be strongest with doxycycline compared to minocycline or tetracycline.22 Importantly, clinical studies of doxycycline in rosacea have demonstrated similar reductions in inflammatory lesions with antimicrobial (100 mg) and subanti-microbial (40 mg) doses, meaning that use of this antibiotic at low doses can be effective without increasing risk for selection of resistant bacteria.23

Corticosteroids in Rosacea Corticosteroids are highly potent agents with a myriad of poten-tial side effects. Side effects of topical corticosteroids include atrophy and telangiectasia, which may be confused with the underlying disease and can be irreversible. Because of these side effects, use of corticosteroids for rosacea and other facial inflam-matory conditions should be limited to the shortest possible duration and lowest effective dose. Nevertheless, some patients may be using topical corticosteroids for chronic disease manage-ment. Discontinuing corticosteroids in these patients can be a challenge, as symptoms may flare when patients stop applying the agent. Some patients may be able to tolerate the burning and other symptoms, but most will require some kind of additional agent to facilitate discontinuation. For example, topical calcineurin inhibitors may be used while the corticosteroid is tapered and eventually discontinued. Prescription moisturizers may also help minimize symptoms. Finally, low-dose doxycycline (ie, 40 mg) may be considered for its anti-inflammatory effects.

In summary, the treatment of rosacea may include agents targeting erythema, inflammation, and the cathelicidin pathway. Brimonidine is approved for the treatment of erythema in rosacea and is safe and effective in most patients, although some may develop a rebound of redness following treatment. New anti-inflammatory agents available for rosacea include ivermectin and azelaic acid, both of which have demonstrated efficacy in clinical trials. Finally, agents targeting the cathelicidin pathway, such as tetracycline-family antibiotics, have also demonstrated efficacy in rosacea.

References1. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: A

chronic vascular and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20:623-629.

2. Del Rosso JQ. Advances in understanding and managing rosacea: Part 1: Connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012;5:16-25.

3. Piwnica D, Rosignoli C, de Ménonville ST, et al. Vasoconstriction and anti-inflammatory properties of the selective α-adrenergic receptor agonist brimonidine. J Dermatol Sci. 2014;75:49-54.

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 of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166:633-641.


■ FIGURE Pathways of Cathelicidin-Mediated Inflammation in Normal Skin and Rosacea.19,20

*KLK5 is also known as SCTE (stratum corneum tryptic enzyme)

Cathelicidin PrecursorNormal

KLK5*-mediated processing

• Angiogenic• Bactericidal• Chemotactic

Rosacea

Pro-inflammatory activities(chemotatic and angiogenic)

LL-37 andvariant peptides

KLK5*

LL-37

Effective innate immunity Chronic in

flam

ma

tion

n n n Facial Dermatitis and Rosacea

Joseph F. Fowler, Jr, MD


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 cell 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 down-regulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase 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 enzymes 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 matrix metalloproteinase activity in diabetes: 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.

Onychomycosis is a common fungal infection affecting the nails. In the general population, the prevalence of onychomycosis is low—about 4% in one systematic

review1—but the prevalence is much higher in certain popula-tions, such as elderly patients (16%), those with diabetes (14%), psoriasis (16%), or human immunodeficiency virus (11%), or those receiving dialysis (14%) or renal transplant (7%). It is espe-cially important in immunosuppressed or immunocompromised patients, who may harbor unusual fungal species (eg, saprophytes rather than dermatophytes). Onychomycosis may be considered a cosmetic problem by many clinicians, but the condition can lead to pedal pain and breaks in the skin that both facilitate lower extremity cellulitis and allow for exposure of the bloodstream to infectious fungal agents.

The diagnosis of onychomycosis is typically performed through microscopy with potassium hydroxide (KOH) preparation, histo-pathologic analysis with periodic acid–Schiff (PAS) staining, and/or fungal culture.2 The PAS technique is generally considered the most sensitive of these tests (88%-93% sensitivity in one study).2 However, the most sensitive test for diagnosis of onychomycosis is polymerase chain reaction (PCR), and commercial PCR kits are available for this purpose in some industrialized countries. PCR can be adjusted to identify specific fungal species and has

demonstrated strong sensitivity (83%), specificity (84%), and posi-tive (71%) and negative (91%) predictive values.3-5 However, PCR cannot differentiate viable from nonviable fungi; in other words, PCR is a sensitive method for diagnosis but a poor method to confirm cure. Following treatment, only culture can confirm the absence of viable fungi.

Treatment of Onychomycosis Treatments for onychomycosis include topical and oral medi-cations, as well as nonpharmacologic approaches. Available approved topical agents include ciclopirox, efinaconazole, and tavaborole. New options are now available for the treatment of onychomycosis.

Outcomes typically reported by studies of antifungal treatment include mycological cure (negative culture and KOH), complete cure (absence of clinical sign plus mycological cure), and “almost complete cure,” in which there remains ≤5% to 10% residual nail abnormality.6,7 Reported rates of complete cure often appear to be relatively low because of the need for absence of clinical signs. For this reason, many studies (and product labels) cite the second outcome of almost complete cure. Furthermore, microscopic analysis may conflict with clinical findings or culture results. This relationship was demonstrated by a review of seven international trials, in which 78.7% of 2,360 culture-negative samples remained positive by KOH analysis.8 Morphologic analysis of these samples identified hyphal breakage or distortion in a majority of the samples, suggesting that the fungi were nonviable.

Older agents approved for onychomycosis include the oral agents terbinafine and itraconazole and the topical agent ciclopirox. Two new topical agents have been approved for onychomycosis: efinaconazole and tavaborole. Efinaconazole is an azole-class drug that interferes with ergosterol biosynthesis by blocking lanosterol demethylase. Tavaborole is a boron-containing compound with a novel mechanism of action. The agent interferes with protein synthesis by blocking the formation of leucine transfer RNA.9 In vitro analysis of these compounds demonstrates a wide range of minimum inhibitory concentrations (MICs) for different organisms (Table 1).10 Of course, it should be noted that in vitro fungal susceptibilities do not always correlate with in vivo efficacy.

Of note, efinaconazole has excellent in vitro activity against both dermatophytes (the most common organisms in onychomycosis) and some saprophytes. The MICs for tavaborole are higher overall, but it must be kept in mind that in vitro susceptibility does not reli-ably predict clinical effect, and tavaborole demonstrates sufficient MIC for clinical efficacy. Furthermore, reliable standards for MIC for dermatophytes have not yet been firmly established.9

Cure rates as reported in product labels and key clinical trials are illustrated in Table 2.11-20 These data must be interpreted with caution, as they do not represent head-to-head trials, and differences in trial designs (eg, subject demographics, degree of nail involvement, allowable trimming practices) may also influ-ence outcomes.

n AbstractOnychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Two newly approved topical agents for onychomycosis are efinaconazole and tavaborole, both of which have demonstrated respectable cure rates in clinical studies. For tinea pedis, naftifine 2% and luliconazole 1% are new agents, both administered for relatively short courses, that may foster greater adherenceSemin Cutan Med Surg 35(supp6):S110-S113 © 2016 published by Frontline Medical Communications

n Keywords Efinaconazole; luliconazole; naftifine; onychomycosis; tavaborole; tinea pedis

Tinea and OnychomycosisTheodore Rosen, MD*

* Professor of Dermatology, Baylor College of Medicine, Houston, Texas


Dr Rosen has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Theodore Rosen, MD: Scientific Advisory Board: Anacor Pharmaceuticals, Inc., Merz, Valeant.

Address reprint requests to: Theodore Rosen, MD, 1977 Butler Blvd, Suite E6.200, Houston, TX 77030; [email protected]

S110 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 6S, June 2016© 2016 Frontline Medical Communications 1085-5629/13/$-see front matter

doi:10.12788/j.sder.2016.035


Both of the new topical agents have good penetration (including through nail polish) and are formulated to promote spreading into lateral nail folds and under the nail bed. Both are also well tolerated.16-20 Limitations of available data for these agents include treatment duration, degree of nail involvement, amount of subungual debris, and nail thickness. The pivotal studies for these agents lasted 48 weeks, and long-term treatment may be required to achieve reported results. Older patients may require even longer duration of therapy, as nail growth slows with age, possibly requiring 12 to 18 months for the toenail to grow out. Also, nails in these studies had 20% to 60% involvement and did not extend to the matrix; cure rates and/or treatment duration may differ in nails with greater involvement. Finally, patients with large amounts of subungual debris or thick nails were not included in these studies.16-20

Early Intervention Recent studies suggest advantages to early intervention. Efinaconazole, for example, was more effective when used to treat early disease (<1 year duration) compared with longer durations of disease (1-5 years or >5 years).21 Many dermatologists may delay treatment of onychomycosis in patients with more serious comorbid conditions that require attention, but these data suggest that delaying therapy will ultimately make the condition even harder to treat. Finally, a post hoc analysis of two efinaconazole studies demonstrated that treatment of concomitant tinea pedis significantly increased complete cure rates for onychomycosis.22

This finding is logical, as fungi on the skin of the foot can easily colonize the nails, even following treatment for onychomycosis. Thus, eradication of a fungal reservoir on the pedal skin should promote better results when treating affected nails.

Other Agents and Therapies for Onychomycosis Additional approaches to the treatment of onychomycosis include lasers, photodynamic therapy, electrically generated plasma, nail drilling, and posaconazole. The mechanism of action of laser therapy remains unknown, but studies have demonstrated suffi-cient effectiveness to support the approval of several devices.23 However, the improvements demonstrated to date are modest and may not be durable. Accordingly, lasers are currently approved only for temporary cosmetic improvement of onychomycosis.23 Other physical modalities remain investigational.

Posaconazole is an azole antifungal indicated for the prophy-laxis of invasive Aspergillus and Candida infections in severely immunocompromised patients and for oropharyngeal candi-diasis.24 The agent has high potency and a broad spectrum of coverage. In a phase II trial, subjects treated with posaconazole demonstrated significantly greater rates of complete cure at 48 weeks compared to subjects treated with placebo and at least comparable to those treated with terbinafine.25 These results illustrate the utility of posaconazole for immunocompromised patients with onychomycosis and for patients infected with unusual organisms.

n 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

Trichophyton mentagrophytes 2–8 0.03–0.5 0.004–0.06 0.001–0.03

Trichophyton tonsurans 2–4 ≤0.5 0.25 0.016

Epidermophyton floccosum ≤0.5 0.25–0.5 0.13–0.25 ≤0.002–0.0078

Microsporum audouinii 2 1 — —

Microsporum canis 2 0.25–0.5 >4 0.13–0.25

Microsporum gypseum 2 0.25–0.5 0.063–0.13 0.0039–0.016

Nondermatophyte molds

Aspergillus fumigatus 0.25 0.25–0.50 >4 0.031–0.5

Fusarium solani ≤0.5 ≥4 >4 0.5

Yeasts

Candida albicans 1.0 0.06–0.5 ≤0.03–8 <0.0005–>0.25

Candida glabrata ≤0.5 0.13–0.5 2–>8 0.0039–0.13

Candida krusei 1 0.13–0.25 0.13–0.5 0.0078–0.063

Candida parapsilosis ≤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

Cryptococcus neoformans 0.25 ≤0.031 ≤0.016–0.13 0.002–0.0039

Malassezia furfur 1 ≤0.5 — —

Malassezia pachydermatis 1 ≤0.5 — —

Malassezia sympodialis 1 ≤0.5 — —

Source: Adapted from Gupta AK, Daigle D.10

Theodore Rosen, MD

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Recurrence Following Treatment Even following mycological cure, onychomycosis may recur. Recurrence rates vary substantially between studies and agents. For example, reported recurrence rates following mycological cure with terbinafine range from 6% to 23%, and 24% to 100% following cure with itraconazole.26-30 Tips to limit risk for recur-rence include sanitizing footwear, washing feet and changing socks frequently, using medicated powders in shoes and socks, and avoiding walking barefoot in public areas such as hotel rooms or locker rooms.31-33

Tinea PedisTinea pedis and onychomycosis commonly co-occur, and the presence of tinea pedis may increase the risk for onychomycosis, even after effective treatment. More than a dozen topical agents are available for the treatment of tinea pedis (Table 3). The newest agents are naftifine 2% and luliconazole 1%, both of which are administered every day for 2 weeks, a relatively short course of treatment that may foster greater adherence.

Cure rates with these agents are similar: high mycological cure rates (72%, naftifine; 78%, luliconazole), lower complete cure rates (25%, naftifine; 21%, luliconazole), and modest rates of “effective treatment,” defined as elimination of itching (60%, naftifine; 43%, luliconazole).34,35

In summary, effective new agents are available for onycho-mycosis and tinea pedis, but complete elimination of fungal infections is challenging, and recurrence often follows mycolog-ical cure. When managing patients with onychomycosis or tinea pedis, clinicians must be sure to identify and treat both conditions to reduce the risk for recurrence following treatment of one but not the other condition.

References1. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail

onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015;29:1039-1044.

2. Jung MY, Shim JH, Lee JH, et al. Comparison of diagnostic methods for onychomycosis, and proposal of a diagnostic algorithm. Clin Exp Dermatol. 2015;40:479-484.

3. Spesso MF, Nuncira CT, Burstein VL, Masih DT, Dib MD, Chiapello LS. Microsatellite-primed PCR and random primer amplification polymorphic DNA for the identification and epidemiology of dermatophytes. Eur J Clin Microbiol Infect Dis. 2013;32:1009-1015.

4. Kondori N, Tehrani PA, Strömbeck L, Faergemann J. Comparison of dermato-phyte PCR kit with conventional methods for detection of dermatophytes in skin specimens. Mycopathologia. 2013;176:237-241.

5. Garg J, Tilak R, Garg A, Prakash P, Gulati AK, Nath G. Rapid detection of dermatophytes from skin and hair. BMC Res Notes. 2009;2:60.

6. Gupta AK, Studholme C. How do we measure efficacy of therapy in onycho-mycosis: Patient, physician, and regulatory perspectives. J Dermatolog Treat. 2016:1-7.

7. Scher RK, Tavakkol A, Sigurgeirsson B, et al. Onychomycosis: Diagnosis and definition of cure. J Am Acad Dermatol. 2007;56(6):939-944.

n 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%

n 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

Terbinafine 1% Cream, gel, sprayOnce a day × 1–4 weeks (gel) Twice a day × 1–4 weeks (cream, spray)

Butenafine 1% Cream Once a day × 4 weeks

Oxiconazole 1% Cream, lotion Once/twice a day × 4 weeks

Naftifine 1% Cream, gelOnce a day × 4 weeks (cream) 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 nitrate 2% Cream Twice a day × 4 weeks

Ciclopirox 0.77% Cream, gel, lotion, powder, solution, suspension Twice a day × 4 weeks

Miconazole 2% Cream, gel, liquid spray, powder, solution Twice a day × 4 weeks

Clotrimazole 2% Cream, lotion, solution Twice a day × 4–8 weeks

Ketoconazole 2% Cream,gel Once a day × 6 weeks


n n n Tinea and Onychomycosis


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 antifungals: 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 Trichophyton rubrum 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 luli-conazole cream 1% once daily for 7 days in patients aged ≥12 years with tinea cruris. 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.

Theodore Rosen, MD


Acne vulgaris affects a majority of young people worldwide and is one of the most prevalent skin conditions in the general population.1 A common approach to the treatment

of moderate to severe acne is the use of antibiotics to target both Propionibacterium acnes and inflammation. However, the poten-tial for antibiotic resistance is a serious consideration. According to the Centers for Disease Control and Prevention (CDC), at least 2 million Americans become infected with resistant bacteria each year, and 23,000 die as a result of these infections.2 What does the potential for antibiotic resistance mean for the treatment of acne?

Factors that affect the risk for the development of antibiotic resistance include the dose and duration of antibiotic treatment. Finding the most effective dose, frequency, and duration of admin-istration for the treatment of acne could limit the risk for ineffective dosing or approaches that may increase the risk for the develop-ment of resistance. For example, a 12-week dose-ranging study of extended-release minocycline in subjects with moderate to severe acne (N=233) found no difference in efficacy between doses of 1, 2, or 3 mg once daily, although higher doses were associated with a higher incidence of adverse events.3 This study clearly suggests no advantage to higher doses of minocycline for the treatment of acne.

A similar 12-week dose-ranging study of doxycycline (0.6, 1, 2, or 2.4 mg/kg/day) found that only the highest dose (2.4 mg/kg/day, equivalent to approximately 160 mg/day) was statistically superior to placebo for improving acne.4 However, conflicting results were found in 2 studies looking at lower doses of doxycy-cline (ie, below antimicrobial doses), which both suggest potential efficacy for acne. A small randomized study of adults with moderate acne (N=51) compared low-dose doxycycline (20 mg twice daily) to placebo for 6 months.5 At study end, the doxycy-cline group showed significantly greater reductions in the number of comedones and inflammatory and non-inflammatory lesions compared to placebo. Treatment with low-dose doxycycline had no detectable antimicrobial effect on the cultivable skin flora and did not increase resistance to antibiotics.

A recent, larger study of subjects with moderate to severe acne (N=662) compared subantimicrobial (40 mg, modified-release) and routine (100 mg) doses of doxycycline to placebo for 16 weeks.6 The subantimicrobial dose of modified-release doxy-cycline was associated with statistically greater reduction in the mean number of inflammatory lesions compared to placebo (16.1 vs 12.6; P=0.006) and compared to doxycycline 100 mg (16.1 vs 12.9; P=0.024). Other outcomes were equivalent between doxycycline groups (and superior to placebo), such as percent reduction of total lesions and Investigator Global Assessment (IGA) success rate. These findings suggest that subantimicrobial doses of doxycycline are at least as effective as antimicrobial doses for the treatment of acne. Indeed, it may be that targeting P. acnes is not essential; rather, the anti-inflammatory effects of antibiotics may account for their efficacy in acne.

Are Antibiotics Even Necessary? Another question is whether oral antibiotics are even necessary for the successful treatment of acne. For example, a random-ized study compared oral doxycycline (100 mg once daily) with or without topical adapalene 0.1%/benzoyl peroxide 2.5%.7 Although the doxycycline monotherapy group showed improve-ment in IGA scores by 8-12 weeks, the combination group had significantly greater improvements at these time points. As illus-trated in the Figure, only 8% of subjects taking oral doxycycline monotherapy were clear or almost clear of acne by week 12, whereas adding a potent topical agent quadrupled the proportion of subjects achieving this target. Based on such data, it appears that oral antibiotics contribute to therapeutic effect but have limited utility as monotherapy.

The Risks of Tapering Antibiotics Tapering of antibiotics used for the treatment of acne has been routinely used in clinical practice. However, evidence indicates that there is no need to taper antibiotics. Studies of combina-tion therapy with oral antibiotics and topical agents show that efficacy is maintained in a significant number of patients when the antibiotic is discontinued after 3 months, while the topical agent is continued.8,9

n AbstractAcne vulgaris is one of the most prevalent skin conditions. Antibiotics, when considered, are most effective in combi-nation with other therapies, and limited evidence suggests that submicrobial doses of antibiotics may improve acne without increasing the risk for antibiotic resistance. A small but significant risk for inflammatory bowel disease has also been identified in children treated with multiple courses of antibiotics. New topical agents are expanding therapeutic options for acne. Semin Cutan Med Surg 35(supp6):S114-S116 © 2016 published by Frontline Medical Communications

n Keywords Acne vulgaris; antibiotics; inflammatory bowel disease; topical therapy

Acne: What’s New Linda F. Stein Gold, MD*

* Director of Dermatology Research, Henry Ford Health System, Detroit, Michigan


Dr Stein Gold has received an honorarium for her participation in this activity. She acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Linda F. Stein Gold, MD: Consultant and Scientific Advisory Board: Anacor Pharmaceuticals, Inc., Bayer, Eli Lilly and Company, Foamix Pharmaceuticals Inc., Galderma Laboratories, L.P., LEO Pharma Inc., Medimetrix Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Taro Pharmaceutical Industries Ltd.

Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood Drive, Bloomfield Hills, MI 48302; [email protected].

© 2016 Frontline Medical Communications 1085-5629/13/$-see front matter doi:10.12788/j.sder.2016.036

In fact, this practice may increase risk for the development of resistance. The reason has to do with minimum antimicrobial serum drug levels and bacterial selection pressures. If antibi-otic serum levels exceed this minimum antimicrobial threshold and then drop below the threshold, there is an increased risk that only the weaker bacteria will be killed, leaving more robust bacteria unaffected. This association also underlies the risks of poor adherence to antibiotic therapy, potentially leading to the selection of more resistant bacteria. For the same reason, clini-cians should use caution when selecting subantimicrobial doses of antibiotics for the treatment of acne. As demonstrated in a pharmacokinetic study, doxycycline dosed at 20 mg twice daily does not exceed the minimum antimicrobial level, but a 50-mg dose exceeds the threshold for a few hours per day, theoretically increasing risk for the selection of resistance.5

Antibiotics and Inflammatory Bowel Disease: How Great Is the Risk? In 2010, a report was published on a retrospective study of 94,487 patients with acne who were treated with tetracycline-type antibi-otics.10 Patients were treated with antibiotics for at least 1 month and followed for at least 1 year. Overall, the hazard ratio (HR) for developing inflammatory bowel disease (IBD) was 1.39 (95% CI, 1.02-1.90) for patients with any exposure to a tetracycline anti-biotic. Risk for IBD was greatest for developing Crohn’s disease among patients treated with doxycycline (HR, 2.25; 95% CI, 1.27-4.00). A second study used a nested case-control design, matching 2,234 patients with IBD to 22,346 controls.11 Information on antibiotic use was extracted from a comprehensive prescription database. The use of more than 3 courses of antibiotics was asso-ciated with an odds ratio (OR) for IBD of 1.5 (95% CI, 1.3-1.8). Dose-response relationships were identified between antibiotic use and risk for both ulcerative colitis and Crohn’s disease.

More recently, a meta-analysis of 11 observational studies (N=7208 with IBD) found a significant relationship between anti-biotic exposure and Crohn’s disease (OR, 1.74; 95% CI, 1.35-1.94) but not ulcerative colitis.12 Children with antibiotic exposure had the greatest increase in risk for Crohn’s disease (OR, 2.75; 95% CI, 1.72-4.38). The risk for IBD in children was further evalu-ated in a retrospective cohort study from 464 ambulatory care centers in the United Kingdom, including 1,072,426 patients.13 In this study, the risk for IBD with antibiotic use decreased with older age at time of exposure. Antibiotic use before 1 year of age had the greatest risk (HR, 5.51; 95% CI, 1.66-18.28). The 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 children with acne.

Topical Agents Several topical formulations of antibiotics are currently avail-able and used in some patients with acne (eg, erythromycin, clindamycin). New topical antibiotic formulations in development have demonstrated promise, including minocycline foam and gel. A 12-week study of once-daily minocycline foam demonstrated a dose-response relationship, with 4% minocycline achieving statis-tical superiority to vehicle for reducing acne lesions and achieving an IGA score <2.14

New fixed-combination topical agents have been approved for use in acne. One contains a higher dose of adapalene (0.3%), combined with benzoyl peroxide 2.5%. This combination was compared to vehicle and the regular-strength combina-tion (adapalene 0.1%/benzoyl peroxide 2.5%) in a randomized,

12-week study.15 Approximately half the subjects enrolled in this trial had severe acne, a substantially larger proportion than any other topical acne trial. Overall, 33.5% of subjects treated with the high-dose adapalene formulation achieved IGA success (ie, clear or almost clear), compared to 11.5% of the vehicle group (P<0.001). Among patients with severe acne, IGA success was achieved by 31.2% of the high-dose adapalene group, compared to 21% of the regular-dose adapalene group and 13.3% of the vehicle group. Only the high-dose group was statistically supe-rior to vehicle in patients with severe acne (P=0.029). Tolerability was not significantly different between the adapalene groups, and local irritation generally faded after the first 2 weeks of treatment.

A new formulation of dapsone containing 7.5% active drug was recently approved by the US Food and Drug Administration for once-daily use (compared with 5% dapsone, which is applied twice daily). A recent study randomized 2,102 patients with moderate acne to once-daily dapsone gel 7.5% or vehicle for 12 weeks.16 At weeks 8 and 12, significantly more subjects treated with dapsone gel achieved treatment success compared to vehicle (P<0.05 and P<0.001, weeks 8 and 12, respectively).

A recently approved combination topical gel consists of clindamycin 1.2% plus benzoyl peroxide 3.75%. In a 12-week trial (N=498), once-daily application of this agent produced significantly greater reductions in comedonal and inflammatory lesions compared to vehicle (P<0.001, all comparisons). Also, statistically more patients achieved a two-grade improvement in investigator’s global improvement compared to vehicle.17

Topical Agents to Reduce Sebum Production? Until recently, no topical agent has demonstrated the ability to reduce sebum production, which contributes to the pathophys-iology of acne. Currently, three topical agents in development have shown the ability to affect sebum production. The first is SB204, a topical agent that releases nitric oxide. Nitric oxide has both antimicrobial and anti-inflammatory activities and may also reduce sebum production.18,19 In a phase IIa trial, 2 doses of SB204 (1% and 4%) were compared to vehicle in 153 subjects with acne.20 At 4 weeks, the 4% dose of SB204 demonstrated a statistically significant reduction in both non-inflammatory and inflammatory lesions compared to vehicle.


Linda F. Stein Gold, MD

10

20

40

Perc

en

tag

e

Baseline 4 Weeks 8 Weeks 12 Weeks

10%

3%

32%

8%

*P<0.001

Adap-BPO + doxycycline (n=232)Vehicle + doxycycline (n=227)

n FIGURE Percentage of Patients Achieving Treatment Success (Clear or Almost Clear) on Investigator Global Assessment With Oral Doxycycline Compared With Oral Doxycycline Plus Adapalene/Benzoyl Peroxide.BPO=benzoyl peroxide. Source: Stein Gold L, Cruz A, Eichenfield L, et al.7

A second drug that may decrease sebum production is DRM01. This agent targets acetyl coenzyme-A carboxylase (ACC), which is a key regulator of sebum production. A phase IIa trial random-ized 108 subjects to DRM01 7.5% twice daily or to vehicle for 12 weeks.21 Statistical improvement in all efficacy parameters was demonstrated with DRM01, including significantly greater reduc-tions in inflammatory and non-inflammatory lesions compared to placebo (P=0.0005 and 0.0025, respectively).

The third topical agent is a potent antiandrogen called CB-03-01 (cortexolone 17α-propionate 1%).22 Initial study compared this agent to tretinoin 0.05% and vehicle in 77 men with facial acne.23 After 8 weeks, CB-03-01 produced significantly greater reductions in total and inflammatory lesion counts compared to vehicle, and at least comparable efficacy to tretinoin.

SummaryThe treatment of acne continues to advance, with new agents and combinations of agents in development and approved for clinical use. Emerging data also suggest limiting the use of oral antibiotics in patients with acne—in particular, minimizing exposure of children to oral antibiotics. Finally, new topical agents that reduce sebum production offer possible novel thera-peutic approaches for our acne patients.

References1. 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 doxycycline 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 tazarotene 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.

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 designed, large, multicenter, randomized, placebo-controlled trials. Presented at: Winter Clinical Dermatology Conference; January 15-20, 2016; Kauai, HI.

17. Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed combi-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. 2014;13:1083-1089.

18. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.

19. Niedbala W, Alves-Filho JC, Fukada SY, et al. Regulation of type 17 helper T-cell function by nitric oxide during inflammation. Proc Natl Acad Sci U S A. 2011;108:9220-9225.

20. Rico J, et al. Data on file. Novan, Inc. www.novantherapeutics.com. Accessed April 13, 2016.

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 vulgaris. Presented at: 24th European Academy of Dermatology and Venereology Congress. October 7-11, 2015; Copenhagen, Denmark.

22. Celasco G, Moro L, Bozzella R, et al. Biological profile of cortexolone 17α-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist. Arzneimittelforschung. 2004;54:881-886.

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 acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011;165:177-183.

n n n Acne: What’s New


New soft tissue augmentation products (also called fillers) have become available in recent years, and others are in late stages of development. Fillers are used for the correction

of age-related changes in areas of the face, such as the nasolabial folds, vertical lip lines, marionette lines around the mouth, and the thinning lip.1 These products are injected into these regions to address the loss of subcutaneous volume that accompanies aging, thereby improving cosmesis and self-image.

The most common material used for fillers is hyaluronic acid (HA).2 How the HA is produced affects its physiochemical properties and clinical application. These properties include concentration, molecular weight, extent and method of cross-linking, and particle size. The related clinical performance characteristics include durability, stiffness (called G′), spread-ability, volumization, and cohesivity.

For example, the Hylacross® products are cross-linked, smooth gels with high HA concentration and high cohesivity. The high HA concentration provides durability, whereas the high cohesivity provides lift. However, clinicians needed addi-tional products with different characteristics, such as products that can have a high lifting capacity or the opposite products that are spreadable and have a very low lifting capacity.3 The newer Vycross® family of products uses a mixture of cross-linked

high- and low-molecular-weight HA designed to improve dura-bility and reduce swelling of the gel. Products within this family are tailored to provide different degrees of lift and spreadability. The main differences between Hylacross and Vycross products are the length and molecular weight of the HA chains and extent of cross-linking: Hylacross consists of cross-linked, long-chain, mostly high-molecular-weight HA; Vycross is a proprietary mixture of low- and high-molecular-weight, short- and long-chain HA that is highly crosslinked.3 The same method of cross-linking is used in both products (1,4-butanediol diglycidyl ether, or BDDE). The low-molecular-weight HA and high degree 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 illustrated in the Table.4-8 Overall, the Vycross products absorb less water than Hylacross products, meaning that the final volume will be similar to the injected volume.

In preclinical studies, the Vycross products demonstrated a balance between cohesivity and G′, high initial moldability, and good integration into host tissue.3,9 Integration is believed to contribute to the natural appearance of the product with move-ments of the face. Vycross Voluma®, which is approved for use in the United States, demonstrated durability up to 24 months in trials, although clinical experience suggests longevity closer to 1 year, after which reinjection may be considered.4,10 This filler is very thick and provides volume and lift.

Adverse events do occur with Vycross products, although they are rare. One adverse event that may be specific to these prod-ucts is the development of delayed nodules. In a retrospective chart review study (N=2,342), aesthetic results lasted at least 12 months, and side effects were mostly transient and mild. However, 21 patients (<0.5%) developed delayed, non-tender nodules.11 The nodules were successfully managed with conser-vative measures. In clinical practice, nodules typically develop within 4 to 6 months.

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, injection of hyaluronidase may help remove some of the HA and reduce the nodule. Intralesional triamcinolone may also reduce nodules.

Volbella has a very fine consistency and flows quickly during injection. Its main uses are for lip hydration and perioral lines, not for volume per se. Each injection lasts approximately 9 to 12 months.5 In one clinical study, 48.3% of subjects main-tained ≥1-point improvement in the Lip Fullness Scale (LFS) at 12 months, compared to 98.3% at 1 month. Clinical experience suggests that Volbella should be injected underneath the dermis in small amounts and then blended by hand to reduce fine lines.

The characteristics of Volift place it between Voluma and Volbella. The product is best suited for marionette lines, smile lines, and other mild to moderate lines around the face.

n AbstractSoft tissue augmentation products (or fillers) are used for the correction of age-related changes in areas of the face. The most common filler material is hyaluronic acid, which is synthetically cross-linked. These materials are generally safe, but some side effects do occur. New fillers are expected to be approved in the United States in the near future. Semin Cutan Med Surg 35(supp6):S117-119 © 2016 published by Frontline Medical Communications

n Keywords Delayed nodules; fillers; hyaluronic acid; NASHA; soft tissue augmentation

Fillers: What’s Here and What’s AheadNowell Solish, MD, FRCP(C)*

* Assistant Professor, University of Toronto, Toronto, Ontario, Canada


Dr Solish has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Nowell Solish, MD, FRCP(C): Consultant/Grant/Research Support: Allergan, Inc., Galderma Laboratories, L.P., Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., Valeant.

Address reprint requests to: Nowell Solish, MD, 66 Avenue Road, Suite 1, Toronto, Ontario M5R3N8; [email protected]

1085-5629/13/$-see front matter © 2016 Frontline Medical Communications doi:110.12788/j.sder.2016.037 Vol. 35, No. 6S, June 2016, Seminars in Cutaneous Medicine and Surgery S117

Non-Animal Stabilized HA (NASHA)Traditional cross-linking involves treating natural HA with a reagent (often BDDE) to generate a synthetically cross-linked gel. Non-animal stabilized HA (NASHA) is generated by preserving the naturally occurring HA network, in which the HA chains are entangled, and contains minimal synthetic cross-links.12,13 NASHA products demonstrate greater resistance to deformation than other HA products.13 The size of the parti-cles of NASHA can be selected using screens of different sizes, creating a range of products from small to large particle size.

A recent study randomized 220 subjects to no treatment or treatment with a small-particle NASHA plus lidocaine for lip augmentation and perioral rhytides.14 Treatment success was

defined as at least a one-grade increase from baseline in the Medicis Lip Fullness Scale (MLFS). At 8 weeks in the intent-to-treat population, 76.1% to 80.2% of treated subjects demonstrated response on the MLFS, compared to 11.6% to 18.4% of untreated subjects (P<0.001, all comparisons). Significant improvements in perioral rhytides were noted at weeks 12 (37.1% vs 20%) and 16 (35.4% vs 17.5%) with NASHA compared to no treatment (P<0.05, both comparisons).

The NASHA product tested in the study described above is branded Restylane Silk in the United States.15 Overall, this product is a smooth, fast-flowing filler that can be used to improve the definition of lips but does not provide much volume. It also provides hydration of the lip, giving the patient the appearance of wearing lip gloss. It is not very hygroscopic.

n TABLE 1 Characteristics of Vycross Family of Products4-8

Volbella* Volift* Voluma

Indication Lips Nasolabial folds Check 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

(G′ @ 5 Hz)†271 Pa 340 Pa 398 Pa

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.

Yes

Resolved

Fluctuant?

Puncture, drain, culture; Initiate antibiotics

If not resolved after 1 mo,+/– Biopsy for culture/histo

No; “Cold nodules” can be observed and may resolve on their own; if problematic consider treatment below

As per clinical judgement, 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)

Yes No; Red?

n 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.

n n n Fillers: What’s Here and What’s Ahead


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.

References1. 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 lip augmentation 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.




As we age, bone and fat volume in the face and neck natu-rally decrease. Furthermore, rotational descent of the face occurs with aging, contributing to a lengthening of the

face and the creation of lines, folds, and shadows. Youthful faces often have a heart-shaped pattern, but with age the face becomes more oval (elongated) or square (broadened, bottom heavy). For example, a baby’s face has a shape similar to an inflated beach ball, round and unlined. But the muscular atrophy, photodamage, and fat atrophy that occur with aging lead to an appearance more like a wrinkled, deflated beach ball.

In the midface, aging often increases fat in the lower areas and decreases volume in upper areas. The bone also resorbs and remodels. Resorption is common in the frontal bone, contributing to a convexity of the bone and ptosis of the brow. Resorption of the zygomatic angle makes the angle more acute, and the malar fat pad sags medially and creates or worsens the nasolabial fold. Other changes that contribute to the appearance of aging include periorbital hollowing, marionette lines, submalar hollowing, and periocular rhytidosis.

The goal of treating the aging face is to restore facial balance and modify shadows. For example, the infraorbital fat pad tends to protrude as people age. Part of the cosmetic problem caused by this change is the shadow that the pad creates; filling below the protruding pad can reduce this shadow and create a more

youthful appearance. The facial evaluation, therefore, should focus on areas of volume loss and opportunities to use neuro-modulators (eg, botulinum toxin A) and the use of fillers.

Neuromodulators and the Aging FaceInjections of neuromodulators relax specific muscle groups and can reduce wrinkles and improve cosmesis. There are several common facial targets for neuromodulators. The forehead is a complex region with corrugator muscles that adjust brow height and volume. The pattern of movement of these muscles varies by individual, and several patterns have been described (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 pattern involves medial contraction of the corrugators and often includes the nasalis muscles. Neuromodulator injections should be focused centrally. The omega pattern involves the frontalis and procerus muscles, and injections focus on the central areas. The U-shaped pattern typically responds well to treatment and may need less neuromodulator. Finally, the converging arrow patterns typically involve deep central lines on the forehead. When treated with neuromodulators, this pattern often shows the greatest improvements.

Other facial sites for neuromodulators include the masseter muscles. Hypertrophy of the masseters may occur even in young patients, contributing to a bottom-heavy facial appearance. Injection of these muscles can ameliorate this hypertrophy.

Fillers and the Aging FaceNeuromodulators can improve cosmesis of the forehead by relaxing muscles that contribute to folds and wrinkles. But volume loss can also contribute to poor cosmesis. For example, an arched eyebrow is generally considered more youthful and attrac-tive; fillers can be used in the forehead to achieve this arched or rounded appearance. The safest zone for the injection of fillers in the forehead is in the mid-forehead at the level of the periosteum, which can help avoid an intra-arterial injection. A typical volume 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 desired look. Blending is easy in this region because the filler is injected on the periosteum.

Fillers can also be used to increase brow height. Caution should be exercised when injecting filler into the brow, and a cannula may be safer than a needle. The general approach involves injecting at the lower margin of the brow from the peak of the brow and continuing laterally. The temples are another site that may benefit from application of fillers. Injection should be performed 1 cm above the orbital rim and 1 cm medial to the temporal fusion plane, with a finger pressed behind the needle to prevent the filler from flowing into the hairline. Up to 1 mL of filler per side may be needed to eliminate shadows. Injecting filler in this spot is generally quite safe.

n AbstractThe goal of treating the aging face is to restore facial balance and modify shadows. A facial evaluation should focus on areas of volume loss and opportunities to use neuromodulators (eg, botulinum toxin A) and the use of fillers. A thorough understanding of facial anatomy, including muscles, nerves, bone, and fat pads, is essential for effective and safe treatment. Semin Cutan Med Surg 35(supp6):S120-S121 © 2016 published by Frontline Medical Communications

n Keywords Aging face; botulinum toxin A; fillers; neuromodulators

The Aging Face: Global Approach With Fillers and Neuromodulators Nowell Solish, MD, FRCP(C)*

* Assistant Professor, University of Toronto, Toronto, Ontario, Canada


Dr Solish has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Nowell Solish, MD, FRCP(C): Consultant/Grant/Research Support: Allergan, Inc., Galderma Laboratories, L.P., Indeed Labs, Inc., Merz, Revance Therapeutics, Inc., Valeant.

Address reprint requests to: Nowell Solish, MD, 66 Avenue Road, Suite 1, Toronto, Ontario M5R3N8; [email protected]


A youthful orbit is characterized by a long, flat, and full eyelid, with the upper lid concealed by skin. The bony orbit is not visible. With aging, the orbit loses volume and becomes more skeleton-ized. The typical finding with age is called the A-frame deformity. Fillers can be used to replace this volume loss, although injecting in this area requires advanced technique, and use of a cannula is recommended. Small volumes of filler (eg, approximately 0.1 mL) are usually sufficient to rectify A-frame deformities.

The midface is one of the most important areas to address in aging. The focus should be on the cheek, lower lid, and submalar area. A common finding that occurs with aging is the malar

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 injected below the lateral canthus to provide lift.

The submalar area can be injected with small amounts of filler (approximately 0.05-0.1 mL per injection) in a grid pattern in the subcutaneous plane (Figure 2).

Finally, in the lower face, areas for fillers include the mario-nette lines, chin apex, and the pre- and post-jowl sulci. However, some patients who complain about jowls actually have protru-sion of the submandibular gland. This protrusion can usually be managed with application of neuromodulator (eg, 5-8 units botulinum toxin A on each side), often with rapid resolution.

In summary, use of fillers and neuromodulators is an effective strategy for the treatment of age-related facial changes. A thor-ough understanding of facial anatomy, including muscles, nerves, bone, and fat pads, is essential for effective and safe treatment.

Reference1. Shaw Jr RB, Kahn DM. Aging of the midface bony elements: A three-dimensional

computed tomographic study. Plast Reconstr Surg. 2007;119:675.



13

24

n 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).

n FIGURE 1 Patterns of Corrugator Movement and Sites for Neuromodulator Injection. From top: V pattern, inverted omega, omega pattern, U pattern, and converging arrows. Sites for injection of neuromodulator are noted in red dots below each pair of images.


Laser skin resurfacing remains a major therapeutic tool for facial rejuvenation and the treatment of acne scars and other skin damage. The technologies work by altering the epidermis

and dermis, either by full field treatment or fractionated delivery of coagulative or ablative injury, thereby inducing regrowth of new epidermis and growth of new collagen and elastin in the dermis. The first lasers introduced to dermatology were ablative lasers, such as the CO2 and erbium:YAG (yttrium-aluminum-garnet) lasers, both of which target water. Although traditional laser resurfacing techniques are still considered the gold stan-dard by many dermatologists, a variety of new laser systems have become available, with each device inducing different patterns of focal injury and subsequent outcomes.

Fractionated Non-Ablative and Ablative LasersScars, facial photodamage, and normal photoaging have all been well treated in the past with chemical peels, dermabrasion, and traditional laser resurfacing techniques. Various non-ablative heating technologies such as the CoolTouch® (1320 nm) laser were developed in the hope that this would improve acne scarring, skin tightness, and aging changes, but early results were mixed.1 Rox Anderson and Dieter Manstein first considered the concept of fractionation as a method to create universal benefit by inducing myriad tiny areas of injury, much akin to the lawn aerator benefit for a lawn. The first device manufactured by Reliant delivered multiple microbeams using a computer-controlled scanner.1,2 These are characterized by having normal unaffected epidermis and dermis between the areas of laser-treated skin, preserving a reservoir of healthy cells that expedite healing.3 Subsequently, Reliant developed an ablative device with similar characteristics, 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-ries of 150 µm or less, many useful devices create injuries of up to 400-500 µm, which are still small enough to allow the intervening skin cells to promote healing.

Among the advantages of fractionated laser treatment is a reduced incidence of side effects of the traditional devices. This includes an absence of delayed onset loss of pigmentation, which occurred in about 25% of CO2 laser resurfacing patients, a reduced amount of persistent erythema, and other side effects such as scarring and infection. Another advantage is the ability to treat nonfacial areas, such as the neck or chest, which are challenging to treat with traditional lasers. Healing following treatment with an ablative fractionated device is relatively fast; induced defi-cits generally close within 24-48 hours (Figure 1).4 Importantly, 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 low-density injuries to the skin (for example, 5% of the target area), the entire target area will respond uniformly with forma-tion of new epidermis.

As with any device, the laser surgeon must consider laser tissue interactions. For those who have darker skin types, or in areas that are underprivileged with regard to numbers of adnexal glands such as the neck and chest, the fractional density should be reduced to prevent post-inflammatory hyperpigmentation and the potential for scarring, respectively. The relationship between more aggressive treatment, including higher density, and better outcomes may not be supported for all applications, particularly with acne scarring. Repeated and immediate scanning of the same region of skin may result in bulk heating of the skin with loss of selectivity, possibly leading to scarring. Once an area has been scanned with the device, it is important to move to a different area to allow the skin to cool before rescanning (if necessary).

n AbstractFor decades, devices and peels have been used for facial rejuvenation and the treatment of skin damage. In recent years, new laser systems have been developed, including fractionated ablative and non-ablative lasers which, while not as effective as the traditional laser resurfacing, can provide nice results with reduced side effects. While fractionated hybrid systems, picosecond lasers, and daylight photodynamic therapy have all been rolled out for clinicians to assess their efficacy, future technology, including TRASER (total reflection amplification of spontaneous emission of radiation) technology, should be just around the corner. These technologies offer new potential applications, efficacy, and recovery periods. Semin Cutan Med Surg 35(supp6):S122-S124 © 2016 published by Frontline Medical Communications

n Keywords Ablative lasers; daylight photodynamic therapy; facial rejuvenation; fractionated lasers; picosecond lasers, TRASER

Facial Rejuvenation: 40th Anniversary Review Christopher B. Zachary, MBBS, FRCP*

* Professor and Chair, Department of Dermatology, University of California, Irvine, Irvine, California


Dr Zachary has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Josh Kilbridge, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

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].


48 Hours 7 Days 1 Month 3 Months

Wavelength and Absorption The wavelength generated by the laser determines its absorption by skin structures and therefore its clinical effect. The thulium fiber laser with a 1927 nm wavelength, for example, has roughly 10 times the absorption in skin compared to erbium fiber 1550 nm wavelength lasers. The thulium 1927 nm laser has very little dose-response in terms of lesion depth with increasing pulse energy; this contrasts with the erbium 1550 nm laser, which demonstrates a robust dose-response relationship. Clinically, this difference translates into more superficial tissue heating, similar to a very superficial high energy, short pulsed CO2 laser, though without the epidermal vaporization and with the absence of bleeding or fluid loss, and with less need for wound care (Figure 2).

Hybrid LasersHybrid laser systems combine ablative and non-ablative wave-lengths in one device. For example, a new device manufactured by Sciton combines 2940 nm and 1470 nm wavelengths, each of which can be adjusted for coverage and depth of penetration. The 2940 nm wavelength removes superficial epidermis and can allow the 1470 nm to immediately and sequentially treat the underlying dermal tissue. These wavelengths target epidermal and dermal pigmented lesions, dermal elastosis, fine lines, texture, and pore size. Although treatment with this system produces less pain than some other fractionated devices, patients should be warned that the treated area may look worse for 2-3 days after treatment, before the skin regenerates.

Picosecond LasersPicosecond lasers, which use pulse durations in the picosecond range, may produce superior results to nanosecond lasers for certain applications, such as tattoo removal. For example, a small study of patients with multicolor tattoos reported at least 75% clearance of blue and green pigments after one or two treatments with a picosecond 755 nm alexandrite laser, including tattoos that resisted previous treatments.5 Other potential applications for picosecond lasers include pigmented lesions, nevi, and melasma.

Total Reflection Amplification of Spontaneous Emission of Radiation A new, non-laser, non–intense pulsed light (IPL) technology, called TRASER (total reflection amplification of spontaneous emission of radiation), has been developed that can target blood vessels and hair follicles. The TRASER device is capable of very

high power output, variable wavelengths, and pulse durations from 0.45 to more than 100 msec. Photons generated by two flash lamps are absorbed by a dye, which then produces photons of a specific wavelength based on the characteristic of the dye. Changing the dye and its concentration will change the wave-length output. It can emulate a potassium-titanyl-phosphate (KTP) laser, pulsed dye laser, and a ruby hair removal laser. As such, the device could be used to treat port-wine stain in one patient, then (once the dye is switched) hair removal in the next.

Daylight Photodynamic Therapy Dermatologists are familiar with conventional photodynamic therapy (cPDT). Daylight PDT (dPDT) is a novel approach that delivers continuous low-level activation of protoporphyrin IX


n FIGURE 2 Histology Comparison of Skin Treated With 1927 nm Thulium Fiber Laser and Superficial CO2 Laser. Treatment with 1927 nm laser shows tissue damage similar to that of superficial CO2 but an intact stratum corneum, increasing the safety profile of the treatment. Source: ??????????????????????????????????????????????????????????????????????????????????????????????????????????????

Christopher B. Zachary, MBBS, FRCP

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

Superficial Non-Ablative 1927 nm

Superficial Ablative CO2 Treatment

(PpIX) for the treatment of photoaged skin and actinic keratoses. cPDT uses artificial light sources, but dPDT has been demon-strated to have at least comparable results.6 The technique involves degreasing the face, gentle curettage of any thicker lesions, and application of aminolevulinic acid for 60 minutes. A chemical sunscreen is applied 30 minutes into this incubation. Then the skin is exposed to shaded daylight for 2-2.5 hours, after which the patient should remain indoors for 48 hours. The technique may also be used for treatment of other skin conditions, such as acne. In one trial, PDT produced at least moderate improvement in acne in a greater proportion of subjects than intense pulsed light therapy or blue-red light-emitting diode therapy.7 Our results of dPDT in recalcitrant acne have been quite impressive, with almost compete clearing after 4-5 treatments.

In summary, lasers have long been used in dermatology prac-tices. New types of lasers have been developed that differ in the type of injury produced in the skin and therefore the potential application, efficacy, and recovery of patients.

References1. 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.


n n n Facial Rejuvenation: 40th Anniversary Review

Highlights of Skin Disease Education Foundation’s 40th Annual Hawaii Dermatology Seminar Post-Test

Original Release Date: June 2016Expiration 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].


1. In the registration clinical trial, the mycological cure rate of efinaconazole 10% for treatment of onychomycosis was approximately what?A. 30%B. 50%C. 70%D. 90%

2. Which of the following describes the mechanism of action of tavaborole? A. Blocks lanosterol demethylase B. Inhibits pro-inflammatory cytokinesC. Blocks formation of leucine transfer RNAD. Inhibits function of fungal DNA topoisomerase

3. Observational studies have identified increased risk for inflammatory bowel disease associated with antibiotic use in children. In which patient group was this risk greatest? A. Children younger than 1 yearB. Adolescents aged 10-16 years C. Children with very severe acne D. Patients with pre-existing bowel symptoms

4. When considering the use of fillers for soft tissue augmentation, a filler with which of the following characteristics would be appropriate for very fine lines? A. Larger-sized gel particles B. Greater resistance to deformationC. Lower degree of cross-linkingD. High molecular weight and concentration of

hyaluronic acid

5. The use of a cannula is recommended when applying soft tissue filler to which of the following facial regions? A. Chin apexB. Malar creaseC. Nasolabial fold D. A-frame deformity of the orbit

6. Which of the following agents is FDA-approved for the treatment of facial erythema associated with rosacea? A. BrimonidineB. OxymetazolineC. Ivermectin cream D. Low-molecular-weight hyaluronic acid

7. A phase III trial comparing ivermectin cream to metronidazole cream for the treatment of rosacea reported all of the following results, EXCEPT: A. Similar overall tolerability between groups B. Better local tolerability with metronidazole creamC. Significantly higher rate of treatment success with

ivermectin D. Significantly greater reductions in inflammatory

lesions with ivermectin

8. Advantages of fractionated lasers compared to non-fractionated lasers for facial rejuvenation include all of the following, EXCEPT:A. Reduced post-procedural pain B. Faster post-procedural healingC. Reduced incidence of loss of pigmentation D. Production of high-density injury to the target area

9. After 12 weeks of treatment with etanercept in a phase III trial for pediatric psoriasis, what proportion of patients achieved PASI-75?A. 25%B. 39%C. 57%D. 78%

10. To support approval of a biosimilar agent, the FDA requires all of the following, EXCEPT: A. Toxicity studies in animalsB. Identical amino acid sequence to original biologicC. Pharmacokinetic and pharmacodynamic studies

in humans D. Clinical trials to demonstrate safety and efficacy for

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.

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

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

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 hoursTo 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.

If you do not feel confident that you can achieve the above objectives to some extent, please describe why not.______________________________________________________________________________________________________________________________________Based on the content of this activity, what will you do differently in the care of your patients/regarding your professional responsibilities? (check one)

Implement a change in my practice/workplace. Seek additional information on this topic.Implement a change in my practice/workplace and seek additional information on this topic.Do nothing differently. Current practice/job responsibilities reflect activity recommendations.Do nothing differently. Content was not convincing. Do nothing differently. System barriers prevent me from changing my practice/workplace.

If you anticipate changing one or more aspects of your practice/professional responsibilities as a result of your participation in this activity, please briefly describe how you plan to do so.______________________________________________________________________________________________________________________________________

If you plan to change your practice/professional responsibilities, may we contact you in 2 months to see how you are progressing?

Yes No I don’t plan to make a change.

If you are not able to effectively implement what you learned in this activity, please tell us what the system barriers are (eg, institutional systems, lack of resources, etc)._________________________________________________________________________________________________________________________________________________________________________________________________________

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 therapies for common and uncommon dermatologic diseases. 5 4 3 2 1

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 of the face. 5 4 3 2 1

Compare and contrast the efficacy and safety of agents, devices, and techniques currently available in aesthetic and procedural dermatology. 5 4 3 2 1

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

What issue(s) are you experiencing in your practice/regarding your professional responsibilities that could be addressed in future programming?______________________________________________________________________________________________________________________________

Please provide additional comments pertaining to this activity and any suggestions for improvement.______________________________________________________________________________________________________________________________

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

Joseph F. Fowler, Jr, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1

Author was organized in the written materials. 5 4 3 2 1

Theodore Rosen, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Jeffrey M. Sobell, MD Author demonstrated current knowledge of the topic. 5 4 3 2 1


Nowell Solish, MD, FRCP(C) Author demonstrated current knowledge of the topic. 5 4 3 2 1


Linda F. Stein Gold, MD Author demonstrated current knowledge of the topic. 5 4 3 2 1


Christopher B. Zachary, MBBS, FACPAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


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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.

Documents

Highlights of Skin Disease Education Foundation’s 40th ... · Onychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Newly approved