Journal of Drugs in Dermatology EDITOR-IN-CHIEF Perry Robins MD CO-EDITOR-IN-CHIEF Deborah S

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ISSN: 1545 9616 July 2019 • Volume 18 • Issue 7 JDD

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CONTINUING EDUCATION: Patient-focused Treatments in Rosacea Management

Knowledge Gaps in SOC Aesthetic Treatment

A Survey-Based Comparison of Sun Safety Practices

Review of Treatment for Impetigo

Laser-Assisted Delivery of Treatment for Plantar Warts

Topical Collagen Powder vs Primary Closure for Punch Biopsy Wounds

RESIDENT ROUNDS NEWS, VIEWS, & REVIEWS PIPELINE PREVIEWS CLINICAL TRIAL REVIEW ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY c2 heliocare 1 page

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SENIOR EDITORS Macrene Alexiades MD PhD Dee Anna Glaser MD Ronald L. Moy MD Gerhard Sattler MD Robert Baran MD C. William Hanke MD Keyvan Nouri MD James M. Spencer MD Joseph B. Bikowski MD William Levis MD Neil S. Sadick MD Susan H. Weinkle MD

SENIOR ASSOCIATE ASSOCIATE EDITORS Neil Alan Fenske MD Cleire Paniago-Pereira MD EDITORS Dale M. Abadir MD Rebecca Fitzgerald MD Anna C. Pavlick MD Kenneth Beer MD William Abramovits MD Alina A. Fratila MD Christopher R. Payne MD Martin Braun MD Andrew F. Alexis MD MPH Alejandro Camps Fresnada MD António Picoto MD Jeffrey Phillip Callen MD Shawn Allen MD Ellen C. Gendler MD Sheldon V. Pollack MD Jean Carruthers MD Rex A. Amonette MD Dore Gilbert MD Babar K. Rao MD James Q. Del Rosso DO Robert Anolik MD David J. Goldberg MD Wendy E. Roberts MD Lawrence F. Eichenfield MD Martha P. Arroyo MD Leonard H. Goldberg MD Amy E. Rose MD Patricia Farris MD Robin Ashinoff MD Robert H. Gotkin MD Steven Rosenberg MD Norman Goldstein MD Marc R. Avram MD Gloria F. Graham MD Lidia Rudnicka MD Aditya K. Gupta MD PhD David E. Bank MD John Hawk MD Bijan Safai MD Elizabeth Hale MD Jay G. Barnett MD Michael P. Heffernan MD Eli R. Saleeby MD Sherry H. Hsiung MD Eliot F. Battle Jr. MD William L. Heimer II MD Fitzgeraldo A. Sanchez-Negron MD Leon Kircik MD Richard G. Bennett MD N. Patrick Hennessey MD Miguel Sanchez-Viera MD Mark Lebwohl MD Diane S. Berson MD Alysa R. Herman MD Julie Schaffer MD Henry W. Lim MD Ronald R. Branacaccio MD George J. Hruza MD Bryan C. Schultz MD Flor Mayoral MD Rana Anadolu Brasie MD Shasa Hu MD Daniel Mark Siegel MD Maurizio Podda MD PhD Jeremy A. Brauer MD Mark J. Jaffe MD Arthur J. Sober MD Jeffrey Orringer MD Gary Brauner MD Do NotJared Copy Jagdeo MD Nicholas A. Soter MD Maritza Perez MD Neil Brody MD PhD PenaltiesS. BrianApply Jiang MD Jennifer Stein MD Kevin Pinski MD Lance H. Brown MD Bruce E. Katz MD Fernando Stengel MD Luigi Rusciani Scorza MD Isaac Brownell MD PhD Mark D. Kaufmann MD Hema Sundaram MD Ritu Saini MD Karen E. Burke MD PhD Amor Khachemoune MD Susan C. Taylor MD Jerome l. Shupack MD Mariano Busso MD Poong Myung Kim MD Emily Tierney MD Amy Taub MD Francisco M. Camacho-Martinez MD Christine Ko MD George-Sorin Tiplica MD PhD Danny Vleggaar MD Marian Cantisano-Zilkha MD David Kriegel MD Ella L. Toombs MD Brian Zelickson MD Alastair Carruthers MD Pearon G. Lang MD Irene J. Vergilis-Kalner MD Roger I. Ceilley MD Aimee Leonard MD Steven Wang MD Clay J. Cockerell MD Mary P. Lupo MD Ken Washenik MD PhD David E. Cohen MD Alan Matarasso MD Jeffrey Weinberg MD Julian S. Conejo-Mir MD Alan Menter MD Robert A. Weiss MD Elizabeth Alvarez Connelly MD Warwick L. Morison MD W. Phillip Werschler MD FEATURE EDITORS Ira Davis MD Rhoda S. Narins MD Ronald G. Wheeland MD Kendra G. Bergstrom MD Calvin Day MD Mark Naylor MD Jai Il Youn MD Joel L. Cohen MD Doris Day MD Kishwer S. Nehal MD John Zic MD Adam Friedman MD Jeffrey S. Dover MD Martino Neumann MD John A. Zitelli MD James L. Griffith MD Zoe Diana Draelos MD Nelson Lee Novick MD Marissa Heller MD Madeleine D. Duvic MD Jorge J. Ocampo Candiani MD Isaac Zilinsky MD Mohamed L. Elsaie MD Philip Orbuch MD Joseph C. English III MD Ariel Ostad MD

PAST CO-EDITORS-IN-CHIEF Elizabeth Hale MD (2004) Impact Factor Susan H. Weinkle MD (2005-2008) Impact Factor Score: 1.527* ® * Keyvan Nouri MD (2005-2008) Normalized Eigenfactor Score: 0.660 Article Influence Score: 0.409* Sherry H. Hsiung MD (2008) *Clarivate Analytics, Formerly the IP & Science Business of James M. Spencer MD (2009-2013) Thomson Reuters, June 2018 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

CONTINUING EDUCATION ARTICLE 606 Patient-focused Solutions in Rosacea Management: Treatment Challenges in Special Patient Groups Ahuva Cices MD, Andrew F. Alexis MD MPH

GUEST EDITORIAL 615 Global Perspectives of the Patient of Color Cheryl M. Burgess MD FAAD

ORIGINAL ARTICLES Do Not Copy 616 Myths and Knowledge Gaps in the Aesthetic Treatment of Patients With Skin of Color Penalties Apply Andrew F. Alexis MD MPH, Julius Few MD, Valerie D. Callender MD, Pearl Grimes MD, Jeanine Downie MD MA, Charles Boyd MD, Conor J. Gallagher PhD

623 Understanding the Female Hispanic and Latino American Facial Aesthetic Patient Sabrina Fabi MD, José Raúl Montes MD FACS FACCS, Shino Bay Aguilera DO, Vivian Bucay MD FAAD, Stephanie Manson Brown MBBS MRCS MFPM, Nazanin Ashourian PhD

633 Understanding the Female Asian American Facial Aesthetic Patient Annie Chiu MD, Kavita Mariwalla MD, Andrea Hui-Austin MD, Vic Narurkar MD, Carola de la Guardia PhD

642 In Vitro and In Vivo Efficacy and Tolerability of a Non-Hydroquinone, Multi-Action Skin Tone Correcting Cream Pearl E. Grimes MD, David H. McDaniel MD, Mitchell Wortzman PhD, Diane Nelson RN MPH

649 A Survey-Based Comparison of Sun Safety Practices in a Representative Cohort of the General Public Versus Attendees of a Skin Cancer Screening Emily C. Murphy BS, Stephanie Kao BA, Huan Wang MS, Dechang Chen PhD, Hong Nguyen MD MPH, Adam J. Friedman MD Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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12 Kamedis Eczema 8 10.9 Therapy Cream Kamedis Eczema Therapy Cream Vehicle 9.61 7 Vehicle 10 6.79 8.87 Comparator Comparator 8.27 6 8.48 5.5 8 7.16 7.06 5 4.72 4.7

6 4 6.19 BSA (%) (%) BSA 3.79 4.12 5.26 3 4 3.78 1.89 3.38

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2 1.37 1 1.29

0.21 0 0 0 1 2 3 4 0 1 2 3 4 Duration (Weeks #) Duration (Weeks #)

ORIGINAL ARTICLES (CONTD) 655 Topical Ozenoxacin Cream 1% for Impetigo: A Review Lawrence Schachner MD FAAD, Anneke Andriessen PhD, Neal Bhatia MD, Ayman Grada MD MS, Dillon Patele

663 Laser-Assisted Delivery of Topical Cidofovir in the Treatment of Plantar Warts Margaret Coates BA, Jigar Patel MD, Courtney Powers PA-C, Claude Burton MD

667 A Head-to-Head Comparison of Topical Collagen Powder to Primary Closure for Acute Full-Thickness Punch Biopsy-Induced Human Wounds: An Internally Controlled Pilot Study Azam Qureshi BA, Emily Murphy BS, Rose Milando BA, Monica Rengifo-Pardo MD, Courtney Clayton, Adam Friedman MD FAAD

675 Non-Submental Applications of Injectable Deoxycholic Acid: A Systematic Review Calvin T. Sung MD, Alfred Lee BA, Franchesca Choi BS RPh, Margit Juhasz MD, Natasha Atanaskova Mesinkovska MD PhD

682 Effective and Safe RepeatedDo Full-Face Not TreatmentsCopy With AbobotulinumtoxinA, Hyaluronic Acid Filler, and PenaltiesSkin Boosting Apply Hyaluronic Acid Per Hedén MD, Doris Hexsel MD, Hugues Cartier MD, Per Bergentz MD, Henry Delmar MD, Fernanda Camozzato MD, Carolina Siega BSc, Cecilia Skoglund PhD, Carolina Edwartz PhD, Maria Norberg PhD, Philippe Kestemont MD

CASE REPORTS 690 An Atypical Presentation of PLEVA: Case Report and Review of the Literature Constance Ediale MS, Kayla Felix MS, Kathryn Anderson MD, Christine Ahn MD, Amy J. McMichael MD

693 Treatment of Solitary Keratoacanthoma of the Nose With Intralesional Methotrexate and Review of the Literature Laura Doerfler MD, C. William Hanke MD MPH

Publishers Associate Publisher Shelley N. Tanner Nick Gillespie Lawrence E. Robins Executive Editor Scientific Publications Liaison Karin Beehler Luz Figueroa Associate Editor Design Kathleen Leary RN Karen Rebbe STILL AVAILABLE OFFCAL BLCATON OF

Journal of Drugs in Dermatology (JDD) (ISSN 1545-9616) is published monthly for $300 per year US Individual subscriptions/ $350 per year International Individual subscriptions/(Corporate and Institutional rates contact Sales for a quote) by Issues & the Journal of Drugs in Dermatology, 115 E. 23rd Street, 3rd Floor, Unit 322, New York, NY 10010. Periodicals postage paid at New York, NY and additional mailing offices. Considerations for ADVERTISING & CORPORATE & INSTITUTIONAL SALES: Contact Nick Gillespie at 646-453-5711 Do Not Copy e-mail: [email protected] Optimal Outcomes in REPRINTS & PERMISSIONS: Contact Luz Figueroa at 646-736-4338 Penalties Apply e-mail: [email protected] SUBSCRIPTIONS: Email [email protected] or call 212-213-5434 ext. 4 Acne Management POSTMASTER: Send address changes to the Journal of Drugs in Dermatology, 115 E. 23rd Street, 3rd Floor, Unit 322, New York, NY 10010. JOURNAL-BASED ENDURING CE ACTIVITY Journal of Drugs in Dermatology (JDD) is indexed in MEDLINE®/PubMed® and is published monthly by the Journal of Drugs in Dermatology 115 E. 23rd Street, 3rd Floor, Unit 322, New York, NY 10010 telephone: 212-213-5434 | fax: 212-213-5435 | JDDonline.com

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in Funded by an educational grant provided electrical or other forms or by any means without prior written permission from the Journal by Galderma Laboratories, L.P. of Drugs in Dermatology (JDD). This publication has been registered with the Library of Con- gress (ISSN: 1545 9616). The publisher and the organizations appearing herein assume no responsibility for any injury and/or damage to persons or property as a matter of product liabil- ity, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. No suggested test or procedure should be carried out unless, in the reader’s judgment, its risk is justified. Because of the rapid advances in the medical sciences, we recommend that independent verification of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medical procedures, choice of drugs, and drug dosages are the responsibility of the authors. Statements and opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the editors, publisher, or staff. The editors, publisher, and staff disclaim any responsibility for such material and do not guarantee, warrant, or endorse any product or service advertised in this publication nor do they guarantee any claim made by the manufacturer of such product or service.

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FOR THE TREATMENT OF ADULTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS WHO ARE CANDIDATES FOR SYSTEMIC THERAPY OR PHOTOTHERAPY AND ADULTS WITH ACTIVE PSORIATIC ARTHRITIS1 A DIFFERENT KIND OF ANTI-TNF1-4

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Co-primary endpoints were PASI 75 and PGA 0/1.1,5,6 A majority of patients responded at Week 16, with 200 mg every other week maintenance dosing, (N=1020. 113 female subjects treated with 200 mg Q2W).1,5-7 Of the 850 patients randomized to CIMZIA or placebo, 30% had prior biologic therapy.1 Do Not Copy Penalties Apply

Indications regions where mycoses are endemic; with underlying conditions that may predispose • Cases of acute and chronic leukemia were reported with TNF blocker use. DRUG INTERACTIONS them to infection. Monitor patients closely for the development of signs and symptoms • Do not use CIMZIA in combination with other biological DMARDS. • CIMZIA is indicated for the treatment of adults with moderate-to-severe plaque of infection during and after treatment with CIMZIA, including the possible development HEART FAILURE psoriasis who are candidates for systemic therapy or phototherapy. of TB in patients who tested negative for latent TB infection prior to initiating therapy. • Worsening and new onset congestive heart failure (CHF) have been reported with AUTOIMMUNITY • CIMZIA is indicated for the treatment of adults with active psoriatic arthritis. • Do not start CIMZIA during an active infection, including localized infections. TNF blockers. Exercise caution and monitor carefully. • Treatment with CIMZIA may result in the formation of autoantibodies and, rarely, HYPERSENSITIVITY in development of a lupus-like syndrome. Discontinue treatment if symptoms of a • Patients older than 65 years, patients with co-morbid conditions, and/or patients taking lupus-like syndrome develop. Important Safety Information concomitant immunosuppressants may be at greater risk of infection. • Angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, CONTRAINDICATIONS IMMUNIZATIONS • If an infection develops, monitor carefully and initiate appropriate therapy. and urticaria have been reported following CIMZIA administration. If a serious • CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to allergic reaction occurs, stop CIMZIA and institute appropriate therapy. The needle • Patients on CIMZIA should not receive live or live-attenuated vaccines. certolizumab pegol or to any of the excipients. Reactions have included angioedema, MALIGNANCY shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative ADVERSE REACTIONS anaphylaxis, serum sickness, and urticaria. Lymphoma and other malignancies, some fatal, have been reported in children and of natural rubber latex which may cause an allergic reaction in individuals sensitive • The most common adverse reactions in CIMZIA clinical trials (≥8%) were upper adolescent patients treated with TNF blockers, of which CIMZIA is a member. CIMZIA is to latex. respiratory infections (18%), rash (9%), and urinary tract infections (8%). SERIOUS INFECTIONS not indicated for use in pediatric patients. Patients treated with CIMZIA are at increased risk for developing serious infections that HEPATITIS B VIRUS REACTIVATION • Consider the risks and benefits of CIMZIA treatment prior to initiating or continuing may lead to hospitalization or death. Most patients who developed these infections were • Use of TNF blockers, including CIMZIA, may increase the risk of reactivation therapy in a patient with known malignancy. Please see Brief Summary of full Prescribing Information taking concomitant immunosuppressants such as methotrexate or corticosteroids. of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have • In clinical trials, more cases of malignancies were observed among on following pages. Discontinue CIMZIA if a patient develops a serious infection or sepsis. been fatal. CIMZIA-treated patients compared to control patients. Reported infections include: • Test patients for HBV infection before initiating treatment with CIMZIA. • In CIMZIA clinical trials, there was an approximately 2-fold higher rate of lymphoma References: 1. CIMZIA [prescribing information]. Smyrna, GA: UCB, Inc.; 2019. 2. Nesbitt A, Fossati G, • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have than expected in the general U.S. population. Patients with rheumatoid arthritis, • Exercise caution in patients who are carriers of HBV and monitor them before Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other frequently presented with disseminated or extrapulmonary disease. Test patients for particularly those with highly active disease, are at a higher risk of lymphoma than and during CIMZIA treatment. anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis. 2007;13(11):1323-1332. 3. Pasut G. latent TB before CIMZIA use and during therapy. Initiate treatment for latent TB prior the general population. • Discontinue CIMZIA and begin antiviral therapy in patients who develop HBV Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab to CIMZIA use. pegol. BioDrugs. 2014;28 (suppl 1):S15-S23. 4. Porter C, Armstrong-Fisher S, Kopotsha T, et al. • Malignancies, some fatal, have been reported among children, adolescents, reactivation. Exercise caution when resuming CIMZIA after HBV treatment. Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): consequences for FcRn-mediated • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, and young adults being treated with TNF blockers. Approximately half of the cases NEUROLOGIC REACTIONS in vitro transcytosis and ex vivo human placental transfer. J Reprod Immunol. 2016;116:7-12. aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or 5. Gottlieb AB, Blauvelt A, Thaçi D, et al. Certolizumab pegol for the treatment of chronic plaque were lymphoma, while the rest were other types of malignancies, including rare • TNF blockers, including CIMZIA, have been associated with rare cases of new onset other invasive fungal infections may present with disseminated, rather than localized, psoriasis: results through 48 weeks from two phase 3, multicenter, randomized, double-blinded, types associated with immunosuppression and malignancies not usually seen in this or exacerbation of central nervous system and peripheral demyelinating diseases, disease. Antigen and antibody testing for histoplasmosis may be negative in some placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018;79(2):302- patient population. including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, 6. patients with active infection. Consider empiric anti-fungal therapy in patients at risk 314.e6. Lebwohl M, Blauvelt A, Paul C, et al. Certolizumab pegol for the treatment of chronic • Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell and Guillain-Barré syndrome. plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double-blinded, for invasive fungal infections who develop severe systemic illness. etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018;79(2):266-276.e5. lymphoma, have been reported in patients treated with TNF blockers, including HEMATOLOGIC REACTIONS • Bacterial, viral, and other infections due to opportunistic pathogens, including CIMZIA. These cases have had a very aggressive disease course and have been fatal. 7. Data on file. Smyrna, GA: UCB, Inc. • Rare reports of pancytopenia, including aplastic anemia, have been reported with Legionella and Listeria. The majority of reported TNF blocker cases have occurred in patients with Crohn’s TNF blockers. Medically significant cytopenia has been infrequently reported Carefully consider the risks and benefits of treatment with CIMZIA prior to initiating disease or ulcerative colitis, and the majority were in adolescent and young adult with CIMZIA. therapy in the following patients: with chronic or recurrent infection; who have been males. Almost all of these patients had received treatment with azathioprine exposed to TB; with a history of opportunistic infection; who resided in or traveled in or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. • Consider stopping CIMZIA if significant hematologic abnormalities occur. Carefully assess the risks and benefits of treating with CIMZIA in these patient types. CIMZIA® is a registered trademark of the UCB Group of Companies. ©2019 UCB, Inc., Smyrna, GA 30080. All rights reserved. June, 2019. US-P-CZ-PSO-1900048

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PROFESSIONAL BRIEF SUMMARY—CONSULT PACKAGE blockers. Patients have frequently presented with disseminated rather than of therapy ≤ 18 years of age), of which CIMZIA is a member. Approximately Test patients for HBV infection before initiating treatment with CIMZIA. For Clinical Trials Experience Table 1: Adverse Reactions Reported by ≥3% of Patients INSERT FOR FULL PRESCRIBING INFORMATION localized disease. half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s patients who test positive for HBV infection, consultation with a physician Because clinical studies are conducted under widely varying and controlled Treated with CIMZIA Dosed Every Other Week during Treatment with CIMZIA should not be initiated in patients with an active lymphoma. The other cases represented a variety of different malignancies with expertise in the treatment of hepatitis B is recommended. Adequate conditions, adverse reaction rates observed in clinical studies of a drug cannot Placebo-Controlled Period of Rheumatoid Arthritis Studies, CIMZIA® (certolizumab pegol) infection, including clinically important localized infections. Patients and included rare malignancies usually associated with immunosuppression data are not available on the safety or efficacy of treating patients who be directly compared to rates in the clinical studies of another drug, and with Concomitant Methotrexate. greater than 65 years of age, patients with co-morbid conditions, and/or and malignancies that are not usually observed in children and adolescents. are carriers of HBV with anti-viral therapy in conjunction with TNF blocker may not predict the rates observed in a broader patient population in clinical WARNINGS: patients taking concomitant immunosuppressants (e.g. corticosteroids or The malignancies occurred after a median of 30 months of therapy (range therapy to prevent HBV reactivation. Patients who are carriers of HBV and practice. CIMZIA 200 methotrexate) may be at a greater risk of infection. The risks and benefits 1 to 84 months). Most of the patients were receiving concomitant require treatment with CIMZIA should be closely monitored for clinical and In premarketing controlled trials of all patient populations combined the most Placebo+ mg EOW + SERIOUS INFECTIONS of treatment should be considered prior to initiating therapy in patients: immunosuppressants. These cases were reported post-marketing and are laboratory signs of active HBV infection throughout therapy and for several common adverse reactions (≥ 8%) were upper respiratory infections (18%), Adverse Reaction MTX# (%) MTX(%) derived from a variety of sources including registries and spontaneous post- Patients treated with CIMZIA are at increased • with chronic or recurrent infection months following termination of therapy. rash (9%) and urinary tract infections (8%). (Preferred Term) N =324 N =640 marketing reports. CIMZIA is not indicated for use in pediatric patients. risk for developing serious infections that may • who have been exposed to tuberculosis In patients who develop HBV reactivation, discontinue CIMZIA and initiate Adverse Reactions Most Commonly Leading to Discontinuation of Treatment In the controlled portions of clinical trials of all the TNF blockers, more cases Upper respiratory tract lead to hospitalization or death [see Warnings and effective anti-viral therapy with appropriate supportive treatment. The in Premarketing Controlled Trials • with a history of an opportunistic infection of lymphoma have been observed among patients receiving TNF blockers infection 2 6 Precautions and Adverse Reactions]. Most patients who safety of resuming TNF blocker therapy after HBV reactivation is controlled The proportion of patients with Crohn’s disease who discontinued treatment • who have resided or traveled in areas of endemic tuberculosis or compared to control patients. In controlled studies of CIMZIA for Crohn’s developed these infections were taking concomitant is not known. Therefore, exercise caution when considering resumption of due to adverse reactions in the controlled clinical studies was 8% for CIMZIA Headache 4 5 endemic mycoses, such as histoplasmosis, coccidioidomycosis, or disease and other investigational uses, there was one case of lymphoma immunosuppressants such as methotrexate or CIMZIA therapy in this situation and monitor patients closely. and 7% for placebo. The most common adverse reactions leading to the blastomycosis among 2,657 Cimzia-treated patients and one case of Hodgkin’s lymphoma corticosteroids. discontinuation of CIMZIA (for at least 2 patients and with a higher incidence Hypertension 2 5 among 1,319 placebo-treated patients. Neurologic Reactions • with underlying conditions that may predispose them to infection Use of TNF blockers, of which CIMZIA is a member, has been associated than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea CIMZIA should be discontinued if a patient develops a Nasopharyngitis 1 5 serious infection or sepsis. Tuberculosis In the CIMZIA RA clinical trials (placebo-controlled and open label) a total with rare cases of new onset or exacerbation of clinical symptoms and/or (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% Cases of reactivation of tuberculosis or new tuberculosis infections have been of three cases of lymphoma were observed among 2,367 patients. This is radiographic evidence of central nervous system demyelinating disease, placebo). Reported infections include: approximately 2-fold higher than expected in the general population. Patients Back pain 1 4 observed in patients receiving CIMZIA, including patients who have previously including multiple sclerosis, and with peripheral demyelinating disease, The proportion of patients with rheumatoid arthritis who discontinued • Active tuberculosis, including reactivation of latent with RA, particularly those with highly active disease, are at a higher risk for or concomitantly received treatment for latent or active tuberculosis. Reports including Guillain-Barré syndrome. Exercise caution in considering the use treatment due to adverse reactions in the controlled clinical studies was Pyrexia 2 3 tuberculosis. Patients with tuberculosis have frequently the development of lymphoma. In the CIMZIA PsO clinical trials (placebo- included cases of pulmonary and extrapulmonary (i.e., disseminated) of CIMZIA in patients with pre-existing or recent-onset central or peripheral 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions presented with disseminated or extrapulmonary controlled and open label) there was one case of Hodgkin’s lymphoma. tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent nervous system demyelinating disorders. Rare cases of neurological disorders, leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and Pharyngitis 1 3 disease. Patients should be tested for latent infection prior to initiating CIMZIA and periodically during therapy. Rates in clinical studies for CIMZIA cannot be compared to the rates of clinical including seizure disorder, optic neuritis, and peripheral neuropathy have been pyrexia, urticaria, pneumonia, and rash (0.3%). tuberculosis before CIMZIA use and during therapy. trials of other TNF blockers and may not predict the rates observed when reported in patients treated with CIMZIA [see Adverse Reactions]. Rash 1 3 Treatment for latent infection should be initiated prior Treatment of latent tuberculosis infection prior to therapy with TNF-blocking Controlled Studies with Crohn’s Disease agents has been shown to reduce the risk of tuberculosis reactivation during CIMZIA is used in a broader patient population. Patients with Crohn’s disease Hematological Reactions Acute bronchitis 1 3 to CIMZIA use. that require chronic exposure to immunosuppressant therapies may be at The data described below reflect exposure to CIMZIA at 400 mg subcutaneous therapy. Prior to initiating CIMZIA, assess if treatment for latent tuberculosis Rare reports of pancytopenia, including aplastic anemia, have been dosing in studies of patients with Crohn’s disease. In the safety population higher risk than the general population for the development of lymphoma, Fatigue 2 3 • Invasive fungal infections, including histoplasmosis, is needed; and consider an induration of 5 mm or greater a positive tuberculin reported with TNF blockers. Adverse reactions of the hematologic system, in controlled studies, a total of 620 patients with Crohn’s disease received coccidioidomycosis, candidiasis, aspergillosis, even in the absence of TNF blocker therapy [see Adverse Reactions]. The skin test result, even for patients previously vaccinated with Bacille Calmette- including medically significant cytopenia (e.g., leukopenia, pancytopenia, CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including #EOW = Every other Week, MTX = Methotrexate. blastomycosis, and pneumocystosis. Patients with Guerin (BCG). potential role of TNF blocker therapy in the development of malignancies in thrombocytopenia) have been infrequently reported with CIMZIA [see Adverse adults is not known. subjects randomized to placebo in Study CD2 following open label dosing histoplasmosis or other invasive fungal infections Consider anti-tuberculosis therapy prior to initiation of CIMZIA in patients with Reactions]. The causal relationship of these events to CIMZIA remains of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 Hypertensive adverse reactions were observed more frequently in patients may present with disseminated, rather than a past history of latent or active tuberculosis in whom an adequate course of Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type unclear. patients received CIMZIA at some dose level, of whom 1,350 patients receiving CIMZIA than in controls. These adverse reactions occurred more localized disease. Antigen and antibody testing for treatment cannot be confirmed, and for patients with a negative test for latent of T-cell lymphoma that has a very aggressive disease course and is usually Although no high risk group has been identified, exercise caution in patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% frequently among patients with a baseline history of hypertension and histoplasmosis may be negative in some patients with tuberculosis but having risk factors for tuberculosis infection. Despite previous fatal, have been reported in patients treated with TNF blockers, including being treated with CIMZIA who have ongoing, or a history of, significant were male, and 94% were Caucasian. The majority of patients in the active among patients receiving concomitant corticosteroids and non-steroidal active infection. Empiric anti-fungal therapy should or concomitant treatment for latent tuberculosis, cases of active tuberculosis CIMZIA. The majority of reported TNF blocker cases occurred in adolescent hematologic abnormalities. Advise all patients to seek immediate medical group were between the ages of 18 and 64. anti-inflammatory drugs. and young adult males with Crohn’s disease or ulcerative colitis. Almost be considered in patients at risk for invasive fungal have occurred in patients treated with CIMZIA. Some patients who have been attention if they develop signs and symptoms suggestive of blood dyscrasias Patients receiving CIMZIA 400 mg as monotherapy every 4 weeks in all of these patients had received treatment with the immunosuppressants During controlled clinical studies, the proportion of patients with serious infections who develop severe systemic illness. successfully treated for active tuberculosis have redeveloped tuberculosis while or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. rheumatoid arthritis controlled clinical trials had similar adverse reactions to azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF adverse reactions was 10% for CIMZIA and 9% for placebo. The most being treated with CIMZIA. Consultation with a physician with expertise in the Consider discontinuation of CIMZIA therapy in patients with confirmed those patients receiving CIMZIA 200 mg every other week. • Bacterial, viral and other infections due to opportunistic blocker at or prior to diagnosis. It is uncertain whether the occurrence of common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and pathogens including Legionella and Listeria. treatment of tuberculosis is recommended to aid in the decision of whether significant hematologic abnormalities. with a higher incidence compared to placebo) in controlled clinical studies with initiating anti-tuberculosis therapy is appropriate for an individual patient. HSTCL is related to use of a TNF blocker or a TNF blocker in combination with Other Adverse Reactions The risks and benefits of treatment with CIMZIA should these other immunosuppressants. The potential risk of using a TNF blocker in Use with Biological Disease-Modifying Antirheumatic Drugs CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, Other infrequent adverse reactions (occurring in less than 3% of RA patients) Strongly consider tuberculosis in patients who develop a new infection during viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated be carefully considered prior to initiating therapy in combination with azathioprine or 6-MP should be carefully considered. (Biological DMARDs) were similar to those seen in Crohn’s disease patients. CIMZIA treatment, especially in patients who have previously or recently patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) patients with chronic or recurrent infection. Patients Cases of acute and chronic leukemia have been reported in association with Serious infections were seen in clinical studies with concurrent use of anakinra Psoriatic Arthritis Clinical Study traveled to countries with a high prevalence of tuberculosis, or who have had (an interleukin-1 antagonist) and another TNF blocker, etanercept, with in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and should be closely monitored for the development of signs close contact with a person with active tuberculosis. post-marketing TNF-blocker use in RA and other indications. Even in the arthralgia (6% CIMZIA, 4% placebo). CIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a and symptoms of infection during and after treatment absence of TNF-blocker therapy, patients with RA may be at a higher risk no added benefit compared to etanercept alone. A higher risk of serious placebo-controlled trial. The safety profile for patients with PsA treated with with CIMZIA, including the possible development of Monitoring Do Not Copy (approximately 2-fold) than the general population for the development of infections was also observed in combination use of TNF blockers with Other Adverse Reactions CIMZIA was similar to the safety profile seen in patients with RA and previous tuberculosis in patients who tested negative for latent Patients should be closely monitored for the development of signs and leukemia. abatacept and rituximab. Because of the nature of the adverse events seen The most commonly occurring adverse reactions in controlled trials of Crohn’s experience with CIMZIA. with this combination therapy, similar toxicities may also result from the use tuberculosis infection prior to initiating therapy. symptoms of infection during and after treatment with CIMZIA, including disease were described above. Other serious or significant adverse reactions [see Penalties Apply Melanoma and Merkel cell carcinoma have been reported in patients of CIMZIA in this combination. Therefore, the use of CIMZIA in combination Ankylosing Spondylitis Clinical Study Warnings and Precautions and Adverse Reactions]. the development of tuberculosis in patients who tested negative for latent treated with TNF blockers, including CIMZIA. Periodic skin examinations are reported in controlled and uncontrolled studies in Crohn’s disease and other tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis with other biological DMARDs is not recommended [see Drug Interactions]. diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other CIMZIA has been studied in 325 patients with axial spondyloarthritis of whom MALIGNANCY recommended for all patients, particularly those with risk factors for skin the majority had ankylosing spondylitis (AS) in a placebo-controlled study infection may also be falsely negative while on therapy with CIMZIA. Autoimmunity doses include: Lymphoma and other malignancies, some fatal, have cancer. (AS-1). The safety profile treated with CIMZIA was similar to the safety profile CIMZIA should be discontinued if a patient develops a serious infection or Treatment with CIMZIA may result in the formation of autoantibodies and Blood and lymphatic system disorders: Anemia, leukopenia, seen in patients with RA. been reported in children and adolescent patients treated sepsis. A patient who develops a new infection during treatment with CIMZIA Heart Failure rarely, in the development of a lupus-like syndrome. If a patient develops lymphadenopathy, pancytopenia, and thrombophilia. with TNF blockers, of which CIMZIA is a member [see should be closely monitored, undergo a prompt and complete diagnostic Cases of worsening congestive heart failure (CHF) and new onset CHF symptoms suggestive of a lupus-like syndrome following treatment with Non-radiographic Axial Spondyloarthritis Clinical Study Warnings and Precautions]. CIMZIA is not indicated for have been reported with TNF blockers, including CIMZIA. CIMZIA has not Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac workup appropriate for an immunocompromised patient, and appropriate CIMZIA, discontinue treatment [see Adverse Reactions]. failure, hypertensive heart disease, myocardial infarction, myocardial CIMZIA has been studied in 317 patients with non-radiographic axial use in pediatric patients. antimicrobial therapy should be initiated. been formally studied in patients with CHF; however, in clinical studies in spondyloarthritis (nr-axSpA-1). The safety profile for patients with nr-axSpA patients with CHF with another TNF blocker, worsening congestive heart Immunizations ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack. treated with CIMZIA was similar to the safety profile seen in patients with RA Invasive Fungal Infections failure (CHF) and increased mortality due to CHF were observed. Exercise Patients treated with CIMZIA may receive vaccinations, except for live or and previous experience with CIMZIA. INDICATIONS AND USAGE For patients who reside or travel in regions where mycoses are endemic, caution in patients with heart failure and monitor them carefully [see Adverse live attenuated vaccines. No data are available on the response to live Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis. CIMZIA is indicated for reducing signs and symptoms of Crohn’s disease and invasive fungal infection should be suspected if they develop a serious Reactions]. vaccinations or the secondary transmission of infection by live vaccines in Plaque Psoriasis Clinical Studies General disorders and administration site conditions: Bleeding and injection In clinical studies, a total of 1112 subjects with plaque psoriasis were treated maintaining clinical response in adult patients with moderately to severely systemic illness. Appropriate empiric antifungal therapy should be considered patients receiving CIMZIA. site reactions. active disease who have had an inadequate response to conventional therapy. while a diagnostic workup is being performed. Antigen and antibody testing Hypersensitivity Reactions with CIMZIA. Of these, 779 subjects were exposed for at least 12 months, The following symptoms that could be compatible with hypersensitivity In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no Elevated liver enzymes and hepatitis. CIMZIA is indicated for the treatment of adults with moderately to severly for histoplasmosis may be negative in some patients with active infection. Hepatobiliary disorders: 551 for 18 months, and 66 for 24 months. reactions have been reported rarely following CIMZIA administration to difference was detected in antibody response to vaccine between CIMZIA and active rheumatoid arthritis (RA). CIMZIA is indicated for the treatment of Immune system disorders: Alopecia totalis. Data from three placebo-controlled studies (Studies PS-1, PS-2, and PS-3) in When feasible, the decision to administer empiric antifungal therapy in these patients: angioedema, anaphylaxis, dyspnea, hypotension, rash, serum placebo treatment groups when the pneumococcal polysaccharide vaccine adult patients with active psoriatic arthritis (PsA). CIMZIA is indicated for Anxiety, bipolar disorder, and suicide attempt. 1020 subjects (mean age 46 years, 66% males, 94% white) were pooled to patients should be made in consultation with a physician with expertise in sickness, and urticaria. Some of these reactions occurred after the first and influenza vaccine were administered concurrently with CIMZIA. Similar Psychiatric disorders: the treatment of adults with active ankylosing spondylitis (AS). CIMZIA is evaluate the safety of CIMZIA [see Clinical Studies (14)]. the diagnosis and treatment of invasive fungal infections and should take administration of CIMZIA. If such reactions occur, discontinue further proportions of patients developed protective levels of anti-vaccine antibodies Renal and urinary disorders: Nephrotic syndrome and renal failure. indicated for the treatment of adults with moderate-to-severe plaque psoriasis into account both the risk for severe fungal infection and risks of antifungal administration of CIMZIA and institute appropriate therapy. There are no between CIMZIA and placebo treatment groups; however patients receiving Reproductive system and breast disorders: Menstrual disorder. Placebo-Controlled Period (Week 0-16) (PsO) who are candidates for systemic therapy or phototherapy. CIMZIA is therapy. data on the risks of using CIMZIA in patients who have experienced a severe CIMZIA and concomitant methotrexate had a lower humoral response In the placebo-controlled period of Studies PS-1, PS-2 and PS-3 in the 400 indicated for adults with active non-radiographic axial spondyloarthritis with Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and hypersensitivity reaction towards another TNF blocker; in these patients compared with patients receiving CIMZIA alone. The clinical significance of mg group, adverse events occurred in 63.5% of subjects in the CIMZIA group objective signs of inflammation. Malignancies urticaria. caution is needed . The needle shield inside the this is unknown. compared to 61.8% of subjects in the placebo group. The rates of serious In the controlled portions of clinical studies of some TNF blockers, more cases [see Adverse Reactions] Vascular disorders: Thrombophlebitis, vasculitis. CONTRAINDICATIONS of malignancies have been observed among patients receiving TNF blockers removable cap of the CIMZIA prefilled syringe contains a derivative of natural Immunosuppression adverse events were 4.7% in the CIMZIA group and 4.5% in the placebo CIMZIA is contraindicated in patients with a history of hypersensitivity reaction compared to control patients. During controlled and open-labeled portions rubber latex which may cause an allergic reaction in individuals sensitive to Since TNF mediates inflammation and modulates cellular immune responses, Controlled Studies with Rheumatoid Arthritis group. Table 2 summarizes the adverse reactions that occurred at a rate of at to certolizumab pegol or to any of the excipients. Reactions have included of CIMZIA studies of Crohn’s disease and other diseases, malignancies latex. the possibility exists for TNF blockers, including CIMZIA, to affect host CIMZIA was studied primarily in placebo-controlled trials and in long-term least 1% and at a higher rate in the CIMZIA group than in the placebo group. follow-up studies. The data described below reflect the exposure to CIMZIA in angioedema, anaphylaxis, serum sickness, and urticaria [see Warnings (excluding non-melanoma skin cancer) were observed at a rate (95% Hepatitis B Virus Reactivation defenses against infections and malignancies. The impact of treatment and Precautions]. confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 with CIMZIA on the development and course of malignancies, as well as 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 Use of TNF blockers, including CIMZIA, has been associated with exposed for at least one year and 282 for at least 2 years; and 1,774 WARNINGS AND PRECAUTIONS CIMZIA-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years active and/or chronic infections, is not fully understood [see Warnings and among 1,319 placebo-treated patients. During CIMZIA studies of psoriasis, reactivation of hepatitis B virus (HBV) in patients who are chronic carriers Precautions and Adverse Reactions]. The safety and efficacy of CIMZIA in in adequate and well-controlled studies. In placebo-controlled studies, the Risk of Serious Infections (see also Boxed Warning) of this virus. In some instances, HBV reactivation occurring in conjunction population had a median age of 53 years at entry; approximately 80% were Patients treated with CIMZIA are at an increased risk for developing serious malignancies (excluding non-melanoma skin cancer) were observed patients with immunosuppression has not been formally evaluated. corresponding to an incidence rate of 0.5 (0.2, 1.0) per 100 subject-years with TNF blocker therapy has been fatal. The majority of reports have females, 93% were Caucasian and all patients were suffering from active infections involving various organ systems and sites that may lead to occurred in patients concomitantly receiving other medications that suppress ADVERSE REACTIONS rheumatoid arthritis, with a median disease duration of 6.2 years. Most hospitalization or death. among a total of 995 subjects who received CIMZIA. The size of the control The most serious adverse reactions were: group and limited duration of the controlled portions of the studies precludes the immune system, which may also contribute to HBV reactivation. patients received the recommended dose of CIMZIA or higher. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, the ability to draw firm conclusions. • Serious Infections [see Warnings and Precautions] Table 1 summarizes the reactions reported at a rate of at least 3% in patients viral, parasitic, or other opportunistic pathogens including aspergillosis, • Malignancies [see Warnings and Precautions] Malignancies, some fatal, have been reported among children, adolescents, treated with CIMZIA 200 mg every other week compared to placebo (saline blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, • Heart Failure [see Warnings and Precautions)] formulation), given concomitantly with methotrexate. listeriosis, pneumocystosis and tuberculosis have been reported with TNF and young adults who received treatment with TNF-blocking agents (initiation

PROFESSIONAL BRIEF SUMMARY—CONSULT PACKAGE blockers. Patients have frequently presented with disseminated rather than of therapy ≤ 18 years of age), of which CIMZIA is a member. Approximately Test patients for HBV infection before initiating treatment with CIMZIA. For Clinical Trials Experience Table 1: Adverse Reactions Reported by ≥3% of Patients INSERT FOR FULL PRESCRIBING INFORMATION localized disease. half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s patients who test positive for HBV infection, consultation with a physician Because clinical studies are conducted under widely varying and controlled Treated with CIMZIA Dosed Every Other Week during Treatment with CIMZIA should not be initiated in patients with an active lymphoma. The other cases represented a variety of different malignancies with expertise in the treatment of hepatitis B is recommended. Adequate conditions, adverse reaction rates observed in clinical studies of a drug cannot Placebo-Controlled Period of Rheumatoid Arthritis Studies, CIMZIA® (certolizumab pegol) infection, including clinically important localized infections. Patients and included rare malignancies usually associated with immunosuppression data are not available on the safety or efficacy of treating patients who be directly compared to rates in the clinical studies of another drug, and with Concomitant Methotrexate. greater than 65 years of age, patients with co-morbid conditions, and/or and malignancies that are not usually observed in children and adolescents. are carriers of HBV with anti-viral therapy in conjunction with TNF blocker may not predict the rates observed in a broader patient population in clinical WARNINGS: patients taking concomitant immunosuppressants (e.g. corticosteroids or The malignancies occurred after a median of 30 months of therapy (range therapy to prevent HBV reactivation. Patients who are carriers of HBV and practice. CIMZIA 200 methotrexate) may be at a greater risk of infection. The risks and benefits 1 to 84 months). Most of the patients were receiving concomitant require treatment with CIMZIA should be closely monitored for clinical and In premarketing controlled trials of all patient populations combined the most Placebo+ mg EOW + SERIOUS INFECTIONS of treatment should be considered prior to initiating therapy in patients: immunosuppressants. These cases were reported post-marketing and are laboratory signs of active HBV infection throughout therapy and for several common adverse reactions (≥ 8%) were upper respiratory infections (18%), Adverse Reaction MTX# (%) MTX(%) derived from a variety of sources including registries and spontaneous post- Patients treated with CIMZIA are at increased • with chronic or recurrent infection months following termination of therapy. rash (9%) and urinary tract infections (8%). (Preferred Term) N =324 N =640 marketing reports. CIMZIA is not indicated for use in pediatric patients. risk for developing serious infections that may • who have been exposed to tuberculosis In patients who develop HBV reactivation, discontinue CIMZIA and initiate Adverse Reactions Most Commonly Leading to Discontinuation of Treatment In the controlled portions of clinical trials of all the TNF blockers, more cases Upper respiratory tract lead to hospitalization or death [see Warnings and effective anti-viral therapy with appropriate supportive treatment. The in Premarketing Controlled Trials • with a history of an opportunistic infection of lymphoma have been observed among patients receiving TNF blockers infection 2 6 Precautions and Adverse Reactions]. Most patients who safety of resuming TNF blocker therapy after HBV reactivation is controlled The proportion of patients with Crohn’s disease who discontinued treatment • who have resided or traveled in areas of endemic tuberculosis or compared to control patients. In controlled studies of CIMZIA for Crohn’s developed these infections were taking concomitant is not known. Therefore, exercise caution when considering resumption of due to adverse reactions in the controlled clinical studies was 8% for CIMZIA Headache 4 5 endemic mycoses, such as histoplasmosis, coccidioidomycosis, or disease and other investigational uses, there was one case of lymphoma immunosuppressants such as methotrexate or CIMZIA therapy in this situation and monitor patients closely. and 7% for placebo. The most common adverse reactions leading to the blastomycosis among 2,657 Cimzia-treated patients and one case of Hodgkin’s lymphoma corticosteroids. discontinuation of CIMZIA (for at least 2 patients and with a higher incidence Hypertension 2 5 among 1,319 placebo-treated patients. Neurologic Reactions • with underlying conditions that may predispose them to infection Use of TNF blockers, of which CIMZIA is a member, has been associated than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea CIMZIA should be discontinued if a patient develops a Nasopharyngitis 1 5 serious infection or sepsis. Tuberculosis In the CIMZIA RA clinical trials (placebo-controlled and open label) a total with rare cases of new onset or exacerbation of clinical symptoms and/or (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% Cases of reactivation of tuberculosis or new tuberculosis infections have been of three cases of lymphoma were observed among 2,367 patients. This is radiographic evidence of central nervous system demyelinating disease, placebo). Reported infections include: approximately 2-fold higher than expected in the general population. Patients Back pain 1 4 observed in patients receiving CIMZIA, including patients who have previously including multiple sclerosis, and with peripheral demyelinating disease, The proportion of patients with rheumatoid arthritis who discontinued • Active tuberculosis, including reactivation of latent with RA, particularly those with highly active disease, are at a higher risk for or concomitantly received treatment for latent or active tuberculosis. Reports including Guillain-Barré syndrome. Exercise caution in considering the use treatment due to adverse reactions in the controlled clinical studies was Pyrexia 2 3 tuberculosis. Patients with tuberculosis have frequently the development of lymphoma. In the CIMZIA PsO clinical trials (placebo- included cases of pulmonary and extrapulmonary (i.e., disseminated) of CIMZIA in patients with pre-existing or recent-onset central or peripheral 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions presented with disseminated or extrapulmonary controlled and open label) there was one case of Hodgkin’s lymphoma. tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent nervous system demyelinating disorders. Rare cases of neurological disorders, leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and Pharyngitis 1 3 disease. Patients should be tested for latent infection prior to initiating CIMZIA and periodically during therapy. Rates in clinical studies for CIMZIA cannot be compared to the rates of clinical including seizure disorder, optic neuritis, and peripheral neuropathy have been pyrexia, urticaria, pneumonia, and rash (0.3%). tuberculosis before CIMZIA use and during therapy. trials of other TNF blockers and may not predict the rates observed when reported in patients treated with CIMZIA [see Adverse Reactions]. Rash 1 3 Treatment for latent infection should be initiated prior Treatment of latent tuberculosis infection prior to therapy with TNF-blocking Controlled Studies with Crohn’s Disease agents has been shown to reduce the risk of tuberculosis reactivation during CIMZIA is used in a broader patient population. Patients with Crohn’s disease Hematological Reactions Acute bronchitis 1 3 to CIMZIA use. that require chronic exposure to immunosuppressant therapies may be at The data described below reflect exposure to CIMZIA at 400 mg subcutaneous therapy. Prior to initiating CIMZIA, assess if treatment for latent tuberculosis Rare reports of pancytopenia, including aplastic anemia, have been dosing in studies of patients with Crohn’s disease. In the safety population higher risk than the general population for the development of lymphoma, Fatigue 2 3 • Invasive fungal infections, including histoplasmosis, is needed; and consider an induration of 5 mm or greater a positive tuberculin reported with TNF blockers. Adverse reactions of the hematologic system, in controlled studies, a total of 620 patients with Crohn’s disease received coccidioidomycosis, candidiasis, aspergillosis, even in the absence of TNF blocker therapy [see Adverse Reactions]. The skin test result, even for patients previously vaccinated with Bacille Calmette- including medically significant cytopenia (e.g., leukopenia, pancytopenia, CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including #EOW = Every other Week, MTX = Methotrexate. blastomycosis, and pneumocystosis. Patients with Guerin (BCG). potential role of TNF blocker therapy in the development of malignancies in thrombocytopenia) have been infrequently reported with CIMZIA [see Adverse adults is not known. subjects randomized to placebo in Study CD2 following open label dosing histoplasmosis or other invasive fungal infections Consider anti-tuberculosis therapy prior to initiation of CIMZIA in patients with Reactions]. The causal relationship of these events to CIMZIA remains of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 Hypertensive adverse reactions were observed more frequently in patients may present with disseminated, rather than a past history of latent or active tuberculosis in whom an adequate course of Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type unclear. patients received CIMZIA at some dose level, of whom 1,350 patients receiving CIMZIA than in controls. These adverse reactions occurred more localized disease. Antigen and antibody testing for treatment cannot be confirmed, and for patients with a negative test for latent of T-cell lymphoma that has a very aggressive disease course and is usually Although no high risk group has been identified, exercise caution in patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% frequently among patients with a baseline history of hypertension and histoplasmosis may be negative in some patients with tuberculosis but having risk factors for tuberculosis infection. Despite previous fatal, have been reported in patients treated with TNF blockers, including being treated with CIMZIA who have ongoing, or a history of, significant were male, and 94% were Caucasian. The majority of patients in the active among patients receiving concomitant corticosteroids and non-steroidal active infection. Empiric anti-fungal therapy should or concomitant treatment for latent tuberculosis, cases of active tuberculosis CIMZIA. The majority of reported TNF blocker cases occurred in adolescent hematologic abnormalities. Advise all patients to seek immediate medical group were between the ages of 18 and 64. anti-inflammatory drugs. and young adult males with Crohn’s disease or ulcerative colitis. Almost be considered in patients at risk for invasive fungal have occurred in patients treated with CIMZIA. Some patients who have been attention if they develop signs and symptoms suggestive of blood dyscrasias Patients receiving CIMZIA 400 mg as monotherapy every 4 weeks in all of these patients had received treatment with the immunosuppressants During controlled clinical studies, the proportion of patients with serious infections who develop severe systemic illness. successfully treated for active tuberculosis have redeveloped tuberculosis while or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. rheumatoid arthritis controlled clinical trials had similar adverse reactions to azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF adverse reactions was 10% for CIMZIA and 9% for placebo. The most being treated with CIMZIA. Consultation with a physician with expertise in the Consider discontinuation of CIMZIA therapy in patients with confirmed those patients receiving CIMZIA 200 mg every other week. • Bacterial, viral and other infections due to opportunistic blocker at or prior to diagnosis. It is uncertain whether the occurrence of common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and pathogens including Legionella and Listeria. treatment of tuberculosis is recommended to aid in the decision of whether significant hematologic abnormalities. with a higher incidence compared to placebo) in controlled clinical studies with initiating anti-tuberculosis therapy is appropriate for an individual patient. HSTCL is related to use of a TNF blocker or a TNF blocker in combination with Other Adverse Reactions The risks and benefits of treatment with CIMZIA should these other immunosuppressants. The potential risk of using a TNF blocker in Use with Biological Disease-Modifying Antirheumatic Drugs CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, Other infrequent adverse reactions (occurring in less than 3% of RA patients) Strongly consider tuberculosis in patients who develop a new infection during viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated be carefully considered prior to initiating therapy in combination with azathioprine or 6-MP should be carefully considered. (Biological DMARDs) were similar to those seen in Crohn’s disease patients. CIMZIA treatment, especially in patients who have previously or recently patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) patients with chronic or recurrent infection. Patients Cases of acute and chronic leukemia have been reported in association with Serious infections were seen in clinical studies with concurrent use of anakinra Psoriatic Arthritis Clinical Study traveled to countries with a high prevalence of tuberculosis, or who have had (an interleukin-1 antagonist) and another TNF blocker, etanercept, with in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and should be closely monitored for the development of signs close contact with a person with active tuberculosis. post-marketing TNF-blocker use in RA and other indications. Even in the arthralgia (6% CIMZIA, 4% placebo). CIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a and symptoms of infection during and after treatment absence of TNF-blocker therapy, patients with RA may be at a higher risk no added benefit compared to etanercept alone. A higher risk of serious placebo-controlled trial. The safety profile for patients with PsA treated with with CIMZIA, including the possible development of Monitoring (approximately 2-fold) than the general population for the development of infections was also observed in combination use of TNF blockers with Other Adverse ReactionsDo Not Copy CIMZIA was similar to the safety profile seen in patients with RA and previous tuberculosis in patients who tested negative for latent Patients should be closely monitored for the development of signs and leukemia. abatacept and rituximab. Because of the nature of the adverse events seen The most commonly occurring adverse reactions in controlled trials of Crohn’s experience with CIMZIA. with this combination therapy, similar toxicities may also result from the use tuberculosis infection prior to initiating therapy. symptoms of infection during and after treatment with CIMZIA, including disease were described above. Other serious or significant adverse reactions [see Melanoma and Merkel cell carcinoma have been reported in patients of CIMZIA in this combination. Therefore, the use of CIMZIA in combination Penalties Apply Ankylosing Spondylitis Clinical Study Warnings and Precautions and Adverse Reactions]. the development of tuberculosis in patients who tested negative for latent treated with TNF blockers, including CIMZIA. Periodic skin examinations are reported in controlled and uncontrolled studies in Crohn’s disease and other tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis with other biological DMARDs is not recommended [see Drug Interactions]. diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other CIMZIA has been studied in 325 patients with axial spondyloarthritis of whom MALIGNANCY recommended for all patients, particularly those with risk factors for skin the majority had ankylosing spondylitis (AS) in a placebo-controlled study infection may also be falsely negative while on therapy with CIMZIA. Autoimmunity doses include: Lymphoma and other malignancies, some fatal, have cancer. (AS-1). The safety profile treated with CIMZIA was similar to the safety profile CIMZIA should be discontinued if a patient develops a serious infection or Treatment with CIMZIA may result in the formation of autoantibodies and Blood and lymphatic system disorders: Anemia, leukopenia, seen in patients with RA. been reported in children and adolescent patients treated sepsis. A patient who develops a new infection during treatment with CIMZIA Heart Failure rarely, in the development of a lupus-like syndrome. If a patient develops lymphadenopathy, pancytopenia, and thrombophilia. with TNF blockers, of which CIMZIA is a member [see should be closely monitored, undergo a prompt and complete diagnostic Cases of worsening congestive heart failure (CHF) and new onset CHF symptoms suggestive of a lupus-like syndrome following treatment with Non-radiographic Axial Spondyloarthritis Clinical Study Warnings and Precautions]. CIMZIA is not indicated for have been reported with TNF blockers, including CIMZIA. CIMZIA has not Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac workup appropriate for an immunocompromised patient, and appropriate CIMZIA, discontinue treatment [see Adverse Reactions]. failure, hypertensive heart disease, myocardial infarction, myocardial CIMZIA has been studied in 317 patients with non-radiographic axial use in pediatric patients. antimicrobial therapy should be initiated. been formally studied in patients with CHF; however, in clinical studies in spondyloarthritis (nr-axSpA-1). The safety profile for patients with nr-axSpA patients with CHF with another TNF blocker, worsening congestive heart Immunizations ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack. treated with CIMZIA was similar to the safety profile seen in patients with RA Invasive Fungal Infections failure (CHF) and increased mortality due to CHF were observed. Exercise Patients treated with CIMZIA may receive vaccinations, except for live or and previous experience with CIMZIA. INDICATIONS AND USAGE For patients who reside or travel in regions where mycoses are endemic, caution in patients with heart failure and monitor them carefully [see Adverse live attenuated vaccines. No data are available on the response to live Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis. CIMZIA is indicated for reducing signs and symptoms of Crohn’s disease and invasive fungal infection should be suspected if they develop a serious Reactions]. vaccinations or the secondary transmission of infection by live vaccines in Plaque Psoriasis Clinical Studies General disorders and administration site conditions: Bleeding and injection In clinical studies, a total of 1112 subjects with plaque psoriasis were treated maintaining clinical response in adult patients with moderately to severely systemic illness. Appropriate empiric antifungal therapy should be considered patients receiving CIMZIA. site reactions. active disease who have had an inadequate response to conventional therapy. while a diagnostic workup is being performed. Antigen and antibody testing Hypersensitivity Reactions with CIMZIA. Of these, 779 subjects were exposed for at least 12 months, The following symptoms that could be compatible with hypersensitivity In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no Elevated liver enzymes and hepatitis. CIMZIA is indicated for the treatment of adults with moderately to severly for histoplasmosis may be negative in some patients with active infection. Hepatobiliary disorders: 551 for 18 months, and 66 for 24 months. reactions have been reported rarely following CIMZIA administration to difference was detected in antibody response to vaccine between CIMZIA and active rheumatoid arthritis (RA). CIMZIA is indicated for the treatment of Immune system disorders: Alopecia totalis. Data from three placebo-controlled studies (Studies PS-1, PS-2, and PS-3) in When feasible, the decision to administer empiric antifungal therapy in these patients: angioedema, anaphylaxis, dyspnea, hypotension, rash, serum placebo treatment groups when the pneumococcal polysaccharide vaccine adult patients with active psoriatic arthritis (PsA). CIMZIA is indicated for Anxiety, bipolar disorder, and suicide attempt. 1020 subjects (mean age 46 years, 66% males, 94% white) were pooled to patients should be made in consultation with a physician with expertise in sickness, and urticaria. Some of these reactions occurred after the first and influenza vaccine were administered concurrently with CIMZIA. Similar Psychiatric disorders: the treatment of adults with active ankylosing spondylitis (AS). CIMZIA is evaluate the safety of CIMZIA [see Clinical Studies (14)]. the diagnosis and treatment of invasive fungal infections and should take administration of CIMZIA. If such reactions occur, discontinue further proportions of patients developed protective levels of anti-vaccine antibodies Renal and urinary disorders: Nephrotic syndrome and renal failure. indicated for the treatment of adults with moderate-to-severe plaque psoriasis into account both the risk for severe fungal infection and risks of antifungal administration of CIMZIA and institute appropriate therapy. There are no between CIMZIA and placebo treatment groups; however patients receiving Reproductive system and breast disorders: Menstrual disorder. Placebo-Controlled Period (Week 0-16) (PsO) who are candidates for systemic therapy or phototherapy. CIMZIA is therapy. data on the risks of using CIMZIA in patients who have experienced a severe CIMZIA and concomitant methotrexate had a lower humoral response In the placebo-controlled period of Studies PS-1, PS-2 and PS-3 in the 400 indicated for adults with active non-radiographic axial spondyloarthritis with Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and hypersensitivity reaction towards another TNF blocker; in these patients compared with patients receiving CIMZIA alone. The clinical significance of mg group, adverse events occurred in 63.5% of subjects in the CIMZIA group objective signs of inflammation. Malignancies urticaria. caution is needed . The needle shield inside the this is unknown. compared to 61.8% of subjects in the placebo group. The rates of serious In the controlled portions of clinical studies of some TNF blockers, more cases [see Adverse Reactions] Vascular disorders: Thrombophlebitis, vasculitis. CONTRAINDICATIONS of malignancies have been observed among patients receiving TNF blockers removable cap of the CIMZIA prefilled syringe contains a derivative of natural Immunosuppression adverse events were 4.7% in the CIMZIA group and 4.5% in the placebo CIMZIA is contraindicated in patients with a history of hypersensitivity reaction compared to control patients. During controlled and open-labeled portions rubber latex which may cause an allergic reaction in individuals sensitive to Since TNF mediates inflammation and modulates cellular immune responses, Controlled Studies with Rheumatoid Arthritis group. Table 2 summarizes the adverse reactions that occurred at a rate of at to certolizumab pegol or to any of the excipients. Reactions have included of CIMZIA studies of Crohn’s disease and other diseases, malignancies latex. the possibility exists for TNF blockers, including CIMZIA, to affect host CIMZIA was studied primarily in placebo-controlled trials and in long-term least 1% and at a higher rate in the CIMZIA group than in the placebo group. follow-up studies. The data described below reflect the exposure to CIMZIA in angioedema, anaphylaxis, serum sickness, and urticaria [see Warnings (excluding non-melanoma skin cancer) were observed at a rate (95% Hepatitis B Virus Reactivation defenses against infections and malignancies. The impact of treatment and Precautions]. confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 with CIMZIA on the development and course of malignancies, as well as 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 Use of TNF blockers, including CIMZIA, has been associated with exposed for at least one year and 282 for at least 2 years; and 1,774 WARNINGS AND PRECAUTIONS CIMZIA-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years active and/or chronic infections, is not fully understood [see Warnings and among 1,319 placebo-treated patients. During CIMZIA studies of psoriasis, reactivation of hepatitis B virus (HBV) in patients who are chronic carriers Precautions and Adverse Reactions]. The safety and efficacy of CIMZIA in in adequate and well-controlled studies. In placebo-controlled studies, the Risk of Serious Infections (see also Boxed Warning) of this virus. In some instances, HBV reactivation occurring in conjunction population had a median age of 53 years at entry; approximately 80% were Patients treated with CIMZIA are at an increased risk for developing serious malignancies (excluding non-melanoma skin cancer) were observed patients with immunosuppression has not been formally evaluated. corresponding to an incidence rate of 0.5 (0.2, 1.0) per 100 subject-years with TNF blocker therapy has been fatal. The majority of reports have females, 93% were Caucasian and all patients were suffering from active infections involving various organ systems and sites that may lead to occurred in patients concomitantly receiving other medications that suppress ADVERSE REACTIONS rheumatoid arthritis, with a median disease duration of 6.2 years. Most hospitalization or death. among a total of 995 subjects who received CIMZIA. The size of the control The most serious adverse reactions were: group and limited duration of the controlled portions of the studies precludes the immune system, which may also contribute to HBV reactivation. patients received the recommended dose of CIMZIA or higher. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, the ability to draw firm conclusions. • Serious Infections [see Warnings and Precautions] Table 1 summarizes the reactions reported at a rate of at least 3% in patients viral, parasitic, or other opportunistic pathogens including aspergillosis, • Malignancies [see Warnings and Precautions] Malignancies, some fatal, have been reported among children, adolescents, treated with CIMZIA 200 mg every other week compared to placebo (saline blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, • Heart Failure [see Warnings and Precautions)] formulation), given concomitantly with methotrexate. listeriosis, pneumocystosis and tuberculosis have been reported with TNF and young adults who received treatment with TNF-blocking agents (initiation

Table 2: Adverse Reactions Occurring in ≥1% of Subjects in The majority of cases occurred in countries with high endemic rates of TB. patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, other adverse pregnancy outcomes. However, certolizumab pegol plasma intravenous doses up to 100 mg/kg (about 2.4 times the recommended Pregnancy the CIMZIA Group and More Frequently than in the Placebo Reports include cases of disseminated (miliary, lymphatic, and peritoneal) respectively). In Study RA-III, too few patients developed antibodies to allow concentrations obtained from two studies of CIMZIA use during the third human dose of 400 mg, based on the surface area) and have revealed no Advise patients that there is a pregnancy registry that monitors pregnancy Group in the Plaque Psoriasis Studies PS-1, PS-2, and PS-3. as well as pulmonary TB. The median time to onset of TB for all patients for meaningful analysis of ACR20 response by antibody status. In Study RA-IV trimester of pregnancy demonstrated that placental transfer of certolizumab evidence of harm to the fetus due to cTN3 PF. outcomes in women exposed to CIMZIA during pregnancy; patients can call exposed to CIMZIA across all indications was 345 days. In the studies with (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive pegol was negligible in most infants at birth, and low in other infants at Lactation 1-877-311-8972 [see Use in Specific Populations]. Cimzia Cimzia CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, versus antibody-negative status, respectively [see Clinical Pharmacology]. No birth (see Data). There are risks to the mother and fetus associated with 400 mg 200 mg5 Risk Summary Preparation and Administration of CIMZIA Using the Placebo including some fatal cases. Rare cases of opportunistic infections have also association was seen between antibody development and the development active rheumatoid arthritis or Crohn’s disease. The theoretical risks of Adverse every other every other In a multicenter clinical study of 17 lactating women treated with CIMZIA at Prefilled Syringe n (%) been reported in these clinical trials. In Phase 2 and Phase 3 studies with of adverse events. administration of live or live-attenuated vaccines to the infants exposed in Instruct patients and caregivers on how to inject the Prefilled Syringe. Reactions week week CIMZIA in plaque psoriasis, there were 2 cases of TB among 1112 exposed to CIMZIA should be weighed against the benefits of vaccinations 200 mg every 2 weeks or 400 mg every 4 weeks, minimal certolizumab N=157 Approximately 8% (22/265) and 19% (54/281) of subjects with psoriasis utero (see pegol concentrations were observed in breast milk. No serious adverse Complete instructions are provided in the Instructions for Use packaged in n (%) n (%) patients [see Warnings and Precautions]. . No adverse developmental effects were observed in who received CIMZIA 400 mg every 2 weeks and CIMZIA 200 mg every Clinical Considerations) reactions were noted in the 17 infants in the study. There are no data on each CIMZIA Prefilled Syringe kit. N=342 N=350 Malignancies 2 weeks for 48 weeks, respectively, developed antibodies to certolizumab animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFa pegylated Fab’ fragment (cTN3 PF) the effects on milk production. In a separate study, certolizumab pegol Upper respiratory In clinical studies of CIMZIA, the overall incidence rate of malignancies was pegol. Of the subjects who developed antibodies to certolizumab pegol, concentrations were not detected in the plasma of 9 breastfed infants at 4 1 similar to certolizumab pegol during organogenesis at up to 2.4 times the tract infections 75 (21.9) 68 (19.4) 33 (21.0) similar for CIMZIA-treated and control patients. For some TNF blockers, more 45% (27/60) had antibodies that were classified as neutralizing. Antibody weeks post-partum (see Data). The developmental and health benefits of cases of malignancies have been observed among patients receiving those formation was associated with lowered drug plasma concentration and recommended human dose of 400 mg every four weeks. Headache2 13 (3.8) 10 (2.9) 4 (2.5) breastfeeding should be considered along with the mother’s clinical need for TNF blockers compared to control patients [see Warnings and Precautions]. reduced efficacy. The estimated background risk of major birth defects and miscarriage for the CIMZIA and any potential adverse effects on the breastfed infant from CIMZIA indicated population(s) are unknown. All pregnancies have a background Injection site Heart Failure A more sensitive and drug tolerant electrochemiluminescence (ECL)-based or from the underlying maternal condition. 3 risk of birth defect, loss, or other adverse outcomes. In the U.S. general reactions 11 (3.2) 6 (1.7) 1 (0.6) In placebo-controlled and open-label studies, cases of new or worsening heart bridging assay was used for the first time in the nr-axSpA-1 study, resulting in population, the estimated background risks of major birth defects and Data failure have been reported for CIMZIA-treated patients. The majority of these a greater proportion of samples having measurable antibodies to certolizumab Cough 11 (3.2) 4 (1.1) 3 (1.9) miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, A multicenter clinical study designed to evaluate breast milk was conducted cases were mild to moderate and occurred during the first year of exposure pegol and thus a greater incidence of patients being classed as antibody 4 respectively. in 17 lactating women who were at least 6 weeks post-partum and had Herpes infections 5 (1.5) 5 (1.4) 2 (1.3) [see Warnings and Precautions]. positive. In the placebo-controlled trial in patients with non-radiographic axial received at least 3 consecutive doses of CIMZIA 200 mg every 2 weeks spondyloarthritis, after up to 52 weeks of treatment, the overall incidence Clinical Considerations or 400 mg every 4 weeks for rheumatological disease or Crohn’s disease. 1: Upper respiratory tract infection cluster includes upper respiratory tract Hypersensitivity Reactions of patients who were antibody positive to certolizumab pegol was 97% infection, pharyngitis bacterial, pharyngitis streptococcal, upper respiratory The following symptoms that could be compatible with hypersensitivity Disease-Associated Maternal and/or Embryo/Fetal Risk The effects of certolizumab pegol on milk production were not studied. The (248/255 patients). Of these antibody positive patients, higher titers were Published data suggest that the risk of adverse pregnancy outcomes in tract infection bacterial, viral upper respiratory tract infection, viral reactions have been reported rarely following CIMZIA administration to concentration of certolizumab pegol in breast milk was not measurable in 77 associated with reduced certolizumab pegol plasma levels. women with rheumatoid arthritis or Crohn’s disease is correlated with pharyngitis, viral sinusitis, and nasopharyngitis. patients: angioedema, allergic dermatitis, dizziness (postural), dyspnea, hot (56 %) of the 137 samples taken over the dosing periods using an assay maternal disease activity and that active disease increases the risk of adverse flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum The data above reflect the percentage of patients whose test results were that can measure certolizumab pegol concentrations at or above 0.032 mcg/ 2: Headache includes headache and tension headache. considered positive for antibodies to certolizumab pegol in an ELISA, or pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks sickness, and (vasovagal) syncope [see Warnings and Precautions]. mL. The median of the estimated average daily infant doses was 0.0035 3: Injection site reactions cluster includes injection site reaction, injection site ECL-based bridging assay, and are highly dependent on the sensitivity and of gestation), low birth weight (less than 2500 g) and small for gestational mg/kg/day (range: 0 to 0.01 mg/kg/day). The percentage of the erythema, injection site bruising, injection site discoloration, injection site Autoantibodies specificity of the assay. age birth. maternal dose (200 mg CIMZIA dosed once every 2 weeks), that reaches pain, and injection site swelling. In clinical studies in Crohn’s disease, 4% of patients treated with CIMZIA and Fetal/Neonatal Adverse Reactions an infant ranged from 0.56% to 4.25% based on samples with measurable 2% of patients treated with placebo that had negative baseline ANA titers Postmarketing Experience 4: Herpes infections cluster includes oral herpes, herpes dermatitis, herpes The following adverse reactions have been identified during post-approval use Due to its inhibition of TNFα, CIMZIA administered during pregnancy could certolizumab pegol concentration. No serious adverse reactions were noted in zoster, and herpes simplex. developed positive titers during the studies. One of the 1,564 Crohn’s disease affect immune responses in the in utero-exposed newborn and infant. The the 17 breastfed infants in the study. patients treated with CIMZIA developed symptoms of a lupus-like syndrome. of CIMZIA. Because these reactions are reported voluntarily from a population 5: Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by of uncertain size, it is not always possible to estimate reliably their frequency clinical significance of BLQ or low levels is unknown for in utero-exposed In a separate study, plasma certolizumab pegol concentrations were collected 200 mg every other week. In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some or establish a causal relationship to drug exposure. infants. Additional data available from one exposed infant suggest that 4 weeks after birth in 9 breastfed infants whose mothers had been currently patients have developed ANA. Four patients out of 2,367 patients treated CIMZIA may be eliminated at a slower rate in infants than in adults (see taking CIMZIA (regardless of being exclusively breastfed or not). Certolizumab Elevated Liver Enzymes with CIMZIA in RA clinical studies developed clinical signs suggestive of a Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers. Data). The safety of administering live or live-attenuated vaccines in exposed pegol in infant plasma was not measurable i.e., below 0.032 mcg/mL. Elevated liver enzymes were reported more frequently in the CIMZIA-treated lupus-like syndrome. The impact of long-term treatment with CIMZIA on infants is unknown. subjects (4.3% in the 200 mg group and 2.3% in the 400 mg group) than Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic Pediatric Use the development of autoimmune diseases is unknown [see Warnings and Data in the placebo-treated subjects (2.5%). Of CIMZIA-treated subjects who had Precautions]. epidermal necrolysis, erythema multiforme, and new or worsening psoriasis Safety and effectiveness in pediatric patients have not been established. Due elevation of liver enzymes, two subjects were discontinued from the trial. (all sub-types including pustular and palmoplantar, and lichenoid skin reaction) Human Data to its inhibition of TNFα, CIMZIA administered during pregnancy could affect Immunogenicity have been identified during post-approval use of TNF blockers. A limited number of pregnancies have been reported in the ongoing immune responses in the in utero-exposed newborn and infant [see Use in In controlled Phase 3 studies of CIMZIA in adults with PsO with a controlled As with all therapeutic proteins, there is potential for immunogenicity. The period duration ranging from 0 to 16 weeks, AST and/or ALT elevations ≥5 x pregnancy exposure registry. Due to the small number of CIMZIA-exposed Specific Populations)]. detection of antibody formation is highly dependent on the sensitivity and Immune System Disorders: sarcoidosis pregnancies with known outcomes (n=54), no meaningful comparisons ULN occurred in 0.9% of CIMZIA 200 mg or CIMZIA 400 mg arms and none specificity of the assay. Additionally, the observed incidence of antibody Neoplasms benign, malignant and unspecified (including cysts and polyps): Geriatric Use in placebo arm. between the exposed group and control groups may be conducted to (including neutralizing antibody) positivity in an assay may be influenced Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) determine an association with CIMZIA and major birth defects or adverse Clinical studies of CIMZIA did not include sufficient numbers of patients aged Psoriasis-Related Adverse Events by several factors including assay methodology, sample handling, timing of [see Warnings and Precautions]. pregnancy outcomes. 65 and over to determine whether they respond differently from younger In controlled clinical studies in psoriasis, change of plaque psoriasis into a sample collection, concomitant medications, and underlying disease. For subjects. Other reported clinical experience has not identified differences different psoriasis sub-types (including erythrodermic, pustular and guttate), DRUG INTERACTIONS A multicenter clinical study was conducted in 16 women treated with CIMZIA in responses between the elderly and younger patients. Population these reasons, comparisonDo of theNot incidence of Copy antibodies to certolizumab Use with Anakinra, Abatacept, Rituximab, and Natalizumab at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks was observed in <1% of CIMZIA treated subjects. pegol in the studies described below with the incidence of antibodies in other pharmacokinetic analyses of patients enrolled in CIMZIA clinical studies An increased risk of serious infections has been seen in clinical studies of other during the third trimester of pregnancy for rheumatological diseases or Crohn’s concluded that there was no apparent difference in drug concentration Adverse Reactions of Special Interest Across Indications studies or to other products may be misleading. TNF-blocking agents used in combination with anakinra or abatacept, with disease. The last dose of CIMZIA was given on average 11 days prior to Patients with Crohn’sPenalties disease were tested at multiple Apply time points for regardless of age. Because there is a higher incidence of infections in the Infections no added benefit. Formal drug interaction studies have not been performed delivery (range 1 to 27 days). Certolizumab pegol plasma concentrations elderly population in general, use caution when treating the elderly with The incidence of infections in controlled studies in Crohn’s disease was antibodies to certolizumab pegol during Studies CD1 and CD2. In patients were measured in samples from mothers and infants using an assay that with rituximab or natalizumab. Because of the nature of the adverse events CIMZIA [see Warnings and Precautions]. 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The continuously exposed to CIMZIA, the overall percentage of patients who seen with these combinations with TNF blocker therapy, similar toxicities can measure certolizumab pegol concentrations at or above 0.032 mcg/ infections consisted primarily of upper respiratory infections (20% for CIMZIA, were antibody positive to CIMZIA on at least one occasion was 8%; may also result from the use of CIMZIA in these combinations. There is not mL. Certolizumab pegol plasma concentrations measured in the mothers at OVERDOSAGE 13% for placebo). The incidence of serious infections during the controlled approximately 6% were neutralizing in vitro. No apparent correlation of enough information to assess the safety and efficacy of such combination delivery (range: 4.96 to 49.4 mcg/mL) were consistent with non-pregnant The maximum tolerated dose of certolizumab pegol has not been established. clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% antibody development to adverse events or efficacy was observed. Patients therapy. Therefore, the use of CIMZIA in combination with anakinra, women’s plasma concentrations in Study RA-I [see Clinical Studies]. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have for placebo-treated patients. Serious infections observed included bacterial and treated with concomitant immunosuppressants had a lower rate of antibody abatacept, rituximab, or natalizumab is not recommended [see Warnings and Certolizumab pegol plasma concentrations were not measurable in 13 out been administered without evidence of dose-limiting toxicities. In cases of viral infections, pneumonia, and pyelonephritis. development than patients not taking immunosuppressants at baseline Precautions]. of 15 infants at birth. The concentration of certolizumab pegol in one infant overdosage, it is recommended that patients be monitored closely for any The incidence of new cases of infections in controlled clinical studies in (3% and 11%, respectively). The following adverse events were reported was 0.0422 mcg/mL at birth (infant/mother plasma ratio of 0.09%). In a adverse reactions or effects, and appropriate symptomatic treatment instituted in Crohn’s disease patients who were antibody-positive (N = 100) at an Live Vaccines immediately. rheumatoid arthritis was 0.91 per patient-year for all CIMZIA-treated patients Avoid use of live (including attenuated) vaccines concurrently with CIMZIA second infant, delivered by emergency Caesarean section, the concentration incidence at least 3% higher compared to antibody-negative patients (N = was 0.485 mcg/mL (infant/mother plasma ratio of 4.49%). At Week 4 and 0.72 per patient-year for placebo-treated patients. The infections [see Warnings and Precautions]. PATIENT COUNSELING INFORMATION consisted primarily of upper respiratory tract infections, herpes infections, 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, and Week 8, all 15 infants had no measurable concentrations. Among 16 See FDA-approved patient labeling (Medication Guide) injection site erythema, injection site pain, pain in extremity, and upper Laboratory Tests exposed infants, one serious adverse reaction was reported in a neonate urinary tract infections, and lower respiratory tract infections. In the controlled Risk of Serious Infections rheumatoid arthritis studies, there were more new cases of serious infection respiratory tract infection. Interference with certain coagulation assays has been detected in patients who was treated empirically with intravenous antibiotics due to an increased treated with CIMZIA. Certolizumab pegol may cause erroneously elevated white blood cell count; blood cultures were negative. The certolizumab pegol Inform patients that CIMZIA may lower the ability of the immune system adverse reactions in the CIMZIA treatment groups, compared to the placebo In two long-term (up to 7 years of exposure), open-label Crohn’s disease to fight infections. Instruct patients of the importance of contacting their groups (0.06 per patient-year for all CIMZIA doses vs. 0.02 per patient-year studies, overall 23% (207/903) of patients developed antibodies against activated partial thromboplastin time (aPTT) assay results in patients without plasma concentrations for this infant were not measurable at birth, Week 4, coagulation abnormalities. This effect has been observed with the PTT-Lupus or Week 8. doctor if they develop any symptoms of infection, including tuberculosis for placebo). Rates of serious infections in the 200 mg every other week certolizumab pegol on at least one occasion. Of the 207 patients who were and reactivation of hepatitis B virus infections. Because caution should be dose group were 0.06 per patient-year and in the 400 mg every 4 antibody positive, 152 (73%) had a persistent reduction of drug plasma Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin In another clinical study conducted in 10 pregnant women with Crohn’s time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL exercised in prescribing CIMZIA to patients with clinically important active weeks dose group were 0.04 per patient-year. Serious infections included concentration, which represents 17% (152/903) of the study population. disease treated with CIMZIA (400 mg every 4 weeks for every mother), infections, advise patients of the importance of informing their health care The data from these two studies do not suggest an association between the APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, certolizumab pegol concentrations were measured in maternal blood as well providers about all aspects of their health [see Warnings and Precautions]. no serious infection occurred in more than one subject. There is no evidence of development of antibodies and adverse events. Laboratories. Other aPTT assays may be affected as well. Interference with as in cord and infant blood at the day of birth with an assay that can measure increased risk of infections with continued exposure over time [see Warnings thrombin time (TT) and prothrombin time (PT) assays has not been observed. concentrations at or above 0.41 mcg/mL. The last dose of CIMZIA was Malignancies The overall percentage of patients with antibodies to certolizumab pegol There is no evidence that CIMZIA therapy has an effect on coagulation. and Precautions (5.1)]. detectable on at least one occasion was 7% (105 of 1,509) in the in vivo given on average 19 days prior to delivery (range 5 to 42 days). Plasma Counsel patients about the possible risk of lymphoma and other malignancies In controlled clinical studies in psoriasis, the incidence rates of infections rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 USE IN SPECIFIC POPULATIONS certolizumab pegol concentrations ranged from not measurable to 1.66 mcg/ while receiving CIMZIA [see Warnings and Precautions]. were similar in the CIMZIA and placebo groups. The infections consisted of 1,509) of these patients had antibodies with neutralizing activity in vitro. Pregnancy mL in cord blood and 1.58 mcg/mL in infant blood; and ranged from 1.87 to Other Medical Conditions primarily of upper respiratory tract infections and viral infections (including Patients treated with concomitant immunosuppressants (MTX) had a lower Pregnancy Exposure Registry 59.57 mcg/mL in maternal blood. Plasma certolizumab pegol concentrations Advise patients to report any signs of new or worsening medical conditions herpes infections). Serious adverse events of infection occurred in CIMZIA- rate of antibody development than patients not taking immunosuppressants There is a pregnancy exposure registry that monitors pregnancy outcomes were lower (by at least 75%) in the infants than in mothers suggesting such as heart disease, neurological disease, or autoimmune disorders. Advise treated patients during the placebo-controlled periods of the pivotal studies at baseline. Patients treated with concomitant immunosuppressant therapy in women exposed to CIMZIA during pregnancy. For more information, low placental transfer of certolizumab pegol. In one infant, the plasma patients to report promptly any symptoms suggestive of a cytopenia such as (pneumonia, abdominal abscess, and hematoma infection) and Phase 2 (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation healthcare providers or patients can contact: certolizumab pegol concentration declined from 1.02 to 0.84 mcg/mL over bruising, bleeding, or persistent fever [see Warnings and Precautions]. study (urinary tract infection, gastroenteritis, and disseminated tuberculosis). overall than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). MotherToBaby Pregnancy Studies conducted by the Organization of Teratology 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults. Hypersensitivity Reactions Tuberculosis and Opportunistic Infections Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at Advise patients to seek immediate medical attention if they experience any concomitant use of MTX were associated with reduced immunogenicity. Product manufactured by: In completed and ongoing global clinical studies in all indications 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/ Animal Data symptoms of severe hypersensitivity reactions. Advise latex-sensitive patients UCB, Inc.,1950 Lake Park Drive, Smyrna, GA 30080 Antibody formation was associated with lowered drug plasma concentration Because certolizumab pegol does not cross-react with mouse or rat TNFa, US License No. 1736 including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is Risk Summary that the needle shield inside the removable cap of the CIMZIA prefilled syringe For more information, go to www.CIMZIA.com or call 1-866-424-6942. reproduction studies were performed in rats using a rodent anti-murine TNFa ® approximately 0.61 per 100 patient-years across all indications. and reduced efficacy. In patients receiving the recommended CIMZIA dosage Limited data from the ongoing pregnancy registry on use of CIMZIA in contains a derivative of natural rubber latex [see Warnings and Precautions]. CIMZIA is a registered trademark of the UCB Group of Companies. of 200 mg every other week with concomitant MTX, the ACR20 response pregnant women are not sufficient to inform a risk of major birth defects or pegylated Fab’ fragment (cTN3 PF) similar to certolizumab pegol. Animal ©2019 UCB, Inc., Smyrna, GA 30080. All rights reserved. was lower among antibody-positive patients than among antibody-negative reproduction studies have been performed in rats during organogenesis at

Table 2: Adverse Reactions Occurring in ≥1% of Subjects in The majority of cases occurred in countries with high endemic rates of TB. patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, other adverse pregnancy outcomes. However, certolizumab pegol plasma intravenous doses up to 100 mg/kg (about 2.4 times the recommended Pregnancy the CIMZIA Group and More Frequently than in the Placebo Reports include cases of disseminated (miliary, lymphatic, and peritoneal) respectively). In Study RA-III, too few patients developed antibodies to allow concentrations obtained from two studies of CIMZIA use during the third human dose of 400 mg, based on the surface area) and have revealed no Advise patients that there is a pregnancy registry that monitors pregnancy Group in the Plaque Psoriasis Studies PS-1, PS-2, and PS-3. as well as pulmonary TB. The median time to onset of TB for all patients for meaningful analysis of ACR20 response by antibody status. In Study RA-IV trimester of pregnancy demonstrated that placental transfer of certolizumab evidence of harm to the fetus due to cTN3 PF. outcomes in women exposed to CIMZIA during pregnancy; patients can call exposed to CIMZIA across all indications was 345 days. In the studies with (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive pegol was negligible in most infants at birth, and low in other infants at Lactation 1-877-311-8972 [see Use in Specific Populations]. Cimzia Cimzia CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, versus antibody-negative status, respectively [see Clinical Pharmacology]. No birth (see Data). There are risks to the mother and fetus associated with 400 mg 200 mg5 Risk Summary Preparation and Administration of CIMZIA Using the Placebo including some fatal cases. Rare cases of opportunistic infections have also association was seen between antibody development and the development active rheumatoid arthritis or Crohn’s disease. The theoretical risks of Adverse every other every other In a multicenter clinical study of 17 lactating women treated with CIMZIA at Prefilled Syringe n (%) been reported in these clinical trials. In Phase 2 and Phase 3 studies with of adverse events. administration of live or live-attenuated vaccines to the infants exposed in Instruct patients and caregivers on how to inject the Prefilled Syringe. Reactions week week CIMZIA in plaque psoriasis, there were 2 cases of TB among 1112 exposed to CIMZIA should be weighed against the benefits of vaccinations 200 mg every 2 weeks or 400 mg every 4 weeks, minimal certolizumab N=157 Approximately 8% (22/265) and 19% (54/281) of subjects with psoriasis utero (see pegol concentrations were observed in breast milk. No serious adverse Complete instructions are provided in the Instructions for Use packaged in n (%) n (%) patients [see Warnings and Precautions]. . No adverse developmental effects were observed in who received CIMZIA 400 mg every 2 weeks and CIMZIA 200 mg every Clinical Considerations) reactions were noted in the 17 infants in the study. There are no data on each CIMZIA Prefilled Syringe kit. N=342 N=350 Malignancies 2 weeks for 48 weeks, respectively, developed antibodies to certolizumab animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFa pegylated Fab’ fragment (cTN3 PF) the effects on milk production. In a separate study, certolizumab pegol Upper respiratory In clinical studies of CIMZIA, the overall incidence rate of malignancies was pegol. Of the subjects who developed antibodies to certolizumab pegol, concentrations were not detected in the plasma of 9 breastfed infants at 4 1 similar to certolizumab pegol during organogenesis at up to 2.4 times the tract infections 75 (21.9) 68 (19.4) 33 (21.0) similar for CIMZIA-treated and control patients. For some TNF blockers, more 45% (27/60) had antibodies that were classified as neutralizing. Antibody weeks post-partum (see Data). The developmental and health benefits of cases of malignancies have been observed among patients receiving those formation was associated with lowered drug plasma concentration and recommended human dose of 400 mg every four weeks. Headache2 13 (3.8) 10 (2.9) 4 (2.5) breastfeeding should be considered along with the mother’s clinical need for TNF blockers compared to control patients [see Warnings and Precautions]. reduced efficacy. The estimated background risk of major birth defects and miscarriage for the CIMZIA and any potential adverse effects on the breastfed infant from CIMZIA indicated population(s) are unknown. All pregnancies have a background Injection site Heart Failure A more sensitive and drug tolerant electrochemiluminescence (ECL)-based or from the underlying maternal condition. reactions3 11 (3.2) 6 (1.7) 1 (0.6) risk of birth defect, loss, or other adverse outcomes. In the U.S. general In placebo-controlled and open-label studies, cases of new or worsening heart bridging assay was used for the first time in the nr-axSpA-1 study, resulting in Data a greater proportion of samples having measurable antibodies to certolizumab population, the estimated background risks of major birth defects and Cough 11 (3.2) 4 (1.1) 3 (1.9) failure have been reported for CIMZIA-treated patients. The majority of these miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, A multicenter clinical study designed to evaluate breast milk was conducted cases were mild to moderate and occurred during the first year of exposure pegol and thus a greater incidence of patients being classed as antibody 4 respectively. in 17 lactating women who were at least 6 weeks post-partum and had Herpes infections 5 (1.5) 5 (1.4) 2 (1.3) [see Warnings and Precautions]. positive. In the placebo-controlled trial in patients with non-radiographic axial received at least 3 consecutive doses of CIMZIA 200 mg every 2 weeks spondyloarthritis, after up to 52 weeks of treatment, the overall incidence Clinical Considerations or 400 mg every 4 weeks for rheumatological disease or Crohn’s disease. 1: Upper respiratory tract infection cluster includes upper respiratory tract Hypersensitivity Reactions of patients who were antibody positive to certolizumab pegol was 97% infection, pharyngitis bacterial, pharyngitis streptococcal, upper respiratory The following symptoms that could be compatible with hypersensitivity Disease-Associated Maternal and/or Embryo/Fetal Risk The effects of certolizumab pegol on milk production were not studied. The (248/255 patients). Of these antibody positive patients, higher titers were Published data suggest that the risk of adverse pregnancy outcomes in concentration of certolizumab pegol in breast milk was not measurable in 77 tract infection bacterial, viral upper respiratory tract infection, viral reactions have been reported rarely following CIMZIA administration to associated with reduced certolizumab pegol plasma levels. pharyngitis, viral sinusitis, and nasopharyngitis. women with rheumatoid arthritis or Crohn’s disease is correlated with (56 %) of the 137 samples taken over the dosing periods using an assay patients: angioedema, allergic dermatitis, dizziness (postural), dyspnea, hot maternal disease activity and that active disease increases the risk of adverse flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum The data above reflect the percentage of patients whose test results were that can measure certolizumab pegol concentrations at or above 0.032 mcg/ 2: Headache includes headache and tension headache. considered positive for antibodies to certolizumab pegol in an ELISA, or pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks sickness, and (vasovagal) syncope [see Warnings and Precautions]. mL. The median of the estimated average daily infant doses was 0.0035 3: Injection site reactions cluster includes injection site reaction, injection site ECL-based bridging assay, and are highly dependent on the sensitivity and of gestation), low birth weight (less than 2500 g) and small for gestational mg/kg/day (range: 0 to 0.01 mg/kg/day). The percentage of the erythema, injection site bruising, injection site discoloration, injection site Autoantibodies specificity of the assay. age birth. maternal dose (200 mg CIMZIA dosed once every 2 weeks), that reaches pain, and injection site swelling. In clinical studies in Crohn’s disease, 4% of patients treated with CIMZIA and Fetal/Neonatal Adverse Reactions an infant ranged from 0.56% to 4.25% based on samples with measurable 2% of patients treated with placebo that had negative baseline ANA titers Postmarketing Experience 4: Herpes infections cluster includes oral herpes, herpes dermatitis, herpes The following adverse reactions have been identified during post-approval use Due to its inhibition of TNFα, CIMZIA administered during pregnancy could certolizumab pegol concentration. No serious adverse reactions were noted in zoster, and herpes simplex. developed positive titers during the studies. One of the 1,564 Crohn’s disease affect immune responses in the in utero-exposed newborn and infant. The the 17 breastfed infants in the study. patients treated with CIMZIA developed symptoms of a lupus-like syndrome. of CIMZIA. Because these reactions are reported voluntarily from a population 5: Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by of uncertain size, it is not always possible to estimate reliably their frequency clinical significance of BLQ or low levels is unknown for in utero-exposed In a separate study, plasma certolizumab pegol concentrations were collected 200 mg every other week. In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some or establish a causal relationship to drug exposure. infants. Additional data available from one exposed infant suggest that 4 weeks after birth in 9 breastfed infants whose mothers had been currently patients have developed ANA. Four patients out of 2,367 patients treated CIMZIA may be eliminated at a slower rate in infants than in adults (see taking CIMZIA (regardless of being exclusively breastfed or not). Certolizumab Elevated Liver Enzymes with CIMZIA in RA clinical studies developed clinical signs suggestive of a Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers. Data). The safety of administering live or live-attenuated vaccines in exposed pegol in infant plasma was not measurable i.e., below 0.032 mcg/mL. Elevated liver enzymes were reported more frequently in the CIMZIA-treated lupus-like syndrome. The impact of long-term treatment with CIMZIA on infants is unknown. subjects (4.3% in the 200 mg group and 2.3% in the 400 mg group) than Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic Pediatric Use the development of autoimmune diseases is unknown [see Warnings and Data in the placebo-treated subjects (2.5%). Of CIMZIA-treated subjects who had Precautions]. epidermal necrolysis, erythema multiforme, and new or worsening psoriasis Safety and effectiveness in pediatric patients have not been established. Due elevation of liver enzymes, two subjects were discontinued from the trial. (all sub-types including pustular and palmoplantar, and lichenoid skin reaction) Human Data to its inhibition of TNFα, CIMZIA administered during pregnancy could affect Immunogenicity have been identified during post-approval use of TNF blockers. A limited number of pregnancies have been reported in the ongoing immune responses in the in utero-exposed newborn and infant [see Use in In controlled Phase 3 studies of CIMZIA in adults with PsO with a controlled As with all therapeutic proteins, there is potential for immunogenicity. The period duration ranging from 0 to 16 weeks, AST and/or ALT elevations ≥5 x pregnancy exposure registry. Due to the small number of CIMZIA-exposed Specific Populations)]. detection of antibody formation is highly dependent on the sensitivity and Immune System Disorders: sarcoidosis pregnancies with known outcomes (n=54), no meaningful comparisons ULN occurred in 0.9% of CIMZIA 200 mg or CIMZIA 400 mg arms and none specificity of the assay. Additionally, the observed incidence of antibody Neoplasms benign, malignant and unspecified (including cysts and polyps): Geriatric Use in placebo arm. between the exposed group and control groups may be conducted to (including neutralizing antibody) positivity in an assay may be influenced Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) determine an association with CIMZIA and major birth defects or adverse Clinical studies of CIMZIA did not include sufficient numbers of patients aged Psoriasis-Related Adverse Events by several factors including assay methodology, sample handling, timing of [see Warnings and Precautions]. pregnancy outcomes. 65 and over to determine whether they respond differently from younger In controlled clinical studies in psoriasis, change of plaque psoriasis into a sample collection, concomitant medications, and underlying disease. For subjects. Other reported clinical experience has not identified differences different psoriasis sub-types (including erythrodermic, pustular and guttate), DRUG INTERACTIONS A multicenter clinical study was conducted in 16 women treated with CIMZIA in responses between the elderly and younger patients. Population these reasons, comparison of the incidence of antibodies to certolizumab Use with Anakinra, Abatacept, Rituximab, and Natalizumab at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks Do Not Copy was observed in <1% of CIMZIA treated subjects. pegol in the studies described below with the incidence of antibodies in other pharmacokinetic analyses of patients enrolled in CIMZIA clinical studies An increased risk of serious infections has been seen in clinical studies of other during the third trimester of pregnancy for rheumatological diseases or Crohn’s concluded that there was no apparent difference in drug concentration Adverse Reactions of Special Interest Across Indications studies or to other products may be misleading. TNF-blocking agents used in combination with anakinra or abatacept, with disease. The last dose of CIMZIA was given on average 11 days prior to Patients with Crohn’s disease were tested at multiple time points for regardless of age.Penalties Because there is a higher incidence Apply of infections in the Infections no added benefit. Formal drug interaction studies have not been performed delivery (range 1 to 27 days). Certolizumab pegol plasma concentrations elderly population in general, use caution when treating the elderly with The incidence of infections in controlled studies in Crohn’s disease was antibodies to certolizumab pegol during Studies CD1 and CD2. In patients were measured in samples from mothers and infants using an assay that with rituximab or natalizumab. Because of the nature of the adverse events CIMZIA [see Warnings and Precautions]. 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The continuously exposed to CIMZIA, the overall percentage of patients who seen with these combinations with TNF blocker therapy, similar toxicities can measure certolizumab pegol concentrations at or above 0.032 mcg/ infections consisted primarily of upper respiratory infections (20% for CIMZIA, were antibody positive to CIMZIA on at least one occasion was 8%; may also result from the use of CIMZIA in these combinations. There is not mL. Certolizumab pegol plasma concentrations measured in the mothers at OVERDOSAGE 13% for placebo). The incidence of serious infections during the controlled approximately 6% were neutralizing in vitro. No apparent correlation of enough information to assess the safety and efficacy of such combination delivery (range: 4.96 to 49.4 mcg/mL) were consistent with non-pregnant The maximum tolerated dose of certolizumab pegol has not been established. clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% antibody development to adverse events or efficacy was observed. Patients therapy. Therefore, the use of CIMZIA in combination with anakinra, women’s plasma concentrations in Study RA-I [see Clinical Studies]. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have for placebo-treated patients. Serious infections observed included bacterial and treated with concomitant immunosuppressants had a lower rate of antibody abatacept, rituximab, or natalizumab is not recommended [see Warnings and Certolizumab pegol plasma concentrations were not measurable in 13 out been administered without evidence of dose-limiting toxicities. In cases of viral infections, pneumonia, and pyelonephritis. development than patients not taking immunosuppressants at baseline Precautions]. of 15 infants at birth. The concentration of certolizumab pegol in one infant overdosage, it is recommended that patients be monitored closely for any The incidence of new cases of infections in controlled clinical studies in (3% and 11%, respectively). The following adverse events were reported was 0.0422 mcg/mL at birth (infant/mother plasma ratio of 0.09%). In a adverse reactions or effects, and appropriate symptomatic treatment instituted in Crohn’s disease patients who were antibody-positive (N = 100) at an Live Vaccines second infant, delivered by emergency Caesarean section, the concentration immediately. rheumatoid arthritis was 0.91 per patient-year for all CIMZIA-treated patients Avoid use of live (including attenuated) vaccines concurrently with CIMZIA incidence at least 3% higher compared to antibody-negative patients (N = was 0.485 mcg/mL (infant/mother plasma ratio of 4.49%). At Week 4 and 0.72 per patient-year for placebo-treated patients. The infections [see Warnings and Precautions]. PATIENT COUNSELING INFORMATION consisted primarily of upper respiratory tract infections, herpes infections, 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, and Week 8, all 15 infants had no measurable concentrations. Among 16 See FDA-approved patient labeling (Medication Guide) injection site erythema, injection site pain, pain in extremity, and upper Laboratory Tests exposed infants, one serious adverse reaction was reported in a neonate urinary tract infections, and lower respiratory tract infections. In the controlled Risk of Serious Infections rheumatoid arthritis studies, there were more new cases of serious infection respiratory tract infection. Interference with certain coagulation assays has been detected in patients who was treated empirically with intravenous antibiotics due to an increased treated with CIMZIA. Certolizumab pegol may cause erroneously elevated white blood cell count; blood cultures were negative. The certolizumab pegol Inform patients that CIMZIA may lower the ability of the immune system adverse reactions in the CIMZIA treatment groups, compared to the placebo In two long-term (up to 7 years of exposure), open-label Crohn’s disease to fight infections. Instruct patients of the importance of contacting their groups (0.06 per patient-year for all CIMZIA doses vs. 0.02 per patient-year studies, overall 23% (207/903) of patients developed antibodies against activated partial thromboplastin time (aPTT) assay results in patients without plasma concentrations for this infant were not measurable at birth, Week 4, coagulation abnormalities. This effect has been observed with the PTT-Lupus or Week 8. doctor if they develop any symptoms of infection, including tuberculosis for placebo). Rates of serious infections in the 200 mg every other week certolizumab pegol on at least one occasion. Of the 207 patients who were and reactivation of hepatitis B virus infections. Because caution should be dose group were 0.06 per patient-year and in the 400 mg every 4 antibody positive, 152 (73%) had a persistent reduction of drug plasma Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin In another clinical study conducted in 10 pregnant women with Crohn’s time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL exercised in prescribing CIMZIA to patients with clinically important active weeks dose group were 0.04 per patient-year. Serious infections included concentration, which represents 17% (152/903) of the study population. disease treated with CIMZIA (400 mg every 4 weeks for every mother), infections, advise patients of the importance of informing their health care The data from these two studies do not suggest an association between the APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, certolizumab pegol concentrations were measured in maternal blood as well providers about all aspects of their health [see Warnings and Precautions]. no serious infection occurred in more than one subject. There is no evidence of development of antibodies and adverse events. Laboratories. Other aPTT assays may be affected as well. Interference with as in cord and infant blood at the day of birth with an assay that can measure increased risk of infections with continued exposure over time [see Warnings thrombin time (TT) and prothrombin time (PT) assays has not been observed. concentrations at or above 0.41 mcg/mL. The last dose of CIMZIA was Malignancies The overall percentage of patients with antibodies to certolizumab pegol There is no evidence that CIMZIA therapy has an effect on coagulation. and Precautions (5.1)]. detectable on at least one occasion was 7% (105 of 1,509) in the in vivo given on average 19 days prior to delivery (range 5 to 42 days). Plasma Counsel patients about the possible risk of lymphoma and other malignancies In controlled clinical studies in psoriasis, the incidence rates of infections rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 USE IN SPECIFIC POPULATIONS certolizumab pegol concentrations ranged from not measurable to 1.66 mcg/ while receiving CIMZIA [see Warnings and Precautions]. were similar in the CIMZIA and placebo groups. The infections consisted of 1,509) of these patients had antibodies with neutralizing activity in vitro. Pregnancy mL in cord blood and 1.58 mcg/mL in infant blood; and ranged from 1.87 to Other Medical Conditions primarily of upper respiratory tract infections and viral infections (including Patients treated with concomitant immunosuppressants (MTX) had a lower Pregnancy Exposure Registry 59.57 mcg/mL in maternal blood. Plasma certolizumab pegol concentrations Advise patients to report any signs of new or worsening medical conditions herpes infections). Serious adverse events of infection occurred in CIMZIA- rate of antibody development than patients not taking immunosuppressants There is a pregnancy exposure registry that monitors pregnancy outcomes were lower (by at least 75%) in the infants than in mothers suggesting such as heart disease, neurological disease, or autoimmune disorders. Advise treated patients during the placebo-controlled periods of the pivotal studies at baseline. Patients treated with concomitant immunosuppressant therapy in women exposed to CIMZIA during pregnancy. For more information, low placental transfer of certolizumab pegol. In one infant, the plasma patients to report promptly any symptoms suggestive of a cytopenia such as (pneumonia, abdominal abscess, and hematoma infection) and Phase 2 (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation healthcare providers or patients can contact: certolizumab pegol concentration declined from 1.02 to 0.84 mcg/mL over bruising, bleeding, or persistent fever [see Warnings and Precautions]. study (urinary tract infection, gastroenteritis, and disseminated tuberculosis). overall than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). MotherToBaby Pregnancy Studies conducted by the Organization of Teratology 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults. Hypersensitivity Reactions Tuberculosis and Opportunistic Infections Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at Advise patients to seek immediate medical attention if they experience any concomitant use of MTX were associated with reduced immunogenicity. Product manufactured by: In completed and ongoing global clinical studies in all indications 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/ Animal Data symptoms of severe hypersensitivity reactions. Advise latex-sensitive patients UCB, Inc.,1950 Lake Park Drive, Smyrna, GA 30080 Antibody formation was associated with lowered drug plasma concentration Because certolizumab pegol does not cross-react with mouse or rat TNFa, US License No. 1736 including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is Risk Summary that the needle shield inside the removable cap of the CIMZIA prefilled syringe For more information, go to www.CIMZIA.com or call 1-866-424-6942. reproduction studies were performed in rats using a rodent anti-murine TNFa ® approximately 0.61 per 100 patient-years across all indications. and reduced efficacy. In patients receiving the recommended CIMZIA dosage Limited data from the ongoing pregnancy registry on use of CIMZIA in contains a derivative of natural rubber latex [see Warnings and Precautions]. CIMZIA is a registered trademark of the UCB Group of Companies. of 200 mg every other week with concomitant MTX, the ACR20 response pregnant women are not sufficient to inform a risk of major birth defects or pegylated Fab’ fragment (cTN3 PF) similar to certolizumab pegol. Animal ©2019 UCB, Inc., Smyrna, GA 30080. All rights reserved. was lower among antibody-positive patients than among antibody-negative reproduction studies have been performed in rats during organogenesis at

PATIENT-FOCUSED SOLUTIONS IN ROSACEA MANAGEMENT: TREATMENT CHALLENGES IN SPECIAL PATIENT GROUPS Release Date: July 1, 2019 Termination Date: June 30, 2020 Estimated Time to Complete This CE Activity: 1.0 hours Medium or Combination of Media Used: Written article Method of Physical Participation: Journal article, Journal post-test, web-based post-test, and evaluation Hardware/Software Requirements: High speed internet connection, any web browser

Statement of Need Reports show 16 million individuals in the US are affected by • Define rosacea treatment strategies based on individual di- rosacea and account for up to 3% of all cases seen in dermatol- agnosis, disease classification, and patients’ self-reported ogy practice. Recent reports show rosacea is more common in issues patients with darker skin types than previously recognized and in skin types III-VI, rosacea may be more difficult to distinguish • Identify challenges to early diagnosis and treatment in pain the early stages; these patients may not seek treatment until tients with darker versus lighter skin, male versus female their symptoms are quite severe. Rosacea has a considerable patients, and other select patient types psychosocial impact and is the cause of embarrassment, anxiety, and low self-esteem. Men are more likely than women to • Develop and implement ongoing clinician-patient dialogue feel ridiculed for their appearance despite higher disease prev- to assess the impact, extent, and the burden of rosacea on alence in women. Current treatments aid in the management the individual patient to enable better personalized treat- of rosacea signs and symptoms and therapeutic goals and ment outcomes decisions should include individual, patient-identified issues. Current recommendations for achieving optimal treatment Target Audience results include achieving clear/almost clear skin and improv- This activity is intended for dermatologists, residents, and fellows ing key patient-reported outcomes. Therefore, there is need for in dermatology, and physician assistants, nurse practitioners, increased medical knowledge on features, benefits, Doand limits Not andCopy other healthcare providers with an interest in cutaneous of available treatment modalities, their effect on minimizing diseases and disorders affecting patients of all skin types. rosacea symptoms, and formulation of optimal individualizedPenalties Apply rosacea treatment plans in special patient groups often not al- Credit Statements ways considered to be at high risk. Dermatology providers of Category 1: Creighton University Health Sciences Education all levels of training and experience require tools to establish designates this live activity for a maximum of 1.0 AMA PRA ongoing clinician-patient communication relating to the iden- Category 1 Credit(s)™. Physicians should claim only the credit tification of patient-reported disease impact and the burden of commensurate with the extent of their participation in the ac- the condition on daily life. tivity.

Educational Objectives AAPA accepts AMA Category 1 credit for the PRA from The overall information and educational goals of this enduring organizations accredited by ACCME. activity are to expand awareness of the impact of rosacea on quality of life of patients of all ages and genders and skin types Nurse CE: Creighton University Health Sciences Continuing including those with darker skin, summarize current rosacea Education designates this activity for 1.0 contact hour for treatment strategies and the unique challenges rosacea nurses. Nurses should claim only credit commensurate with presents when treating patients with darker skin types, men the extent of their participation in the activity. versus women, and other special patient types, and formulate effective, individualized rosacea treatment regimens that Accreditation Statement address patients’ self-reported concerns on the impact of their disease on their overall quality of life.

Upon completion of this continuing education activity participants should be able to:

• Recognize the impact of rosacea on various patient popula- In support of improving patient care, this activity has been tions including skin types III-IV, younger men, and others planned and implemented by Creighton University Health Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Sciences Continuing Education (HSCE) and Physicians from Almirall, Galderma, and Leo and serves as a consultant to Continuing Education Corporation. Creighton University Health Galderma and Leo. Ahuva Cices, MD has no relevant disclosures Sciences Continuing Education (HSCE) is jointly accredited by to report. The planning committee for this activity have no relevant the Accreditation Council for Continuing Medical Education financial disclosures to report. (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), Disclosure of Unlabeled Use: This educational activity may contain to provide continuing education for the healthcare team. discussion of published and/or investigational uses of agents that are not indicated by the US FDA. Creighton University Health How to Obtain CE Credit Sciences Continuing Education (HSCE), the Journal of Drugs in You can earn one (1.0) AMA PRA Category 1 Credit™ reading Dermatology, and the activity supporters do not recommend the the article contained in this issue and completing a Journal post- use of any agent outside of the labeled indications. The opinions test, web-based post-test, and evaluation. Test is valid through expressed in the educational activity are those of the faculty and June 30, 2020 (no credit will be given after this date). do not necessarily represent the views of the Creighton University Health Sciences Continuing Education (HSCE), the Journal of To receive credit for this activity, please go to www.JDDonline. Drugs in Dermatology, and the activity supporters. Please refer to com and click on CME Activities under “Library.” You will find the official prescribing information for each product for discussion instructions for taking the post-test and completing the program of approved indications, contraindications, and warnings. evaluation. You must earn a passing score of at least 70% and complete and submit the activity evaluation form in order to Disclosure of Commercial Support: This activity is supported by an receive a certificate for 1.0 AMA PRA Category 1 Credit™. There educational grant provided by Galderma Laboratories, L.P. is no fee for this CME activity. Once you have completed the form online, you will be able to print your certificate directly. You Contact Information can also receive credit for this activity by completing the post- If you need technical support or have questions about the test and evaluation printed in this issue and faxing or mailing it course, please e-mail [email protected]. to JDD, 115 East 23rd Street, Third Floor, Unit 322, New York, NY 10010 or fax to 212-213-5439. Creighton University Health Sciences Continuing Do Not EducationCopy (HSCE) CME Privacy Policy Faculty Credentials All information provided by course participants is confidential Andrew F. Alexis, MD, MPH is Chairman, DepartmentPenalties of and Apply will not be shared with any other parties for any reason Dermatology and Director, Skin of Color Center at Mount Sinai without permission. St. Luke’s and Mount Sinai West, and Associate Professor, Icahn School of Medicine at Mount Sinai, New York, NY. Ahuva Cices, Copyright MD is associated with the Skin of Color Center, Mount Sinai West All of the content in this educational activity is copyrighted by the and Icahn School of Medicine at Mount Sinai, New York, NY. Journal of Drugs in Dermatology. Creighton University Health Sciences Continuing Education (HSCE) has obtained permission Peer Reviewer Credentials from the Journal of Drugs in Dermatology to use the content in Perry Robins, MD is Professor Emeritus of Dermatology at New this educational activity. York University Medical Center, New York, NY.

Disclosures Policy on Faculty and Provider Disclosure: It is the policy of Creighton University Health Sciences Continuing Education (HSCE) to ensure fair balance, independence, objectivity, and scientific rigor in all activities. All faculty participating in CME activities sponsored by Creighton University Health Sciences Continuing Education (HSCE) are required to present evidence-based data, identify and reference off-label product use, and disclose all relevant financial relationships with those supporting the activity or others whose products or services are discussed. Any real or apparent conflicts of interest have been addressed through a peer review process, as required by ACCME. The faculty/authors have disclosed the following relationships with commercial interests: Andrew F. Alexis, MD, MPH has received grant/research support Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

July 2019 608 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLES Journal of Drugs in Dermatology SPECIAL TOPIC Patient-focused Solutions in Rosacea Management: Treatment Challenges in Special Patient Groups Ahuva Cices MD, Andrew F. Alexis MD MPH Skin of Color Center, Mount Sinai West, Icahn School of Medicine at Mount Sinai, New York, NY

ABSTRACT

Rosacea is among the most common facial skin conditions diagnosed by dermatologists. Typical clinical features include erythema, flushing, telangiectasia, papules, and pustules distributed on the central face. While the prevalence of rosacea is highest among white populations of Northern European descent, recent reports have found that rosacea frequently occurs in people from a broad range of racial/ethnic backgrounds and skin types. When rosacea presents in darker skin types, the diagnosis is often more challenging due to masking of features by increased epidermal melanin. As such, under-diagnosis and underreporting may contribute to misconceptions about the prevalence of rosacea in populations with skin of color. Recognizing the unique presentations and complications associated with darker skin types is necessary to reduce the disparities in rosacea treatment, especially as the American population continues to become increasingly heterogeneous. Although rosacea is most common in middle-aged females, patients of other demographics may have more negative impacts on quality of life due to their disease. In this article, we review rosacea management with a focus on special patient groups: people with skin of color, and less common forms of rosacea, in order to diminish the physical and psychosocial burden of rosacea in all patient groups. Due to the variability inherent to rosacea, we advocate for an individualized, patient-centered approach to disease management.

J Drugs Dermatol. 2019;18(7):608-612.

INTRODUCTION Do Not Copy osacea is a common, chronic facial condition presenting with various combinations of erythema,Penalties flushing, FIGURE Apply 1. Type IV skin with rhinophyma. telangiectasia, edema, papules, and pustules most R 1,2 often affecting fair-skinned individuals. Although most prevalent in light-skinned populations with Fitzpatrick skin types I-II, rosacea affects a broad spectrum of populations, including those with skin of color. The prevalence of rosacea in nonwhite racial/ethnic populations is less studied, but recent data suggest that it is more prevalent than previously reported.3 In order to effectively diminish the physical and psychosocial burden of rosacea, considering the diverse populations groups affected by this condition is paramount. Until recently, rosacea was widely considered to be a disease almost exclusively affecting light-skinned individuals. How- Epidemiology ever, the prevalence of rosacea in skin of color populations is The prevalence of rosacea is estimated at about 10 percent of increasingly being recognized. A study analyzing data from the predominantly fair-skinned populations and affects approxi- National Ambulatory Medical Care Survey from 1993-2010 to mately 16 million American adults.4,5 The onset of rosacea is determine racial and ethnic makeup of patients with rosacea often after 30 years of age and displays a female predominance found that of all patients diagnosed with rosacea, 2% were with the exception of phymatous rosacea (Figure 1), which is black, 2.3% were Asian or Pacific Islander, and 3.9% were His- more common in older males.4 In younger populations with panic or Latino.8 These findings challenge the long held belief rosacea, this female predilection is amplified.1 Prevalence of that rosacea is a disease largely limited to white individuals of rosacea in Germany and Russia based on general population Northern European heritage with Fitzpatrick skin types I-III. screening found 18% of subjects with rosacea were aged 18-30 years.6 Though more common in adult females, studies evalu- The lower prevalence rates of rosacea in non-white populations ating disease severity support the prevalence of more severe is likely due to a combination of factors including under-report- disease in subjects of male gender and less than 60 years of age.7 ing, under-recognition (due to a low index of suspicion and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

609 Journal of Drugs in Dermatology A. Cices, A.F. Alexis July 2019 • Volume 18 • Issue 7

diagnostic challenges), protective effects of melanin from ultra- FIGURE 2. Granulomatous rosacea in black skin. violet (UV) radiation, and a lower incidence of genes conferring susceptibility in diverse populations.3,4 Recognizing diagnostic challenges posed by masking of clinical features by increased epidermal melanin are necessary to prevent delayed diagnosis, disease progression, and advanced disease, which result in greater morbidity and even disfigurement.3

Pathophysiology Pathophysiology of rosacea is likely multifactorial, involving abnormal responses to environmental stressors in individuals with genetic predispositions leading to immune and neuro- vascaular dysregulation.9 Genetically predisposed individuals to another over time.5,11 These shortcomings were addressed have an abnormal response to environmental stressors such as by the global ROSacea COncensus (ROSCO) consensus panel, UV exposure, temperature changes, microbial antigens (eg, De- which put forth the first set of guidelines for phenotype driven modex folliculorum, Heliobacter pylori), and emotional stress management, which will be further discussed in the manage- that results in Th1/Th17 polarization.4 ment section of this paper.11

Studies finding increased risk with positive family history, Overall, ETR is the most common subtype of rosacea, fol- twin studies with high concordance, and genome association lowed by PPR.2 Important differences in skin of color include studies support the important role of genetics in rosacea.4 A higher reported frequency of PPR compared to ETR (likely due cohort-based twin study evaluating the role of genetics and to difficulty recognizing features of ETR in dark skin), as well environmental factors in rosacea calculated the genetic con- as increased prevalence of the granulomatous subtype (Figure tribution to rosacea development to be 46%.9 Genome-wide 2).3 Phymatous changes, most often seen in older males, are association studies isolated three human leukocyte antigen frequently observed in combination with ETR or PPR.2 Ocular (HLA) alleles with known association to autoimmune disease rosacea is frequently diagnosed when other features of rosacea including type I DM and celiac disease within a large populationDo Not areCopy present to aid in the diagnosis, with nearly 50% of patients of European descent.10 Additional studies are needed to further experiencing onset of cutaneous symptoms prior to ocular elucidate the complex interplay of genetics and environmentPenalties symptoms. Apply5 in rosacea. Recently, there has been a shift towards a phenotype-led ap- Diagnosis and Classification proach, which more accurately reflects patients seen in clinical Rosacea is a clinical diagnosis based on physical exam and practice and has important therapeutic implications, further history that can have a wide range of presentations.5 Guide- discussed in the treatment portion of this review.11 This is lines from the National Rosacea Society (NRS) published in especially significant in patients with disease not fitting the pro- 2012 pioneered criteria for rosacea diagnosis and categoriza- totypical descriptions such as those with skin of color who are tion defined by the presence of one or more primary features: less likely to be identified as having predominant telangiectasia flushing, persistent erythema, papules, pustules, and telangi- and erythematous changes in the skin. Additionally, the current ectasia with variable presence of secondary features: burning, classification system perpetuates the lack of evidence-based re- stinging, erythematous plaques, dryness, edema, ocular mani- search and investigation of less prevalent, but high morbidity festations, and phymatous changes.2 Furthermore, the NRS subtypes such as phymatous and ocular rosacea.11 identified four rosacea subtypes: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular, with one Rosacea remains under recognized in skin of color, how- variant: granulomatous based on presence of combinations of ever, there are tools readily available to assist with this various primary and secondary disease features.2 Though this oftentimes-challenging diagnosis. Patient history can provide classification of rosacea is still currently in use and enabled vital information that is not obtainable on exam: this can in- the development of significant clinical and therapeutics ad- clude a description of burning or stinging sensations, a family vancements in rosacea management, it falls short in its failure history of rosacea or mixed heritage, and even a history of acne to accurately address the broader scope of clinical presenta- that failed to respond to standard treatments.3 On exam, it may tions.5 Oversimplification of the disease into distinct categories be difficult to appreciate features of erythema and telangiec- overlooks the fact that often features of multiple subtypes are tasia due to masking by constitutive skin pigmentation, but present simultaneously creating a more complex clinical picture other features such as dryness and edema may be visible on and furthermore, there is often progression from one subtype the central face or acneiform papular and pustular lesions in Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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the absence of comedones or acneiform lesions on the body FIGURE 3. Rosacea in non-white populations (Skin type IV-VI). (Figure 3).3 Furthermore, strategies to further assess erythema and telangiectasia in darker skin include use of dermoscopy, (3A) (3B) diascopy to test for blanching, and photography against a dark blue background.3

Diagnosis of rosacea requires exclusion of differential diagnoses that may present with centrofacial erythema and must be excluded on a case-by-case basis including seborrheic dermatitis, malar rash of acute cutaneous lupus or systemic lupus erythematosus, chronic photodamage, contact dermatitis, carcinoid syndrome, and niacin ingestion.3,5 Given the high prevalence of systemic lupus erythematosus and sarcoidosis in (3C) (3D) individuals of African descent, black patients presenting with central facial erythema sparing the nasolabial folds or edematous plaques should undergo appropriate work up in order to rule out these conditions including serological evaluation (eg, antinuclear antibody or angiotensin converting enzyme, respectively), punch biopsy, and referral to rheumatology or pulmonology colleagues if indicated.12

Quality of Life Rosacea has significant adverse effects on quality of life (QOL). percent agreed that they “worry how people will react when Physical discomfort due to symptoms such as irritation, itching, they see my rosacea,” and 43 and 59 percent strongly agreed burning, or stinging understandably affect an individual’s well- that they feel their rosacea is unattractive to others despite being.13 Psychosocial affects related to skin changes of rosacea more than 90% of both cohorts self-identifying as having mild that are typically highly visible and have a substantialDo effect Not on toCopy moderate disease.15 Another important finding in the litera- physical appearance have been shown to cause shame, embar- ture is the reversal of psychological symptoms with therapy; rassment, low self-esteem, low self-confidence, negativePenalties body though Apply the number of studies evaluating this outcome are lim- image, and anxiety.14,15 Physical appearance has been shown to ited future studies will likely continue to evaluate these changes have a significant impact on a wide variety of social outcomes as important measures of treatment success.16 from personal relationships and mate selection to workplace success.14 A German study using willingness to pay as a cor- Management relate for disease burden found women and those with more Diagnosis of rosacea should promptly be followed by educa- extensive facial involvement willing to pay more, and likely tion regarding the chronicity and relapsing nature of the disease to experience greater negative QOL due to their rosacea than as well as the importance of gentle skin care, regular photo- their counterparts who are of male gender or have less facial protection with sun protection factor 30 or greater, and trigger involvement.16 The associated stigmatization and frustration ex- avoidance.4,5,11 Identification of patient-specific triggers is essen- perienced by patients are well documented, as are increased tial to preventing disease flares.17 Use of gentle skin cleansers, rates of psychiatric comorbidities such as social anxiety, depres- frequent use of emollients, and avoiding exacerbating factors sion, and social phobia.14 Notably, males are more susceptible such as sunlight, temperature changes, and emotional stress, to stigmatization in setting of rosacea, possibly due to more are primary interventions for managing secondary features severe phenotypes such as rhinophyma.14 Increased stigmatiza- namely dry, itchy, painful, burning skin.11 Counseling should be tion from rosacea has also been associated with higher rates of provided in a culturally sensitive manner, taking into account depression and social avoidance behaviors. that recommendations may differ significantly from traditional cultural practices in non-white populations such as regular The psychosocial impact on QOL is often underestimated by consumption of spicy foods, aggressive exfoliation, or regular physicians, likely in part due to the fact that the objective dis- use of abrasive skin brightening and lightening products.3 Many ease severity does not correlate with the magnitude of effect darker skinned individuals report not using sunscreen out of on QOL, with the exception of depression.13,14 A web-based unfamiliarity or cultural discordance and may struggle to find a cross-sectional study of 600 adults with ETR and PPR cohorts, cosmetically suitable product.18 respectively, found that 45 and 53 percent disagreed that they were satisfied with their appearance due to rosacea, 42 and 27 Evidence-based guidelines for rosacea are limited by the fact Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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thema and telangiectasia (moderate quality evidence).11 FIGURE 4. Summary of ROSCO panel guidelines. High quality RCTs in rosacea are increasing and improving

our therapeutic arsenal, however there remains a large gap in Transient Persistent Papules Telangiectasia Phyma knowledge in less common subtypes, namely phymatous and Erythema Erythema Pustules ocular rosacea, as well as the spectrum of rosacea in skin of col- General X X X X X or.11 The lack of large controlled trials for the treatment of less Skincare* common phymatous and ocular subtypes is exemplified by the Topical alpha X X 2015 Cochrane review of rosacea interventions, which found no adrenergics RCTs for phymatous rosacea and concluded that more stud- Oral Beta X ies are warranted to evaluate treatments for ocular rosacea.19 Blocker ROSCO recommends treatment of inflamed phymatous rosa- Topical Azaleic X** cea with lasers, oral doxycycline, or isotretinoin; therapies for Acid non-inflamed phymas can include CO2 lasers, microdermabra- Topical X sion, and surgical excision based on patient preferences.4,11 Ivermectin Initial treatments for ocular rosacea include education on eye Topical X** care and lid hygiene, use of lubricating drops, and increased Metronidazole dietary intake or supplementation with omega-3 fatty acids. Oral Doxycycline X X*** Collaboration with ophthalmology is recommended for more (40 mg) advanced cases.4,11

Physical X X Modalities Treatment approach for rosacea in non-white populations is the same as that used in white populations, with the excep- Isotretinoin X X*** tion that special consideration must be given to avoid post inflammatory hyperpigmentation.3,12 Few rosacea studies have Laser therapy X X significant numbers of subjects with skin of color as the general

*Gentle skin care, trigger avoidance, sun protection with minimum SPF 30, Domoisturizers Not dearthCopy of non-white subjects in clinical trials is amplified in ro- ** Monotherapy in mild to moderate disease only sacea, which is less prevalent in these populations. Individual *** Inflamed phyma that most rosacea clinical trials rely on the 2012 NRSPenalties subtypes studies Apply for oral doxycycline and topical oxymetazoline showed for inclusion criteria and assess efficacy based on outcome equivalent efficacy in subjects with Fitzpatrick skin phototypes measures specific to the disease subtype rather than the phe- I-III and phototypes IV-VI.3,21 Vascular lasers are effective in the notype, which more accurately reflects the constellation of treatment of vascular components of rosacea in skin of color, features that would ideally be treated simultaneously.11 Rec- however IPL is generally not advised in types IV-VI due to high- ognizing the lack of concordance between the archetypal NRS er risks of dyspigmentation.3,12 Use of longer wavelengths and subtypes and real world patients, the ROSCO panel established lower fluence in skin of color is advised to minimize the risk of consensus treatment guidelines (Figure 4) that encourages pigmentary alterations or scarring.3 targeting individual features of rosacea and use of multiple therapies to achieve desired results.11 Given the heterogeneity of rosacea, there is no single best therapy, and often multiple treatment modalities including gentle Randomized control trials (RCT) are an integral part of evi- skin care, trigger avoidance, topical agents, oral medications, dence based medicine, and their data support the use of topical and laser- or light-based therapies targeting specific disease azelaic acid, metronidazole, and ivermectin, as well as oral dox- manifestations are employed in order to achieve desired re- ycycline for the treatment of mild to moderate PPR and the use sults.4,5 Use of multiple therapies should be based on the of topical ivermectin and oral doxycycline for severe PPR.19,20 patient’s desire for treatment of multiple disease features, and Inflammatory lesions of PPR, active phyma, and ocular features should target specific complaints rather than disease severity can be managed with doxycycline 40 mg as an anti-inflamma- given the large role of patient perception on disease impact.11 tory at subantimicrobial doses.11 Effective treatments targeting Maintenance therapy is dependent on treatment modality and the erythema of ETR include topical alpha-adrenergics (eg, patient preference.11 A comprehensive approach is appropriate oxymetazoline, briminodine), as well as intense pulsed light (Figure 5). This model highlights the importance of commu- (IPL), and pulsed-dye laser (PDL) at 585-595 nm.11 Telangiectasia nication with patients to shape personalized treatment plans. require physical modalities for eradication such as electrodessi- Patients should be reassessed regularly to maintain an optimal cation, IPL, or laser therapies.11 Importantly, the 2015 Cochrane treatment plan as the disease presentation may change over review found no difference in efficacy of IPL and PDL for ery- time. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

612 Journal of Drugs in Dermatology A. Cices, A.F. Alexis July 2019 • Volume 18 • Issue 7

FIGURE 5. Personalized rosacea management plan. is essential. A patient centered approach targeting disease features most bothersome to patients contributes to improved Confirm diagnosis – history and exam, additional testing to rule out differential diagnoses as needed outcomes including QOL. Future studies should continue to evaluate efficacy in diverse populations to accurately reflect the

patients in need of treatment.

Asses disease impact – evaluate psychosocial burden, associated comorbidities REFERENCES 1. Bolognia J, Jorizzo, Joseph L.Schaffer, Julie V. Dermatology. Vol 37. Philadel- phia: Elsevier Saunders; 2012. 2. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Identify triggers and goals of therapy – foundation for individualized treatment plan Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584-587. 3. Alexis AF, Callender VD, Baldwin HE, Desai SR, Rendon MI, Taylor SC. Global epidemiology and clinical spectrum of rosacea, highlighting skin of color:

Review and clinical practice experience. J Am Acad Dermatol. 2018. 4. Rainer BM, Kang S, Chien AL. Rosacea: Epidemiology, pathogenesis, and treatment. Dermatoendocrinol. 2017;9(1):e1361574. General counseling – disease course, trigger avoidance, gentle skin care, photo-protection 5. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunc- tive skin care. Cutis. 2013;92(5):234-240. 6. Tan J, Schofer H, Araviiskaia E, Audibert F, Kerrouche N, Berg M. Prevalence of rosacea in the general population of Germany and Russia - The RISE study. Targeted therapies – taking into account assessment of disease impact and treatment goals J Eur Acad Dermatol Venereol. 2016;30(3):428-434. 7. Alinia H, Tuchayi SM, James SM, et al. Measurement of disease severity in a population of rosacea patients. Dermatol Clin. 2018;36(2):97-102. 8. Al-Dabagh A, Davis SA, McMichael AJ, Feldman SR. Rosacea in skin of color: not a rare diagnosis. Dermatol Online J. 2014;20(10). 9. Aldrich N, Gerstenblith M, Fu P, et al. Genetic vs environmental factors that Reassess and adjust treatment plan accordingly – re-evaluate at regular intervals to ensure adequate correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. disease control 2015;151(11):1213-1219. 10. Chang ALS, Raber I, Xu J, et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol. 2015;135(6):1548- Rosacea treatment aims to eliminate and maintain clearance 1555. of signs and symptoms of the disease in order to eliminate 11. Schaller M, Almeida LM, Bewley A, et al. Rosacea treatment update: rec- Do Not Copyommendations from the global ROSacea COnsensus (ROSCO) panel. Br J negative effects the condition has on an individual’s QOL. Com- Dermatol. 2017;176(2):465-471. munication with patients is necessary to reveal anPenalties individual’s 12. Apply Callender VD, Barbosa V, Burgess CM, et al. Approach to treatment of medical and cosmetic facial concerns in skin of color patients. Cutis. personal concerns, goals, and desires, which often differ from 2017;100(6):375-380. that predicted by clinicians.14 For example, erythema has been 13. van der Linden MM, van Rappard DC, Daams JG, Sprangers MA, Spuls PI, described as the most troublesome symptom, however, these de Korte J. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015;95(4):395-400. findings come from predominantly fair-skinned populations and 14. Oussedik E, Bourcier M, Tan J. Psychosocial burden and other impacts of it is plausible that erythema is not as bothersome in non-white rosacea on patients' quality of life. Dermatol Clin. 2018;36(2):103-113. 15. Zeichner JA, Eichenfield LF, Feldman SR, Kasteler JS, Ferrusi IL. Quality of populations. Alternatively, erythema may not be appreciated life in individuals with erythematotelangiectatic and papulopustular rosacea: by clinicians, but nonetheless can be bothersome to patients, findings from a web-based survey.J Clin Aesthet Dermatol. 2018;11(2):47- 52. highlighting the need for individually tailored patient care re- 16. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea flecting the patient’s wishes.14 Optimal results and improved and the influence of current management options. J Am Acad Dermatol. patient outcomes are achieved by understanding the patient’s 2014;71(5):973-980. 1 7. Buddenkotte J, Steinhoff M. Recent advances in understanding and manag- subjective disease severity and goals of treatment prior to ini- ing rosacea. F1000Res. 2018;7. tiating therapy.11 Choice of therapy should incorporate patient 18. Diffey BL, Fajuyigbe D, Wright CY. Sunburn and sun protection in black skin. Int J Dermatol. 2019. preferences and values that can include cost of procedural 19. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. therapies that are typically not covered by health insurance or Interventions for rosacea. Cochrane Database Syst Rev. 2015(4):Cd003262. 11 20. Que SK, Fraga-Braghiroli N, Grant-Kels JM, Rabinovitz HS, Oliviero M, Scope preference for topical vs oral or frequency of administration. A. Through the looking glass: basics and principles of reflectance confocal microscopy. J Am Acad Dermatol. 2015;73(2):276-284. CONCLUSION 2 1. Alexis AF, Webster G, Preston NJ, Caveney SW, Gottschalk RW. Effective- ness and safety of once-daily doxycycline capsules as monotherapy in pa- Rosacea is a chronic inflammatory skin condition due to tients with rosacea: an analysis by Fitzpatrick skin type. J Drugs Dermatol. immune and neurovascular dysfunction that has significant ef- 2012;11(10):1219-1222. fects on QOL. Though more prevalent in patients with fair skin, rosacea occurs in people of all races and ethnicities and until AUTHOR CORRESPONDENCE recently has been largely under recognized in nonwhite popu- Andrew Alexis MD MPH lations. In order to optimize treatment of rosacea, recognizing E-mail:...... ……...... [email protected] more subtle or less typical features in special patient groups Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

CME Post-Test: For fastest results, please complete this activity online by scanning the QR code below or visiting www.JDDonline.com in the Medical Education Library, where you will be able to receive your CME certificate immediately upon achieving the passing score. Successful completion of the Post-Test is required to earn 1.0 AMA PRA Category 1 CME Credits™ and ANCC Credits. You must earn a passing score of at least 70% and complete the activity evaluation form in order to complete the course and receive a certificate for 1.0 AMA PRA Category 1 CME Credits™ and ANCC Credit. You can take the test online as many times as you require to achieve the passing score. Alternatively, you may select your best answer for each of the following questions and insert them into the Answer Grid found on the Evaluation/Certificate Request Form on page 614 and return your completed Evaluation/Certificate Request Form to JDD, 115 East 23rd Street, Third Floor, Unit 322, New York, NY 10010 or fax to 212-213-5439.

1. What is the estimated prevalence of rosacea globally 4. Which treatment option is best for a patient with Fitzpat- (inclusive of white and non-white populations)? rick skin type IV requesting treatment for telangiectasia?

a. 1% a. Doxycycline

b. 2% b. Oxymetazoline

c. 10% c. IPL

d. 20% d. PDL

2. Which subtype of rosacea has a male predominance?Do Not 5.Copy Which of the following adverse psychosocial effects is correlated with disease severity? a. Erythematotelangiectatic Penalties Apply a. Stigmatization b. Papulopustular b. Anxiety c. Phymatous c. Depression d. Ocular d. Social anxiety disorder

3. A 36-year-old female with skin type VI presents with an erythematous plaque on the central face, which condition 6. Which of the following therapies is contraindicated in a is the least likely diagnosis? rosacea patient with type IV skin?

a. Lupus a. Brimonidine

b. Tinea faciei b. Oxymetazoline

c. Rosacea c. IPL

July 2019 614 Volume 18 • Issue 7 Copyright © 2019Journal of Drugs in DermatologyCMEA. Cices, A.F. Alexis Journal of Drugs in Dermatology July 2019 • Volume 18 • Issue 7 Evaluation Form PATIENT-FOCUSED SOLUTIONS IN ROSACEA MANAGEMENT: TREATMENT CHALLENGES IN SPECIAL PATIENT GROUPS To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this Evaluation/Certificate Form.For fastest results, please complete this form online at JDDonline.com in the Medical Education Library. You must complete and submit this form or complete the CME activity online to receive credits for completing this activity. There is no fee for this CME activity. You must earn a passing score of at least 70% and complete the activity evaluation form in order to complete the course and receive a certificate for 1.0 AMA PRA Category 1 CME Credit(s)™. Alternatively, you may return this form to JDD by fax to (718) 407-0898, or by mail to 115 E. 23rd Street, 3rd Floor, New York, NY 10016. Request for Credit Name Degree

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I participated in the entire activity and claim 1.0 AMA PRA Category 1 Credit(s)™ and ANCC Credit. Please answer the following questions using the appropriate rating: 1 = Strongly Disagree 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree

1. The information presented was timely and will Impact of the Activity influence how I practice. 1. Name one new strategy you learned as a result of completing this activity:

1 2 3 4 5 ______2. The information presented enhanced my current knowledge base 2. Name one thing you intend to change in your practice as a result of completing this activity: 1 2 3 4 5 3. The information presented addressed my most ______pressing questions 3. Please provide any additional comments onthis activity: 1 2 3 4 5 4. The activity provided new ideas or information ______I expect to use 4. Please list any topics you would like to see addressed in future 1 2 3 4 5 educational activities: 5. The activity addressed competencies identified ______by my specialty 1 2 3 4 5 6. The activity avoided commercial bias or influence 1 2 3 4 5 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

he special focus of JDD helps to share knowledge from experienced key opinion leaders to help us better identify the critical differences in management of special Tpatient populations, cosmetic concerns, and therapeutic of women and people of color.

I commend the authors for deciphering between myths and knowledge gaps in aesthetic treatment of patients of color in this special focus issue. The issue is comprehensive in addressing specific concerns of the Black, Hispanic, Latino, and Asian female patients.

Cheryl M. Burgess, MD, FAAD Many cultures associate beauty with an even complexion. It has been shown in many reported references, the major cosmetic concern in patients of color is discoloration. This issue addresses discoloration of individuals of color and the use of a multitude of preparations that can blend the complexion. Authors in Asia, Sweden, France, and Brazil discuss the use of injectable deoxycholic acid in non- submental regions and hyaluronic acid for skin boosting, an off-label usage or procedures in the United States. Skin boosting improves hydration and the smoothness of the skin. Additionally, international methods of treating cosmetic patients with multiple modalities are discussed.

The JDD issue also includes an article on rosacea treatments with a focus on darker skin types. Additionally, the supplement addresses a novel treatment for seborrheic keratoses and specifically, reviews the risks related to treating skin of color. The need of prompt diagnosis and treatment of skin cancer reinforces the need to be more aware of the risk factors, the aggressive nature of melanoma, and the need for adequate sun protection. Do Not Copy Further study of how we approach treatment of special population groups, particularly women, in aesthetic areas is merited. We should further understand the emotional impact ofPenalties a woman when sheApply doesn’t exude a clear complexion. Clarity of the skin and appearance is the precursor to how a woman feels about herself, and we should shine a light on gaining a deeper understanding of the psychology of women in improving treatment regimens. Is a dermatologist simply improving or clearing a woman’s skin, or are we giving her greater power and freedom to live her best life?

July 2019 616 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Myths and Knowledge Gaps in the Aesthetic Treatment of Patients With Skin of Color Andrew F. Alexis MD MPH,a Julius Few MD,B Valerie D. Callender MD,c Pearl Grimes MD,D Jeanine Downie MD MA,E Charles Boyd MD,f Conor J. Gallagher PhDg aIcahn School of Medicine at Mount Sinai, New York, NY BThe Few Institute for Aesthetic Plastic Surgery, Chicago, IL cCallender Dermatology and Cosmetic Center, Glenn Dale, MD DThe Vitiligo & Pigmentation Institute of Southern California, Los Angeles, CA EImage Dermatology, Montclair, NJ fBoyd Beauty, Birmingham, MI gAllergan plc, Irvine, CA

ABSTRACT

Background: Misperceptions about facial aesthetic treatments in individuals with skin of color (SOC) may influence treatment selection. Objective: We aimed to identify knowledge gaps and myths concerning facial aesthetic treatment in individuals with SOC. Methods: A PubMed search identified articles concerning patients with SOC receiving facial aesthetic treatments. The experience of experts in aesthetic treatment of patients with SOC was also considered. Results: Knowledge gaps included not seeking injectable filler treatment of lips, risk of developing keloids with injectable filler treatment, risk of hyperpigmentation precluding surgical procedures and nonsurgical injectable filler treatment, melasma being a minor cosmetic concern with limited treatments, and racial/ethnic groups being homogeneous with respect to facial characteristics and aesthetic concerns. Dispelled myths included perceptions that: individuals with SOC do not need sunscreen; dermal fillers and neuromodulators are not necessary or useful for patients with darker skin; laser treatments cannot be used on darker skin; facial products are unnecessary; and only medical providers with SOC can understand how to treat patients with SOC. Conclusions: Knowledge gaps and myths concerningDo facial Not aesthetic Copy treatment in individuals with SOC exist. These patients may undergo various facial aesthetic procedures safely andPenalties effectively, as long Apply as nuances in treatment approaches are recognized. J Drugs Dermatol. 2019;18(7):616-622.

INTRODUCTION This paper aims to examine knowledge gaps that may exist in he number of surgical and nonsurgical cosmetic pro- the medical community and to dispel patient-held myths asso- cedures performed in the United States increased by ciated with skin care and aesthetic treatment in SOC. Tmore than 30% between 2010 and 2016, with the percentage of procedures performed in non-Caucasians increasing METHODS from 19% to 25%.1,2 Despite substantial and increasing inter- Based on their clinical experience, the authors, who are experts est in aesthetic procedures from individuals with SOC, only a in the aesthetic treatment of individuals with SOC, identified few treatment guidelines or recommendations touch on race or and reached consensus on myths and knowledge gaps in the ethnicity in discussions of safety and efficacy.3-7 Dermatologists aesthetic treatment of individuals with SOC. PubMed searches and plastic surgeons may thus be hesitant to treat patients with were conducted on these areas and the results were reviewed SOC, based on inadequate guidance for that population. A na- for relevance to individuals with SOC. tional survey of Australian dermatologists found that 75% were not confident in performing cosmetic procedures for patients KNOWLEDGE GAPS IN THE MEDICAL COMMUNITY with SOC, and a majority expressed a desire for more training Gap: Darker-Skinned Patients of African Descent Do Not on medical conditions and surgical and cosmetic issues in SOC, Seek Injectable Filler Treatment of the Lips emphasizing the need for education on treating these patients.8 Response Further, widespread and often unsubstantiated anecdotal in- Darker-skinned patients of African descent may be less likely to formation regarding treatment preferences and outcomes in undergo enhancement of the lips, but they do request restora- people with SOC has encouraged myths about skin care and tion of lip volume lost through aging, generally presenting at aesthetic treatment that may prevent this population from re- an older age than Caucasian patients seeking lip enhancement ceiving the best possible care. (Figure 1).9 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

617 Journal of Drugs in Dermatology A.F. Alexis, J. Few, V.D. Callender, et al July 2019 • Volume 18 • Issue 7

FIGURE 1. Photos of a 74-year-old black female with Fitzpatrick skin FIGURE 2. Melasma in a patient with skin of color before (A) and after phototype VI who received a total of 2.4 mL HYC-24L (Juvéderm Ultra (B) combination therapy (chemical peels and hydroquinone 6%). XC) at initial and touch-up treatment in her upper and lower lips, oral Images published with permission from P. Grimes. commissures, and philtral columns. Patient is shown before treatment (A) and at 3 months after treatment (B). Reprinted with permission from Allergan plc, Dublin, Ireland. (A) (B) (A) (B)

Gap: Melasma Is a Minor Cosmetic Concern With No Effec- tive Treatment Options Beyond Sun Protection and Periodic Use of Hydroquinone10 Response Dyschromia, including post-inflammatory hyperpigmentation (PIH) and melasma (Figure 2), is one of the most common con- 2% to 17% of patients (6% of injection sites) with Fitzpatrick ditions diagnosed in darker-skinned patients and is an important skin phototypes IV through VI receiving hyaluronic acid filler concern in patients with SOC.11,12 Dyschromia, including PIH and injections for correction of nasolabial folds, but was generally melasma, was the second-most common condition (19.9% of mild and transient.21-23 In one study, injection techniques using visits) diagnosed in black individuals in a retrospective chart multiple or serial punctures were associated with an increased review of 1412 patient visits at a large dermatology practice risk of hyperpigmentation.21 Hyperpigmentation may be effec- specializing in treating patients with SOC.11 Melasma, which can tively treated with topical prescription skin-lightening agents adversely affect quality of life,13,14 is more common in Fitzpatrick or cosmeceuticals.24 The authors agreed that injecting filler too skin phototypes IV through VI and in geographic regionsDo thatNot superficiallyCopy or too quickly, or using serial epidermal punctures, receive more sun exposure.10 Topical hydroquinone 4% is the may increase the risk of hyperpigmentation. standard of care, but other treatments, including Penaltiesazelaic acid, Apply kojic acid, niacinamide, alpha-hydroxy acid products, ascorbic Gap: Patients With SOC Have a Substantial Risk of Develop- acid, and retinoid topical therapies, are effective if used with ing Keloids With Injectable Filler Treatment or Surgery appropriate caution.10,15 Superficial and medium-depth chemi- Response cal peels and laser treatment may also be effective16 but both Product labeling for injectable fillers indicates that the safety of therapies require further study and should be used with caution, these products in patients with known susceptibility to keloid as they themselves are associated with a risk of hyperpigmen- formation has not been evaluated. However, a number of prod- tation.15 Deeper peels and (nonfractional) ablative lasers are ucts were not associated with keloid development in clinical contraindicated in patients with darker skin, based on the au- trial participants with SOC.21-23,25-29 The experience of the authors thors’ clinical experience, because of greater risk of scarring and suggests that the development of keloids following treatment dyspigmentation. It should be emphasized that sunscreen use is with injectable fillers is rare in individuals with SOC. No keloids an integral, essential component of any treatment regimen for were reported in patients with SOC in post-approval studies of melasma. injectable filler treatments,21,22,27 in a long-term study comparing patients with Fitzpatrick skin phototypes I through III versus IV Gap: Patients With SOC Should Not Undergo Surgical through VI,29 or in a case review of 60 patients that included 20 Procedures or Even Receive Nonsurgical Injectable Filler patients with Fitzpatrick skin phototypes IV through VI.26 Treatment Because There Is a Risk of Developing Hyperpig- mentation In aesthetic surgery, less invasive options with smaller incisions Response are generally preferred for patients with SOC.30-32 Optimal inci- In 2016, 1.6 million Hispanics, 1.3 million African Americans, and sion placement, meticulous technique, and closure of surgical 1.1 million Asian Americans selected to undergo cosmetic pro- wounds with minimal tension are particularly important in pa- cedures.17 Patients with SOC are at greater risk of PIH, which can tients with SOC to minimize the risk of hypertrophic scarring.31,32 be a sequela of inflammatory dermatoses (eg, acne) or cosmetic Clinical experience suggests that dermal injury from 27-gauge and surgical procedures (eg, chemical peel, laser treatment).18-20 needle puncture does not appear to be associated with signifi- Hyperpigmentation was reported in one study in approximately cant keloid risk. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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FIGURE 3. Reported use of sunscreen by women (A) and by men (B) in FIGURE 4. Superficial exfoliation and erythema from a sunburn in a a recent facial aging study (N=1048), by race/ethnicity.39,40 patient with Fitzpatrick skin type V. Image published with permission from V. Callender. (A)

100 Rarely/never Sometimes 80 Often Always

60 57

38 40 34 31 30 30 37 25 27 among individuals with SOC. In National Health and Nutrition Respondents (%) 21 19 18 20 15 17 17 Examination Survey data (N=4412), the percentage of respon- 12 11 dents who never used sunscreen was greatest for non-Hispanic blacks, followed by Hispanics, then non-Hispanic whites.38 Simi- 0 Caucasian Asian Black Latino/Hispanic larly, the proportion of individuals with SOC in a recent facial aging study (N=4086) who reported never or rarely using sun- Race/Ethnicity (B) screen was substantially greater in respondents with SOC, especially black individuals, compared with Caucasians (Figure 100 Rarely/never 3).39,40 82 Sometimes 80 Often Always Response The degree of natural protection across the spectrum of skin 58 60 54 types is highly variable; it depends on the size and distribu- 45 tion of melanosomes that, in turn, vary by constitutive melanin 40 41 32 pigmentation. Photoaging and UVR exposure–mediated skin 29 Do Not Copy 26 disorders, including skin cancers, occur in all skin types, albeit Respondents (%) 42,43 20 17 Penalties15 at Apply different rates and clinical presentations. Patients with Fitz- 10 10 44 7 6 patrick skin phototypes IV, V, or VI can get sunburned (Figure 4). 4 5 3 0 Identifying sunburns may be more challenging in darker-skinned Caucasian Asian Black Latino/Hispanic individuals; therefore, these individuals may underestimate their photosensitivity. Although nonmelanoma skin cancer is Race/Ethnicity less prevalent in darker skin types, morbidity and mortality is of- Gap: Racial and Ethnic Groups Are Relatively Homogeneous ten higher in patients with SOC.43 Patchy dyschromia, including With Respect to Their Facial Characteristics and Aesthetic melasma, and isolated dark spots on the skin or diffuse, patchy Concerns darkening may occur in SOC if sun protection is not used.36 Response While some common observations can be made with racial/eth- Sunscreen with a sun protection factor (SPF) of at least 3044 nic groups, it is important to recognize individual variations and should be used to protect against UVR-induced sunburn, skin the diverse spectrum of features that can be observed within the cancer, photoimmunosuppression, and photoaging of the skin, categories of race, ethnicity, and skin types.7,32 Addressing each as well as melasma and photo-induced pigmentation.6,36 UVR patient's unique concerns and facial characteristics individually exposure can reduce skin elasticity, which contributes to skin is crucial.4,33,34 sagging31; therefore, use of sunscreen may potentially reduce sagging. Sunscreen is also important in the management of MYTHS HELD BY PATIENTS PIH20 and post-therapy care for patients undergoing in-office Myth: Individuals With Darker Skin Do Not Need to Use procedures, such as chemical peels or laser treatments.6,15,19 Pa- Sunscreen tients with SOC who use sunscreen should consider vitamin D Background supplementation, given the high prevalence of vitamin D defi- The higher melanin content in SOC confers some degree of ciency in darker skin types and the importance of vitamin D in natural protection against the deleterious effects of ultraviolet maintaining bone health. Low levels of vitamin D are also asso- radiation (UVR) from the sun; however, all skin types are sus- ciated with nonskeletal health conditions, such as diabetes and ceptible to photodamage.35,36 Rates of sunscreen use are lower heart disease.45 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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FIGURE 5. Postinflammatory hyperpigmentation and acne scars before FIGURE 6. Pseudofolliculitis barbie and postinflammatory hyper- (A) and after (B) 3 treatments with Xeo™ Laser Genesis (Cutera, pigmentation secondary to hirsutism before (A) and after (B) treatment Brisbane, CA). Images published with permission from P. Grimes. with long pulse Nd-YAG laser 1064 nm. Images published with (A) (B) permission from P. Grimes. (A) (B)

Myth: As Dark Skin Protects Against Age-related Lines and Response Wrinkles, Dermal Fillers, and Neuromodulators Are Not A knowledgeable clinician can successfully use laser treatment Necessary or Useful for Patients With Darker Skin on SOC using the optimal laser or device and the appropriate Background parameters (ie, fluence, pulse duration) for the indication and The protection afforded by darker skin may reduce or slow skin type (Figures 5 and 6). Comprehensive recommendations photoaging from UVR.9,31,35 Individuals with darker skin con- for darker skin types have been published.18 Depending on the sequently tend to develop lines and rhytids later in life than type of procedure, risk of pigmentary alteration can be mini- Caucasians.9 In the recent facial aging study, black respondents mized by using longer wavelength lasers, lower fluences, lower showed less severe signs of facial aging compared with Cauca- treatment densities, and epidermal cooling techniques.44,49 sian, Hispanic/Latino, and Asian respondents.39 Individuals with SOC demonstrated a delay in the onset of signs of aging by 10 For most laser procedures, test spots (to guide optimal setting to 20 years relative to Caucasians.39,40 While lighter-skinned indi- selection) or conservative treatment settings are useful ap- viduals tend to display more lines and wrinkles, darker-skinned proaches to reducing the risk of pigmentary complications in individuals display more volume depletion and sagging,Do with Not SOC.Copy19 Spot tests are strongly advised when the 800- to 810-nm consequent folds.9,19,31 diode laser is used in patients with skin phototypes V and VI. PenaltiesThe Apply clinician should wait ≥2 days,50 but optimally 2 to 3 weeks, Response after a spot test to confirm tolerance before proceeding with Patients of all skin types will experience aging effects that may treatment.50 Patients should be counseled regarding the risk of prompt them to seek aesthetic treatment.19 Volume restoration pigment changes with laser treatment and about possible cor- for sagging skin is common for individuals with SOC. Notably, rective treatments, if needed.19 For procedures involving injury soft-tissue filler treatment and neuromodulator injections are to the dermis, assessing the risk of keloid formation based on among the most popular minimally invasive aesthetic treat- degree of injury and personal or family history of keloids is ments for individuals with SOC.17 Studies in patients with SOC paramount. Intense pulsed light (IPL) may be cautiously consid- suggested that such treatment is safe and effective.46,47 In a post ered for hair removal in patients with skin phototype IV but is hoc analysis comparing the response and safety of abobotuli- not recommended for use in those with skin phototypes V or VI num toxin type A treatment of glabellar lines in patients with because of a higher risk of dyspigmentation. Results of a chart SOC and Caucasians, the response rate after 30 days was signif- review of 56 patients with Fitzpatrick skin phototypes IV through icantly greater in patients with SOC versus Caucasians (P≤.03), VI support the safety of a 755-nm picosecond laser with the dif- with similar adverse event rates between groups.47 fractive lens array for treatment of scars, pigmented lesions, or striae; although hyperpigmentation occurred in 6 patients, all Myth: Laser Treatments Cannot Be Used on Dark Skin cases were transient.51 Background The greater amount and density of melanin in darker skin can Myths: Individuals With Darker Skin Do Not Need to Use act as a competing chromophore during laser and light-based Skin Cleansers or Moisturizers; Oily Skin Is Protective procedures in SOC, particularly with visible and near-infrared Background devices.48 Therefore, laser and light-based treatments in patients Sebum secretion may be higher in individuals with SOC versus with SOC are associated with a greater risk of tissue damage and those with lighter skin,52 although at least 1 study53 found no dif- resultant hyper- or hypopigmentation and scarring.48 In addition, ference between blacks and Caucasians in skin surface sebum. post-treatment inflammation from laser or other energy-based Studies suggest that facial cleansing practices do vary with eth- devices may induce postinflammatory pigment alteration. nicity: In a survey of 423 Californians, Latino respondents had Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

620 Journal of Drugs in Dermatology A.F. Alexis, J. Few, V.D. Callender, et al July 2019 • Volume 18 • Issue 7

TABLE 1. lower rates of use of both skin cleansers and moisturizers compared with black, white, and Asian respondents.54 In another Recommended Strategies for the Successful Treatment of Patients With Skin of Color study,40 the proportion of respondents who rarely or never used Consider- facial moisturizers was greater in black (43%) and Latino (40%) Recommended Strategy ation women than in Caucasian (33%) women. Maintain an up-to-date understanding of issues related to treatment Response Overall A balance between facial cleansing and the preservation of skin Understand patient concerns and expectations in light of ethnic background and physical oil/skin moisture is necessary for optimal aesthetic outcomes. characteristics Facial cleansers remove dirt, excess sebum, microorganisms, Counsel patients to use sunscreen (SPF of ≥30) exfoliated corneum cells, and other foreign substances, such and explain the risks associated with not using 55,56 as cosmetics and medications, from the skin surface. Se- sunscreen. Recommend vitamin D supplementation 57 58,59 bum has naturally occurring antioxidant and antimicrobial in patients who use sunscreen General properties and may potentially contribute to the maintenance of Encourage the use of moisturizers and washing skin care good skin quality attributes, such as smoothness. the face and neck at least nightly, followed by a light cleanse or rinse in the morning, especially for Cleansers with an acidic pH, moisturizers, and high rinsability patients with conditions that may compromise the are recommended; those that contain non-ionic/silicone-based skin barrier surfactants combined with moisturizers may cause the least dis- Choice of effective pharmaceutical and ruption to the skin barrier and to the normal skin flora.55 Gentle cosmeceutical agents, although topical Treatment hydroquinone 4% remains the standard of care soap-free cleansers may be an option for some patients. While of melasma removal of all oil is not the goal, the removal of excess oil that Recommend sunscreen use as a component of any traps dead skin debris is key, while using a moisturizer to restore treatment regimen for melasma the protective barrier. We recommend washing the face and Collect a thorough medical history to understand neck at least nightly while considering the use of therapeutic the risk of adverse reactions in individual patients topical agents, such as retinol, at night, and then lightly cleans- Provide the patient with an accurate understanding ing or rinsing in the morning to prevent overdrying ofDo the skin. Not Copy of the risks associated with the procedure In addition, we recommend gentle cloths and gentle makeup When performing laser treatments, consider removers for facial cleansing, and daytime moisturizersPenalties with an Apply using longer wavelength lasers, lower fluences, lower treatment densities, and epidermal cooling SPF of 30. Moisturizers can maintain skin hydration and restore techniques to prevent tissue damage barrier function that may be disrupted by cleanser use, and may Use test spots before carrying out laser treatments also reduce the dryness of skin in individuals with SOC.55,56,60 Procedural to determine how the skin may respond (strongly recommended for any new laser device acquired by Dermatologists and plastic surgeons consider the use of topi- a practice) cal cleansers and moisturizers to be an important component of When using dermal fillers, consider adjustments in skin disease management, especially in patients with compro- injection technique (eg, deeper placement of fillers mised skin barrier function.61 However, even among individuals in the dermis, avoiding serial epidermal puncture with chronic dermatologic conditions, the use of moisturizers trauma) that may limit the risk of PIH and cleansers is low,61 suggesting that physicians must clear- Discuss posttreatment care with the patient and ly communicate their recommendations on the use of facial explain how following recommendations may cleansers and moisturizers.56 reduce the risk of adverse events PIH, postinflammatory hyperpigmentation; SPF, sun protection factor. Myth: Only a Medical Provider With SOC Can Understand the Nuances of Treating Patients With SOC Background that racially concordant physicians understood their health There is evidence to suggest that black, Hispanic, and Asian pa- problems (27% vs 12%) and to anticipate being more at ease tients disproportionately receive care from racially concordant with racially concordant physicians (27% vs 20%).63 In a separate physicians, and that patients who select their physicians are survey of 118 patients from 2 dermatology practices, patient and more likely than those assigned to a physician to have a clinician physician racial concordance did not affect patients’ perception of the same race or ethnicity.62 In the experience of the authors, of satisfaction and trust; however, patients with SOC who had this is true of facial aesthetics practices as well. A survey of 1205 Caucasian health care providers indicated issues relating to hav- black and white residents in Ohio found that black respondents ing all of their questions answered, feeling that the provider had were significantly more likely than white respondents to believe listened to them, and comfort with their treatment plan.64 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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Response Medica, Theraplex LLC, ThermiRF, and Valeant; as a researcher While racial/ethnic concordance may facilitate cultural under- for Allergan plc, Alphaeon, BioPharmx, Endo Therapeutics, standing, the training, experience, and cultural competence of Evidera, Johnson & Johnson, Merz Aesthetics, Neothetics, individual physicians, not their own cultural, ethnic, or racial Ranbaxy, Revance, and Skin Medica; as a lecturer for Allergan background, is of paramount importance.64 Although consensus plc, BTL, Cutera, Exeltis, Galderma, Johnson & Johnson, Lifes guidelines do not always include information specific to patients 2 Good, Nutrafol, Perigee Medical, Sente, Solta, Stratpharma, with SOC, numerous publications outline the use of a range of Skin Medica, and ThermiRF; and as an advisory board mem- different aesthetic treatments in patients with SOC, highlighting ber for IntraDerm, Sensus, and Sente; she is also a shareholder issues that should be considered when treating SOC (Supple- in Medmetriks and RegimenMD. C. Boyd serves as a speaker/ mentary Table 1).5,18,21,22,24,33,34,48,65-70 Recommendations for the trainer and serves on advisory boards for Allergan plc, Evolus, successful treatment of patients with SOC are summarized in Galderma, and Revance. C.J. Gallagher was an employee of Al- Table 1. lergan plc at the time of this research and owned stock/options in the company. The opinions expressed in this article are those CONCLUSIONS of the authors. The authors received no honoraria or fees Both practitioners and patients are concerned about treatment related to the development of this article. Funding Disclosures: involving SOC. Some concerns are based in fact, such as the Research for this manuscript was funded by Allergan plc. Medi- risk of PIH, while others are based on broad generalizations that cal writing and editorial assistance was provided to the authors may not be relevant to currently available, minimally invasive by Adrienne Drinkwater, PhD, of Peloton Advantage, an OPEN treatment options and accepted techniques. Patients with SOC Health company, and funded by Allergan plc. can undergo aesthetic procedures safely and effectively, as long as nuances to the treatment approach are recognized and ad- ACKNOWLEDGMENTS dressed. Writing and editorial assistance was provided to the authors by Peloton Advantage, an OPEN Health company, and funded by More information is needed in some areas, such as reduction Allergan plc, Dublin, Ireland. of the risk of dyschromia and more effective treatment for the condition, as are safer and more effective lasers and devices for REFERENCES patients with SOC. Future research on these topics, along with 1. Cosmetic Surgery National Data Bank Statistics 2010. 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Food Chem Toxicol. 2010;48(11):3109-3119. 25. Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume 55. Kuehl BL, Fyfe KS, Shear NH. Cutaneous cleansers. Skin Therapy Lett. deficit: 2-year results from a pivotal single-blind randomized controlled study. 2003;8(3):1-4. Dermatol Surg. 2013;39(11):1602-1611. 56. Draelos ZD. Concepts in skin care maintenance. Cutis. 2005;76(suppl 6):19-25. 26. Odunze M, Cohn A, Few JW. Restylane and people of color. Plast Reconstr 5 7. Passi S, De Pita O, Puddu P, et al. Lipophilic antioxidants in human sebum Surg. 2007;120(7):2011-2016. and aging. Free Radic Res. 2002;36(4):471-477. 2 7. Marmur ES, Taylor SC, Grimes PE, et al. Six-month safety results of calcium 58. Miller SJ, Aly R, Shinefeld HR, et al. In vitro and in vivo antistaphylococcal ac- hydroxylapatite for treatment of nasolabial folds in Fitzpatrick skin types IV tivity of human stratum corneum lipids. Arch Dermatol. 1988;124(2):209-215. to VI. Dermatol Surg. 2009;35(suppl 2):1641-1645. Do Not 59.Copy Drake DR, Brogden KA, Dawson DV, et al. Thematic review series: skin lipids. 28. Karnik J, Baumann L, Bruce S, et al. A double-blind, randomized, multicenter, Antimicrobial lipids at the skin surface. J Lipid Res. 2008;49(1):4-11. controlled trial of suspended polymethylmethacrylate microspheres for the 60. Feng L, Hawkins S. Reduction of "ashiness" in skin of color with a lipid-rich correction of atrophic facial acne scars. J Am Acad Dermatol.Penalties 2014;71(1):77- Applymoisturizing body wash. J Clin Aesthet Dermatol. 2011;4(3):41-44. 83. 6 1. Berson D. Recommendation of moisturizers and cleansers: a study of unmet 29. Bassichis B, Blick G, Conant M, et al. Injectable poly-L-lactic acid for human needs among dermatology patients. Cutis. 2005;76(suppl 6):3-6. immunodeficiency virus-associated facial lipoatrophy: cumulative year 2 in- 62. Traylor AH, Schmittdiel JA, Uratsu CS, et al. The predictors of patient-physi- terim analysis of an open-label study (FACES). Dermatol Surg. 2012;38(7 Pt cian race and ethnic concordance: a medical facility fixed-effects approach. 2):1193-1205. Health Serv Res. 2010;45(3):792-805. 30. Harris MO. The aging face in patients of color: minimally invasive surgical 63. Malat J, van Ryn M, Purcell D. Blacks' and whites' attitudes toward race and facial rejuvenation-a targeted approach. Dermatol Ther. 2004;17(2):206-211. nativity concordance with doctors. J Natl Med Assoc. 2009;101(8):800-807. 3 1. Boyd CM. Approaches to the aging face in African American patients. Facial 64. Harvey VM, Ozoemena U, Paul J, et al. Patient-provider communication, con- Plast Surg Clin North Am. 2002;10(4):377-380. cordance, and ratings of care in dermatology: Results of a cross-sectional 32. Brissett AE, Naylor MC. The aging African-American face. Facial Plast Surg. study. Dermatol Online J. 2016;22(11). 2010;26(2):154-163. 65. Heath CR, Taylor SC. Fillers in the skin of color population. J Drugs Dermatol. 33. Alexis AF, Alam M. Racial and ethnic differences in skin aging: implications 2011;10(5):494-498. for treatment with soft tissue fillers.J Drugs Dermatol. 2012;11(8):s30-s32. 66. Geria AN, Lawson CN, Halder RM. Topical retinoids for pigmented skin. 34. Rossi A, Alexis AF. Cosmetic procedures in skin of color. G Ital Dermatol J Drugs Dermatol. 2011;10(5):483-489. Venereol. 2011;146(4):265-272. 6 7. Sarkar R, Bansal S, Garg VK. Chemical peels for melasma in dark-skinned 35. Kaidbey KH, Agin PP, Sayre RM, et al. Photoprotection by melanin—a com- patients. J Cutan Aesthet Surg. 2012;5(4):247-253. parison of black and Caucasian skin. J Am Acad Dermatol. 1979;1(3):249- 68. Callender VD, St Surin-Lord S, Davis EC, et al. Postinflammatory hyperpig- 260. mentation: etiologic and therapeutic considerations. Am J Clin Dermatol. 36. Baumann L, Rodriguez D, Taylor SC, et al. Natural considerations for skin of 2011;12(2):87-99. color. Cutis. 2006;78(suppl 6):2-19. 69. Taylor CT, Kelly AP, Lim HW, et al. Taylor and Kelly's Dermatology for Skin of 3 7. Summers P, Bena J, Arrigain S, et al. Sunscreen use: Non-Hispanic Color. 2nd ed. Columbus, OH: McGraw-Hill Education; 2016. Blacks compared with other racial and/or ethnic groups. Arch Dermatol. 70. Grimes PE, Alexis AF. Darker skin types. In: Carruthers J, Carruthers A, eds. 2011;147(7):863-864. Botulinum Toxin. 3rd ed. Philadelphia, PA: Saunders; 2013:142-150. 38. Zamoiski RD, Cahoon EK, Michal Freedman D, et al. Self-reported sunscreen use and urinary benzophenone-3 concentrations in the United States: AUTHOR CORRESPONDENCE NHANES 2003-2006 and 2009-2012. Environ Res. 2015;142:563-567. 39. Rossi A, Eviatar J, Green JB, et al. Signs of facial aging in men in a diverse, multinational study: timing and preventive behaviors. Dermatol Surg. Andrew F. Alexis MD MPH 2017;43(suppl 2):S210-S220. E-mail:...... ……...... [email protected] 40. Alexis AF, Grimes P, Boyd C, et al. Racial and ethnic differences in self-reported facial aging in women: results from a multinational study. Dermatol Surg. 2019; in press. 4 1. Taylor SC. Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol. 2002;46(suppl 2):S41-62. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

July 2019 623 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Understanding the Female Hispanic and Latino American Facial Aesthetic Patient Sabrina Fabi MD,a José Raúl Montes MD FACS FACCS,b Shino Bay Aguilera DO,c Vivian Bucay MD FAAD,d Stephanie Manson Brown MBBS MRCS MFPM,e Nazanin Ashourian PhDf ªCosmetic Laser Dermatology, San Diego, CA BJosé Raúl Montes Eyes & Facial Rejuvenation, San Juan, Puerto Rico cSHINO BAY Cosmetic Dermatology & Laser Institute, Fort Lauderdale, FL dBucay Center for Dermatology and Aesthetics, San Antonio, TX EAllergan plc, Marlow, UK fAllergan plc, Madison, NJ

ABSTRACT

Background: Among the growing aesthetic patient population, Hispanic/Latinos represent the largest proportion of non-Caucasians patients. While treatment of Caucasian facial aging patterns are well documented, far less information describes the aesthetic needs of the Hispanic/Latino patient. Objective: An online study was designed to survey facial aesthetic concerns, treatment priorities, and future treatment considerations among a US-based population of Hispanic/Latino American women. Materials and Methods: A total of 401 participants ages 30 to 65 years reported their attitudes toward facial aging, current facial conditions, most bothersome facial areas, areas most/least likely to be treated first, awareness of treatment options and their consideration rates, and motives and barriers that factor into consideration of injectable treatments. Results: Most participants wanted to look good for their age and treatment interests reflected predominant conditions: facial wrinkles, periorbital signs of aging, and uneven skin tone. Most bothersome facial areas included the submental area, periorbital area, and forehead, which were also among the areas most-likely to treat first. The majority of participants would consider injectables. Cost and safety/side effects were cited as frequent concerns. Conclusion: An understanding of the facial aesthetic concernsDo Not and treatment Copy priorities specific to Hispanic/Latino women will enhance the practitioner’s patient-centric treatment approach.Penalties Apply J Drugs Dermatol. 2019;18(7):623-632.

INTRODUCTION he growing popularity of cosmetic procedures has in- minican). Hispanic/Latino Americans are also represented by a creased the racial and ethnic diversity of the aesthetic range of cultures, languages, and biological ancestry which in- practitioner's patient population. This growing diversity clude Asian, African, European, and native North, Central, and T 4 is reflected by a 52% increase in the total number of Hispanic South American. As facial structure and skin type contribute to patients who received cosmetic procedures within the past the characteristic and the progression of facial aging, it must be decade in the USA.1,2 Minimally-invasive facial aesthetic treat- appreciated that the diversity within the Hispanic/Latino popu- ments are also an increasing trend and accounted for 90% of lation makes this facial aesthetic patient also potentially the all procedures performed in the USA in 2017 with neuromod- most diverse to treat.5-8 The practitioner will need to evaluate ulators and dermal fillers representing mainstay treatment and sort out the patient’s predominant phenotype with respect modalities.2 Among the growing aesthetic patient population, to skin type and baseline facial structure to determine the best Hispanic/Latinos have represented the largest proportion of treatment approach. non-Caucasian patients (versus African Americans and Asian Americans) receiving neuromodulators and dermal fillers for While there is much published on the treatment approaches the last 5 years in a row.3 suitable for non-Hispanic white patients, there are far fewer that address the specific aesthetic needs of the Hispanic/Latino The descriptors “Hispanic” and “Latino” (also known as Mes- patient. An individual’s racial and ethnic identity also imbues a tizo) define an ethnic group which includes individuals of cultural influence on standards of beauty, attitudes toward ap- Mexican, Central-to-South American descent, and those of pearance, and priorities in the management of facial aging.9-11 Spanish-Caribbean descent (eg, Cuban, Puerto Rican, and Do- For the culturally-competent practitioner, an awareness of not Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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only the structural and cutaneous signs of aging but also the FIGURE 1. Diagram used to select most bothersome facial areas and patient’s attitudes toward aging are integral in a patient-centric treatment priorities. treatment plan.

The current study aimed to survey the facial aesthetic concerns and treatment priorities among a population of Hispanic/Latino American women who were aesthetically-oriented yet naïve to facial injectable treatment use. The data encompassed: 1) attitudes toward signs of facial aging and current facial conditions; 2) facial areas that are most bothersome; 3) facial areas most/ least likely considered a priority in a future aesthetic treatment plan; 4) awareness of available aesthetic treatments and their consideration rates, and 5) motives and barriers factoring into consideration of injectable treatments. The data presented here is a subset of a larger study which consisted of 1205 women and also included African American and Asian American par- disagree) to 6 (completely agree)?” Existing concerns were ticipants.12 identified from a list of options paired with the following question: “Would you consider talking to a physician about a METHODS treatment for any of the following within the next 2 years?” Participants and Study Design Participants were recruited through online river sampling Most Bothersome Facial Areas and Treatment Priorities (banner ads, pop-up ads, instant capture promotions) by the Questionnaires Lieberman Research Worldwide (LRW) agency between March A 15-point facial diagram and a 6-point Likert scale (1, “not at and April 2016. Primary inclusion criteria were: 1) females ages all bothered” to 6, “very bothered”) were used to assess how 30 to 65 years old living in the USA; 2) aesthetically-oriented, bothersome each area was if at all (Figure 1). A Maximum Dif- qualified by level of agreement on an aesthetic orientation ference (MaxDiff) ranking methodology, also referred to as screening questionnaire; 3) household annual incomeDo >$50,000 Not “Best/WorstCopy scaling” was then used to generate a rank order with some discretionary spending flexibility; 4) naïve to facial of each area as it related to treatment priority.16 Nine different injectable treatments; 5) aware of BOTOX® Cosmetic;Penalties and 6) iterations Apply of the facial diagram were shown, each consisting of considering a medical facial aesthetic treatment within the next 3 facial areas at a time until all 15 features were presented. With 2 years. each iteration, 1 area was selected as the “most likely to be treated first” and 1 area as the “least likely to be treated first”. Participants identified their ethnic background as one of the MaxDiff ranking scores were represented by a “relative impor- following: Mexican, Mexican American, Puerto Rican, Cu- tance value”. An average ranking of importance was established ban, or “Other Spanish, Hispanic, or Latino”. A questionnaire among all areas combined. Areas ranking above average repre- adapted from the Skin Cancer Foundation website was used sented greater importance and priority relative to those areas to categorize participants by Fitzpatrick Skin Phototype (FSP) ranking close to or below the average. I through VI.13,14 The questionnaire took into account eye color, natural hair color, skin color (non-exposed areas, presence/ Awareness of Aesthetic Procedures and Future Treatment absence of freckles (non-exposed areas), and skin response to Considerations Questionnaires ultraviolet radiation (UVR), including the susceptibility of facial Treatment procedure awareness and future treatment con- and body skin to burn or turn brown (tan) following exposure. siderations were identified from a list of options paired with Participants also identified their pigmentary characteristics by the questions: “Which treatments that are administered in a selecting a color most representative of their natural skin tone physician's office have you ever heard of?” and “Which facial from a range of 11 skin codes (colors).15 treatments that are administered in a physician's office would you consider within the next 2 years?” MEASURES AND ANALYSIS Attitudes Toward Facial Aesthetics and Existing Facial Con- Motives and Barriers Impacting Consideration Rate of In- cerns Questionnaires jectable Treatment Questionnaires Attitudes toward improving facial aesthetics were assessed Motives and barriers were identified from a list of options by the aesthetic orientation screening questionnaire which in- paired with the questions: “Which of the following describes cluded a list of options paired with the question “How strongly why you would consider a facial injectable treatment for facial do you agree with each statement on a scale of 1 (completely lines, wrinkles, and folds in the next 2 years?” and “Which of Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 1. TABLE 2. Participant Demographics Proportions of Fitzpatrick Skin Phototypes (FSPs) and Ethnicities % Total Respondents % Total Respondents Characteristic, Statistic Characteristic, Statistic (N = 401) (N = 401)

Age Fitzpatrick Skin Phototype

30 - 44 57 I - II 24 45 - 65 43 III - IV 71

USA Region of Current Residence V - VI 5

Northeast 20 Ethnic Background * South 35 Mexican 46 Midwest 13 Puerto Rican 19 West 32 Cuban 10 ** Born in the USA 83 Other Hispanic 25 Marital Status Married 83 Fitzpatrick Skin Phototype Among Different Ethnic Backgrounds Single (Never Married) 9 % Fitzpatrick Skin Phototype Separated/Divorced/Widowed 8 Ethnic Background I - II III - IV V - VI Education Mexican (n = 183) 23 72 5 High school or Less 8 Puerto Rican (n = 75) 22 76 2 Some College or College Graduate 64 Cuban (n = 42) 37 58 5 Post Graduate 28 Other Hispanic (n = 101) 23 71 6 Household Income *Includes Mexican American and Chicano **Includes all other Spanish, Hispanic, or Latino origins Less than $ 75,000 29 $ 75,000 - $ 150,000 56 Do Not Copy $ 150,000 or More 15 Monthly Spend on Products and Services for Facial AestheticsPenalties* treatment Apply (59%; Table 1). The majority were categorized as FSP Less than $ 250 70 III or IV (71%) and a large proportion (46%) self-identified with a $ 250 or More 29 Mexican ethnic background (Table 2). Maximum Spend on a Single Medical Facial Treatment Attitudes Toward Improving Facial Aesthetics and Existing Less than $ 250 41 Facial Concerns $ 250 or More 59 Most participants agreed with the statement that they wanted *1% preferred not to answer their face to look good for their age (84%). A large propor- the following are the top 3 reasons why you would consider a tion was interested in treatments that could make them look facial injectable treatment for facial lines, wrinkles, and folds less tired (72%), and that would address facial lines/wrinkles/ but have never tried it before?” signs of aging (68%) as well as hyper/hypo-pigmentation (63%) (Figure 2). Facial wrinkles (56%), dark under-eye circles (55%), Data Analysis uneven skin tone/color (47%), and bags under the eyes (45%) Max Diff analyses and analysis for correlation between bother- were among the most frequently-reported conditions (Figure 3). some facial areas and their treatment priorities were conducted by the LRW agency and presented descriptively by percent or Most Bothersome Facial Areas by average. The most bothersome areas included sagging underneath the chin/double chin (41%), under-eye/tear trough area (37%), RESULTS crow’s feet lines (CFLs) (37%), and forehead lines (FHLs) (36%). Participants These were followed by glabellar lines (GLs) (31%) and areas of The majority of the 401 participants included in the study were the mid-to-lower face, including nasolabial folds (NLFs) (34%), 30 to 44 years old (57%), born in the USA (83%), married (83%), oral commissures (OCs) (32%), chin (27%), and marionette lines with household income > $75,000 (71%), an average spending (MLs) (27%; Figure 4). Perioral lines (25%), jawline (23%), lips of < $250/month on facial aesthetic products/services (70%), (22%), cheeks (20%), and temples (16%) were the least bother- and had previously spent ≥ $250 on a single medical facial some areas. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

626 Journal of Drugs in Dermatology S. Fabi, J.R. Montes, S.B. Aguilera, et al July 2019 • Volume 18 • Issue 7

FIGURE 2. Attitudes toward improving facial aesthetics.

FIGURE 3. Existing facial concerns.

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627 Journal of Drugs in Dermatology S. Fabi, J.R. Montes, S.B. Aguilera, et al July 2019 • Volume 18 • Issue 7

Treatment Priorities DISCUSSION The treatment priorities of each facial area (represented by rela- The rate of onset, severity, and pattern of facial aging is influenced tive importance scores) ranged from 27 to 77 with treatment by race and ethnicity, while the motives that prompt an individ- priorities tending to correlate with bothersome facial areas ual to seek treatment may be based more on social and cultural (R2 =.81, data not shown). In younger participants (ages 30 to ideals of beauty and attitudes about improving their facial aes- 44), areas of the upper face had the highest priorities and in- thetics.9-11 In this survey of 401 Hispanic/Latino American women cluded the under-eye/tear trough area (77) and CFLs (75; Figure aged 30 to 65, the predominant aesthetic concerns and goals 5a). Other areas of high importance were FHLs (64), sagging were reported, which may help familiarize practitioners with underneath the chin/double chin (64), GLs (56), OCs (55), and this patient population and help guide relevant treatment plans. NLFs (54). Mid-to-lower facial areas such as chin (44), MLs (43), jawline (38), and cheeks (35) were lower priorities, and perioral Attitudes Toward Improving Facial Aesthetics lines (32), temples (31), and lips (27) were the least likely to be Participant attitudes about facial aesthetic treatments suggested prioritized for treatment. that attitudes and treatment interests may stem from current skin and facial conditions, which are also influenced by an in- For the older participants (ages 45 to 65), under-eye/tear dividual’s ethnic background. A high proportion of responders trough area (70) and CFLs (68) remained a top priority but considered treatments that would make them look less tired sagging underneath the chin/double chin had increased (72%) and address facial wrinkles and lines (68%) and hyper/ importance (67; Figure 5b). hypo-pigmentation (63%); correspondingly, a majority also reported having facial wrinkles (56%), dark circles under the eyes Subsequent priorities were NLFs (61), OCs (59), FHLs (59), and (55%), uneven skin tone/color (47%), and bags under eyes (45%). GLs (56), followed by MLs (49), jawline (44), and chin (42). Mid- Although the greater melanin content in more darkly pigmented to-lower facial areas such as perioral lines (36) and cheeks (33) skin types affords some protection against the immediate ef- were lower priorities, and lips (27) and temples (27) were the fects of UV exposure (eg, sun burn), photodamage still occurs lowest priorities. and results in pigmentary changes (eg, freckling, solar lentigo, and melasma) and increases an individual’s risk factor for post- Awareness of Treatments Options and Future Treatment inflammatory hyperpigmentation (PIH) following inflammation Consideration Rates Do Not orCopy injury.17,18 Melasma and hyperpigmentation are believed to Most participants were aware of the treatments or procedures occur more frequently in Hispanic and Latino ethnicities, with used to enhance skin quality such as microdermabrasionPenalties (89%), as Apply many as half of all Mexican women reporting melasma as- laser skin resurfacing (88%), skin tightening procedures (83%), sociated with pregnancy.19 and chemical peels (79%; Figure 6a), and high consideration rates were observed for those treatments within the next 2 Most Bothersome Facial Areas and Treatment Priorities years (43 - 64%; Figure 6b). Furthermore, all were aware of Bothersome facial areas correlated somewhat with treatment neuromodulators (100%), most were aware of un der chin fat priorities (R2 =.81, data not shown), and any discrepancy (ie, low- reduction (79%) and dermal fillers (70%) products, with 69%, er importance for short, thinning lashes) might represent areas 32%, and 35% consideration rates, respectively. more easily enhanced by the application of cosmetics versus those that are not. The most bothersome facial areas reported Motives and Barriers Impacting Consideration Rate of by all were sagging underneath the chin/double chin, under-eye/ Injectable Treatments tear trough, CFLs, and FHLs. While these all translated to areas Among the 84% (341/401) who would consider an injectable with high treatment priority, differences between the younger treatment, the most common motives were wanting their face and older age groups were observable. Among the more ad- to look good for their age (64%) and to look more youthful (52%; vanced age group (45 to 65-year-olds) sagging underneath the Figure 7). Interestingly, a much smaller proportion agreed with chin/double chin and areas of the lower face (OCs and NLFs) wanting to maintain a competitive edge in the workforce (15%) increased in relative importance in comparison to the younger and to improve dating prospects or relationship prospects age group (30 to 44-year-olds). This result is expected since in- (10%). The top 3 most common barriers cited for not having creasing midface ptosis, which accompanies facial aging, can tried injectable treatments yet were cost (49%), concerns about exacerbate grooves and folds in the lower face and displace safety and side effects (37%), and concerns about injecting a the importance assigned to areas of the upper face (under-eye/ foreign substance into their body (36%; Figure 8). In alignment tear trough, CFLs, and FHLs) at a younger age. Also aligned with with this, among the 16% of participants who would not con- that reasoning is the change in the importance of the marionette sider injectables, the primary barriers included concerns about lines (MLs) and the jawline, which were scored as lower priori- safety and side effects (66%), injecting a foreign substance into ties by the younger group but increased in importance in the their body (52%), and concern that their face would not look older group. natural (34%) (data not shown). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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FIGURE 5A AND 5B. Treatment priorities based on the relative importance of each facial area.

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FIGURE 7. Motives for treatment among those who would consider facial injectables.

FIGURE 8. Barriers to treatment among those who would consider facial injectables.

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Overall, areas of the upper face (under-eye/tear trough and increasing skin laxity can be associated with increased severity CFLs) were assigned greater relative importance than the lower of tear troughs, which are characterized by a concavity sepa- face. Although this is expected as areas of the upper face tend rating the lower eyelid from the cheek.22,23 Therefore, this may to reveal more of the initial signs of aging, it is important to imply that dark circles under the eyes is a common phenom- note that participants were not given the option to differentiate enon in the Hispanic/Latino population, and may represent key between under-eye and tear trough. The cause of dark under-eye aesthetic concerns for this patient population. circles are multifactorial and could be attributable to periocular inflammation, blood stasis, uneven pigmentation, or may be the Mestizo or Hispanic individuals with Native American origins result of shadowing caused by tear trough deformity.20,21 With share greater craniofacial similarity with Asians than with aging, the orbital bone resorption, loss of midface volume, and whites.24 In this light, it should be considered that some His- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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panic/Latino patients may also share some of the facial aging The strengths of this study include a large participant population, patterns observed with the Asian ethnicities.25 While both His- a cross-sectional design, and the use of MaxDiff methodology panic and Asian facial shape can be characterized as broad (wide to minimize scale bias, as compare to using paired compari- bizygomatic and bigonial distance) with heavier malar fat pads, sons. The data collected and presented here characterizes the certain Asian ethnicities also tend to have less anteromedial priorities and treatment awareness among a diverse popula- midface projection, which may contribute to the gravitational tion of Hispanic/Latino Americans naïve to facial injectable use descent that exposes the tear trough.26,27 In another similarity and helps clinicians to understand this population and to plan with Asians, aging of the Mestizo face may include an increase treatments accordingly. Two case examples of Hispanic/Latino in the forehead-glabella supraorbital prominence contributing patients treated by the authors are presented in Figure 9 and to superior concavity and shadowing of the forehead.28 Orbital Figure 10. bone resorption also contributes to descent of the lateral third of the eye brow, and for Mestizo individuals, heaviness of the brow and hooding of the eyelids may also be more pronounced due to a thicker, heavier skin type.29,30 FIGURE 9. Facial rejuvenation using injectable treatments with a patient representative of a 30 to 44-year-old age range. Left, pre- The high importance level and priority assigned to sagging treatment. Center, treatment diagram showing placement of hyaluronic underneath the chin/double chin in both older and younger acid filler (yellow) (2.1 mL total) for upper and lower eyelids, midface, participants may reflect gravity-induced changes associated and onabotulinumtoxinA (45 U total) for glabellar and crow’s feet lines, masseter, depressor anguli oris (DAO), and chin. Right, approximately 2 with a heavier, thicker skin type in the Hispanic/Latino popula- weeks post-treatment. Patient photos courtesy of Dr. JR Montes. tion. This is in contrast to descent due to increased skin laxity accompanied by jowling that is observed more often in Cauca- sians.7 Other anatomical contributors may include a recessed chin position, a facial characteristic observed more often in the Asian and Hispanic/Latino ethnicities that may exacerbate the appearance of the submental fat.26,27 It is, however, important to note that participants were not able to differentiate between “sagging underneath the chin” and “double chin.” BodyDo mass Not Copy index (BMI) can contribute more significantly to the appearance of submental fullness than skin laxity or sagging. PenaltiesAs BMI was Apply not measured in this study, we cannot determine if the high prevalence of sagging underneath the chin/double chin in the Hispanic/Latino population may be a consequence of differences in the BMI in this group. FIGURE 10. Facial rejuvenation using injectable treatment with a patient representative of a 45 to 65-year-old age range. Left, pre-treatment. Consideration Rates for Future Treatments Including Inject- Center, treatment diagram showing placement of hyaluronic acid filler (yellow) (4 mL total) for upper and lower eyelids, temples, midface, ables marionette lines, and jawline; deoxycholic acid (orange) (2 mL total) for Although there appeared to be a high awareness of injectable submental region; and onabotulinumtoxinA (52.5 U total) for forehead, treatments involving under chin fat reduction and dermal fill- glabellar, and crow’s feet lines, oral commissures, depressor anguli ers, they corresponded with lower consideration rates than oris (DAO), and mentum. Right, approximately 2 months post-treatment. other minimally-invasive treatments such as microdermabra- Patient photos courtesy of Dr. JR Montes. sion, chemical peels, and laser skin resurfacing. Interestingly, although underneath the chin area was a high priority and 79% of participants were aware of the injectable treatments available for this area, only 35% would consider having this treatment. This observation may reflect a gap in patient knowledge. There was a higher consideration rate for neuromodulators compared with all other minimally-invasive treatment options. This observation agrees with previous studies highlighting the aesthetic preferences of Hispanic/Latino patients and is exemplified by the fact that this population makes up the greatest proportion of ethnic minority patients receiving treatment with neuromodulators.3 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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fillers?Plast Reconstr Surg Glob Open. 2016;4:e842. 26. Cobo R, García CA. Aesthetic surgery for the Mestizo/Hispanic patient: special considerations. Facial Plast Surg. 2010;26(2):164-713. 2 7. Liew S, Wu WT, Chan HH, Ho WW, et al. Consensus on changing trends, attitudes, and concepts of Asian beauty. Aesthetic Plast Surg. 2016;40(2):193-201. 28. Kang GC, Hsiao YC, Huang JJ, Chen JP, et al. Aesthetic Durable forehead contouring in asians with fat grafting and botulinum toxin. Ann Plast Surg. 2019;82(1S Suppl 1):S59-S65. 29. Molina F. Aesthetic facial osteotomies in Latin Americans. Clin Plast Surg. 2007;34(3):e31-36. 30. Plowes Hernandez O, Montes Bracchini JJ. Management of the heavy brows: long-term surgical options. facial plast surg. 2018;34(1):36-42.

AUTHOR CORRESPONDENCE

Sabrina Fabi MD E-mail:...... ……...... [email protected]

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To Treat or Not To Treat: Systemic Therapy Considerations for Psoriasis in the Setting of Malignancy | Dr. David Rosmarin

I’m a biologic girl in a biologic world...or so I think myself and never say out loud when reviewing therpeutic options for moderate to severe psoriasis. We are so fortunate to have so many wonderful options, however certain clinica scenarios may limit our ability to capitalize on said armament mostly due to limited experience and data. Enter previous malignancy - in most phase 3 studies these patients are weeded out or the history of malignancy must be at least 5 years prior to entry. So what to do? Our colleagues at Tufts Medical Center asked this very question. Tune in to hear what Dr. David Rosmarin, Assistant Professor of Dermatology and Residency Program Director learned from performing a retrospective chart review and how his work and his experience guides his clinical decision making when managing psoriasis. Don’t flake (or is it scale?)....check it out.

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CONCLUSIONS development of this article. This study was funded by Allergan, Hispanic/Latino Americans are a growing patient population for Inc. Writing and editorial support for this article was provided by aesthetic practitioners. As much of the literature pertaining to Erika von Grote, PhD, Allergan plc, Irvine, CA. The authors would facial aesthetic rejuvenation is focused on Caucasian women, like to thank Garrett T. Shumate of Allergan plc for his invaluable there is a need to explore the facial aging process among His- assistance in the interpretation of data and in the development panic/Latino women and identify the attitudes that factor into of this manuscript their consideration of the different treatments. Compared to other racial/ethnic groups, Hispanic/Latino women comprise a REFERENCES diverse racial and ethnic background with signs of facial aging 1. 2008 ASAPS Statistics: Complete Plastic Surgery Statistics Report. Ameri- can Society for Aesthetic Plastic Surgery. Available from: http://www.sur- that may share common patterns and characteristic of other gery.org/sites/default/files/2008stats.pdf.Accessed October 2018. racial/ethnic groups, but the practitioner will need to keenly 2. 2017 ASAPS Statistics: Complete Plastic Surgery Statistics Report. American identify them. Society for Aesthetic Plastic Surgery. Available from: http://www.surgery. org/sites/default/files/2017stats.pdf.Accessed October 2018. 3. https://www.plasticsurgery.org/news/plastic-surgery-statistics. Accessed This survey highlighted key aesthetic concerns common among October 2018. 4. Bertoni B, Budowle B, Sans M, Barton SA, et al. Admixture in Hispanics: the Hispanic/Latino American women and revealed the most distribution of ancestral population contributions in the continental United bothersome areas for this population as the under-eye/tear States. Hum. Biol. 2003;75:1-11. 5. Talakoub L, Wesley NO. Differences in perceptions of beauty and cos- trough area, CFLs, FHLs, and the submental area. With ad- metic procedures performed in ethnic patients. Semin Cutan Med Surg. vancing age, priorities shifted slightly from upper facial areas 2009;28(2):115-129. to include more of the mid and lower facial areas. In addition, 6. Davis EC, Callender VD. Aesthetic dermatology for aging ethnic skin. Derma- tol Surg. 2011;37(7):901-917. the discrepancy between the high level of aesthetic concern 7. Alexis AF, Alam M. Racial and ethnic differences in skin aging: implications for underneath the chin area and low consideration rate for the for treatment with soft tissue fillers.J Drugs Dermatol. 2012;11(8):s30-s32; discussion s2. injectable treatments for this suggest there may be opportuni- 8. Vashi NA, de Castro Maymone MB, Kundu RV. Aging differences in ethnic ties to educate patients regarding available treatments that may skin. J Clin Aesthet Dermatol. 2016;9(1):31-38. 9. Cobo R. Trends in facial plastic surgery in Latin America. Facial Plast Surg. help them achieve aesthetic goals. 2013;29(3):149-53. 10. Broer PN, Juran S, Liu YJ, Weichman K, et al. The impact of geographic, eth- Among participants who would not consider injectables, the nic, and demographic dynamics on the perception of beauty. J Craniofac Surg. 2014;25(2):e157-161. main reasons cited were concerns about safety/sideDo effects, Not 11.Copy Montes JR. Ethnic and Gender Considerations in the Use of Facial Inject- concerns about putting a foreign substance into their body, ables: Latino Patients. Plast Reconstr Surg. 2015;136(5 Suppl):32S-39S. 12. Boyd C, Chui A, Montes JR, Narurkar V, et al. Differential facial aesthetic and concern that their face will not look natural. EducatingPenalties and Applytreatment considerations for skin of color populations: African American, counseling patients on these barriers may increase patient ac- Asian and Hispanic. Poster presented at: The Skin of Color Seminar Series; May, 2018; New York, NY. ceptability of a broader range of treatment options and comfort 13. Fitzpatrick TB. The validity and practicality of sun reactive skin types I-VI. Arch them in knowing there is a reinforcement on “naturalness” in Dermatol. 1988;124:869-871. medical aesthetic treatments. By lessening the barriers to in- 14. https://blog.skincancer.org/2018/09/13/are-you-at-risk-for-skin-cancer/As- sessed February 2019. jectables, patients may ultimately achieve a more impactful 15. Ho BK, Robinson JK. Color bar tool for skin type self-identification: A cross- and longer lasting treatment results. Also, discussing treatment sectional study. J Am Acad Dermatol. 2015;73(2):312-3.e1. 16. The MaxDiff System Technical Paper, Version 8. Sawtooth Software strategies that address existing pigmentary issues and mini- 2015;Available at: URL: http://www.sawtoothsoftware.com/support/techni- mize the risk of PIH may help strengthen the patient-practitioner cal-papers/maxdiff-best-worst-scaling/maxdiff-technical-paper-2013. 1 7. Del Bino S, Duval C, Bernerd F. Clinical and biological characterization of skin bond. pigmentation diversity and its consequences on UV impact. Int J Mol Sci. 2018;19(9). pii: E2668. With the observations presented here, this study hopes to con- 18. de Rigal J, Des Mazis I, Diridollou S, Querleux B, et al. The effect of age on skin color and color heterogeneity in four ethnic groups. Skin Res Technol. tribute to a first step in providing practitioners with a more 2010;16(2):168-178. patient-centric and culturally-competent approach to their treat- 19. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2003; 21:689- 697. ment of Hispanic/Latino facial aesthetic patients. 20. Friedmann DP, Goldman MP. Dark circles: etiology and management options. Clin Plast Surg. 2015;42(1):33-50. DISCLOSURES 2 1. Matsui MS, Schalka S, Vanderover G, Fthenakis CG, et al. Physiological and lifestyle factors contributing to risk and severity of peri-orbital dark circles in S Fabi serves as a consultant, researcher, and advisory board the Brazilian population. An Bras Dermatol. 2015;90(4):494-503. member for Allergan plc. JR Montes serves as a speaker and 22. Kahn DM, Shaw RB Jr. Aging of the bony orbit: a three-dimensional com- puted tomographic study. Aesthet Surg J. 2008;28(3):258-264. trainer for Allergan plc. SB Aguilera serves as a speaker and 23. Glaser DA, Lambros V, Kolodziejczyk J, et al. Relationship between midface trainer for Allergan plc. V Bucay serves as a speaker and con- volume deficits and the appearance of tear troughs and nasolabial folds.Der- matol Surg. 2018;44(12):1547-1554. sultant for Allergan plc. S Manson Brown and N Ashourian are 24. Dudzik B, Jantz RL. Misclassifications of Hispanics Using Fordisc 3.1: com- employees of Allergan plc and may own stock/options in the paring cranial morphology in Asian and Hispanic populations. J Forensic Sci. 2016;61(5):1311-1318. company. The opinions expressed in this article are those of 25. Oranges CM, Gohritz A, Haug M, Harder Y, Schaefer DJ. Universal and eth- the authors. The authors received no honoraria related to the nic-specific considerations on facial rejuvenation: where do you inject your Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

July 2019 633 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Understanding the Female Asian American Facial Aesthetic Patient Annie Chiu MD,a Kavita Mariwalla MD,b Andrea Hui-Austin MD,c Vic Narurkar MD,d† Carola de la Guardia PhDe ªThe Derm Institute, North Redondo Beach, CA BMariwalla Dermatology, West Islip, NY cBay Area Cosmetic Dermatology, San Francisco, CA DBay Area Laser Institute, San Francisco, CA †Deceased prior to journal submission EAllergan plc, Marlow, UK

ABSTRACT

Background: As facial aesthetic procedures have become more widely accepted, the racial and ethnic diversity of aesthetic patient populations has increased. Asian Americans represent a growing segment of this population and have specific aesthetic concerns that should be differentiated from the broader Caucasian population. Objective: An online study was designed to survey facial aesthetic concerns, treatment priorities, and future treatment considerations among a US-based population of Asian American women. Materials and Methods: A total of 403 participants ages 30 to 65 years reported perspectives on facial aging, current facial conditions, most bothersome facial areas, most/least likely to be treated first, awareness of treatment options and consideration rates, and motives/barriers impacting the consideration rate of injectable treatments. Results: Treatment interests reflected predominant issues; uneven skin tone, wrinkles, and sun damage. Most bothersome facial areas included the periorbital area, forehead, and submental area, and also among areas designated as most likely to treat first. The majority of participants would consider injectables. However, safety/side effects, cost, and concerns about not looking natural were primary barriers. Conclusion: Understanding the aesthetic concerns andDo priorities Not specific Copy to Asian American women may help guide treatment plans more aligned with the goals and expectations of thisPenalties patient population. Apply J Drugs Dermatol. 2019;18(7):633-641.

INTRODUCTION s the number of aesthetic procedures increases, it is all cosmetic procedures performed in the US in 2017.1 Similar important for physicians to understand who comprises to this trend in aesthetics, Asian patients primarily seek non- the expanding population seeking such treatments. In surgical, minimally-invasive treatment modalities, and express A 3 recent years it is clear that as procedures become more widely concerns for maintaining a natural appearance. accepted and commonplace, the patient population seeking them has also grown in terms of its racial, ethnic, and cultural The descriptor “Asian American” encompasses a diverse diversity. While many published treatment algorithms in the US population with ethnic origins in East Asia (eg, China, Korea, are suitable for Caucasian patients, there are far fewer that fo- Japan, Taiwan), South Asia (eg, Bangladesh, Nepal, Pakistan, cus on the aesthetic concerns and needs specific to the Asian Sri Lanka), and Southeast Asia (eg, Thailand, Singapore, In- patient. In addition, very little data exists focusing on Asian donesia, Philippines). Among this diverse population, there is Americans which is a broad community of people representing also a wide range of facial morphologies and Fitzpatrick Skin several countries. Phototypes (FSPs).4 Importantly, variations in skin type and underlying structural anatomy impact the rate, pattern, and Over the past decade, the total number of Asian patients who severity of facial aging among different ethnicities.5-8 How- received cosmetic procedures in the US increased by 33% with ever, social and cultural influences ultimately have a defining a growing number of younger patients (ie, 18 to 40 years of influence in perceptions of beauty and motivations for seek- age) among them.1-3 A predominance of minimally-invasive fa- ing treatment.9-11 For the aesthetic physician, understanding cial aesthetic treatments has grown to represent at least 90% of not only the structural and cutaneous components of aging Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

634 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

but also the treatment preferences and motivations relevant to FIGURE 1. Diagram used to select most bothersome facial areas and Asian American women may help guide treatment plans more treatment priorities. aligned with the goals and expectations of this patient population.

The current study surveyed Asian American women who were aesthetically-oriented but naïve to facial injectable treatments with the objective to characterize their facial aesthetic concerns and treatment priorities. Evaluations included: 1) attitudes toward signs of facial aging and existing facial concerns; 2) facial areas that are most bothersome; 3) facial areas most/least likely to represent a priority in a future aesthetic treatment plan; 4) awareness of available aesthetic treatments and their consideration rates; and 5) motives/barriers factoring into their consideration of injectable treatments. The data presented here is a segment of a larger study consisting of 1205 women which considered a higher treatment priority relative to those areas also included African American and Hispanic/Latino American ranked below the average. Awareness of aesthetic procedures, participants.12 future treatment considerations, and motives and barriers impacting the consideration rate of injectable treatments were METHODS assessed by questionnaire. Participants and Study Design Participants living in the US were recruited through online river Data Analysis sampling (banner ads, pop-up ads, instant capture promotions) Max Diff analyses and analysis for correlation between bother- by the Lieberman Research Worldwide (LRW) agency between some facial areas and their treatment priorities were conducted March and April 2016. Primary inclusion criteria were 1) females by the LRW agency and presented descriptively by percent or ages 30 to 65 years living in the US; 2) aesthetically-oriented, by average. as determined by level of agreement on an aestheticDo orienta Not- Copy tion questionnaire; 3) household annual income >$50,000 RESULTS with some discretionary spending flexibility; 4) naïvePenalties to facial Participants Apply injectable treatments; 5) aware of BOTOX® Cosmetic; and 6) The majority of the 403 participants included in the study were considering having a medical facial aesthetic treatment within 30 to 44 years old (57%), born outside of the US (55%), married the next 2 years. (82%), with household incomes > $75,000 (74%), an average spending of < $250/month on products or services for facial Participants identified their most predominant ethnic back- aesthetics (79%), and had spent ≥ $250 on a single medical fa- ground as one of the following: Asian Indian, Chinese, Filipino, cial treatment (55%) (Table 1). The majority were categorized Japanese, Korean, Vietnamese, American Indian/Alaskan Na- as FSP III or IV (89%) and a large proportion identified with a tive, Native Hawaiian, or other Pacific Islander (ie, Samoan, Southeast Asian (Asian Indian, Filipino, Vietnamese, n = 147) or Guamanian, or Chamorro). Participant’s FSP was categorized Chinese (n = 119) ethnic background (Table 2). as I through VI using a questionnaire adapted from the Skin Cancer Foundation website in combination with their selection Attitudes Toward Improving Facial Aesthetics and Existing of a color that most represented their natural skin tone from a Facial Concerns range of 11 skin codes (colors).13-15 Most agreed with wanting their face to look good for their age (86%), cared about improving their facial appearance (78%), Measures and Analysis were interested in treatments that addressed hyper/hypo-pig- The study design and questionnaire format have been previ- mentation (72%), facial wrinkles and lines (64%) and treatments ously described.16 Briefly, attitudes toward improving facial that would make them look less tired (63%) (Figure 2). Uneven aesthetics and existing concerns were assessed by question- skin tone/color (64%), facial wrinkles (50%), and sun damage naire. Most bothersome facial areas and treatment priorities (48%) were the most frequently-reported facial concerns (Fig- were assessed using a 15-point facial diagram (Figure 1) and ure 3). a Maximum Difference (MaxDiff) ranking methodology was used to identify the relative importance of each area.17 MaxDiff Most Bothersome Facial Areas scores were represented by a “relative importance value”. Areas Areas of the upper face were the most bothersome and includ- ranked above average indicated greater importance and were ed the under-eye/tear trough area (32%), crow’s feet lines (CFLs) Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

635 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

Age Fitzpatrick Skin Phototype

30 - 44 57 I - II 3 45 - 65 43 III - IV 89

US Region of Current Residence V - VI 8

Northeast 21 Ethnic Background South 20 Chinese 30 Midwest 13 Japanese 16 West 46 Asian Indian 16 Born in the US 45 Filipino 14 Marital Status Korean 10 Married 82 Vietnamese 7 * Single (Never Married) 14 Other Asian 7 Separated/Divorced/Widowed 4 % Fitzpatrick Skin Phototype Among Different Ethnic Backgrounds Education Fitzpatrick Skin Phototype Highschool or Less 1 Ethnic Background I - II III - IV V - VI Some College or College Graduate 64 Chinese 5 90 5 Post Graduate 35 Japanese 5 85 10 Household Income Asian Indian -- 86 14 Less than $ 75,000 26 Filipino -- 89 11 $ 75,000 - $ 150,000 47 Do Not CopyKorean 5 90 5 $ 150,000 or More 27 Vietnamese -- 100 -- Monthly Spend on Products and Services for Facial AestheticsPenalties* Apply Other Asian* 5 92 3 Less than $ 250 79 *Includes American Indian, Alaskan Native, Native Hawaiian or other Pacific Islander $ 250 or More 20 (including Samoan, Guamanian, or Chamorro) Maximum Spend on a Single Medical Facial Treatment Less than $ 250 45 $ 250 or More 55

*1% preferred not to answer

636 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

FIGURE 3. Existing facial concerns.

FIGURE 4. Most bothersome facial areas.

Do Not Copy Penalties Apply

(29%), and forehead lines (FHLs) (29%) (Figure 4). These were (61), and GLs (59), followed by NLFs (55), and OCs (54). Areas of followed by sagging underneath the chin/double chin (26%), lower relative importance included MLs (42), chin (37), jawline nasolabial folds (NLFs) (23%), glabellar lines (GLs) (21%), mari- (36), and cheeks (35). Perioral lines (32), temples (31), and lips onette lines (MLs) (20%), and oral commissures (OCs) (18%). (26) were among the least important. Among the older group Areas selected with less frequency were the chin (16%), cheeks (ages 45 to 65) (Figure 5b), the under-eye/tear trough area (77) (14%), jawline (13%), perioral lines (12%), temples (11%), and and CFLs (70) were also selected as highest priorities followed lips (10%). by sagging underneath the chin/double chin (62), FHLs (62), and NLFs (61), GLs (56), OCs (56), and MLs (52). Areas of lower Treatment Priorities relative importance included jawline (39), chin (38), cheeks (34). The relative importance ranking of each area ranged from 19 to Perioral lines (29), temples (27), and lips (19). 77 across the 15 facial areas; overall bothersome facial areas tended to correlate with the treatment priorities (R2 =.82, data Awareness of Treatments Options and Future Treatment not shown). Among the younger group (ages 30 to 44) (Figure Consideration Rates 5a), the facial areas of highest priority (represented by relative A high proportion of participants were aware of surgical pro- importance values above the average) included the under-eye/ cedures (facial plastic surgery and liposuction, 93-95%) (Figure tear trough area (75) and CFLs (75). Other areas of high impor- 6a) which corresponded with lower consideration rates com- tance were FHLs (66), sagging underneath the chin/double chin pared to minimally-invasive treatments (Figure 6b). A high Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

637 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

FIGURE 5A AND 5B. Treatment priorities based on the relative importance of each facial area.

638 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

FIGURE 7. Motives for treatment among those who would consider facial injectables.

FIGURE 8. Barriers to treatment among those who would consider facial injectables.

Do Not Copy Penalties Apply

proportion were aware of treatments to enhance skin quality Motives and Barriers Impacting Consideration Rate of In- such as skin tightening procedures (88%), laser skin resurfacing jectable Treatments (87%), microdermabrasion (85%), and chemical peels (84%), Among participants who would consider injectables (74%, which also corresponded with high treatment consideration 300/403), a high proportion wanted to look good for their age rates for those kinds of procedures (37 - 64%). Regarding inject- (68%) and look more youthful (55%) (Figure 7). Twenty-three able treatments, all or most were aware of neuromodulators percent agreed that they would consider injectables because (100%), under chin fat reduction (76%) and dermal fillers (72%), they have seen, read, or heard positives things about them and were reflected by future consideration rates of 33%, 20%, and there is more information now available about those treat- and 18%, respectively. ments (22%). A smaller proportion was motivated by wanting Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

639 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

to maintain a competitive edge in the workforce (12%) or im- FIGURE 9. Facial rejuvenation using injectable treatments with a prove dating prospects or relationships (7%). patient representative of a 30 to 44-year-old age range. Left, pre- treatment. Center, treatment diagram showing placement of hyaluronic The top 3 barriers for not having tried injectable treatments yet acid filler (yellow) for lower tear troughs (0.15 mL total), medial malar region (0.5 mL total), pyriform fossa (0.2 mL total), zygoma (0.4 mL total), cited concerns about safety and side effects (57%), cost (43%), nasal bridge (0.5 mL total), jawline and mentum (1.0 mL total). Right, and concerns about their face not looking natural (38%) (Figure immediately post-treatment. Patient photos courtesy of Dr. A Chiu. 8). Among the 26% who would not consider injectables, the top 3 reasons included 1) concerns about injecting a foreign substance into their body (60%), 2) concerns about safety and side effects (55%), and 3) dislike of needles (32%) (data not shown). DISCUSSION As facial aging occurs, bone resorption, fat loss, and increasing laxity of soft tissues accentuate the effects of gravity and the appearance of wrinkles and folds. While these elements of aging affect everyone, it is important to keep anatomic differences between races/ethnicities intact so that when corrections are FIGURE 10. Festoon correction using injectable treatment with a discussed with patients, they are not being made to appear ho- patient representative of a 45 to 65-year-old age range. Left, pre- mogenous within the general population. Whether or not signs treatment. Center, treatment diagram showing placement of hyaluronic of facial aging are bothersome to an individual and prompts acid filler (yellow) (1.0 mL total) for medial midface and tear troughs. them to seek treatment is heavily dependent on their social and Right, immediately post-treatment. Patient photos courtesy of Dr. A Hui cultural ideals of beauty and how motivated they are to main- Austin. tain or improve their facial aesthetics.

Attitudes Toward Improving Facial Aesthetics Not surprisingly, the data showed that attitudes toward facial aesthetics were aligned with facial concerns. Notably,Do a high Not Copy proportion would consider treatments for hyper/hypo-pigmentation (72%) which reflected a high incidence of unevenPenalties skin tone/ Apply color (64%) and facial sun damage (48%). This data is expected the application of cosmetics versus those that are more struc- given that dyschromia has may be more apparent in FSPs III tural. Regardless of age, Asian participants were most bothered through VI, and the majority of these participants (89%) were by areas of the upper face which included the under-eye/tear in the FSP III and IV categories. An advantage that comes with trough area, CFLs, and FHLs. While under-eye/tear trough, CFLs, greater melanin content (primary determinant of pigmentation) and FHLs were also ranked among the highest treatment priority is added protection against the immediate effects of UV expo- for both age groups, areas of the mid and lower face (NLFs, OCs, sure (eg, sunburn), but photodamage still occurs and is more and MLs) were ranked with higher relative importance among obvious over time after it has caused pigmentary disorders (eg, the older group. This shift in importance is also expected as it re- freckling, solar lentigo, melasma, and seborrheic keratosis).18,19 flects the increasing structural changes and midface ptosis that Greater melanin content also increases an individual’s predis- accompanies facial aging. Furthermore, anatomical characteris- position toward a post-inflammatory hyperpigmentation (PIH) tics shared by many Asian ethnicities, which include a weaker reaction following inflammation or injury.19 While correcting un- skeletal facial framework, a wide zygomaticomalar region, less even skin tone may represent a concern for many individuals, projection of the anteromedial midface, and heavier malar fat a high level of interest among Asian participants, although pre- pads, provide no support or resistance to the midface ptosis that dominantly younger (57% ages 30 - 44) may also reflect a strong exposes the tear trough and accentuate redundant skin (folds) in cultural aesthetic standard to preserve and maintain clear and the lower face.3,21-23 even-toned facial skin.9,11,20 It is important to note that while these observations highlight Most Bothersome Facial Areas and Treatment Priorities this as a key treatment area for this patient population, par- Bothersome facial areas tended to correlate with treatment pri- ticipants were not given the option to differentiate this area orities (R2 =.82, data not shown) although some bothersome specifically as “under-eye”, under-eye bags, and/or “tear trough”. areas translated to lower priorities (eg, short, thinning lashes). The under-eye area may involve dark circles which includes a Discrepancies between bothersome areas and treatment priori- vascular or pigmentary basis, distinct from a tear trough.24 Ma- ties might reflect the difference between areas amendable with lar ptosis can contribute to formation of under-eye bags (orbital Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

640 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

fat pad pseudo-herniation) and tear trough depression; a result ate between “sagging underneath the chin” and “double chin”. which is further exacerbated by increasing infraorbital skin lax- Body mass index likely plays more of a role in the appearance ity and orbital bone loss.24,25 Because these fat compartments of submental fullness than laxity or sagging. Regardless of the are no longer forming a smooth plane, surface shadowing be- contributing factors, these observations highlight that softening comes more obvious. of the cervicomental angle is a strong enough aesthetic concern among Asian women to motivate a desire for treatment and Surprisingly, the treatment priority for CFLs was high among may represent another key treatment area. the younger group and declined in importance for the older group, although this decline may be the result of shifting priori- The strengths of the study included such factors as a large ties as age-related changes in the mid and lower face become participant population, a cross-sectional design, and use of increasingly more bothersome. Another reason suggested for the MaxDiff methodology to minimize scale bias versus using this, observed in practice by contributing authors, is that their paired comparisons. The value in these data is the Asian aes- Asian patients associate a minimal amount of CFLs with a more thetic perspective with the potential influence of US or Western natural expressive appearance. The initial appearance and se- cultural standards, as 45% were US-born. As the Asian Ameri- verity of CFLs result from dynamic movement of the orbicularis can population becomes more multicultural, such perspectives oculi muscle which can also be exacerbated by accumulated may be more relevant than those reporting on traditional aes- photodamage. A classification of CFLs delineates them as up- thetic standards observed by Asians residing in their country of per, lower, and bidirectional, with the bidirectional type usually origin. Two case examples of Asian American patients treated by only becoming more common as people age.26,27 However, in the authors are presented in Figure 9 and Figure 10. comparisons with a Caucasian population, the presence of bidirectional CFLs has been observed in a higher proportion among The study questionnaires were designed to suit a racially/eth- Asians beginning at a younger age.26 The high priority for CFLs nically diverse group participants which limited the number among the younger group of participants may be aligned with of facial areas evaluated to those most common among all. In such a predisposition, but more so highlights that CFLs may doing so, several key treatment areas that are predominant in represent another key treatment area among Asian women re- Asia (ie, nose and masseters) where not evaluated in this study. gardless of age. Similar to CFLs, a decline in the importance of Future studies should include evaluation of these 2 areas in ad- FHLs among the older group may simply indicate a shiftDo in prior Not- ditionCopy to a more granular evaluation of the key treatment areas, ities, as they are displaced by areas of the mid (NLFs) and lower under-eye and submental area, highlighted here. (MLs) facial areas which increased in importance. However,Penalties the Apply forehead area is an important aesthetic unit by East Asian beau- CONCLUSIONS ty standards, and the impact of aging may include an increase in Asian Americans are a growing segment of the patient popula- forehead-glabella supraorbital prominence which contributes to tion for aesthetic physicians. Since much of the literature and superior concavity and shadowing of the forehead.28 instructional training in injectables has been focused on the aging patterns of Caucasian women, there is a need to evaluate A high priority was also given to the treatment of sagging un- how this process occurs among Asian women of varying eth- derneath the chin/double chin and was of similar importance nicities and in what way it may motivate them to seek treatment. among both age groups. While aging of the submental area isn’t In this survey of 403 Asian American women, aged 30 to 65, the defined by race or ethnicity, the effects of aging on the submen- facial areas ranked with the highest importance and priority in- tal area have been suggested to be more pronounced in more cluded the under-eye/tear trough, CFLs, FHLs, and the submental heavily pigmented skin types. This is proposed to be due to the areas with priorities shifting slightly from upper facial lines to gravity-induced descent of a thicker and heavier skin type op- mid and lower facial folds and creases with advancing age. posed to descent due to increased skin laxity (accompanied by more jowling) in thinner, less pigmented skin types.29 It may also Although awareness of injectable treatments was high, and the may be due to the fact that initial signs aging for photo-protect- majority would consider having them, they were secondary to ed skin types are volumetric and structural versus those that are the skin-focused treatments (eg, skin tightening procedures, la- more cutaneous (eg, fine lines and wrinkles) for less pigmented, ser skin resurfacing, microdermabrasion, and chemical peels). less protected skin types. Other anatomical contributors may Among participants who would consider injectable treatments include a more recessed chin position with greater posterior but haven’t tried them yet, the greatest barriers were concerns angulation of the lower mentum, a characteristic observable about safety and side effects, cost, and unnatural appearance. in varying degrees among some Asian ethnicities.7,30 This lack Among participants who would not consider injectables, the of skeletal support against tissue descent may exacerbate the main reasons cited were concerns about putting a foreign sub- appearance of submental fat.30,31 However, it is important to stance into their body, safety and side effects, and a dislike of note that participants were not given the option to differenti- needles. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

641 Journal of Drugs in Dermatology A. Chiu, K. Mariwalla, A. Hui-Austin, et al July 2019 • Volume 18 • Issue 7

12. Boyd C, Chui A, Montes JR, Narurkar V, et al. Differential facial aesthetic Educating and counseling patients with these barriers in mind treatment considerations for skin of color populations: African American, may increase patient acceptability of a broader range of treat- Asian and Hispanic. Poster presented at: The Skin of Color Seminar Series; May, 2018; New York, NY. ment options, which will help them achieve more impactful and 13. Fitzpatrick TB. The validity and practicality of sun reactive skin types I-VI. Arch longer lasting treatment results, and comfort them in expressing Dermatol. 1988;124:869-871. there is a growing reinforcement of maintaining “naturalness” 14. https://blog.skincancer.org/2018/09/13/are-you-at-risk-for-skin-cancer/As- sessed February 2019. with all medical aesthetic treatments. Ultimately, the practitio- 15. Ho BK, Robinson JK. Color bar tool for skin type self-identification: A cross- ner’s best approach for introducing new aesthetic treatments sectional study. J Am Acad Dermatol. 2015;73(2):312-3.e1. 16. Fabi S, Montes JR, Aguilera SB, Bucay V, Manson S, Ashourian N. Under- may be by starting with primary skin quality concerns using standing the female Hispanic/Latino American facial aesthetic patient. treatment strategies that minimize the risk of PIH and address J Drugs Dermatol. 2019;18(7):623. 1 7. The MaxDiff System Technical Paper, Version 8. Sawtooth Software existing dyschromia and sun damage. This strategy may help 2015;Available at: URL: http://www.sawtoothsoftware.com/support/techni- strengthen the patient-practitioner bond and overcome barriers cal-papers/maxdiff-best-worst-scaling/maxdiff-technical-paper-2013. with their Asian American patients. This study intends to pro- 18. de Rigal J, Des Mazis I, Diridollou S, Querleux B, et al. The effect of age on skin color and color heterogeneity in four ethnic groups. Skin Res Technol. vide physicians with advice for achieving a more patient-centric 2010;16(2):168-78. approach in their treatment of Asian American facial aesthetic 19. Yu SS, Grekin RC. Aesthetic analysis of Asian skin. Facial Plast Surg Clin North Am. 2007;15(3):361-5. patients. 20. Galzote C, Estanislao R, Suero MO, Khaiat A, et al. Characterization of facial skin of various Asian populations through visual and non-invasive instru- DISCLOSURE mental evaluations: influence of age and skincare habits. Skin Res Technol. 2013;19(4):454-65. A Chiu serves as a consultant and clinical investigator for Al- 2 1. Sykes JM. Management of the aging face in the Asian patient. Facial Plast Surg Clin North Am. 2007;15(3):353-360. lergan plc. K Mariwalla has served on an advisory board for 22. Oranges CM, Gohritz A, Haug M, Harder Y, Schaefer DJ. Universal and eth- Allergan plc. A Hui-Austin serves as a consultant for Allergan nic-specific considerations on facial rejuvenation: where do you inject your plc. V Narurkar has served as a consultant and clinical investiga- fillers? Plast Reconstr Surg Glob Open. 2016;4:e842. 23. Kapoor KM, Chatrath V, Anand C, Shetty R, et al. Consensus recommenda- tor for Allergan plc. C de la Guardia is an employee of Allergan tions for treatment strategies in indians using botulinum toxin and hyaluronic plc and may own stock/options in the company. The opinions acid fillers.Plast Reconstr Surg Glob Open. 2017;5(12):e1574. 24. Friedmann DP, Goldman MP. Dark circles: etiology and management options. expressed in this article are those of the authors. The authors Clin Plast Surg. 2015;42(1):33-50. received no honoraria related to the development of this article. 25. Glaser DA, Lambros V, Kolodziejczyk J, Magyar A, et al. Relationship be- This study was funded by Allergan, Inc. Writing and editorial tween midface volume deficits and the appearance of tear troughs and nasolabial folds. Dermatol Surg. 2018;44(12):1547-54. support for this article was provided by Erika von Grote,Do PhD, Not 26.Copy Kane MA. Classification of crow’s feet patterns among Caucasian women: Allergan plc, Irvine, CA. The authors would like to thank Garrett the key to individualizing treatment. Plast Reconstr Surg. 2003;112(Suppl 5):33S. T. Shumate of Allergan plc for his invaluable assistancePenalties in the 2 7.Apply Park DH, Han DG, Shim JS, Lee YJ, et al. Analysis of the patterns of lateral interpretation of data and in the development of this manuscript canthal rhytids and reference for botulinum toxin treatment in orientals. Aes- thetic Plast Surg. 2012 Oct;36(5):1211-5. 28. Kang GC, Hsiao YC, Huang JJ, Chen JP, et al. Aesthetic durable forehead REFERENCES contouring in Asians with fat grafting and botulinum toxin. Ann Plast Surg. 1. 2017 ASAPS Statistics: Complete Plastic Surgery Statistics Report. Ameri- 2019;82(1S Suppl 1):S59-65. can Society for Aesthetic Plastic Surgery. Available from: http://www.sur- 29. Alexis AF, Alam M. Racial and ethnic differences in skin aging: implications gery.org/sites/default/files/2017stats.pdf.Accessed October 2018. for treatment with soft tissue fillers.J Drugs Dermatol. 2012;11(8):s30-s32; 2. 2008 ASAPS Statistics: Procedures by ethnicity. American Society for Aes- discussion s2. thetic Plastic Surgery. Available from: http://www.surgery.org/sites/default/ 30. Shirakabe Y, Suzuki Y, Lam SM. A new paradigm for the aging Asian face. files/2008stats.pdf.Accessed October 2018. Aesthetic Plast Surg. 2003;27(5):397-402. 3. Liew S, Wu WTL, Chan HH, Ho WWS, et al. Consensus on changing trends, 3 1. Shaw RB, Jr., Katzel EB, Koltz PF, Yaremchuk MJ, et al. Aging of the facial attitudes, and concepts of asian beauty. Aesth Plast Surg. 2016. 40:193-201. skeleton: aesthetic implications and rejuvenation strategies. Plast Recon- 4. Sundaram H, Huang PH, Hsu NJ, Huh CH, et al. Aesthetic applications of struct Surg. 2011;127(1):374-83. botulinum toxin A in Asians: An international, multidisciplinary, Pan-Asian consensus. Plast Reconstr Surg Glob Open. 2016;4(12):e872. AUTHOR CORRESPONDENCE 5. Talakoub L, Wesley NO. Differences in perceptions of beauty and cosmetic procedures performed in ethnic patients. Semin Cutan Med Surg. 2009;28(2):115-129. Annie Chiu MD 6. Davis EC, Callender VD. Aesthetic dermatology for aging ethnic skin. Derma- E-mail:...... ……...... [email protected] tol Surg. 2011;37(7):901-917. 7. Vashi NA, de Castro Maymone MB, Kundu RV. Aging differences in ethnic skin. J Clin Aesthet Dermatol. 2016;9(1):31-38. 8. Alexis A, Grimes P, Boyd C, Downie J, et al. Racial and ethnic differences in self-reported facial aging in women: results from a multinational study. Ac- cepted by Dermatol Surg. January 2019. 9. Porcheron A, Latreille J, Jdid R, Tschachler E, et al. Influence of skin ageing features on Chinese women's perception of facial age and attractiveness. Int J Cosmet Sci. 2014;36(4):312-20. 10. Narurkar V, Shamban A, Sissins P, Stonehouse A, et al. Facial treatment preferences in aesthetically aware women. Dermatol Surg. 2015;41 Suppl 1:S153-60. 11. Wu WT, Liew S, Chan HH, Ho WW, et al. Consensus on current injectable treatment strategies in the Asian face. Aesthetic Plast Surg. 2016;40(2):202- 14. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

June 2019 542 Volume 18 • Issue 6 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC A Phase 2, Multicenter, Double-Blind, Randomized, Vehicle- Controlled Clinical Study to Compare the Safety and Efficacy of a Novel Tazarotene 0.045% Lotion and Tazarotene 0.1% Cream in the Treatment of Moderate-to-Severe Acne Vulgaris Emil A. Tanghetti MD,a Leon H. Kircik MD,b Lawrence J. Green MD,c Eric Guenin PharmD PhD,d Susan Harris MS,e Gina Martin MOT,f Radhakrishnan Pillai PhDf aCenter for Dermatology and Laser Surgery, Sacramento, CA bIndiana University School of Medicine, Indianapolis, IN, Physicians Skin Care, PLLC, Louisville, KY, Icahn School of Medicine at Mount Sinai, New York, NY cDepartment of Dermatology, George Washington University School of Medicine, Washington, DC dOrtho Dermatologics, Bridgewater, NJ eBausch Health, Bridgewater, NJ fBausch Health Americas, Inc., Petaluma, CA

ABSTRACT

Background: Tazarotene has been extensively studied in clinical trials and is widely used to treat acne vulgaris (acne). Irritation potential has limited its use. Objective: To compare efficacy, safety, and tolerability of a novel formulation tazarotene 0.045% lotion based on polymeric emulsion technology, and tazarotene 0.1% cream in patients with moderate-to-severe acne. Methods: A total of 210 patients, 12 years and older were randomized to receive tazarotene 0.045% lotion, tazarotene 0.1% cream, or respective vehicle in double-blind, randomized, vehicle-controlled, 12-week study evaluating safety and efficacy (inflammatory and noninflammatory lesion counts and using Evaluator GlobalDo SeverityNot ScoresCopy [EGSS]). In addition, patients completed a patient satisfaction survey (PSS), and acne-specific quality of life (QoL) questionnaire. Safety and cutaneous tolerability were assessed throughout. Results: A novel tazarotene 0.045% lotion demonstratedPenalties statistically Applysignificant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts P( =.006 and P<.001) and clearly more effective in treatment success at week 12. In addition, at less than half the concentration, tazarotene 0.045% lotion was numerically more effective than tazarotene 0.1% cream. Mean percent reductions in inflammatory and noninflammatory lesions were 63.8% and 56.9%, compared with 60.0% and 54.1% with tazarotene 0.1% cream at week 12. Treatment success assessed by the investigator or patients’ self-assessment was also numerically greater with tazarotene 0.045% lotion. There were no significant differences in patient satisfaction or QoL between the two active treatments. Both were well-tolerated, however, there were more treatment-related adverse events with tazarotene 0.1% cream (5.6% versus 2.9%); most common being application site pain. Limitations: This study was primarily designed to direct the phase 3 program and some of the results are post hoc analyses. Conclusions: A novel tazarotene 0.045% lotion provides statistically significant greater efficacy than vehicle in terms of lesion reduction, and numerically better treatment success than tazarotene 0.1% cream; with a highly favorable safety and tolerability profile in moderate-to-severe acne patients.

J Drugs Dermatol. 2019;18(6):542-548.

INTRODUCTION opical retinoids (eg, tazarotene, tretinoin, adapalene) be highly effective in acne, and they are recommended as the have played an important role in the management of cornerstone of topical therapy.11 Comparative studies between acne vulgaris (acne). They reduce visible lesions and in- tazarotene, tretinoin and adapalene have generally reported T 1-3 12-20 hibit the development of microcomedones and new lesions. greater efficacy with tazarotene, but more irritation. Retinoids normalize the abnormal desquamation process by reducing keratinocyte proliferation and promoting differen- A key aspect of acne management has been the ongoing evolu- tiation,4 as well as modulating several important inflammatory tion of topical treatments that use innovative delivery solutions pathways.4-10 Extensive clinical data have shown retinoids to and optimal formulations to help minimize irritation, without Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

543 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

compromising efficacy. A novel lotion formulation was devel- vestigator. Primary efficacy endpoints included mean absolute oped using a polymeric emulsion, with the aim of improving change from baseline to week 12 in inflammatory and nonin- both efficacy and tolerability. This polymeric emulsion tech- flammatory lesion counts, and the proportion of patients who nology provides a more uniform distribution of active and achieved at least a 2-grade reduction from baseline to week 12 moisturizing excipients at the surface of the skin, which should in EGSS and were ‘clear’ or ‘almost clear’. Other efficacy end- enhance efficacy and minimize irritation. points included mean percent change from baseline to week 12 in inflammatory and noninflammatory lesion counts. Data for In this report data from a comparative phase 2 clinical study vehicle lotion and cream were pooled for the efficacy analysis. where patients with moderate-to-severe acne were treated with tazarotene 0.045% lotion, tazarotene 0.1% cream, or vehicle are Additional analyses were performed to evaluate the impact of presented. treatment on other patient outcomes. These included a Patient Satisfaction Survey (PSS) with scores ranging from 1-10 (where METHODS 10 was the most satisfied); a validated Acne-Specific Quality of Study Design Life (Acne-QoL) questionnaire (Merck & Co, Inc. Whitehouse, This was a multicenter, randomized, double-blind, vehicle- NJ); and a Subject Self-Assessment (SSA) scale (using a 7-point controlled, clinical study in patients with moderate-to-severe scale, where 0=worse and 6=clear). The SSA was assessed at acne who met specific inclusion/exclusion criteria as described baseline and weeks 2, 4, 8, and 12; PSS and Acne-QoL were below. Protocol received approval from the appropriate in- completed at baseline and week 12. stitutional review board (IRB) for each center before patient enrollment and were conducted in accordance with the Dec- Safety Evaluation laration of Helsinki and Good Clinical Practices (GCP) and in Cutaneous safety (erythema, scaling, hypopigmentation, and compliance with local regulatory requirements. All patients hyperpigmentation) and tolerability (itching, burning, and were informed of the study details and provided written con- stinging) were assessed using a 4-point scale where 0=none, sent. 1=mild, 2=moderate and 3=severe. The investigator assessed erythema, scaling, and hyper-/hypopigmentation at the time Patients were enrolled with an Evaluator Global Severity Score of the study visit. Itching, burning, and stinging were solicited [EGSS] score of 3 (moderate) or 4 (severe). TreatmentsDo were Not fromCopy the patient and recorded as an average of the patient’s randomized (2:2:1:1) to tazarotene 0.045% lotion, tazarotene symptoms during the period since the previous visit. 0.1% cream, and vehicle lotion or cream (to ensurePenalties blinding). Apply Data on vehicle are combined in the result presented here. All Safety was also evaluated through reported adverse events patients applied study medication to the face once-daily in the (AEs), which were summarized by treatment group, severity, evening for 12 weeks; after being instructed to gently washing and relationship to study medication. their face with a non-medicated cleanser. Statistical Analysis Study Population The intent-to-treat (ITT) population comprised all patients ran- Approximately 210 patients were planned for enrollment. Eli- domized and provided with study drug and vehicle. The safety gible patients were of any gender, race and ethnicity aged 12 population comprised all randomized patients who were pre- years and older who presented with 20 to 40 inflammatory sumed to have used the study medication or vehicle at least lesions (papules, pustules, and nodules), 20 to 100 noninflam- once and who provided at least one post baseline evaluation. matory lesions (open and closed comedones), and two nodules The primary method of handling missing efficacy data in the or less. Women of childbearing potential were required to have ITT analysis set was last observation carried forward (LOCF). a negative urine pregnancy test result and to agree to use an No imputations were made for missing safety data. effective form of contraception for the duration of the study. A washout period of up to 1 month was required for patients Reductions in lesion counts are presented as means and con- who used previous prescription and over-the-counter acne trast p-values are from a ranked analysis of covariance with treatments (and six months for systemic retinoids). Investiga- factor of treatment and the respective baseline lesion count as tor approved non-mediated facial cleanser, moisturizer, and covariate. Significance of EGSS reductions were obtained from sunscreen was allowed. a Cochran-Mantel-Haenszel (CMH) test.

Efficacy Evaluation All statistical analyses were conducted using SAS® version 9.3 Efficacy evaluations comprised inflammatory, and noninflam- or later. Statistical significance was based on 2-tailed tests of matory lesion counts and an EGSS at screening, baseline, and the null hypothesis resulting in P values of 0.05 or less. during treatment (at weeks 2,4, 8, and 12) performed by the in- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

544 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

All AEs occurring during the studies were recorded and clas- FIGURE 1. Patient disposition ITT population (all randomized subjects, sified on the basis of medical dictionary for drug regulatory N=210). activities terminology (MedDRA) for the safety population. The frequency of patients with one or more AEs during the study was tabulated by treatment group.

RESULTS Baseline Characteristics Total of 210 patients were enrolled across 16 investigative sites in the United States, randomly assigned to tazarotene 0.045% lotion (N=69), tazarotene 0.1% cream (N=72), or vehicle (N=69) and included in the ITT analysis, see Figure 1. Patients were treated with vehicle lotion (N=34) or vehicle cream (N=35) to ensure blinding, however vehicle results are combined in these analyses. Overall, 189 patients (90%) completed the study, including 65 patients (94.2%) on tazarotene 0.045% lotion, 63 patients (87.5%) on tazarotene 0.1% cream, 61 patients (88.4%) on combined vehicle. The most common reasons for study discontinuation were ‘lost to follow-up (N=12)’ or ‘subject request TABLE 1. (N=5)’. One patient treated with tazarotene 0.1% cream discon- Demographics and Baseline Characteristics (ITT population) tinued due to adverse event. Four patients were excluded from Tazarotene Tazarotene Combined the safety population due to no post-baseline safety assess- 0.045% Lotion 0.1% Cream Vehicle ment. (N=69) (N=72) (N=69) Age Demographic data (Table 1) was similar across the treatment Mean years (SD) 23.3 (10.20) 22.0 (8.96) 21.2 (8.44) groups. The mean age was 21.2 to 23.3 years. There was a slightly higher proportion of female patients overallDo (55.2%); Not CopySex N (%) 61.4% were Caucasian, with 28.6% Black or African American. Male 32 (46.4%) 31 (43.1%) 31 (44.9%) There were no noticeable differences betweenPenalties treatment Apply Female 37 (53.6%) 41 (56.9%) 38 (55.1%) groups in regard to baseline lesion counts, or EGSS. At base- Ethnicity N (%) line, the mean number of inflammatory and noninflammatory Hispanic or Latino 27 (39.1%) 29 (40.8%) 25 (36.2%) lesions ranged from 27.2 to 28.3 and 36.6 to 37.6, respectively. Not Hispanic or 42 (60.9%) 42 (59.2%) 44 (63.8%) At baseline, 92.4% of patients had moderate acne (EGSS=3). Latino Race N (%) Efficacy American Indian 1 (1.4%) 0 (0.0%) 2 (2.9%) Lesion Counts or Alaska Native Tazarotene 0.045% lotion resulted in statistically significant Asian 4 (5.8%) 4 (5.6%) 2 (2.9%) reductions in both inflammatory and noninflammatory lesion Black or African reductions compared to combined vehicle at week 12. Mean 21 (30.4%) 16 (22.2%) 23 (33.3%) American percentage change from baseline to week 12 in inflammatory lesion counts was 63.8% versus 51.4% with the combined ve- Native Hawaiian or Other Pacific 1 (1.4%) 0 (0.0%) 1 (1.4%) hicle (P=.006), and in noninflammatory lesion counts 56.9% Islander versus 35.2% with vehicle (P<.001), see Figures 2 and 3. Tazaro- tene 0.045% lotion showed a greater reduction from baseline to White 41 (59.4%) 50 (69.4%) 38 (55.1%) week 12 in inflammatory and noninflammatory lesions when Other 1 (1.4%) 2 (2.8%) 3 (4.3%) compared with tazarotene 0.1% cream, but differences were Evaluator’s Global Severity Score N (%) not significant P( =.680 and .612). 3 – Moderate 64 (92.8%) 66 (91.7%) 64 (92.8%) 4 – Severe 5 (7.2%) 6 (8.3%) 5 (7.2%) Median percent change from baseline to week 12 in inflam- Inflammatory Lesion Count matory and noninflammatory lesion counts with tazarotene Mean (SD) 28.3 (6.00) 27.3 (5.95) 27.2 (5.49) 0.045% lotion was 72.4% and 62.5% versus 66.7% and 56.4% Noninflammatory Lesion Count with tazarotene 0.1% cream and 60.0% and 42.3% with vehicle, respectively. Mean (SD) 37.6 (14.70) 36.6 (13.31) 36.6 (13.17) Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

545 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

FIGURE 2. Percent change in mean inflammatory lesions from baseline to week 12. (ITT population): Comparison of Tazarotene 0.045% lotion, Tazarotene 0.1% cream, and vehicle.

FIGURE 3. Percent change in mean noninflammatory lesions from baseline to week 12 (ITT population): Comparison of Tazarotene 0.045% lotion, Tazarotene 0.1% cream, and vehicle.

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Treatment Success Subject Self-Assessment (SSA) Treatment success was defined as at least a 2-grade improve- Tazarotene 0.045% lotion showed a greater numerical treatment ment in global severity by EGSS and ‘clear’ or ‘almost clear’. success (‘clear’ or ‘almost clear’) at week 12 in terms of SSA At week 12, 18.8% of patients achieved treatment success with when compared with tazarotene 0.1% cream (P=.768). Treat- tazarotene 0.045% lotion compared to 10.1% with combined ment success was achieved in 38.5% of patients, compared with vehicle (P=.148; Figure 4). Tazarotene 0.045% lotion showed 35.9% and 24.6% (tazarotene 0.01% cream and combined ve- a greater treatment success at week 12 when compared with hicle [P=.096], respectively). tazarotene 0.1% cream (16.7%), but differences were not significant. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

546 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

FIGURE 4. Treatment success based on Evaluator’s Global Severity Scores (ITT population): Comparison of Tazarotene 0.045% lotion, Tazarotene 0.1% cream, and vehicle.

FIGURE 5. Subject Self-Assessment (SSA) at each evaluation (ITT Population ’Clear’ or ‘Almost Clear’ [>=90%]): Comparison of Tazarotene 0.045% lotion, Tazarotene 0.1% cream, and vehicle.

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Patient Satisfaction (PSS) and Quality of Life Acne-QoL assessments in each of the 4 evaluated domains. Im- There were no significant differences in PSS mean scores at provements in self-perception, role-emotional, and role-social week 12 between tazarotene 0.045% lotion and tazarotene 0.1% were similar with tazarotene 0.045% lotion and tazarotene 0.1% cream (P=.372) or combined vehicle (P=.242). Overall, patients cream, and markedly greater than those achieved in the com- treated with tazarotene 0.045% lotion assessed their treatment bined vehicle groups. In terms of acne symptoms improvement, satisfaction higher than tazarotene 0.1% cream (mean score of the absolute change from baseline with tazarotene 0.045% lo- 7.7 versus 7.4). tion was again greater than that achieved with the combined vehicle, however tazarotene 0.1% cream only demonstrated an There were also no statistically significant differences in the improvement similar to that achieved with vehicle. improvement between treatment groups based on the mean Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

547 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

TABLE 2. Safety A higher proportion of patients treated with tazarotene 0.1% Treatment-Emergent and Related Adverse Event (AE) Characteristics through Week 12 (Safety population, N=206) cream (26.8%) reported treatment-emergent AEs compared with tazarotene 0.045% lotion (14.7%) or combined vehicle Tazarotene Tazarotene Combined Lotion Cream Vehicle (13.4%). TEAEs were mostly mild or moderate and unrelated to (N=68) (N=71) (N=67) study drug (Table 2). Treatment-related AEs were more common with tazarotene 0.1% cream. There were two reports of applica- Patients reporting any TEAE 10 (14.7%) 19 (26.8%) 9 (13.4%) tion site pain (2.9%) with tazarotene 0.045% lotion; compared Patients reporting any SAE 0 (0.0%) 0 (0.0%) 0 (0.0%) with three reports with tazarotene 0.1% cream (4.2%). Patients who died 0 (0.0%) 0 (0.0%) 0 (0.0%) Patients who discontinued 0 (0.0%) 1 (1.4%) 0 (0.0%) Cutaneous Safety and Tolerability due to TEAE Each of the signs and symptoms of cutaneous safety Severity of AEs reported and tolerability (scaling, erythema, hypopigmentation, Mild 6 (8.8%) 12 (16.9%) 9 (13.4%) hyperpigmentation, itching, burning, and stinging) showed Moderate 2 (2.9%) 7 (9.9%) 0 (0.0%) improvements from baseline to week 12. There were slight Severe 2 (2.9%) 0 (0.0%) 0 (0.0%) increases in mean scores for scaling, burning and stinging at Relationship to study drug week 4, consistent with tazarotene’s safety profile, but these reduced at subsequent study visits. All mean scores were ≤0.6 Related 2 (2.9%) 4 (5.6%) 0 (0.0%) (where a score of 1=mild); scores being similar or slightly lower Unrelated 8 (11.8%) 15 (21.1%) 9 (13.4%) at interim study visits with tazarotene 0.045% lotion compared Treatment Related AEs reported by ≥1% patients with tazarotene 0.1% cream, especially in terms of scaling, itch- Application site pain 2 (2.9%) 3 (4.2%) 0.(0.0%) ing, burning, and stinging at weeks 2 and 4. Application site erythema 0 (0.0%) 1 (1.4%) 0 (0.0%) Application site DISCUSSION 0 (0.0%) 1 (1.4%) 0 (0.0%) exfoliation Despite recommendations to use retinoids as first-line acne Application site dryness 0 (0.0%) 1 (1.4%) 0 (0.0%) treatment,11,21 they remain underutilized.22-24The slow onset of Erythema 0 (0.0%) 1 (1.4%) 0 (0.0%) action in the treatment of inflammatory lesions,25 and theDo widely Not Copy recognized irritation potential of these agents have somewhat limited their use. Consequently, several attemptsPenalties have been arotene Apply 0.1% cream in patients with moderate-to-severe acne. made to alleviate these efficacy and tolerability issue using new Tazarotene 0.045% lotion was significantly superior to vehicle in delivery technology. The clinical benefits observed with tazaro- reducing both inflammatory and noninflammatory lesions; and tene 0.1% foam,26,27 0.1% cream,28 and 0.1% gel29 appear similar, numerically more effective than tazarotene 0.1% cream despite although no direct comparisons exist in the literature. the two-fold difference in tazarotene concentration. Median reductions in inflammatory and noninflammatory lesions with The rationale behind the development of a novel lotion formula- tazarotene 0.045% lotion were 72% and 63%, respectively, at 12 tion of tazarotene stemmed from its proven efficacy in acne and weeks. the fact that a lotion formulation is the easiest and most accept- able formulation for application to the face; but also the potential The only treatment-related AE with tazarotene 0.045% lotion for tazarotene cream (and to a lesser extent foam26) to cause observed was application site pain (2.9%). Skin reactions (such concentration dependent skin irritation and dryness, which had as scaling, burning, and stinging) were infrequent, had onsets been shown to be both bothersome in many patients and may early in the treatment period, were mostly mild and appeared impact adherence and successful acne treatment. For example, transient. Erythema and itching noted at baseline improved pro- pooled results from several clinical studies showed that 14% gressively with daily tazarotene 0.045% lotion treatment. Again, of patients treated with tazarotene 0.1% foam reported irrita- these data concur with those in other clinical trials of retinoids tion and 7% dryness, compared with only 1% using vehicle.30 where the peak of cutaneous irritation typically occurs within the first 1-2 weeks and subsides.31 Tazarotene 0.045% lotion is a novel topical treatment for moderate-to-severe acne leveraging polymeric emulsion technology CONCLUSIONS with the aim to improve both efficacy and tolerability. The poly- Tazarotene 0.045% lotion was developed using a polymeric meric emulsion technology affords more uniform deposition emulsion technology. In this phase 2 study of patients with mod- of active, excipients and moisturizers onto the skin surface. erate-to-severe acne, tazarotene 0.045% lotion was as effective This phase 2 study is the first to compare a novel formulation as the higher concentration tazarotene 0.1% cream, with fewer of tazarotene 0.045% lotion with commercially available taz- treatment-emergent adverse events. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

548 Journal of Drugs in Dermatology E.A. Tanghetti, L.H. Kircik, L.J. Green, et al June 2019 • Volume 18 • Issue 6

DISCLOSURES non-dermatologists in the management of acne vulgaris. J Am Acad Derma- tol 2016;74:1252–1254. Drs Tanghetti, Kircik and Green were study investigators. Dr Kir- 23. Balkrishnan R, Fleischer AB Jr, Paruthi S, Feldman SR. Physicians under- utilize topical retinoids in the management of acne vulgaris: analysis of US cik and Green are advisors to Ortho Dermatologics. Dr Guenin, National Practice Data. J Dermatolog Treat 2003;14:172–176. Pillai, and Ms Harris and Martin are employees of Bausch Health 24. Balkrishnan R, Bhosle MJ, Camacho F, at al. Prescribing patterns for topical Americas, Inc. retinoids: analyses of 15 years of data from the national ambulatory medical care survey. J Dermatolog Treat 2010;21:193–200. 25. Leyden J, Stein Gold L, Weiss J. Why topical retinoids are the mainstay of ACKNOWLEDGMENT therapy for acne. Dermatol Ther 2017;7:293-304. 26. Jarratt M, Werner CP, Alió Saenz AB. Tazarotene foam versus tazarotene gel: The authors acknowledge Brian Bulley, MSc, of Konic Limited a randomized relative bioavailability study in acne vulgaris. Clin Drug Investig for medical writing support. Ortho Dermatologics funded Kon- 2013;33:283–289. 2 7. Feldman SR, Werner CP, Alió AS. The efficacy and tolerability of tazarotene ic’s activities pertaining to this manuscript. foam, 0.1%, in the treatment of acne vulgaris in 2 multicenter, randomized, vehicle-controlled, double-blind studies. J Drugs Dermatol 2013;12(4):438- REFERENCES 446. 28. Shalita AR, Berson DS, Thiboutot DM, et al. Effects of tazarotene 0.1 % 1. Thielitz A, Abdel-Naser MB, Fluhr JW, et al. Topical retinoids in acne–an evi- cream in the treatment of facial acne vulgaris: pooled results from two mul- dence-based overview. J Dtsch Dermatol Ges 2008;6:1023–1031. ticenter, double-blind, randomized, vehicle-controlled, parallel-group trials. 2. Thielitz A, Helmdach M, Ropke EM, et al. Lipid analysis of follicular casts Clin Ther 2004;26:1865-1873. from cyanoacrylate strips as a new method for studying therapeutic effects 29. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effec- of antiacne agents. Br J Dermatol 2001;145:19–27. tive in the treatment of acne vulgaris: a multicenter, double-blind, vehicle- 3. Del Rosso JQ. Pharmacotherapy review: topical tazarotene, a composite controlled study. Cutis 1999;63:349-354. review of clinical and research experience with focus on optimal use and 30. Epstein EL, Stein Gold L. Safety and efficacy of tazarotene foam for the safety. J Am Osteopath Coll Dermatol 2004;1(2):55–59. treatment of acne vulgaris. Clin Cosmet Investig Dermatol 2013;6:123-125. 4. Czernielewski J, Michel S, Bouclier M, et al. Adapalene biochemistry and the 3 1. Leyden J, Grove G, Zerweck C. Facial tolerability of topical retinoid therapy. evolution of a new topical retinoid for treatment of acne. J Eur Acad Derma- J Drugs Dermatol 2004;3:641–651. tol Venereol 2001;15(Suppl 3):5–12. 5. Michel S, Jomard A, Demarchez M. Pharmacology of adapalene. Br J Der- matol 1998;139(Suppl 52):3–7. AUTHOR CORRESPONDENCE 6. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol Emil Tanghetti MD 2003;49:S1–37. 7. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy E-mail:...... ……...... [email protected] and safety. Am J Clin Dermatol 2008;9:369–81. 8. Yeh L, Bonati LM, Silverberg NB. Topical retinoids for acne. Semin Cutan Med Surg 2016;35:50–56. 9. Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol 2003;4(2):75–80. Do Not Copy 10. Thiboutot DM, Gollnick HP.Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies.Penalties J Drugs Der- Apply matol 2006;5(8):785–794. 11. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(945–73):e33. 12. Pariser D, Colón LE, Johnson LA, Gottschalk RW. Adapalene 0.1% gel compared to tazarotene 0.1% cream in the treatment of acne vulgaris. J Drugs Dermatol. 2008;7(6 Suppl):s18-23. 13. Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol 2008;7(6 Suppl):s3–s10. 14. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis 2001;67:4–9. 15. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 2002;69:12–19. 16. Dosik JS, Arsonnaud S. Tolerability comparison of adapalene gel, 0.3% versus tazarotene cream 0.05% in subjects with healthy skin. J Drugs Dermatol 2007;6(6):632-638. 1 7. Kircik LH. Tretinoin microsphere gel pump 0.04% versus tazarotene cream 0.05% in the treatment of mild-to-moderate facial acne vulgaris. J Drugs Dermatol 2009;8(7):650-654. 18. Webster GF, Guenther L, Poulin YP, et al. A multi-center, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1 % gel and adapalene 0.1 % gel for the treatment of facial acne vulgaris. Cutis 2002; 69: 4–11. 19. Shalita A, Miller B, Menter A, et al. Tazarotene cream versus adapalene cream in the treatment of facial acne vulgaris: a multicenter, double-blind, randomized, parallel-group study. J Drugs Dermatol 2005;4:153-158. 20. Tanghetti EA, Dhawan S, Green L, et al. Randomized comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel in the treatment of patients with at least moderate facial acne vulgaris. J Drugs Dermatol 2010;9(5):549-558. 2 1. Nast A, Dreno B, Bettoli V, et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol 2012;26(Suppl 1):1–29. 22. Pena S, Hill D, Feldman SR. Use of topical retinoids by dermatologists and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

July 2019 649 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC A Survey-Based Comparison of Sun Safety Practices in a Representative Cohort of the General Public Versus Attendees of a Skin Cancer Screening Emily C. Murphy BS,a,b Stephanie Kao BA,a Huan Wang MS,c Dechang Chen PhD,d Hong Nguyen MD MPH,e,f Adam J. Friedman MDa aDepartment of Dermatology, The George Washington School of Medicine and Health Sciences, Washington, DC BGeorgetown University, School of Medicine, Washington, DC cDepartment of Biostatistics, The George Washington University, Washington, DC DDepartment of Preventive Medicine & Biostatistics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences,Washington, DC EThe George Washington University Hospital Cancer Registry, Washington, DC fAlexandria Campus, Northern Virginia Community College, Alexandria, VA

ABSTRACT

A large proportion of data on photoprotective practices is yielded from free skin cancer screenings. However, the sun safety practices of populations who seek these skin cancer screenings may differ from the general public. To examine differences in skin cancer prevention practices and risk factors, we surveyed pedestrians at six locations in Washington, DC (public group, n=285) and attendees of a free skin cancer screening (screening group, n=144) using an IRB-approved survey. The screening group was older and included more individuals with fair skin than the public group. Respondents from the screening group were significantly more likely to always wear sunscreen, always seeks shade, and always or sometimes wear sun-protective clothing than the public group (P<0.05). To examine whether younger and non-white participants, who were less likely to attend our free screening, have different practices and risk factors than older and white participants, respectively, we compared survey answers for all participants by age and race. White participants were more likely to always or sometimes wear sunscreenDo and Not sun-protective Copy clothing than non-white participants (P<0.05). Patients over 61 years were more likely to always seek shade and wear sun-protective clothing than those younger than 31 years (P<0.05). Therefore, free skin cancer screenings need to bePenalties better popularized Apply among non-white and younger populations or more effective educational vehicles are needed.

J Drugs Dermatol. 2019;18(7):649-653.

INTRODUCTION roper photoprotective practices are critical for the pre- percentage of men attending screenings decreased over time. vention of melanoma and non-melanoma skin cancers. A Given melanoma deaths are higher among men than women,2 significant proportion of data on these practices is yield- the authors stated that men, especially white men, are a critical P 1 ed from intake forms for free skin cancer screenings, such as group to screen for skin cancer. through the American Academy of Dermatology’s SPOTme program. This program was started in 1985 and is one of the largest However, it is possible that the knowledge and perceptions of cancer screening programs.1 The risk profile, care access, and populations who seek skin cancer screenings may differ from examination results of SPOTme’s screening population from the general public, leading to different photoprotective prac- 1986 to 2014 was recently examined by Okhovat et al.1 Nearly tices among these populations. This is especially relevant in the two million screenings were reviewed, which showed that the US where the demographics of our largest skin cancer screen- SPOTme program detected thousands of skin cancers that may ing program was not representative of the general population.1 have gone undetected given 52% of those screened would not The SPOTme program is clearly valuable as it has identified have seen a doctor otherwise.1 Compared to the general United over 20,000 melanomas, 32,000 squamous cell carcinomas, States (US) population, the screening sample was older (only and 129,000 basal cell carcinomas,1 but the data gathered from 8.9% of participants were 15 to 29 years old) and included more this program includes only patients who self-select to attend white individuals (90.3% of the sample was Caucasian). The free screenings. screening population also included only 37.7% men, and the Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

650 Journal of Drugs in Dermatology E.C. Murphy, S. Kao, H. Wang, et al July 2019 • Volume 18 • Issue 7

TABLE 1. We sought to examine the differences between the population who chooses to attend screenings and the general population Demographics of Survey Respondents in the Screening Group and Public Group by surveying pedestrians in a major city and attendees of a free Screening Group Public Group skin cancer screening. By examining differences in demograph- Demographic % of Respondents % of Respondents ics, photoprotective practices, and skin cancer risk factors, this study highlights future directions needed for skin cancer pre- Gender vention efforts. Female 69.8 64.5 Male 30.2 35.5 METHODS Age An IRB-approved survey was randomly administered at six loca- <31 years 15.5 47.0 tions in Washington, DC (public group, n=285) and to attendees 31 – 60 years 40.4 40.0 of a free skin cancer screening at George Washington Univer- >60 years 44.1 13.0 sity School of Medicine and Health Sciences (screening group, n=144). The survey included eight questions on demographics Race (Table 1) as well as sun protective practices and risk factors for White 73.0 48.2 skin cancer (Table 2). Based on the Centers for Disease Control Black 13.9 28.7 and Prevention (CDC) definition of sun-protective behaviors, Hispanic 7. 3 5.7 the participants were asked about their sunscreen use, shade- Asian 2.9 12.4 seeking practices to avoid peak sun, and use of sun-protective Mixed/Other 2.9 5.0 clothing to cover up from sun exposure.3 Further, the survey assessed two risk factors associated with an increased risk of skin cancer: number of sunburns and indoor tanning practices.4–6 Statistical analysis was performed using GraphPad Prism, ver- Due to the limited number of survey responses for some races sion 7.0 (GraphPad Software Inc.). Chi-square tests were used to (Hispanic, Asian, mixed, and other races), race was compared compare answers between the public group and survey group. dichotomously by white versus non-white (including Black, His- Additionally, survey answers from the public and screening panic, Asian, and Mixed/Other) participants. A P-value of less groups were combined to compare answers by age Doand race. Not thanCopy or equal to 0.05 was considered statistically significant. TABLE 2. Penalties Apply Responses to Survey Questions Regarding Photoprotective Practices and Skin Cancer Risk Factors for the Screening (n=144) and Public (n=285) Groups Answer Question % of Respondents 1. Do you use sunscreen?* Always Sometimes Rarely Never Screening Group 34.3 43.3 14.9 7. 5 Public Group 18.7 47.3 16.6 1 7. 3 2. Do you seek shade when possible?* Always Sometimes Rarely Never Screening Group 51.5 36.6 9.0 3.0 Public Group 32.3 52.8 12.4 2.5 3. Do you wear sun-protective clothing?* Always Sometimes Rarely Never Screening Group 16.4 56.7 14.9 11. 9 Public Group 9.2 48.1 28.3 14.5 4. How many blistering sunburns did you have prior 0 to 3 4 to 6 7 to 10 11 or more to age 20? Screening Group 70.0 16.2 9.2 4.6 Public Group 73.2 14.3 5.4 7. 1 5. Approximately how many times over your lifetime 0 1 to 10 11 to 20 21 or more have you used indoor tanning equipment? Screening Group 82.0 10.2 2.3 1.6 Public Group 79.9 14.5 1.4 2.1

651 Journal of Drugs in Dermatology E.C. Murphy, S. Kao, H. Wang, et al July 2019 • Volume 18 • Issue 7

RESULTS not vary by race. Patients over 60 years old were more likely to Table 1 presents the demographics for the screening group and always seek shade (53.2% for >60 years versus 24.0% for <31 public group. The gender distribution did not significantly differ years; P<0.0001) and wear sun-protective clothing (17.0% for >60 between the two groups, although there was a larger percent- years versus 9.7% for <31 years; P=0.018) than those younger age of female participants in both groups (69.8% female for than 31 years (Figure 2). Sunscreen use did not vary by age. screening group, 64.5% female for public group). The screening These age- and race-based relationships reinforce the need to group was older with 44.1% being over 60 years old compared target non-white and younger populations for sun safety educa- to 13.0% of the public group (P<0.0001). A higher percentage of tion, who were less likely to attend our skin cancer screening. the screening group was white compared to the public group (73.0% white in screening group versus 48.2% white in public Alternatively, white participants reported more blistering sun- group; P<0.0001). burns than non-white participants (40.3% with ≥4 sunburns for white versus 12.0% with ≥4 sunburns for non-white; P<0.0001). The survey responses for the screening and public groups re- Therefore, sun sensitivity in fair-skinned individuals may en- garding sun safety practices and risk factors are presented in courage proper sun safety practices. White respondents also Table 2. More respondents from the screening group always reported more indoor tanning uses (18.7% ≥5 uses for white wear sunscreen (P=0.001), always seeks shade (P=0.002), and versus 3.8% ≥5 uses for non-white; P<0.0001) than non-white always or sometimes wear sun-protective clothing (P=0.002) respondents. The number of blistering sunburns and indoor tan- compared to the public group. Responses between the groups ning uses did not differ by age. did not differ for the number of blistering sunburns prior to age 20 and the number of indoor tanning uses, suggesting equal DISCUSSION risk for both groups. Together, these data show that those who attend skin cancer screenings are more likely to wear sunscreen, seek shade, and Given the screening group was older and included more white wear sun-protective clothing than a randomly sampled popula- participants than the public group, these demographic population. These photoprotective behaviors defined by the CDC3 can tions may have superior photoprotective practices compared to reduce patients’ sun exposure and therefore, their risk of squa- younger and non-white populations, respectively. To examine mous cell carcinoma, basal cell carcinoma, and melanoma.6–8 this, we combined all the survey responses for the Doscreening Not ForCopy melanoma specifically, exposure to ultraviolet radiation and public groups and compared the answers by white versus accounts for more than 90% of the cases in the US.7, 8 Indoor non-white participants and for three age groups (<31Penalties years, 31- Apply 60 years, and >60 years). White participants were more likely FIGURE 2. Responses to survey questions for all participants (screening to always or sometimes wear sunscreen (84.2% for white ver- and public groups combined) regarding photoprotective practices, sus 52.2% for non-white; P<0.0001) and sun-protective clothing separated by age: <31 years (n=154), 31-60 years (n=165), and >60 (67.5% for white versus 55.4% for non-white; P=0.012) than (n=94). *Indicates significant differences between age groups P( <0.05). non-white participants (Figure 1). Shade-seeking practices did

FIGURE 1. Responses to survey questions for all participants (screening and public groups combined) regarding photoprotective practices, separated by white (n=228) versus non-white (n=184) respondents. *Indicates significant differences between white and non-white individuals (P<0.05). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

652 Journal of Drugs in Dermatology E.C. Murphy, S. Kao, H. Wang, et al July 2019 • Volume 18 • Issue 7

tanning use was equal among the screening and public groups, truly representative of the general public. In addition, the dichot- meaning that all patients need to be educated on indoor tanning omous categorization of race (white versus non-white) could risks,4 especially fair-skinned individuals who reported higher have overlooked other race-based mediators of sun-protective use in this survey. behaviors, such as differences in cultural practices. Future larger studies should delve further into race-based differences in pho- The screening group was older and included more individu- toprotective behaviors. als with fair skin, highlighting the need to target younger and non-white populations for sun safety education. Despite the Despite these limitations, this survey-study highlights the need US Preventive Services Task Force (USPSTF) recommendation to tailor future skin cancer prevention programs to younger to target fair-skinned individuals for skin cancer prevention and non-white populations, who we are missing with free skin counsuling,9 survival from melanoma is significantly lower for cancer screenings, which comprise the majority of our current non-white groups, making these critical populations to reach.10 efforts. A more comprehensive skin cancer prevention program Prior research has demonstrated that many individuals with could reach a more diverse population, with the goal of reduc- darker skin types believe that they are not at risk for skin can- ing new skin cancers among all patient populations. cer and that their dark skin provides more sun protection than lighter skin.11,12 Tailored sun safety education may be useful for DISCLOSURES individuals with dark skin to alter their perceptions that skin The authors have no conflict of interest to declare. cancer is not a risk and to encourage good photoprotective practices among patients of all skin colors.11,13 In terms of age, REFERENCES while the incidence of melanoma increases with age,2 sunburns 1. Okhovat J-P, Beaulieu D, Tsao H, et al. The first 30 years of the American 14 Academy of Dermatology skin cancer screening program: 1985-2014. J Am at an early age are associated with a later risk of melanoma. Acad Dermatol. 2018;79(5):884-891. doi:10.1016/j.jaad.2018.05.1242 Therefore, encouraging sun safety in younger populations will 2. Guy GP, Thomas CC, Thompson T, et al. Vital signs: melanoma incidence and decrease the risk of skin cancer for patients now and later in mortality trends and projections - United States, 1982-2030. MMWR Morb Mortal Wkly Rep. 2015;64(21):591-596. their lives. 3. Saraiya M, Glanz K, Briss P, et al. Preventing skin cancer: findings of the Task Force on Community Preventive Services On reducing Exposure to Ultravio- let Light. MMWR Recomm Rep. 2003;52(RR-15):1-12. That said, educating populations who seek skin cancer screen- 4. Wehner MR, Shive ML, Chren M-M, Han J, Qureshi AA, Linos E. Indoor tan- ings is still important given 22% of our screening cohort ning and non-melanoma skin cancer: systematic review and meta-analysis. Do Not CopyBMJ. 2012;345:e5909. doi:10.1136/bmj.e5909 reported rarely or never wearing sunscreen, underscoring 5. Dennis LK, Vanbeek MJ, Beane Freeman LE, Smith BJ, Dawson DV, Cough- this program’s value. However, a comprehensive Penaltiesskin cancer Applylin JA. Sunburns and risk of cutaneous melanoma: does age matter? A com- prevention program should offer more than total body skin ex- prehensive meta-analysis. Ann Epidemiol. 2008;18(8):614-627. doi:10.1016/j. annepidem.2008.04.006 aminations. To prevent skin cancer though increased sunscreen 6. Iannacone MR, Wang W, Stockwell HG, et al. Patterns and timing of sunlight use and reduced sunburns, the Community Preventative Servic- exposure and risk of basal cell and squamous cell carcinomas of the skin--a case-control study. BMC Cancer. 2012;12:417. doi:10.1186/1471-2407-12-417 es Task Force recommends multicomponent, community-wide 7. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma interventions, including school-based interventions.15–17 An ex- induced by ultraviolet radiation. N Engl J Med. 1999;340(17):1341-1348. doi:10.1056/NEJM199904293401707 ample of such a program is Australia’s SunSmart skin cancer 8. Armstrong BK, Kricker A. How much melanoma is caused by sun exposure? prevention program.18 This comprehensive campaign includes Melanoma Res. 1993;3(6):395-401. school- and workplace-based programs, practitioner education, 9. Behavioral Counseling to Prevent Skin Cancer: Recommendation Statement - U.S. Preventive Services Task Force - American Family Physician. https:// media campaigns, and resource dissemination. From 1988 to www.aafp.org/afp/2012/1015/od3.html. Accessed October 15, 2018. 2003, SunSmart was estimated to prevent 9,000 new melanoma 10. Dawes SM, Tsai S, Gittleman H, Barnholtz-Sloan JS, Bordeaux JS. Racial disparities in melanoma survival. J Am Acad Dermatol. 2016;75(5):983-991. cases and 1,000 melanoma deaths in the state of Victoria. Fur- doi:10.1016/j.jaad.2016.06.006 thermore, the program saved $2.30 for every $1 spent.18 Based 11. Tan MG, Nag S, Weinstein M. Parental use of sun protection for their children—does skin color matter? Pediatr Dermatol. 2018;35(2):220-224. on this program and the doubling of the incidence of melanoma doi:10.1111/pde.13433 in the US from 1982 to 2011, the CDC estimated that a compre- 12. Kim M, Boone SL, West DP, Rademaker AW, Liu D, Kundu RV. Perception of hensive skin cancer program could prevent 20% of melanoma Skin Cancer Risk by Those With Ethnic Skin. Arch Dermatol. 2009;145(2):207- 208. doi:10.1001/archdermatol.2008.566 cases and reduce spending on new melanomas by $2.7 billion 13. Gloster HM, Neal K. Skin cancer in skin of color. J Am Acad Dermatol. from 2020 to 2030.2 A multicomponent, multiple-setting program 2006;55(5):741-760; quiz 761-764. doi:10.1016/j.jaad.2005.08.063 14. Oliveria SA, Saraiya M, Geller AC, Heneghan MK, Jorgensen C. Sun expo- in the US would likely reach broader demographic populations sure and risk of melanoma. Arch Dis Child. 2006;91(2):131-138. doi:10.1136/ than skin cancer screenings alone. adc.2005.086918 15. Skin Cancer: Multicomponent Community-Wide Interventions. The Guide to Community Preventive Services (The Community Guide). https://www. Limitations of this study include a small sample size and pos- thecommunityguide.org/findings/skin-cancer-multicomponent-community- sible selection bias given the sampling for the public group was wide-interventions. Published April 16, 2014. Accessed February 17, 2019. 16. Skin Cancer: Interventions in Outdoor Recreational and Tourism Settings. done near a university, which may include a more educated The Guide to Community Preventive Services (The Community Guide). population. Thus, it is unknown whether our public group is https://www.thecommunityguide.org/findings/skin-cancer-interventions- outdoor-recreational-and-tourism-settings. Published October 14, 2016. Ac- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

653 Journal of Drugs in Dermatology E.C. Murphy, S. Kao, H. Wang, et al July 2019 • Volume 18 • Issue 7

cessed February 17, 2019. 1 7. Skin Cancer: Primary and Middle School-Based Interventions. The Guide to Community Preventive Services (The Community Guide). https://www.thecommunityguide.org/findings/skin-cancer-primary-and-middle-school-based- interventions. Published April 16, 2014. Accessed February 17, 2019. 18. Shih ST-F, Carter R, Sinclair C, Mihalopoulos C, Vos T. Economic evaluation of skin cancer prevention in Australia. Preventive Medicine. 2009;49(5):449- 453. doi:10.1016/j.ypmed.2009.09.008

AUTHOR CORRESPONDENCE

Adam J. Friedman MD E-mail:...... ……...... [email protected]

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July 2019 655 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Topical Ozenoxacin Cream 1% for Impetigo: A Review Lawrence Schachner MD FAAD,a Anneke Andriessen PhD,B Neal Bhatia MD,c Ayman Grada MD MS,d Dillon Patele aDivision of Pediatric Dermatology, Department of Dermatology and Cutaneous Surgery; Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL BRadboud UMC Nijmegen, Andriessen Consultants, Malden, The Netherlands cDSB Consulting LLC, Del Mar, CA DDepartment of Dermatology, Boston University School of Medicine, Boston, MA EBiochemistry and Cell Biology, UC San Diego, Class of 2017, San Diego, CA

ABSTRACT

Background: Impetigo, a bacterial infection that is highly contagious, involves the superficial skin. Topical treatment for impetigo includes amongst other bacitracin, gentamycin, mupirocin, retapamulin, and more recently, ozenoxacin 1% cream. For more severe conditions systemic antibiotics are prescribed and may be combined with a topical treatment. The current review explored the challenges in treating impetigo in pediatric and adult populations and examined the role of ozenoxacin 1% cream as a safe and effective treatment option. Methods: We performed PubMed and Google Scholar searches of the English-language literature (2010-2018) using the terms impetigo, bullous impetigo, non-bullous impetigo, antimicrobial and antibiotic resistance, mupirocin, retapamulin, and ozenoxacin. The selected publications were manually reviewed for additional resources. Results: Although guidelines were updated regularly, the recommended treatments have not changed much since 2014. Emerging antimicrobial resistance is a growing concern in dermatology and pediatrics. Impetigo therapy choices should consider the resistance pattern of S. aureus. Ozenoxacin 1% cream is a prescription medicine for topical treatment of impetigo in adults and children 2 months or older. Ozenoxacin has a low probability of selecting spontaneous resistant mutants in quinolone-susceptible or quinolone-resistant bacterial strains and has shown to be active against MRSADo isolates.Not CopyOzenoxacin 1% cream has potent bactericidal activity and was shown to be effective and safe for the treatment of impetigo in two well-controlled Phase 3 trials. Conclusions: Resistance patterns in a wide range ofPenalties pathogens against Apply oral or topical antibiotics and antiseptics used for the treatment of dermatological conditions, such as impetigo have been observed. When making treatment decisions for impetigo MRSA and other antimicrobial resistance has to be taken into account. Ozenoxacin 1% cream offers a potent bactericidal activity and has demonstrated clinical efficacy and safety. Combined with its favorable features, such as a low dosing frequency and a 5 days treatment regimen, ozenoxacin 1% cream is an important option for the treatment of impetigo for pediatric and adult populations.

J Drugs Dermatol. 2019;18(7):655-661.

INTRODUCTION mpetigo is a highly contagious bacterial infection involv- contagiosa) is the most common and accounts for around 70% ing the superficial skin, primarily due toS. aureus, less fre- of cases and in the industrialized world is caused by mainly by Iquently S. pyogenes, or both. It occurs most frequently in S. aureus.2 However, S. pyogenes remains a common cause of children ages two to six year but may affect younger and older nonbullous impetigo in developing nations. Clinically, nonbul- children and adults as well. Self-inoculation and small family lous impetigo presents as erythematous pustules or vesicles or communities outbreaks are common. There are more than (red sores) that quickly evolve into superficial erosions with 3 million cases of impetigo in the United States every year.1 a characteristic "honey-colored" crusts. Lesions usually in- Impetigo may be classified as a primary (direct bacterial inva- volve the face, around the nose and mouth, but can be seen sion of an intact skin) or secondary infection of pre-existing skin on extremities and trunk. The lesions are often smaller than disease or traumatized skin (atopic dermatitis, scabies, cuts, 2 cm, not or minimally painful and without erythema or con- abrasions, insect bites, and chickenpox)2,3 Secondary impetigo stitutional symptoms, although regional adenopathy may be is sometimes referred to as "impetiginization." present.1,2 More severe forms of impetigo may be associated with pruritus, erythema, crusted erosions, fissures, and odor. Two clinical forms of impetigo are recognized: (1) nonbullous Bullous impetigo is less common, usually intertriginous areas, and (2) bullous. The nonbullous type (also known as impetigo and is caused by strains of S. aureus that produce exfoliative Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

656 Journal of Drugs in Dermatology L. Schachner, A. Andriessen, N. Bhatia, et al July 2019 • Volume 18 • Issue 7

TABLE 1. toxin A, a toxin that causes cleavage of very superficial epidermal layers by targeting the protein desmoglein.1 Lesions are Current Topical Antibiotics for Impetigo usually large, transparent superficial flaccid bullae before rup- Type of Ozenoxacin Mupirocin Retapamulin 28 30 29 turing, leaving round erosions that become crusted often with Treatment 1% Cream 2% Ointment 1% Ointment erythematous plaques. Bullous impetigo occurs frequently Indication Impetigo due Impetigo due S. aureus in intertriginous areas and is exclusively caused by S. aureus to S. aureus, to S. aureus or (methicillin- including S. pyogenes susceptible which is often colonized from the nose.2 The skin infection does MRSA, or in patients 2 isolates only) not penetrate below the epidermal-dermal junction and is to be S. pyogenes months of age or S. pyogenes distinguished from eg herpes simplex infections, Pseudomo- in patients 2 and older. in patients aged nas aeruginosa infections, scabies, thermal injury, and allergic months of age 9 months and contact dermatitis.2,4 Impetigo typically resolves within two to and older. older. three weeks without scarring and complications.5 Complica- Frequency Twice daily 3 Times daily Twice daily tions of non-bullous impetigo are rare but local and systemic and period of for 5 days for 7-10 days for 5 days spread of infection can occur that may result in cellulitis, lym- application phangitis, or septicemia. Non-infectious complications of S. Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes (S. pyogenes) pyogenes infection include scarlet fever, guttate psoriasis, and 5 post-streptococcal glomerulonephritis. TABLE 2. Current Oral Antibiotics for Impetigo Treatment options include topical antibiotics such as mupi- Extensive Infection: Oral Antibiotics rocin, retapamulin or oral antibiotic therapy eg, amoxicillin/ clavulanate, dicloxacillin, cephalexin, clindamycin, doxycycline, Not MRSA infection MRSA Infection minocycline, trimethoprim/ sulfamethoxazole, and macrolides. Dicloxacillin 250 mg 4 times Vancomycin +/- Rifampin 300 mg There are increasing concerns about antibiotic and antiseptic daily for 1 week 3 times a day for 10 days 6 resistance, especially those that are applied topically. Cephalexin 250 mg 4 times Clindamycin 300 to 600 mg 4 daily for 1 week times daily for 7 days METHODS *Erythromycin 250 mg 4 times Trimethoprim-Sulfamethoxazole The target group of this review included dermatologists,Do Notpe- Copydaily for 1 week 160/800 mg twice daily for 7 days diatricians and general practitioners involved in impetigo Amoxicillin/Clavulanate 875 Tetracycline 500 mg 4 times daily treatment. To explore challenges in treating impetigo,Penalties particular- Applymg/125 mg PO BID for 7 days for 7 days ly in a pediatric population, and to review the role of ozenoxacin Telavancin 1% cream, we performed PubMed and Google Scholar searches Linezolid of the English-language literature (2010-2018) using the terms Daptomycin impetigo, bullous impetigo, non-bullous impetigo, antimicrobi- Methicillin-resistant Staphylococcus aureus (MRSA) al resistance, antibiotic resistance, mupirocin, retapamulin, and ozenoxacin. Relevant publications were manually reviewed for additional resources. cline, trimethoprim/ sulfamethoxazole, and macrolides (Table 2).3,7-10 Second line therapies comprise among others intrave- Therapeutic Options for Impetigo nous antibiotics and topical antiseptics, and third line therapies Both mild- to- moderate non-bullous and bullous types of impe- include systemic antibiotics, topical antibiotics, plus a treatment tigo typically resolve within two to three weeks without scarring addressing S aureus to reduce nasal and pharyngeal coloniza- and complications.5 Severe disease, however, can result in cel- tion to prevent cross infection.3,7-10 In case of a suspected MRSA lulitis, osteomyelitis, or septicemia.5 infection, oral antibiotics such as vancomycin, tetracycline, or linezolid are considered.7-10 For additional treatment and/or Therapeutics recommended in guidelines7-10 and from a meta- maintenance bleach baths with hypochlorites twice a week for analysis have been updated9 regularly but did not change much 10 minutes may be used.7-10 since 2014.9,10 Cleansing and crust removal is a part of the treatment of impetigo.3, 7-10 Previously FDA-approved topical Antibiotic and Antiseptic Resistance in Skin Infections therapies included mupirocin and retapamulin.3,7-10 Other topical The World Health Organization (WHO) recognizes antimicrobial therapies for treating impetigo include bacitracin, polymyxin, resistance (AR) as a “rapidly evolving health issue extending erythromycin, neomycin, gentamycin, mupirocin, retapamu- far beyond the human health sector”. 11,12 Antimicrobial stew- lin, and more recently, ozenoxacin (Table 1).3,7-10 Oral treatment ardship is critical to optimizing the use of antibiotics while options for antibiotic therapy include amoxicillin/clavulanate, preventing the development of resistance and improving pa- dicloxacillin, cephalexin, clindamycin, doxycycline, minocy- tient outcomes.11 Antimicrobial stewardship has been defined Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

657 Journal of Drugs in Dermatology L. Schachner, A. Andriessen, N. Bhatia, et al July 2019 • Volume 18 • Issue 7

as “the optimal selection, dosage, and duration of antimicro- medications. Therefore, these topical treatments are preferred bial treatment that results in the best clinical outcome for the for localized mild-to-moderate impetigo.3,7-10 treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance”.13 Ozenoxacin Cream 1%: Efficacy and Safety Ozenoxacin (XepiTM, Cutanea Life Sciences) 1% cream is the only The authors of the current review noted that dermatologists FDA approved non-fluorinated quinolone for the topical treat- are among the most frequent prescribers of topical antibiot- ment of impetigo in adults and children 2 months or older.19,20 ics. Resistance patterns in a wide range of pathogens against Ozenoxacin acts as a potent selective inhibitor of DNA replica- oral or topical antibiotics and antiseptics used for the treatment tion, blocking the bacterial DNA gyrase A and the topoisomerase of dermatological conditions, such as atopic dermatitis, acne, IV enzymes, which are critical enzymes for the transcription and and impetigo have been observed.14-16 AR such as in methicil- replication processes of bacterial DNA.21-23,24 The 1% cream lin-resistant Staphylococcus aureus (MRSA) is threatening to has been shown to have potent bactericidal activity against compromise the effectiveness of crucial medical treatments.12 Gram-positive pathogens associated with skin infections.19-23, 25 S. aureus resistance against erythromycin and cloxacillin A multicenter, randomized, placebo-controlled, parallel, blinded treatment has moved therapy towards first-generation cepha- study20 compared ozenoxacin 1% cream with its vehicle (place- losporins and/or topical antimicrobials.14-16 Moreover, there is bo) and retapamulin 1% ointment. In this trial, retapamulin was an increase in resistance against clindamycin, its susceptibility included as an internal validity control. Treatments were applied decreased from 90% to 83%.17 twice daily for 5 days and assessments during follow-up visits were carried out at 3-4 days, 6-7 days, and 10-13 days. The 335 Retapamulin is indicated for the topical treatment of impetigo included pediatric patients of 2 years of age and older had non- due to Staphylococcus aureus (methicillin-susceptible isolates bullous (368 (79.3%) and bullous (96 (20.7%) impetigo. Clinical only) or Streptococcus pyogenes in patients aged 9 months or success was defined as a total Skin Infection Rating Scale (SIRS) older.7-10 score 0 for exudates/pus, crusting, tissue warmth and pain, and no more than 1 for each for erythema/inflammation, tissue Topical mupirocin was frequently used for the treatment of edema, and itching. No additional antimicrobial therapy of the impetigo and has been an important component in MRSA pre- baseline affected areas necessary. The clinical success rate de- vention, however; reports of increasing mupirocin resistanceDo Not finedCopy as clinical cure for ozenoxacin 1% cream was significantly are of serious concern.14,16 A retrospective study evaluated 358 superior to placebo (success rate 54 (34.8%) versus 30 (19.2%); S. aureus isolates taken between May 2012 andPenalties September P Apply=0.003.20 Expanded criteria for clinical success including clini- 2013, from 249 children who visited an outpatient dermatology cal cure and improvement were also assessed as a post hoc clinic.18 At the time of the first culture, 19.3% had mupirocin-re- analysis. (Figure 1). Microbiological success after 3-4 days was sistant S. aureus isolates, 22.1% of subjects presenting with an 109 (70.8%) for ozenoxacin 1% cream and 58 (38.2%) for placebo S. aureus infection had a mupirocin-resistant isolate and 31.3% and 122 (79.2%) for ozenoxacin 1% cream versus 86 (56.6%) of all collected S. aureus isolates showed resistance to mupi- for placebo after 6-7 days (Figure 2).20 Moreover, ozenoxacin rocin.18 Prior mupirocin impetigo treatment the children had 1% cream application resulted in a more rapid microbiological received was strongly correlated (odds ratio [OR]26.5; P<0.001) clearance than retapamulin.20 with mupirocin resistance.18 Rosen et al conducted a randomized clinical trial19 evaluating A cross-sectional study of children and adults evaluated samples and comparing clinical efficacy and safety of ozenoxacin 1% of those diagnosed with atopic dermatitis and S. aureus coloni- cream and placebo in 139 adults and 272 children with non- zation.6 A total of 91 subjects were included and 100 S. aureus bullous and bullous impetigo. Ozenoxacin 1% cream or placebo isolates were analyzed.6 All strains were methicillin-susceptible was applied twice daily for 5 days. Cure/clinical success was de- S. aureus.6 The study showed a prevalence of mupirocin resis- fined as a total Skin Infection Rating Scale (SIRS) score 0 for tance of 5.9%, fusidic acid resistance of 1.1%, and high levels of exudates/pus, crusting, tissue warmth and pain, and no more neomycin and bacitracin resistance (42.6% and 100%, respec- than 1 for each for erythema/inflammation, tissue edema, and tively).6 Fusidic acid resistance was found to be associated with itching. No additional antimicrobial therapy of the baseline af- more severe atopic dermatitis.6 fected areas necessary.19 Clinical improvement was defined as >10% decrease in total Skin Infection Rating Scale (SIRS) score Topical agents that are effective in treating skin infections compared with baseline.19 Expanded criteria consider clinical caused by resistant strains are developed that may help to success as clinical cure and improvement. avoid resistance and adverse effects from the use of antibiotics. Moreover, topical formulations deliver treatment directly to the The clinical cure rate for ozenoxacin 1% cream at the 6-7 days site of infection with low systemic absorption compared to oral assessment was significantly superior to placebo 112 (54.4%) Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

658 Journal of Drugs in Dermatology L. Schachner, A. Andriessen, N. Bhatia, et al July 2019 • Volume 18 • Issue 7

FIGURE 1. Clinical response at the end of the therapy. Cure/clinical success was defined as a total Skin Infection Rating Scale (SIRS) score 0 for exudates/pus, crusting, tissue warmth and pain, and no more than 1 for each for erythema/inflammation, tissue edema, and itching. No additional antimicrobial therapy of the baseline affected areas necessary.26 Expanded criteria consider clinical success as clinical cure and improvement. Clinical improvement was not presented and therefore is not comparable to other topical antibiotics where assessment of efficacy also includes clinical improvement.

P=0.0276 P=0.085 90.00% 85.20% 83.10% 80.00% 73.70% 70.00%

60.00% Figure 2: BacteriologicalP=0.003 responseP=0.001 at day 3-4 and at day 6-7 (end of therapy). 50.00% Eradication/microbiological success was defined as: The absence of the original 37.70% 40.00% 34.80% pathogen(s) from visit 1 in specimen taken from the baseline affected area (with 30.00%

19.20% 26 or20.00% without the presence of any new microorganisms). At 3-4 days follow up,

10.00% P-values for microbiologicaln = 54 n =30 success:n = 58 ozenoxacinn vs= 132 placebo, n = 115 P < 0.0001;n = 128 0.00% retapamulin vsClinical placebo, Success (primaryP=0.0004; end point) ozenoxacin Clinical vs Success retapamulin, with expanded P=0.0087. criteria (post-hoc At 6- analysis) 7 days follow up (end of study),Ozenoaxacin P valuesPlacebo for microbiologicalRetapamulin success:

Do Not Copy ozenoxacin vs placebo, P<0.0001; retapamulin vs placebo, P<0.0001; FIGURE 2. Bacteriological response at day 3-4 and at day Penalties6-7 (end of therapy). ApplyEradication/microbiological success was defined as: The absence of the original pathogen(s)Figureozenoxacin from visit1: Clinical 1 invs specimen retapamulin, response taken from Pat=1.0000. thethe baselineend 26of affectedthe therapy area (with. Cure or without/clinical the success presence was of any new microorganisms).26 At 3-4 days follow up, P-values for microbiological success: ozenoxacin vs placebo, P< 0.0001; retapamulin vs placebo, P=0.0004; ozenoxacin vs retapamulin, P=0.0087. At 6-7 days follow up (end of study), P values for microbiological success: ozenoxacin vs placebo, P<0.0001; retapamulin

vs placebo, P<0.0001;defined ozenoxacin as avs total retapamulin, Skin Infection P=1.0000.26 Rating Scale (SIRS) score 0 for exudates/pus,

crusting, tissue warmth and pain, and no more than 1 for each for 90.00% 81.70% 79.20% erythema/inflammation,80.00% tissue edema, and itching. No additional antimicrobial 70.80% therapy70.00% of the baseline affected areas necessary.26 Expanded criteria consider

60.00% 56.90% 56.60% clinical success as clinical cure and improvement. Clinical improvement was 50.00% not presented and therefore is not comparable to other topical antibiotics where 40.00% 38.20%

assessment30.00% of efficacy alsoP<0.0001 includes clinical improvement.

20.00%

10.00%

n = 109 n = 58 n = 87 n = 122 n = 86 n = 86 0.00% Visit 2 (day 3-4) Visit 3 (day 6-7)

Ozenoxacin Placebo Retapamulin

659 Journal of Drugs in Dermatology L. Schachner, A. Andriessen, N. Bhatia, et al July 2019 • Volume 18 • Issue 7

FIGURE 3. Clinical response at the end (day 6-7 assessment) of the therapy in ITT population. Cure/clinical success was defined as a total Skin Infection Rating Scale (SIRS) score 0 for exudates/pus, crusting, tissue warmth and pain, and no more than 1 for each for erythema/inflammation, tissue edema, and itching.Fig 3: ClinicalNo additional response antimicrobial at the endtherapy (day of 6-7the assessment)baseline affected of theareas therapy necessary. in ITT19 For population the main outcome, the treatment comparison used only the outcomes of success and clinical failure. Clinical improvement was defined as >10% decrease in total Skin Infection Rating Scale (SIRS) score compared with baseline.19 Expanded criteria consider clinical success as clinical cure and improvement.

100% P = 0.003 88.8% 90% P < 0.001 78% 80%

70%

60% 54.4% 50% 38% 40% 30% Clinical success (%) 20%

10% n = 122 n = 78 n = 183 n = 161 0% Clinical Success (primary endpoint) Clinical Success with expanded criteria (secondary endpoint) Ozenoxacin Placebo

Do Not Copy FIGURE 4. Microbiological response at day 3-4 and at dayPenalties 6-7 (end of therapy) Apply in the ITT population. Overall microbiological success was defined as eradication, a compositeCure/clinical of documented success was eradication defined as(absence a total ofSkin the Infection original pathogen Rating Scale from (SIRS)the posttreatment score 0 for culture of the specimen obtained from the original site of infection) and presumed eradication (complete resolution of signs and symptoms associated with the absence of culturable material).exudates/pus,19 P values were crusting, calculated tissue using warmth the χ2 test and (without pain, and continuity no more correction). than 1 19for each for

erythema/inflammation, tissue edema, and itching. No additional antimicrobial therapy of 100.00% 19 92.00% the baseline affected87.20% areas necessary. For the main outcome, the treatmentP<0.005 comparison 90.00% P<0.002

80.00%used only the outcomes of success and clinical failure. 73.10% 70.00% Clinical improvement was defined63.90% as >10% decrease in total Skin Infection Rating Scale 60.00% (SIRS) score compared with baseline.19 Expanded criteria consider clinical success as clinical 50.00%

40.00%cure and improvement.

30.00%

20.00% 10.00% n = 109 n = 76 n = 115 n = 87 0.00% Visit 2 (day 3-4) Visit 3 (day 6-7)

Ozenoxacin Placebo

Figure 4: Microbiological response at day 3-4 and at day 6-7 (end of therapy) in the ITT population. Overall microbiological success was defined as eradication, a composite of documented eradication (absence of the original pathogen from the posttreatment culture of the specimen obtained from the original site of infection) and presumed eradication (complete resolution of signs and symptoms associated with the absence of culturable material).19 P values were calculated using the χ2 test (without continuity correction).19

660 Journal of Drugs in Dermatology L. Schachner, A. Andriessen, N. Bhatia, et al July 2019 • Volume 18 • Issue 7

versus 78 (37.9%); P<0.001 (Figure 3). Expanded criteria for clini- absorption suggesting a favorable safety profile. cal success which included clinical cure and improvement were also assessed as a secondary outcome (Figure 3).19 Microbio- DISCLOSURES logical success after 3-4 days was 109 (87.2%) for ozenoxacin 1% The authors disclosed receipt of the following financial support cream and 76 (63.9%) for placebo (P<0.002) and 115 (92.0%) for for the research, authorship, and/or publication of this article: ozenoxacin 1% cream versus 87 (73.1%) for placebo (P<0.005) This work was supported by an unrestricted educational grant after 6-7 days (Figure 4).19 from Cutanea Life Sciences.

Overall, the rate of selection of resistant mutants of ozenoxa- REFERENCES cin is lower than the observed with ciprofloxacin and similar 1. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048837.htm 2. Bacterial Diseases. In: Bolognia J, Jorizzo JL, Schaffer JV, ed. Dermatology. or lower than the observed with levofloxacin in methicillin‐sen- 3rd ed. Elsevier Saunders; 2012:1187-1189. sitive S. aureus (MSSA), methicillin‐sensitive S. epidermidis 3. Simkin DJ, Grossberg AL, Cohen BA. Bullous impetigo rapid diagnostic and (MSSE) and MRSA organisms.23 Ozenoxacin has demonstrated therapeutic quiz: a model for assessing basic dermatology knowledge of primary care providers. Pediatr Dermatol. 2016 Nov;33(6):627-631. efficacy versusS. aureus (including MRSA, Mupirocin-resistant 4. Bowen AC, Mahé A, Hay RJ, Andrews RM, Steer AC, Tong SYC, et al. Staph aureus, Ciprofloxacin resistant Staph aureus) and S. pyo- The global epidemiology of impetigo: a systematic review of the population prevalence of impetigo and pyoderma. Reid SD, editor. PLoS One. 19,20,23 genes. 2015;10(8):e0136789 5. Koning S, van der Sande R, Verhagen AP, et al. Interventions for impetigo. Cochrane Database Syst Rev. 2012;(1):CD003261. Ozenoxacin demonstrated clinical and microbiological success 6. Bessa GR, Quinto VP, Machado DC, et al. Staphylococcus aureus resistance in pediatric and adult subjects treated for impetigo.19,20 The faster to topical antimicrobials in atopic dermatitis. Anais Brasileiros de Dermato- microbiological success of the ozenoxacin 1% cream compared logia. 2016;91(5):604-610. 7. Stevens BL, Bisno AL, Chambers HF, et al. Practice guidelines for the diag- to retapamulin could lead to a more rapid resolution of infectiv- nosis and management of skin and soft skin infections; 2014 update by the ity for the individual and their contacts. Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):147-159. 8. Van Bijnen EME, Paget J, den Heijer CDJ, et al. Evidence-based primary care treatment guidelines for skin infections in Europe: A comparative analysis. The in vitro activity of ozenoxacin against Pseudomonas aeru- European J Gen Practice. 2014;20:294-300. 9. Lebwohl, Heymann WR, Berth-Jones J, et al. Treatment of Skin Disease: ginosa has been shown to be greater than that of nadifloxacin, Comprehensive Therapeutic Strategies, 4th ed. Elsevier. 2014. 332-334. clindamycin, erythromycin, and gentamicin, but less than that 10. Lebwohl MG, Heymann WR, Berth-Jones J, et al, Treatment of skin disease of ofloxacin and levofloxacin. However, the therapeutic efficacy comprehensive therapeutic strategies 5th Edition Elsevier 2018 369-371. Do Not 11.Copy Palmer GH, Call DR. Antimicrobial resistance: a global public health chal- of ozenoxacin against Pseudomonas aeruginosa has not been lenge requiring a global One Health strategy [commentary]. Washington, evaluated.24 Penalties ApplyDC: Institute of Medicine of the National Academies; 2013. http://www.iom. edu/Global/ Perspectives/2013/AntimicrobialResistance. Accessed Septem- ber 3, 2018. Dermal application studies measuring ozenoxacin levels dem- 12. Wernli D, Jørgensen PS, Harbarth S, et al. Antimicrobial resistance: The complex challenge of measurement to inform policy and the public. PLOS Med. onstrated negligible systemic absorption suggesting a safety 2017; (8):1-9. https://doi.org/10.1371/journal.pmed.1002378 advantage versus oral antibiotics.26 Moreover, ozenoxacin 1% 13. Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc. cream offers a safe and effective alternative for existing topical 2011;86(11):1113-1123 14. Thum D, Seidl HP, Hein R, et al. Current resistance patterns of Staphylo- therapies such as fusidic acid27 and mupirocin4 that have shown coccus aureus towards topical antibiotics and relevant antiseptics in pa- resistance patterns in a wide range of pathogens, used for the tients with atopic dermatitis and impetigo. J Dtsch Dermatol Ges. 2013 Sep;11(9):875-8. doi: 10.1111/ddg.12111. treatment of dermatological conditions such as impetigo. 15. Bangert S, Levy M, Hebert AA. Bacterial resistance and impetigo treatment trends: a review. Pediatr Dermatol. 2012;29(3):243–248. CONCLUSIONS 16. Poovelikunnel T, Gethin G, Humphreys H. Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA. J Antimicrob Emerging antimicrobial resistance is a growing concern in der- Chemother. 2015; 70: 2681–2692 matology. Treatment decisions for impetigo should consider 1 7. Sutter DE, Milburn E, Chukwuma U, et al. Changing susceptibility of Staphy- lococcus aureus in a US pediatric population. Pediatrics. 2016 April;137(4) resistance pattern of S. aureus. Ozenoxacin 1% cream is a novel e20153099; DOI: 10.1542/peds.2015-3099. prescription medicine, FDA-approved for the topical treatment 18. Antonov NK, Garzon MC, Morel KD, Whittier S, Planet PJ, Lauren CT. High prevalence of mupirocin resistance in Staphylococcus aureus iso- of impetigo in adults and children 2 months or older. Efficacy lates from a pediatric population. Antimicrobial Agents and Chemotherapy. and safety of ozenoxacin cream 1% for the treatment of impeti- 2015;59(6):3350-3356. 19. Rosen T, Albareda N, Rosenberg N, et al. Efficacy and safety of ozenoxacin go has been demonstrated in two adequate and well-controlled cream for treatment of adult and pediatric patients with impetigo a random- Phase 3 trials. Ozenoxacin has demonstrated potent bactericidal ized clinical trial. JAMA Dermatol. 2018;154(7):806-813. doi:10.1001/jamader- activity and has shown to be active against MRSA isolates and matol.2018.1103 20. Gropper S, Albareda N, Chelius K, et al. Ozenoxacin 1% cream in the treat- has a low probability of selecting spontaneous resistant mu- ment of impetigo: a multicenter, randomized, placebo- and retapamulin- tants in quinolone-susceptible or quinolone-resistant bacterial controlled clinical trial. Future Microbiol. 2014;9(9):1013-23. doi: 10.2217/ fmb.14.78. strains. Ozenoxacin 1% cream offers a lower dosing frequen- 2 1. López Y, Tato M, Espinal P et al. In vitro activity of ozenoxacin against qui- cy and shorter treatment regimen. Dermal application studies nolone-susceptible and quinolone-resistant Gram-positive bacteria. Antimi- crob. Agents Chemother. 2013;57:6389–6392. measuring ozenoxacin levels demonstrate negligible systemic 22. Sissi C., Palumbo M. In front of and behind the replication fork: bacterial type Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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IIA topoisomerases. Cell Mol Life Sci. 2010; 67:2001–2024. 23. Tarrago´ C, Perez Esquirol L, Arano A, Lachamp L, D’Aniello F, Zsolt I. Ther- apeutic efficacy of ozenoxacin in animal models of dermal infection with Staphylococcus aureus. Future Microbiol. 2018;13(6s): 21–30. 24. Yamakawa T, Mitsuyama J, Hayashi K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J Antimicrob Chemoth- er. 2002 Mar;49(3):455-65. PubMed PMID: 11864945. 25. Canton R, Morrissey I, Vila J, Tato M, García-Castillo M, López Y, Gargallo-Vi- ola D, Zsolt I. Comparative in vitro antibacterial activity of ozenoxacin against Gram-positive clinical isolates. Future Microbiol. 2018 May 1;13:3-19. doi: 10.2217/fmb-2017-0289. PubMed PMID: 29745242. 26. Gropper S, Albareda N, Santos B, Febbraro Sl. Systemic bioavailability, safety and tolerability of topical ozenoxacin in healthy adult volunteers. Future Mi- crobiol. 2014;9(8)(suppl):S11-S16. 2 7. Alsterholm M, Fytström I, Bergbrant JM, Faergemann J. Fusidic acid resistant S aureus in impetigo contagiosa and secondarily infected atopic dermatitis. Acta Derm Venereol. 2010;90(1):52-57. 28. Ozenoxacin 1% cream, Reference ID:4191582: https://www.accessdata.fda. gov/drugsatfda_docs/nda/2017/208945orig1s000sumr.pdf 29. Retapamulin 1% ointment, Reference ID: 3236062: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022055s002lbl.pdf 30. Mupirocin 2% ointment, Reference ID: 4094349: https://www.accessdata. fda.gov/drugsatfda_docs/label/2017/050591s034lbl.pdf 3 1. Silverberg N, Block S. Uncomplicated skin and skin structure infections in children: diagnosis and current treatment options in the United States. Clin Pediatr (Phila). 2008;47(3):211–219.

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July 2019 663 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Laser-Assisted Delivery of Topical Cidofovir in the Treatment of Plantar Warts Margaret Coates BA,a Jigar Patel MD,b Courtney Powers PA-C,b Claude Burton MDb aDuke University School of Medicine, Durham, NC bDuke University Medical Center, Durham, NC

ABSTRACT

Recalcitrant plantar warts pose a therapeutic challenge. Cidofovir is a viral DNA polymerase inhibitor that has been used in treatment of verrucae with greater success than traditional treatments in some cases. Laser-assisted drug delivery enhances drug penetration beyond the epidermis and is particularly well-suited, though under-utilized, to target palmoplantar verrucae. We report the use of an erbium:yttrium-aluminum-garnet (Er:YAG) ablative fractional laser (AFL) followed by topical cidofovir in treating recalcitrant plantar warts. Two patients were treated with a 2940-nm Er:YAG laser at depths of 1.2-1.5 mm followed by topical application of cidofovir 75 mg/mL. Both patients exhibited a significant reduction in lesion size and improvement in symptoms. AFL-assisted delivery of topical cidofovir represents a promising therapeutic option for recalcitrant plantar warts.

J Drugs Dermatol. 2019;18(7):663-665.

INTRODUCTION he treatment of plantar warts is challenging and current options for recalcitrant warts, with clearance rates reported be- therapies often do not result in satisfactory clearance of tween 47% and 100%.14 For example, one study showed that Tverrucae.1 A large number of plantar warts, particularly treatment with Er:YAG followed by topical podophyllotoxin those that are large and hyperkeratotic, are recalcitrantDo to first- Not resultedCopy in complete lesion clearance in 89% of patients with line treatments. For instance, cryotherapy and salicylic acid plantar warts.15 In this report, we describe two cases of refrac- have not demonstrated superiority compared to a wait-and-seePenalties tory Apply plantar verrucae treated with Er:YAG and topical cidofovir. approach.2 CASE REPORTS Numerous therapeutic modalities have been utilized in the Patient 1 treatment of plantar warts, including topical cantharidin-podo- A 59-year-old male presented with an eight-year history of a phyllotoxin-salicylic acid,3 topical trichloroacetic acid,4 topical gradually enlarging painful verrucous tumor on the right heel 5% imiquimod,5 intralesional mumps, Candida, or Trichophyton that made it difficult to wear closed footwear. A biopsy was antigen,6 and intralesional 5-fluorouracil.7 Cidofovir, a nucleo- consistent with verruca. This lesion had been previously treated tide analogue, is a potent inhibitor of viral DNA polymerase but with excision, salicylic acid, and cantharidin. He then received is nephrotoxic when administered systemically.8 Local adminis- three treatments with pulsed dye laser and 40% urea cream; ini- tration of this medication shows significant promise for treating tial improvement was noted, but the lesions exhibited recurrent HPV-related verrucous neoplasms. Treatment with intralesional growth within weeks. A trial of AFL-assisted delivery of topical cidofovir has demonstrated complete clearance of plantar warts cidofovir 75mg/mL was proposed. Pre-treatment examination in up to 98% of patients.9 Despite recent advances in therapeu- demonstrated a 5.5 x 4 cm yellow hyperkeratotic verrucous tic options for plantar warts, patients with symptomatic, large tumor on the right posterior heel (Figure 1A). Treatment was ini- verrucous nodules and tumors remain a therapeutic challenge. tiated with a 2940-nm Er:YAG laser with a 5-mm-spot size, short pulse pattern with a density of 11% and 1.5 mm depth. Following Ablative fractional lasers (AFLs) can be utilized to facilitate drug each laser treatment, 1 mL of cidofovir 75mg/mL was applied delivery beyond the stratum corneum and target lesions located topically to the treated area and was covered with an occlusive within the deeper epidermis and dermis. This technique, known transparent medical dressing for 1 hour (Figure 1B). Following as laser-assisted drug delivery (LAD), has been utilized for nine serial treatments every two to six weeks, the lesion demon- various cutaneous applications in treating actinic keratoses,10 strated approximately 60% decrease in tumor size with islands non-melanoma skin cancers,11,12 and hypertrophic scars.13 Sev- of complete clearance and markedly decreased hyperkeratosis; eral AFLs, including erbium:yttrium-aluminum-garnet (Er:YAG) furthermore, the patient was able to resume wearing closed and carbon dioxide (CO2), are emerging as new treatment footwear (Figure 1C). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

664 Journal of Drugs in Dermatology M. Coates, J. Patel, C. Powers, C. Burton July 2019 • Volume 18 • Issue 7

Techniques such as paring down the verruca with a scalpel have FIGURE 1. (A) Patient 1 pre-treatment. (B) Application of topical 17 cidofovir after treatment with AFL. (C) Patient 1 after 9 treatments. been used to improve drug delivery. A new approach to increasing drug absorption beyond the stratum corneum is the (A) (B) (C) use of AFLs. AFLs are able to create microthermal zones: multiple vertical cylinders of thermal ablation that penetrate the epidermis.18 These microthermal zones facilitate drug delivery by allowing increased absorption of topical medications.

Cidofovir, a nucleoside analog, has broad activity against many DNA viruses including all herpes viruses. However, systemic cidofovir has numerous side effects including nephrotoxicity.19 Topical and intralesional treatment of refractory verruca with ci- Patient 2 dofovir has shown promising clearance rates in multiple case A 44-year-old male presented with a two-year history of plantar studies.9,20,21 Local delivery of this antiviral via intralesional injec- warts on the right forefoot and right medial fourth toe associated tions has shown complete clearance in both immunocompetent with pain on ambulation. He had previously received treatment and immunocompromised patients.9 Padilla et al. have reported with liquid nitrogen every two weeks for six months without im- 80% of patients demonstrating improvement with topical cido- provement. He then underwent four treatments with a pulsed fovir alone.21 We extended this therapeutic concept by utilizing dye laser without any improvement in lesion size or symptoms. an AFL to further enhance delivery of cidofovir to the target tis- Pre-treatment examination demonstrated numerous verrucous sue. Our two patients with recalcitrant verruca treated with AFL papules coalescing into a plaque on the right plantar forefoot and topical cidofovir demonstrated a modest to significant re- and a six mm verrucous papule on the right plantar fourth toe duction in lesion size and improvement in symptoms. (Figure 2A). Subsequently, he received five treatments with a 2940-nm Er:YAG laser and 0.5 mL of 75 mg/mL cidofovir as in CONCLUSION the same protocol described above. After five treatments, the Plantar warts, particularly large, hyperkeratotic nodules and tu- right forefoot demonstrated 80% clearance and the right fourth mors, are challenging to treat effectively and most conventional toe demonstrated 100% clearance (Figure 2B). Do Not treatmentsCopy yield unsatisfactory results. The use of AFLs to create microthermal zones has been utilized in drug delivery for FIGURE 2. (A) Patient 2 pre-treatment. (B) Patient 2 after Penalties5 treatments. various Apply dermatological applications. We described two cases of Er:YAG-assisted delivery of topical cidofovir for the treatment of (A) (B) recalcitrant plantar warts with positive results. Although these results are promising, additional studies are needed to further validate this treatment modality and develop a standardized protocol. DISCLOSURES The authors declare no disclosures. REFERENCES Both patients demonstrated a substantial decrease in the size 1. Vlahovic TC, Khan MT. The human papillomavirus and its role in plantar warts: a comprehensive review of diagnosis and management. Clin Podiatr Med of their verrucous lesions. Furthermore, there was a significant Surg. 2016;33(3):337-353. improvement in symptoms. There was mild localized erythema 2. Bruggink SC, Gussekloo J, Berger MY, et al. Cryotherapy with liquid nitrogen and edema following each treatment that resolved within 24 versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010;182(15):1624-1630. hours. 3. Lopez Lopez D, Vilar Fernandez JM, Losa Iglesias ME, et al. Safety and effectiveness of cantharidin-podophylotoxin-salicylic acid in the treatment of DISCUSSION recalcitrant plantar warts. Dermatol Ther. 2016;29(4):269-273. 4. Pezeshkpoor F, Banihashemi M, Yazdanpanah MJ, Yousefzadeh H, Sharghi AFLs are a promising therapeutic option for difficult-to-treat M, Hoseinzadeh H. Comparative study of topical 80% trichloroacetic acid with 35% trichloroacetic acid in the treatment of the common wart. J Drugs cutaneous lesions, including plantar warts. Topical medications Dermatol. 2012;11(11):e66-69. are often ineffective in treating these keratotic neoplasms in 5. Stefanaki C, Lagogiani I, Kouris A, Kontochristopoulos G, Antoniou C, Kat- large part due to impaired drug delivery to deeper zones of viral sarou A. Cryotherapy versus imiquimod 5% cream combined with a kerato- lytic lotion in cutaneous warts in children: A randomized study. J Dermatolog replication.1 The stratum corneum serves as a physical barrier Treat. 2016;27(1):80-82. to environmental insults and exposures, including medications; 6. Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: a single- 16 absorption of topical medications is generally less than 5%. blinded, randomized, and controlled trial. Arch Dermatol. 2005;141(5):589-594. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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7. Yazdanfar A, Farshchian M, Fereydoonnejad M, Farshchian M. Treatment of common warts with an intralesional mixture of 5-fluorouracil, lidocaine, and epinephrine: a prospective placebo-controlled, double-blind randomized trial. Dermatol Surg. 2008;34(5):656-659. 8. Toro JR, Sanchez S, Turiansky G, Blauvelt A. Topical cidofovir for the treatment of dermatologic conditions: verruca, condyloma, intraepithelial neo- plasia, herpes simplex and its potential use in smallpox. Dermatol Clin. 2003;21(2):301-309. 9. Broganelli P, Chiaretta A, Fragnelli B, Bernengo MG. Intralesional cidofovir for the treatment of multiple and recalcitrant cutaneous viral warts. Dermatol STILL Ther. 2012;25(5):468-471. 10. Togsverd-Bo K, Haak CS, Thaysen-Petersen D, Wulf HC, Anderson RR, Haed- ersdal M. Intensified photodynamic therapy of actinic keratoses with fractional CO2 laser: a randomized clinical trial. Br J Dermatol. 2012;166(6):1262- AVAILABLE 1269. 11. Wenande E, Olesen UH, Nielsen MM, et al. Fractional laser-assisted topical delivery leads to enhanced, accelerated and deeper cutaneous 5-fluorouracil uptake. Expert Opin Drug Deliv. 2017;14(3):307-317. 12. Roozeboom MH, Aardoom MA, Nelemans PJ, et al. Fractionated 5-ami- nolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up. J Am Acad Dermatol. 2013;69(2):280-287. 13. Waibel JS, Wulkan AJ, Shumaker PR. Treatment of hypertrophic scars using laser and laser assisted corticosteroid delivery. Lasers Surg Med. 2013;45(3):135-140. 14. Nguyen J, Korta DZ, Chapman LW, Kelly KM. Laser Treatment of Nongenital Verrucae: A Systematic Review. JAMA Dermatol. 2016;152(9):1025-1034. 15. Wollina U. Er:YAG laser followed by topical podophyllotoxin for hard-to-treat palmoplantar warts. J Cosmet Laser Ther. 2003;5(1):35-37. 16. Nino M, Calabro G, Santoianni P. Topical delivery of active principles: the field of dermatological research. Dermatol Online J. 2010;16(1):4. Matrix Revisited: 1 7. Lichon V, Khachemoune A. Plantar warts: a focus on treatment modalities. Dermatol Nurs. 2007;19(4):372-375. 18. Shin MK, Park JM, Lim HK, et al. Characterization of microthermal zones induced by fractional radiofrequency using reflectance confocal microscopy: Innovative Approach a preliminary study. Lasers Surg Med. 2013;45(8):503-508. 19. Vora SB, Brothers AW, Englund JA. Renal toxicity in pediatric patients receiving cidofovir for the treatment of adenovirus infection. J Pediatric Infect Dis Soc. 2017;6(4):399-402. Do Not Copy for Tretinoin 20. Gupta M, Bayliss SJ, Berk DR. Topical cidofovir for refractory verrucae in children. Pediatr Dermatol. 2013;30(1):131-134. 2 1. Padilla Espana L, Del Boz J, Fernandez Morano T, ArenasPenalties Villafranca J, Apply de Troya Martin M. Topical cidofovir for plantar warts. Dermatol Ther. 2014;27(2):89-93. This supplement to the AUTHOR CORRESPONDENCE Journal of Drugs in Dermatology is funded by Ortho Dermatologics. Margaret Coates BA E-mail:...... ……...... [email protected] Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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July 2019 667 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC A Head-to-Head Comparison of Topical Collagen Powder to Primary Closure for Acute Full-Thickness Punch Biopsy-Induced Human Wounds: An Internally Controlled Pilot Study Azam Qureshi BA,a Emily Murphy BS,b,c Rose Milando BA,b Monica Rengifo-Pardo MD,b Courtney Clayton,b Adam Friedman MD FAADb,c aUniversity of Maryland School of Medicine, Baltimore, MD BGeorge Washington University School of Medicine and Health Sciences, Washington, DC cGeorgetown University School of Medicine, Washington, DC dGeorge Washington Medical Faculty Associates, Washington, DC

ABSTRACT

Background: Collagen-based products have been implemented in wound healing due to collagen’s hemostatic properties, low antigenicity, and poor culture ability. Objective: To compare the rate and quality of full-thickness wound healing for topical collagen powder and primary closure. Methods: Eight volunteers received one 4 mm punch biopsy on each thigh. One wound was managed with primary closure while the other received daily collagen powder. Wounds were biopsied at four weeks for histopathological analysis. Subjects rated itch, pain, and treatment preferences at weeks 1, 2, 4, 6, and 12. Results: Six out of eight collagen-treated wounds were completely healed 4 weeks after initial wounding. Histologic analysis of the wounds revealed epidermal re-epithelization in both groups. More organized granulation tissue was noted in collagen-treated wounds and confirmed using Masson trichrome and CD31 staining for collagen and neoangiogenesis, respectively. Subjects reported similar itch and pain metrics between wounds. Both subjects and blinded dermatologists preferred the early cosmetic appearance of collagen- treated wounds over primarily closed wounds. Limitations: Small sample size, absence of negative control.Do Not Copy Conclusion: These data suggest that collagen powderPenalties is non-inferior toApply primary closure at the macro- and microscopic levels, while possibly leading to superior early cosmetic outcomes and accelerated histologic wound maturation. Ethics/Clinical Trials Registration: Study was approved by the George Washington University Institutional Review Board (IRB protocol #121745). ClinicalTrials.gov: NCT03481907.

J Drugs Dermatol. 2019;18(7):667-673.

INTRODUCTION ollagen, an essential component of the extracellular rial growth.9,10 Additionally, collagen promotes thrombosis and matrix (ECM), is a triple helical structure composed of hemostasis and has hydrophilic properties useful for absorb- Cthree polypeptide chains.1–3 During normal wound healing fluid in exuding wounds.11,12 These factors make collagen an ing, collagen acts as a scaffold for cellular ingrowth and orga- ideal wound therapy agent. nized deposition of new collagen.2,4 Proteases degrade native collagen, releasing polypeptide fragments that act as chemo- Punch biopsies are frequently performed for diagnostic purpos- tactic molecules to recruit inflammatory mediators, promote es and are often closed primarily with non-absorbable sutures, keratinocyte migration, and stimulate the proliferation of fibro- but may also be left to heal by secondary intention. In a recent blasts and subsequent collagen deposition.2,4,5 Collagen-based survey distributed by the present authors to providers on the dressings and fractionated collagen powders have been devel- Orlando Dermatology Aesthetic and Clinical Conference email- oped for wound therapy as they are thought to replace degrad- ing list, 877 (29.6% response rate) providers completed a survey ed collagen by bypassing enzymatic breakdown.2,4,6 Further- in which only 5.13% of respondents indicated that they leave a more, powdered collagen supports ECM production and acts as 4mm punch biopsy wound open to heal by secondary intention a signaling molecule, recruiting inflammatory cells, fibroblasts, (data not published). Most respondents were MD/DOs (98.6%), and keratinocytes.7, 8 Collagen has low antigenicity and can be with many being in practice for more than 10 years (38.4%, data left in wounds without causing irritation or enhancing bacte- not published). While clearly commonly used, it is important Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

668 Journal of Drugs in Dermatology A. Qureshi, E. Murphy, R. Milando, et al July 2019 • Volume 18 • Issue 7

to note that primary closure (PC) with non-absorbable sutures Biopsy and Treatment requires patients to return to clinic in 1-2 weeks for suture re- Each patient received a single 4 mm punch biopsy on the same moval, which is associated with approximately $250,000 in level of each mid-anterior thigh to provide for internalized con- direct and indirect costs per year based on findings from a sin- trols. One wound was managed with PC, while the other was gle academic center.13 Furthermore, potential adverse effects of treated with daily topical collagen powder for up to four weeks. primary closure include skin allergies to suture materials and Prior to each biopsy, the areas were cleansed with an alcohol infections, with the suture serving as a nidus for infection by swab and anesthetized using 1 mL of 2% lidocaine with epi- promoting microbial adherence and wound contamination.14–18 nephrine. An Integra Miltex 4.0 mm Standard Biopsy Punch Mechanical irritation from the suture can also result in pruritus. instrument was used to create full-thickness wounds and pressure was applied with gauze until hemostasis. Given collagen powder can support ECM development at the wound site without increasing the risk of allergy or infection, Up to one gram of type 1, 100% bovine collagen powder (Nu- management of biopsy wounds with collagen powder may vagenTM, CPN Biosciences, Inc., Largo, FL) was placed on one lead to similar or improved healing outcomes compared to PC. wound before covering it with a non-adherent sterile dressing. Collagen powder also eliminates the need for suture removal, The other wound underwent PC with two epidermal sutures which reduces costs associated with a subsequent clinic visit. (4-0 Ethilon Nylon Sutures, Ethicon, Somerville, NJ) and was This pilot study is the first to compare the utility of topical col- similarly covered with a sterile dressing after application of lagen powder on the rate and quality of full-thickness wound petroleum jelly. At the four week follow-up, wounds were re- healing compared to the gold standard, PC, through histopath- biopsied following the same procedures. ological analysis of healing, and comparison of symptoms and early cosmetic outcomes. For home treatment, patients were provided with collagen powder in one-gram containers and dressings along with the METHODS following instructions: 1) Irrigate the wound with tap water or Patient Selection saline solution, 2) Dry the wound gently with dry gauze, 3) Ap- Approval for this study (ClinicalTrials Registration: NCT03481907) ply up to one gram of collagen powder to the wound, and 4) was obtained from the George Washington University Institu- Apply a sterile dressing. This procedure was repeated daily for tional Review Board (Protocol #121745). Eight healthy volunteersDo Not fourCopy weeks after the first biopsy and until wound closure after 18-75 years old were enrolled after providing informed consent. the second biopsy. For wounds closed primarily, patients were Inclusion and exclusion criteria are presented in TablePenalties 1. instructed Apply to apply petroleum jelly before covering the wounds with sterile dressings once daily until suture removal (two weeks after placement).

TABLE 1. Inclusion and Exclusion Criteria Used in Selection of Eight Healthy Participants. Exclusion criteria included chronic diseases, tobacco use, pregnancy, and other factors that could affect wound healing. Patients with a history of bleeding disorders, keloids, or hypertrophic scars were excluded to minimize adverse effects. DM: Diabetes mellitus. Inclusion: 1. Outpatients 2. Age 18 to 75 years old Exclusion: 1. Presence of any medical (DM) or skin condition that could impair wound healing 2. Recent use of systemic immunosuppressive medications (2 months or 5 half-lives) 3. Recent application of topical steroids to the thigh(s) (2 weeks) 4. Recent participation in investigational study of a drug or device (4 weeks) 5. Current use of systemic antimicrobials 6. History of DM 7. History of bleeding disorders or concomitant treatment with anticoagulants 8. History of keloids or hypertrophic scars 9. Known allergy or sensitivity to any component collagen powder (including bovine products), sutures, or lidocaine and epinephrine 10. Current or previous use of tobacco products 11. Recent alcohol or drug abuse 12. Pregnant females or nursing mothers Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

669 Journal of Drugs in Dermatology A. Qureshi, E. Murphy, R. Milando, et al July 2019 • Volume 18 • Issue 7

Histopathology and Outcome Assessments are reported ± the standard error of the mean (SEM). P-values Immunohistochemical and histopathological processing was were calculated using the two-sample t-test for equal variances performed by HistoWiz, Inc. (Brooklyn, NY) on one baseline with P-values ≤ 0.05 considered significant. sample and both four-week samples, including hematoxylin and eosin (H&E), CD31 (platelet-derived endothelial cell adhe- RESULTS sion molecule-1), and Masson trichrome staining. H&E staining Patient Population was used to examine the quality of the epidermis and colla- All eight subjects (mean age: 37, range: 23-59 years) completed gen bundles as well as to observe the amount of inflammatory the study. Two subjects were female and six were male. One granulation tissue. CD31 antibody staining was performed to as- subject was Fitzpatrick Skin Type (FST) I, three were FST II, one sess the level of angiogenesis. Staining identified to be artifact, was FST III, two were FST III/IV, and one was FST V. All subjects related to large vessels, and outside the wound bed, was ex- reported no, occasional, or moderate alcohol consumption (1 cluded. Masson trichrome staining was used to assess collagen drink per day for women, 2 drinks per day for men). deposition. To determine the percent area stained by Masson trichrome, the number of pixels staining above a threshold in- Process of Collagen Treatment tensity on images of histopathology slides was calculated using Collagen powder was applied daily for four weeks after the first ImageJ 1.48v (National Institutes of Health, Bethesda, MD) and biopsy and for an average of 25.38±3.46 days after the second normalized to the total number of pixels. Forty high-power fields biopsy until subjective wound closure. In addition to application (HPF) were reviewed per treatment arm (5 per wound) to tabu- of pressure and collagen powder after the biopsy, one out of late CD31-positive cells. eight patients required hyfrecation for hemostasis, which did not impact the patient’s overall outcome. Three out of eight patients Photographs of the wounds were taken at 0, 1, 2, 4, 6, and 12 reported that the collagen powder treatment was “annoying” weeks with a ruler in frame to allow ImageJ size calibration. but no patients thought it was “difficult.” Overall, patients felt Wound edges were traced and surface areas were calculated that treatment with collagen powder was more time intensive using ImageJ. Measurements were performed by two observ- than PC, requiring careful placement of powder and dressings ers and averaged. over the wounds to prevent spillage.

Subjects rated itch at 1, 2, 4, 6, and 12 weeks usingDo the PruNot- WoundCopy Closure ritus Numerical Rating Scale (PNRS), a validated and reliable Wound size reduced by 28.95±5.09%, 55.76±6.29%, and instrument with scores ranging from 1-10 with higherPenalties num- 95.94±3.53% Apply after 1, 2, and 4 weeks of collagen powder treat- bers indicating worse itch.19 Itch and pain improvement were ment following the initial biopsy, respectively (Figure 1). After also measured using the Patient Overall Assessment Scale, the second biopsy, wound size reduced by 75.71±5.63% after a scale developed for this study which ranges from 1-4 for 2 weeks (Figure 1). Interestingly, this reduction in wound size each symptom with 1 = excellent improvement, 2 = moderate was significantly greater than the reduction 2 weeks after the improvement, 3 = no change, and 4 = worsening. After suture re- first biopsy P( <0.04). Six out of eight collagen-treated sites were moval at weeks 2 and 6, patients rated pain with suture removal completely healed 4 weeks after the first biopsy, and all wounds on a scale from 0-10, with higher numbers indicating worse were completely healed 8 weeks after the second biopsy. Com- pain. Subjects also reported overall wound treatment prefer- parisons of collagen powder- and PC-treated wounds at each ence and cosmetic preference at each visit. At the conclusion of study visit are shown in Figure 1 for two representative patients. the study, subjects were asked about their overall opinions of collagen powder treatment and whether the application process Histopathology was “annoying” or “difficult.” Histopathology revealed a well-formed epidermis with some artefactual epidermal/dermal separation for collagen- and PC- Using photographs, three faculty dermatologists blinded to treated wounds. However, collagen-treated wounds displayed treatment method reported their cosmetic preferences for each less inflammatory granulation tissue, and more organized and wound four weeks after the first biopsy and eight weeks after well-formed collagen bundles on H&E (Figure 2A) and Mas- the second biopsy. son trichrome staining (Figure 2B) compared to PC. Collagen staining intensity was significantly greater in collagen-treated Statistical Analysis wounds, with a mean staining intensity of 173.40+9.33 versus Statistical analysis was performed with Microsoft Excel 2013 125.8+7.31 for PC (Figure 3A; P<0.0001). CD31 staining (Figure and GraphPad Prism, version 7.0. Pain, pruritus, and preference 2C) revealed increased neoangiogenesis for collagen-treated measures were analyzed using data from a single visit or data wounds compared to PC-treated wounds (Figure 3B) (8.55±0.25 summed for several visits. Mean values of continuous variables versus 4.10±0.17, respectively; P<0.0001). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

670 Journal of Drugs in Dermatology A. Qureshi, E. Murphy, R. Milando, et al July 2019 • Volume 18 • Issue 7

FIGURE 1. Head-to-head comparison of the wound healing course for two representative patients throughout the study. White scale bar in upper right corner of the first collagen powder wound image is 0.5cm. All images presented are scaled similarly and are in the following sequence from left to right: baseline, week 1, week 2, week 4 prior to second wounding, week 4 after second wounding, week 6, and week 12. The bottom row presents mean (± SEM) percent healing for collagen powder-treated wounds for all patients. Discrepancy in wound size reduction at 2 weeks after first and second biopsies was statistically significant.P * <0.04 SEM: Standard error of the mean.

Do Not Copy Penalties Apply

FIGURE 2. Histopathological assessment of collagen-treated wounds versus primarily closed wounds. Collagen-treated wounds displayed less inflammatory granulation tissue, and more organized and well-formed collagen bundles both on H&E(A) , and Masson trichrome staining (B) as compared to PC. CD31 staining (C) revealed increased neoangiogenesis for collagen-treated wounds compared to wounds treated with primary closure.

671 Journal of Drugs in Dermatology A. Qureshi, E. Murphy, R. Milando, et al July 2019 • Volume 18 • Issue 7

FIGURE 3. Quantification of collagen intensity and CD31+ vessels Cosmetic and Overall Outcomes per HPF. (A) Mean collagen staining intensity was significantly Patients significantly preferred the cosmetic outcomes of greater in collagen-treated wounds (173.40+9.33) compared to PC- wounds treated with collagen powder compared to PC, with treated wounds (125.80+7.31). *P<0.0001. (B) CD31 staining revealed 4.19±0.23 total cumulative responses preferring collagen pow- increased neoangiogenesis for collagen-treated wounds compared to der and only 0.69±0.25 total cumulative responses favoring wounds treated with PC based on HPF vessel counts (8.55±0.25 versus PC over the course of study (Table 2; P<0.001). Dermatologist 4.10±0.17, respectively). *P<0.0001. evaluation of the cosmetic appearances of wounds also supported the superiority of collagen-treated wounds, with 72.92% of responses (35/48 wound images) preferring collagen powder versus 27.08% for PC (13/48 wound images; P<0.0001). Further, overall patient preferences reflected an insignificant favoring of collagen powder treatment over PC (P=0.22; Table 2).

Adverse Events Four out of eight patients reported skin irritation including erythema and pruritus from the adhesive dressings overlying collagen-treated sites. No reactions were reported from the collagen powder itself. Three patients reported minor pain after the biopsies, and one patient felt the pain was worse with re- Pain and Pruritus wounding at 4 weeks. No wound dehiscence or infection was No significant differences in pain and pruritus improvement or noted at either of the treated sites in any subject. mean PNRS scores were noted between PC- and collagen-treated sites at visit 2, visits 2-4 combined, or visits 5-6 combined DISCUSSION (Table 2). Of note, six out of eight patients commented that re- Results of this internally-controlled pilot study demonstrate ported itch was actually sensed in areas around the adhesive that acute full-thickness wounds treated with collagen powder dressings rather than areas treated with collagen powder. Pain heal at least as well as those treated with the standard of care, with suture removal was reported as an average of 1.06±0.29Do Notout PC,Copy and that collagen powder can be applied safely for at least of 10 for all patients. Penaltiesfour Apply weeks. Furthermore, collagen powder treatment leads to

TABLE 2. Summary of Patient Reported Outcomes. No significant differences were found between wounds in level of pruritus, pain or pruritus improvement, or overall preferences. Cosmetically, collagen powder treatment was preferred. For cosmetic and overall preferences, mean total cumulative votes per patient were reported. Mean ± SEM scores per patient are presented. SEM: Standard error of mean, POAS: Patient overall assessment scale, PNRS: Pruritus numerical rating scale. Primary Closure Collagen Powder Assessment Scale Visits P-value (N=8) (N=8) 2 1.50±0.27 1.38±0.18 0.71 Pain Improvement POAS 2-4 4.50±0.65 4.25±0.53 0.77 5-6 4.00±0.69 3.63±0.73 0.72 2 1.88±0.40 1.63±0.32 0.63 Pruritus Improvement POAS 2-4 5.75±0.67 5.00±0.60 0.42 5-6 4.38±0.73 4.25±0.82 0.91 2 3.00±1.12 2.38±0.92 0.69 Pruritus PNRS 2-4 4.63±1.31 3.50±1.07 0.52 5-6 1.88±0.95 2.56±1.41 0.69 2-4 1.44±0.48 1.56±0.48 0.86 Overall Preference Votes 2-6 1.88±0.69 3.13±0.69 0.22 2-4 0.69±0.25 2.19±0.23 <0.001 Cosmetic Preference Votes 2-6 0.69±0.25 4.19±0.23 <0.001 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

672 Journal of Drugs in Dermatology A. Qureshi, E. Murphy, R. Milando, et al July 2019 • Volume 18 • Issue 7

significantly improved early cosmetic outcomes eight weeks net reimbursement of $15-20/gram. Reimbursement rates from post-wounding. private insurances vary. Given its potential reimbursement, the use of collagen powder may be an inexpensive means to close Overall, patient-reported pain and itch were similar for colla- a punch biopsy site. gen-treated and primarily closed wounds, with most patients reporting that the itching was due to the adhesive dressings Limitations of this study include a small sample size and lack rather than the wounds. Four weeks after the first biopsy, 75% of of negative control group. Although underpowered, this pilot collagen-treated wounds were completely healed and wounds study provides foundational evidence that collagen powder can treated with collagen powder healed significantly faster after the be an effective treatment for punch biopsies and supports fur- second biopsy in comparison to the first biopsy. Although an ther study with larger trials. We chose PC with sutures as our untreated control is not available for comparison, the presence comparison given a recent survey performed in which only of collagen powder in the wound bed may have enabled faster 5.13% of resident and practicing dermatologist respondents healing after the second biopsy. Indeed, accelerated maturation indicated preference for leaving a 4mm punch biopsy open to was visualized histologically for collagen-treated wounds com- heal by secondary intention (data not published). Further, we pared to primarily-closed wounds. had ethical concerns about excessively wounding patients, while only treating one out of three wounds with the standard Histopathology also demonstrated that collagen treatment in- of care. Previous work compared PC to secondary intention for creased neoangiogenesis, which may create a stronger, more 4mm punch biopsy wounds and found that physician-rated cos- vascularized wound bed that enhances healing. In vitro stud- metic appearances were similar for both treatments.13 Given our ies have shown that type I collagen increases endothelial cell data conveying that collagen powder-treatment leads to signifi- proliferation and migration and that fragmented collagen may cantly better early cosmetic outcomes than PC, we hypothesize be more effective at doing so than its intact form.20–22 Collagen that early cosmetic outcomes of collagen powder treatment are can also support the development of capillary-like structures in likely better than early outcomes from healing by secondary in- vitro, possibly due to its ability to suppress cyclic AMP and pro- tention. tein kinase A, leading to the formation of necessary actin stress fibers.20,23 Clinical trials have also demonstrated that collagen Future research elucidating the optimal duration of collagen can promote angiogenesis.24–26 Compared to untreatedDo wounds, Not therapyCopy is needed, as less than four weeks may be sufficient. modified collagen gel treatment was shown to contribute to Shortened treatment courses would decrease the cost and ef- acute inflammatory cell and fibroblast recruitment,Penalties collagen I fort Apply required by patients. Future studies should also investigate deposition, increased endothelial cells, upregulated vascular the efficacy of collagen powder in healing larger wounds and in endothelial growth factor, and improved blood flow.24,25 comparison to healing by secondary intention.

Our results suggest that collagen powder may be used as an CONCLUSION alternative to PC for 4mm punch biopsy wounds. Based on a This is the first study to compare the use of collagen powder cost analysis by Christenson et al, the average medical cost per and PC to heal punch biopsy wounds in humans. Using an in- suture placement and removal is $15.13, which amounts to an ternally-controlled design, results show that collagen powder annual cost of $99,858 for all punch biopsies performed at an is safe when applied daily for four weeks, confers healing ca- academic center.13 This includes both the suture costs as well pability that is at a minimum non-inferior to PC, may enhance as physicians’ and nurses’ time for placement and removal. the strength and maturity of the healing wound/scar based on Notably, this does not include the cost to procure, maintain, histopathology, and provides superior early cosmetic outcomes and sterilize instruments. Indirect costs to the patient, includ- compared to PC. Future work should aim to ease the delivery ing transportation and sacrificed work time, adds an additional of topical collagen powder while elucidating additional pa- $145,332 to the annual cost of punch biopsies.13 Using collagen rameters for administration including duration of therapy and powder to manage punch biopsies instead of PC will save time candidate wound sizes. for physicians and nurses and has the potential to increase net reimbursements to clinics. Practitioners can purchase 1 gram DISCLOSURES packages of collagen powder to assist with hemostasis and to The authors have no relevant conflicts of interest to declare. CPN demonstrate the application process to patients following the Biosciences, Inc. provided the support to carry out the study. biopsy. In our study, hemostasis was achieved with pressure and collagen powder in 7 of 8 participants. Daily 1 gram doses REFERENCES of collagen powder can be ordered for patients for up to 30 days. 1. Purna SK, Babu M. Collagen based dressings - A review. Burns. 2000;26(1):54-62. doi:10.1016/S0305-4179(99)00103-5. Based on the 2019 published fee schedule, Medicare will reim- 2. Fleck CA, Simman R. Modern collagen wound dressings: Function and burse $35.66/gram of collagen powder, generally resulting in a purpose. J Am Col Certif Wound Spec. 2010;2(3):50-54. doi:10.1016/j. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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jcws.2010.12.003. 26. Seandel M, Noack-Kunnmann K, Zhu D, Aimes RT, Quigley JP. Growth 3. Gould BS, Woessner JF. Biosynthesis of collagen; the influence of ascorbic factor-induced angiogenesis in vivo requires specific cleavage of fibrillar acid on the proline, hydroxyproline, glycine, and collagen content of regener- type I collagen. Blood. 2001;97(8):2323-2332. http://www.ncbi.nlm.nih.gov/ ating guinea pig skin. J Biol Chem. 1957;226(1):289-300. pubmed/11290594. Accessed November 27, 2018. 4. Brett D. A Review of Collagen and Collagen-based Wound Dressings. Wounds. 2008;20(12):1-11. 5. Janis JE, Harrison B. Wound healing: part I. Basic science. Plast Reconstr AUTHOR CORRESPONDENCE Surg. 2014;133(2):199e-207e. doi:10.1097/01.prs.0000437224.02985.f9. 6. Stötzel S, Schurink M, Wienk H, et al. Molecular organization of various Adam Friedman MD FAAD collagen fragments as revealed by atomic force microscopy and diffusion- ordered NMR spectroscopy. ChemPhysChem. 2012;13(13):3117-3125. E-mail:...... ……...... [email protected] doi:10.1002/cphc.201200284. 7. Ramadass SK, Perumal S, Gopinath A, Nisal A, Subramanian S, Madhan B. Sol-gel assisted fabrication of collagen hydrolysate composite scaffold: A novel therapeutic alternative to the traditional collagen scaffold. ACS Appl Mater Interfaces. 2014;6(17):15015-15025. doi:10.1021/am502948g. 8. Landsman A, Taft D, Riemer K. The role of collagen bioscaffolds, foamed collagen, and living skin equivalents in wound healing. Clin Podiatr Med Surg. 2009;26(4):525-533. doi:10.1016/j.cpm.2009.08.012. 9. Motta G, Ratto GB, Barbieri A De, et al. Can heterologous collagen enhance the granulation tissue growth? An experimental study. Ital J Surg Sci. 1983;13(2):101-108. 10. Chattopadhyay S, Raines RT. Review collagen-based biomaterials for wound healing. Biopolymers. 2014;101(8):821-833. doi:10.1002/bip.22486. 11. Smith KJ, Skelton HG, Barrett TL, Welch M, Beard J. Histologic and immunohistochemical features in biopsy sites in which bovine collagen matrix was used for hemostasis. J Am Acad Dermatol. 1996;34(3):434-438. doi:10.1016/ S0190-9622(96)90435-1. 12. Boateng JS, Matthews KH, Stevens HNE, Eccleston GM. Wound healing dressings and drug delivery systems: A review. J Pharm Sci. 2008;97(8):2892- 2923. doi:10.1002/jps.21210. 13. Christenson LJ, Phillips PK, Weaver AL, Otley CC. Primary closure vs second-intention treatment of skin punch biopsy sites: A randomized trial. Arch Dermatol. 2005. doi:10.1001/archderm.141.9.1093. 14. Yip C, Bowen K, Chew BK. A report of rare adverse tissue reaction to Ethi- lon® Nylon Suture. J Surg Case Reports. 2018;2018(3):rjy037. doi:10.1093/ jscr/rjy037. 15. Osterberg B, Blomstedt B. Effect of suture materials on bacterial survival in infected wounds. An experimental study. Acta Chir Scand. 1979;145(7):431-Do Not Copy 434. http://www.ncbi.nlm.nih.gov/pubmed/539325. Accessed November 12, 2018. 16. Katz S, Izhar M, Mirelman D. Bacterial adherence to surgicalPenalties sutures. A pos- Apply sible factor in suture induced infection. Ann Surg. 1981;194(1):35-41. http:// www.ncbi.nlm.nih.gov/pubmed/7018429. Accessed November 12, 2018. 1 7. Chu CC, Williams DF. Effects of physical configuration and chemical structure of suture materials on bacterial adhesion. A possible link to wound infection. Am J Surg. 1984;147(2):197-204. http://www.ncbi.nlm.nih.gov/ pubmed/6364858. Accessed November 12, 2018. 18. Ogbechie OA, Paul S, Schalock PC. A technique for identifying vicryl suture hypersensitivity. Dermatitis. 2014. doi:10.1097/DER.0000000000000085. 19. Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92(5):502-507. doi:10.2340/00015555-1246. 20. Whelan MC, Senger DR. Collagen I initiates endothelial cell morphogen- esis by inducing actin polymerization through suppression of cyclic AMP and protein kinase A. J Biol Chem. 2003;278(1):327-334. doi:10.1074/jbc. M207554200. 2 1. Kirkpatrick CJ, Kampe M, Rixen H, Fischer EG, Ruchatz D, Mittermayer C. In vitro studies on the expansion of endothelial cell monolayers on components of the basement membrane. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;58(3):207-213. http://www.ncbi.nlm.nih.gov/pubmed/1970682. Accessed November 9, 2018. 22. Madri JA, Pratt BM, Yannariello-Brown J. Matrix-driven cell size change modulates aortic endothelial cell proliferation and sheet migration. Am J Pathol. 1988;132(1):18-27. http://www.ncbi.nlm.nih.gov/pubmed/3394798. Accessed November 9, 2018. 23. Peterson AW, Caldwell DJ, Rioja AY, Rao RR, Putnam AJ, Stegemann JP. Vasculogenesis and Angiogenesis in Modular Collagen-Fibrin Microtissues. Biomater Sci. 2014;2(10):1497-1508. doi:10.1039/C4BM00141A. 24. Elgharably H, Ganesh K, Dickerson J, et al. A modified collagen gel dressing promotes angiogenesis in a preclinical swine model of chronic ischemic wounds. Wound Repair Regen. 2014. doi:10.1111/wrr.12229. 25. Elgharably H, Roy S, Khanna S, et al. A modified collagen gel enhances healing outcome in a preclinical swine model of excisional wounds. Wound Re- pair Regen. 2013. doi:10.1111/wrr.12039. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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Patient-focused Solutions in Rosacea Management: Treatment Challenges in Special Patient Groups

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This journal-based enduring activity is funded through an educational grant provided by Galderma Laboratories, L.P. JDD

July 2019 675 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Non-Submental Applications of Injectable Deoxycholic Acid: A Systematic Review Calvin T. Sung MD,ab Alfred Lee BA,ª Franchesca Choi BS RPh,B Margit Juhasz MD,B Natasha Atanaskova Mesinkovska MD PhDb ªUniversity of California, Riverside School of Medicine, Riverside, CA BUniversity of California, Irvine, Department of Dermatology, Irvine, CA

ABSTRACT

Introduction: Injectable deoxycholic acid (DCA; Kybella; Allergan, Irvine, CA) is currently approved only for treatment of persistent submental fat (SMF). Many cosmetic surgeons use DCA off-label to treat fat tissue in other areas of the body. There is no review summarizing the off-label uses of injectable DCA. Methods: A systematic literature search was conducted through PubMed, Cochrane, CINAHL, and Web of Science databases using search terms “ATX-101 OR Kybella OR deoxycholic OR deoxycholate NOT amphotericin NOT bile” in accordance to PRISMA guidelines to identify off-label uses for injectable DCA or ATX-101. Results: Ten pertinent articles were identified for review. Anatomic areas treated include the face, brassiere line, foot, and gluteotrochanteric region. Indications include facial contouring, paradoxical adipose hyperplasia, HIV/HAART-associated buccal fat pad lipodystrophy, and reduction of lipomatous tumors. DCA is efficacious at causing lipolysis and safe with minimal side effects. Most patients treated for cosmetic indications reported high patient satisfaction. Conclusion: Off-label use of injectable DCA demonstrate a similar safety profile, effectiveness, and overall patient satisfaction compared to FDA-approved use for persistent SMF. DCA appears to be a safe and efficacious alternative to surgical reduction of unwanted adipose tissue in non-submental areas. Larger-scale studies are warranted to explore further cosmetic and potential medical applications.

J Drugs Dermatol. 2019;18(7):675-680. Do Not Copy Penalties Apply INTRODUCTION MATERIALS AND METHODS njectable deoxycholic acid (DCA) is currently United States Literature Search Federal Drug Association (FDA) indicated for treatment of This systematic review was done in accordance to the Preferred moderate-to-severe submental fat (SMF), typically present- Reporting Items for Systematic Reviews and Meta-Analyses I 4 ing as excessive inferior jawline fullness, or colloquially, “dou- (PRISMA). A primary literature search was conducted using ble chin.”1 Prior to the discovery and use of DCA, phosphatidyl- PubMed, Cochrane, Web of Science and CINAHL. Two authors choline (PC), a naturally occurring phospholipid that emulsifies (CS/FC) independently screened the above-mentioned databas- fat, was used as a lipolytic agent to prevent or treat venous fat es using the search term, “ATX-101 OR Kybella OR deoxycholic embolism. Eventually, its use evolved to include local reduction OR deoxycholate NOT amphotericin NOT bile,” utilizing Medi- of adipose tissue for aesthetic purposes. cal Subject Headings (MeSH®) controlled vocabulary and text words. Systematic literature search was conducted on Novem- DCA is the lipolytic component of human bile acid that disrupts ber 26, 2018. adipocyte cell membranes, which results in cell death while sparing protein-rich skin and muscle tissue remains unaffect- Study Selection and Appraisal ed.2 Necrosis following lipolysis reduces adipocyte size through Two reviewers (CS/FC) independently screened all article titles inflammatory, cell-mediated fibroblast activation and collagen and abstracts to include clinical trials, cohort studies, case-con- deposition, while simultaneously strengthening structural in- trol studies, case series, cross-sectional studies, or case reports, tegrity of underlying tissue.3 Histologically, inflammation is written in English, on off-label use of deoxycholic acid or deoxy- localized to the pannus. Several preclinical and clinical studies cholate in human subjects apart from its approved indication of have established a favorable safety profile for injectable DCA submental fat reduction. Animal studies and articles not avail- and efficacy for SMF reduction.1 This manuscript will system- able in English were excluded. There were no date exclusions atically review and discuss pertinent findings from all available applied to this search. Subsequently identified studies were literature regarding off-label injectable DCA application for li- subjected to full-text review. Authors were contacted for miss- polysis in non-submental regions of the body. ing data. Bias risk and methodological quality were assessed Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

676 Journal of Drugs in Dermatology C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska July 2019 • Volume 18 • Issue 7

according to the Cochrane Handbook for Systematic Reviews FIGURE 1. PRISMA flow diagram summarizing literature search. of Interventions. Rationales for exclusion and article appraisals were recorded at every stage. Final decision on study selection was reached by discussion. References of included and excluded studies were reviewed for potential studies not identified through initial search strategy.

Data Extraction and Analysis Included studies were summarized using a data extraction form. Studies were graded using the Oxford Center for Evidence- Based Medicine 2011 Levels of Evidence.5 RESULTS Initially, across four literature databases, 8907 non-duplicate articles from the years 1923 to 2018 were identified. After title/ abstract screening, 13 articles met criteria for inclusion. These articles were subjected to full-text screen and 10 studies were included in this systematic review as depicted by the PRISMA

4 flow diagram (Figure 1). Results of included studies are sum- encedFIGURES improvement of bra line adiposity and decreased skin marized in Table 1. thickness. 10,11 The first case series described two middle-aged fe- Figure 1: PRISMA flow diagram summarizing literature search. male patients receiving injectable DCA (10mg/ml). One patient Face received bilateral 2ml (4ml total) injections in the upper back, Two case reports described single-patient experiences with in- just above the horizontal bra line, while the other patient re- jectable PC/DCA in the jowl and lower face, in conjunction with ceived bilateral 1ml (2ml total) injections lateral to both breasts hyaluronic acid (HA) and botulinum toxin type A (BTX-A), as at the axillary tail of Spence. Injections were given in 0.15ml an alternative to surgery.6,7 In one case, a young Asian woman volumes spaced 0.5-1.0cm apart in each treatment area. Both desired non-operative lower facial contouring and underwentDo Not patientsCopy required only one treatment session and reported high 11 injection-only treatments over a 26-month period with PC/ satisfaction with the gradual reduction of fat bulging based on DCA lipolysis of the lower jowl, face, and chin, HAPenalties augmenta- patient-reported Apply visual self-assessment over a three to nine- tion of the chin, cheek, and nose, and BTX-A contouring of the month period. lower face.6 A total of four PC/DCA treatments were given at ten weeks, five months, nine months, and 22.5 months after ini- The second case series included five patients treated with DCA tial treatment. Her non-operative transformation produced the injections, over a 12-week period, for persistent posterior-supe- desired heart-shaped face by slimming the lower cheeks and rior bra line liposis.11 Each patient received a total dose of 2mg/ improving jawline definition. cm2 bilaterally in 0.2ml injection intervals every four weeks and patients experienced an average 5.2mm reduction in skin pinch The second case reported a one-stage, combination jowl rejuve- thickness of the posterior back and 17-percent reduction in their nation procedure in a middle-aged female with BTX-A, HA, and posterior bra-bulge, similar to Jegasothy’s experience. DCA injections to the depressor anguli oris, marionette lines, and the subcutaneous-fat-rich jowl area, respectively.7 Results Gluteotrochanteric/Trochanteric Region of the Face-Q, a validated patient-reported outcome instrument, Two larger-scale studies (n=63) reported on the use of completed 3-months post-treatment indicated significant im- DCA-containing injections for aesthetic reduction of the gluteo- provement in facial appearance from baseline (84.5% vs 44%), trochanteric regions.12 One controlled study (n=26) using 10ml and an independent standardized wrinkle assessment scale 5% PC/4.3% DCA/ethanol subcutaneous injections into the right (WAS) assessment (0=no wrinkle, 5=very deep wrinkle) per- posterior trochanteric area twice, three weeks apart. Reduction formed by five independent plastic surgeons were consistent, of adipose tissue was evaluated by ultrasound and an optical with an average of 2-point improvement from baseline.8,9 device (Lipometer®; Moeller Messtechnik, Graz, Styria, Austria) at baseline, 8 weeks, and 20 weeks, and photography at baseline Brassiere Line and 20 weeks. At week 20, there was no statistically significant Two case series (n=7) explored off-label use of DCA injections difference between the right and left areas using Lipometer, ul- to the brassiere (bra) line using one to three treatments per site. trasound nor qualitative photographic. No patients evaluated Six patients received injections to the posterior bra line, and one the procedure positively, and only two patients (7.7%) opted to patient received anterior injections. All seven patients experi- receive contralateral injections. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

677 Journal of Drugs in Dermatology C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska July 2019 • Volume 18 • Issue 7

TABLE 1. Summary of Included Studies Study Type Authors; (Level of Off-label Use Subjects Intervention Outcomes Adverse Events Year Evidence)

Face

Wong et al. Case report Lower face 20-year-old Eleven treatments using (1) Aesthetic enhance- None reported. 20186 (LOE 5) and jaw healthy botulinum toxin, (2) HA, and (3) PC/ ment of face shape, remodeling Asian DCA (50mg/ml PC, 42mg/ml DCA). jaw contour, and jowl female definition. Patient A total of four PC/DCA treatments was satisfied with were given at: cosmetic result. - 10 weeks (750mg) - 5 months (875mg) - 9 months (937.5mg) - 22.5 months (593mg) - 3155.5mg PCA/DCA total. Mess 20177 Case report Marionette 55-year-old Sequential treatment using (1) Satisfaction with Self-limited injection- (LOE 5) lines and female botulinum toxin, (2) HA, (3) DCA. facial appearance site bruising and jowls at 3 months: 84.5% edema. compared to 44% at baseline (FaceQ). Brassiere Line Jegasothy Case series Bra-line Case A: 1 injection of Kybella treatment Both subjects Self-limited injection 201810 (LOE 4) lipolysis 46-year-old seated upright: reported gradual site edema, tender- healthy - Case A: 2 ml (20mg) DCA bra line fat decrease ness, and itching; Caucasian on each side (upper back) beginning at 1 month resolved within 7 days. female - Case B: 1 ml (10mg) DCA and continuing Case B: onDo each Not side (lateral Copy breasts). until 3- and 9-months 47-year-old post-treatment, healthy Penalties Apply respectively; no re- East Indian accumulation of fat female in treated areas. Verma et al. Case series Bra-line 5 healthy 20 mg DCA every 4 weeks. Average 5.2 mm re- Self-resolving injection 201811 (LOE 4) lipolysis females duction (4-9 mm) in site pain, swelling/ skin pinch thickness edema, and bruising. and 17% (10-24%) reduction in posterior bra-bulge from baseline. Gluteotrochanteric/Trochanteric Region Salti et al. Double- Gynoid 37 healthy Treatments randomized per side: Overall reduction of Self-resolving pain, 200713 blind lipodystrophy females - One side: 50/25mg/ml PC/NaDC local fat in 91.9% of bruising, and palpable random- (1000/500mg total) patients without sig- subcutaneous nodule ized trial - Other side: 47.5mg/ml NaDC nificant differences with both treatments; (LOE 2) (475mg total) between the treated pain and bruising were sides. more intense with Given 4 treatments per side, every NaDC. 8 weeks. Systemic cholinergic effects: dizziness/ lightheadedness (n=2, 5.4%), nausea/malaise (n=4, 10.6%), and diarrhea/steatorrhea (n=6, 16.2%) of unknown etiology; resolved within 24 hours. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

678 Journal of Drugs in Dermatology C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska July 2019 • Volume 18 • Issue 7

TABLE 1. (CONTINUED) Summary of Included Studies Study Type Authors; Off-label (Level of Subjects Intervention Outcomes Adverse Events Year Use Evidence) Gluteotrochanteric/Trochanteric Region Kopera Cohort Trochanteric 26 healthy 3 treatments with 10ml of No significant de- Not reported. 200712 study bulges females 5%PC/4.3%NaDC/ethanol to the crease in trochan- (LOE 3) right posterior trochanteric region. teric bulge between sides. Zero patients evaluated treatment positively. Feet Turkmani Case report Piezogenic 34-year-old 0.05ml to 0.1ml of 1% DCA. Nodules completely None reported. 201814 (LOE 5) pedal pap- obese (121 disappeared after ules kg) woman 2 weeks; no more with in- pain with walking or tense heel standing. pain for 10 months

Paradoxical Adipose Hyperplasia

Ward et al. Case report Paradoxi- 58-year-old 4 ml 1% DCA 3 times: Waist circumference Self-resolving erythema, 201815 (LOE 5) cal adipose healthy - Initial: 1.7ml (left), 2.3ml (right) decreased from 30.5 swelling, and mild hyperplasia Caucasian - Remaining: 2ml per side. inches to 29.5 inches tenderness around the secondary female after 3 treatments. injection site within 2-3 to cryolipol- days. ysis at lower abdomen Do Not Copy Highly Active Antiretroviral Therapy (HAART)-Associated Lipodystrophy of the Buccal Fat Pad Rotunda et Case report HIV/HAART- 48-year-old Penalties1 ml 1% NaDC and Apply0.25 ml 2% Both lesions de- Not reported. al. 201116 (LOE 5) related HIV-posi- lidocaine; given 3 times. creased in size and lipohyper- tive male became asymptom- trophy on HAART atic. with bilateral buccal lipoma-like growths over previous 2 years Lipoma Rotunda et Cohort Lipoma 6 patients; 1%, 2.5% or 5% NaDC at intervals of All lipomas de- 2 and 5% DCA associ- al. 200517 study 12 lipomas 2-20 weeks. creased in size (mean ated with burning and (LOE 3) area reduction 75% prolonged swelling; took Injection volumes (ml) equaled half [37-100%]) after up to 6 weeks to resolve. the largest lipoma dimensions. an average of 2.2 Two patients experi- treatments. Several enced injection-site lipomas fragmented cutaneous paresthesia or became softer in with 5% DCA; took up to addition to decreas- 6 weeks to resolve. ing in volume. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

679 Journal of Drugs in Dermatology C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska July 2019 • Volume 18 • Issue 7

A double-blind, self-controlled, randomized study (n=37 females) four treatments). All lipomatous tumors decreased in size with a investigated the use of PC/DCA (50/25mg/ml) versus DCA alone mean area reduction of 75% (37-100%) after an average 2.2 treat- (47.5mg/ml) in patients with localized gynoid lipodystrophy. Four ments, while some tumors fragmented and/or became softer treatments were administered to the gluteotrochanteric region after injection. Most importantly, change in lipoma size did not every eight weeks to allow for post-infiltrative nodular resolu- correlate with DCA concentration as patients treated with the tion.13 Each patient received 1000/500mg of PC/DCA on one side lowest dose achieved similar clinical response to those receiv- and 475mg DCA alone on the contralateral side. After both solu- ing higher doses.17 tions were diluted in saline, a total of 80 infiltrations (40ml) per side were administered over 1cm intervals during each treat- DISCUSSION ment. Outcome was assessed using thigh circumference at the Minimally invasive cosmetic procedures continue to gain pop- level of the sub-gluteal fold, ultrasonographic measurement of ularity over time, evidenced by a 186% increase in national trochanteric fat pad thickness, and photographs at baseline and utilization between 2000 and 2017 (versus a six-percent drop in eight weeks after the last treatment. Thirty-four patients (91.9%) cosmetic surgical procedures over the same period).18 Injectable achieved reduction in thigh circumference and trochanteric fat DCA is among several minimally invasive cosmetic procedures pad thickness without significant difference bilaterally; three pa- popularized by social media, alongside botulinum toxin injec- tients (8.1%) were non-responders.13 tions and soft tissue fillers, which prompts further investigation into safety and efficacy as popular interest and indications Feet continue to expand. Cosmetic and medical outcomes of DCA One case report described treatment of symptomatic piezogenic lipolysis injections achieved desirable results according to pa- pedal papules (pressure-induced papules) on the foot and heel tients and providers. The overall high patient satisfaction and in a 34-year-old obese woman using 0.05-0.1ml (based on pap- minimal side effects associated with non-submental DCA injec- ule size) of 1% DCA solution. The patient achieved complete tions mirrors the level of success associated with submental resolution of papules and bilateral heel pain in two weeks.14 DCA injections and further highlights the potential of less-invasive alternatives to aggressive surgical treatments for adipose Treatment of Paradoxical Adipose Hyperplasia tissue removal. For example, combination therapies using in- One 58-year-old Caucasian female was treated with injectable jectable DCA in conjunction with HA and BTX-A for lower face DCA (10mg/ml) for abdominal paradoxical adipose hyperplasiaDo Not contouringCopy may spare future patients from undergoing genio- (PAH) after two prior cryolipolysis treatments.15 A total of three, plasty or mandibuloplasty.19,20 DCA injections of the jowls and 4ml treatments were given at 0, 6, and 16 weeks Penaltiesresulting in lower Apply face provides an alternative to traditional rhytidectomy gradual reduction of lower abdominal fullness. Positive results or facelift for facial rejuvenation.21 Notably, patient and physi- were maintained five months after the third treatment despite no cian/evaluator-reported assessments of aesthetic outcomes change in caloric intake or expenditure. The patient was highly were concordant in studies on the face, brassiere line, feet, satisfied decreased waist circumference from 30.5 to 29.5 inches. PAH, lipodystrophy and lipomas reported in this article. Future studies may be strengthened by incorporating more patients, Treatment of HIV-Associated Lipodystrophy of the Buccal Fat Pad utilizing standardized treatments, and using validated tools to One case of highly active antiretroviral therapy (HAART)-asso- measure treatment outcomes, such as the Face-Q or Body-Q, or ciated buccal fat pad lipodystrophy in a 48-year old male was quantitative measurements with high-resolution ultrasound or treated with three bilateral injections of DCA at baseline, 14 days MRI.8,22 Although DCA injection has unanimously demonstrated and 24 days.16 Each 4cm mass was treated with four intralesion- superior efficacy in smaller anatomic areas, conflicting evidence al injections of 1ml 1% DCA. Clinical reduction and magnetic reported for DCA injections in reducing gluteotrochanteric and resonance imaging (MRI) assessment three-months after initial trochanteric fat suggests the need for further research on the treatment confirmed a decrease in maximum buccal fat pad depth efficacy of DCA on larger anatomic areas.12,13 from 12-14 to 10mm. At six months, the lesions measured approximately 1cm and regrowth to 1.5cm after one year, and they Side effects associated with injectable DCA ranged from no were reinjected with 1ml of 1% DCA with no further follow-up. side effects, as seen in treatment of piezogenic pedal papules, to systemic side effects (nausea, dizziness, and diarrhea) Treatment of Lipoma potentially associated with large-volume gluteotrochanteric A small prospective study (n=6) detailed the use of isolated DCA DCA injections.13,14 High-volume DCA injections may have sev- in the treatment of 12 lipomas, ranging from 1cm to 3.5cm in eral volume-related local effects not seen with smaller-volume largest dimension, at intervals of 2 to 20 weeks. Patients were DCA injections may cause compression of local structures or injected with DCA at concentrations of 10, 25, or 50mg/ml at increased hydrostatic pressure at the injection site. On a simi- volumes equaling half the largest lipoma dimension in centi- lar note, patients experienced less pain and inflammatory meters until satisfactory tumor reduction was achieved (one to response, without a significant difference in fat reduction using Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

680 Journal of Drugs in Dermatology C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska July 2019 • Volume 18 • Issue 7

a combination PC/DCA.13 This therapy may be utilized in areas REFERENCES that experience friction and pressure from functional move- 1. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, random- 11 ized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an inject- ments, such as the brassiere line. Higher concentrations of able drug for submental fat reduction. Dermatol Surg. 2016;42(1):38-49. DCA does not equate to greater clinical fat reduction according 2. Rotunda AM, Suzuki H, Moy RL, Kolodney MS. Detergent effects of sodium to Rotunda et al.’s study which achieved statistically compara- deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg. 2004;30(7):1001-1008. ble efficacy in terms of lipoma reduction even when using the 3. Young VL. Lipostabil: the effect of phosphatidylcholine on subcutaneous fat. lowest 1% DCA concentration.17 This phenomenon is further Aesthet Surg J. 2003;23(5):413-417. 23 4. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting supported by findings from Walker et al.’s recent clinical trial. systematic reviews and meta-analyses of studies that evaluate healthcare Further work remains to determine different effects of DCA in interventions: explanation and elaboration. BMJ. 2009;339:b2700. neoplastic versus native fat cells and ideal dosing for minimiz- 5. Howick J, Chalmers I, Glasziou P, et al. The Oxford 2011 Levels of Evidence. In:2011. ing side effects in different anatomic areas. 6. Wong GR, Chen WP. Phosphatidylcholine/deoxycholate lipolysis and hyaluronic acid augmentation to enhance nonsurgical lower facial contouring using botulinum toxin type A. J Cosmet Dermatol. 2011;10(2):159-162. Economic burden associated with DCA injections was found to 7. Mess SA. Lower Face Rejuvenation with Injections: Botox, Juvederm, and be a major factor of consideration for patients according to a Kybella for Marionette Lines and Jowls. Plast Reconstr Surg Glob Open. 2017;5(11):e1551. pooled analysis of four clinical trials of injectable DCA. Patel and 8. Kappos EA, Temp M, Schaefer DJ, Haug M, Kalbermatten DF, Toth BA. Vali- Kridel estimated that clinical trial patients receiving injectable dating Facial Aesthetic Surgery Results with the FACE-Q. Plast Reconstr DCA incurred an average $6,426 in expenses (186mg of drug per Surg. 2017;139(4):839-845. 9. Buchner L, Vamvakias G, Rom D. Validation of a photonumeric wrinkle as- patient), compared to $2,976 as the average cost incurred by pa- sessment scale for assessing nasolabial fold wrinkles. Plast Reconstr Surg. tients for liposuction. However, these values may not accurately 2010;126(2):596-601. 10. Jegasothy SM. Deoxycholic acid injections for bra-line lipolysis. Dermatol reflect the charges incurred in clinical practice, as the amount Surg. 2018;44(5):757-760. of DCA required can vary drastically based on treated anatomi- 11. Verma KD, Somenek MT. Deoxycholic acid injection as an effective treatment for reduction of posterior upper torso brassiere strap adiposity. Plast Recon- cal location. Evaluation of the average number of injections per str Surg. 2018;141(1):200e-202e. patient in clinical practice, in addition to characterizing primary 12. Kopera D, Horejsi R, Werner S, Moeller R. Injection lipolysis for reduction of payor, is needed to determine the true economic burden of each saddlebag trochanteric bulges--half-side controlled pilot study. J Dtsch Der- matol Ges. 2008;6(4):287-290. procedure in the clinical setting.24 13. Salti G, Ghersetich I, Tantussi F, Bovani B, Lotti T. Phosphatidylcholine and sodium deoxycholate in the treatment of localized fat: a double-blind, randomized study. Dermatol Surg. 2008;34(1):60-66; discussion 66. Off-label use of injectable DCA is not limited to aestheticDo purNot- 14.Copy Turkmani MG. Piezogenic pedal papules treated successfully with deoxycho- poses as injectable DCA treats painful piezogenic pedal papules, lic acid injection. JAAD Case Rep. 2018;4(6):582-583. 14,16 15. Ward CE, Li JY, Friedman PM. ATX-101 (deoxycholic acid injection) for para- lipomas, and HAART-associated-lipodystrophy. GivenPenalties DCA’s Applydoxical adipose hyperplasia secondary to cryolipolysis. Dermatol Surg. potential to cause DNA damage through production of reactive 2018;44(5):752-754. oxygen species and modulation of interactions between steroid 16. Rotunda AM, Jones DH. Human immunodeficiency virus-associated lipohy- pertrophy (buccal fat pad lipoma-like lesions) reduced with subcutaneously ligands and their receptors, DCA may possess anti-tumor prop- injected sodium deoxycholate. Dermatol Surg. 2010;36(8):1348-1354. erties warranting further translational research for treatment of 1 7. Rotunda AM, Ablon G, Kolodney MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol. 2005;53(6):973-978. 25,26 malignant fatty tissue. Despite promising results, the limited 18. American Society of Plastic Surgeons National Clearinghouse of Plastic Sur- literature and number of patients who have undergone non-sub- gery Procedural Statistics. Published 2017. Accessed January 7, 2019. 19. Kantor J. Synergistic effect of combination deoxycholic acid and botulinum mental DCA injections should prompt further experimentation toxin (the Bellatox technique) for the treatment of submental fullness. J Am of new anatomical applications, indications, and dosages, in ad- Acad Dermatol. 2017;76(6):e209-e211. dition to establishing safety profiles. 20. Lee J, Lee S. Facial contouring surgery-mandibuloplasty: genioplasty and mandible angle correction. Plast Reconstr Surg Glob Open. 2017;5(10):e1296. 2 1. Derby BM, Codner MA. Evidence-Based Medicine: Face Lift. Plast Reconstr CONCLUSION Surg. 2017;139(1):151e-167e. 22. Poulsen L, McEvenue G, Klassen A, Hoogbergen M, Sorensen JA, Pusic A. Pa- Most non-submental applications of injectable DCA appear to tient-reported outcome measures: BODY-Q. Clin Plast Surg. 2019;46(1):15-24. demonstrate a similar safety profile, efficacy, and patient sat- 23. Walker PS, Monheit GD, Smith SR, et al. Multicenter, randomized, double- blind, placebo-controlled, parallel-group study of the safety and efficacy of isfaction comparable to FDA-approved use for persistent SMF. ATX-101 (sodium deoxycholate for injection) intralipomal injections for the Current experiences of off-label DCA injection demonstrate treatment of superficial lipomas. In:2015. favorable cosmetic results and may be a viable alternative to sur- 24. Patel S, Kridel R. Current trends in management of submental liposis: a pooled analysis and survey. JAMA Facial Plast Surg. 2018;20(3):202-206. gical adipose tissue removal, cryolipolysis in PAH-prone patients 25. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as car- or patients that cannot receive cryolipolysis, or other non-inva- cinogens in human gastrointestinal cancers. Mutat Res. 2005;589(1):47-65. 26. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an sive methods of lipolysis. Larger-scale studies are warranted orphan nuclear receptor. Science. 1999;284(5418):1365-1368. to explore further cosmetic and potential medical applications. AUTHOR CORRESPONDENCE DISCLOSURES The authors have no conflicts of interest to disclose. Calvin T. Sung MD The authors received no financial funding for this research. E-mail:...... ……...... [email protected] Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

STILL AVAILABLE

Atopic Dermatitis: A Review of Topical Treatment

A SUPPLEMENT TO

An overview of recent advances Doin AD, Not Copy specifically topical corticosteroids,Penalties Apply which remain a fundamental component of treatment algorithms

This research was supported by a grant from Almirall, LLC., Exton, PA 19341. JDD

Atopic Dermatitis: A Review of Topical Treatment

July 2019 682 Volume 18 • Issue 7 Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Effective and Safe Repeated Full-Face Treatments With AbobotulinumtoxinA, Hyaluronic Acid Filler, and Skin Boosting Hyaluronic Acid Per Hedén MD,a Doris Hexsel MD,B Hugues Cartier MD,c Per Bergentz MD,a Henry Delmar MD,d Fernanda Camozzato MD,B Carolina Siega BSc,b Cecilia Skoglund PhD,e Carolina Edwartz PhD,e Maria Norberg PhD,E Philippe Kestemont MDD aAkademikliniken, Stockholm, Sweden BBrazilian Center for Studies in Dermatology, Porto Alegre, RS, Brazil cCentre Medical Saint-Jean, Arras, France dMediti – Clinique Science et Beauté, Juan-les-Pins, France eGalderma Aesthetics, Medical Affairs, Uppsala, Sweden

ABSTRACT

Background: It is important to study full-face aesthetic combination treatments to establish well-founded individual treatment plans. Objective: To evaluate clinical outcome and perception of treatment with either abobotulinumtoxinA (ABO) or hyaluronic acid (HA) filler followed by repeated combined treatment with ABO, HA filler, and Restylane® Skinboosters (RSB). Methods & Materials: This study was conducted at four sites in Sweden, France, and Brazil and included subjects aged 35-50 years with mild/moderate nasolabial folds and moderate/severe upper facial lines. Monotherapy was ≤125 s.U ABO in at least two upper facial indications with optional touch-up or ≤1 mL HA filler in nasolabial folds/cheeks. At months 6 and 12, both cohorts received ≤125 s.U. ABO in upper facial lines with optional touch-up, ≤2 mL HA filler in nasolabial folds/cheeks (and other facial areas as applicable), and ≤1 mL RSB. Assessments included global facial aesthetic appearance and improvement, first impression, perceived age, wrinkle severity, satisfaction questionnaires, and adverse events. Results: Repeated full-face treatment with ABO, HA filler,Do and Not RSB Copywas associated with better aesthetic outcome and higher levels of satisfaction than treatment with ABO or HA filler alone. However, even modest volumes of HA filler achieved good aesthetic outcomes and high satisfaction. Treatment of several indicationsPenalties was well tolerated. Apply Conclusion: Aesthetic improvement and subject satisfaction was high and increased with each treatment. All treatments were well tolerated. These data may be used as support when establishing individual treatment plans.

J Drugs Dermatol. 2019;18(7):682-689.

INTRODUCTION esthetic treatment with either botulinum toxin type A The objective of this study was to collect data on subjects re- (BoNT-A) or hyaluronic acid (HA) filler(s) is generally ceiving monotherapy with either ABO or HA filler followed by Amore common than combination treatment1-4; approxi- repeated combination treatment with ABO, HA filler, and RSB mately one-third of patients receive a combination of injectable to provide guidance to practitioners for individual treatment treatments.5 plans. BoNT-A in up to three upper facial indications has not previously been studied in combination with HA filler and RSB. Upper facial aesthetic indications of BoNT-A include glabellar lines, lateral canthal lines, and horizontal forehead lines.6-10 METHODS The marketing authorization for abobotulinumtoxinA (ABO) Study Design includes treatment of hyperfunctional facial lines in Brazil and This was an 18-month study conducted at four sites in Sweden, moderate-to-severe glabellar lines and lateral canthal lines in France, and Brazil (Figure 1). ABO cohort data up to 6 months many European countries including France and Sweden. have been published.20 The study protocol was approved by independent Ethics Committees and conformed to the Declaration HA fillers are most commonly used for aesthetic soft-tissue of Helsinki, Good Clinical Practice, and local regulations. augmentation of the mid and lower face.11- 16 Restylane® Skin- boosters (RSB [Galderma Aesthetics, Sweden])17-19 are used for Eligibility Criteria skin rejuvenation and improved skin quality. Subjects between 35 and 50 years who provided signed in- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

683 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

FIGURE 1. Study design and treatments. D: Day, M: Month, T-u: Touch-up, W: Weeks.

1st combination 2nd combination Monotherapy treatment treatment

2W: optional t-u; 2W: optional t-u; 2W: optional t-u; ≤125 s.U ABO ≤125 s.U ABO ≤125 s.U ABO

D1 M1 M3 M6 M7 M9 M12 M13 M15

Both cohorts: ≤1 mL RSB

ABO cohort: ≤125 s.U ABO in at least Both cohorts: Both cohorts: • • 2 of GL, LCL + FL ≤125 s.U ABO in at least ≤125 s.U ABO in at least 2 of GL, LCL + FL 2 of GL, LCL + FL • ≤2 mL HA in NLFs/cheeks • ≤2 mL HA in NLFs/cheeks HA cohort: + other areas + other areas ≤1 mL HA • ≤1 mL RSB • ≤1 mL RSB in NLFs/cheeks

formed consent and had mild-to-moderate nasolabial folds21 Aesthetics, Sweden). OBT fillers were Restylane Refyne and/ and moderate-to-severe upper facial lines at maximum contrac- or Restylane Defyne; NASHA fillers were Restylane Lidocaine tion22 were eligible for the study. and/or Restylane Lyft Lidocaine. Needle/cannula and injection method were at the Investigator’s discretion. No touch-up was Key exclusion criteria included (1) apparent facial sagging, (2) allowed. facial procedures eliciting an active dermal response duringDo Notthe Copy preceding 6 months, or BoNT-A, HA or collagen treatment with- Combination Treatment in the preceding 12 months, (3) treatment with non-collagenPenalties At Apply months 6 and 12, subjects in both cohorts received up to 125 or non-HA product, or facial surgery, (4) history of dysphagia, s.U ABO in at least two upper facial indications, ≤2 mL HA filler neuromuscular junctional disorders, signs of compensatory in nasolabial folds and/or cheeks (and other areas as applicable), frontalis muscle activity or eyelid ptosis, known hypersensitivity and ≤1 mL Restylane Skinboosters Vital Lidocaine (Europe)/Re- to BoNT-A, HA, lidocaine hydrochloride or other amide-type an- stylane Skinboosters Vital (Brazil) (Figure 1). Touch-up with ABO esthetics, or history of autoimmune disease, (5) inflammation, was allowed after 2 weeks. Each subject received either OBT or active skin disease, scarred, or damaged facial skin. NASHA filler during the study. A second RSB treatment (≤1 mL) was given at month 7. Treatment Procedure Injections were performed in accordance with the Instructions Efficacy Assessments for Use (HA fillers and RSB) and Summary of Product Charac- Subject photographs were taken one month after each treat- teristics (ABO) that were valid at the time. Local anesthesia was ment (months 1, 7, and 13). Global aesthetic facial appearance used by decision of the Investigators. was assessed by blinded evaluators by comparing photographs from months 1 and 7, as well as from month 13. Monotherapy ABO cohort: Subjects received up to 125 s.U ABO (Azzalure®/ Subject photographs were also used for blinded evaluation Dysport® [Ipsen Biopharm Limited, UK]) intramuscularly in at of perceived age and first impression regarding social skills, least two upper facial indications. Recommended doses were academic performance, dating success, occupational success, 50 s.U in 5 injection points for glabellar lines, 60 s.U (30 s.U/side) attractiveness, financial success, relationship success, and ath- in 3 injection points/side for lateral canthal lines, and 20-60 s.U letic success, using a 10-grade scale. Overall first impression in 4-6 injection points for forehead lines. Optional touch-up was was the sum of the scores from all categories, with a maximum allowed after 2 weeks. score of 80.

HA cohort: Subjects were injected in nasolabial folds and/or Aesthetic improvement compared to baseline was assessed us- cheeks with ≤1 mL of either OBT™ or NASHA™ fillers (Galderma ing the 5-grade Global Aesthetic Improvement Scale (GAIS).23 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

684 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

Blinded evaluators used photographs, while subjects and Inves- intervals. The aim was to show that global facial aesthetic ap- tigators did the assessment during the medical appointment. pearance was superior at month 7 compared to month 1, with Wrinkle severity assessment of upper facial indications at rest the 95% confidence interval above 50%. First impression was and at maximum contraction was assessed by Investigators us- presented descriptively and using Wilcoxon signed-rank test. ing a validated 5-grade scale.22 Perceived age assessments were presented descriptively and with paired t-test. Satisfaction questionnaires were analyzed de- Subject and Investigator satisfaction was assessed using ques- scriptively. tionnaires. RESULTS Safety Assessment Figure 2 shows subject disposition. Sixty-five subjects were Methods for collecting safety data included assessment of ad- randomized to monotherapy with either ABO (n=32) or HA filler verse events (AEs). (n=33). Table 1 and Table 2 show demographic and baseline data. Injection data are presented in Table 3 to Table 5. Statistical Methods Two analysis populations were defined for the study. The safety Efficacy population included all subjects who were injected in at least Global Facial Aesthetic Appearance one nasolabial fold/cheek (HA cohort) or one injection point One month after first combination treatment (month 7), most (ABO cohort). The intention-to-treat population was the primary subjects (ABO cohort: 67%; HA cohort: 94%) had a superior population for efficacy analyses and included all subjects who global facial aesthetic appearance compared with after mono- were injected in both nasolabial folds/cheeks or at least two up- therapy (month 1; Figure 3). When the evaluators compared per facial indications. photographs from months 1, 7, and 13, the best result was obtained at month 13 (one month after the second combination Statistical analyses and the randomization list were done using treatment [60% of subjects]), followed by first combination SAS® version 9.4. Analyses of global facial aesthetic appearance, treatment (36%) and monotherapy (4%), both cohorts combined wrinkle severity, and GAIS were done using 95% confidence (Figure 4). Do Not Copy FIGURE 2. Subject disposition. aNasolabial folds not assessed as mild/moderate (n=3), signs/symptoms of eyelid ptosis/compensatory frontalis muscle activity (n=1), active skin disease, inflammation, Penaltiesor related conditions Apply (n=1).b AE (headache). cTreatment with prohibited procedure before (n=1) or during (n=1) the study, consent withdrawal (n=1). dSafety analyses after first combined treatment did not include subjects withdrawn before month 6. eSafety analyses after second combined treatment did not include subjects withdrawn before month 12. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

685 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

TABLE 1. Wrinkle Severity Demographic and Baseline Data Responders to treatment were defined as subjects with at least ABO cohort HA cohort 1-grade improvement of upper facial lines. In general, more (N=32) (N=33) subjects were responders at maximum contraction than at rest, Age, mean (range) 43.9 (35-50) 44.8 (36-50) except forehead lines, for which more subjects were responders Sex, n (%) at rest than at maximum contraction. A majority of subjects were Female 31 (96.9) 32 (97.0) responders at 1 month after each treatment (month 1, month Male 1 (3.1) 1 (3.0) 7, and month 13). Six months after the treatments (month 6, Fitzpatrick skin type24, n (%) month 12, and month 18), the effect had generally subsided. However, more subjects were responders at month 12 than at I 1 (3.1) 1 (3.0) month 6, and also at month 18 than at month 12, except for II 10 (31.3) 8 (24.2) lateral canthal lines at rest (Figure 6). III 14 (43.8) 19 (57.6) IV 3 (9.4) 3 (9.1) First Impression V 4 (12.5) 2 (6.1) Overall first impression was similar between monotherapy and VI -- -- combination treatments; mean scores ranged from 42.4 to 44.6 %=(n/N)*100 during the study, both cohorts combined.

GAIS Perceived Age According to blinded evaluators, 70% of subjects in the ABO Subjects were perceived to look younger after first and second cohort and 61% in the HA cohort were improved on the GAIS combination treatment compared to after monotherapy, mean after monotherapy. After first and second combination treat- difference was -1.3 years (P-0.007) and -2.0 years (P<0.001), re- ment, 90% and 88% of subjects were improved, respectively, spectively, both cohorts combined. Also, most subjects were both cohorts combined. GAIS assessments by subjects and In- assessed as looking younger after the second combination vestigators showed improvement for 88-100% of subjects after treatment than after the first; mean difference was -0.9 years monotherapy and for 94-100% of subjects after both combina- with P=0.043, both cohorts combined. tion treatments (Figure 5). Do Not Copy TABLE 2. Wrinkle Severity22 at Baseline Penalties Apply ABO cohort HA cohort (N=32) (N=33) At max At max At rest At rest contraction contraction n (%) n (%) n (%) n (%) No GL 2 (6.3) -- 1 (3.0) -- Mild GL 21 (65.6) -- 21 (63.6) -- GL Moderate GL 8 (25.0) 14 (43.8) 9 (27.3) 15 (45.5) Severe GL 1 (3.1) 18 (56.3) 2 (6.1) 18 (54.5) Very severe GL ------No LCL 2 (6.3) -- 1 (3.0) -- Mild LCL 21 (65.6) -- 21 (63.6) -- LCL Moderate LCL 8 (25.0) 14 (43.8) 9 (27.3) 15 (45.5) Severe LCL 1 (3.1) 18 (56.3) 2 (6.1) 18 (54.5) Very severe LCL ------No FL 2 (6.3) -- 1 (3.0) -- Mild FL 21 (65.6) -- 21 (63.6) -- FL Moderate FL 8 (25.0) 14 (43.8) 9 (27.3) 15 (45.5) Severe FL 1 (3.1) 18 (56.3) 2 (6.1) 18 (54.5) Very severe FL ------%=(n/N)*100 GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead lines Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

686 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

TABLE 3. TABLE 5. Injection Information Baseline Injection Information: Second Combined Treatment (Month 12) ABO cohort HA cohort ABO cohort HA cohort Both (N=32) (N=33) (N=31) (N=29) (N=60) ABO dose (s.U), mean (range) ABO dose (s.U), mean (range) Baseline (n=32) 47.5 (30.0-58.0) Month 12 46.0 49.2 47.6 GL a b Touch-up (n=11) 16.4 (6.00-26.0) (n=30 /29 ) (25.0-64.0) (32.0-58.0) (25.0-64.0) GL Baseline (n=32) 33.9 (20.0-50.0) Touch-up 20.3 17.1 19.1 LCL (n=11a/7b) (3.0-40.0) (10.0-24.0) (3.0-40.0) Touch-up (n=13) 14.5 (1.50-22.0) Baseline (n=27) 29.2 (7.50-60.0) Month 12 41.0 38.7 39.8 FL (n=29a/29b) (25.0-60.0) (28.0-60.0) (25.0-60.0) Touch-up (n=4) 10.6 (1.00-20.0) LCL Touch-up 14.6 21.4 17.6 HA filler volume mL, mean (range) (n=9a/7b) (3.0-16.0) (16.0-30.0) (3.0-30.0) NLFs (n=33) 0.87 (0.40-1.00) Month 12 29.1 28.0 28.7 a b Cheeks (n=9) 0.44 (0.20-0.60) (n=25 /18 ) (10.0-40.0) (8.0-40.0) (8.0-40.0) FL Touch-up 24.0 31.6 27.8 GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead lines (n=5a/5b) (10.0-40.0) (18-60.0) (10.0-60.0) HA filler volume mL, mean (range) 0.51 0.50 0.51 TABLE 4. NLFs (n=28a/26b) (0.20-1.00) (0.20-1.00) (0.20-1.00) Injection Information: First Combined Treatment (Month 6) 0.82 0.89 0.85 Cheeks (n=29a/25b) ABO cohort HA cohort Both (0.30-1.60) (0.30-2.00) (0.30-2.00) (N=31) (N=31) (N=62) 0.73 0.63 0.69 Otherc (n=27a/22b) ABO dose (s.U), mean (range) (0.20-1.80) (0.20-1.50) (0.20-1.80) Month 6 49.3 51.5 50.4 RSB volume mL, mean (range) (n=31a/31b) (32.0-64.0) (40.0-64.0) (32.0-64.0) GL 0.95 0.94 0.94 Touch-up 19.6 30.2 24.1 Month 12 (n=30a/29b) Do Not Copy (0.50-1.00) (0.40-1.00) (0.40-1.00) (n=12a/9b) (6.0-30.0) (18.0-50.0) (6.0-50.0) PenaltiesGL: Apply Glabellar lines; LCL: Lateral canthal lines; FL: Forehead lines Month 6 38.1 37.7 37.9 aABO cohort (n=30a/31b) (20.0-56.0) (24.0-58.0) (20.0-58.0) bHA cohort LCL cOral commissures, marionette lines, mouth corners, lips, jaw line, chin, tear Touch-up 17.7 19.0 18.3 troughs, perioral lines, forehead, eye area, nose area, glabella, mental crease, (n=10a/9b) (12.0-30.0) (8.0-40.0) (8.0-40.0) pre-jowl, medium cheek, low cheek, mid face. Month 6 28.8 30.3 29.5 (n=28a/23b) (9.0-54.0) (8.0-46.0) (8.0-54.0) FL Touch-up 23.0 23.4 23.2 FIGURE 3. Subjects with superior global facial aesthetic appearance (n=6a/5b) (10.0-40.0) (2.0-40.0) (2.0-40.0) after first combination treatment than after monotherapy. Since the confidence interval was above the predetermined limit (50%; dashed HA filler volume mL, mean (range) line) in the HA cohort and in both cohorts combined, it was shown 0.71 0.61 0.66 NLFs (n=31a/29b) that with 95% confidence, the majority of subjects in the underlying (0.40-1.30) (0.20-1.20) (0.20-1.30) populations had a superior facial aesthetic appearance after 0.77 0.73 0.75 combination treatment than after monotherapy. Cheeks (n=24a/24b) (0.20-1.30) (0.40-1.20) (0.20-1.30) 0.67 0.78 0.72 100 Otherc (n=29a/31b) (0.20-1.60) (0.10-2.00) (0.10-2.00)

HA filler volume mL, mean (range)

0.95 0.95 0.95 Month 6 (n=31a/31b) (0.50-1.00) (0.50-1.00) (0.50-1.00) % subjects

0.94 0.97 0.96 (with 95% CI) Month 7 (n=29a/31b) (0.50-1.00) (0.50-1.00) (0.50-1.00)

GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead lines 0 aABO cohort bHA cohort ort cts c oh Marionette lines, oral commissures, tear troughs, lips, jaw line, nose area, cohort er subje chin, eye area, forehead, perioral lines, mental crease, glabella, mouth BO c ll A A corners, pre-jowls. A fill H Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

687 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

FIGURE 4. Subject photographs. Female subject, age 45, with no FIGURE 5. GAIS score improvement compared to baseline. *Somewhat, previous facial procedures. The subject provided signed consent much, or very much improved. to that photographs of her face could be used publicly for scientific purposes. (A) One month after monotherapy with: 51 + 8 s.U ABO in glabellar lines, 29 + 10 s.U in lateral canthal lines, and 11 s.U in forehead lines. (B) One month after first combination treatment with: 48 s.U ABO in glabellar lines, 23 s.U in lateral canthal lines, and 11 s.U in forehead lines; 1.90 mL HA filler in nasolabial folds, lips, cheeks, nose tip and pre-mental crease; 1 mL RSB in lower face. (C) One month after second combination treatment with: 50 s.U ABO in glabellar lines and 25 s.U in lateral canthal lines; 2.0 mL HA filler in nasolabial folds, cheeks, lips, tear troughs, pre-mental crease and upper eyelids; 1 mL RSB in upper and lower face. (A) (B) (C)

FIGURE 6. Improvement of wrinkle severity of upper facial lines. (A) At rest. (B) At maximum contraction. *Improvement month 18 compared to month 12: P<0.05.

(A)

Subject and Investigator Satisfaction Questionnaire At baseline, approximately one-third of subjects were satisfied with their facial appearance. The proportion of satisfiedDo subjects Not Copy increased from baseline/month 1 to month 7 and month 13 (Fig- ure 7a). Satisfaction with skin quality parameters improvedPenalties from Apply baseline to month 7 and month 13 (Figure 7b). At all timepoints, more than 90% of subjects stated they would do the treatment again and recommend treatment to a friend.

Investigator satisfaction with overall facial aesthetic outcome was high after monotherapy (ABO cohort: 84%; HA cohort: 67%) and after both combination treatments (98-100%, both cohorts combined). (B) Safety Monotherapy Ten subjects (15%, both cohorts combined) had 12 treatment- related AEs of mild or moderate intensity. None were serious; most resolved within 2 weeks. Headache was most common in the ABO cohort, affecting 3 subjects, and injection-site bruising in the HA cohort, also affecting 3 subjects.

First combination treatment Twenty-eight subjects (45%) had 45 treatment-related AEs of mild or moderate intensity; most resolved within 1 week; none were serious. Injection-site bruising after HA filler or RSB injection was most commonly reported, affecting 13 subjects. Headache was most common in the ABO cohort, reported for 2 subjects. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

688 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

FIGURE 7. Subject satisfaction. *Somewhat/very satisfied.

(A) (B)

100

90 88 85 85 82 82 83 82 83 76 76 74 73 73

Baseline

37 Month 7 % satisfied* subjects 25 Month 13 17 15 17 9 2 0 y n ss w ss re ss tio icit e lo e tu e a tn G n c r st f h u mn d s ir Ela So re Str F Hy F

Second combination treatment gator satisfaction than monotherapy. This is in line with results Nineteen subjects (31%) had 36 treatment-related AEs of mild after combination treatment in another study where higher or moderate intensity, most resolved within two weeks; none mean ABO doses and HA filler volumes were injected.1 It should were serious. All but one treatment-related AE were related to be noted though, that combination treatments were adminis- HA filler and/or RSB injection. Injection-site bruising was most tered after monotherapy in our study. commonly reported, affecting 14 subjects. Do Not Copy The volume of HA filler at monotherapy was restricted to DISCUSSION Penaltiesmaximum Apply 1 mL to reflect what was considered feasible for the We previously conducted a study where ABO was administered majority of new aesthetic patients. Although the Investigators in glabellar lines only (Cartier et al, accepted for publication assessed that most subjects (76%) would have benefited from Dermatologic Surgery 2019). The present study was designed having additional filler volume, most subjects (64%) in the HA similarly, but with ABO administered also in lateral canthal lines filler cohort were satisfied with the treatment results after mono- and forehead lines. therapy and Investigators were satisfied with the overall facial aesthetic outcome for 67% of the subjects. As in our previous study (Cartier et al, accepted for publication Dermatologic Surgery 2019), overall aesthetic outcomes were Subject satisfaction with treatment and skin quality improved more beneficial after combination treatment than after mono- over time, suggesting that the addition of Skinbooster was effec- therapy. The first combination treatment achieved a superior tive for improving skin quality, although the assessment could global facial aesthetic appearance over monotherapy in most be influenced by all products included in the combination treat- subjects. Global aesthetic appearance increased further with ments. the second combination treatment. Thus, cumulative treatments over time resulted in better aesthetic outcomes. The wrinkle severity of upper facial lines improved at least 1-grade 1 month after treatment for a majority of subjects, both Most subjects had GAIS score improvement throughout the at rest and at maximum contraction. Improvement was gen- study (61-90%) according to blinded evaluators. Subject/In- erally higher at maximum contraction than at rest, except for vestigator assessments showed improvement for 94-100% of forehead lines for which improvement at rest was comparative- subjects after both combination treatments and after monother- ly high, also at six months after treatment. By reducing muscle apy with ABO, and for 88-91% of subjects after monotherapy movement while maintaining some muscle activity, botulinum with HA filler. toxins have potential to reduce also static wrinkles with natural looking results. Wrinkle severity improvement data for glabellar Combination treatments achieved higher subject and Investi- lines were in line with previous results (Cartier et al, accepted for publication Dermatologic Surgery 2019). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

689 Journal of Drugs in Dermatology P. Hedén, D. Hexsel, H. Cartier, et al July 2019 • Volume 18 • Issue 7

dose-ranging study. Dermatol Surg. 2009;35(10):1478-1486. Both single and combination treatments were well tolerated. 10. Rzany B, Dill-Müller D, Grablowitz D, et al. Repeated botulinum toxin Most treatment-related AEs resolved spontaneously, and all A injections for the treatment of lines in the upper face: a retrospective study of 4,103 treatments in 945 patients. Dermatol Surg. 2007;33(1 Spec were of mild-to-moderate intensity. The most frequently report- No.):S18-25. ed AE was injection-site bruising, an anticipated reaction to the 11. Rzany B, Cartier H, Kestemont P, et al. Full-face rejuvenation using a range study treatments. of hyaluronic acid fillers: efficacy, safety, and patient satisfaction over 6 months. Dermatol Surg. 2012;38(7 Pt 2):1153-1161. 12. Weiss RA, Moradi A, Bank D, et al. Effectiveness and safety of large gel par- This study was limited by the restricted volumes of HA filler, ticle hyaluronic acid with lidocaine for correction of midface volume deficit or contour deficiency.Dermatol Surg. 2016;42(6):699-709. set to reflect a real-life scenario where subjects often have 13. Narins RS, Dayan SH, Brandt FS, Baldwin EK. Persistence and improve- limited resources. Also, since combination treatments were ment of nasolabial fold correction with nonanimal-stabilized hyaluronic acid 100,000 gel particles/mL filler on two retreatment schedules: results up to administered in sequence following monotherapy, potential 18 months on two retreatment schedules. Dermatol Surg. 2008;34 Suppl confounding effects on clinical outcome should be considered. 1:S2-8; discussion S8. 14. Narins RS, Brandt FS, Dayan SH, Hornfeldt CS. Persistence of nasolabial fold correction with a hyaluronic acid dermal filler with retreatment: results of an Efficacy results from this and from our previous study (Cartier 18-month extension study. Dermatol Surg. 2011;37(5):644-650. et al, accepted for publication Dermatologic Surgery 2019) un- 15. Carruthers J, Klein AW, Carruthers A, et al. Safety and efficacy of nonanimal stabilized hyaluronic acid for improvement of mouth corners. Dermatol Surg. derline the benefit of establishing treatment plans based on 2005;31(3):276-280. patients’ individual treatment goals. 16. Rzany B, Bayerl C, Bodokh I, et al. An 18-month follow-up, randomized comparison of effectiveness and safety of two hyaluronic acid fillers for treatment of moderate nasolabial folds. Dermatol Surg. 2016. CONCLUSIONS 1 7. Distante F, Pagani V, Bonfigli A. Stabilized hyaluronic acid of non-animal origin for rejuvenating the skin of the upper arm. Dermatol Surg. 2009;35 Suppl Treatment of several indications with HA products and ABO 1:389-393; discussion 394. was effective and well tolerated. Combination treatment with 18. Williams S, Tamburic S, Stensvik H, Weber M. Changes in skin physiology ABO, HA filler, and RSB, administered in sequence after mono- and clinical appearance after microdroplet placement of hyaluronic acid in aging hands. J Cosmet Dermatol. 2009;8(3):216-225. therapy, resulted in more beneficial aesthetic outcomes than 19. Kerscher M, Bayrhammer J, Reuther T. Rejuvenating influence of a stabilized monotherapy alone. hyaluronic acid-based gel of nonanimal origin on facial skin aging. Dermatol Surg. 2008;34(5):720-726. 20. Hexsel D, Cartier H, Heden P, et al. Efficacy, safety, and subject satisfac- DISCLOSURES tion after abobotulinumtoxina treatment of upper facial lines. Dermatol Surg. 2018. Galderma funded the study and provided the study products. 2 1. Narins RS, Carruthers J, Flynn TC, et al. Validated assessment scales for the H. Cartier, P. Bergentz, C. Siega, and F. Camozzato haveDo no other Not Copylower face. Dermatol Surg. 2012;38(2 Spec No.):333-342. conflicts of interest to declare; P. Hedén is a consultant for Al- 22. Flynn TC, Carruthers A, Carruthers J, et al. Validated assessment scales for the upper face. Dermatol Surg. 2012;38(2 Spec No.):309-319. lergan, Galderma, and Teoxane; D. Hexsel is a consultantPenalties for 23. Apply Narins RS, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter Galderma and Merz; C. Skoglund, C. Edwartz, and M. Norberg comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29(6):588-595. are employed by Galderma; P. Kestemont is a consultant for Al- 24. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through lergan, Filorga, Galderma, Teoxane, Universkin, and Vivacy. VI. Arch Dermatol. 1988;124(6):869-871.

REFERENCES AUTHOR CORRESPONDENCE 1. Molina B, David M, Jain R, et al. Patient satisfaction and efficacy of full-facial rejuvenation using a combination of botulinum toxin type a and hyaluronic Philippe Kestemont MD acid filler.Dermatol Surg. 2015;41 Suppl 1:S325-332. 2. Fabi SG, Goldman MP, Mills DC, et al. Combining microfocused ultrasound E-mail:...... ……...... [email protected] with botulinum toxin and temporary and semi-permanent dermal fillers: safety and current use. Dermatol Surg. 2016;42 Suppl 2:S168-176. 3. Narurkar VA, Cohen JL, Dayan S, et al. A comprehensive approach to multimodal facial aesthetic treatment: injection techniques and treatment characteristics from the HARMONY study. Dermatol Surg. 2016;42 Suppl 2:S177- 19 1. 4. Carruthers J, Carruthers A. A multimodal approach to rejuvenation of the lower face. Dermatol Surg. 2016;42 Suppl 2:S89-93. 5. Press release: Market Research Proves Success of Galderma’s Harmony Programme for Aesthetic Practice [press release]. Lausanne, Switzerland: Galderma2017. 6. Rzany B, Ascher B, Monheit G. Treatment of glabellar lines with botulinum toxin type A (Speywood Unit): a clinical overview. J Eur Acad Dermatol Vene- reol. 2010;24 Suppl 1:1-14. 7. Ascher B, Talarico S, Cassuto D, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit)--Part I: Upper facial wrinkles. J Eur Acad Dermatol Venereol. 2010;24(11):1278- 1284. 8. Karsai S, Adrian R, Hammes S, et al. A randomized double-blind study of the effect of Botox and Dysport/Reloxin on forehead wrinkles and electromyo- graphic activity. Arch of Dermatol. 2007;143(11):1447-1449. 9. Ascher B, Rzany BJ, Grover R. Efficacy and safety of botulinum toxin type A in the treatment of lateral crow's feet: double-blind, placebo-controlled, Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

An Atypical Presentation of PLEVA: Case Report and Review of the Literature Constance Ediale MS,ª Kayla Felix MS,B Kathryn Anderson MD,c Christine Ahn MD,c Amy J. McMichael MDc aAugusta University/ University of Georgia Medical Partnership, Athens, GA BWake Forest University School of Medicine, Winston-Salem, NC cDepartment of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC

ABSTRACT

Pityriasis lichenoides et varioliformis acuta (PLEVA) is a rare, self-limited, cutaneous disorder of unknown etiology. Clinically, PLEVA is characterized by the sudden onset of scaly, erythematous macules and papules localized to the trunk and proximal extremities. We report the case of a patient who presented with multiple erythematous papules and plaques on the palms, forearms, and dorsal feet.

J Drugs Dermatol. 2019;18(7):690-691.

REPORT OF A CASE 62-year-old woman presented for evaluation of recurrent itchy lesions distributed over her upper and lower FIGURE 1. Clinical Image Multiple erythematous and hyperpigmented Do Not scalingCopy papules and plaques on both palms and forearms. Aextremities including her hands and feet. She reported that the rash had been present for several months, Penaltiesbut that she Apply had a similar rash one year before. At her previous evaluation one year before, she reported the lesions had also occurred on the hands and feet but were accompanied by lesions in the mouth. At that time, she was diagnosed with Hand, Foot, and Mouth disease via biopsy and positive coxsackie titers. After treatment with clobetasol 0.05% cream, the lesions resolved, until this current episode.

Physical examination at the time of her current outbreak revealed multiple erythematous and hyperpigmented scaling, 1-3 cm papules and plaques on both palms and forearms, some with a collarette of the scale and others with necrotic changes and excoriations. Also, there were several similar hyperpig- FIGURE 2. Histopathologic Image Punch biopsy specimen from mented papules on the dorsal feet and ankles. Oral lesions the center of a papule on the left palm (hematoxylin-eosin, original were absent. Two 4 mm punch biopsy specimens were obtained magnification ×10). from the left palm and right wrist.

Histopathologic examination revealed parakeratosis and a brisk lichenoid inflammation with scattered dyskeratotic keratinocytes and erythrocyte extravasation. These histologic findings were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA). The patient tested negatively for syphilis and antinuclear antibody laboratory results were within normal limits. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

691 Journal of Drugs in Dermatology C. Ediale, K. Felix, K. Anderson, C. Ahn, A.J. McMichael July 2019 • Volume 18 • Issue 7

DISCUSSION DISCLOSURES Pityriasis lichenoides is a cutaneous inflammatory disease Amy J. McMichael MD is a consultant for Aclaris, Allergan, Bion- with unknown etiology. It is considered to be on a spectrum, iz, Cassiopea, Covance, eResearch Technology, Inc., Galderma, with both acute and chronic forms.1 The acute type, called Pit- Guthey Renker, Incyte, Johnson & Johnson, Keranetics, Merck yriasis lichenoides et varioliformis acuta (PLEVA), also known & Co., Inc., Merz Pharmaceuticals, Pfizer, Proctor & Gamble, Sa- as Mucha-Habermann disease, can be found in patients of all mumed, and received Royalties from Informa Healthcare and ages but is most commonly seen in individuals in their second UpToDate. Dr. McMichael performed researche for Cassiopea, or third decade of life.2 Currently, there is no established etiol- Proctor & Gamble, and Samumed. All other authors do not have ogy, though proposed theories include lymphoproliferation, an conflicts of interest. inflammatory reaction to a viral infection, and possible immune- complex-mediated vasculitis.3 REFERENCES 1. Fernandes NF, Rozdeba PJ, Schwartz RA, Kihiczak G, Lambert WC. Pityriasis lichenoides et varioliformis acuta: a disease spectrum. International Journal Patients with PLEVA often present with erythematous pap- of Dermatology. 49(3):257-261. doi:10.1111/j.1365-4632.2008.03915.x ules, with a light micaceous scale and a central punctum, that 2. Patel DG, Kihiczak G, Schwartz RA, Janniger CK, Lambert WC. Pityriasis li- progress into necrotic papules.4 Papules are usually present in chenoides. Cutis. 2000;65(1):17-20, 23. 3. Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad several different stages of development, which is a hallmark of Dermatol. 2006;55(4):557-572; quiz 573-576. doi:10.1016/j.jaad.2005.07.058 diagnosis. Lesions are typically concentrated proximally, with 4. Longley J, Demar L, Feinstein RP, Miller RL, Silvers DN. Clinical and histologic features of pityriasis lichenoides et varioliformis acuta in children. Arch heaviest involvement of the trunk, proximal limbs, and flexor Dermatol. 1987;123(10):1335-1339. surfaces and are often asymptomatic but can be pruritic or 5. Ersoy-Evans S, Greco MF, Mancini AJ, Subaşi N, Paller AS. Pityriasis lichenoi- 3 des in childhood: a retrospective review of 124 patients. J Am Acad Derma- associated with a burning sensation. Involvement of distal ap- tol. 2007;56(2):205-210. doi:10.1016/j.jaad.2006.08.023 pendages is not common, especially as the only location for the 6. Nair PS. A clinical and histopathological study of pityriasis lichenoides. Indian disease process.2 J Dermatol Venereol Leprol. 2007;73(2):100-102. AUTHOR CORRESPONDENCE Previously, the patient was diagnosed with coxsackie virus because of the positive coxsackie titers, though it is not clear Constance Ediale MS if they were germane to the skin eruption. While there were E-mail:...... ……...... [email protected] papular lesions in the mouth as well as on the palms,Do soles Not of Copy the feet, and gluteal area and biopsy results showed confluent necrosis, parakeratosis and hyperkeratosis, a specificPenalties histopath- Apply ologic diagnosis for the previous rash was not possible due to the superficial nature of the biopsy.

A definitive diagnosis of PLEVA can only be made with his- tological findings from a skin biopsy. Histologically, there is parakeratosis, spongiosis, exocytosis of lymphocytes and erythrocytes into the epidermis, epidermal necrosis, and an edematous dermis with wedge-shaped lymphohistiocytic peri- vascular infiltrate.3,5,6 Vasculitis is rare.

In patients with asymptomatic lesions, treatment may be limited to close monitoring without pharmacologic intervention. Sys- temic antibiotic therapy with tetracyclines or erythromycin and phototherapy are used for the treatment of symptomatic disease. Methotrexate is reserved for the treatment of patients who have failed oral antibiotics and phototherapy. Topical corticosteroids may be useful for improving symptoms and accelerating the resolution of individual lesions.

Uncommon localizations of PLEVA, such as that seen in this case of distal extremity lesions only, pose a diagnostic challenge, which may result in delayed diagnosis. This case highlights an atypical manifestation of PLEVA localized to distal extremities, specifically the forearms, hands, and feet. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

STILL AVAILABLE

Implications of Treatment Vehicles in Effective Topical Therapy

A SUPPLEMENT TO

To provide dermatology providersDo Not Copy with an educational referencePenalties tool Apply exploring the important role of vehicle technology, the advancements in vehicle formulation and the role of vehicles in optimizing JDD therapeutic outcomes in cutaneous diseases including acne vulgaris and plaque psoriasis. Im plicat ions of This supplement is funded by an in E Treat ffecti ment V educational grant provided by Mayne ve Top ehicle ical Th s Pharma Group Limited. erapy Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Treatment of Solitary Keratoacanthoma of the Nose With Intralesional Methotrexate and Review of the Literature Laura Doerfler MD,a C. William Hanke MD MPHb aWake Forest School of Medicine, Winston-Salem, NC bLaser and Skin Surgery Center of Indiana, Indianapolis, IN

ABSTRACT

Keratoacathoma (KA) is a unique clinical pathological entity that is difficult to categorize. Differentiating a KA from a squamous cell carcinoma (SCC) is important for treatment implications but is often challenging. We report a patient with a solitary KA of the skin of the right ala successfully treated with intralesional (IL) injections of methotrexate (MTX). We also provide a review of the literature on IL-MTX as a treatment modality for KA.

J Drugs Dermatol. 2019;18(7):693-696.

INTRODUCTION eratoacathoma (KA) is a unique clinical pathological entity that is difficult to categorize. Differentiating a KA FIGURE 1. 53-year-old woman developed a 1cm keratoacanthoma on Kfrom a squamous cell carcinoma (SCC) is important for the nasal ala. treatment implications but is often challenging. Clinically, aggressive SCC may present similarly to KA with rapid growth over weeks. Furthermore, it is often challenging, histologically,Do Not Copy to distinguish between KA and SCC without an excisional biopsy.1-3 While some KAs have shown the ability to spontaneouslyPenalties Apply involute,4 others have progressed to high-risk SCC or metasta- sized.5,6 A malignant course in suspected KA is thought to be more likely the result of diagnostic confusion with SCC rather than malignant transformation.3 FIGURE 2. The keratoacanthoma demonstrated necrosis one week following intralesional methotrexate injection. We report a patient with a solitary KA of the skin of the right ala successfully treated with intralesional (IL) injections of methotrexate (MTX). We also provide a review of the literature on IL-MTX as a treatment modality for KA. REPORT OF A CASE A 53-year-old woman presented with an eight week history of a rapidly enlarging 1cm in diameter nodule on the right nasal ala (Figure 1). Incisional biopsy revealed a squamous cell carcinoma, keratoacanthoma type, with lesional tissue extending to the base of the biopsy. The lesion was injected with 1cc of metho- FIGURE 3. The keratoacanthoma has undergone considerable shrinkage two weeks post intralesional methotrexate injection. trexate (25 mg methotrexate/mL) three times, with an interval of one week between injections. After each treatment, involution of the lesion was observed (Figure 2, 3). Four weeks after the first treatment, the lesion had completely resolved. No recurrence of the lesion was noted during a follow-up at 6 months (Figure 4). DISCUSSION There is a great deal still unknown of the etiology and patho- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

694 Journal of Drugs in Dermatology L. Doerfler, C.W. Hanke July 2019 • Volume 18 • Issue 7

FIGURE 4. The tumor has totally resolved 6 months following chitecture of the tumor shows a central keratin-filled crater intralesional methotrexate injection. The skin appears clinically normal surrounded by symmetrical, cup-shaped invaginations of thin without scarring. atrophic epidermis with overhanging edges. There is a sharp de- marcation between tumor and stroma. The cellular component is similar to SCC with well-differentiated keratinocytes with a glassy cytoplasm. Cytologic atypia is minimal. If hyperchromat- ic nuclei or abnormal mitoses are present, the diagnosis of an invasive SCC is favored. As the lesion regresses, the cup shaped architecture flattens, and fibrosis develops at the base.20

Discriminating between KA and SCC is difficult when the biopsy physiology of KA. Even classifying it as a malignant versus transects the base of the lesion. Though it may appear to be a benign tumor is controversial. With so much uncertainty, there KA, without the base, an invasive SCC cannot be ruled out. Thus, are no clear guidelines to follow in management of KAs. biopsies that are fully representative of the lesion are helpful though not always practical for a large KA or KAs in cosmetical- Etiology ly sensitive areas.2,21 There are no reliable immunohistochemical KA is assumed to originate from the hair follicle as it exhib- staining markers used in differentiating KA from SCC.22 its markers consistent with those in the follicular isthmus and infundibulum.1 The classic KA evolves in 3 clinical stages: prolif- Treatment for Solitary KAs erative, stabilization, and regression. There are several variants The ambiguity between a KA and SCC creates a dilemma with of KA including solitary sporadic, solitary iatrogenic, multiple regard to the management of KAs. Though there is a tendency iatrogenic, multiple familial, and centifugum et marginatum. Ul- for spontaneous involution, most do not recommend waiting for traviolet exposure is a predominant risk factor for most of these the tumor to self-resolve due to the uncertainty of behavior.25 In variants.7-9 addition, therapeutic intervention may hasten resolution, limit damage to vital structures and provide an improved cosmetic Clinical Manifestations result. Many treatment modalities have been reported with vari- Solitary sporadic KA is a rapidly enlarging neoplasmDo appear Not- ousCopy success rates and side effects. ing mainly on sun-exposed areas of the skin. Men are affected up to 3 times more frequently than women. The classicPenalties lesion Surgical Apply removal is the gold standard regimen when possible. presents as a dome-shaped nodule with a central hyperkeratotic Standard surgical excision with 5 mm margins, Mohs surgery or plug. There may be associated pain or tenderness. KAs usually curettage and electrodessication is commonly used in small (<1 enlarge rapidly to full size within 6 to 10 weeks. Most KAs grow cm), solitary KAs.22 to a diameter of 1 to 2 cm and 0.5cm in thickness. Larger KAs (more than 3 cm) are referred to as Giant KA. Spontaneous in- Intralesional (IL) chemotherapy may be warranted for solitary volution tends to begin around 8-12 weeks and can take up to 4 large KAs or those adjacent to vital structures that may often re- to 6 months to fully resolve. The resulting scar is often hypopig- quire extensive reconstruction. Methotrexate (MTX) is preferred mented and atrophic.3 as an intralesional drug, with 5-fluorouracil (5-FU), bleomycin or interferons being other options.23 MTX has an appealing mecha- Iatrogenic KA can be induced by medical procedures that create nism of action for a rapidly growing KA. It is a folic acid analog trauma to the skin or in response to systemic chemotherapy. that inhibits DNA synthesis in actively dividing cells. KAs treat- They can be solitary or multiple. Solitary KA along prior exci- ed with IL-MTX show high cure rates of 71-92%.21,23-27 sion areas can mimic tumor regrowth.10 Multiple/Eruptive KAs are rapidly growing nodules that can also occur along prior ex- There is no standard protocol for administering IL-MTX injec- cision areas. Multiple KAs may also be associated with prurigo tions. Current data show 1-4 injections are generally required nodularis, usually on the lower limbs of elderly women with with many resolving in 2 injections. Injections are separated by sun-damaged skin.11 There are reports of KAs following esthet- 2 to 3 weeks. The concentrations used per injection show ex- ic procedures on sun damaged skin including chemical peels, treme variation from 0.3 to 2.0 mL in a concentration of 25 mg/ dermabrasion, and resurfacing laser procedures.13-17 Systemic mL or 12.5 mg/mL.21,23-27 Annest and colleagues showed a 92% chemotherapy notably BRAF inhibitors and Hedgehog pathway cure rate among 38 KAs treated with a mean cumulative dose inhibitors are associated with KAs.18,19 of IL-MTX of 38.2 mg.25 Small KAs are injected at a single central point at the base of the lesion. Large KAs are injected into 4 Histology quadrants at the central base of the lesion. MTX is injected until KAs have a distinct histologic appearance. The distinctive ar- an end point of uniform tumor blanching is achieved. Though Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

695 Journal of Drugs in Dermatology L. Doerfler, C.W. Hanke July 2019 • Volume 18 • Issue 7

rare, there are reports of pancytopenia following a single 25 mg excisions and reconstructions that may compromise functional dose of IL-MTX.28,29 Both cases occurred in patients with hemo- and esthetic outcome. A poor response to IL-MTX indicates a dialysis-dependent renal failure. Thus, obtaining a baseline and more aggressive entity and must be re-evaluated. 1-week post injection complete blood cell count is reasonable, particularly in patients with kidney disease. REFERENCES 1. Schwartz RA. Keratoacanthoma: a clinico-pathologic enigma. Dermatol Surg.

23,30 2004;30:326-333. IL-5FU has also shown success in treating KAs. Many prefer 2. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from IL-MTX compared to IL-5FU for practical reasons. IL-5FU often keratocanthoma using histopathological criteria. Is it possible? A study of requires pretreatment with local anesthesia while IL-MTX is gen- 296 cases. Dermatology. 1999;199:208-12. 3. Savage JA, Maize JC Sr. Keratoacanthoma clinical behavior: a systematic erally well tolerated without the use of local anesthesia. IL-5FU review. Am J Dermatopathol. 2014;36:422-429. also requires weekly injections while IL-MTX requires injections 4. Ramselaar CG, Ruitenberg EJ, Kruizinga W. Regression of induced keratoacanthomas in anagen (hair growth phase) skin grafts in mice. Cancer Res. 25 performed at 2 to 3-week intervals. 1980;40:1668-1673. 5. Hodak E, Jones RE, Ackerman AB. Solitary keratoacanthoma is a squamouos cell carcinoma: three examples with metastases. Am J Dermatopathol. While cure rates are high, factors that predict when a KA will 1993;15:332-42. not respond to IL-MTX are not well established. Rossi and col- 6. Misago N, Inoue T, Nagase K, et al. Crater/ulcerated form of infundibular leagues studied response rates of IL-MTX in solitary KAs of the squamous cell carcinoma: a possible distinct entity as a malignant (or high- grade) counterpart to keratoacanthoma. J Dermatol. 2015;42:667-673. head and neck.21 Potential factors were identified that may be 7. Sullivan JJ. Keratoacanthoma: the Australian experience. Australas J Derma- associated with treatment failures. They found that persistent tol. 1997;38(Suppl 1):S36-S39. 8. Sina B, Adrian RM. Multiple keratoacanthomas possibly induced by psoralens pain and sustained growth post two treatments of IL-MTX may and ultraviolet A photochemotherapy. J Am Acad Dermatol. 1983;9:686-688. suggest an underlying aggressive SCC. In addition, immu- 9. Craddock KJ, Rao J, Lauzon GJ, Tron VA. Multiple keratoacanthomas arising post-UVB therapy. J Cutan Med Surg. 2004; 8:239-243. nosuppression may also raise concern for a more aggressive 10. Pattee SF, Silvis NG. Keratoacanthoma developing in sites of previous trau- SCC tumor. Some Larger KAs have also shown to have poor ma: a report of two cases and review of the literature. J Am Acad Dermatol. response. Annest et al found the average tumor diameter for 2003;48(Suppl):S35-S38. 11. Goldberg LH, Silapunt S, Beyrau KK, Peterson SR, Friedman PM, Alam M. nonresponding lesions was larger than the average tumor for Keratoacanthoma as a postoperative complication of skin cancer excision. J responsive lesions (2.8 vs 1.9 cm).25 Am Acad Dermatol. 2004;50:753-758. 12. Wu TP, Miller K, Cohen DE, Stein JA. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. J Am Acad IL-MTX is an attractive treatment modality for KA. It is relatively Dermatol. 2013;69:426-430. Do Not 13.Copy Mohr B III, Fernandez MP, Krejci-Manwaring J. Eruptive keratoacanthomas noninvasive, inexpensive, quickly administered, safe, relatively after Jessners and trichloroacetic acid peel for actinic keratosis. Dermatol painless, tissue sparing with good cosmetic outcomes.Penalties In sum- ApplySurg. 2013;39:331-333. mary, if the clinical and diagnostic biopsy suggest a diagnosis of 14. Cox S. Rapid development of keratoacanthomas after a body peel. Dermatol Surg. 2003;29:201-203. KA, approximately 1 mL of MTX in a concentration of either 12.5 15. Mamelak AJ, Goldberg LH, Marquez D, Hosler GA, Hinckley MR, Friedman or 25 mg/mL is injected directly in the base of the tumor. This PM. Eruptive keratoacanthomas on the legs after fractional photothermoly- sis: report of two cases. Dermatol Surg. 2009;35:513-518. should be repeated at 2 week intervals until tumor resolution. If 16. Gewirtzman A, Meirson DH, Rabinovitz H. Eruptive keratoacanthomas fol- the tumor does not respond after two treatments, surgical treat- lowing carbon dioxide laser resurfacing. Dermatol Surg. 1999;25:666-668. 1 7. Gogia R, Grekin RC, Shinkai K. Eruptive self-resolving keratoacanthomas ment should be considered as the diagnosis may be invasive developing after treatment with photodynamic therapy and microdermabra- SCC. Monitor for MTX-induced cytopenias in renal failure pa- sion. Dermatol Surg. 2013;39:1717-1720. tients. 18. Aasi S, Silkiss R, Tang JY, et al. New onset of keratoacanthomas after vis- modegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol. 2013;149:242-243. Treatment for Multiple KAs 19. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous- cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 31,32 Multiple KAs have been managed with systemic retinoids. 2012;366:207-215. Patients have a marked response while on the retinoid. When 20. Kwittken J. A histologic chronology of the clinical course of the keratocarci- noma (so-called keratoacanthoma). M Sinai J Med. 1975;42:127-135. the medication is discontinued however there is frequently 2 1. Rossi AM1, Park B, Qi B, Lee EH, Busam KJ, Nehal KS. Solitary Large Kerato- regrowth. The dosage varies from 0.5 to 1.0 mg/kg of acitretin acanthomas of the Head and Neck: An Observational Study. Dermatol Surg. at the beginning of treatment and tapered as needed. Smaller 2017 Jun;43(6):810-816. 22. Kwiek B, Schwartz RA. Keratoacanthoma (KA): An update and review. J doses of 20 to 20 mg/day are often necessary to sustain clinical Am Acad Dermatol. 2016 Jun;74(6):1220-33. doi: 10.1016/j.jaad.2015.11.033. response. IL corticosteroids are occasionally used with good re- Epub 2016, Feb 4. 23. Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin can- 33 sponse either as monotherapy or with systemic retinoids. cer: a practical review. J Am Acad Dermatol. 2010;63:689-702. 24. Moss M, Weber E, Hoverson K, Montemarano AD. Management of kera- CONCLUSION toacanthoma: 157 tumors managed with surgery or intralesional methotrexate. Dermatol Surg. Epub 2019, Jan 2. While the majority of KAs are benign acting, the diagnostic 25. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrex- ambiguity has led to treatment standards toward that used for ate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol. 2007;56:989-993. well-differentiated SCC. The increasing data on the effectiveness 26. Aubut N, Alain J, Claveau J. Intralesional methotrexate treatment for kera- of IL-MTX is promising and prevents overtreatment with large toacanthoma tumors: a retrospective case series. J Cutan Med Surg. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

696 Journal of Drugs in Dermatology L. Doerfler, C.W. Hanke July 2019 • Volume 18 • Issue 7

2012;16:212-217. 32. Robertson SJ, Bashir SJ, Pichert G, Robson A, Whittaker S. Severe exacerba- 2 7. Yoo M, Kim I. Intralesional methotrexate for the treatment of keratoacanth- tion of multiple self-healing squamous epithelioma (Ferguson-Smith disease) oam. retrospective study and review of the Korean literature. Ann Dermatol. with radiotherapy, which was successfully treated with acitretin. Clin Exp 2014;26(2)172-176. Dermatol. 2010;35:e100-e102. 28. Goebeler M, Lurz C, Kolve-Goebeler ME, Brocker EB. Pancytopenia after 33. Sanders S, Busam KJ, Halpern AC, Nehal KS. Intralesional corticosteroid treatment of keratoacanthoma by single lesional methotrexate infiltration. treatment of multiple eruptive keratoacanthomas: case report and review of Arch Dermatol. 2001;137:1104-5. a controversial therapy. Dermatol Surg. 2002;28:954-958. 29. Cohen PR, Schulze KE, Nelson BR. Pancytopenia after a single intradermal infiltration of methotrexate.J Drugs Dermatol. 2005;4:648-51. AUTHOR CORRESPONDENCE 30. Klein E, Helm F, Milgrom H, Stoll HL Jr, Traenkle HL. Tumors of the skin. II. Keratoacanthoma; local effect of 5-fluorouracil.Skin. 1962;1:153-156. 3 1. LaPresto L, Cranmer L, Morrison L, Erickson CP, Curiel-Lewandrowski C. A Laura Doerfler MD novel therapeutic combination approach for treating multiple vemurafenib- E-mail:...... ……...... [email protected] induced keratoacanthomas: systemic acitretin and intralesional fluorouracil. JAMA Dermatol. 2013;149:279-281.

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A Giant Cutaneous Horn: One of the Largest Recorded Dillon Nussbaum BSc, Julia Schwartz MD, Adam Friedman MD FAAD George Washington University School of Medicine and Health Sciences, Washington, DC

ABSTRACT

We present a case of one of the largest cutaneous horns recorded in the known literature as an opportunity to explore diagnostic considerations and treatment options. Cutaneous horns are common exophytic neoplasms composed of dense keratin that are always secondary to primary lesions, which can be benign or malignant. Due to the variance of the primary lesion, diagnostic biopsies are necessary to rule out a malignant origin. Several case reports of giant cutaneous horns may suggest that a larger size indicates a verrucous origin, although a biopsy is necessary as this association has only been noted in very few cases. If the primary lesion is found to be malignant and extending to the biopsy margins, further treatment is required, whereas a benign origin usually requires no further treatment.

J Drugs Dermatol. 2019;18(7):697-698.

MANUSCRIPT 65-year-old African American female presented to an outpatient dermatology clinic with an occasionally pru- FIGURE 1A. Zoomed out image of a giant cutaneous horn situated on the center of the back and can be compared to the size of the entire ritic and painful “abnormal skin growth” on her back A back. for 22 years. On the mid back was a 22-centimeter tan-brown, horn shaped growth, with a well vascularized base,Do attached Not Copy to a pedunculated flesh colored plaque. A shave biopsy was performed below the base of the lesion. Pathology Penaltiesrevealed an Apply acanthotic endophytic cellular pattern with protruding columns of parakeratosis, consistent with a cutaneous horn arising from a verruca. Cutaneous horns are compact growths of keratin usually arising from either a verruca, an actinic keratosis, or more concerning, squamous or basal cell carcinoma. In fact, 23% of cutaneous horns develop from malignant cutaneous neoplasms underscoring the importance of histologic analysis and appropriate follow up. Fortunately, the margins on the biopsy specimen were negative/clear and the patient has yet to return with recurrence. FIGURE 1B. 22cm giant cutaneous horn with a large well vascularized A literature search of various synonyms of the words “giant base hanging from a pedunculated flesh colored plaque. cutaneous horn” suggests that this reported case of a 22-centimeter horn is possibly the largest to ever be described. In looking at similar cases, it appears that cutaneous horns of such a considerable size tend to be secondary to verruca rather than the more dangerous malignant neoplasms.1,2 Although no genetic analysis was performed on this biopsy, one previous case was found to have extensive horn like growths induced by human papillomavirus type two.3 It can be hypothesized that such large horns, and such extensive growth are result of verrucae that may have a genetic predilection in their viral DNA to tremendous angiogenic and proliferative abilities. Cutane- a much more disordered pattern, as would be expected with ous horns secondary to malignant neoplasms tend to grow in malignant cells, compared to horns secondary to verrucae. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

698 Journal of Drugs in Dermatology D. Nussbaum, J. Schwartz, A. Friedman July 2019 • Volume 18 • Issue 7

FIGURE 2. Significant epidermal acanthosis without atypia and one protruding column of parakeratosis making up the giant cutaneous horn.

A top practice management and career building resource for Residents and Young Dermatologists Next Steps in Derm Content Highlights Derm In- Review Pop Quiz – Each Friday, a new Pop Quiz question is posted to the Next Steps in Derm website, courtesy of Derm In-Review! Test your knowledge each week with these questions! Cutaneous horns, or “cornu cutaneum” in Latin, are described th first in the 16 century, those with horns at the time were used Patient Buzz Series - Do you ever field odd-ball patient for show. Horns are common among various animals; the main questions and wonder where the information they distinction of animal horns and cutaneous horns are animal presented came from? The monthly “Patent Buzz” series horns tend to grow off bones giving them strength and cutane- addresses recent dermatology news from the consumer ous horns have no bony structure. Similarly, animal horns tend press and provides background on the conditions and to be common among a species and the same cannot be said treatments your patients may ask about at their next for cutaneous horns in humans.4 All human cutaneous horns office visit. Find the latest in the series under the Derm are pathologic in nature and require a diagnostic biopsy. Again, Topics section on NextStepsinDerm.com the differential diagnosis consists of a cutaneous horn second- JDD Editorial Highlights – Editorial highlights each ary to a verruca, squamous or basal cell carcinoma, or actinic Do Not Copymonth from the Journal of Drugs in Dermatology (JDD), keratosis. Further treatment may be required if the origin is ma- as well as podcasts and the “Ask the Investigator” series. lignant and extending to the margins of the biopsyPenalties or if the Apply initial biopsy does not resolve an underlying verruca or actinic Genoderms Made Ludicrously Easy: Tumor keratosis. Previous literature may indicate that the larger and Syndromes Webinar: Dr. Finch brings a special more structured a cutaneous horn appears may point to a ver- webinar presentation from his wildly popular book, rucous, rather than malignant origin but more inquiry needs to Genoderms Made Ludicrously Easy. In this webinar, Dr. be conducted to affirm such an association. Justin Finch reviews the clinical spectrum of genetic disorders with malignant potential and examines key DISCLOSURES dermatologic clues to the diagnosis of genetic tumor The authors have no conflicts of interest to declare. syndromes, including PTEN hamartoma syndromes, Reed syndrome, Gardner syndrome, Rombo syndrome REFERENCES and others. The discussion of important clinical features 1. Gould JW, Brodell RT. Giant cutaneous horn associated with verruca vul- is facilitated by high-yield visual mnemonic cartoons. garis. Cutis. 1999;64(2):111-112. 2. Sanjeeva KK, Ali P, Pinto M, Rao S, Rai AS. Giant cutaneous horn overlying a verruca at an uncommon site: medical marvel vs superstitious dilemma. J Clin Diagn Res. 2015;9(4):PD13-14. NextStepsInDerm.com 3. Chen W, Wei W, Yan-Jun L, et al. Multiple huge cutaneous horns overlying @NextSteps_Derm @nextstepsinderm @NextStepsinDerm verrucae vulgaris induced by human papillomavirus type 2: a case report. Wiley Online Library. Br J Dermatol. 2018;156(4). 4. Bondeson J. Everard Home, John Hunter, and cutaneous horns: a historical review. Am J Dermatopathol. 2001;23(4):362-369. If you would like to contribute to Next Steps in Derm, visit https://nextstepsinderm.com/contributor/ or email AUTHOR CORRESPONDENCE us at [email protected] and a team member will get back with you Adam J. Friedman MD E-mail:...... ……...... [email protected] Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

BRIEF SUMMARY OF PRESCRIBING INFORMATION USE IN SPECIFIC POPULATIONS This brief summary does not include all the information needed to use BRYHALI safely and Pregnancy effectively. See full prescribing information for BRYHALI. Risk Summary BRYHALI™ (halobetasol propionate) lotion, 0.01% for topical use There are no available data on BRYHALI use in pregnant women to inform a drug- Initial U.S. Approval: 1990 associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. INDICATIONS AND USAGE In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oral administration of halobetasol propionate during BRYHALI™ (halobetasol propionate) Lotion, 0.01% is indicated for the topical treatment of organogenesis to pregnant rats and rabbits. The available data do not support relevant plaque psoriasis in adults. comparisons of systemic halobetasol propionate exposures achieved in the animal studies CONTRAINDICATIONS to exposures observed in humans after topical use of BRYHALI. None. The background risk of major birth defects and miscarriage for the indicated population is WARNINGS AND PRECAUTIONS unknown. In the U.S. general population, the estimated background risk of major birth Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to BRYHALI has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis. 20%, respectively. Systemic effects of topical corticosteroids may include reversible HPA axis suppression with Data the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon Animal Data withdrawal of treatment with the topical corticosteroid. Halobetasol propionate has been shown to cause malformations in rats and rabbits when The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with BRYHALI was given orally during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and evaluated in a study of 19 adult subjects with moderate to severe plaque psoriasis involving 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in ≥20% of their body surface area (BSA). HPA axis suppression was reported for 1 (5.6%) rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats but subject at Week 4 and for 3 (15.8%) subjects at Week 8. All 3 subjects had normal HPA axis not in rabbits. suppression test with discontinuation of treatment [see Clinical Pharmacology in full Lactation Prescribing Information]. Risk Summary Because of the potential for systemic absorption, use of topical corticosteroids, including There are no data on the presence of halobetasol propionate or its metabolites in human BRYHALI, may require that patients be evaluated periodically for evidence of HPA axis milk, the effects on the breastfed infant, or the effects on milk production after suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis treatment with BRYHALI. suppression include the use of more potent corticosteroids, use over large surface areas, Systemically administered corticosteroids appear in human milk and could suppress occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid- growth, interfere with endogenous corticosteroid production, or cause other untoward containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) effects. It is not known whether topical administration of corticosteroids could result in stimulation test may be helpful in evaluating patients for HPA axis suppression. sufficient systemic absorption to produce detectable quantities in human milk. If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the The developmental and health benefits of breastfeeding should be considered along with frequency of application, or substitute a less potent steroid. Manifestations of adrenal the mother’s clinical need for BRYHALI and any potential adverse effects on the breastfed insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis child from BRYHALI. function is generally prompt and complete upon discontinuation of topical corticosteroids. Clinical Considerations Systemic effects of topical corticosteroids may also include Cushing’s syndrome, Advise breastfeeding women not to apply BRYHALI directly to the nipple and areola to avoid hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at direct infant exposure. the same time may increase the total systemic exposure to corticosteroids. Pediatric Pediatric Use patients may be more susceptible than adults to systemic toxicity from the use of topical Safety and effectiveness of BRYHALI in pediatric patients under the age of 18 years have corticosteroids due to their larger surface-to-body mass ratios [see Use in not been evaluated. Specific Populations]. Because of higher skin surface area to body mass ratios, pediatric patients are at a greater Local Adverse Reactions risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated Local adverse reactions from topical corticosteroids may include atrophy, striae,Do Notwith Copy topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, during or after withdrawal of treatment. Adverse reactions including striae have been hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and reported with use of topical corticosteroids in infants and children [see Warnings miliaria. These may be more likely with occlusive use, prolonged use, or usePenalties of higher and Apply Precautions]. potency corticosteroids, including BRYHALI. Some local adverse reactions may HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, be irreversible. and intracranial hypertension have been reported in children receiving topical Concomitant Skin Infections corticosteroids. Manifestations of adrenal suppression in children include low plasma Use an appropriate antimicrobial agent if a skin infection is present or develops. If a cortisol levels and an absence of response to ACTH stimulation. Manifestations of favorable response does not occur promptly, discontinue use of BRYHALI until the infection intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema . has been adequately treated. [see Warnings and Precautions] Geriatric Use Allergic Contact Dermatitis Of 284 subjects exposed to BRYHALI in clinical trials, 61 subjects were 65 years or older. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to Clinical trials of BRYHALI did not include sufficient numbers of subjects age 65 years and heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis older to determine whether they respond differently from younger subjects. of allergic contact dermatitis by appropriate patch testing. Discontinue BRYHALI if allergic contact dermatitis occurs. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility ADVERSE REACTIONS Long-term animal studies have not been performed to evaluate the carcinogenic potential Clinical Trials Experience of halobetasol propionate. Because clinical trials are conducted under widely varying conditions, adverse reaction Halobetasol propionate was not genotoxic in the Ames assay, in the sister chromatid rates observed in the clinical trials of a drug cannot be directly compared to rates in the exchange test in Chinese hamster somatic cells, in chromosome aberration studies of clinical trials of another drug and may not reflect the rates observed in clinical practice. germinal and somatic cells of rodents, or in a mammalian spot test. Positive mutagenicity In randomized, double-blind, multicenter, vehicle-controlled clinical trials, 426 adults with effects were observed in a mouse lymphoma gene mutation assay in vitro and in a Chinese plaque psoriasis were treated with BRYHALI and had post-baseline safety data. Subjects hamster micronucleus test. applied BRYHALI once daily for up to eight weeks. Table 1 presents adverse reactions that Studies in rats following oral administration of halobetasol propionate at dose levels up to occurred in at least 1% of subjects treated with BRYHALI and more frequently than in 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance. vehicle-treated patients. PATIENT COUNSELING INFORMATION Table 1: Adverse Reactions Occurring in ≥1% of the Subjects Treated with Advise the patient to read the FDA-approved patient labeling (Patient Information). BRYHALI through Week 8 Manufactured for: Dow Pharmaceutical Sciences, a division of Valeant Pharmaceuticals North America LLC BRYHALI Vehicle Bridgewater, NJ 08807 USA (N=284) (N=142) By: Adverse Reaction % % Valeant Pharmaceuticals International, Inc. Upper Respiratory Tract Infection 2% 1% Laval, Quebec H7L 4A8, Canada U.S. Patent Numbers: 6,517,847 and 8,809,307 Application Site Dermatitis 1% 0 BRYHALI is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. © 2018 Valeant Pharmaceuticals North America LLC Hyperglycemia 1% 0 Based on 9652102 November 2018 BRY.0032.USA.18

BRYHALITM FOR ADULTS WITH PLAQUE PSORIASIS ( )%

CHART A COURSE TO SYMPTOMATIC RELIEF

The eﬃ cacy of Class 1 halobetasol with safety proven for up to 8 weeks of dosing1,2

A NEW POTENCY CLASS OF STEROID LOTION

2 PIVOTAL PHASE 3 TRIALS Indication BRYHALI™ (halobetasol propionate) Lotion, 0.01% is a corticosteroid indicated for the topical treatment of plaque psoriasis in adults. Do1 Not Copy POTENT TO SUPERPOTENT CLEARANCE : Important Safety Information Penalties WarningsApply and Precautions 4 weeks post treatment1 Continued results • BRYHALI Lotion has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis during treatment or Signifi cant symptomatic relief as early as week 22 upon cessation of treatment; periodic evaluation may be required. • Systemic eff ects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. No increased epidermal atrophy • Children may be more susceptible to systemic toxicity when observed through 8 weeks of treatment2 treated with topical corticosteroids. • Local adverse reactions may include atrophy, striae, Local adverse reactions from topical corticosteroids may include telangiectasias, hypopigmentation, and allergic contact atrophy, striae, telangiectasias, hypopigmentation and allergic contact dermatitis. Some local adverse reactions may be irreversible. dermatitis. Some local adverse reactions may be irreversible. • Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist. STUDY RESULTS: 36.5% of patients in trial 1 and 38.4% in trial 2 achieved treatment success* at week 8 (primary endpoint) vs 8.1% and 12.0% of patients with vehicle, respectively (P<0.001 • Use an appropriate antimicrobial agent if a skin infection is present in both trials).2 or occurs, and if prompt response is not seen, discontinue use STUDY DESIGN: The safety and effi cacy of BRYHALI Lotion were assessed in 2 prospective, until infection has been adequately treated. multicenter, randomized, double-blind, phase 3 clinical trials in 430 adult patients with • Discontinue BRYHALI Lotion if allergic contact dermatitis occurs. moderate-to-severe plaque psoriasis. Patients were treated with BRYHALI Lotion or vehicle lotion, applied once daily. Primary effi cacy endpoint was treatment success evaluated at week Adverse Reactions 8. Secondary effi cacy endpoint was treatment success evaluated at weeks 2, 4, 6, and 12 (4 weeks post treatment). Tertiary effi cacy endpoint was a 2-grade improvement from • The most common adverse reactions (≥1%) were upper respiratory baseline at each time point for the individual signs of psoriasis (erythema, plaque elevation, tract infection, application site dermatitis, and hyperglycemia. and scaling).2 * Treatment success was defi ned as at least a 2-grade improvement from baseline in the To report SUSPECTED ADVERSE REACTIONS, contact Customer Investigator’s Global Assessment score, and a score of “clear” or “almost clear” (primary Service at 1-800-321-4576 or FDA at 1-800-FDA-1088. endpoint at week 8).2 References: 1. BRYHALI Lotion [prescribing information]. Bridgewater, NJ. Please see Brief Summary of full Prescribing Information on Valeant Pharmaceuticals North America LLC. 2. Data on fi le. following page.

VALE5034 BRYHALI Journal Ad JDD 4/C Page Live: .125" from Trim File format: PDF/X-1A Carling Communications 3/14/19 Trim: 8.25"x10.875" Bleed: 8.50"x11.125”