A CME/CE CERTIFIED SUPPLEMENT TO

SUPPLEMENT 3 VOL. 37, NO. 3S JUNE 2018

EDITORS Kenneth A. Arndt, MD Philip E. LeBoit, MD Bruce U. Wintroub, MD

Acne and Rosacea: Applying Emerging Science to Improve Outcomes

GUEST EDITORS Linda F. Stein Gold, MD, Chair Andrew F. Alexis, MD, MPH Julie C. Harper, MD Jerry K. L. Tan, MD, FRCPC

Introduction S59

Current Concepts in Acne Pathogenesis: Pathways to Inflammation S60

Advances in Acne and Rosacea Therapy S63

Treating Acne in Adult Women S67

Treating Acne in Patients With Skin of Color S71

CME/CE Post-Test and Evaluation Form S74 Acne and Rosacea: Applying Emerging Science to Improve Outcomes Original Release Date: June 2018 Learning Objectives Expiration Date: June 30, 2020 By reading and studying this supplement, participants should be better able to: Estimated Time to Complete Activity: 2.0 hours • Design a comprehensive treatment plan for patients with acne based on clinical guidelines and updated research, incorporating pharmacologic and Participants should read the activity information, review the activity in its physical modalities entirety, and complete the online post-test and evaluation. Upon completing • Discuss and design treatment plans for patients of color, pregnant patients, this activity as designed and achieving a passing score on the post-test, you and those with truncal acne, scarring, and photoaging will be directed to a Web page that will allow you to receive your certificate of • Recognize the significant impact of acne in patients’ lives, and of treating credit via e-mail or you may print it out at that time. The online post-test and promptly and appropriately evaluation can be accessed at https://tinyurl.com/acnerosaceasupp2018. • Apply treatment strategies, based on knowledge of the indications, efficacy, Inquiries about CME accreditation may be directed to the University of and risks of available rosacea therapies, to achieve therapeutic goals in Louisville Office of Continuing Medical Education & Professional Development rosacea treatment (CME & PD) at [email protected] or 502-852-5329. Disclosure Declarations CME/CE Accreditation Statements Individuals in a position to control the content of this educational activity are Physicians: This activity has been planned and implemented in accordance required to disclose: 1) the existence of any relevant financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or with the accreditation requirements and policies of the Accreditation Council services consumed by, or used on, patients with the exemption of non-profit or for Continuing Medical Education (ACCME) through the joint providership of government organizations and non-health care related companies, within the the University of Louisville and Global Academy for Medical Education, LLC. past 12 months; and 2) the identification of a commercial product/device that is The University of Louisville is accredited by the ACCME to provide continuing unlabeled for use or an investigational use of a product/device not yet approved. education for physicians. Andrew F. Alexis, MD, MPH, Consultant: Allergan plc, BioPharmX, Inc., The University of Louisville Office of Continuing Medical Education & Galderma Laboratories, L.P. Contracted Research: Allergan plc, BioPharmX, Professional Development designates this enduring activity for a maximum Inc., Galderma Laboratories, L.P., Novan, Inc. of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit Julie C. Harper, MD, Consultant: Allergan plc, Bayer AG, BioPharmX, Inc., commensurate with the extent of their participation in the activity. Galderma Laboratories, L.P., La Roche-Posay, Novan, Inc., Ortho Dermatologics. Joint Accreditation Statement Contracted Research: Bayer AG. Speakers Bureau: Allergan plc, Bayer AG, La Roche-Posay, Ortho Dermatologics. In support of improving patient care, this activity has been planned and implemented by Postgraduate Institute for Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., Medicine and Global Academy for Medical Education. Postgraduate Institute Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, for Medicine is jointly accredited by the Accreditation Council for Continuing Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Medical Education (ACCME), the Accreditation Council for Pharmacy Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals Education (ACPE), and the American Nurses Credentialing Center (ANCC) to International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., provide continuing education for the healthcare team. Valeant Pharmaceuticals International, Inc. Continuing Nursing Education Jerry K. L. Tan, MD, FRCPC, Consultant: Allergan plc, Galderma Laboratories, L.P., The maximum number of hours awarded for this Continuing Nursing Valeant Pharmaceuticals International, Inc. Contracted Research: Dermira, Inc., Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Speakers Education activity is 2.0 contact hours. Designated for 0.6 contact hours of Bureau: Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. pharmacotherapy credit for Advance Practice Nurses. University of Louisville CME & PD Advisory Board and Staff Disclosures: Target Audience The CME & PD Advisory Board and Staff have nothing to disclose. This journal supplement is intended for dermatologists, nurse practitioners, CME/CE Reviewers: Cindy E. Owen, MD, Clinical Assistant Professor, Division registered nurses, physician assistants, and other clinicians who treat patients of Dermatology, Department of Medicine, University of Louisville School of with acne and rosacea. Medicine, has nothing to disclose. The Postgraduate Institute of Medicine planners and managers have nothing to disclose. Educational Needs Global Academy for Medical Education Staff: Eileen A. McCaffrey, MA; Acne and rosacea are common skin conditions that, if inadequately treated, Tristan M. Nelsen, MNM, CMP, HMCC; Sylvia H. Reitman, MBA, DipEd; and can significantly affect an individual’s quality of life. Clinicians need to Ron Schaumburg have nothing to disclose. stay current on recent scientific research that is revealing the underlying Off-Label/Investigational Use Disclosure pathophysiology of these conditions, because such knowledge can support This CME/CE activity discusses the off-label use of certain approved medi- the choice of appropriate therapy to improve outcomes. Inflammation is now cations as well as data from clinical trials on investigational agents. Such known to be a primary factor in acne and may persist throughout the lesion material is identified within the text of the articles. life cycle, even beyond the disappearance of visible lesions. Proliferation of Propionibacterium acnes bacteria contributes to the inflammatory process; The Guest Editors acknowledge the editorial assistance of Global the cytokines activated by P acnes infection have been identified as targets Academy for Medical Education and Eileen A. McCaffrey, MA, medical for acne therapy, including the use of new and emerging topical and systemic writer, in the development of this supplement. The manuscript was agents. Clinicians should be familiar with new data on traditional, novel, and reviewed and approved by the Guest Editors as well as the Editors of emerging therapies for rosacea, their mechanisms of action, and their efficacy Seminars in Cutaneous Medicine and Surgery. The ideas and opinions and safety as monotherapy and in combination. Clinicians should also be expressed in this supplement are those of the Guest Editors and do not familiar with acne treatment strategies targeted for special populations, necessarily reflect the views of the supporter, Global Academy for Medical Education, University of Louisville, Postgraduate Institute for Medicine, or including adult women (especially those who are or want to become the publisher. pregnant) and in individuals with skin of color.

Jointly provided by Supported by an independent educational grant from Bayer STATEMENT OF PURPOSE Seminars 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 specifc disorders of the skin, as well as the application of the latest scientifc fndings 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 offces. POSTMASTER: Send address changes to Seminars in Cutaneous Medicine and Surgery, Subscription Services, 110255 W Higgins Road, Suite 280, Rosemont, IL 60018. RECIPIENT: To change your address, contact Subscription Services at 1-800-480-4851. EDITORS Editorial correspondence should be addressed to Kenneth A. Arndt, MD, SkinCare Physicians of Chestnut Hill, 1244 Boylston St., Suite 302, Chestnut Hill, MA 02467. Correspondence regarding subscriptions or change of address should be directed to the Publisher, Subscription Kenneth A. Arndt, MD Services, 10255 W Higgins Road, Suite 280, Rosemont, IL 60018. Subscriptions: Individual/Institution, USA: $133.00 p.a.; student, Clinical Professor of Dermatology, resident, intern, USA: $39.00. Individual, Canada/Mexico: $190.00 p.a.; Emeritus institution, Canada/Mexico: $162.00 p.a. Individual, all other nations: $243.00 (surface mail), $311.00 (air mail); institution, all other nations: $188. Harvard Medical School For back issues, call (800) 480-4851 to charge to your credit card. Adjunct Professor of Surgery Written requests will be accepted and must be accompanied by check Dartmouth Medical School or money order. Send payment and request to Seminars in Cutaneous Medicine and Surgery, Subscription Service, 10255 W Higgins Road, Hanover, New Hampshire Suite 280, Rosemont, IL 60018. Adjunct Professor of Dermatology Copyright © 2018 by Frontline Medical Communications Inc. No part Brown Medical School of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, Providence, Rhode Island or any information storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Licensing/Reprints/Eprints: Wright’s Media, 2407 Timberloch Place, Suite B, The Woodlands, TX 77386; Tel: 877-652-5295; Fax: 281-419-5712; Email: [email protected]. Philip E. LeBoit, MD Advertising representative: Sally Cioci, 7 Century Drive, Suite 302, Professor of Parsippany, NJ 07054-4609. Phone: 973-290-8215; Fax: 973-206-9378; Email: [email protected]. Clinical Dermatology Publication of an advertisement in Seminars in Cutaneous Medicine and School of Medicine Surgery does not imply endorsement of its claims by the Editor(s) or University of California, Publisher of the journal. San Francisco The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily refect those of the Editors or Publisher. San Francisco, California 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 Bruce U. Wintroub, MD in this periodical. The reader is advised to check the appropriate Associate Dean medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, Professor and Chair the method and duration of administration, or contraindications. of Dermatology It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge School of Medicine of the patient, to determine drug dosages and the best treatment for University of California, the patient. San Francisco Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/MEDLINE. San Francisco, California June 2018, Vol. 37, No. 3S TABLE OF CONTENTS

Acne and Rosacea: Applying Emerging Science to Improve Outcomes

S59 Introduction Linda F. Stein Gold, MD S60 Current Concepts in Acne Pathogenesis: Pathways to Inflammation Jerry K. L. Tan, MD, FRCPC, Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, and Julie C. Harper, MD S63 Advances in Acne and Rosacea Therapy Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, Julie C. Harper, MD, and Jerry K. L. Tan, MD, FRCPC S67 Treating Acne in Adult Women Julie C. Harper, MD, Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, and Jerry K. L. Tan, MD, FRCPC S71 Treating Acne in Patients With Skin of Color Andrew F. Alexis, MD, MPH, Julie C. Harper, MD, Linda F. Stein Gold, MD, and Jerry K. L. Tan, MD, FRCPC S74 CME/CE Post-Test and Evaluation Form

GUEST EDITORS

Linda F. Stein Gold, MD, Chair Julie C. Harper, MD Director of Dermatology Clinical Research Clinical Associate Professor of Dermatology Division Head of Dermatology University of Alabama at Birmingham Henry Ford Hospital Dermatology and Skin Care Center Detroit, Michigan of Birmingham Birmingham, Alabama

Andrew F. Alexis, MD, MPH Jerry K. L. Tan, MD, FRCPC Chair, Department of Dermatology Adjunct Professor Director of The Skin of Color Center Schulich School of Medicine & Dentistry Mount Sinai St. Luke’s and Mount Sinai West Western University Associate Professor of Dermatology Windsor, Ontario, Canada Icahn School of Medicine at Mount Sinai New York, New York Vol. 37, No. 3S, June 2018

INTRODUCTION

cne, one of the most common skin conditions in the United States, challenges the clinician in multiple ways. Research illuminating the pathophysiology of acne has revealed the centrality of infammation in the development of acne and identifed new potential Atargets of therapy. It also has identifed new and investigational therapies for rosacea, another infammatory skin disease. This supplement represents the perspectives of myself and three of my colleagues on the pathophysiology of acne and the management of acne and rosacea. Jerry K. L. Tan, MD, FRCPC, explains current concepts in acne pathogenesis and the research linking infammation, insulin-like growth factor-1, diet, sebum quantity and composition, and Propionibacterium acnes overgrowth and virulence. He also explains that some P acnes strains may be healthy. Andrew F. Alexis, MD, MPH, describes the differences in clinical presentation, patient concerns, and sequelae of acne based on Fitzpatrick skin type. Postinfammatory hyperpigmentation (PIH), a darkened area of skin following trauma or cutaneous infammation following acne, appears to be more common in non-Caucasian patients. PIH may be more distressing to patients with darker skin tones than to Caucasian patients. The need for early aggressive treatment of acne to prevent PIH must be balanced against the importance of avoiding skin irritation, which can cause dyspigmentation and aggravate PIH. Dr Alexis reviews the data for the effcacy of various topical therapies on acne and PIH in patients with skin of color (Fitzpatrick skin types IV-VI). Julie C. Harper, MD, discusses considerations when treating acne in adult women, including childbearing potential, use of or desire for systemic contraception, addressing or avoiding exacerbation of other skin conditions such as dryness or photoaging, compatibility with cosmetics, and maintaining a professional appearance. Dr Harper discusses the evidence for use of topical therapies in adult women, the use of and contraindications to combined oral contraception for acne, off-label treatment of acne with spironolactone in adult women, use of isotretinoin, and evidence related to treatment of acne during pregnancy and lactation. I review evidence for new and investigational topical therapies in the management of patients with moderate to severe acne—a patient group whose options have been limited. New topical therapies have demonstrated effcacy in up to half of patients with severe acne. A topical treatment has been studied in patients with truncal acne—another diffcult-to-treat population. Data evaluating new topical therapies for rosacea—and a new regimen using existing topical therapies—also are presented. Advances in our understanding of acne pathophysiology are opening new possibilities for therapies, some of which are refected in investigational agents. Familiarity with the special considerations when managing acne in adult women and patients with skin of color— as well as with the data evaluating the use of newer therapies in these populations—can improve our ability to address our patients’ needs.

Linda F. Stein Gold, MD, Chair Director of Dermatology Clinical Research Division Head of Dermatology Henry Ford Hospital Detroit, Michigan Publication of this CME/CE article was jointly provided by University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education, LLC, and is supported by an educational grant from Bayer. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Eileen A. McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Address reprint requests to: Linda F. Stein Gold, MD, Henry Ford Health System, 6530 Farmington Road, West Bloomfeld, MI 48322; [email protected]

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.023 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S59 Current Concepts in Acne Pathogenesis: Pathways to Inflammation Jerry K. L. Tan, MD, FRCPC,* Linda F. Stein Gold, MD,† Andrew F. Alexis, MD, MPH,‡ and Julie C. Harper, MD§

cne pathogenesis is characterized by hyperproliferation ■ Abstract and abnormal differentiation of the follicular epithelium; Acne is a disease of pilosebaceous inflammation. Pivotal Aexcess sebum production; infammation; and prolifer- in pathogenesis are the roles of hormones (insulin, insulin- ation and biofilm formation of Propionibacterium acnes.1,2 like growth factor-1, androgens), Propionibacterium acnes, Infammation is present in all acne lesions, including preclinical lipogenesis, and a proinflammatory lipid profile. Innate microcomedones.3,4 Immunohistochemical studies show higher immune responses are induced through interaction with levels of CD4 cells, macrophages, and interleukin (IL)-1–alpha toll-like receptors and inflammasome activation initially in uninvolved skin of patients with acne compared with skin of and subsequently through adaptive immune activation. These insights into pathogenic inflammatory pathways can those without acne. These fndings suggest that infammation 4 translate into novel therapeutic approaches for acne. precedes hyperproliferation in the development of acne. Semin Cutan Med Surg 37(supp3):S60-S62 “Noninfammatory acne” is thus a misnomer; it appears that all © 2018 published by Frontline Medical Communications primary acne lesions are infammatory. ■ Keywords Although serum androgens have been viewed as the major hormonal trigger in acne during puberty, recent evidence suggests Acne; caspase-1; inflammasome; nitric oxide; P acnes a pivotal role for insulin-like growth factor (IGF)-1. Individuals phylotypes; pathophysiology; toll-like receptor congenitally defcient in IGF-1 due to Laron syndrome do not * Adjunct Professor, Schulich School of Medicine & Dentistry, Western develop acne, for example. However, high-dose IGF-1 replacement University, Windsor, Ontario, Canada therapy leads to acne and hyperandrogenism.5 † Director of Dermatology Clinical Research, Division Head of Multiple mechanisms of IGF-1 may promote the develop- Dermatology, Henry Ford Hospital, Detroit, Michigan ment of acne. IGF-1 has been shown to: (1) induce androgen ‡ Chair, Department of Dermatology, Director of The Skin of Color synthesis and increase the cutaneous availability of dihydrotestos- Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate terone; (2) disinhibit the forkhead box O1 (FoxO1) transcription Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York factor, which normally suppresses the androgen receptor; and (3) § Clinical Associate Professor of Dermatology, University of Alabama activate peroxisome proliferator-activated receptor–gamma, liver X at Birmingham, Dermatology and Skin Care Center of Birmingham, receptor–alpha, and sterol regulatory element binding protein-1c Birmingham, Alabama (SREBP-1c). The latter actions increase sebum triglycerides and Publication of this CME/CE article was jointly provided by University fatty acid desaturation, leading to a proinfammatory and come- of Louisville, Postgraduate Institute for Medicine, and Global Academy dogenic monosaturated fatty acid profile.6 Increased sebum for Medical Education, LLC, and is supported by an educational production also leads to increased levels of squalene. Squalene grant from Bayer. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance monohydroperoxide is comedogenic and results from ultraviolet of Eileen A. McCaffrey, MA, medical writer, and Global Academy A–triggered photooxidation of squalene in sebum.7 for Medical Education in the development of this continuing medical Compelling evidence on the roles of hyperglycemic carbohy- education journal article. drates (high glycemic index), dairy products, and saturated fats Jerry K. L. Tan, MD, FRCPC, Consultant: Allergan plc, Galderma in promoting acne has been reported.6 Refned carbohydrates and Laboratories, L.P., Valeant Pharmaceuticals International, Inc. dairy products lead to disinhibition of FoxO1 and activation of Contracted Research: Dermira, Inc., Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Speakers Bureau: Galderma the mechanistic target of rapamycin complex 1 (mTORC1) through Laboratories, L.P., Valeant Pharmaceuticals International, Inc. escalation of insulin and IGF-1 levels. Saturated fats directly activate Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., mTORC1. The effect of the latter is stimulation of SREBP-1c, which Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks is central to sebaceous lipogenesis, sebum fatty acid production, Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, and monosaturation.2,6 Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Diet-mediated changes in sebum quantity and composition Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., promote P acnes overgrowth and biofilm formation. P acnes Valeant Pharmaceuticals International, Inc. produces triglyceride lipase, which increases levels of free palmitic Andrew F. Alexis, MD, MPH, Consultant: Allergan plc, BioPharmX, Inc., and oleic acids. Palmitic acid, along with P acnes–derived damage- Galderma Laboratories, L.P. Contracted Research: Allergan plc, associated molecular patterns, stimulates toll-like receptor 2 BioPharmX, Inc., Galderma Laboratories, L.P., Novan, Inc. (TLR2), thereby triggering infammasome activation and IL-1– Julie C. Harper, MD, Consultant: Allergan plc, Bayer AG, BioPharmX, beta signaling. Oleic acid stimulates P acnes adhesion, keratinocyte Inc., Galderma Laboratories, L.P., La Roche-Posay, Novan, Inc., Ortho proliferation, and IL-1–alpha release.8-10 Furthermore, oleic acid Dermatologics. Contracted Research: Bayer AG. Speakers Bureau: 6,11,12 Allergan plc, Bayer AG, La Roche-Posay, Ortho Dermatologics. can induce formation of comedones (Figure). Address reprint requests to: Jerry K. L. Tan, MD, FRCPC, Schulich School P acnes acts on the innate immune system through multiple 3,13 of Medicine & Dentistry, Western University, 2224 Walker Road, proinfammatory pathways. It activates TLR2 on monocytes, Suite 300, Windsor, Ontario, N8W 5L7 Canada; [email protected] leading to the release of proinfammatory cytokines IL-12 and

© 2018 Frontline Medical Communications 1085-5629/13/$-see front matter S60 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 doi: 10.12788/j.sder.2018.024 Jerry K. L. Tan, MD, FRCPC, Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, and Julie C. Harper, MD

P acnes

Lipases

Free fatty acids (oleic, palmitic acid)

Comedones

Inflammasome Papules, Adaptive activation/ IL-1β pustules, immunity Lipid quantity + innate immunity nodules FoxO1 + ∆ lipid quality mTORC1 (saturated and monounsaturated FAs) Squalene

Hormonal triggers monohydroperoxide, IL-1α Comedones

(eg, androgens, IGF-1, insulin) oleic acid

■ FIGURE Pathways to Inflammation in Acne Pathogenesis Hormonal initiators in acne include elevated insulin, IGF-1, and androgen levels. These lead to disinhibition of FoxO1 and activation of mTORC1, resulting in increased local pilosebaceous androgenesis, lipogenesis, and increased squalene, fatty acid production, and desaturation. Increased sebum production results in proliferation of Propionibacterium acnes, and the attendant lipase catalysis of triglycerides to the free fatty acids palmitic and oleic acid, leading to inflammasome activation. The latter, plus IL-1–beta upregulation and subsequent adaptive immune response activation, leads to development of inflammatory papules, pustules, and nodules. Comedo formation results from the direct effect of squalene monohydroperoxide and oleic acid from lipogenesis (oleic acid) and UVA photooxidation of squalene (monohydroperoxide) or from the degradative effect of P acnes lipases on triglycerides (oleic acid). FAs=fatty acids; FoxO1=forkhead box O1; IGF-1=insulin-like growth factor-1; IL=interleukin; mTORC1=mechanistic target of rapamycin complex 1; UVA=ultraviolet A. Sources: Melnik BC6; Lovászi M, et al.12

IL-8.14 It promotes secretion of the proinflammatory cyto- P acnes is not always pathogenic, however. The organism is kines IL-1–beta and IL-18 through an infammasome pathway present in both healthy and acne-affected skin, and all P acnes involving caspase-1 and the nucleotide oligomerization domain- strains do not exert the same effects. Immune system responses to like receptor protein (NLRP) 3.15,16 The infammasome is a group P acnes rather than microbial density may infuence progression of intracellular proteins that convert procaspase-1 to caspase-1. to disease. Some P acnes phylotypes are associated with healthy Caspase-1 converts the inactive precursor of IL-1–beta to its skin rather than with skin affected by acne; others are more active form.17 Additionally, P acnes induces monocyte production likely found in skin affected by acne than in healthy skin.21 Acne- of matrix metalloproteinases. These enzymes are associated with associated P acnes phylotypes have been shown to induce higher numerous infammatory conditions and may play a role in matrix levels of IFN-gamma and IL-17 in peripheral blood mononuclear degradation and formation of acne scars.18,19 cells than those associated with healthy skin. In recent studies, P acnes also stimulates an adaptive immune response, inducing phylotypes associated with healthy skin induced higher levels of IL-17A and interferon (IFN)-gamma secretion from CD4+ T cells IL-10, an anti-infammatory cytokine.22,23 Future studies might in vitro. Type 17 helper T cells (TH17) and type 1/type 17 helper determine whether P acnes strains associated with healthy skin 23 T cells (TH1/TH17) that react to P acnes stimulation are found in can reduce TH1 or TH17 infammation. the peripheral blood of patients with and without acne, but cells These current pathogenic concepts suggest new targets for from patients with acne displayed stronger responses to P acnes.20 therapy, including FoxO1, mTORC1, TLR2, the NLRP3 infam- P acnes infuences the development of acne in ways beyond masome, caspase-1, and IL-1–beta.14,15 Consumption of foods that promoting infammation. P acnes bioflm formation has been increase FoxO1 or inhibit mTORC1 and infammasome activation detected in the sebaceous follicles of patients with acne. Bioflm should alleviate acne. A paleolithic diet—ie, eliminating hypergly- formation leads to increased P acnes virulence, manifested in part cemic carbohydrates and dairy products—and consumption of by the increased expression of P acnes triglyceride lipase, which vegetables, berries, sea fsh, and green tea may be a nutritional increases the sebum concentration of palmitic and oleic acids. therapy for acne.6 These changes in sebum lipid composition contribute to inducing Treatments eradicating P acnes may leave a microbiome infammatory acne. As noted, oleic acid increases P acnes adher- vacuum that could be repopulated by P acnes strains promoting ence and growth. Therefore, P acnes triglyceride lipase may anti-infammatory profles. Sebum production and altered proin- indirectly contribute to bioflm formation by promoting increased fammatory lipid content represent additional targets for acne concentration of oleic acid.8 therapies. An analysis of clinical trials found that sebum reduction

Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S61 ■ ■ ■ Current Concepts in Acne Pathogenesis: Pathways to Inflammation is associated with acne improvement.24 Acetyl coenzyme A carbox- 13. Thiboutot DM. Infammasome activation by Propionibacterium acnes: The story of IL-1 in acne continues to unfold. J Invest Dermatol. 2014;134:595-597. ylase (ACC) catalyzes the rate-limiting step in synthesis of fatty 14. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like receptor 2 in acne triggers 25 acids that become components of sebaceous lipids. IGF-1 infammatory cytokine responses. J Immunol. 2002;169:1535-1541. and androgens upregulate expression of a transcription factor 15. Qin M, Pirouz A, Kim MH, Krutzik SR, Garban HJ, Kim J. Propionibacterium acnes that promotes ACC expression.26 Investigational acne therapies induces IL-1ß secretion via the NLRP3 infammasome in human monocytes. J Invest Dermatol. 2014;134:381-388. include a topical antiandrogen medication and a topical inhibitor 16. Kistowska M, Gehrke S, Jankovic D, et al. IL-1ß drives infammatory responses to of ACC (see Advances in Acne and Rosacea Therapy, page S63). Propionibacterium acnes in vitro and in vivo. J Invest Dermatol. 2014;134:677-685. Another potential intervention involves nitric oxide. Nitric- 17. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of infammatory diseases. oxide–releasing nanoparticles (NO-np) have been shown to Blood. 2011;117:3720-3732. 18. Jalian HR, Liu PT, Kanchanapoomi M, Phan JN, Legaspi AJ, Kim J. All-trans retinoic suppress IL-1–beta, tumor necrosis factor–alpha, and IL-8 acid shifts Propionibacterium acnes-induced matrix degradation expression profle toward release from human monocytes, and IL-8 and IL-6 release from matrix preservation in human monocytes. J Invest Dermatol. 2008;128:2777-2782. human keratinocytes. NO-np reduce IL-1–beta secretion in part 19. Sato T, Kurihara H, Akimoto N, Noguchi N, Sasatsu M, Ito A. Augmentation of gene 27 expression and production of promatrix metalloproteinase 2 by Propionibacterium acnes- by inhibition of caspase-1. NO-np also kill P acnes in vitro. derived factors in hamster sebocytes and dermal fbroblasts: A possible mechanism for A nitric-oxide–releasing macromolecule formulated in an alco- acne scarring. Biol Pharm Bull. 2011;34:295-299. 28 holic gel is under study for the treatment of acne. (For more 20. Kistowska M, Meier B, Proust T, et al. Propionibacterium acnes promotes TH17 and TH17/ T 1 responses in acne patients. J Invest Dermatol. 2015;135:110-118. information, see Advances in Acne and Rosacea Therapy, page H 21. Fitz-Gibbon S, Tomida S, Chiu BH, et al. Propionibacterium acnes strain populations in S63.) Current therapies address some elements of pathogenic the human skin microbiome associated with acne. J Invest Dermatol. 2013;133:2152-2160. pathways. Azelaic acid 15% gel; an oral contraceptive (drospire- 22. Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in infammation and none 3 mg/ethinyl estradiol 20 μg); the topical retinoids adapalene, autoimmune disease. Crit Rev Immunol. 2012;32:23-63. 23. Yu Y, Champer J, Agak GW, Kao S, Modlin RL, Kim J. Different Propionibacterium tazarotene, and tretinoin; and oral isotretinoin have each been acnes phylotypes induce distinct immune responses and express unique surface associated with reduced expression of TLR2.29-34 Azelaic acid has and secreted proteomes. J Invest Dermatol. 2016;136:2221-2228. demonstrated anti-infammatory action in vitro by inhibiting the 24. Janiczek-Dolphin N, Cook J, Thiboutot D, Harness J, Clucas A. Can sebum reduction generation of reactive oxygen species.35 predict acne outcome? Br J Dermatol. 2010;163:683-688. 25. Munday MR. Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans. Summary 2002;30:1059-1064. 26. Melnik BC. Olumacostat glasaretil, a promising topical sebum-suppressing agent Infammation plays a central role in acne pathogenesis and insulin. that affects all major pathogenic factors of acne vulgaris. J Invest Dermatol. IGF-1 and androgens are prime orchestrators, with initiation likely 2017;137:1405-1408. due to consumption of dairy foods and a high glycemic index diet. 27. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced infammation by both clearing the organism and The hormones lead to increased sebum production and a more inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. infammatory composition of sebaceous lipids. These changes 2015;135:2723-2731. promote P acnes overgrowth and infammation through multiple 28. Baldwin H, Blanco D, McKeever C, et al. Results of a phase 2 effcacy and safety study with SB204, an investigational topical nitric oxide-releasing drug for the treatment of pathways, triggering both innate and adaptive immune activation acne vulgaris. J Clin Aesthet Dermatol. 2016;9:12-18. (Figure). TLR2, caspase-1, the infammasome, IL-1–beta, and 29. Rocha MAD, Guadanhim LRS, Sanudo A, Bagatin E. Modulation of toll like mediators of sebum production offer possible therapeutic targets receptor-2 on sebaceous gland by the treatment of adult female acne. Dermatoendocrinol. 2017;9:e1361570. in acne. All P acnes phylotypes do not act in the same way; some 30. Jones DA. The potential immunomodulatory effects of topical retinoids. Dermatol Online J. have been associated with healthy skin, rather than acne, and have 2005;11:3. anti-infammatory effects. Benefcial P acnes phylotypes may lend 31. Dispenza MC, Wolpert EB, Gilliland KL, et al. Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. J Invest themselves to future therapies. Dermatol. 2012;132:2198-2205. 32. Gregoriou S, Kritsotaki E, Katoulis A, Rigopoulos D. Use of tazarotene foam for the References treatment of acne vulgaris. Clin Cosmet Investig Dermatol. 2014;7:165-170. 1. Isard O, Knol AC, Ariès MF, et al. Propionibacterium acnes activates the IGF-1/IGF-1R system in the epidermis and induces keratinocyte proliferation. J Invest Dermatol. 33. Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CD1d and IL-10 2011;131:59-66. by adapalene on normal human skin and acne infammatory lesions. Exp Dermatol. 2007;16:500-506. 2. Melnik BC. p53: Key conductor of all anti-acne therapies. J Transl Med. 2017;15:195. 34. Zuliani T, Khammari A, Chaussy H, Knol AC, Dréno B. Ex vivo demonstration of a 3. Dreno B, Gollnick HP, Kang S, et al; Global Alliance to Improve Outcomes in Acne. synergistic effect of adapalene and benzoyl peroxide on infammatory acne lesions. Exp Understanding innate immunity and infammation in acne: Implications for management. Dermatol. 2011;20:850-853. J Eur Acad Dermatol Venereol. 2015;29(suppl 4):3-11. 35. Jones DA. Rosacea, reactive oxygen species, and azelaic acid. J Clin Aesthet Dermatol. 4. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Infammatory events 2009;2:26-30. are involved in acne lesion initiation. J Invest Dermatol. 2003;121:20-27. 5. Ben-Amitai D, Laron Z. Effect of insulin-like growth factor-1 defciency or administration on the occurrence of acne. J Eur Acad Dermatol Venereol. 2011;25:950-954. 6. Melnik BC. Linking diet to acne metabolomics, infammation, and comedogenesis: An update. Clin Cosmet Investig Dermatol. 2015;8:371-388. 7. Chiba K, Yoshizawa K, Makino I, Kawakami K, Onoue M. Comedogenicity of squalene monohydroperoxide in the skin after topical application. J Toxicol Sci. 2000;25:77-83. 8. Gribbon EM, Cunliffe WJ, Holland KT. Interaction of Propionibacterium acnes with skin lipids in vitro. J Gen Microbiol. 1993;139:1745-1751. 9. Katsuta Y, Iida T, Hasegawa K, Inomata S, Denda M. Function of oleic acid on epidermal barrier and calcium infux into keratinocytes is associated with N-methyl D-aspartate-type glutamate receptors. Br J Dermatol. 2009;160:69-74. 10. Katsuta Y, Iida T, Inomata S, Denda M. Unsaturated fatty acids induce calcium infux into keratinocytes and cause abnormal differentiation of epidermis. J Invest Dermatol. 2005;124:1008-1013. 11. Choi EH, Ahn SK, Lee SH. The changes of stratum corneum interstices and calcium distribution of follicular epithelium of experimentally induced comedones (EIC) by oleic acid. Exp Dermatol. 1997;6:29-35. 12. Lovászi M, Szegedi A, Zouboulis CC, Tör˝ocsik D. Sebaceous-immunobiology is orchestrated by sebum lipids. Dermatoendocrinol. 2017:9:e1375636.

S62 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Advances in Acne and Rosacea Therapy Linda F. Stein Gold, MD,* Andrew F. Alexis, MD, MPH,† Julie C. Harper, MD,‡ and Jerry K. L. Tan, MD, FRCPC§

Overview ■ Abstract Patients with moderate or severe acne that does not respond to New topical therapies have demonstrated efficacy topical therapies often receive systemic antibiotic therapy or in patients with moderate or severe acne who might isotretinoin. The American Academy of Dermatology (AAD) otherwise have required therapy with systemic antibiotics or guidelines for management of acne recommend limiting the duration isotretinoin. Increasing knowledge about the pathogenesis of systemic antibiotics and avoiding monotherapy with them to of acne has facilitated the development of therapies with reduce the risk of antibiotic resistance (see Revisiting Antibiotic novel modes of action. New and investigational therapies Treatment).1 Topical therapy that can improve moderate to severe also are available or in development for the treatment of acne without the need for systemic antibiotics or oral isotretinoin both the papulopustular and erythematous manifestations is needed. New topical therapies have demonstrated effcacy in up of rosacea. 2,3 Semin Cutan Med Surg 37(supp3):S63-S66 to half of patients with severe acne. A new treatment has been 4 © 2018 published by Frontline Medical Communications studied in truncal acne as well (see Truncal Acne). Investigational ■ Keywords therapies with novel mechanisms of action in acne include a topical nitric-oxide–releasing macromolecule,5 a melanocortin receptor-5 Acne; adapalene; azelaic acid; ivermectin; rosacea; topical 6 7 minocycline; truncal acne antagonist, and an antiandrogen cream (CB-03-01 1%). New therapies for rosacea include a 15% foam formulation of azelaic acid, an antiparasitic agent (ivermectin 1% cream), * Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan an alpha1A-adrenergic receptor agonist (topical oxymetazoline † Chair, Department of Dermatology, Director of The Skin of Color hydrochloride cream 1%), and a cationic antimicrobial peptide Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate (omiganan). Separate formulations of topical minocycline are in Professor of Dermatology, Icahn School of Medicine at Mount Sinai, development for acne and rosacea. New York, New York ‡ Clinical Associate Professor of Dermatology, University of Alabama at Birmingham, Dermatology and Skin Care Center of Birmingham, Revisiting Antibiotic Treatment Birmingham, Alabama The current AAD guidelines and a recent consensus statement § Adjunct Professor, Schulich School of Medicine & Dentistry, Western from the Global Alliance to Improve Outcomes in Acne recommend University, Windsor, Ontario, Canada limiting antibiotic use in acne therapy to reduce the risk of antibiotic Publication of this CME/CE article was jointly provided by University resistance, as follows1,8: of Louisville, Postgraduate Institute for Medicine, and Global Academy • Use topical and systemic antibiotics in combination with for Medical Education, LLC, and is supported by an educational nonantibiotic therapies (eg, topical benzoyl peroxide [BPO], grant from Bayer. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance topical retinoids) of Eileen A. McCaffrey, MA, medical writer, and Global Academy – Monotherapy with antibiotics is not recommended for Medical Education in the development of this continuing medical • Use systemic antibiotics for the shortest possible duration, education journal article. with reevaluation after 3 to 4 months Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., – Evaluate response time in 6 to 8 weeks8 Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals Truncal Acne International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., Approximately half of patients with acne have disease manifesta- Valeant Pharmaceuticals International, Inc. tions on the back and/or chest.9 Because patients may incorrectly Andrew F. Alexis, MD, MPH, Consultant: Allergan plc, BioPharmX, Inc., report no acne in these areas, physical examination by the clinician Galderma Laboratories, L.P. Contracted Research: Allergan plc, is mandatory.10 The difficulty of applying topical therapies to all of the BioPharmX, Inc., Galderma Laboratories, L.P., Novan, Inc. affected truncal areas, and the time required to do so, can compli- Julie C. Harper, MD, Consultant: Allergan plc, Bayer AG, BioPharmX, cate use of this approach. For this reason, oral therapies are often Inc., Galderma Laboratories, L.P., La Roche-Posay, Novan, Inc., Ortho prescribed for truncal acne in clinical practice. However, their use Dermatologics. Contracted Research: Bayer AG. Speakers Bureau: Allergan plc, Bayer AG, La Roche-Posay, Ortho Dermatologics. is limited by AAD guidelines meant to reduce the risk of antibiotic resistance (see Revisiting Antibiotic Treatment).1 Jerry K. L. Tan, MD, FRCPC, Consultant: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. A recent open-label study evaluated the efficacy of azelaic acid Contracted Research: Dermira, Inc., Galderma Laboratories, L.P., 15% foam in moderate truncal acne. Twice-daily foam application Valeant Pharmaceuticals International, Inc. Speakers Bureau: Galderma resulted in a 1-grade reduction on the 5-grade Investigator Global Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Assessment (IGA) scale for 16 of 18 patients with acne. After 16 weeks Address reprint requests to: Linda F. Stein Gold, MD, Henry Ford of therapy, 8 of 18 patients (44%) were judged to be clear or almost Health System, 6530 Farmington Road, West Bloomfeld, MI 48322; clear. The medication also improved facial acne.4 [email protected]

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.025 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S63 ■ ■ ■ Advances in Acne and Rosacea Therapy

What’s New in Acne? creatine phosphokinase, and decreased white blood cell count. The 15 Approved Agents 1.5-mg/kg dose has entered phase 3 development. Adapalene 0.3% / benzoyl peroxide 2.5% (ADAP 0.3% / BPO 2.5%) SB204. This agent contains a nitric oxide–releasing macromolecule 16 gel. In a randomized, double-blind study on ADAP 0.3%/BPO formulated in an alcoholic gel. Nitric oxide has been shown 2.5% applied once daily, about one-third of patients with moderate to inhibit Propionibacterium acnes growth as well as P acnes- or severe infammatory acne achieved an IGA score of clear/almost stimulated release of interleukin (IL)-1–beta and other cytokines.5 clear with at least a 2-grade improvement on the IGA scale at week Once-daily therapy with SB204 4% significantly reduced the 12 (Table 1).3,11-13 The mean reduction in baseline in infammatory percentage of infammatory lesions from baseline by week 4 and and noninfammatory lesion counts was signifcantly greater with the absolute infammatory and noninfammatory lesion count ADAP 0.3%/BPO 2.5% than with vehicle. Skin irritation (2.8%) at week 12, compared with vehicle, in subjects with moderate or and a burning sensation (0.9%) were the most common treatment- severe acne.17 A study including patients with mild disease produced related adverse events (AEs).3 similar fndings.16 The rate of TEAEs was similar across treatment Improvements also occurred among patients with severe acne at groups. The rate of IGA success (clear/almost clear and ≥2-grade baseline. Nearly one-third of these patients demonstrated at least improvement vs baseline) with SB204 4% was low (2.0%) and did a 3-grade improvement to clear/almost clear on the IGA scale at not differ from that of vehicle (1.9%).16 12 weeks with single-agent topical therapy (31.9% vs 11.8%; 95% Topical olumacostat glasaretil (OG) 7.5%. Following an announce- confdence interval, 6.0%-34.2%; P=0.029).3 ment that this agent did not meet any of its coprimary endpoints in Clindamycin 1.2% / BPO 3.75% gel. This therapy demonstrated two phase 3 trials, development of this therapy is not proceeding at effcacy compared with vehicle in a randomized trial of patients the time of this writing. with moderate or severe acne (Table 1).11 More than half (55.1%) of patients with severe acne attained at least a 2-grade reduction in Melanocortin receptor-5 antagonist (MTC896). A phase 2, dose- Evaluator Global Severity Score (EGSS) at week 12.2 The overall ranging study of MTC896 delivered in a topical gel and applied 18 rates of treatment-emergent adverse events (TEAEs) with active twice daily is ongoing. therapy in the main trial and both subgroups (severe acne and Topical minocycline. Minocycline 4% foam applied once daily adolescents) were similar to that of vehicle.2,11,14 demonstrated effcacy in a phase 2, 12-week-long trial (N=139; Dapsone 7.5% gel. This agent, applied once daily, has demonstrated moderate or severe acne). More than one-third of patients (36.2%) effcacy in two identically designed randomized, vehicle-controlled achieved at least a 2-grade improvement on the IGA scale at week studies in adults and adolescents with moderate acne (Table 1).12,13 12 with topical minocycline, compared with 15.2% for vehicle The rate of TEAEs was similar for dapsone 7.5% gel and vehicle.12,13 (P=0.021). Topical minocycline 4% foam produced a signifcantly greater mean percentage reduction from baseline in infammatory Investigational Therapies Sarecycline is a once-daily, oral, narrow-spectrum, tetracycline- and noninflammatory lesion count compared with vehicle. 19 derived antibiotic with anti-infammatory properties. At 1.5 and Tolerability did not differ signifcantly between treatment groups. 3.0 mg/kg, it signifcantly reduced infammatory lesion counts In two identical phase 3 studies of this agent (N=466, N=495), from baseline compared with placebo (by 52.7%, 51.8%, and the change from baseline to week 12 in absolute infammatory 38.3%, respectively), with no signifcant difference from placebo in lesion count for topical minocycline 4% foam was signifcantly noninfammatory lesion counts in a phase 2 trial of patients with greater than that observed with a foam vehicle. The other coprimary moderate or severe acne. The rate of TEAEs was similar across endpoint—IGA score of clear or almost clear plus at least a 2-grade treatment groups. AEs leading to discontinuation from sarecycline improvement from baseline—was signifcant in only one of the two and considered treatment-related were hypoesthesia, increased phase 3 studies.20

■ TABLE 1 New Therapies for Acne: Efficacy Data

Agent Study Population Results (12 weeks) ADAP 0.3%/BPO 2.5% gel N=503; 50:50 Clear/almost clear and ≥2-grade IGA improvement: 33.7% active once daily vs vehicle3 moderate:severe acne therapy; 11.0% vehicle (P<0.001)

Clindamycin 1.2%/BPO N=498; 82.7% with Change in inflammatory lesion counts: 60.6% vs 31.4% with vehicle 3.75% gel once daily moderate acne (P<0.001) vs vehicle11 Noninflammatory lesion counts: 51.6% vs 27.4% with vehicle (P<0.001) 34.3% vs 15.6% with vehicle achieved ≥2-grade reduction in EGSS (P<0.001) Dapsone 7.5% gel N=2,238 and N=2,102 GAAS, 0 or 1: 29.9% and 29.8%, respectively, with dapsone vs 21.2% and vs vehicle12,13 aged ≥12 years, 20.9%, respectively, with vehicle (P<0.001) moderate acne Total lesion count decreased by 48.7% and 48.9%, respectively, vs 42.4% and 43.2% with vehicle (P<0.001)

ADAP=adapalene; BPO=benzoyl peroxide; EGSS=Evaluator Global Severity Score; GAAS=Global Acne Assessment Score; IGA=Investigator Global Assessment. Sources: Stein Gold L, et al3; Pariser DM, et al11; Stein Gold LF, et al12; Eichenfield LF, et al.13

S64 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, Julie C. Harper, MD, and Jerry K. L. Tan, MD, FRCPC

21 A phase 3 trial is ongoing. A phase 2b, 12-week-long, dose-ranging Topical oxymetazoline hydrochloride cream 1%. An alpha1A- trial of a topical minocycline gel (1% or 2% vs vehicle) in patients adrenergic receptor agonist that causes vasoconstriction of the with moderate or severe infammatory acne has been completed.22 skin microvasculature, this agent received US Food and Drug CB-03-01 1% cream. In an 8-week, phase 2 trial, this once-daily Administration approval in January 2017 for persistent facial antiandrogen cream was statistically superior to placebo at 8 weeks erythema associated with rosacea in adults. Signifcantly larger in terms of total lesion count, infammatory lesion count, and acne proportions of patients achieved at least a 2-grade improvement on severity index (N=77 men; mild to moderate acne).7 It was not both the Clinician Erythema Assessment (CEA) and Subject Self- superior to placebo in its effect on IGA score.23 Phase 3 studies are Assessment (SSA) after 29 days of treatment with oxymetazoline in progress.24,25 hydrochloride cream compared with vehicle, in two pivotal phase 3, vehicle-controlled studies in patients with moderate or severe facial What’s New in Rosacea? erythema of rosacea (Table 2).29,30 New Topical Agents Investigational Therapies Azelaic acid (AZA) 15% foam. Signifcantly higher proportions of Omiganan (CONTRols001). A synthetic, cationic antimicrobial patients achieved an IGA score of clear/almost clear plus at least peptide, omiganan is in phase 3 development for the treatment of a 2-point improvement at week 12 with AZA foam than with severe papulopustular rosacea.33-36 vehicle (Table 2).26-30 Change in infammatory lesion count also was Topical minocycline. Three topical minocycline products are signifcantly greater with AZA 15% foam (−13.2 ± 9.5 vs −10.3 ± 9.8; under study for the treatment of rosacea. In a phase 2, randomized, P <0.001). Application-site pain, pruritus, and dryness were reported vehicle-controlled study, topical minocycline 1.5% and 3% foam more frequently with AZA 15% foam than with vehicle.26 each reduced the infammatory lesion count signifcantly more Ivermectin 1% cream. Signifcantly higher proportions of those than vehicle after 12 weeks of therapy in a study population of treated with ivermectin 1% cream achieved IGA scores of clear/ 232 patients with moderate to severe facial papulopustular rosacea (21.1 and 19.1 vs 7.8, respectively; P<0.001). Signifcantly more almost clear compared with vehicle, in two 12-week studies patients receiving active therapy achieved IGA scores of clear/ (Table 2).27,28 Dermatologic AEs were less common with ivermectin 27 almost clear and at least a 2-grade IGA improvement at week 12 than with vehicle. The rate of treatment-related dermatologic AEs (41.8%, 33.3%, and 17.9%; 1.5% and 3.0% topical minocycline was numerically lower with ivermectin 1% cream in a long-term foam and vehicle, respectively; P<0.01). Rates of patients extension trial of both studies (7.8% vs 12.9%, and 9.8% vs 16.3%; reporting treatment-related AEs were 2.5%, 5.3%, and 6.4%, with ivermectin and vehicle, respectively). Statistical comparisons were topical minocycline 1.5% and 3% foam, and vehicle, respectively. not performed.28 No serious treatment-related AEs were reported.37 A phase 3 Ivermectin cream and brimonidine gel have reduced study and a long-term safety study of the 1.5% formulation are papulopustular lesions and erythema, respectively.27,31 More than underway.38,39 60% of subjects with moderate or severe rosacea randomized to Two topical minocycline gels are in phase 2 or phase 1/2 studies concomitant therapy with both agents for 12 weeks (ivermectin in patients with moderate to severe papulopustular rosacea.39,40 1% cream, brimonidine 0.33% gel) attained IGA scores of clear/ Summary almost clear at the end of treatment (week 12; 3 hours after New and investigational topical therapies are expanding the brimonidine application [61.2% vs 36.8% with vehicle, respectively; options for patients with moderate or severe acne, potentially P=0.007]). Half of the patients who received ivermectin 1% cream enabling a larger number of patients to avoid systemic antibiotic for 12 weeks with vehicle gel for 4 weeks and brimonidine gel for or isotretinoin therapy. New treatments are increasing the options 8 weeks attained clear/almost clear IGA scores at 12 weeks.32 for rosacea as well.

■ TABLE 2 New Therapies for Rosacea: Efficacy Data

Agent Study Population Results

Azelaic acid 15% foam N=961; moderate or severe PPR 12 weeks: Clear/almost clear and ≥2-grade IGA improvement: twice daily vs vehicle26 32.0% vs 23.5% with vehicle (P<0.001)

Ivermectin 1% cream vs N=683 and N=688; moderate 12 weeks: Clear/almost clear: 38.4% and 40.1% vs 11.6% and 18.8% vehicle once daily27,28 or severe PPR; 12 weeks with vehicle (P<0.001) 40 weeks (N=622, N=636)a: Clear/almost clear: 71.1% and 76.0%

Topical oxymetazoline N=440; moderate or severe CEA and SSA successb; day 29, hours post dose (active therapy vs vehicle): hydrochloride cream 1% facial erythema of rosacea 3 hours: 11.9% vs 5.5%; P<0.05; 6 hours: 15.5% vs 8.3%; P<0.05; vs vehicle29 9 hours: 17.7% vs 6.0%; P<0.001; 12 hours: 14.8% vs 6.0%; P<0.01

Topical oxymetazoline N=445; moderate or severe CEA and SSA successb; day 29, hours post dose (active therapy vs vehicle): hydrochloride cream 1% facial erythema of rosacea 3 hours: 14.3% vs 7.4%; P<0.05; 6 hours: 13.4% vs 4.8%; P<0.01; vs vehicle30 9 hours: 15.5% vs 8.5%; P<0.05; 12 hours: 12.3% vs 6.1%; P<0.05

CEA=Clinician Erythema Assessment; PPR=papulopustular rosacea; SSA=Subject Self-Assessment. ªLong-term extension of the two 12-week studies. bDefined as ≥2-grade decrease (composite success) from baseline on both the CEA and SSA at 3, 6, 9, and 12 hours post dose on day 29. Sources: Draelos ZD, et al26; Stein Gold L, et al27; Stein Gold L, et al28; Kircik LH, et al29; Baumann L, et al.30

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30. Baumann L, Goldberg DJ, Stein Gold L, et al. Pivotal trial of the effcacy and safety of References oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with 1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of rosacea: Findings from the second REVEAL trial. J Drugs Dermatol. 2018;17:290-298. acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33. 31. Fowler J Jr, Jackson M, Moore A, et al. Effcacy and safety of once-daily topical 2. Stein Gold L. Effcacy and tolerability of a fxed combination of clindamycin phosphate brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of (1.2%) and benzoyl peroxide (3.75%) aqueous gel in moderate and severe acne vulgaris rosacea: Results of two randomized, double-blind, and vehicle-controlled pivotal studies. subpopulations. J Drugs Dermatol. 2015;14:969-974. J Drugs Dermatol. 2013;12:650-656. 3. Stein Gold L, Weiss J, Rueda MJ, Liu H, Tanghetti E. 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Updated January 25, 2018. NCT02547441. Propionibacterium acnes-induced infammation by both clearing the organism and 35. ClinicalTrials.gov. Study to evaluate the long-term safety of a once-daily omiganan inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. topical gel. Updated January 25, 2018. NCT02576847. 2015;135:2723-2731. 36. Rubinchik E, Dugourd D, Algara T, Pasetka C, Friedland HD. Antimicrobial and 6. Eisinger M, Li WH, Anthonavage M, et al. A melanocortin receptor 1 and 5 antagonist antifungal activities of a novel cationic antimicrobial peptide, omiganan, in experimental inhibits sebaceous gland differentiation and the production of sebum-specifc lipids. skin colonisation models. Int J Antimicrob Agents. 2009;34:457-461. J Dermatol Sci. 2011;63:23-32. 37. Mrowietz U, Kedem TH, Keynan R, et al. A phase II, randomized, double-blind clinical 7. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone study evaluating the safety, tolerability, and effcacy of a topical minocycline foam, 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne FMX103, for the treatment of facial papulopustular rosacea. Am J Clin Dermatol. 2018. vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin doi:10.1007/s40257-017-0339-0. 0.05% cream. Br J Dermatol. 2011;165:177-183. 38. ClinicalTrials.gov. A study to evaluate the safety and effcacy of FMX103 1.5% topical 8. Thiboutot DM, Dréno B, Abanmi A, et al. Practical management of acne for clinicians: minocycline foam in the treatment of facial papulopustular rosacea. Updated September An international consensus from the Global Alliance to Improve Outcomes in Acne. 6, 2017. NCT03142451. J Am Acad Dermatol. 2018;78(suppl):S1-S23.e1. 39. ClinicalTrials.gov. A study to evaluate the long-term safety of topical administration 9. Del Rosso JQ, Bikowski JB, Baum E, et al. A closer look at truncal acne vulgaris: of FMX103 in the treatment of moderate to severe papulopustular rosacea. Updated Prevalence, severity, and clinical signifcance. J Drugs Dermatol. 2007;6:597-600. October 25, 2017. NCT03276936. 10. Tan JK, Tang J, Fung K, et al. Prevalence and severity of facial and truncal acne in a 40. ClinicalTrials.gov. Study to evaluate the safety and effcacy of topical minocycline gel in referral cohort. J Drugs Dermatol. 2008;7:551-556. patients with papulopustular rosacea. Updated February 26, 2018. NCT03263273. 11. Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fxed combination 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. 12. Stein Gold LF, Jarratt MT, Bucko AD, et al. Effcacy 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, vehicle-controlled trials. J Drugs Dermatol. 2016;15:553-561. 13. Eichenfeld LF, Lain T, Frankel EH, et al. Effcacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: Second of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15:962-969. 14. Cook-Bolden FE. Effcacy and tolerability of a fxed combination of clindamycin phosphate (1.2%) and benzoyl peroxide (3.75%) aqueous gel in moderate or severe adolescent acne vulgaris. J Clin Aesthet Dermatol. 2015;8:28-32. 15. Leyden JJ, Sniukiene V, Berk DR, Kaoukhov A. Effcacy and safety of sarecycline, a novel, once-daily, narrow spectrum antibiotic for the treatment of moderate to severe facial acne vulgaris: Results of a phase 2, dose-ranging study. J Drugs Dermatol. 2018;17:333-338. 16. Baldwin H, Blanco D, McKeever C, et al. Results of a phase 2 effcacy and safety study with SB204, an investigational topical nitric oxide-releasing drug for the treatment of acne vulgaris. J Clin Aesthet Dermatol. 2016;9:12-18. 17. Eichenfeld LF, Gold LS, Nahm WK, Cook-Bolden FE, Pariser DM. Results of a phase 2, randomized, vehicle-controlled study evaluating the effcacy, tolerability, and safety of daily or twice daily SB204 for the treatment of acne vulgaris. J Drugs Dermatol. 2016;15:1496-1502. 18. ClinicalTrials.gov. A study to determine the effcacy of topically applied MTC896 gel in subjects with acne vulgaris. Updated June 16, 2016. NCT02395549. 19. Shemer A, Shiri J, Mashiah J, Farhi R, Gupta AK. Topical minocycline foam for moderate to severe acne vulgaris: Phase 2 randomized double-blind, vehicle-controlled study results. J Am Acad Dermatol. 2016;74:1251-1252. 20. Stein Gold L, Dhawan S, Weiss J, Draelos Z, Ellman H. The effcacy and safety of FMX101, minocycline foam 4%, for the treatment of acne vulgaris: A pooled analysis of phase 2 and phase 3 studies. Presented at: Fall Clinical Dermatology Conference; October 11-15, 2017; Las Vegas, NV. 21. ClinicalTrials.gov. A study to evaluate the effcacy and safety of topical administration of FMX101 in the treatment of moderate-to-severe acne vulgaris. Updated September 1, 2017. NCT03271021. 22. ClinicalTrials.gov. BPX-01 minocycline topical gel in the treatment of acne vulgaris (OPAL). Updated April 14, 2017. NCT02815332. 23. Celasco G, Piacquadio D, Moro L. Cortexolone 17a-propionate 1% cream, a new potent antiandrogen: A frst-in-man assessment in the treatment of acne vulgaris. J Am Acad Dermatol. 2012;66:AB15. 24. ClinicalTrials.gov. A study to evaluate the safety and effcacy of CB-03-01 cream, 1% in subjects with facial acne vulgaris (25). Updated November 29, 2017. NCT02608450. 25. ClinicalTrials.gov. A study to evaluate the safety and effcacy of CB-03-01 cream, 1% in subjects with facial acne vulgaris (26). Updated October 26, 2017. NCT02608476. 26. 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 papulopustular rosacea. Cutis. 2015;96:54-61. 27. Stein Gold L, Kircik L, Fowler J, et al. Effcacy 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. 28. Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating infammatory lesions of rosacea: Results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13:1380-1386. 29. Kircik LH, DuBois J, Draelos ZD, et al. Pivotal trial of the effcacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: Findings from the frst REVEAL trial. J Drugs Dermatol. 2018;17:97-105.

S66 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Treating Acne in Adult Women Julie C. Harper, MD,* Linda F. Stein Gold, MD,† Andrew F. Alexis, MD, MPH,‡ and Jerry K. L. Tan, MD, FRCPC§

signifcantly higher in women than in men, according to a survey ■ Abstract conducted in medical center waiting areas and a campus library Acne can persist into adulthood or erupt de novo at any point (N=1,013).1 More than half (51%) of women and 43% of men after adolescence. Adult acne is more common in women reported having acne in their 20s, with percentages dropping to 26% than in men. Considerations for treating acne in adult women and 12% in their 40s, and 15% and 7% in those 50 and older (women include childbearing potential, pregnancy, lactation, and and men, respectively). An online survey found that one-third concomitant skin conditions. of adult women with facial acne (33.7% of 208 women aged 25- Semin Cutan Med Surg 37(supp3):S67-S70 2 © 2018 published by Frontline Medical Communications 45 years) reported that the condition was diagnosed in adulthood. The treatment of acne in adult women is similar in many respects ■ Keywords to that of men and younger females, although treatment choices Acne; adult women; lactation; oral contraceptives; pregnancy will be infuenced by a woman’s childbearing potential, pregnancy, use of or desire for systemic contraception, and lactation status. Other considerations particular to adult women may include the lthough acne most often appears in adolescence, it can need to address—or at least avoid—exacerbating multiple skin continue into adulthood or can develop de novo during that conditions (eg, dryness, hyperpigmentation, photoaging) along stage of life. The self-reported prevalence of adult acne is A with acne. Optimally, acne therapy should be compatible with cosmetics or other facial care products. * Clinical Associate Professor of Dermatology, University of Alabama Table 1 lists considerations for taking a history of an adult woman at Birmingham, Dermatology and Skin Care Center of Birmingham, with acne.3-5 Birmingham, Alabama † Director of Dermatology Clinical Research, Division Head of Topical Therapies Dermatology, Henry Ford Hospital, Detroit, Michigan Topical Retinoid Therapy ‡ Chair, Department of Dermatology, Director of The Skin of Color These medications offer the advantage of effcacy in postinfamma- Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate Professor of Dermatology, Icahn School of Medicine at Mount Sinai, tory hyperpigmentation and photodamage, as well as in acne. Side New York, New York effects include skin irritation.5 § Adjunct Professor, Schulich School of Medicine & Dentistry, Western Adapalene (ADAP) 0.3% demonstrated superiority to vehicle University, Windsor, Ontario, Canada in adult women (18-41 years old; n=117) in reducing infamma- Publication of this CME/CE article was jointly provided by University tory, noninfammatory, and total lesion counts after 12 weeks of of Louisville, Postgraduate Institute for Medicine, and Global Academy therapy, in a post hoc analysis of data from two clinical studies.6 for Medical Education, LLC, and is supported by an educational grant from Bayer. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance ■ TABLE 1 Taking a History of an Adult Woman of Eileen A. McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical With Acne education journal article. • Age of first onset; history of any adolescent acne Julie C. Harper, MD, Consultant: Allergan plc, Bayer AG, BioPharmX, Inc., Galderma Laboratories, L.P., La Roche-Posay, Novan, Inc., Ortho • Other clinicians consulted for acne Dermatologics. Contracted Research: Bayer AG. Speakers Bureau: • Previous acne treatments, including over-the-counter and Allergan plc, Bayer AG, La Roche-Posay, Ortho Dermatologics. prescription medications, facials, peels, light therapy, or Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., microdermabrasion Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, • History of birth control: use of hormonal agents, including Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals oral contraceptives; spironolactone; intrauterine or Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals implanted devices; or injectable agents International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. • Signs/symptoms of androgen excess, eg, hirsutism, Andrew F. Alexis, MD, MPH, Consultant: Allergan plc, BioPharmX, Inc., alopecia, irregular or missed menses, or inability to Galderma Laboratories, L.P. Contracted Research: Allergan plc, conceive a child BioPharmX, Inc., Galderma Laboratories, L.P., Novan, Inc. • Concomitant medical conditions Jerry K. L. Tan, MD, FRCPC, Consultant: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. • Current medications Contracted Research: Dermira, Inc., Galderma Laboratories, L.P., • All products used on the face and hair, including Valeant Pharmaceuticals International, Inc. Speakers Bureau: Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. cosmetics, moisturizers, and personal hygiene products Address reprint requests to: Julie C. Harper, MD, Dermatology and Skin • Expectations regarding results of therapy Care Center of Birmingham, 2470 Rocky Ridge Road, Birmingham, AL Sources: Del Rosso JQ, et al3; Del Rosso JQ, et al4; Del Rosso JQ, et al.5 35243; [email protected]

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.026 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S67 ■ ■ ■ Treating Acne in Adult Women

■ TABLE 2 Combination Oral Contraceptives Indicated for Treatment of Acne

Drug Acne Indication Norgestimate 0.180, 0.215, or Moderate acne vulgaris in females aged ≥15 years who have achieved menarche, have no known 0.250 mg/ethinyl estradiol 35 μg13 contraindication to oral contraceptive therapy, and desire oral contraception for birth control. Norethindrone acetate 1 mg/ Moderate acne vulgaris in females aged ≥15 years who have achieved menarche, have ethinyl estradiol 20, 30, or 35 μg + no known contraindication to oral contraceptive therapy, desire oral contraception for birth ferrous fumarate in the hormone- control, and are unresponsive to topical anti-acne medications. Should be used for the free interval14 treatment of acne only if the patient plans to stay on it for ≥6 months. Drospirenone 3 mg/ethinyl Moderate acne for women aged ≥14 years who have achieved menarche, have no known estradiol 20 μg15 contraindications to oral contraceptive therapy, and desire oral contraception for birth control. Sources: Ortho Tri-Cyclen [package insert]13; Estrostep Fe [package insert]14; Yaz [package insert].15

ADAP 0.1%/benzoyl peroxide (BPO) 2.5% reduced the risk of scar Spironolactone formation compared with vehicle in a small (N=38) study of adult Although not FDA-approved for this use, the oral aldosterone men and women. Participants applied active therapy and vehicle to antagonist and potassium-sparing diuretic spironolactone is separate halves of the face. Scar counts remained stable with active accepted as an option for the treatment of acne.16 In a retrospec- therapy but increased by about 25% with vehicle over a 6-month tive evaluation of data from adult women treated with low-dose treatment period. The proportion of patients rated almost clear (≤150 mg/day) spironolactone, treatment was deemed successful (ie, hardly visible scars) at 6 months rose from 10% to 45% with in 90% of patients for whom full data were available. Success was 7 ADAP/BPO but did not change from baseline with vehicle. A defned as no more than 2 superfcial infammatory lesions, no study of higher-strength ADAP (0.3%)/BPO 2.5% (N=67) also more than 5 retentional lesions (open or closed comedones), no demonstrated reduction and prevention of scarring, again using nodules on the face, and fewer than 5 superfcial infammatory intraindividual comparison. At week 24, change from baseline in lesions on the trunk, including the neck. Median time to response scar count rose by 14.4% with vehicle and decreased by 15.5% with 18 ADAP/BPO (P<0.0001). Higher proportions achieved scores of was 6 months. clear/almost clear on the Scar Global Assessment at week 24 with In another retrospective study, 94 of 110 patients demonstrated ADAP/BPO than with vehicle (32.9% vs 16.4%; P<0.01).8 improvement and 65 were characterized as clear after four or fewer Dapsone 5% / 7.5% has demonstrated effcacy in treatment of follow-up visits. A total of 37 women were clear after the frst acne in adult women.4,9 Compared with adolescent females (n=347), follow-up visit, at a median of 4 weeks. Most patients (101/110) a higher proportion of adult women (n=434) achieved a rating of were started on spironolactone 100 mg/day.19 Reported side effects clear or almost clear after 12 weeks of therapy with dapsone 5% included breakthrough vaginal bleeding, lightheadedness, dizziness, applied twice daily (53.5% vs 45.3%; P=0.022).4 Regardless of low blood pressure, and breast tenderness.18,19 age, a higher proportion of females (n=753) than males (n=700) achieved a rating of clear or almost clear after 12 weeks of therapy with dapsone 5% than with vehicle (48.6% vs 34.4%; P=0.0003).10 ■ TABLE 3 Contraindications to Use of Higher proportions of females than males achieved a Global Combination Oral Contraceptives Acne Assessment Score (GAAS) of 0 or 1 after 12 weeks of therapy with once-daily dapsone 7.5% (33.9% and 24.7%, respectively) in • Pregnancy a pooled subgroup analysis of data from two identical trials. The • Smoking (any amount) and aged >35 years GAAS success rate (score 0 or 1) at week 12 for participants treated with dapsone 7.5% was signifcantly higher for females than males • Uncontrolled hypertension at week 12 (odds ratio, 0.80; 95% confdence interval, 0.68-0.93).9 • Breastfeeding <6 months postpartum Clindamycin 1.2% / B P O 3 . 7 5 % g e l once daily. A post hoc anal- • History ysis of data from 72 adult women (aged ≥25 years) demonstrated – Breast cancer (past or current) superior effcacy of clindamycin 1.2%/BPO 3.75% compared – Ischemic heart disease with vehicle, with 44% of women receiving active therapy rating – Migraine and aged >35 years themselves as clear/almost clear compared with 13.5% of those – Migraine with focal symptoms 11 using vehicle (P=0.026). Another post hoc analysis reported – Stroke higher effcacy among females than males treated with clinda- – Venous thromboembolic disease mycin 1.2%/BPO 3.75%.12 • Hypercholesterolemia (low-density lipoprotein >160 mg/dL) Combination Oral Contraceptives Table 2 lists combination oral contraceptives (COCs) that are • Diabetes and aged >35 years or evidence of end organ damage approved by the US Food and Drug Administration (FDA) for use in acne.13-15 COCs may be used with other topical and oral • Viral hepatitis therapies for acne. Patients should be counseled that at least three • Cirrhosis monthly cycles may pass before acne lesion counts decrease appre- ciably. Side effects of COCs can include nausea, breast tenderness, • Liver tumor (benign or malignant) 16 breakthrough bleeding, and weight gain. Note that progestin-only • Major surgery with prolonged immobilization contraceptives, including injectables or intrauterine devices, can 17 cause or worsen acne.3 Table 3 lists contraindications to COCs.17 Source: Frangos JE, et al.

S68 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Julie C. Harper, MD, Linda F. Stein Gold, MD, Andrew F. Alexis, MD, MPH, and Jerry K. L. Tan, MD, FRCPC

Spironolactone carries a warning to monitor serum potassium One study following 96 patients given isotretinoin (0.5-1 mg/ because of its association with hyperkalemia,20 but its approved kg/dL, with a cumulative dose of 120-150 mg/kg) reported acne uses are in patients with heart failure, hypertension, primary relapses in eight patients during the frst posttreatment year and hyperaldosteronism, and edema associated with cirrhosis.20 A retro- in 16 patients during the second posttreatment year.22 A system- spective analysis of more than 13 years of data from 974 healthy atic literature review including 20 studies found that the cumulative young women taking spironolactone for acne revealed a hyperka- dose required to induce remission varied with disease severity.23 lemia rate of 0.72%, equivalent to the 0.76% baseline rate for this population. Routine monitoring of serum potassium is unnecessary Managing Acne During Pregnancy in otherwise healthy young women taking spironolactone for acne.21 and Lactation Isotretinoin Table 4 lists therapies for acne and their FDA pregnancy risk cate- Oral isotretinoin is highly teratogenic and must be prescribed with gories.24-27 The topical agents azelaic acid, BPO, and clindamycin strict adherence to the federally mandated iPLEDGE risk manage- (known by the mnemonic “ABC”) and the systemic medications ment program (https://www.ipledgeprogram.com/), which, among amoxicillin, cephalexin, and erythromycin (mnemonic “ACE”) can other strategies, mandates the use of two effective forms of contra- be used during pregnancy, although under the restrictions noted ception in women of childbearing potential. in Table 4.

■ TABLE 4 Acne Therapies: Pregnancy Categories

Pregnancy Acne Severity Medication Category Comments

Topicals

Azelaic acid B About 4%-8% absorption; no known fetal effects24 Benzoyl peroxide C May be used on limited areas24 Clindamycin, erythromycin B Minimal data; no known fetal effects24 Dapsone C Limited data; use during pregnancy has not been associated with increased risk of fetal malformations25 Glycolic acid N No evidence of adverse effects during pregnancy25 Salicylic acid C Low risk if restricted to local areas for limited duration25 Topical retinoids C-X Not recommended during pregnancy24,25

Mild/ Systemic medications moderate/ severe Amoxicillin B Short-term; avoid in first trimester—associated with oral clefts24,25 Cephalexin B No malformations in animal studies25 Macrolides (erythromycin is B Short-term use; avoid in first trimester; AVOID erythromycin estolate, drug of choice) as it is associated with hepatotoxicity in the second trimester25 Spironolactone D Feminization of male fetus24 Tetracyclines D Contraindicated after the 15th week of pregnancy24 Zinc C <75 mg/day; no increased risk of fetal abnormalities in animal and human studies25,26

Photodynamic therapy

Narrowband and broadband Considered acceptable during pregnancy25 ultraviolet B light Isotretinoin X Teratogenic; contraindicated in females of childbearing potential unless patient is not pregnant or breastfeeding and agrees to comply with mandatory contraceptive measures (eg, concurrent use of two forms of contraception) in accordance with the System to Manage Accutane Related Severe/ 27 acne Teratogenicity™ (SMART™) fulminans Oral glucocorticoids C Human studies showed an increased risk of oral cleft and a slight increase in miscarriage rates and preterm births; short-term use after first trimester24 Doses limited to <20 mg/day over a course of ≤1 month during the third trimester25 Sources: Murase JE, et al24; Chien AL, et al25; Dréno B, Blouin E26; Isotretinoin capsules [package insert].27

Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S69 ■ ■ ■ Treating Acne in Adult Women

The Drugs and Lactation Database (LactMed) offered by 22. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in nodulocystic acne with and without polycystic ovary syndrome: Effcacy and determinants of relapse. Int J Dermatol. the National Institutes of Health (https://toxnet.nlm.nih.gov/ 2013;52:371-376. newtoxnet/lactmed.htm or LactMed@NIH) and available as a 23. Tan J, Knezevic S, Boyal S, Waterman B, Janik T. Evaluation of evidence for acne remis- mobile phone app (LactMed) enables users to search medications sion with oral isotretinoin cumulative dosing of 120-150 mg/kg. J Cutan Med Surg. 2016;20:13-20. for compatibility with lactation. Short-term use of oral azithro- 24. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy mycin, clarithromycin, doxycycline, erythromycin (oral or topical), and lactation: Part I. Pregnancy. J Am Acad Dermatol. 2014;70:401.e1-401.e14. minocycline, or tetracycline is considered compatible with lactation. 25. Chien AL, Qi J, Rainer B, Sachs DL, Helfrich YR. Treatment of acne in pregnancy. J Am Oral clindamycin may cause adverse gastrointestinal (GI) effects in Board Fam Med. 2016;29:254-262. 26. Dréno B, Blouin E. Acne, pregnant women and zinc salts: A literature review [in French]. the breastfed infant. Topical azelaic acid, topical clindamycin, and Ann Dermatol Venereol. 2008;135:27-33. oral spironolactone are considered acceptable for use during breast- 27. Isotretinoin capsules [package insert]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2017. feeding. Tetracycline may cause rash or GI effects in the infant.28 28. US National Library of Medicine. Drugs and Lactation Database (LactMed). https:// toxnet.nlm.nih.gov/newtoxnet/lactmed.htm. Accessed April 8, 2018. Summary Acne is not uncommon in adult women.1 Treatment consider- ations specifc to adult women include childbearing potential, pregnancy, lactation, the presence of other dermatologic concerns (eg, photoaging, hyperpigmentation, dryness), and the patient’s desire to use acne therapies with cosmetics or other skin products. Familiarity with the options for managing medical care for women in the childbearing years and during pregnancy and lactation can enhance the clinician’s capacity to address acne throughout a woman’s adult years. References 1. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59. 2. Tanghetti EA, Kawata AK, Daniels SR, Yeomans K, Burk CT, Callender VD. Understanding the burden of adult female acne. J Clin Aesthet Dermatol. 2014;7:22-30. 3. Del Rosso JQ, Harper JC, Graber EM, et al. Status report from the American Acne & Rosacea Society on medical management of acne in adult women, part 1: Overview, clinical characteristics, and laboratory evaluation. Cutis. 2015;96:236-241. 4. Del Rosso JQ, Kircik L, Gallagher CJ. Comparative effcacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris. J Clin Aesthet Dermatol. 2015;8:31-37. 5. Del Rosso JQ, Harper JC, Graber EM, Thiboutot D, Silverberg NB, Eichenfeld LF. Status report from the American Acne & Rosacea Society on medical management of acne in adult women, part 2: Topical therapies. Cutis. 2015;96:321-325. 6. Berson D, Alexis A. Adapalene 0.3% for the treatment of acne in women. J Clin Aesthet Dermatol. 2013;6:32-35. 7. Dréno B, Tan J, Rivier M, Martel P, Bissonnette R. Adapalene 0.1%/benzoyl peroxide 2.5% gel reduces the risk of atrophic scar formation in moderate infammatory acne: A split-face randomized controlled trial. J Eur Acad Dermatol Venereol. 2017;31:737-742. 8. Dréno B, Bissonnette R, Gagné-Henley A, et al. Prevention and reduction of atrophic acne scars with adapalene 0.3%/benzoyl peroxide 2.5% gel in subjects with moderate or severe facial acne: Results of a 6-month randomized, vehicle-controlled trial using intra-individual comparison. Am J Clin Dermatol. 2018;19:275-286. 9. Draelos ZD, Rodriguez DA, Kempers SE, et al. Treatment response with once-daily topical dapsone gel, 7.5% for acne vulgaris: Subgroup analysis of pooled data from two randomized, double-blind studies. J Drugs Dermatol. 2017;16:591-598. 10. Tanghetti E, Harper JC, Oefelein MG. The effcacy and tolerability of dapsone 5% gel in female vs male patients with facial acne vulgaris: Gender as a clinically relevant outcome variable. J Drugs Dermatol. 2012;11:1417-1421. 11. Zeichner JA. The effcacy and tolerability of a fxed combination clindamycin (1.2%) and benzoyl peroxide (3.75%) aqueous gel in adult female patients with facial acne vulgaris. J Clin Aesthet Dermatol. 2015;8:21-25. 12. Harper JC. The effcacy and tolerability of a fxed combination clindamycin (1.2%) and benzoyl peroxide (3.75%) aqueous gel in patients with facial acne vulgaris: Gender as a clinically relevant outcome variable. J Drugs Dermatol. 2015;14:381-384. 13. Ortho Tri-Cyclen [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2015. 14. Estrostep Fe [package insert]. Rockaway, NJ: Warner Chilcott (US) LLC; 2009. 15. Yaz [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2017. 16. Del Rosso JQ, Harper JC, Graber EM, Thiboutot D, Silverberg NB, Eichenfeld LF. Status report from the American Acne & Rosacea Society on medical management of acne in adult women, part 3: Oral therapies. Cutis. 2015;96:376-382. 17. Frangos JE, Alavian CN, Kimball AB. Acne and oral contraceptives: Update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786. 18. Isvy-Joubert A, Nguyen JM, Gaultier A, et al. Adult female acne treated with spirono- lactone: A retrospective data review of 70 cases. Eur J Dermatol. 2017;27:393-398. 19. Charny JW, Choi JK, James WD. Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. Int J Womens Dermatol. 2017;3:111-115. 20. Aldactone [package insert]. New York, NY: Pfzer Inc; 2018. 21. Plovanich M, Weng Q, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151:941-944.

S70 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Treating Acne in Patients With Skin of Color Andrew F. Alexis, MD, MPH,* Julie C. Harper, MD,† Linda F. Stein Gold, MD,‡ and Jerry K. L. Tan, MD, FRCPC§

Prevalence ■ Abstract At least one study (N=2,895)—an evaluation based on photographs— Patients with skin of color are more likely to develop acne and reported that acne is more common in African American and postinflammatory hyperpigmentation (PIH). Many therapies Hispanic women (37% and 32%, respectively) than in Continental for acne have demonstrated efficacy in darker skin types and Indian, Caucasian, and Asian women (23%, 24%, and 30%, respec- in the treatment of PIH. 3 Semin Cutan Med Surg 37(supp3):S71-S73 tively). Findings await confrmation by a comparable study. © 2018 published by Frontline Medical Communications Postinflammatory Hyperpigmentation ■ Keywords Postinfammatory hyperpigmentation (PIH), a darkened area of Acne; Fitzpatrick skin types IV-VI; postinflammatory hyperpig- skin following trauma or cutaneous infammation following acne, mentation; skin of color results from an abnormal release or overproduction of melanin (Figure).4,5 It is more common in African American and Hispanic cne has been reported as one of the most common dermato- women than in Continental Indian, Asian, or Caucasian women, logic conditions in numerous racial/ethnic groups studied.1,2 according to a survey of 208 adult women with facial acne (49% AAlthough differences in acne prevalence between racial/ non-Caucasian, 51% Caucasian).1,3 Nearly half (49.5%) of the non- ethnic groups have not been well established, distinct variations in Caucasian women reported “a lot” or “extensive” PIH, compared clinical presentation, exacerbating factors, and sequelae of acne are with 22.5% of Caucasian women.1 A study of photographs from frequently observed in patients with skin of color (ie, Fitzpatrick 2,895 females aged 10 to 70 years old also found that hyperpig- skin types [FST] IV-VI). These distinctions inform patient care. mentation was more common in African American and Hispanic women (65% and 48%, respectively) than in Continental Indian, * Chair, Department of Dermatology, Director of The Skin of Color Asian, and Caucasian (10%, 18%, and 25%, respectively) women.3 Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate PIH may be more distressing to people of color than to lighter- Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York skinned patients; it was rated as “severely troublesome” by nearly † Clinical Associate Professor of Dermatology, University of Alabama half (48.5%) of non-Caucasian women with acne in one study.1 at Birmingham, Dermatology and Skin Care Center of Birmingham, Another analysis confrmed this fnding.6 PIH-associated discol- Birmingham, Alabama oration may persist well beyond the acne lesions that triggered it. ‡ Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan Epidermal PIH may persist for 6 to 12 months; dermal PIH can § Adjunct Professor, Schulich School of Medicine & Dentistry, Western last for years.5,7 University, Windsor, Ontario, Canada Publication of this CME/CE article was jointly provided by University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education, LLC, and is supported by an educational grant from Bayer. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Eileen A. McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Andrew F. Alexis, MD, MPH, Consultant: Allergan plc, BioPharmX, Inc., Galderma Laboratories, L.P. Contracted Research: Allergan plc, BioPharmX, Inc., Galderma Laboratories, L.P., Novan, Inc. Julie C. Harper, MD, Consultant: Allergan plc, Bayer AG, BioPharmX, Inc., Galderma Laboratories, L.P., La Roche-Posay, Novan, Inc., Ortho Dermatologics. Contracted Research: Bayer AG. Speakers Bureau: Allergan plc, Bayer AG, La Roche-Posay, Ortho Dermatologics. Linda F. Stein Gold, MD, Consultant: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Medimetriks Pharmaceuticals, Inc., Novan, Inc., Valeant Pharmaceuticals International, Inc. Contracted Research: Allergan plc, Dermira, Inc., Foamix Pharmaceuticals Ltd., Galderma Laboratories, L.P., Novan, Inc., Valeant Pharmaceuticals International, Inc. Speakers Bureau: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Jerry K. L. Tan, MD, FRCPC, Consultant: Allergan plc, Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Contracted Research: Dermira, Inc., Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Speakers Bureau: Galderma Laboratories, L.P., Valeant Pharmaceuticals International, Inc. Address reprint requests to: Andrew F. Alexis, MD, MPH, Mount Sinai ■ FIGURE Postinflammatory Hyperpigmentation St. Luke’s and Mount Sinai West, 100 Amsterdam Avenue, Suite 11B, New York, NY 10025; [email protected] Source: Courtesy of Andrew F. Alexis, MD, MPH

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.027 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S71 ■ ■ ■ Treating Acne in Patients With Skin of Color

A histological examination of acne lesions from black females Once-daily tazarotene 0.1% cream has demonstrated effcacy showed marked infammation, beyond what would be expected compared with vehicle in the treatment of PIH in 74 patients with based on clinical examination. Skin taken from sites not near skin of color.17 the acne lesions also displayed infammation. Hyperpigmented A recent post hoc analysis of data from a 12-week, phase 3 macules with melanin granules were identifed in the epidermis, study of adapalene 0.3%/benzoyl peroxide 2.5% (ADAP 0.3%/ with pigment-flled macrophages detected in the dermis.8 According BPO 2.5%) found that the active therapy was signifcantly superior to an analysis of patients seen at a single center specializing in the to vehicle for reduction of both infammatory and noninfamma- care of skin of color, acne hyperpigmented macules were identifed tory lesions. When the study population was analyzed by FST, the in 65.3% of 239 African American patients, 52.7% of 55 Hispanic proportion of subjects achieving scores of clear or almost clear patients, and 47.4% of 19 Asian patients. These fndings could on the Investigator Global Assessment (IGA) with active therapy account for the development of PIH in patients with skin of color.9 was superior to vehicle only for those with lighter skin (FST I-III; 18 Patient History and Education n=128, ADAP 0.3%/BPO 2.5%; n=43, vehicle). These authors The use of certain hair oils and emollients to moisturize the hair noted that only a small number of subjects were randomized to and scalp can result in pomade acne, characterized by closely vehicle in the FST IV-VI group (n=89, ADAP 0.3%/BPO 2.5%; packed, closed comedones and small papules along the hairline.10 n=26, vehicle), reducing the statistical power of the analysis. Makeup or skin care products may induce or worsen acne, or may They also speculated that the presence of PIH lesions might irritate or dry the skin. Skin lightening or bleaching creams may have affected the IGA. This study did not examine the impact of irritate the skin or cause acne, especially if they contain steroids. therapy on PIH. Patient history should include a list of all skin, hair, and cosmetic Topical Antibiotics products used. Some products may lead to dryness or irritation A post hoc analysis of data from a phase 3, 12-week, vehicle- when combined with topical acne medications.11 Educating patients to avoid substances that may contribute to their acne or PIH is an controlled clinical trial of clindamycin 1.2%/BPO 3.75% gel found important aspect of therapy. that effcacy in Hispanic subjects (n=136) with moderate to severe Daily sunscreen use can reduce the intensity of PIH, even acne was similar to that of the general study population. The in people with darker skin.12 A study in African American and treatment was well tolerated in the Hispanic cohort; no treatment- Hispanic individuals who did not use sunscreen found that 8 weeks related adverse events were reported, and no subjects discontinued of sunscreen use with sun protection factor 30 or 60 lightened therapy due to adverse events.19 facial and hand pigmentary abnormalities.13 Patients who do not Dapsone use sunscreen should be educated to do so.14 Topical dapsone 5% is recommended for the treatment of In a study of patients of Afro-Caribbean ancestry, family history infammatory acne, especially in adult females.2 In a study of 68 was associated with the formation of keloid scars in multiple sites rather than a single site.15 adult women with acne and skin of color (FST IV-VI), topical More than two-thirds of Caucasian and non-Caucasian women dapsone gel 5% monotherapy applied twice daily for 12 weeks alike expected to see results from acne treatment within 2 weeks, signifcantly reduced the investigator-rated 5-point Global Acne according to a patient survey. Some expected benefts overnight.1 To Assessment Score (GAAS) from baseline (mean, −1.2; 95% conf- set expectations and promote adherence to therapy, patients should be dence interval, −1.4 to −1.0; P<0.001; 39% improvement). Nearly educated that resolution of acne and PIH often takes several weeks.4,5 43% of subjects had a GAAS of 0 or 1 at week 12. No treat- ment-related adverse events were observed.20 Race (Caucasian/ Topical Therapy for Acne and PIH non-Caucasian) did not affect the effcacy of dapsone 7.5% gel Early, aggressive treatment is recommended in patients with skin in a pooled subgroup analysis of data from two phase 3 trials of color to minimize the risk of PIH and scarring. This imperative (N=4,340; moderate infammatory and noninfammatory acne).21 must be balanced by the need to avoid skin irritation due to therapy, A pooled analysis of data from two phase 3 trials of dapsone 7.5% which can result in dyspigmentation and can worsen PIH.4,5,11 and vehicle in patients (N=4,327) with moderate acne stratifed by Treatment of acne is key to the management of PIH to prevent or reduce the risk of further dark marks. In patients with PIH and FST (I-III, IV-VI) supported these fndings, reporting effcacy in 22 acne, consider therapies that address both conditions. both groups. Several therapies recommended in the management of acne and/or Azelaic Acid PIH have data supporting their effcacy in patients with skin of color. A pilot study of azelaic acid 15% gel twice daily led to improvement Topical Retinoids of both acne and PIH in adults (N=20) with FST IV and mild or These agents represent frst-line acne therapy both in patients with moderate acne and moderate or severe PIH.23 After 16 weeks, 85% skin of color and in Caucasian patients.2,11 Starting at a lower of patients had achieved at least a 2-point improvement in IGA for concentration (0.025% tretinoin, for example) or applying every acne, and all (100%) had at least a 2-point improvement in IGA other day is recommended in patients with skin of color to reduce for PIH.23 the risk of irritation. Topical retinoids are an attractive option in patients with skin Hydroquinone of color because they can treat acne and may lighten areas of Topical hydroquinone is considered the gold standard therapy hyperpigmentation in black patients (P<0.001 vs vehicle after 40 for skin lightening and is often the frst therapy used in treating weeks of therapy). In one study, half of 24 subjects randomized PIH.4,11 Hydroquinone 4% combined with 0.15% retinol and anti- to topical tretinoin 0.1% developed retinoid reactions where the oxidants can reduce lesion size, pigmentation, and disease severity medication was applied; reactions diminished in severity, dura- in patients with hyperpigmentation on the face and body (FST tion, and frequency as the study progressed.16 II-VI).24

S72 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018

Andrew F. Alexis, MD, MPH, Julie C. Harper, MD, Linda F. Stein Gold, MD, and Jerry K. L. Tan, MD, FRCPC

To avoid unwanted lightening of normal skin, hydroquinone 6. Gorelick J, Daniels SR, Kawata AK, et al. Acne-related quality of life among female should be applied only to areas of PIH. In our practice, we limit adults of different races/ethnicities. J Dermatol Nurses Assoc. 2015;7:154-162. the use of hydroquinone to lesions large enough to be amenable 7. Lacz NL, Vafaie J, Kihiczak NI, Schwartz RA. Postinfammatory hyperpigmentation: A common but troubling condition. Int J Dermatol. 2004;43:362-365. to spot application (>4 mm). For smaller areas, consider using 8. Halder RM, Holmes YC, Bridgeman-Shah S, Kligman AM. A clinicohistopathologic study topical retinoids or azelaic acid because these agents can be of acne vulgaris in black females [abstract]. J Invest Dermatol. 1996;106:888. applied to normal as well as affected skin. Exogenous ochronosis, 9. Taylor SC, Cook-Bolden F, Rahman Z, Strachan D. Acne vulgaris in skin of color. J Am a blue-black darkening of the skin, is a risk of long-term hydro- Acad Dermatol. 2002;46(2 suppl understanding):S98-S106. quinone use.25 10. Davis EC, Callender VD. A review of acne in ethnic skin: Pathogenesis, clinical manifestations, and management strategies. J Clin Aesthet Dermatol. 2010;3:24-38. Procedural Therapies for PIH 11. Callender VD, Barbosa V, Burgess CM, et al. Approach to treatment of medical and Topical agents, considered to be frst-line choices for PIH, are more cosmetic facial concerns in skin of color patients. Cutis. 2017;100:375-380. likely to be effcacious in epidermal than dermal lesions. Superfcial 12. Maymone MBC, Neamah HH, Wirya SA, Patzelt NM, Zancanaro PQ, Vashi NA. Sun-protective behaviors in patients with cutaneous hyperpigmentation: A cross-sectional chemical peels and laser therapy offer alternatives for treating study. J Am Acad Dermatol. 2017;76:841-846.e2. dermal lesions and in those that respond inadequately to topical 13. Halder R, Rodney I, Munhutu M, et al. Evaluation and effectiveness of a photoprotection options.26 Caution must be exercised because these interventions composition (sunscreen) on subjects of skin of color [abstract]. J Am Acad Dermatol. can cause or exacerbate PIH.3 Medium-depth peels are associated 2015;72(suppl):AB215. with a higher risk of postprocedure PIH than superfcial chemical 14. Davis EC, Callender VD. Postinflammatory hyperpigmentation: A review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet peels. Deep peels are contraindicated in patients with skin of color Dermatol. 2010;3:20-31. 4 due to the effects on skin pigment and risk of scarring. 15. Bayat A, Arscott G, Ollier WE, McGrouther DA, Ferguson MW. Keloid disease: Clinical relevance of single versus multiple site scars. Br J Plast Surg. 2005;58:28-37. Superficial Chemical Peels 16. Bulengo-Ransby SM, Griffths CE, Kimbrough-Green CK, et al. Topical tretinoin Adding serial glycolic acid peels (every 3 weeks) to a topical (retinoic acid) therapy for hyperpigmented lesions caused by infammation of the skin in regimen containing hydroquinone 2%, tretinoin 0.05%, and hydro- black patients. N Engl J Med. 1993;328:1438-1443. cortisone 1% improved the results of facial PIH treatment in 17. Grimes P, Callender V. Tazarotene cream for postinfammatory hyperpigmentation and 30 patients with FST III-V, compared with the topical acne vulgaris in darker skin: A double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45-50. regimen alone.25 Patients were treated for 18 weeks. The mean 18. Alexis AF, Cook-Bolden FE, York JP. Adapalene/benzoyl peroxide gel 0.3%/2.5%: A safe Hyperpigmentation Area and Severity Index score at 12 and 21 and effective acne therapy in all skin phototypes. J Drugs Dermatol. 2017;16:574-581. 27 weeks showed signifcantly greater improvement with the peels. 19. Alexis AF, Cook-Bolden F, Lin T. Treatment of moderate-to-severe acne vulgaris in a Salicylic acid peels have demonstrated efficacy in PIH when Hispanic population: A post-hoc analysis of the effcacy and tolerability of clindamycin combined with topical therapy but not as monotherapy.4,28-31 1.2%/benzoyl peroxide 3.75% gel. J Clin Aesthet Dermatol. 2017;10:36-43. In our practice, we instruct patients to stop retinoid therapy 20. Alexis AF, Burgess C, Callender VD, et al. The effcacy and safety of topical dapsone gel, 5% for the treatment of acne vulgaris in adult females with skin of color. J Drugs 1 week prior to chemical peel therapy to reduce the risk of crusting, Dermatol. 2016;15:197-204. erosion, and PIH. BPO, azelaic acid, or dapsone can be used up to 21. Draelos ZD, Rodriguez DA, Kempers SE, et al. Treatment response with once-daily the day of the peel. topical dapsone gel, 7.5% for acne vulgaris: Subgroup analysis of pooled data from two randomized, double-blind studies. J Drugs Dermatol. 2017;16:591-598. Laser Therapy 22. Taylor SC, Cook-Bolden FE, McMichael A, et al. Effcacy, safety, and tolerability of The quality of the evidence for the use of lasers in the treatment topical dapsone gel, 7.5% for treatment of acne vulgaris by Fitzpatrick skin phototype. J Drugs Dermatol. 2018;17:160-167. of PIH for patients with skin of color is low; most data come from 4 23. Kircik LH. Effcacy and safety of azelaic acid (AzA) gel 15% in the treatment of post- small, nonrandomized clinical trials, case reports, and case studies. infammatory hyperpigmentation and acne: A 16-week, baseline-controlled study. J Drugs Dermatol. 2011;10:586-590. Summary 24. Cook-Bolden FE, Hamilton SF. An open-label study of the effcacy and tolerability PIH and scarring occur more often in patients with skin of color of microencapsulated hydroquinone 4% and retinol 0.15% with antioxidants for the than in Caucasian patients. These sequelae may be more distressing treatment of hyperpigmentation. Cutis. 2008;81:365-371. to the patient than acne. The need for early, aggressive treatment of 25. Hydroquinone 4% cream [package insert]. Bronx, NY: Perrigo; 2017. acne to prevent PIH and scarring must be balanced with the need to 26. Vashi NA, Wirya SA, Inyang M, Kundu RV. Facial hyperpigmentation in skin of color: avoid skin irritation, which itself can cause dyspigmentation. Many Special considerations and treatment. Am J Clin Dermatol. 2017;18:215-230. therapies for acne have been studied in patients with skin of color. 27. Sarkar R, Parmar NV, Kapoor S. Treatment of postinfammatory hyperpigmentation with a combination of glycolic acid peels and a topical regimen in dark-skinned patients: Treatments that address both acne and PIH are good choices for A comparative study. Dermatol Surg. 2017;43:566-573. patients with both conditions. 28. Joshi SS, Boone SL, Alam M, et al. Effectiveness, safety, and effect on quality of life of topical salicylic acid peels for treatment of postinfammatory hyperpigmentation in dark References skin. Dermatol Surg. 2009;35:638-644. 1. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, 29. Grimes PE. The safety and effcacy of salicylic acid chemical peels in darker racial-ethnic perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet groups. Dermatol Surg. 1999;25:18-22. Dermatol. 2014;7:19-31. 30. Mohamed Ali BM, Gheida SF, El Mahdy NA, Sadek SN. Evaluation of salicylic acid 2. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of peeling in comparison with topical tretinoin in the treatment of postinfammatory acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33. hyperpigmentation. J Cosmet Dermatol. 2017;16:52-60. 3. Perkins AC, Cheng CE, Hillebrand GG, Miyamoto K, Kimball AB. Comparison of the 31. Ahn HH, Kim IH. Whitening effect of salicylic acid peels in Asian patients. Dermatol epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African Surg. 2006;32:372-375. American women. J Eur Acad Dermatol Venereol. 2011;25:1054-1060. 4. Kaufman BP, Aman T, Alexis AF. Postinfammatory hyperpigmentation: Epidemiology, clinical presentation, pathogenesis and treatment. Am J Clin Dermatol. 2017. doi: 0.1007/540257-017-0333-6. 5. Yin NC, McMichael AJ. Acne in patients with skin of color: Practical management. Am J Clin Dermatol. 2014;15:7-16.

Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S73 Acne and Rosacea: Applying Emerging Science to Improve Outcomes FOR REVIEW PURPOSES ONLY. CME/CE Post-Test and Evaluation Form MUST BE COMPLETED ONLINE. Original Release Date: June 2018 • Expiration Date: June 30, 2020 • Estimated Time to Complete Activity: 2.0 hours To get instant CME/CE credits online, assist us in evaluating the effectiveness of this activity, and to make recommendations for future educational offerings, go to https://tinyurl.com/acnerosaceasupp2018. 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. CME/CE credit letters and long-term credit retention information will only be issued upon completion of the post-test and evaluation online. If you have any questions or difficulties, please contact the Global Academy for Medical Education office at [email protected]. 1. Which of the following accurately describes the use of C. Is not responsive to the use of sunscreen in patients with 8. Research indicates that Propionibacterium acnes: medications for acne during pregnancy: darker skin A. Is always pathogenic A. Any topical medication is safe D. Is best treated separately from, and after resolution of, the B. Includes some phylotypes associated with healthy skin and B. Topical retinoids should not be used at any time during acne with which it is associated anti-inflammatory effects pregnancy 5. What percentage of patients with moderate or severe rosacea C. Overgrowth is triggered by hormones (insulin-like growth C. All systemic medications for acne should be avoided achieved an Investigator Global Assessment (IGA) score of factor–1, insulin, and androgens), which promote increased during all of pregnancy clear/almost clear after concomitant use of ivermectin 1% sebum production and a change in sebum quality D. Large studies generating high-quality data document the cream and brimonidine 0.33% gel for 12 weeks? D. B and C appropriate use of acne medications during pregnancy A. <30% 9. According to the AAD guidelines and a consensus statement 2. Truncal acne: B. 35% to 45% from the Global Alliance to Improve Outcomes in Acne: A. Is present in no more than a quarter of patients with acne C. 50% to 60% A. Monotherapy with systemic antibiotics is not B. Is not responsive to topical treatments D. >60% recommended; short-term monotherapy (3 months) with C. Has responded to therapy with azelaic acid foam 15% in a topical antibiotics is acceptable 6. Which of the following topical therapies has been small open-label study B. Monotherapy with antibiotics—either topical or systemic— associated with reduced risk of scar formation due to acne? D. Is an exception to the American Academy of Dermatology is not recommended (AAD) guidelines’ recommended limits on the use of A. Dapsone 5% C. Long-term systemic antibiotic use is acceptable in systemic antibiotics B. Adapalene (ADAP) 0.1%/BPO 2.5% and ADAP 0.3%/BPO combination with nonantibiotic therapy and with 3. Which of the following acne therapies also is efficacious in 2.5% appropriate monitoring the treatment of photodamage? C. Clindamycin 1.2%/BPO 3.75% gel D. Combining two antibiotic therapies is an acceptable alternative A. Topical antibiotics D. Azelaic acid 15% gel to combining an antibiotic and a nonantibiotic therapy B. Topical azelaic acid 7. Procedural therapies for PIH: 10. What percentage of patients with moderate or severe C. Topical benzoyl peroxide (BPO) A. Are first-line alternatives for treating both epidermal and papulopustular rosacea achieved an IGA score of clear/ D. Topical retinoids dermal lesions almost clear and ≥2-grade improvement after 12 weeks of 4. Data suggest that postinflammatory hyperpigmentation (PIH): B. Cannot worsen PIH azelaic acid 15% foam twice daily? A. Is more common in African American and Hispanic women C. Include superficial peels that can be combined with A. <20% than in Continental Indian, Asian, or Caucasian women topical therapies B. 20% to 30% B. Virtually always resolves at the same time as the acne D. Include deep peels, which can be especially successful in C. 30% to 40% lesions that triggered it patients with skin of color D. 40% to 50%

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

LEARNING OBJECTIVES: Having completed this activity, you are better able to: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree Design a comprehensive treatment plan for patients with acne based on clinical guidelines and updated research, 5 4 3 2 1 incorporating pharmacologic and physical modalities Discuss and design treatment plans for patients of color, pregnant patients, and those with truncal acne, scarring, 5 4 3 2 1 and photoaging Recognize the significant impact of acne in patients’ lives, and of treating promptly and appropriately 5 4 3 2 1 Apply treatment strategies, based on knowledge of the indications, efficacy, and risks of available rosacea therapies, to 5 4 3 2 1 achieve therapeutic goals in rosacea treatment

If you do not feel confident that you can achieve the above objectives to some extent, please If you anticipate changing one or more aspects of your practice/professional responsibilities as a describe why not. result of your participation in this activity, please briefly describe how you plan to do so. ______If you plan to change your practice/workplace, may we contact you in 2 months to see how you Based on the content of this activity, what will you do differently in the care of your patients/ are progressing? regarding your professional responsibilities? (check one) Yes. E-mail address: ______Implement a change in my practice/workplace. No. I don’t plan to make a change. Seek additional information on this topic. If you are not able to effectively implement what you learned in this activity, please tell us what Do nothing differently. Current practice/job responsibilities reflect activity recommendations. the system barriers are (eg, institutional systems, lack of resources, etc)? Do nothing differently as the content was not convincing. ______Do nothing differently. System barriers prevent me from changing my practice/workplace. ______

OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree The information presented increased my awareness/understanding of the subject. 5 4 3 2 1 The information presented will influence how I practice/do my job. 5 4 3 2 1 The information presented will help me improve patient care/my job performance. 5 4 3 2 1 The program was educationally sound and scientifically balanced. 5 4 3 2 1 Overall, the program met my expectations. 5 4 3 2 1 I would recommend this program to my colleagues. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Andrew F. Alexis, MD, MPH Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Julie C. Harper, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Linda F. Stein Gold, MD Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Jerry K. L. Tan, MD, FRCPC Author was organized in the written materials. 5 4 3 2 1 What topics do you want to hear more about, and what issue(s) regarding your practice/professional Please provide additional comments pertaining to this activity and any suggestions responsibilities will they address? for improvement. ______The University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education thank you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patients’ care.

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