(PDF) Current Concepts in Acne Pathogenesis: Pathways to Inflammation

Acne is a disease of pilosebaceous inflammation. Pivotal in pathogenesis are the roles of hormones (insulin, insulin-like growth factor-1, androgens), Propionibacterium acnes, lipogenesis, and a proinflammatory lipid profile. Innate immune responses are induced through interaction with toll-like receptors and inflammasome activation initially and subsequently through adaptive immune activation. These insights into pathogenic inflammatory pathways can translate into novel therapeutic approaches for acne. Semin Cutan Med Surg 37(supp3):S60-S62 ©2018 published by Frontline Medical Communication.

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 Expiration Date: June 30, 2020 Estimated Time to Complete Activity: 2.0 hours Participants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it out at that time. The online post-test and evaluation can be accessed at https://tinyurl.com/acnerosaceasupp2018. Inquiries about CME accreditation may be directed to the University of Louisville Office of Continuing Medical Education & Professional Development (CME & PD) at cmepd@louisville.edu or 502-852-5329. CME/CE Accreditation Statements Physicians: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the University of Louisville and Global Academy for Medical Education, LLC. The University of Louisville is accredited by the ACCME to provide continuing education for physicians. The University of Louisville Office of Continuing Medical Education & Professional Development designates this enduring activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Joint Accreditation Statement In support of improving patient care, this activity has been planned and implemented by Postgraduate Institute for Medicine and Global Academy for Medical Education. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. Continuing Nursing Education The maximum number of hours awarded for this Continuing Nursing Education activity is 2.0 contact hours. Designated for 0.6 contact hours of pharmacotherapy credit for Advance Practice Nurses. Target Audience This journal supplement is intended for dermatologists, nurse practitioners, registered nurses, physician assistants, and other clinicians who treat patients with acne and rosacea. Educational Needs Acne and rosacea are common skin conditions that, if inadequately treated, can significantly affect an individual’s quality of life. Clinicians need to stay current on recent scientific research that is revealing the underlying pathophysiology of these conditions, because such knowledge can support the choice of appropriate therapy to improve outcomes. Inflammation is now known to be a primary factor in acne and may persist throughout the lesion life cycle, even beyond the disappearance of visible lesions. Proliferation of Propionibacterium acnes bacteria contributes to the inflammatory process; the cytokines activated by P acnes infection have been identified as targets for acne therapy, including the use of new and emerging topical and systemic agents. Clinicians should be familiar with new data on traditional, novel, and emerging therapies for rosacea, their mechanisms of action, and their efficacy and safety as monotherapy and in combination. Clinicians should also be familiar with acne treatment strategies targeted for special populations, including adult women (especially those who are or want to become pregnant) and in individuals with skin of color. Jointly provided by Learning Objectives By reading and studying this supplement, participants should be better able to: • Design a comprehensive treatment plan for patients with acne based on clinical guidelines and updated research, incorporating pharmacologic and physical modalities • Discuss and design treatment plans for patients of color, pregnant patients, and those with truncal acne, scarring, and photoaging • Recognize the significant impact of acne in patients’ lives, and of treating promptly and appropriately • Apply treatment strategies, based on knowledge of the indications, efficacy, and risks of available rosacea therapies, to achieve therapeutic goals in rosacea treatment Disclosure Declarations Individuals in a position to control the content of this educational activity are required to disclose: 1) the existence of any relevant financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients with the exemption of non-profit or government organizations and non-health care related companies, within the past 12 months; and 2) the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved. 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. University of Louisville CME & PD Advisory Board and Staff Disclosures: The CME & PD Advisory Board and Staff have nothing to disclose. CME/CE Reviewers: Cindy E. Owen, MD, Clinical Assistant Professor, Division of Dermatology, Department of Medicine, University of Louisville School of Medicine, has nothing to disclose. The Postgraduate Institute of Medicine planners and managers have nothing to disclose. Global Academy for Medical Education Staff: Eileen A. McCaffrey, MA; Tristan M. Nelsen, MNM, CMP, HMCC; Sylvia H. Reitman, MBA, DipEd; and Ron Schaumburg have nothing to disclose. Off-Label/Investigational Use Disclosure This CME/CE activity discusses the off-label use of certain approved medications as well as data from clinical trials on investigational agents. Such material is identified within the text of the articles. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Eileen A. McCaffrey, MA, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporter, Global Academy for Medical Education, University of Louisville, Postgraduate Institute for Medicine, or the publisher. 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 specific disorders of the skin, as well as the application of the latest scientific findings to patient care. Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is published quarterly by Frontline Medical Communications Inc., 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue are March, June, September, and December. Periodicals postage paid at Parsippany, NJ, and additional mailing offices. 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 Kenneth A. Arndt, MD Clinical Professor of Dermatology, Emeritus Harvard Medical School Adjunct Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Adjunct Professor of Dermatology Brown Medical School Providence, Rhode Island 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 Services, 10255 W Higgins Road, Suite 280, Rosemont, IL 60018. Subscriptions: Individual/Institution, USA: $133.00 p.a.; student, resident, intern, USA: $39.00. Individual, Canada/Mexico: $190.00 p.a.; institution, Canada/Mexico: $162.00 p.a. Individual, all other nations: $243.00 (surface mail), $311.00 (air mail); institution, all other nations: $188. For back issues, call (800) 480-4851 to charge to your credit card. Written requests will be accepted and must be accompanied by check or money order. Send payment and request to Seminars in Cutaneous Medicine and Surgery, Subscription Service, 10255 W Higgins Road, Suite 280, Rosemont, IL 60018. Copyright © 2018 by Frontline Medical Communications Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, 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: frontline@wrightsmedia.com. Philip E. LeBoit, MD Professor of Clinical Dermatology School of Medicine University of California, San Francisco San Francisco, California Bruce U. Wintroub, MD Associate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California Advertising representative: Sally Cioci, 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Phone: 973-290-8215; Fax: 973-206-9378; Email: scioci@mdedge.com. Publication of an advertisement in Seminars in Cutaneous Medicine and Surgery does not imply endorsement of its claims by the Editor(s) or Publisher of the journal. The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily reflect those of the Editors or Publisher. Publication of an advertisement or other product mention in Seminars in Cutaneous Medicine and Surgery should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the products mentioned. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/MEDLINE. 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 Division Head of Dermatology Henry Ford Hospital Detroit, Michigan Clinical Associate Professor of Dermatology University of Alabama at Birmingham Dermatology and Skin Care Center of Birmingham Birmingham, Alabama Andrew F. Alexis, MD, MPH Jerry K. L. Tan, MD, FRCPC Chair, Department of Dermatology Director of The Skin of Color Center Mount Sinai St. Luke’s and Mount Sinai West Associate Professor of Dermatology Icahn School of Medicine at Mount Sinai New York, New York Adjunct Professor Schulich School of Medicine & Dentistry Western University Windsor, Ontario, Canada Vol. 37, No. 3S, June 2018 INTRODUCTION A 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 inflammation in the development of acne and identified new potential targets of therapy. It also has identified new and investigational therapies for rosacea, another inflammatory 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 inflammation, 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. Postinflammatory hyperpigmentation (PIH), a darkened area of skin following trauma or cutaneous inflammation 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 efficacy 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 efficacy in up to half of patients with severe acne. A topical treatment has been studied in patients with truncal acne—another difficult-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 reflected 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 Bloomfield, MI 48322; lstein1@hfhs.org 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§ ■ Abstract Acne is a disease of pilosebaceous inflammation. Pivotal in pathogenesis are the roles of hormones (insulin, insulinlike growth factor-1, androgens), Propionibacterium acnes, lipogenesis, and a proinflammatory lipid profile. Innate immune responses are induced through interaction with toll-like receptors and inflammasome activation initially and subsequently through adaptive immune activation. These insights into pathogenic inflammatory pathways can translate into novel therapeutic approaches for acne. Semin Cutan Med Surg 37(supp3):S60-S62 © 2018 published by Frontline Medical Communications ■ Keywords Acne; caspase-1; inflammasome; nitric oxide; P acnes phylotypes; pathophysiology; toll-like receptor * Adjunct Professor, Schulich School of Medicine & Dentistry, Western University, Windsor, Ontario, Canada † Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan ‡ Chair, Department of Dermatology, Director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York § Clinical Associate Professor of Dermatology, University of Alabama at Birmingham, Dermatology and Skin Care Center of Birmingham, Birmingham, Alabama 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. 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. 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. 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. Address reprint requests to: Jerry K. L. Tan, MD, FRCPC, Schulich School of Medicine & Dentistry, Western University, 2224 Walker Road, Suite 300, Windsor, Ontario, N8W 5L7 Canada; jerrytan@bellnet.ca S60 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 A cne pathogenesis is characterized by hyperproliferation and abnormal differentiation of the follicular epithelium; excess sebum production; inflammation; and proliferation and biofilm formation of Propionibacterium acnes. 1,2 Inflammation is present in all acne lesions, including preclinical microcomedones.3,4 Immunohistochemical studies show higher levels of CD4 cells, macrophages, and interleukin (IL)-1–alpha in uninvolved skin of patients with acne compared with skin of those without acne. These findings suggest that inflammation precedes hyperproliferation in the development of acne. 4 “Noninflammatory acne” is thus a misnomer; it appears that all primary acne lesions are inflammatory. Although serum androgens have been viewed as the major hormonal trigger in acne during puberty, recent evidence suggests a pivotal role for insulin-like growth factor (IGF)-1. Individuals congenitally deficient in IGF-1 due to Laron syndrome do not develop acne, for example. However, high-dose IGF-1 replacement therapy leads to acne and hyperandrogenism.5 Multiple mechanisms of IGF-1 may promote the development of acne. IGF-1 has been shown to: (1) induce androgen synthesis and increase the cutaneous availability of dihydrotestosterone; (2) disinhibit the forkhead box O1 (FoxO1) transcription factor, which normally suppresses the androgen receptor; and (3) activate peroxisome proliferator-activated receptor–gamma, liver X receptor–alpha, and sterol regulatory element binding protein-1c (SREBP-1c). The latter actions increase sebum triglycerides and fatty acid desaturation, leading to a proinflammatory and comedogenic monosaturated fatty acid profile.6 Increased sebum production also leads to increased levels of squalene. Squalene monohydroperoxide is comedogenic and results from ultraviolet A–triggered photooxidation of squalene in sebum.7 Compelling evidence on the roles of hyperglycemic carbohydrates (high glycemic index), dairy products, and saturated fats in promoting acne has been reported.6 Refined carbohydrates and dairy products lead to disinhibition of FoxO1 and activation of the mechanistic target of rapamycin complex 1 (mTORC1) through escalation of insulin and IGF-1 levels. Saturated fats directly activate mTORC1. The effect of the latter is stimulation of SREBP-1c, which is central to sebaceous lipogenesis, sebum fatty acid production, and monosaturation.2,6 Diet-mediated changes in sebum quantity and composition promote P acnes overgrowth and biofilm formation. P acnes produces triglyceride lipase, which increases levels of free palmitic and oleic acids. Palmitic acid, along with P acnes–derived damageassociated molecular patterns, stimulates toll-like receptor 2 (TLR2), thereby triggering inflammasome activation and IL-1– beta signaling. Oleic acid stimulates P acnes adhesion, keratinocyte proliferation, and IL-1–alpha release.8-10 Furthermore, oleic acid can induce formation of comedones (Figure).6,11,12 P acnes acts on the innate immune system through multiple proinflammatory pathways.3,13 It activates TLR2 on monocytes, leading to the release of proinflammatory cytokines IL-12 and © 2018 Frontline Medical Communications 1085-5629/13/$-see front matter 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 K P acnes Lipases Free fatty acids (oleic, palmitic acid) Hormonal triggers (eg, androgens, IGF-1, insulin) Comedones L FoxO1 + K mTORC1 K Lipid quantity + ∆ lipid quality (saturated and monounsaturated FAs) Inflammasome activation/ innate immunity IL-1β Adaptive immunity Squalene monohydroperoxide, oleic acid IL-1α Comedones Papules, pustules, nodules ■ 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 cytokines IL-1–beta and IL-18 through an inflammasome pathway involving caspase-1 and the nucleotide oligomerization domainlike receptor protein (NLRP) 3.15,16 The inflammasome is a group of intracellular proteins that convert procaspase-1 to caspase-1. Caspase-1 converts the inactive precursor of IL-1–beta to its active form.17 Additionally, P acnes induces monocyte production of matrix metalloproteinases. These enzymes are associated with numerous inflammatory conditions and may play a role in matrix degradation and formation of acne scars.18,19 P acnes also stimulates an adaptive immune response, inducing IL-17A and interferon (IFN)-gamma secretion from CD4+ T cells in vitro. Type 17 helper T cells (TH17) and type 1/type 17 helper T cells (TH1/TH17) that react to P acnes stimulation are found in the peripheral blood of patients with and without acne, but cells from patients with acne displayed stronger responses to P acnes.20 P acnes influences the development of acne in ways beyond promoting inflammation. P acnes biofilm formation has been detected in the sebaceous follicles of patients with acne. Biofilm formation leads to increased P acnes virulence, manifested in part by the increased expression of P acnes triglyceride lipase, which increases the sebum concentration of palmitic and oleic acids. These changes in sebum lipid composition contribute to inducing inflammatory acne. As noted, oleic acid increases P acnes adherence and growth. Therefore, P acnes triglyceride lipase may indirectly contribute to biofilm formation by promoting increased concentration of oleic acid.8 P acnes is not always pathogenic, however. The organism is present in both healthy and acne-affected skin, and all P acnes strains do not exert the same effects. Immune system responses to P acnes rather than microbial density may influence progression to disease. Some P acnes phylotypes are associated with healthy skin rather than with skin affected by acne; others are more likely found in skin affected by acne than in healthy skin.21 Acneassociated P acnes phylotypes have been shown to induce higher levels of IFN-gamma and IL-17 in peripheral blood mononuclear cells than those associated with healthy skin. In recent studies, phylotypes associated with healthy skin induced higher levels of IL-10, an anti-inflammatory cytokine.22,23 Future studies might determine whether P acnes strains associated with healthy skin can reduce TH1 or TH17 inflammation.23 These current pathogenic concepts suggest new targets for therapy, including FoxO1, mTORC1, TLR2, the NLRP3 inflammasome, caspase-1, and IL-1–beta.14,15 Consumption of foods that increase FoxO1 or inhibit mTORC1 and inflammasome activation should alleviate acne. A paleolithic diet—ie, eliminating hyperglycemic carbohydrates and dairy products—and consumption of vegetables, berries, sea fish, and green tea may be a nutritional therapy for acne.6 Treatments eradicating P acnes may leave a microbiome vacuum that could be repopulated by P acnes strains promoting anti-inflammatory profiles. Sebum production and altered proinflammatory lipid content represent additional targets for acne 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 carboxylase (ACC) catalyzes the rate-limiting step in synthesis of fatty acids that become components of sebaceous lipids.25 IGF-1 and androgens upregulate expression of a transcription factor that promotes ACC expression.26 Investigational acne therapies include a topical antiandrogen medication and a topical inhibitor of ACC (see Advances in Acne and Rosacea Therapy, page S63). Another potential intervention involves nitric oxide. Nitricoxide–releasing nanoparticles (NO-np) have been shown to suppress IL-1–beta, tumor necrosis factor–alpha, and IL-8 release from human monocytes, and IL-8 and IL-6 release from human keratinocytes. NO-np reduce IL-1–beta secretion in part by inhibition of caspase-1. NO-np also kill P acnes in vitro.27 A nitric-oxide–releasing macromolecule formulated in an alcoholic gel is under study for the treatment of acne.28 (For more information, see Advances in Acne and Rosacea Therapy, page S63.) Current therapies address some elements of pathogenic pathways. Azelaic acid 15% gel; an oral contraceptive (drospirenone 3 mg/ethinyl estradiol 20 μg); the topical retinoids adapalene, tazarotene, and tretinoin; and oral isotretinoin have each been associated with reduced expression of TLR2.29-34 Azelaic acid has demonstrated anti-inflammatory action in vitro by inhibiting the generation of reactive oxygen species.35 Summary Inflammation plays a central role in acne pathogenesis and insulin. IGF-1 and androgens are prime orchestrators, with initiation likely due to consumption of dairy foods and a high glycemic index diet. The hormones lead to increased sebum production and a more inflammatory composition of sebaceous lipids. These changes promote P acnes overgrowth and inflammation through multiple pathways, triggering both innate and adaptive immune activation (Figure). TLR2, caspase-1, the inflammasome, IL-1–beta, and mediators of sebum production offer possible therapeutic targets in acne. All P acnes phylotypes do not act in the same way; some have been associated with healthy skin, rather than acne, and have anti-inflammatory effects. Beneficial P acnes phylotypes may lend themselves to future therapies. References 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. 2011;131:59-66. 2. Melnik BC. p53: Key conductor of all anti-acne therapies. J Transl Med. 2017;15:195. 3. Dreno B, Gollnick HP, Kang S, et al; Global Alliance to Improve Outcomes in Acne. Understanding innate immunity and inflammation in acne: Implications for management. J Eur Acad Dermatol Venereol. 2015;29(suppl 4):3-11. 4. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events 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 deficiency or administration on the occurrence of acne. J Eur Acad Dermatol Venereol. 2011;25:950-954. 6. Melnik BC. Linking diet to acne metabolomics, inflammation, 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 influx 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 influx 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, Törőcsik 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 13. Thiboutot DM. Inflammasome activation by Propionibacterium acnes: The story of IL-1 in acne continues to unfold. J Invest Dermatol. 2014;134:595-597. 14. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002;169:1535-1541. 15. Qin M, Pirouz A, Kim MH, Krutzik SR, Garban HJ, Kim J. Propionibacterium acnes induces IL-1ß secretion via the NLRP3 inflammasome in human monocytes. J Invest Dermatol. 2014;134:381-388. 16. Kistowska M, Gehrke S, Jankovic D, et al. IL-1ß drives inflammatory responses to Propionibacterium acnes in vitro and in vivo. J Invest Dermatol. 2014;134:677-685. 17. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720-3732. 18. Jalian HR, Liu PT, Kanchanapoomi M, Phan JN, Legaspi AJ, Kim J. All-trans retinoic acid shifts Propionibacterium acnes-induced matrix degradation expression profile toward matrix preservation in human monocytes. J Invest Dermatol. 2008;128:2777-2782. 19. Sato T, Kurihara H, Akimoto N, Noguchi N, Sasatsu M, Ito A. Augmentation of gene expression and production of promatrix metalloproteinase 2 by Propionibacterium acnesderived factors in hamster sebocytes and dermal fibroblasts: A possible mechanism for acne scarring. Biol Pharm Bull. 2011;34:295-299. 20. Kistowska M, Meier B, Proust T, et al. Propionibacterium acnes promotes TH17 and TH17/ TH1 responses in acne patients. J Invest Dermatol. 2015;135:110-118. 21. Fitz-Gibbon S, Tomida S, Chiu BH, et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol. 2013;133:2152-2160. 22. Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32:23-63. 23. Yu Y, Champer J, Agak GW, Kao S, Modlin RL, Kim J. Different Propionibacterium acnes phylotypes induce distinct immune responses and express unique surface and secreted proteomes. J Invest Dermatol. 2016;136:2221-2228. 24. Janiczek-Dolphin N, Cook J, Thiboutot D, Harness J, Clucas A. Can sebum reduction predict acne outcome? Br J Dermatol. 2010;163:683-688. 25. Munday MR. Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans. 2002;30:1059-1064. 26. Melnik BC. Olumacostat glasaretil, a promising topical sebum-suppressing agent that affects all major pathogenic factors of acne vulgaris. J Invest Dermatol. 2017;137:1405-1408. 27. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731. 28. Baldwin H, Blanco D, McKeever C, et al. Results of a phase 2 efficacy 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. 29. Rocha MAD, Guadanhim LRS, Sanudo A, Bagatin E. Modulation of toll like receptor-2 on sebaceous gland by the treatment of adult female acne. Dermatoendocrinol. 2017;9:e1361570. 30. Jones DA. The potential immunomodulatory effects of topical retinoids. Dermatol Online J. 2005;11:3. 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 Dermatol. 2012;132:2198-2205. 32. Gregoriou S, Kritsotaki E, Katoulis A, Rigopoulos D. Use of tazarotene foam for the treatment of acne vulgaris. Clin Cosmet Investig Dermatol. 2014;7:165-170. 33. Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions. Exp Dermatol. 2007;16:500-506. 34. Zuliani T, Khammari A, Chaussy H, Knol AC, Dréno B. Ex vivo demonstration of a synergistic effect of adapalene and benzoyl peroxide on inflammatory acne lesions. Exp Dermatol. 2011;20:850-853. 35. Jones DA. Rosacea, reactive oxygen species, and azelaic acid. J Clin Aesthet Dermatol. 2009;2:26-30. 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§ ■ Abstract New topical therapies have demonstrated efficacy in patients with moderate or severe acne who might otherwise have required therapy with systemic antibiotics or isotretinoin. Increasing knowledge about the pathogenesis of acne has facilitated the development of therapies with novel modes of action. New and investigational therapies also are available or in development for the treatment of both the papulopustular and erythematous manifestations of rosacea. Semin Cutan Med Surg 37(supp3):S63-S66 © 2018 published by Frontline Medical Communications ■ Keywords Acne; adapalene; azelaic acid; ivermectin; rosacea; topical minocycline; truncal acne * Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan † Chair, Department of Dermatology, Director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York ‡ Clinical Associate Professor of Dermatology, University of Alabama at Birmingham, Dermatology and Skin Care Center of Birmingham, Birmingham, Alabama § Adjunct Professor, Schulich School of Medicine & Dentistry, Western 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. 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. 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. 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: Linda F. Stein Gold, MD, Henry Ford Health System, 6530 Farmington Road, West Bloomfield, MI 48322; lstein1@hfhs.org 1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.025 Overview Patients with moderate or severe acne that does not respond to topical therapies often receive systemic antibiotic therapy or isotretinoin. The American Academy of Dermatology (AAD) guidelines for management of acne recommend limiting the duration of systemic antibiotics and avoiding monotherapy with them to reduce the risk of antibiotic resistance (see Revisiting Antibiotic Treatment).1 Topical therapy that can improve moderate to severe acne without the need for systemic antibiotics or oral isotretinoin is needed. New topical therapies have demonstrated efficacy in up to half of patients with severe acne.2,3 A new treatment has been studied in truncal acne as well (see Truncal Acne).4 Investigational therapies with novel mechanisms of action in acne include a topical nitric-oxide–releasing macromolecule,5 a melanocortin receptor-5 antagonist,6 and an antiandrogen cream (CB-03-01 1%).7 New therapies for rosacea include a 15% foam formulation of azelaic acid, an antiparasitic agent (ivermectin 1% cream), an alpha1A-adrenergic receptor agonist (topical oxymetazoline hydrochloride cream 1%), and a cationic antimicrobial peptide (omiganan). Separate formulations of topical minocycline are in development for acne and rosacea. Revisiting Antibiotic Treatment The current AAD guidelines and a recent consensus statement from the Global Alliance to Improve Outcomes in Acne recommend limiting antibiotic use in acne therapy to reduce the risk of antibiotic resistance, as follows1,8: • Use topical and systemic antibiotics in combination with nonantibiotic therapies (eg, topical benzoyl peroxide [BPO], topical retinoids) – Monotherapy with antibiotics is not recommended • Use systemic antibiotics for the shortest possible duration, with reevaluation after 3 to 4 months – Evaluate response time in 6 to 8 weeks8 Truncal Acne Approximately half of patients with acne have disease manifestations on the back and/or chest.9 Because patients may incorrectly report no acne in these areas, physical examination by the clinician is mandatory.10 The difficulty of applying topical therapies to all of the affected truncal areas, and the time required to do so, can complicate use of this approach. For this reason, oral therapies are often prescribed for truncal acne in clinical practice. However, their use is limited by AAD guidelines meant to reduce the risk of antibiotic resistance (see Revisiting Antibiotic Treatment).1 A recent open-label study evaluated the efficacy of azelaic acid 15% foam in moderate truncal acne. Twice-daily foam application resulted in a 1-grade reduction on the 5-grade Investigator Global Assessment (IGA) scale for 16 of 18 patients with acne. After 16 weeks of therapy, 8 of 18 patients (44%) were judged to be clear or almost clear. The medication also improved facial acne.4 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S63 ■ ■ ■ Advances in Acne and Rosacea Therapy What’s New in Acne? Approved Agents Adapalene 0.3% / benzoyl peroxide 2.5% (ADAP 0.3% / BPO 2.5%) gel. In a randomized, double-blind study on ADAP 0.3%/BPO 2.5% applied once daily, about one-third of patients with moderate or severe inflammatory acne achieved an IGA score of clear/almost clear with at least a 2-grade improvement on the IGA scale at week 12 (Table 1).3,11-13 The mean reduction in baseline in inflammatory and noninflammatory lesion counts was significantly greater with ADAP 0.3%/BPO 2.5% than with vehicle. Skin irritation (2.8%) and a burning sensation (0.9%) were the most common treatmentrelated adverse events (AEs).3 Improvements also occurred among patients with severe acne at baseline. Nearly one-third of these patients demonstrated at least a 3-grade improvement to clear/almost clear on the IGA scale at 12 weeks with single-agent topical therapy (31.9% vs 11.8%; 95% confidence interval, 6.0%-34.2%; P=0.029).3 Clindamycin 1.2% / BPO 3.75% gel. This therapy demonstrated efficacy compared with vehicle in a randomized trial of patients 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 Evaluator Global Severity Score (EGSS) at week 12.2 The overall rates of treatment-emergent adverse events (TEAEs) with active therapy in the main trial and both subgroups (severe acne and adolescents) were similar to that of vehicle.2,11,14 Dapsone 7.5% gel. This agent, applied once daily, has demonstrated efficacy in two identically designed randomized, vehicle-controlled studies in adults and adolescents with moderate acne (Table 1).12,13 The rate of TEAEs was similar for dapsone 7.5% gel and vehicle.12,13 Investigational Therapies Sarecycline is a once-daily, oral, narrow-spectrum, tetracyclinederived antibiotic with anti-inflammatory properties. At 1.5 and 3.0 mg/kg, it significantly reduced inflammatory lesion counts from baseline compared with placebo (by 52.7%, 51.8%, and 38.3%, respectively), with no significant difference from placebo in noninflammatory lesion counts in a phase 2 trial of patients with moderate or severe acne. The rate of TEAEs was similar across treatment groups. AEs leading to discontinuation from sarecycline and considered treatment-related were hypoesthesia, increased creatine phosphokinase, and decreased white blood cell count. The 1.5-mg/kg dose has entered phase 3 development.15 SB204. This agent contains a nitric oxide–releasing macromolecule formulated in an alcoholic gel.16 Nitric oxide has been shown to inhibit Propionibacterium acnes growth as well as P acnesstimulated release of interleukin (IL)-1–beta and other cytokines.5 Once-daily therapy with SB204 4% significantly reduced the percentage of inflammatory lesions from baseline by week 4 and the absolute inflammatory and noninflammatory lesion count at week 12, compared with vehicle, in subjects with moderate or severe acne.17 A study including patients with mild disease produced similar findings.16 The rate of TEAEs was similar across treatment groups. The rate of IGA success (clear/almost clear and ≥2-grade improvement vs baseline) with SB204 4% was low (2.0%) and did not differ from that of vehicle (1.9%).16 Topical olumacostat glasaretil (OG) 7.5%. Following an announcement that this agent did not meet any of its coprimary endpoints in two phase 3 trials, development of this therapy is not proceeding at the time of this writing. Melanocortin receptor-5 antagonist (MTC896). A phase 2, doseranging study of MTC896 delivered in a topical gel and applied twice daily is ongoing.18 Topical minocycline. Minocycline 4% foam applied once daily demonstrated efficacy in a phase 2, 12-week-long trial (N=139; moderate or severe acne). More than one-third of patients (36.2%) achieved at least a 2-grade improvement on the IGA scale at week 12 with topical minocycline, compared with 15.2% for vehicle (P=0.021). Topical minocycline 4% foam produced a significantly greater mean percentage reduction from baseline in inflammatory and noninflammatory lesion count compared with vehicle. Tolerability did not differ significantly between treatment groups.19 In two identical phase 3 studies of this agent (N=466, N=495), the change from baseline to week 12 in absolute inflammatory lesion count for topical minocycline 4% foam was significantly greater than that observed with a foam vehicle. The other coprimary endpoint—IGA score of clear or almost clear plus at least a 2-grade improvement from baseline—was significant in only one of the two 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 once daily vs vehicle3 N=503; 50:50 moderate:severe acne Clear/almost clear and ≥2-grade IGA improvement: 33.7% active therapy; 11.0% vehicle (P<0.001) Clindamycin 1.2%/BPO 3.75% gel once daily vs vehicle11 N=498; 82.7% with moderate acne Change in inflammatory lesion counts: 60.6% vs 31.4% with vehicle (P<0.001) 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 vs vehicle12,13 N=2,238 and N=2,102 aged ≥12 years, moderate acne GAAS, 0 or 1: 29.9% and 29.8%, respectively, with dapsone vs 21.2% and 20.9%, respectively, with vehicle (P<0.001) 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 A phase 3 trial is ongoing.21 A phase 2b, 12-week-long, dose-ranging trial of a topical minocycline gel (1% or 2% vs vehicle) in patients with moderate or severe inflammatory acne has been completed.22 CB-03-01 1% cream. In an 8-week, phase 2 trial, this once-daily antiandrogen cream was statistically superior to placebo at 8 weeks in terms of total lesion count, inflammatory lesion count, and acne severity index (N=77 men; mild to moderate acne).7 It was not superior to placebo in its effect on IGA score.23 Phase 3 studies are in progress.24,25 What’s New in Rosacea? New Topical Agents Azelaic acid (AZA) 15% foam. Significantly higher proportions of patients achieved an IGA score of clear/almost clear plus at least a 2-point improvement at week 12 with AZA foam than with vehicle (Table 2).26-30 Change in inflammatory lesion count also was significantly greater with AZA 15% foam (−13.2 ± 9.5 vs −10.3 ± 9.8; P <0.001). Application-site pain, pruritus, and dryness were reported more frequently with AZA 15% foam than with vehicle.26 Ivermectin 1% cream. Significantly higher proportions of those treated with ivermectin 1% cream achieved IGA scores of clear/ almost clear compared with vehicle, in two 12-week studies (Table 2).27,28 Dermatologic AEs were less common with ivermectin than with vehicle.27 The rate of treatment-related dermatologic AEs was numerically lower with ivermectin 1% cream in a long-term extension trial of both studies (7.8% vs 12.9%, and 9.8% vs 16.3%; ivermectin and vehicle, respectively). Statistical comparisons were not performed.28 Ivermectin cream and brimonidine gel have reduced papulopustular lesions and erythema, respectively.27,31 More than 60% of subjects with moderate or severe rosacea randomized to concomitant therapy with both agents for 12 weeks (ivermectin 1% cream, brimonidine 0.33% gel) attained IGA scores of clear/ almost clear at the end of treatment (week 12; 3 hours after brimonidine application [61.2% vs 36.8% with vehicle, respectively; P=0.007]). Half of the patients who received ivermectin 1% cream for 12 weeks with vehicle gel for 4 weeks and brimonidine gel for 8 weeks attained clear/almost clear IGA scores at 12 weeks.32 Topical oxymetazoline hydrochloride cream 1%. An alpha1Aadrenergic receptor agonist that causes vasoconstriction of the skin microvasculature, this agent received US Food and Drug Administration approval in January 2017 for persistent facial erythema associated with rosacea in adults. Significantly larger proportions of patients achieved at least a 2-grade improvement on both the Clinician Erythema Assessment (CEA) and Subject SelfAssessment (SSA) after 29 days of treatment with oxymetazoline hydrochloride cream compared with vehicle, in two pivotal phase 3, vehicle-controlled studies in patients with moderate or severe facial erythema of rosacea (Table 2).29,30 Investigational Therapies Omiganan (CONTRols001). A synthetic, cationic antimicrobial peptide, omiganan is in phase 3 development for the treatment of severe papulopustular rosacea.33-36 Topical minocycline. Three topical minocycline products are under study for the treatment of rosacea. In a phase 2, randomized, vehicle-controlled study, topical minocycline 1.5% and 3% foam each reduced the inflammatory lesion count significantly more than vehicle after 12 weeks of therapy in a study population of 232 patients with moderate to severe facial papulopustular rosacea (21.1 and 19.1 vs 7.8, respectively; P<0.001). Significantly more patients receiving active therapy achieved IGA scores of clear/ almost clear and at least a 2-grade IGA improvement at week 12 (41.8%, 33.3%, and 17.9%; 1.5% and 3.0% topical minocycline foam and vehicle, respectively; P<0.01). Rates of patients reporting treatment-related AEs were 2.5%, 5.3%, and 6.4%, with topical minocycline 1.5% and 3% foam, and vehicle, respectively. No serious treatment-related AEs were reported.37 A phase 3 study and a long-term safety study of the 1.5% formulation are underway.38,39 Two topical minocycline gels are in phase 2 or phase 1/2 studies in patients with moderate to severe papulopustular rosacea.39,40 Summary New and investigational topical therapies are expanding the options for patients with moderate or severe acne, potentially enabling a larger number of patients to avoid systemic antibiotic or isotretinoin therapy. New treatments are increasing the options for rosacea as well. ■ TABLE 2 New Therapies for Rosacea: Efficacy Data Agent Study Population Results Azelaic acid 15% foam twice daily vs vehicle26 N=961; moderate or severe PPR 12 weeks: Clear/almost clear and ≥2-grade IGA improvement: 32.0% vs 23.5% with vehicle (P<0.001) Ivermectin 1% cream vs vehicle once daily27,28 N=683 and N=688; moderate or severe PPR; 12 weeks 12 weeks: Clear/almost clear: 38.4% and 40.1% vs 11.6% and 18.8% with vehicle (P<0.001) 40 weeks (N=622, N=636)a: Clear/almost clear: 71.1% and 76.0% Topical oxymetazoline hydrochloride cream 1% vs vehicle29 N=440; moderate or severe facial erythema of rosacea CEA and SSA successb; day 29, hours post dose (active therapy vs vehicle): 3 hours: 11.9% vs 5.5%; P<0.05; 6 hours: 15.5% vs 8.3%; P<0.05; 9 hours: 17.7% vs 6.0%; P<0.001; 12 hours: 14.8% vs 6.0%; P<0.01 Topical oxymetazoline hydrochloride cream 1% vs vehicle30 N=445; moderate or severe facial erythema of rosacea CEA and SSA successb; day 29, hours post dose (active therapy vs vehicle): 3 hours: 14.3% vs 7.4%; P<0.05; 6 hours: 13.4% vs 4.8%; P<0.01; 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 Vol. 37, No. 3S, June 2018, Seminars in Cutaneous Medicine and Surgery S65 ■ ■ ■ Advances in Acne and Rosacea Therapy References 1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33. 2. Stein Gold L. Efficacy and tolerability of a fixed combination of clindamycin phosphate (1.2%) and benzoyl peroxide (3.75%) aqueous gel in moderate and severe acne vulgaris subpopulations. J Drugs Dermatol. 2015;14:969-974. 3. Stein Gold L, Weiss J, Rueda MJ, Liu H, Tanghetti E. Moderate and severe inflammatory acne vulgaris effectively treated with single-agent therapy by a new fixed-dose combination adapalene 0.3 %/benzoyl peroxide 2.5 % gel: A randomized, double-blind, parallel-group, controlled study. Am J Clin Dermatol. 2016;17:293-303. 4. Hoffman LK, Del Rosso JQ, Kircik LH. The efficacy and safety of azelaic acid 15% foam in the treatment of truncal acne vulgaris. J Drugs Dermatol. 2017;16:534-538. 5. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731. 6. Eisinger M, Li WH, Anthonavage M, et al. A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids. J Dermatol Sci. 2011;63:23-32. 7. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011;165:177-183. 8. Thiboutot DM, Dréno B, Abanmi A, et al. Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018;78(suppl):S1-S23.e1. 9. Del Rosso JQ, Bikowski JB, Baum E, et al. A closer look at truncal acne vulgaris: Prevalence, severity, and clinical significance. J Drugs Dermatol. 2007;6:597-600. 10. Tan JK, Tang J, Fung K, et al. Prevalence and severity of facial and truncal acne in a referral cohort. J Drugs Dermatol. 2008;7:551-556. 11. Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed 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. Efficacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: First of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15:553-561. 13. Eichenfield LF, Lain T, Frankel EH, et al. Efficacy 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. Efficacy and tolerability of a fixed 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. Efficacy 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 efficacy 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. Eichenfield LF, Gold LS, Nahm WK, Cook-Bolden FE, Pariser DM. Results of a phase 2, randomized, vehicle-controlled study evaluating the efficacy, 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 efficacy 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 efficacy 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 efficacy 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 first-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 efficacy 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 efficacy 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, vehiclecontrolled 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. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: Results of two randomized, double-blind, vehiclecontrolled 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 inflammatory 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 efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: Findings from the first REVEAL trial. J Drugs Dermatol. 2018;17:97-105. S66 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 30. Baumann L, Goldberg DJ, Stein Gold L, et al. Pivotal trial of the efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: Findings from the second REVEAL trial. J Drugs Dermatol. 2018;17:290-298. 31. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: Results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650-656. 32. Gold LS, Papp K, Lynde C, et al. Treatment of rosacea with concomitant use of topical ivermectin 1% cream and brimonidine 0.33% gel: A randomized, vehicle-controlled study. J Drugs Dermatol. 2017;16:909-916. 33. ClinicalTrials.gov. Study to evaluate the safety and efficacy of a once-daily CLS001 topical gel versus vehicle. Updated March 2, 2018. NCT02576860. 34. ClinicalTrials.gov. Study to evaluate the safety and efficacy of a once-daily CLS001 topical gel versus vehicle. Updated January 25, 2018. NCT02547441. 35. ClinicalTrials.gov. Study to evaluate the long-term safety of a once-daily omiganan topical gel. Updated January 25, 2018. NCT02576847. 36. Rubinchik E, Dugourd D, Algara T, Pasetka C, Friedland HD. Antimicrobial and antifungal activities of a novel cationic antimicrobial peptide, omiganan, in experimental skin colonisation models. Int J Antimicrob Agents. 2009;34:457-461. 37. Mrowietz U, Kedem TH, Keynan R, et al. A phase II, randomized, double-blind clinical study evaluating the safety, tolerability, and efficacy of a topical minocycline foam, FMX103, for the treatment of facial papulopustular rosacea. Am J Clin Dermatol. 2018. doi:10.1007/s40257-017-0339-0. 38. ClinicalTrials.gov. A study to evaluate the safety and efficacy of FMX103 1.5% topical minocycline foam in the treatment of facial papulopustular rosacea. Updated September 6, 2017. NCT03142451. 39. ClinicalTrials.gov. A study to evaluate the long-term safety of topical administration of FMX103 in the treatment of moderate to severe papulopustular rosacea. Updated October 25, 2017. NCT03276936. 40. ClinicalTrials.gov. Study to evaluate the safety and efficacy of topical minocycline gel in patients with papulopustular rosacea. Updated February 26, 2018. NCT03263273. 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§ ■ Abstract Acne can persist into adulthood or erupt de novo at any point after adolescence. Adult acne is more common in women than in men. Considerations for treating acne in adult women include childbearing potential, pregnancy, lactation, and concomitant skin conditions. Semin Cutan Med Surg 37(supp3):S67-S70 © 2018 published by Frontline Medical Communications ■ Keywords Acne; adult women; lactation; oral contraceptives; pregnancy A lthough acne most often appears in adolescence, it can continue into adulthood or can develop de novo during that stage of life. The self-reported prevalence of adult acne is * Clinical Associate Professor of Dermatology, University of Alabama at Birmingham, Dermatology and Skin Care Center of Birmingham, Birmingham, Alabama † Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan ‡ Chair, Department of Dermatology, Director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York § Adjunct Professor, Schulich School of Medicine & Dentistry, Western 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. 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. 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. 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: Julie C. Harper, MD, Dermatology and Skin Care Center of Birmingham, 2470 Rocky Ridge Road, Birmingham, AL 35243; juharper@yahoo.com 1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.026 significantly higher in women than in men, according to a survey conducted in medical center waiting areas and a campus library (N=1,013).1 More than half (51%) of women and 43% of men reported having acne in their 20s, with percentages dropping to 26% and 12% in their 40s, and 15% and 7% in those 50 and older (women and men, respectively). An online survey found that one-third of adult women with facial acne (33.7% of 208 women aged 2545 years) reported that the condition was diagnosed in adulthood.2 The treatment of acne in adult women is similar in many respects to that of men and younger females, although treatment choices will be influenced 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 need to address—or at least avoid—exacerbating multiple skin conditions (eg, dryness, hyperpigmentation, photoaging) along with acne. Optimally, acne therapy should be compatible with cosmetics or other facial care products. Table 1 lists considerations for taking a history of an adult woman with acne.3-5 Topical Therapies Topical Retinoid Therapy These medications offer the advantage of efficacy in postinflammatory hyperpigmentation and photodamage, as well as in acne. Side effects include skin irritation.5 Adapalene (ADAP) 0.3% demonstrated superiority to vehicle in adult women (18-41 years old; n=117) in reducing inflammatory, noninflammatory, and total lesion counts after 12 weeks of therapy, in a post hoc analysis of data from two clinical studies.6 ■ TABLE 1 Taking a History of an Adult Woman With Acne • Age of first onset; history of any adolescent acne • Other clinicians consulted for acne • Previous acne treatments, including over-the-counter and prescription medications, facials, peels, light therapy, or microdermabrasion • History of birth control: use of hormonal agents, including oral contraceptives; spironolactone; intrauterine or implanted devices; or injectable agents • Signs/symptoms of androgen excess, eg, hirsutism, alopecia, irregular or missed menses, or inability to conceive a child • Concomitant medical conditions • Current medications • All products used on the face and hair, including cosmetics, moisturizers, and personal hygiene products • Expectations regarding results of therapy Sources: Del Rosso JQ, et al3; Del Rosso JQ, et al4; Del Rosso JQ, et al.5 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 0.250 mg/ethinyl estradiol 35 μg13 Moderate acne vulgaris in females aged ≥15 years who have achieved menarche, have no known contraindication to oral contraceptive therapy, and desire oral contraception for birth control. Norethindrone acetate 1 mg/ ethinyl estradiol 20, 30, or 35 μg + ferrous fumarate in the hormonefree interval14 Moderate acne vulgaris in females aged ≥15 years who have achieved menarche, have no known contraindication to oral contraceptive therapy, desire oral contraception for birth control, and are unresponsive to topical anti-acne medications. Should be used for the treatment of acne only if the patient plans to stay on it for ≥6 months. Drospirenone 3 mg/ethinyl estradiol 20 μg15 Moderate acne for women aged ≥14 years who have achieved menarche, have no known 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 formation compared with vehicle in a small (N=38) study of adult men and women. Participants applied active therapy and vehicle to separate halves of the face. Scar counts remained stable with active therapy but increased by about 25% with vehicle over a 6-month treatment period. The proportion of patients rated almost clear (ie, hardly visible scars) at 6 months rose from 10% to 45% with ADAP/BPO but did not change from baseline with vehicle.7 A study of higher-strength ADAP (0.3%)/BPO 2.5% (N=67) also demonstrated reduction and prevention of scarring, again using intraindividual comparison. At week 24, change from baseline in scar count rose by 14.4% with vehicle and decreased by 15.5% with ADAP/BPO (P<0.0001). Higher proportions achieved scores of clear/almost clear on the Scar Global Assessment at week 24 with ADAP/BPO than with vehicle (32.9% vs 16.4%; P<0.01).8 Dapsone 5% / 7.5% has demonstrated efficacy in treatment of acne in adult women.4,9 Compared with adolescent females (n=347), a higher proportion of adult women (n=434) achieved a rating of clear or almost clear after 12 weeks of therapy with dapsone 5% applied twice daily (53.5% vs 45.3%; P=0.022).4 Regardless of 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 Higher proportions of females than males achieved a Global 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 a pooled subgroup analysis of data from two identical trials. The GAAS success rate (score 0 or 1) at week 12 for participants treated with dapsone 7.5% was significantly higher for females than males at week 12 (odds ratio, 0.80; 95% confidence interval, 0.68-0.93).9 Clindamycin 1.2% / BPO 3.75% gel once daily. A post hoc analysis of data from 72 adult women (aged ≥25 years) demonstrated superior efficacy of clindamycin 1.2%/BPO 3.75% compared with vehicle, with 44% of women receiving active therapy rating themselves as clear/almost clear compared with 13.5% of those using vehicle (P=0.026).11 Another post hoc analysis reported higher efficacy among females than males treated with clindamycin 1.2%/BPO 3.75%.12 Combination Oral Contraceptives Table 2 lists combination oral contraceptives (COCs) that are approved by the US Food and Drug Administration (FDA) for use in acne.13-15 COCs may be used with other topical and oral therapies for acne. Patients should be counseled that at least three monthly cycles may pass before acne lesion counts decrease appreciably. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.16 Note that progestin-only contraceptives, including injectables or intrauterine devices, can cause or worsen acne.3 Table 3 lists contraindications to COCs.17 S68 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Spironolactone Although not FDA-approved for this use, the oral aldosterone antagonist and potassium-sparing diuretic spironolactone is accepted as an option for the treatment of acne.16 In a retrospective evaluation of data from adult women treated with low-dose (≤150 mg/day) spironolactone, treatment was deemed successful in 90% of patients for whom full data were available. Success was defined as no more than 2 superficial inflammatory lesions, no more than 5 retentional lesions (open or closed comedones), no nodules on the face, and fewer than 5 superficial inflammatory lesions on the trunk, including the neck. Median time to response was 6 months.18 In another retrospective study, 94 of 110 patients demonstrated improvement and 65 were characterized as clear after four or fewer follow-up visits. A total of 37 women were clear after the first follow-up visit, at a median of 4 weeks. Most patients (101/110) were started on spironolactone 100 mg/day.19 Reported side effects included breakthrough vaginal bleeding, lightheadedness, dizziness, low blood pressure, and breast tenderness.18,19 ■ TABLE 3 Contraindications to Use of Combination Oral Contraceptives • Pregnancy • Smoking (any amount) and aged >35 years • Uncontrolled hypertension • Breastfeeding <6 months postpartum • History – Breast cancer (past or current) – Ischemic heart disease – Migraine and aged >35 years – Migraine with focal symptoms – Stroke – Venous thromboembolic disease • Hypercholesterolemia (low-density lipoprotein >160 mg/dL) • Diabetes and aged >35 years or evidence of end organ damage • Viral hepatitis • Cirrhosis • Liver tumor (benign or malignant) • Major surgery with prolonged immobilization Source: Frangos JE, et al.17 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 because of its association with hyperkalemia,20 but its approved uses are in patients with heart failure, hypertension, primary hyperaldosteronism, and edema associated with cirrhosis.20 A retrospective analysis of more than 13 years of data from 974 healthy young women taking spironolactone for acne revealed a hyperkalemia rate of 0.72%, equivalent to the 0.76% baseline rate for this population. Routine monitoring of serum potassium is unnecessary in otherwise healthy young women taking spironolactone for acne.21 One study following 96 patients given isotretinoin (0.5-1 mg/ kg/dL, with a cumulative dose of 120-150 mg/kg) reported acne relapses in eight patients during the first posttreatment year and in 16 patients during the second posttreatment year.22 A systematic literature review including 20 studies found that the cumulative dose required to induce remission varied with disease severity.23 Isotretinoin Table 4 lists therapies for acne and their FDA pregnancy risk categories.24-27 The topical agents azelaic acid, BPO, and clindamycin (known by the mnemonic “ABC”) and the systemic medications amoxicillin, cephalexin, and erythromycin (mnemonic “ACE”) can be used during pregnancy, although under the restrictions noted in Table 4. Oral isotretinoin is highly teratogenic and must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program (https://www.ipledgeprogram.com/), which, among other strategies, mandates the use of two effective forms of contraception in women of childbearing potential. Managing Acne During Pregnancy and Lactation ■ TABLE 4 Acne Therapies: Pregnancy Categories Acne Severity Medication Pregnancy 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 Mild/ moderate/ severe C-X Not recommended during pregnancy24,25 Systemic medications Amoxicillin B Short-term; avoid in first trimester—associated with oral clefts24,25 Cephalexin B No malformations in animal studies25 Macrolides (erythromycin is drug of choice) B Short-term use; avoid in first trimester; AVOID erythromycin estolate, 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 ultraviolet B light Severe/ acne fulminans Considered acceptable during pregnancy25 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 Teratogenicity™ (SMART™)27 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 the National Institutes of Health (https://toxnet.nlm.nih.gov/ newtoxnet/lactmed.htm or LactMed@NIH) and available as a mobile phone app (LactMed) enables users to search medications for compatibility with lactation. Short-term use of oral azithromycin, clarithromycin, doxycycline, erythromycin (oral or topical), minocycline, or tetracycline is considered compatible with lactation. Oral clindamycin may cause adverse gastrointestinal (GI) effects in the breastfed infant. Topical azelaic acid, topical clindamycin, and oral spironolactone are considered acceptable for use during breastfeeding. Tetracycline may cause rash or GI effects in the infant.28 Summary Acne is not uncommon in adult women.1 Treatment considerations specific 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 efficacy 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, Eichenfield 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 inflammatory 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 efficacy 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 efficacy and tolerability of a fixed 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 efficacy and tolerability of a fixed 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, Eichenfield 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 spironolactone: 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: Pfizer 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 22. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in nodulocystic acne with and without polycystic ovary syndrome: Efficacy and determinants of relapse. Int J Dermatol. 2013;52:371-376. 23. Tan J, Knezevic S, Boyal S, Waterman B, Janik T. Evaluation of evidence for acne remission with oral isotretinoin cumulative dosing of 120-150 mg/kg. J Cutan Med Surg. 2016;20:13-20. 24. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy. J Am Acad Dermatol. 2014;70:401.e1-401.e14. 25. Chien AL, Qi J, Rainer B, Sachs DL, Helfrich YR. Treatment of acne in pregnancy. J Am Board Fam Med. 2016;29:254-262. 26. Dréno B, Blouin E. Acne, pregnant women and zinc salts: A literature review [in French]. Ann Dermatol Venereol. 2008;135:27-33. 27. Isotretinoin capsules [package insert]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2017. 28. US National Library of Medicine. Drugs and Lactation Database (LactMed). https:// toxnet.nlm.nih.gov/newtoxnet/lactmed.htm. Accessed April 8, 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§ ■ Abstract Patients with skin of color are more likely to develop acne and postinflammatory hyperpigmentation (PIH). Many therapies for acne have demonstrated efficacy in darker skin types and in the treatment of PIH. Semin Cutan Med Surg 37(supp3):S71-S73 © 2018 published by Frontline Medical Communications ■ Keywords Acne; Fitzpatrick skin types IV-VI; postinflammatory hyperpigmentation; skin of color A cne has been reported as one of the most common dermatologic conditions in numerous racial/ethnic groups studied.1,2 Although differences in acne prevalence between racial/ ethnic groups have not been well established, distinct variations in clinical presentation, exacerbating factors, and sequelae of acne are frequently observed in patients with skin of color (ie, Fitzpatrick skin types [FST] IV-VI). These distinctions inform patient care. * Chair, Department of Dermatology, Director of The Skin of Color Center, Mount Sinai St. Luke’s and Mount Sinai West, Associate Professor of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York † Clinical Associate Professor of Dermatology, University of Alabama at Birmingham, Dermatology and Skin Care Center of Birmingham, Birmingham, Alabama ‡ Director of Dermatology Clinical Research, Division Head of Dermatology, Henry Ford Hospital, Detroit, Michigan § Adjunct Professor, Schulich School of Medicine & Dentistry, Western 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 St. Luke’s and Mount Sinai West, 100 Amsterdam Avenue, Suite 11B, New York, NY 10025; alexisderm@yahoo.com 1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi: 10.12788/j.sder.2018.027 Prevalence At least one study (N=2,895)—an evaluation based on photographs— reported that acne is more common in African American and Hispanic women (37% and 32%, respectively) than in Continental Indian, Caucasian, and Asian women (23%, 24%, and 30%, respectively).3 Findings await confirmation by a comparable study. Postinflammatory Hyperpigmentation Postinflammatory hyperpigmentation (PIH), a darkened area of skin following trauma or cutaneous inflammation following acne, results from an abnormal release or overproduction of melanin (Figure).4,5 It is more common in African American and Hispanic women than in Continental Indian, Asian, or Caucasian women, according to a survey of 208 adult women with facial acne (49% non-Caucasian, 51% Caucasian).1,3 Nearly half (49.5%) of the nonCaucasian women reported “a lot” or “extensive” PIH, compared with 22.5% of Caucasian women.1 A study of photographs from 2,895 females aged 10 to 70 years old also found that hyperpigmentation was more common in African American and Hispanic women (65% and 48%, respectively) than in Continental Indian, Asian, and Caucasian (10%, 18%, and 25%, respectively) women.3 PIH may be more distressing to people of color than to lighterskinned patients; it was rated as “severely troublesome” by nearly half (48.5%) of non-Caucasian women with acne in one study.1 Another analysis confirmed this finding.6 PIH-associated discoloration may persist well beyond the acne lesions that triggered it. Epidermal PIH may persist for 6 to 12 months; dermal PIH can last for years.5,7 ■ FIGURE Postinflammatory Hyperpigmentation Source: Courtesy of Andrew F. Alexis, MD, MPH 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 showed marked inflammation, beyond what would be expected based on clinical examination. Skin taken from sites not near the acne lesions also displayed inflammation. Hyperpigmented macules with melanin granules were identified in the epidermis, with pigment-filled macrophages detected in the dermis.8 According to an analysis of patients seen at a single center specializing in the care of skin of color, acne hyperpigmented macules were identified in 65.3% of 239 African American patients, 52.7% of 55 Hispanic patients, and 47.4% of 19 Asian patients. These findings could account for the development of PIH in patients with skin of color.9 Patient History and Education The use of certain hair oils and emollients to moisturize the hair and scalp can result in pomade acne, characterized by closely packed, closed comedones and small papules along the hairline.10 Makeup or skin care products may induce or worsen acne, or may irritate or dry the skin. Skin lightening or bleaching creams may irritate the skin or cause acne, especially if they contain steroids. Patient history should include a list of all skin, hair, and cosmetic products used. Some products may lead to dryness or irritation when combined with topical acne medications.11 Educating patients to avoid substances that may contribute to their acne or PIH is an important aspect of therapy. Daily sunscreen use can reduce the intensity of PIH, even in people with darker skin.12 A study in African American and Hispanic individuals who did not use sunscreen found that 8 weeks of sunscreen use with sun protection factor 30 or 60 lightened facial and hand pigmentary abnormalities.13 Patients who do not use sunscreen should be educated to do so.14 In a study of patients of Afro-Caribbean ancestry, family history was associated with the formation of keloid scars in multiple sites rather than a single site.15 More than two-thirds of Caucasian and non-Caucasian women alike expected to see results from acne treatment within 2 weeks, according to a patient survey. Some expected benefits overnight.1 To set expectations and promote adherence to therapy, patients should be educated that resolution of acne and PIH often takes several weeks.4,5 Topical Therapy for Acne and PIH Early, aggressive treatment is recommended in patients with skin of color to minimize the risk of PIH and scarring. This imperative must be balanced by the need to avoid skin irritation due to therapy, which can result in dyspigmentation and can worsen PIH.4,5,11 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 acne, consider therapies that address both conditions. Several therapies recommended in the management of acne and/or PIH have data supporting their efficacy in patients with skin of color. Topical Retinoids These agents represent first-line acne therapy both in patients with skin of color and in Caucasian patients.2,11 Starting at a lower concentration (0.025% tretinoin, for example) or applying every other day is recommended in patients with skin of color to reduce the risk of irritation. Topical retinoids are an attractive option in patients with skin of color because they can treat acne and may lighten areas of hyperpigmentation in black patients (P<0.001 vs vehicle after 40 weeks of therapy). In one study, half of 24 subjects randomized to topical tretinoin 0.1% developed retinoid reactions where the medication was applied; reactions diminished in severity, duration, and frequency as the study progressed.16 S72 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 3S, June 2018 Once-daily tazarotene 0.1% cream has demonstrated efficacy compared with vehicle in the treatment of PIH in 74 patients with skin of color.17 A recent post hoc analysis of data from a 12-week, phase 3 study of adapalene 0.3%/benzoyl peroxide 2.5% (ADAP 0.3%/ BPO 2.5%) found that the active therapy was significantly superior to vehicle for reduction of both inflammatory and noninflammatory lesions. When the study population was analyzed by FST, the proportion of subjects achieving scores of clear or almost clear on the Investigator Global Assessment (IGA) with active therapy was superior to vehicle only for those with lighter skin (FST I-III; n=128, ADAP 0.3%/BPO 2.5%; n=43, vehicle).18 These authors noted that only a small number of subjects were randomized to vehicle in the FST IV-VI group (n=89, ADAP 0.3%/BPO 2.5%; n=26, vehicle), reducing the statistical power of the analysis. They also speculated that the presence of PIH lesions might have affected the IGA. This study did not examine the impact of therapy on PIH. Topical Antibiotics A post hoc analysis of data from a phase 3, 12-week, vehiclecontrolled clinical trial of clindamycin 1.2%/BPO 3.75% gel found that efficacy in Hispanic subjects (n=136) with moderate to severe acne was similar to that of the general study population. The treatment was well tolerated in the Hispanic cohort; no treatmentrelated adverse events were reported, and no subjects discontinued therapy due to adverse events.19 Dapsone Topical dapsone 5% is recommended for the treatment of inflammatory acne, especially in adult females.2 In a study of 68 adult women with acne and skin of color (FST IV-VI), topical dapsone gel 5% monotherapy applied twice daily for 12 weeks significantly reduced the investigator-rated 5-point Global Acne Assessment Score (GAAS) from baseline (mean, −1.2; 95% confidence interval, −1.4 to −1.0; P<0.001; 39% improvement). Nearly 43% of subjects had a GAAS of 0 or 1 at week 12. No treatment-related adverse events were observed.20 Race (Caucasian/ non-Caucasian) did not affect the efficacy of dapsone 7.5% gel in a pooled subgroup analysis of data from two phase 3 trials (N=4,340; moderate inflammatory and noninflammatory acne).21 A pooled analysis of data from two phase 3 trials of dapsone 7.5% and vehicle in patients (N=4,327) with moderate acne stratified by FST (I-III, IV-VI) supported these findings, reporting efficacy in both groups.22 Azelaic Acid A pilot study of azelaic acid 15% gel twice daily led to improvement of both acne and PIH in adults (N=20) with FST IV and mild or moderate acne and moderate or severe PIH.23 After 16 weeks, 85% of patients had achieved at least a 2-point improvement in IGA for acne, and all (100%) had at least a 2-point improvement in IGA for PIH.23 Hydroquinone Topical hydroquinone is considered the gold standard therapy for skin lightening and is often the first therapy used in treating PIH.4,11 Hydroquinone 4% combined with 0.15% retinol and antioxidants can reduce lesion size, pigmentation, and disease severity in patients with hyperpigmentation on the face and body (FST II-VI).24 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 should be applied only to areas of PIH. In our practice, we limit the use of hydroquinone to lesions large enough to be amenable to spot application (>4 mm). For smaller areas, consider using topical retinoids or azelaic acid because these agents can be applied to normal as well as affected skin. Exogenous ochronosis, a blue-black darkening of the skin, is a risk of long-term hydroquinone use.25 Procedural Therapies for PIH Topical agents, considered to be first-line choices for PIH, are more likely to be efficacious in epidermal than dermal lesions. Superficial chemical peels and laser therapy offer alternatives for treating dermal lesions and in those that respond inadequately to topical options.26 Caution must be exercised because these interventions can cause or exacerbate PIH.3 Medium-depth peels are associated with a higher risk of postprocedure PIH than superficial chemical peels. Deep peels are contraindicated in patients with skin of color due to the effects on skin pigment and risk of scarring.4 Superficial Chemical Peels Adding serial glycolic acid peels (every 3 weeks) to a topical regimen containing hydroquinone 2%, tretinoin 0.05%, and hydrocortisone 1% improved the results of facial PIH treatment in 30 patients with FST III-V, compared with the topical regimen alone.25 Patients were treated for 18 weeks. The mean Hyperpigmentation Area and Severity Index score at 12 and 21 weeks showed significantly greater improvement with the peels.27 Salicylic acid peels have demonstrated efficacy in PIH when combined with topical therapy but not as monotherapy.4,28-31 In our practice, we instruct patients to stop retinoid therapy 1 week prior to chemical peel therapy to reduce the risk of crusting, erosion, and PIH. BPO, azelaic acid, or dapsone can be used up to the day of the peel. Laser Therapy The quality of the evidence for the use of lasers in the treatment of PIH for patients with skin of color is low; most data come from small, nonrandomized clinical trials, case reports, and case studies.4 Summary PIH and scarring occur more often in patients with skin of color than in Caucasian patients. These sequelae may be more distressing to the patient than acne. The need for early, aggressive treatment of acne to prevent PIH and scarring must be balanced with the need to avoid skin irritation, which itself can cause dyspigmentation. Many therapies for acne have been studied in patients with skin of color. Treatments that address both acne and PIH are good choices for patients with both conditions. References 1. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31. 6. Gorelick J, Daniels SR, Kawata AK, et al. Acne-related quality of life among female adults of different races/ethnicities. J Dermatol Nurses Assoc. 2015;7:154-162. 7. Lacz NL, Vafaie J, Kihiczak NI, Schwartz RA. Postinflammatory hyperpigmentation: A common but troubling condition. Int J Dermatol. 2004;43:362-365. 8. Halder RM, Holmes YC, Bridgeman-Shah S, Kligman AM. A clinicohistopathologic study of acne vulgaris in black females [abstract]. J Invest Dermatol. 1996;106:888. 9. Taylor SC, Cook-Bolden F, Rahman Z, Strachan D. Acne vulgaris in skin of color. J Am Acad Dermatol. 2002;46(2 suppl understanding):S98-S106. 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. 11. Callender VD, Barbosa V, Burgess CM, et al. Approach to treatment of medical and cosmetic facial concerns in skin of color patients. Cutis. 2017;100:375-380. 12. Maymone MBC, Neamah HH, Wirya SA, Patzelt NM, Zancanaro PQ, Vashi NA. Sun-protective behaviors in patients with cutaneous hyperpigmentation: A cross-sectional study. J Am Acad Dermatol. 2017;76:841-846.e2. 13. Halder R, Rodney I, Munhutu M, et al. Evaluation and effectiveness of a photoprotection composition (sunscreen) on subjects of skin of color [abstract]. J Am Acad Dermatol. 2015;72(suppl):AB215. 14. Davis EC, Callender VD. Postinflammatory hyperpigmentation: A review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3:20-31. 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. 16. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443. 17. Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: A double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45-50. 18. Alexis AF, Cook-Bolden FE, York JP. Adapalene/benzoyl peroxide gel 0.3%/2.5%: A safe and effective acne therapy in all skin phototypes. J Drugs Dermatol. 2017;16:574-581. 19. Alexis AF, Cook-Bolden F, Lin T. Treatment of moderate-to-severe acne vulgaris in a Hispanic population: A post-hoc analysis of the efficacy and tolerability of clindamycin 1.2%/benzoyl peroxide 3.75% gel. J Clin Aesthet Dermatol. 2017;10:36-43. 20. Alexis AF, Burgess C, Callender VD, et al. The efficacy and safety of topical dapsone gel, 5% for the treatment of acne vulgaris in adult females with skin of color. J Drugs Dermatol. 2016;15:197-204. 21. 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. 22. Taylor SC, Cook-Bolden FE, McMichael A, et al. Efficacy, safety, and tolerability of topical dapsone gel, 7.5% for treatment of acne vulgaris by Fitzpatrick skin phototype. J Drugs Dermatol. 2018;17:160-167. 23. Kircik LH. Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of postinflammatory hyperpigmentation and acne: A 16-week, baseline-controlled study. J Drugs Dermatol. 2011;10:586-590. 24. Cook-Bolden FE, Hamilton SF. An open-label study of the efficacy and tolerability of microencapsulated hydroquinone 4% and retinol 0.15% with antioxidants for the treatment of hyperpigmentation. Cutis. 2008;81:365-371. 25. Hydroquinone 4% cream [package insert]. Bronx, NY: Perrigo; 2017. 26. Vashi NA, Wirya SA, Inyang M, Kundu RV. Facial hyperpigmentation in skin of color: Special considerations and treatment. Am J Clin Dermatol. 2017;18:215-230. 27. Sarkar R, Parmar NV, Kapoor S. Treatment of postinflammatory hyperpigmentation with a combination of glycolic acid peels and a topical regimen in dark-skinned patients: A comparative study. Dermatol Surg. 2017;43:566-573. 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 postinflammatory hyperpigmentation in dark skin. Dermatol Surg. 2009;35:638-644. 29. Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. Dermatol Surg. 1999;25:18-22. 2. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33. 30. Mohamed Ali BM, Gheida SF, El Mahdy NA, Sadek SN. Evaluation of salicylic acid peeling in comparison with topical tretinoin in the treatment of postinflammatory hyperpigmentation. J Cosmet Dermatol. 2017;16:52-60. 3. Perkins AC, Cheng CE, Hillebrand GG, Miyamoto K, Kimball AB. Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol. 2011;25:1054-1060. 31. Ahn HH, Kim IH. Whitening effect of salicylic acid peels in Asian patients. Dermatol Surg. 2006;32:372-375. 4. Kaufman BP, Aman T, Alexis AF. Postinflammatory 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 CME/CE Post-Test and Evaluation Form FOR REVIEW PURPOSES ONLY. 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 info@globalacademycme.com. 1. Which of the following accurately describes the use of medications for acne during pregnancy: A. Any topical medication is safe B. Topical retinoids should not be used at any time during pregnancy C. All systemic medications for acne should be avoided during all of pregnancy D. Large studies generating high-quality data document the appropriate use of acne medications during pregnancy 2. Truncal acne: A. Is present in no more than a quarter of patients with acne B. Is not responsive to topical treatments C. Has responded to therapy with azelaic acid foam 15% in a small open-label study D. Is an exception to the American Academy of Dermatology (AAD) guidelines’ recommended limits on the use of systemic antibiotics 3. Which of the following acne therapies also is efficacious in the treatment of photodamage? A. Topical antibiotics B. Topical azelaic acid C. Topical benzoyl peroxide (BPO) D. Topical retinoids 4. Data suggest that postinflammatory hyperpigmentation (PIH): A. Is more common in African American and Hispanic women than in Continental Indian, Asian, or Caucasian women B. Virtually always resolves at the same time as the acne lesions that triggered it EVALUATION FORM MD/DO MSN/BSN/RN C. Is not responsive to the use of sunscreen in patients with darker skin D. Is best treated separately from, and after resolution of, the acne with which it is associated 5. What percentage of patients with moderate or severe rosacea achieved an Investigator Global Assessment (IGA) score of clear/almost clear after concomitant use of ivermectin 1% cream and brimonidine 0.33% gel for 12 weeks? A. <30% B. 35% to 45% C. 50% to 60% D. >60% 6. Which of the following topical therapies has been associated with reduced risk of scar formation due to acne? A. Dapsone 5% B. Adapalene (ADAP) 0.1%/BPO 2.5% and ADAP 0.3%/BPO 2.5% C. Clindamycin 1.2%/BPO 3.75% gel D. Azelaic acid 15% gel 7. Procedural therapies for PIH: A. Are first-line alternatives for treating both epidermal and dermal lesions B. Cannot worsen PIH C. Include superficial peels that can be combined with topical therapies D. Include deep peels, which can be especially successful in patients with skin of color 8. Research indicates that Propionibacterium acnes: A. Is always pathogenic B. Includes some phylotypes associated with healthy skin and anti-inflammatory effects C. Overgrowth is triggered by hormones (insulin-like growth factor–1, insulin, and androgens), which promote increased sebum production and a change in sebum quality D. B and C 9. According to the AAD guidelines and a consensus statement from the Global Alliance to Improve Outcomes in Acne: A. Monotherapy with systemic antibiotics is not recommended; short-term monotherapy (3 months) with topical antibiotics is acceptable B. Monotherapy with antibiotics—either topical or systemic— is not recommended C. Long-term systemic antibiotic use is acceptable in combination with nonantibiotic therapy and with appropriate monitoring D. Combining two antibiotic therapies is an acceptable alternative to combining an antibiotic and a nonantibiotic therapy 10. What percentage of patients with moderate or severe papulopustular rosacea achieved an IGA score of clear/ almost clear and ≥2-grade improvement after 12 weeks of azelaic acid 15% foam twice daily? A. <20% B. 20% to 30% C. 30% to 40% D. 40% to 50% Please indicate your profession/background: (check one) PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator LEARNING OBJECTIVES: Having completed this activity, you are better able to: Student Strongly Agree Other; specify ________________________________ Agree Somewhat Agree Disagree Strongly Disagree Design a comprehensive treatment plan for patients with acne based on clinical guidelines and updated research, incorporating pharmacologic and physical modalities 5 4 3 2 1 Discuss and design treatment plans for patients of color, pregnant patients, and those with truncal acne, scarring, and photoaging 5 4 3 2 1 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 achieve therapeutic goals in rosacea treatment 5 4 3 2 1 If you do not feel confident that you can achieve the above objectives to some extent, please describe why not. ___________________________________________________________________________________ ___________________________________________________________________________________ Based on the content of this activity, what will you do differently in the care of your patients/ regarding your professional responsibilities? (check one) Implement a change in my practice/workplace. Seek additional information on this topic. Do nothing differently. Current practice/job responsibilities reflect activity recommendations. Do nothing differently as the content was not convincing. Do nothing differently. System barriers prevent me from changing my practice/workplace. OVERALL EVALUATION If you anticipate changing one or more aspects of your practice/professional responsibilities as a result of your participation in this activity, please briefly describe how you plan to do so. ___________________________________________________________________________________ If you plan to change your practice/workplace, may we contact you in 2 months to see how you are progressing? Yes. E-mail address: ___________________________________________ No. I don’t plan to make a change. If you are not able to effectively implement what you learned in this activity, please tell us what the system barriers are (eg, institutional systems, lack of resources, etc)? ___________________________________________________________________________________ ___________________________________________________________________________________ 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 Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Author was organized in the written materials. 5 4 3 2 1 Author demonstrated current knowledge of the topic. 5 4 3 2 1 Author was organized in the written materials. 5 4 3 2 1 Andrew F. Alexis, MD, MPH Julie C. Harper, MD Linda F. Stein Gold, MD Jerry K. L. Tan, MD, FRCPC What topics do you want to hear more about, and what issue(s) regarding your practice/professional responsibilities will they address? ___________________________________________________________________________________ ___________________________________________________________________________________ Please provide additional comments pertaining to this activity and any suggestions 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. © 2018 Global Academy for Medical Education, LLC. All Rights Reserved.

RELATED PAPERS

RELATED TOPICS

Log In

Current Concepts in Acne Pathogenesis: Pathways to Inflammation

Current Concepts in Acne Pathogenesis: Pathways to Inflammation

Related Papers

RELATED PAPERS

RELATED TOPICS