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JDD

RESIDENT ROUNDS NEWS, VIEWS, & REVIEWS PIPELINE PREVIEWS CLINICAL TRIAL REVIEW

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

ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

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

SPECIAL FOCUS:

SKIN OF COLOR

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July 2019 595 Volume 18 • Issue 7

Copyright © 2019 EDITORIAL BOARD Journal of Drugs in Dermatology

Impact FactorImpact Factor Score: 1.527*

Normalized Eigenfactor® Score: 0.660*

Article Influence Score: 0.409*

*Clarivate Analytics, Formerly the IP & Science Business of Thomson Reuters, June 2018

SENIOR ASSOCIATE EDITORSKenneth Beer MD

Martin Braun MD

Jeffrey Phillip Callen MD

Jean Carruthers MD

James Q. Del Rosso DO

Lawrence F. Eichenfield MD

Patricia Farris MD

Norman Goldstein MD

Aditya K. Gupta MD PhD

Elizabeth Hale MD

Sherry H. Hsiung MD

Leon Kircik MD

Mark Lebwohl MD

Henry W. Lim MD

Flor Mayoral MD

Maurizio Podda MD PhD

Jeffrey Orringer MD

Maritza Perez MD

Kevin Pinski MD

Luigi Rusciani Scorza MD

Ritu Saini MD

Jerome l. Shupack MD

Amy Taub MD

Danny Vleggaar MD

Brian Zelickson MD

FEATURE EDITORSKendra G. Bergstrom MD

Joel L. Cohen MD

Adam Friedman MD

James L. Griffith MD

Marissa Heller MD

Isaac Zilinsky MD

ASSOCIATE EDITORSDale M. Abadir MD

William Abramovits MD

Andrew F. Alexis MD MPH

Shawn Allen MD

Rex A. Amonette MD

Robert Anolik MD

Martha P. Arroyo MD

Robin Ashinoff MD

Marc R. Avram MD

David E. Bank MD

Jay G. Barnett MD

Eliot F. Battle Jr. MD

Richard G. Bennett MD

Diane S. Berson MD

Ronald R. Branacaccio MD

Rana Anadolu Brasie MD

Jeremy A. Brauer MD

Gary Brauner MD

Neil Brody MD PhD

Lance H. Brown MD

Isaac Brownell MD PhD

Karen E. Burke MD PhD

Mariano Busso MD

Francisco M. Camacho-Martinez MD

Marian Cantisano-Zilkha MD

Alastair Carruthers MD

Roger I. Ceilley MD

Clay J. Cockerell MD

David E. Cohen MD

Julian S. Conejo-Mir MD

Elizabeth Alvarez Connelly MD

Ira Davis MD

Calvin Day MD

Doris Day MD

Jeffrey S. Dover MD

Zoe Diana Draelos MD

Madeleine D. Duvic MD

Mohamed L. Elsaie MD

Joseph C. English III MD

Neil Alan Fenske MD

Rebecca Fitzgerald MD

Alina A. Fratila MD

Alejandro Camps Fresnada MD

Ellen C. Gendler MD

Dore Gilbert MD

David J. Goldberg MD

Leonard H. Goldberg MD

Robert H. Gotkin MD

Gloria F. Graham MD

John Hawk MD

Michael P. Heffernan MD

William L. Heimer II MD

N. Patrick Hennessey MD

Alysa R. Herman MD

George J. Hruza MD

Shasa Hu MD

Mark J. Jaffe MD

Jared Jagdeo MD

S. Brian Jiang MD

Bruce E. Katz MD

Mark D. Kaufmann MD

Amor Khachemoune MD

Poong Myung Kim MD

Christine Ko MD

David Kriegel MD

Pearon G. Lang MD

Aimee Leonard MD

Mary P. Lupo MD

Alan Matarasso MD

Alan Menter MD

Warwick L. Morison MD

Rhoda S. Narins MD

Mark Naylor MD

Kishwer S. Nehal MD

Martino Neumann MD

Nelson Lee Novick MD

Jorge J. Ocampo Candiani MD

Philip Orbuch MD

Ariel Ostad MD

Cleire Paniago-Pereira MD

Anna C. Pavlick MD

Christopher R. Payne MD

António Picoto MD

Sheldon V. Pollack MD

Babar K. Rao MD

Wendy E. Roberts MD

Amy E. Rose MD

Steven Rosenberg MD

Lidia Rudnicka MD

Bijan Safai MD

Eli R. Saleeby MD

Fitzgeraldo A. Sanchez-Negron MD

Miguel Sanchez-Viera MD

Julie Schaffer MD

Bryan C. Schultz MD

Daniel Mark Siegel MD

Arthur J. Sober MD

Nicholas A. Soter MD

Jennifer Stein MD

Fernando Stengel MD

Hema Sundaram MD

Susan C. Taylor MD

Emily Tierney MD

George-Sorin Tiplica MD PhD

Ella L. Toombs MD

Irene J. Vergilis-Kalner MD

Steven Wang MD

Ken Washenik MD PhD

Jeffrey Weinberg MD

Robert A. Weiss MD

W. Phillip Werschler MD

Ronald G. Wheeland MD

Jai Il Youn MD

John Zic MD

John A. Zitelli MD

PAST CO-EDITORS-IN-CHIEFElizabeth Hale MD (2004)

Susan H. Weinkle MD (2005-2008)Keyvan Nouri MD (2005-2008)Sherry H. Hsiung MD (2008)

James M. Spencer MD (2009-2013)

EDITOR-IN-CHIEFPerry Robins MD

CO-EDITOR-IN-CHIEFDeborah S. Sarnoff MD

Macrene Alexiades MD PhD

Robert Baran MD

Joseph B. Bikowski MD

Dee Anna Glaser MD

C. William Hanke MD

William Levis MD

Ronald L. Moy MD

Keyvan Nouri MD

Neil S. Sadick MD

Gerhard Sattler MD

James M. Spencer MD

Susan H. Weinkle MD

SENIOR EDITORS




Copyright © 2019 TABLE OF CONTENTS Journal of Drugs in Dermatology

ORIGINAL ARTICLES

616 Myths and Knowledge Gaps in the Aesthetic Treatment of Patients With Skin of ColorAndrew 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 PatientSabrina 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 PatientAnnie 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 CreamPearl 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 ScreeningEmily C. Murphy BS, Stephanie Kao BA, Huan Wang MS, Dechang Chen PhD, Hong Nguyen MD MPH, Adam J. Friedman MD

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 ColorCheryl M. Burgess MD FAAD



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ORIGINAL ARTICLES (CONTD)

655 Topical Ozenoxacin Cream 1% for Impetigo: A ReviewLawrence 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 WartsMargaret 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 StudyAzam 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 ReviewCalvin T. Sung MD, Alfred Lee BA, Franchesca Choi BS RPh, Margit Juhasz MD, Natasha Atanaskova Mesinkovska MD PhD

682 Effective and Safe Repeated Full-Face Treatments With AbobotulinumtoxinA, Hyaluronic Acid Filler, and Skin Boosting Hyaluronic AcidPer 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 LiteratureLaura Doerfler MD, C. William Hanke MD MPH

697 A Giant Cutaneous Horn: One of the Largest RecordedDillon Nussbaum BSc, Julia Schwartz MD, Adam Friedman MD FAAD





OFFICIAL PUBLICATION OF

Journal of Drugs in Dermatology (JDD) is indexed in MEDLINE®/PubMed® and is published monthly by the Journal of Drugs in Dermatology115 E. 23rd Street, 3rd Floor, Unit 322, New York, NY 10010telephone: 212-213-5434 | fax: 212-213-5435 | JDDonline.com

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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

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

References: 1. CIMZIA [prescribing information]. Smyrna, GA: UCB, Inc.; 2019. 2. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis. 2007;13(11):1323-1332. 3. Pasut G. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol. BioDrugs. 2014;28 (suppl 1):S15-S23. 4. Porter C, Armstrong-Fisher S, Kopotsha T, et al. Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer. J Reprod Immunol. 2016;116:7-12. 5. Gottlieb AB, Blauvelt A, Thaçi D, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from two phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018;79(2):302-314.e6. 6. Lebwohl M, Blauvelt A, Paul C, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double-blinded, etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018;79(2):266-276.e5. 7. Data on file. Smyrna, GA: UCB, Inc.

Indications• CIMZIA is indicated for the treatment of adults with moderate-to-severe plaque

psoriasis who are candidates for systemic therapy or phototherapy.

• CIMZIA is indicated for the treatment of adults with active psoriatic arthritis.

Important Safety InformationCONTRAINDICATIONS• CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to

certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria.

SERIOUS INFECTIONSPatients treated with CIMZIA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.Discontinue CIMZIA if a patient develops a serious infection or sepsis.Reported infections include:• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have

frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before CIMZIA use and during therapy. Initiate treatment for latent TB prior to CIMZIA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with CIMZIA prior to initiating therapy in the following patients: with chronic or recurrent infection; who have been exposed to TB; with a history of opportunistic infection; who resided in or traveled in

regions where mycoses are endemic; with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.• Do not start CIMZIA during an active infection, including localized infections.• Patients older than 65 years, patients with co-morbid conditions, and/or patients taking

concomitant immunosuppressants may be at greater risk of infection.• If an infection develops, monitor carefully and initiate appropriate therapy.

MALIGNANCYLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member. CIMZIA is not indicated for use in pediatric patients.• Consider the risks and benefits of CIMZIA treatment prior to initiating or continuing

therapy in a patient with known malignancy.• In clinical trials, more cases of malignancies were observed among

CIMZIA-treated patients compared to control patients.• In CIMZIA clinical trials, there was an approximately 2-fold higher rate of lymphoma

than expected in the general U.S. population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk of lymphoma than the general population.

• Malignancies, some fatal, have been reported among children, adolescents, and young adults being treated with TNF blockers. Approximately half of the cases were lymphoma, while the rest were other types of malignancies, including rare types associated with immunosuppression and malignancies not usually seen in this patient population.

• Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including CIMZIA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treating with CIMZIA in these patient types.

• Cases of acute and chronic leukemia were reported with TNF blocker use.

HEART FAILURE• Worsening and new onset congestive heart failure (CHF) have been reported with

TNF blockers. Exercise caution and monitor carefully.HYPERSENSITIVITY• Angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness,

and urticaria have been reported following CIMZIA administration. If a serious allergic reaction occurs, stop CIMZIA and institute appropriate therapy. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause an allergic reaction in individuals sensitive to latex.

HEPATITIS B VIRUS REACTIVATION• Use of TNF blockers, including CIMZIA, may increase the risk of reactivation

of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.

• Test patients for HBV infection before initiating treatment with CIMZIA.• Exercise caution in patients who are carriers of HBV and monitor them before

and during CIMZIA treatment.• Discontinue CIMZIA and begin antiviral therapy in patients who develop HBV

reactivation. Exercise caution when resuming CIMZIA after HBV treatment.NEUROLOGIC REACTIONS• TNF blockers, including CIMZIA, have been associated with rare cases of new onset

or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, and Guillain-Barré syndrome.

HEMATOLOGIC REACTIONS• Rare reports of pancytopenia, including aplastic anemia, have been reported with

TNF blockers. Medically significant cytopenia has been infrequently reported with CIMZIA.

• Consider stopping CIMZIA if significant hematologic abnormalities occur.

DRUG INTERACTIONS• Do not use CIMZIA in combination with other biological DMARDS.AUTOIMMUNITY• Treatment with CIMZIA may result in the formation of autoantibodies and, rarely,

in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

IMMUNIZATIONS• Patients on CIMZIA should not receive live or live-attenuated vaccines.ADVERSE REACTIONS• The most common adverse reactions in CIMZIA clinical trials (≥8%) were upper

respiratory infections (18%), rash (9%), and urinary tract infections (8%).

Please see Brief Summary of full Prescribing Information on following pages.

EXP LORE MORE AT C L E A R LY C I M Z I A . C O M

A DIFFERENT KIND OF ANTI-TNF1-4

CLEARLY FOR HER CLEARLY FOR THEM

F O R T H E T R E AT M E N T O F A D U LT S W I T H M O D E R AT E T O S E V E R E P L A Q U E P S O R I A S I S W H O A R E C A N D I D AT E S F O R S Y S T E M I C T H E R A P Y O R P H O T O T H E R A P Y

A N D A D U LT S W I T H A C T I V E P S O R I AT I C A R T H R I T I S 1

UCB5666 CIMZIA Journal Ad JDD 4/C Spread Live: .125" from Trim File Format: Press-Ready PDF Carling Communications 6-27-2019 Trim: 16.5"x10.875” Bleed: 16.75"x11.125"


http://www.cimziahcp.com/plaque-psoriasis?utm_source=ClearlyCIMZIA.com&utm_medium=print&utm_campaign=HCP0print0tactics


PROFESSIONAL BRIEF SUMMARY—CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

CIMZIA® (certolizumab pegol)

WARNINGS:

SERIOUS INFECTIONSPatients treated with CIMZIA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions and Adverse Reactions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.CIMZIA should be discontinued if a patient develops a serious infection or sepsis.Reported infections include:• Active tuberculosis, including reactivation of latent

tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before CIMZIA use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens including Legionella and Listeria.

The risks and benefits of treatment with CIMZIA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. [see Warnings and Precautions and Adverse Reactions].MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member [see Warnings and Precautions]. CIMZIA is not indicated for use in pediatric patients.

INDICATIONS AND USAGECIMZIA is indicated for reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. CIMZIA is indicated for the treatment of adults with moderately to severly active rheumatoid arthritis (RA). CIMZIA is indicated for the treatment of adult patients with active psoriatic arthritis (PsA). CIMZIA is indicated for the treatment of adults with active ankylosing spondylitis (AS). CIMZIA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy. CIMZIA is indicated for adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation.CONTRAINDICATIONSCIMZIA is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria [see Warnings and Precautions].WARNINGS AND PRECAUTIONS Risk of Serious Infections (see also Boxed Warning)Patients treated with CIMZIA are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF

blockers. Patients have frequently presented with disseminated rather than localized disease.Treatment with CIMZIA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

• with chronic or recurrent infection • who have been exposed to tuberculosis• with a history of an opportunistic infection• who have resided or traveled in areas of endemic tuberculosis or

endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis

• with underlying conditions that may predispose them to infectionTuberculosisCases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving CIMZIA, including patients who have previously or concomitantly received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating CIMZIA and periodically during therapy.Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating CIMZIA, assess if treatment for latent tuberculosis is needed; and consider an induration of 5 mm or greater a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).Consider anti-tuberculosis therapy prior to initiation of CIMZIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite previous or concomitant treatment for latent tuberculosis, cases of active tuberculosis have occurred in patients treated with CIMZIA. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with CIMZIA. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision of whether initiating anti-tuberculosis therapy is appropriate for an individual patient.Strongly consider tuberculosis in patients who develop a new infection during CIMZIA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.MonitoringPatients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with CIMZIA.CIMZIA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with CIMZIA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.Invasive Fungal InfectionsFor patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and risks of antifungal therapy.MalignanciesIn the controlled portions of clinical studies of some TNF blockers, more cases of malignancies have been observed among patients receiving TNF blockers compared to control patients. During controlled and open-labeled portions of CIMZIA studies of Crohn’s disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate (95% confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 CIMZIA-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. During CIMZIA studies of psoriasis, malignancies (excluding non-melanoma skin cancer) were observed corresponding to an incidence rate of 0.5 (0.2, 1.0) per 100 subject-years among a total of 995 subjects who received CIMZIA. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation

of therapy ≤ 18 years of age), of which CIMZIA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports. CIMZIA is not indicated for use in pediatric patients. In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of CIMZIA for Crohn’s disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia-treated patients and one case of Hodgkin’s lymphoma among 1,319 placebo-treated patients.In the CIMZIA RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. In the CIMZIA PsO clinical trials (placebo-controlled and open label) there was one case of Hodgkin’s lymphoma. Rates in clinical studies for CIMZIA cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when CIMZIA is used in a broader patient population. Patients with Crohn’s disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy [see Adverse Reactions]. The potential role of TNF blocker therapy in the development of malignancies in adults is not known.Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma that has a very aggressive disease course and is usually fatal, have been reported in patients treated with TNF blockers, including CIMZIA. The majority of reported TNF blocker cases occurred in adolescent and young adult males with Crohn’s disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressants azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk of using a TNF blocker in combination with azathioprine or 6-MP should be carefully considered.Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blockers, including CIMZIA. Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.Heart FailureCases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including CIMZIA. CIMZIA has not been formally studied in patients with CHF; however, in clinical studies in patients with CHF with another TNF blocker, worsening congestive heart failure (CHF) and increased mortality due to CHF were observed. Exercise caution in patients with heart failure and monitor them carefully [see Adverse Reactions].Hypersensitivity ReactionsThe following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, and urticaria. Some of these reactions occurred after the first administration of CIMZIA. If such reactions occur, discontinue further administration of CIMZIA and institute appropriate therapy. There are no data on the risks of using CIMZIA in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients caution is needed [see Adverse Reactions]. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause an allergic reaction in individuals sensitive to latex.Hepatitis B Virus ReactivationUse of TNF blockers, including CIMZIA, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.

Test patients for HBV infection before initiating treatment with CIMZIA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with CIMZIA should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.In patients who develop HBV reactivation, discontinue CIMZIA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of CIMZIA therapy in this situation and monitor patients closely.Neurologic ReactionsUse of TNF blockers, of which CIMZIA is a member, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of CIMZIA in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA [see Adverse Reactions].Hematological ReactionsRare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with CIMZIA [see Adverse Reactions]. The causal relationship of these events to CIMZIA remains unclear.Although no high risk group has been identified, exercise caution in patients being treated with CIMZIA who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. Consider discontinuation of CIMZIA therapy in patients with confirmed significant hematologic abnormalities.Use with Biological Disease-Modifying Antirheumatic Drugs (Biological DMARDs)Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, etanercept, with no added benefit compared to etanercept alone. A higher risk of serious infections was also observed in combination use of TNF blockers with abatacept and rituximab. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the use of CIMZIA in this combination. Therefore, the use of CIMZIA in combination with other biological DMARDs is not recommended [see Drug Interactions].AutoimmunityTreatment with CIMZIA may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with CIMZIA, discontinue treatment [see Adverse Reactions].ImmunizationsPatients treated with CIMZIA may receive vaccinations, except for live or live attenuated vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving CIMZIA.In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in antibody response to vaccine between CIMZIA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with CIMZIA. Similar proportions of patients developed protective levels of anti-vaccine antibodies between CIMZIA and placebo treatment groups; however patients receiving CIMZIA and concomitant methotrexate had a lower humoral response compared with patients receiving CIMZIA alone. The clinical significance of this is unknown.ImmunosuppressionSince TNF mediates inflammation and modulates cellular immune responses, the possibility exists for TNF blockers, including CIMZIA, to affect host defenses against infections and malignancies. The impact of treatment with CIMZIA on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood [see Warnings and Precautions and Adverse Reactions]. The safety and efficacy of CIMZIA in patients with immunosuppression has not been formally evaluated.ADVERSE REACTIONSThe most serious adverse reactions were:

• Serious Infections [see Warnings and Precautions]• Malignancies [see Warnings and Precautions]• Heart Failure [see Warnings and Precautions)]

Clinical Trials ExperienceBecause clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.In premarketing controlled trials of all patient populations combined the most common adverse reactions (≥ 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%).Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled TrialsThe proportion of patients with Crohn’s disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo).The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).Controlled Studies with Crohn’s DiseaseThe data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn’s disease. In the safety population in controlled studies, a total of 620 patients with Crohn’s disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received CIMZIA at some dose level, of whom 1,350 patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and arthralgia (6% CIMZIA, 4% placebo).Other Adverse ReactionsThe most commonly occurring adverse reactions in controlled trials of Crohn’s disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn’s disease and other diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other doses include:Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack.Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis.General disorders and administration site conditions: Bleeding and injection site reactions.Hepatobiliary disorders: Elevated liver enzymes and hepatitis.Immune system disorders: Alopecia totalis.Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.Renal and urinary disorders: Nephrotic syndrome and renal failure.Reproductive system and breast disorders: Menstrual disorder.Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.Vascular disorders: Thrombophlebitis, vasculitis.Controlled Studies with Rheumatoid ArthritisCIMZIA was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to CIMZIA in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6.2 years. Most patients received the recommended dose of CIMZIA or higher.Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with CIMZIA 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate.

Table 1: Adverse Reactions Reported by ≥3% of Patients Treated with CIMZIA Dosed Every Other Week during Placebo-Controlled Period of Rheumatoid Arthritis Studies, with Concomitant Methotrexate.

Adverse Reaction (Preferred Term)

Placebo+ MTX# (%)N =324

CIMZIA 200 mg EOW + MTX(%)N =640

Upper respiratory tract infection 2 6

Headache 4 5

Hypertension 2 5

Nasopharyngitis 1 5

Back pain 1 4

Pyrexia 2 3

Pharyngitis 1 3

Rash 1 3

Acute bronchitis 1 3

Fatigue 2 3#EOW = Every other Week, MTX = Methotrexate.

Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs.Patients receiving CIMZIA 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving CIMZIA 200 mg every other week.Other Adverse ReactionsOther infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn’s disease patients.Psoriatic Arthritis Clinical StudyCIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA.Ankylosing Spondylitis Clinical StudyCIMZIA has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile treated with CIMZIA was similar to the safety profile seen in patients with RA.Non-radiographic Axial Spondyloarthritis Clinical StudyCIMZIA has been studied in 317 patients with non-radiographic axial spondyloarthritis (nr-axSpA-1). The safety profile for patients with nr-axSpA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA.Plaque Psoriasis Clinical StudiesIn clinical studies, a total of 1112 subjects with plaque psoriasis were treated with CIMZIA. Of these, 779 subjects were exposed for at least 12 months, 551 for 18 months, and 66 for 24 months. Data from three placebo-controlled studies (Studies PS-1, PS-2, and PS-3) in 1020 subjects (mean age 46 years, 66% males, 94% white) were pooled to evaluate the safety of CIMZIA [see Clinical Studies (14)]. Placebo-Controlled Period (Week 0-16)In the placebo-controlled period of Studies PS-1, PS-2 and PS-3 in the 400 mg group, adverse events occurred in 63.5% of subjects in the CIMZIA group compared to 61.8% of subjects in the placebo group. The rates of serious adverse events were 4.7% in the CIMZIA group and 4.5% in the placebo group. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the CIMZIA group than in the placebo group.

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Table 2: Adverse Reactions Occurring in ≥1% of Subjects in the CIMZIA Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Studies PS-1, PS-2, and PS-3.

Adverse Reactions

Cimzia 400 mg

every other week n (%) N=342

Cimzia 200 mg5

every other week n (%) N=350

Placebo n (%) N=157

Upper respiratory tract infections1 75 (21.9) 68 (19.4) 33 (21.0)

Headache2 13 (3.8) 10 (2.9) 4 (2.5)

Injection site reactions3 11 (3.2) 6 (1.7) 1 (0.6)

Cough 11 (3.2) 4 (1.1) 3 (1.9)

Herpes infections4 5 (1.5) 5 (1.4) 2 (1.3)

1: Upper respiratory tract infection cluster includes upper respiratory tract infection, pharyngitis bacterial, pharyngitis streptococcal, upper respiratory tract infection bacterial, viral upper respiratory tract infection, viral pharyngitis, viral sinusitis, and nasopharyngitis.

2: Headache includes headache and tension headache. 3: Injection site reactions cluster includes injection site reaction, injection site

erythema, injection site bruising, injection site discoloration, injection site pain, and injection site swelling.

4: Herpes infections cluster includes oral herpes, herpes dermatitis, herpes zoster, and herpes simplex.

5: Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by 200 mg every other week.

Elevated Liver Enzymes Elevated liver enzymes were reported more frequently in the CIMZIA-treated subjects (4.3% in the 200 mg group and 2.3% in the 400 mg group) than in the placebo-treated subjects (2.5%). Of CIMZIA-treated subjects who had elevation of liver enzymes, two subjects were discontinued from the trial. In controlled Phase 3 studies of CIMZIA in adults with PsO with a controlled period duration ranging from 0 to 16 weeks, AST and/or ALT elevations ≥5 x ULN occurred in 0.9% of CIMZIA 200 mg or CIMZIA 400 mg arms and none in placebo arm.Psoriasis-Related Adverse Events In controlled clinical studies in psoriasis, change of plaque psoriasis into a different psoriasis sub-types (including erythrodermic, pustular and guttate), was observed in <1% of CIMZIA treated subjects.Adverse Reactions of Special Interest Across IndicationsInfectionsThe incidence of infections in controlled studies in Crohn’s disease was 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for CIMZIA, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis.The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all CIMZIA-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the CIMZIA treatment groups, compared to the placebo groups (0.06 per patient-year for all CIMZIA doses vs. 0.02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0.06 per patient-year and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time [see Warnings and Precautions (5.1)].In controlled clinical studies in psoriasis, the incidence rates of infections were similar in the CIMZIA and placebo groups. The infections consisted primarily of upper respiratory tract infections and viral infections (including herpes infections). Serious adverse events of infection occurred in CIMZIA-treated patients during the placebo-controlled periods of the pivotal studies (pneumonia, abdominal abscess, and hematoma infection) and Phase 2 study (urinary tract infection, gastroenteritis, and disseminated tuberculosis).Tuberculosis and Opportunistic Infections In completed and ongoing global clinical studies in all indications including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications.

The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of disseminated (miliary, lymphatic, and peritoneal) as well as pulmonary TB. The median time to onset of TB for all patients exposed to CIMZIA across all indications was 345 days. In the studies with CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials. In Phase 2 and Phase 3 studies with CIMZIA in plaque psoriasis, there were 2 cases of TB among 1112 exposed patients [see Warnings and Precautions].MalignanciesIn clinical studies of CIMZIA, the overall incidence rate of malignancies was similar for CIMZIA-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients [see Warnings and Precautions].Heart FailureIn placebo-controlled and open-label studies, cases of new or worsening heart failure have been reported for CIMZIA-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure [see Warnings and Precautions].Hypersensitivity ReactionsThe following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, allergic dermatitis, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see Warnings and Precautions].AutoantibodiesIn clinical studies in Crohn’s disease, 4% of patients treated with CIMZIA and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn’s disease patients treated with CIMZIA developed symptoms of a lupus-like syndrome.In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with CIMZIA in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with CIMZIA on the development of autoimmune diseases is unknown [see Warnings and Precautions].ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Patients with Crohn’s disease were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. In patients continuously exposed to CIMZIA, the overall percentage of patients who were antibody positive to CIMZIA on at least one occasion was 8%; approximately 6% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn’s disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.In two long-term (up to 7 years of exposure), open-label Crohn’s disease studies, overall 23% (207/903) of patients developed antibodies against certolizumab pegol on at least one occasion. Of the 207 patients who were antibody positive, 152 (73%) had a persistent reduction of drug plasma concentration, which represents 17% (152/903) of the study population. The data from these two studies do not suggest an association between the development of antibodies and adverse events.The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro. Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended CIMZIA dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody-positive patients than among antibody-negative

patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively [see Clinical Pharmacology]. No association was seen between antibody development and the development of adverse events.Approximately 8% (22/265) and 19% (54/281) of subjects with psoriasis who received CIMZIA 400 mg every 2 weeks and CIMZIA 200 mg every 2 weeks for 48 weeks, respectively, developed antibodies to certolizumab pegol. Of the subjects who developed antibodies to certolizumab pegol, 45% (27/60) had antibodies that were classified as neutralizing. Antibody formation was associated with lowered drug plasma concentration and reduced efficacy.A more sensitive and drug tolerant electrochemiluminescence (ECL)-based bridging assay was used for the first time in the nr-axSpA-1 study, resulting in a greater proportion of samples having measurable antibodies to certolizumab pegol and thus a greater incidence of patients being classed as antibody positive. In the placebo-controlled trial in patients with non-radiographic axial spondyloarthritis, after up to 52 weeks of treatment, the overall incidence of patients who were antibody positive to certolizumab pegol was 97% (248/255 patients). Of these antibody positive patients, higher titers were associated with reduced certolizumab pegol plasma levels. The data above reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, or ECL-based bridging assay, and are highly dependent on the sensitivity and specificity of the assay. Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of CIMZIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers.Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and new or worsening psoriasis (all sub-types including pustular and palmoplantar, and lichenoid skin reaction) have been identified during post-approval use of TNF blockers.Immune System Disorders: sarcoidosisNeoplasms benign, malignant and unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) [see Warnings and Precautions].DRUG INTERACTIONSUse with Anakinra, Abatacept, Rituximab, and NatalizumabAn increased risk of serious infections has been seen in clinical studies of other TNF-blocking agents used in combination with anakinra or abatacept, with no added benefit. Formal drug interaction studies have not been performed with rituximab or natalizumab. Because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of CIMZIA in these combinations. There is not enough information to assess the safety and efficacy of such combination therapy. Therefore, the use of CIMZIA in combination with anakinra, abatacept, rituximab, or natalizumab is not recommended [see Warnings and Precautions].Live VaccinesAvoid use of live (including attenuated) vaccines concurrently with CIMZIA [see Warnings and Precautions].Laboratory TestsInterference with certain coagulation assays has been detected in patients treated with CIMZIA. Certolizumab pegol may cause erroneously elevated activated partial thromboplastin time (aPTT) assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that CIMZIA therapy has an effect on in vivo coagulation.USE IN SPECIFIC POPULATIONS PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMZIA during pregnancy. For more information, healthcare providers or patients can contact: MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/Risk SummaryLimited data from the ongoing pregnancy registry on use of CIMZIA in pregnant women are not sufficient to inform a risk of major birth defects or

other adverse pregnancy outcomes. However, certolizumab pegol plasma concentrations obtained from two studies of CIMZIA use during the third trimester of pregnancy demonstrated that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth (see Data). There are risks to the mother and fetus associated with active rheumatoid arthritis or Crohn’s disease. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to CIMZIA should be weighed against the benefits of vaccinations (see Clinical Considerations). No adverse developmental effects were observed in animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFa pegylated Fab’ fragment (cTN3 PF) similar to certolizumab pegol during organogenesis at up to 2.4 times the recommended human dose of 400 mg every four weeks.The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal RiskPublished data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn’s disease is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth.Fetal/Neonatal Adverse Reactions Due to its inhibition of TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant. The clinical significance of BLQ or low levels is unknown for in utero-exposed infants. Additional data available from one exposed infant suggest that CIMZIA may be eliminated at a slower rate in infants than in adults (see Data). The safety of administering live or live-attenuated vaccines in exposed infants is unknown. DataHuman DataA limited number of pregnancies have been reported in the ongoing pregnancy exposure registry. Due to the small number of CIMZIA-exposed pregnancies with known outcomes (n=54), no meaningful comparisons between the exposed group and control groups may be conducted to determine an association with CIMZIA and major birth defects or adverse pregnancy outcomes. A multicenter clinical study was conducted in 16 women treated with CIMZIA at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks during the third trimester of pregnancy for rheumatological diseases or Crohn’s disease. The last dose of CIMZIA was given on average 11 days prior to delivery (range 1 to 27 days). Certolizumab pegol plasma concentrations were measured in samples from mothers and infants using an assay that can measure certolizumab pegol concentrations at or above 0.032 mcg/mL. Certolizumab pegol plasma concentrations measured in the mothers at delivery (range: 4.96 to 49.4 mcg/mL) were consistent with non-pregnant women’s plasma concentrations in Study RA-I [see Clinical Studies]. Certolizumab pegol plasma concentrations were not measurable in 13 out of 15 infants at birth. The concentration of certolizumab pegol in one infant was 0.0422 mcg/mL at birth (infant/mother plasma ratio of 0.09%). In a second infant, delivered by emergency Caesarean section, the concentration was 0.485 mcg/mL (infant/mother plasma ratio of 4.49%). At Week 4 and Week 8, all 15 infants had no measurable concentrations. Among 16 exposed infants, one serious adverse reaction was reported in a neonate who was treated empirically with intravenous antibiotics due to an increased white blood cell count; blood cultures were negative. The certolizumab pegol plasma concentrations for this infant were not measurable at birth, Week 4, or Week 8. In another clinical study conducted in 10 pregnant women with Crohn’s disease treated with CIMZIA (400 mg every 4 weeks for every mother), certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood at the day of birth with an assay that can measure concentrations at or above 0.41 mcg/mL. The last dose of CIMZIA was given on average 19 days prior to delivery (range 5 to 42 days). Plasma certolizumab pegol concentrations ranged from not measurable to 1.66 mcg/mL in cord blood and 1.58 mcg/mL in infant blood; and ranged from 1.87 to 59.57 mcg/mL in maternal blood. Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol. In one infant, the plasma certolizumab pegol concentration declined from 1.02 to 0.84 mcg/mL over 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults.Animal DataBecause certolizumab pegol does not cross-react with mouse or rat TNFa, reproduction studies were performed in rats using a rodent anti-murine TNFa pegylated Fab’ fragment (cTN3 PF) similar to certolizumab pegol. Animal reproduction studies have been performed in rats during organogenesis at

intravenous doses up to 100 mg/kg (about 2.4 times the recommended human dose of 400 mg, based on the surface area) and have revealed no evidence of harm to the fetus due to cTN3 PF.LactationRisk SummaryIn a multicenter clinical study of 17 lactating women treated with CIMZIA at 200 mg every 2 weeks or 400 mg every 4 weeks, minimal certolizumab pegol concentrations were observed in breast milk. No serious adverse reactions were noted in the 17 infants in the study. There are no data on the effects on milk production. In a separate study, certolizumab pegol concentrations were not detected in the plasma of 9 breastfed infants at 4 weeks post-partum (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CIMZIA and any potential adverse effects on the breastfed infant from CIMZIA or from the underlying maternal condition. DataA multicenter clinical study designed to evaluate breast milk was conducted in 17 lactating women who were at least 6 weeks post-partum and had received at least 3 consecutive doses of CIMZIA 200 mg every 2 weeks or 400 mg every 4 weeks for rheumatological disease or Crohn’s disease. The effects of certolizumab pegol on milk production were not studied. The concentration of certolizumab pegol in breast milk was not measurable in 77 (56 %) of the 137 samples taken over the dosing periods using an assay that can measure certolizumab pegol concentrations at or above 0.032 mcg/mL. The median of the estimated average daily infant doses was 0.0035 mg/kg/day (range: 0 to 0.01 mg/kg/day). The percentage of the maternal dose (200 mg CIMZIA dosed once every 2 weeks), that reaches an infant ranged from 0.56% to 4.25% based on samples with measurable certolizumab pegol concentration. No serious adverse reactions were noted in the 17 breastfed infants in the study.In a separate study, plasma certolizumab pegol concentrations were collected 4 weeks after birth in 9 breastfed infants whose mothers had been currently taking CIMZIA (regardless of being exclusively breastfed or not). Certolizumab pegol in infant plasma was not measurable i.e., below 0.032 mcg/mL.Pediatric UseSafety and effectiveness in pediatric patients have not been established. Due to its inhibition of TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant [see Use in Specific Populations)]. Geriatric UseClinical studies of CIMZIA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Population pharmacokinetic analyses of patients enrolled in CIMZIA clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with CIMZIA [see Warnings and Precautions].OVERDOSAGEThe maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without evidence of dose-limiting toxicities. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide)Risk of Serious InfectionsInform patients that CIMZIA may lower the ability of the immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis and reactivation of hepatitis B virus infections. Because caution should be exercised in prescribing CIMZIA to patients with clinically important active infections, advise patients of the importance of informing their health care providers about all aspects of their health [see Warnings and Precautions].MalignanciesCounsel patients about the possible risk of lymphoma and other malignancies while receiving CIMZIA [see Warnings and Precautions].Other Medical ConditionsAdvise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report promptly any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever [see Warnings and Precautions].Hypersensitivity ReactionsAdvise patients to seek immediate medical attention if they experience any symptoms of severe hypersensitivity reactions. Advise latex-sensitive patients that the needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex [see Warnings and Precautions].

PregnancyAdvise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to CIMZIA during pregnancy; patients can call 1-877-311-8972 [see Use in Specific Populations]. Preparation and Administration of CIMZIA Using the Prefilled Syringe Instruct patients and caregivers on how to inject the Prefilled Syringe. Complete instructions are provided in the Instructions for Use packaged in each CIMZIA Prefilled Syringe kit.

Product manufactured by:UCB, Inc.,1950 Lake Park Drive, Smyrna, GA 30080US License No. 1736For more information, go to www.CIMZIA.com or call 1-866-424-6942.CIMZIA® is a registered trademark of the UCB Group of Companies.©2019 UCB, Inc., Smyrna, GA 30080. All rights reserved.

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Statement of NeedReports show 16 million individuals in the US are affected by rosacea and account for up to 3% of all cases seen in dermatol-ogy practice. Recent reports show rosacea is more common in patients with darker skin types than previously recognized and in skin types III-VI, rosacea may be more difficult to distinguish in the early stages; these patients may not seek treatment until their symptoms are quite severe. Rosacea has a considerable psychosocial impact and is the cause of embarrassment, anxi-ety, and low self-esteem. Men are more likely than women to feel ridiculed for their appearance despite higher disease prev-alence in women. Current treatments aid in the management of rosacea signs and symptoms and therapeutic goals and decisions should include individual, patient-identified issues. Current recommendations for achieving optimal treatment results include achieving clear/almost clear skin and improv-ing key patient-reported outcomes. Therefore, there is need for increased medical knowledge on features, benefits, and limits of available treatment modalities, their effect on minimizing rosacea symptoms, and formulation of optimal individualized rosacea treatment plans in special patient groups often not al-ways considered to be at high risk. Dermatology providers of all levels of training and experience require tools to establish ongoing clinician-patient communication relating to the iden-tification of patient-reported disease impact and the burden of the condition on daily life.

Educational ObjectivesThe overall information and educational goals of this enduring activity are to expand awareness of the impact of rosacea on quality of life of patients of all ages and genders and skin types including those with darker skin, summarize current rosacea treatment strategies and the unique challenges rosacea presents when treating patients with darker skin types, men versus women, and other special patient types, and formulate effective, individualized rosacea treatment regimens that 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-tions including skin types III-IV, younger men, and others

• Define rosacea treatment strategies based on individual di-agnosis, disease classification, and patients’ self-reported issues

• Identify challenges to early diagnosis and treatment in pa-tients with darker versus lighter skin, male versus female patients, and other select patient types

• Develop and implement ongoing clinician-patient dialogue to assess the impact, extent, and the burden of rosacea on the individual patient to enable better personalized treat-ment outcomes

Target AudienceThis activity is intended for dermatologists, residents, and fellows in dermatology, and physician assistants, nurse practitioners, and other healthcare providers with an interest in cutaneous diseases and disorders affecting patients of all skin types.

Credit StatementsCategory 1: Creighton University Health Sciences Education designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the ac-tivity.

AAPA accepts AMA Category 1 credit for the PRA from organizations accredited by ACCME.

Nurse CE: Creighton University Health Sciences Continuing Education designates this activity for 1.0 contact hour for nurses. Nurses should claim only credit commensurate with the extent of their participation in the activity.

Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by Creighton University Health


Copyright © 2019 CME Journal of Drugs in Dermatology

PATIENT-FOCUSED SOLUTIONS IN ROSACEA MANAGEMENT: TREATMENT CHALLENGES IN SPECIAL PATIENT GROUPSRelease 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



Sciences Continuing Education (HSCE) and Physicians Continuing Education Corporation. Creighton University Health Sciences Continuing Education (HSCE) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

How to Obtain CE CreditYou can earn one (1.0) AMA PRA Category 1 Credit™ reading the article contained in this issue and completing a Journal post-test, web-based post-test, and evaluation. Test is valid through June 30, 2020 (no credit will be given after this date).

To receive credit for this activity, please go to www.JDDonline.com and click on CME Activities under “Library.” You will find instructions for taking the post-test and completing the program evaluation. You must earn a passing score of at least 70% and complete and submit the activity evaluation form in order to receive a certificate for 1.0 AMA PRA Category 1 Credit™. There is no fee for this CME activity. Once you have completed the form online, you will be able to print your certificate directly. You can also receive credit for this activity by completing the post-test and evaluation printed in this issue and faxing or mailing it to JDD, 115 East 23rd Street, Third Floor, Unit 322, New York, NY 10010 or fax to 212-213-5439.

Faculty CredentialsAndrew F. Alexis, MD, MPH is Chairman, Department of Dermatology and Director, Skin of Color Center at Mount Sinai St. Luke’s and Mount Sinai West, and Associate Professor, Icahn School of Medicine at Mount Sinai, New York, NY. Ahuva Cices, MD is associated with the Skin of Color Center, Mount Sinai West and Icahn School of Medicine at Mount Sinai, New York, NY.

Peer Reviewer CredentialsPerry Robins, MD is Professor Emeritus of Dermatology at New York University Medical Center, New York, NY.

DisclosuresPolicy 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

from Almirall, Galderma, and Leo and serves as a consultant to Galderma and Leo. Ahuva Cices, MD has no relevant disclosures to report. The planning committee for this activity have no relevant financial disclosures to report.

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US FDA. Creighton University Health Sciences Continuing Education (HSCE), the Journal of Drugs in Dermatology, and the activity supporters do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the Creighton University Health Sciences Continuing Education (HSCE), the Journal of Drugs in Dermatology, and the activity supporters. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Commercial Support: This activity is supported by an educational grant provided by Galderma Laboratories, L.P.

Contact InformationIf you need technical support or have questions about the course, please e-mail [email protected].

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CopyrightAll of the content in this educational activity is copyrighted by the Journal of Drugs in Dermatology. Creighton University Health Sciences Continuing Education (HSCE) has obtained permission from the Journal of Drugs in Dermatology to use the content in this educational activity.






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 MPHSkin of Color Center, Mount Sinai West, Icahn School of Medicine at Mount Sinai, New York, NY

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.

ABSTRACT

INTRODUCTION

osacea is a common, chronic facial condition present-ing with various combinations of erythema, flushing, telangiectasia, edema, papules, and pustules most

often affecting fair-skinned individuals.1,2 Although most preva-lent 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 sug-gest 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.

Epidemiology The prevalence of rosacea is estimated at about 10 percent of predominantly fair-skinned populations and affects approxi-mately 16 million American adults.4,5 The onset of rosacea is often after 30 years of age and displays a female predominance with the exception of phymatous rosacea (Figure 1), which is more common in older males.4 In younger populations with rosacea, this female predilection is amplified.1 Prevalence of rosacea in Germany and Russia based on general population screening found 18% of subjects with rosacea were aged 18-30 years.6 Though more common in adult females, studies evalu-ating disease severity support the prevalence of more severe disease in subjects of male gender and less than 60 years of age.7

Until recently, rosacea was widely considered to be a disease almost exclusively affecting light-skinned individuals. How-ever, the prevalence of rosacea in skin of color populations is increasingly being recognized. A study analyzing data from the National Ambulatory Medical Care Survey from 1993-2010 to determine racial and ethnic makeup of patients with rosacea found that of all patients diagnosed with rosacea, 2% were black, 2.3% were Asian or Pacific Islander, and 3.9% were His-panic or Latino.8 These findings challenge the long held belief that rosacea is a disease largely limited to white individuals of Northern European heritage with Fitzpatrick skin types I-III.

The lower prevalence rates of rosacea in non-white populations is likely due to a combination of factors including under-report-ing, under-recognition (due to a low index of suspicion and

FIGURE 1. Type IV skin with rhinophyma. RDo Not Copy

Penalties Apply


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Journal of Drugs in DermatologyJuly 2019 • Volume 18 • Issue 7

A. Cices, A.F. Alexis

to another over time.5,11 These shortcomings were addressed by the global ROSacea COncensus (ROSCO) consensus panel, which put forth the first set of guidelines for phenotype driven management, which will be further discussed in the manage-ment section of this paper.11

Overall, ETR is the most common subtype of rosacea, fol-lowed by PPR.2 Important differences in skin of color include higher reported frequency of PPR compared to ETR (likely due to difficulty recognizing features of ETR in dark skin), as well as increased prevalence of the granulomatous subtype (Figure 2).3 Phymatous changes, most often seen in older males, are frequently observed in combination with ETR or PPR.2 Ocular rosacea is frequently diagnosed when other features of rosacea are present to aid in the diagnosis, with nearly 50% of patients experiencing onset of cutaneous symptoms prior to ocular symptoms.5

Recently, there has been a shift towards a phenotype-led ap-proach, which more accurately reflects patients seen in clinical practice and has important therapeutic implications, further discussed in the treatment portion of this review.11 This is especially significant in patients with disease not fitting the pro-totypical descriptions such as those with skin of color who are less likely to be identified as having predominant telangiectasia and erythematous changes in the skin. Additionally, the current classification system perpetuates the lack of evidence-based re-search and investigation of less prevalent, but high morbidity subtypes such as phymatous and ocular rosacea.11

Rosacea remains under recognized in skin of color, how-ever, there are tools readily available to assist with this oftentimes-challenging diagnosis. Patient history can provide vital information that is not obtainable on exam: this can in-clude a description of burning or stinging sensations, a family history of rosacea or mixed heritage, and even a history of acne that failed to respond to standard treatments.3 On exam, it may be difficult to appreciate features of erythema and telangiec-tasia due to masking by constitutive skin pigmentation, but other features such as dryness and edema may be visible on the central face or acneiform papular and pustular lesions in

diagnostic challenges), protective effects of melanin from ultra-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 diagno-sis, 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 have an abnormal response to environmental stressors such as UV exposure, temperature changes, microbial antigens (eg, De-modex folliculorum, Heliobacter pylori), and emotional stress that results in Th1/Th17 polarization.4

Studies finding increased risk with positive family history, twin studies with high concordance, and genome association studies support the important role of genetics in rosacea.4 A cohort-based twin study evaluating the role of genetics and environmental factors in rosacea calculated the genetic con-tribution to rosacea development to be 46%.9 Genome-wide association studies isolated three human leukocyte antigen (HLA) alleles with known association to autoimmune disease including type I DM and celiac disease within a large population of European descent.10 Additional studies are needed to further elucidate the complex interplay of genetics and environment in rosacea.

Diagnosis and Classification Rosacea is a clinical diagnosis based on physical exam and history that can have a wide range of presentations.5 Guide-lines from the National Rosacea Society (NRS) published in 2012 pioneered criteria for rosacea diagnosis and categoriza-tion defined by the presence of one or more primary features: flushing, persistent erythema, papules, pustules, and telangi-ectasia with variable presence of secondary features: burning, stinging, erythematous plaques, dryness, edema, ocular mani-festations, and phymatous changes.2 Furthermore, the NRS identified four rosacea subtypes: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular, with one variant: granulomatous based on presence of combinations of various primary and secondary disease features.2 Though this classification of rosacea is still currently in use and enabled the development of significant clinical and therapeutics ad-vancements in rosacea management, it falls short in its failure to accurately address the broader scope of clinical presenta-tions.5 Oversimplification of the disease into distinct categories overlooks the fact that often features of multiple subtypes are present simultaneously creating a more complex clinical picture and furthermore, there is often progression from one subtype

FIGURE 2. Granulomatous rosacea in black skin.



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percent agreed that they “worry how people will react when they see my rosacea,” and 43 and 59 percent strongly agreed that they feel their rosacea is unattractive to others despite more than 90% of both cohorts self-identifying as having mild to moderate disease.15 Another important finding in the litera-ture is the reversal of psychological symptoms with therapy; though the number of studies evaluating this outcome are lim-ited future studies will likely continue to evaluate these changes as important measures of treatment success.16

Management Diagnosis of rosacea should promptly be followed by educa-tion regarding the chronicity and relapsing nature of the disease as well as the importance of gentle skin care, regular photo-protection with sun protection factor 30 or greater, and trigger avoidance.4,5,11 Identification of patient-specific triggers is essen-tial to preventing disease flares.17 Use of gentle skin cleansers, frequent use of emollients, and avoiding exacerbating factors such as sunlight, temperature changes, and emotional stress, are primary interventions for managing secondary features namely dry, itchy, painful, burning skin.11 Counseling should be provided in a culturally sensitive manner, taking into account that recommendations may differ significantly from tradition-al cultural practices in non-white populations such as regular consumption of spicy foods, aggressive exfoliation, or regular use of abrasive skin brightening and lightening products.3 Many darker skinned individuals report not using sunscreen out of unfamiliarity or cultural discordance and may struggle to find a cosmetically suitable product.18

Evidence-based guidelines for rosacea are limited by the fact

the absence of comedones or acneiform lesions on the body (Figure 3).3 Furthermore, strategies to further assess erythema and telangiectasia in darker skin include use of dermoscopy, diascopy to test for blanching, and photography against a dark blue background.3

Diagnosis of rosacea requires exclusion of differential diag-noses 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 dermati-tis, carcinoid syndrome, and niacin ingestion.3,5 Given the high prevalence of systemic lupus erythematosus and sarcoidosis in individuals of African descent, black patients presenting with central facial erythema sparing the nasolabial folds or edema-tous 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). Physical discomfort due to symptoms such as irritation, itching, burning, or stinging understandably affect an individual’s well-being.13 Psychosocial affects related to skin changes of rosacea that are typically highly visible and have a substantial effect on physical appearance have been shown to cause shame, embar-rassment, low self-esteem, low self-confidence, negative body image, and anxiety.14,15 Physical appearance has been shown to have a significant impact on a wide variety of social outcomes from personal relationships and mate selection to workplace success.14 A German study using willingness to pay as a cor-relate for disease burden found women and those with more extensive facial involvement willing to pay more, and likely to experience greater negative QOL due to their rosacea than their counterparts who are of male gender or have less facial involvement.16 The associated stigmatization and frustration ex-perienced by patients are well documented, as are increased rates of psychiatric comorbidities such as social anxiety, depres-sion, and social phobia.14 Notably, males are more susceptible to stigmatization in setting of rosacea, possibly due to more severe phenotypes such as rhinophyma.14 Increased stigmatiza-tion from rosacea has also been associated with higher rates of depression and social avoidance behaviors.

The psychosocial impact on QOL is often underestimated by physicians, likely in part due to the fact that the objective dis-ease severity does not correlate with the magnitude of effect on QOL, with the exception of depression.13,14 A web-based cross-sectional study of 600 adults with ETR and PPR cohorts, respectively, found that 45 and 53 percent disagreed that they were satisfied with their appearance due to rosacea, 42 and 27

FIGURE 3. Rosacea in non-white populations (Skin type IV-VI).

(3A) (3B)

(3C) (3D)



611



that most rosacea clinical trials rely on the 2012 NRS subtypes for inclusion criteria and assess efficacy based on outcome measures specific to the disease subtype rather than the phe-notype, which more accurately reflects the constellation of features that would ideally be treated simultaneously.11 Rec-ognizing the lack of concordance between the archetypal NRS subtypes and real world patients, the ROSCO panel established consensus treatment guidelines (Figure 4) that encourages targeting individual features of rosacea and use of multiple therapies to achieve desired results.11

Randomized control trials (RCT) are an integral part of evi-dence based medicine, and their data support the use of topical azelaic acid, metronidazole, and ivermectin, as well as oral dox-ycycline for the treatment of mild to moderate PPR and the use of topical ivermectin and oral doxycycline for severe PPR.19,20 Inflammatory lesions of PPR, active phyma, and ocular features can be managed with doxycycline 40 mg as an anti-inflamma-tory at subantimicrobial doses.11 Effective treatments targeting the erythema of ETR include topical alpha-adrenergics (eg, oxymetazoline, briminodine), as well as intense pulsed light (IPL), and pulsed-dye laser (PDL) at 585-595 nm.11 Telangiectasia require physical modalities for eradication such as electrodessi-cation, IPL, or laser therapies.11 Importantly, the 2015 Cochrane review found no difference in efficacy of IPL and PDL for ery-

thema and telangiectasia (moderate quality evidence).11

High quality RCTs in rosacea are increasing and improving our therapeutic arsenal, however there remains a large gap in knowledge in less common subtypes, namely phymatous and ocular rosacea, as well as the spectrum of rosacea in skin of col-or.11 The lack of large controlled trials for the treatment of less common phymatous and ocular subtypes is exemplified by the 2015 Cochrane review of rosacea interventions, which found no RCTs for phymatous rosacea and concluded that more stud-ies are warranted to evaluate treatments for ocular rosacea.19

ROSCO recommends treatment of inflamed phymatous rosa-cea with lasers, oral doxycycline, or isotretinoin; therapies for non-inflamed phymas can include CO2 lasers, microdermabra-sion, and surgical excision based on patient preferences.4,11

Initial treatments for ocular rosacea include education on eye care and lid hygiene, use of lubricating drops, and increased dietary intake or supplementation with omega-3 fatty acids. Collaboration with ophthalmology is recommended for more advanced cases.4,11

Treatment approach for rosacea in non-white populations is the same as that used in white populations, with the excep-tion that special consideration must be given to avoid post inflammatory hyperpigmentation.3,12 Few rosacea studies have significant numbers of subjects with skin of color as the general dearth of non-white subjects in clinical trials is amplified in ro-sacea, which is less prevalent in these populations. Individual studies for oral doxycycline and topical oxymetazoline showed equivalent efficacy in subjects with Fitzpatrick skin phototypes I-III and phototypes IV-VI.3,21 Vascular lasers are effective in the treatment of vascular components of rosacea in skin of color, however IPL is generally not advised in types IV-VI due to high-er risks of dyspigmentation.3,12 Use of longer wavelengths and lower fluence in skin of color is advised to minimize the risk of pigmentary alterations or scarring.3

Given the heterogeneity of rosacea, there is no single best ther-apy, and often multiple treatment modalities including gentle skin care, trigger avoidance, topical agents, oral medications, and laser- or light-based therapies targeting specific disease manifestations are employed in order to achieve desired re-sults.4,5 Use of multiple therapies should be based on the patient’s desire for treatment of multiple disease features, and should target specific complaints rather than disease severity given the large role of patient perception on disease impact.11

Maintenance therapy is dependent on treatment modality and patient preference.11 A comprehensive approach is appropriate (Figure 5). This model highlights the importance of commu-nication with patients to shape personalized treatment plans. Patients should be reassessed regularly to maintain an optimal treatment plan as the disease presentation may change over time.

FIGURE 4. Summary of ROSCO panel guidelines. Transient

Erythema

PersistentErythema

PapulesPustules

Telangiectasia

Phyma

GeneralSkincare*

X X X X X

Topicalalphaadrenergics

X X

OralBetaBlocker

X

TopicalAzaleicAcid

X**

TopicalIvermectin

X

TopicalMetronidazole

X**

OralDoxycycline(40mg)

X X***

PhysicalModalities

X X

Isotretinoin X X***

Lasertherapy X X

*Gentleskincare,triggeravoidance,sunprotectionwithminimumSPF30,moisturizers**Monotherapyinmildtomoderatediseaseonly***Inflamedphyma



612



Rosacea treatment aims to eliminate and maintain clearance of signs and symptoms of the disease in order to eliminate negative effects the condition has on an individual’s QOL. Com-munication with patients is necessary to reveal an individual’s personal concerns, goals, and desires, which often differ from that predicted by clinicians.14 For example, erythema has been described as the most troublesome symptom, however, these findings come from predominantly fair-skinned populations and it is plausible that erythema is not as bothersome in non-white populations. Alternatively, erythema may not be appreciated by clinicians, but nonetheless can be bothersome to patients, highlighting the need for individually tailored patient care re-flecting the patient’s wishes.14 Optimal results and improved patient outcomes are achieved by understanding the patient’s subjective disease severity and goals of treatment prior to ini-tiating therapy.11 Choice of therapy should incorporate patient preferences and values that can include cost of procedural therapies that are typically not covered by health insurance or preference for topical vs oral or frequency of administration.11

CONCLUSIONRosacea is a chronic inflammatory skin condition due to immune and neurovascular dysfunction that has significant ef-fects on QOL. Though more prevalent in patients with fair skin, rosacea occurs in people of all races and ethnicities and until recently has been largely under recognized in nonwhite popu-lations. In order to optimize treatment of rosacea, recognizing more subtle or less typical features in special patient groups

is essential. A patient centered approach targeting disease fea-tures most bothersome to patients contributes to improved outcomes including QOL. Future studies should continue to evaluate efficacy in diverse populations to accurately reflect the patients in need of treatment.

REFERENCES1. 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 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.

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. 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 correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. 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):1548-1555.

11. Schaller M, Almeida LM, Bewley A, et al. Rosacea treatment update: rec-ommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176(2):465-471.

12. Callender VD, Barbosa V, Burgess CM, et al. Approach to treatment of medical and cosmetic facial concerns in skin of color patients. Cutis. 2017;100(6):375-380.

13. van der Linden MM, van Rappard DC, Daams JG, Sprangers MA, Spuls PI, de Korte J. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015;95(4):395-400.

14. Oussedik E, Bourcier M, Tan J. Psychosocial burden and other impacts of 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 life in individuals with erythematotelangiectatic and papulopustular rosacea: findings from a web-based survey. J Clin Aesthet Dermatol. 2018;11(2):47-52.

16. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71(5):973-980.

17. Buddenkotte J, Steinhoff M. Recent advances in understanding and manag-ing rosacea. F1000Res. 2018;7.

18. Diffey BL, Fajuyigbe D, Wright CY. Sunburn and sun protection in black skin. Int J Dermatol. 2019.

19. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. Cochrane Database Syst Rev. 2015(4):Cd003262.

20. Que SK, Fraga-Braghiroli N, Grant-Kels JM, Rabinovitz HS, Oliviero M, Scope A. Through the looking glass: basics and principles of reflectance confocal microscopy. J Am Acad Dermatol. 2015;73(2):276-284.

21. Alexis AF, Webster G, Preston NJ, Caveney SW, Gottschalk RW. Effective-ness and safety of once-daily doxycycline capsules as monotherapy in pa-tients with rosacea: an analysis by Fitzpatrick skin type. J Drugs Dermatol. 2012;11(10):1219-1222.

AUTHOR CORRESPONDENCE

Andrew Alexis MD MPH E-mail:................……................. [email protected]

FIGURE 5. Personalized rosacea management plan.

Confirm diagnosis – history and exam, additional testing to rule out differential diagnoses as needed

Asses disease impact – evaluate psychosocial burden, associated comorbidities

Identify triggers and goals of therapy – foundation for individualized treatment plan

General counseling – disease course, trigger avoidance, gentle skin care, photo-protection

Targeted therapies – taking into account assessment of disease impact and treatment goals

Reassess and adjust treatment plan accordingly – re-evaluate at regular intervals to ensure adequate

disease control



1. What is the estimated prevalence of rosacea globally (inclusive of white and non-white populations)?

a. 1%

b. 2%

c. 10%

d. 20%

2. Which subtype of rosacea has a male predominance?

a. Erythematotelangiectatic

b. Papulopustular

c. Phymatous

d. Ocular

3. A 36-year-old female with skin type VI presents with an erythematous plaque on the central face, which condition is the least likely diagnosis?

a. Lupus

b. Tinea faciei

c. Rosacea

d. Sarcoidosis

4. Which treatment option is best for a patient with Fitzpat-rick skin type IV requesting treatment for telangiectasia?

a. Doxycycline

b. Oxymetazoline

c. IPL

d. PDL

5. Which of the following adverse psychosocial effects is correlated with disease severity?

a. Stigmatization

b. Anxiety

c. Depression

d. Social anxiety disorder

6. Which of the following therapies is contraindicated in a rosacea patient with type IV skin?

a. Brimonidine

b. Oxymetazoline

c. IPL

d. PDL



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Copyright © 2019 EDITORIAL Journal of Drugs in Dermatology

T 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 patient 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.

Many cultures associate beauty with an even complexion. It has been shown in many re-ported 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 ad-dresses 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.

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 of a woman when she 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?

Cheryl M. Burgess, MD, FAAD

Global Perspectives of the Patient of Color

Cheryl M. Burgess, MD, FAAD




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, NYBThe 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, NJfBoyd Beauty, Birmingham, MI

gAllergan plc, Irvine, CA

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 concerning facial aesthetic treatment in individuals with SOC exist. These patients may undergo various facial aesthetic procedures safely and effectively, as long as nuances in treatment approaches are recognized.

J Drugs Dermatol. 2019;18(7):616-622.

ABSTRACT

INTRODUCTION

The number of surgical and nonsurgical cosmetic pro-cedures performed in the United States increased by more than 30% between 2010 and 2016, with the per-

centage of procedures performed in non-Caucasians increasing from 19% to 25%.1,2 Despite substantial and increasing inter-est in aesthetic procedures from individuals with SOC, only a few treatment guidelines or recommendations touch on race or ethnicity in discussions of safety and efficacy.3-7 Dermatologists and plastic surgeons may thus be hesitant to treat patients with SOC, based on inadequate guidance for that population. A na-tional survey of Australian dermatologists found that 75% were not confident in performing cosmetic procedures for patients with SOC, and a majority expressed a desire for more training on medical conditions and surgical and cosmetic issues in SOC, emphasizing the need for education on treating these patients.8 Further, widespread and often unsubstantiated anecdotal in-formation regarding treatment preferences and outcomes in people with SOC has encouraged myths about skin care and aesthetic treatment that may prevent this population from re-ceiving the best possible care.

This paper aims to examine knowledge gaps that may exist in the medical community and to dispel patient-held myths asso-ciated with skin care and aesthetic treatment in SOC.

METHODSBased on their clinical experience, the authors, who are experts in the aesthetic treatment of individuals with SOC, identified and reached consensus on myths and knowledge gaps in the aesthetic treatment of individuals with SOC. PubMed searches were conducted on these areas and the results were reviewed for relevance to individuals with SOC.

KNOWLEDGE GAPS IN THE MEDICAL COMMUNITYGap: Darker-Skinned Patients of African Descent Do Not Seek Injectable Filler Treatment of the LipsResponseDarker-skinned patients of African descent may be less likely to undergo enhancement of the lips, but they do request restora-tion of lip volume lost through aging, generally presenting at an older age than Caucasian patients seeking lip enhancement (Figure 1).9



617


A.F. Alexis, J. Few, V.D. Callender, et al

2% to 17% of patients (6% of injection sites) with Fitzpatrick skin phototypes IV through VI receiving hyaluronic acid filler injections for correction of nasolabial folds, but was generally mild and transient.21-23 In one study, injection techniques using multiple or serial punctures were associated with an increased risk of hyperpigmentation.21 Hyperpigmentation may be effec-tively treated with topical prescription skin-lightening agents or cosmeceuticals.24 The authors agreed that injecting filler too superficially or too quickly, or using serial epidermal punctures, may increase the risk of hyperpigmentation.

Gap: Patients With SOC Have a Substantial Risk of Develop-ing Keloids With Injectable Filler Treatment or SurgeryResponseProduct labeling for injectable fillers indicates that the safety of these products in patients with known susceptibility to keloid formation has not been evaluated. However, a number of prod-ucts were not associated with keloid development in clinical trial participants with SOC.21-23,25-29 The experience of the authors suggests that the development of keloids following treatment with injectable fillers is rare in individuals with SOC. No keloids were reported in patients with SOC in post-approval studies of injectable filler treatments,21,22,27 in a long-term study comparing patients with Fitzpatrick skin phototypes I through III versus IV through VI,29 or in a case review of 60 patients that included 20 patients with Fitzpatrick skin phototypes IV through VI.26

In aesthetic surgery, less invasive options with smaller incisions are generally preferred for patients with SOC.30-32 Optimal inci-sion placement, meticulous technique, and closure of surgical wounds with minimal tension are particularly important in pa-tients with SOC to minimize the risk of hypertrophic scarring.31,32 Clinical experience suggests that dermal injury from 27-gauge needle puncture does not appear to be associated with signifi-cant keloid risk.

Gap: Melasma Is a Minor Cosmetic Concern With No Effec-tive Treatment Options Beyond Sun Protection and Periodic Use of Hydroquinone10

ResponseDyschromia, including post-inflammatory hyperpigmentation (PIH) and melasma (Figure 2), is one of the most common con-ditions diagnosed in darker-skinned patients and is an important concern in patients with SOC.11,12 Dyschromia, including PIH and melasma, was the second-most common condition (19.9% of visits) diagnosed in black individuals in a retrospective chart review of 1412 patient visits at a large dermatology practice specializing in treating patients with SOC.11 Melasma, which can adversely affect quality of life,13,14 is more common in Fitzpatrick skin phototypes IV through VI and in geographic regions that receive more sun exposure.10 Topical hydroquinone 4% is the standard of care, but other treatments, including azelaic acid, kojic acid, niacinamide, alpha-hydroxy acid products, ascorbic acid, and retinoid topical therapies, are effective if used with appropriate caution.10,15 Superficial and medium-depth chemi-cal peels and laser treatment may also be effective16 but both therapies require further study and should be used with caution, as they themselves are associated with a risk of hyperpigmen-tation.15 Deeper peels and (nonfractional) ablative lasers are contraindicated in patients with darker skin, based on the au-thors’ clinical experience, because of greater risk of scarring and dyspigmentation. It should be emphasized that sunscreen use is an integral, essential component of any treatment regimen for melasma.

Gap: Patients With SOC Should Not Undergo Surgical Procedures or Even Receive Nonsurgical Injectable Filler Treatment Because There Is a Risk of Developing Hyperpig-mentation ResponseIn 2016, 1.6 million Hispanics, 1.3 million African Americans, and 1.1 million Asian Americans selected to undergo cosmetic pro-cedures.17 Patients with SOC are at greater risk of PIH, which can be a sequela of inflammatory dermatoses (eg, acne) or cosmetic and surgical procedures (eg, chemical peel, laser treatment).18-20 Hyperpigmentation was reported in one study in approximately

FIGURE 1. Photos of a 74-year-old black female with Fitzpatrick skin phototype VI who received a total of 2.4 mL HYC-24L (Juvéderm Ultra XC) at initial and touch-up treatment in her upper and lower lips, oral 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)

FIGURE 2. Melasma in a patient with skin of color before (A) and after (B) combination therapy (chemical peels and hydroquinone 6%). Images published with permission from P. Grimes.

(A) (B)



618



(A)

(B)

among individuals with SOC.37 In National Health and Nutrition Examination Survey data (N=4412), the percentage of respon-dents who never used sunscreen was greatest for non-Hispanic blacks, followed by Hispanics, then non-Hispanic whites.38 Simi-larly, the proportion of individuals with SOC in a recent facial aging study (N=4086) who reported never or rarely using sun-screen was substantially greater in respondents with SOC, especially black individuals, compared with Caucasians (Figure 3).39,40

Response The degree of natural protection across the spectrum of skin types is highly variable; it depends on the size and distribu-tion of melanosomes that, in turn, vary by constitutive melanin pigmentation.41 Photoaging and UVR exposure–mediated skin disorders, including skin cancers, occur in all skin types, albeit at different rates and clinical presentations.42,43 Patients with Fitz-patrick skin phototypes IV, V, or VI can get sunburned (Figure 4).44 Identifying sunburns may be more challenging in darker-skinned individuals; therefore, these individuals may underestimate their photosensitivity. Although nonmelanoma skin cancer is less prevalent in darker skin types, morbidity and mortality is of-ten higher in patients with SOC.43 Patchy dyschromia, including melasma, and isolated dark spots on the skin or diffuse, patchy darkening may occur in SOC if sun protection is not used.36

Sunscreen with a sun protection factor (SPF) of at least 3044

should be used to protect against UVR-induced sunburn, skin cancer, photoimmunosuppression, and photoaging of the skin, as well as melasma and photo-induced pigmentation.6,36 UVR exposure can reduce skin elasticity, which contributes to skin sagging31; therefore, use of sunscreen may potentially reduce sagging. Sunscreen is also important in the management of PIH20 and post-therapy care for patients undergoing in-office procedures, such as chemical peels or laser treatments.6,15,19 Pa-tients with SOC who use sunscreen should consider vitamin D supplementation, given the high prevalence of vitamin D defi-ciency in darker skin types and the importance of vitamin D in maintaining bone health. Low levels of vitamin D are also asso-ciated with nonskeletal health conditions, such as diabetes and heart disease.45

Gap: Racial and Ethnic Groups Are Relatively Homogeneous With Respect to Their Facial Characteristics and Aesthetic ConcernsResponseWhile some common observations can be made with racial/eth-nic groups, it is important to recognize individual variations and the diverse spectrum of features that can be observed within the categories of race, ethnicity, and skin types.7,32 Addressing each patient's unique concerns and facial characteristics individually is crucial.4,33,34

MYTHS HELD BY PATIENTSMyth: Individuals With Darker Skin Do Not Need to Use SunscreenBackgroundThe higher melanin content in SOC confers some degree of natural protection against the deleterious effects of ultraviolet radiation (UVR) from the sun; however, all skin types are sus-ceptible to photodamage.35,36 Rates of sunscreen use are lower

30 30

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Rarely/neverSometimesOftenAlways

Res

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ents

(%)

Race/Ethnicity

45

58

82

54

32 29

10

26

1710

5

15

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0

20

40

60

80

100

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ents

(%)

Race/Ethnicity

FIGURE 3. Reported use of sunscreen by women (A) and by men (B) in a recent facial aging study (N=1048), by race/ethnicity.39,40

FIGURE 4. Superficial exfoliation and erythema from a sunburn in a patient with Fitzpatrick skin type V. Image published with permission from V. Callender.



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Myth: As Dark Skin Protects Against Age-related Lines and Wrinkles, Dermal Fillers, and Neuromodulators Are Not Necessary or Useful for Patients With Darker SkinBackgroundThe protection afforded by darker skin may reduce or slow photoaging from UVR.9,31,35 Individuals with darker skin con-sequently tend to develop lines and rhytids later in life than Caucasians.9 In the recent facial aging study, black respondents showed less severe signs of facial aging compared with Cauca-sian, Hispanic/Latino, and Asian respondents.39 Individuals with SOC demonstrated a delay in the onset of signs of aging by 10 to 20 years relative to Caucasians.39,40 While lighter-skinned indi-viduals tend to display more lines and wrinkles, darker-skinned individuals display more volume depletion and sagging, with consequent folds.9,19,31

ResponsePatients of all skin types will experience aging effects that may prompt them to seek aesthetic treatment.19 Volume restoration for sagging skin is common for individuals with SOC. Notably, soft-tissue filler treatment and neuromodulator injections are among the most popular minimally invasive aesthetic treat-ments for individuals with SOC.17 Studies in patients with SOC suggested that such treatment is safe and effective.46,47 In a post hoc analysis comparing the response and safety of abobotuli-num toxin type A treatment of glabellar lines in patients with SOC and Caucasians, the response rate after 30 days was signif-icantly greater in patients with SOC versus Caucasians (P≤.03), with similar adverse event rates between groups.47

Myth: Laser Treatments Cannot Be Used on Dark Skin BackgroundThe greater amount and density of melanin in darker skin can act as a competing chromophore during laser and light-based procedures in SOC, particularly with visible and near-infrared devices.48 Therefore, laser and light-based treatments in patients with SOC are associated with a greater risk of tissue damage and resultant hyper- or hypopigmentation and scarring.48 In addition, post-treatment inflammation from laser or other energy-based devices may induce postinflammatory pigment alteration.

Response A knowledgeable clinician can successfully use laser treatment on SOC using the optimal laser or device and the appropriate parameters (ie, fluence, pulse duration) for the indication and skin type (Figures 5 and 6). Comprehensive recommendations for darker skin types have been published.18 Depending on the type of procedure, risk of pigmentary alteration can be mini-mized by using longer wavelength lasers, lower fluences, lower treatment densities, and epidermal cooling techniques.44,49

For most laser procedures, test spots (to guide optimal setting selection) or conservative treatment settings are useful ap-proaches to reducing the risk of pigmentary complications in SOC.19 Spot tests are strongly advised when the 800- to 810-nm diode laser is used in patients with skin phototypes V and VI. The clinician should wait ≥2 days,50 but optimally 2 to 3 weeks, after a spot test to confirm tolerance before proceeding with treatment.50 Patients should be counseled regarding the risk of pigment changes with laser treatment and about possible cor-rective treatments, if needed.19 For procedures involving injury to the dermis, assessing the risk of keloid formation based on degree of injury and personal or family history of keloids is paramount. Intense pulsed light (IPL) may be cautiously consid-ered for hair removal in patients with skin phototype IV but is not recommended for use in those with skin phototypes V or VI because of a higher risk of dyspigmentation. Results of a chart review of 56 patients with Fitzpatrick skin phototypes IV through VI support the safety of a 755-nm picosecond laser with the dif-fractive lens array for treatment of scars, pigmented lesions, or striae; although hyperpigmentation occurred in 6 patients, all cases were transient.51

Myths: Individuals With Darker Skin Do Not Need to Use Skin Cleansers or Moisturizers; Oily Skin Is ProtectiveBackgroundSebum secretion may be higher in individuals with SOC versus those with lighter skin,52 although at least 1 study53 found no dif-ference between blacks and Caucasians in skin surface sebum. Studies suggest that facial cleansing practices do vary with eth-nicity: In a survey of 423 Californians, Latino respondents had

FIGURE 5. Postinflammatory hyperpigmentation and acne scars before (A) and after (B) 3 treatments with Xeo™ Laser Genesis (Cutera, Brisbane, CA). Images published with permission from P. Grimes.

(A) (B)

FIGURE 6. Pseudofolliculitis barbie and postinflammatory hyperpigmentation secondary to hirsutism before (A) and after (B) treatment with long pulse Nd-YAG laser 1064 nm. Images published with permission from P. Grimes.

(A) (B)



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lower rates of use of both skin cleansers and moisturizers com-pared with black, white, and Asian respondents.54 In another study,40 the proportion of respondents who rarely or never used facial moisturizers was greater in black (43%) and Latino (40%) women than in Caucasian (33%) women.

Response A balance between facial cleansing and the preservation of skin oil/skin moisture is necessary for optimal aesthetic outcomes. Facial cleansers remove dirt, excess sebum, microorganisms, exfoliated corneum cells, and other foreign substances, such as cosmetics and medications, from the skin surface.55,56 Se-bum has naturally occurring antioxidant57 and antimicrobial58,59

properties and may potentially contribute to the maintenance of good skin quality attributes, such as smoothness.

Cleansers with an acidic pH, moisturizers, and high rinsability are recommended; those that contain non-ionic/silicone-based surfactants combined with moisturizers may cause the least dis-ruption to the skin barrier and to the normal skin flora.55 Gentle soap-free cleansers may be an option for some patients. While removal of all oil is not the goal, the removal of excess oil that traps dead skin debris is key, while using a moisturizer to restore the protective barrier. We recommend washing the face and neck at least nightly while considering the use of therapeutic topical agents, such as retinol, at night, and then lightly cleans-ing or rinsing in the morning to prevent overdrying of the skin. In addition, we recommend gentle cloths and gentle makeup removers for facial cleansing, and daytime moisturizers with an SPF of 30. Moisturizers can maintain skin hydration and restore barrier function that may be disrupted by cleanser use, and may also reduce the dryness of skin in individuals with SOC.55,56,60

Dermatologists and plastic surgeons consider the use of topi-cal cleansers and moisturizers to be an important component of skin disease management, especially in patients with compro-mised skin barrier function.61 However, even among individuals with chronic dermatologic conditions, the use of moisturizers and cleansers is low,61 suggesting that physicians must clear-ly communicate their recommendations on the use of facial cleansers and moisturizers.56

Myth: Only a Medical Provider With SOC Can Understand the Nuances of Treating Patients With SOCBackgroundThere is evidence to suggest that black, Hispanic, and Asian pa-tients disproportionately receive care from racially concordant physicians, and that patients who select their physicians are more likely than those assigned to a physician to have a clinician of the same race or ethnicity.62 In the experience of the authors, this is true of facial aesthetics practices as well. A survey of 1205 black and white residents in Ohio found that black respondents were significantly more likely than white respondents to believe

that racially concordant physicians understood their health problems (27% vs 12%) and to anticipate being more at ease with racially concordant physicians (27% vs 20%).63 In a separate survey of 118 patients from 2 dermatology practices, patient and physician racial concordance did not affect patients’ perception of satisfaction and trust; however, patients with SOC who had Caucasian health care providers indicated issues relating to hav-ing all of their questions answered, feeling that the provider had listened to them, and comfort with their treatment plan.64

TABLE 1.

Recommended Strategies for the Successful Treatment of Patients With Skin of Color

Consider-ation

Recommended Strategy

Overall

Maintain an up-to-date understanding of issues related to treatment

Understand patient concerns and expectations in light of ethnic background and physical characteristics

General skin care

Counsel patients to use sunscreen (SPF of ≥30) and explain the risks associated with not using sunscreen. Recommend vitamin D supplementation in patients who use sunscreen

Encourage the use of moisturizers and washing the face and neck at least nightly, followed by a light cleanse or rinse in the morning, especially for patients with conditions that may compromise the skin barrier

Treatment of melasma

Choice of effective pharmaceutical and cosmeceutical agents, although topical hydroquinone 4% remains the standard of care

Recommend sunscreen use as a component of any treatment regimen for melasma

Procedural

Collect a thorough medical history to understand the risk of adverse reactions in individual patients

Provide the patient with an accurate understanding of the risks associated with the procedure

When performing laser treatments, consider using longer wavelength lasers, lower fluences, lower treatment densities, and epidermal cooling techniques to prevent tissue damage

Use test spots before carrying out laser treatments to determine how the skin may respond (strongly recommended for any new laser device acquired by a practice)

When using dermal fillers, consider adjustments in injection technique (eg, deeper placement of fillers in the dermis, avoiding serial epidermal puncture trauma) that may limit the risk of PIH

Discuss posttreatment care with the patient and explain how following recommendations may reduce the risk of adverse events

PIH, postinflammatory hyperpigmentation; SPF, sun protection factor.



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ResponseWhile racial/ethnic concordance may facilitate cultural under-standing, the training, experience, and cultural competence of individual physicians, not their own cultural, ethnic, or racial background, is of paramount importance.64 Although consensus guidelines do not always include information specific to patients with SOC, numerous publications outline the use of a range of different aesthetic treatments in patients with SOC, highlighting issues that should be considered when treating SOC (Supple-mentary Table 1).5,18,21,22,24,33,34,48,65-70 Recommendations for the successful treatment of patients with SOC are summarized in Table 1.

CONCLUSIONSBoth practitioners and patients are concerned about treatment involving SOC. Some concerns are based in fact, such as the risk of PIH, while others are based on broad generalizations that may not be relevant to currently available, minimally invasive treatment options and accepted techniques. Patients with SOC can undergo aesthetic procedures safely and effectively, as long as nuances to the treatment approach are recognized and ad-dressed.

More information is needed in some areas, such as reduction of the risk of dyschromia and more effective treatment for the condition, as are safer and more effective lasers and devices for patients with SOC. Future research on these topics, along with the development of new treatments, such as non-hydroquinone therapies for hyperpigmentation and melasma, will further im-prove clinicians’ ability to provide safe and effective treatment to all of their patients. The importance of skin care regimens that may help to minimize or delay the need for facial aesthetic treatment, such as the use of sunscreen for the prevention of UVR damage, cannot be underestimated. All clinicians have a responsibility to remain up-to-date in their understanding of is-sues related to treating patients of any racial/ethnic background or skin type, and to keep their patients informed about the ac-tual risks versus common but unfounded perceptions.

DISCLOSURESA.F. Alexis serves as an investigator and has served on advisory boards for Allergan plc, Galderma, and Valeant, and has served on advisory boards for Beiersdorf, L'Oreal, and Unilever. J. Few has served as a consultant for Allergan plc and Sinclair, and as a consultant and investigator for Galderma, Medicis, Ulthera, and Venus Concepts. V.D. Callender has served on an adviso-ry board, served as a consultant, and received honoraria and research grants from Allergan plc. P. Grimes is an investigator for Allergan plc, Alphaeon, Incyte, and Suneva, and is a consul-tant for Aclaris Therapeutics and Procter & Gamble. J. Downie serves as a consultant for Allergan plc, BTL, Galderma, Inten-dis (Bayer), Johnson & Johnson, Lifes 2 Good, Merz Aesthetics, Nutrafol, Perigee Medical, Proctor & Gamble, Restorsea, Skin

Medica, Theraplex LLC, ThermiRF, and Valeant; as a researcher for Allergan plc, Alphaeon, BioPharmx, Endo Therapeutics, Evidera, Johnson & Johnson, Merz Aesthetics, Neothetics, Ranbaxy, Revance, and Skin Medica; as a lecturer for Allergan plc, BTL, Cutera, Exeltis, Galderma, Johnson & Johnson, Lifes 2 Good, Nutrafol, Perigee Medical, Sente, Solta, Stratpharma, Skin Medica, and ThermiRF; and as an advisory board mem-ber for IntraDerm, Sensus, and Sente; she is also a shareholder in Medmetriks and RegimenMD. C. Boyd serves as a speaker/trainer and serves on advisory boards for Allergan plc, Evolus, Galderma, and Revance. C.J. Gallagher was an employee of Al-lergan plc at the time of this research and owned stock/options in the company. The opinions expressed in this article are those of the authors. The authors received no honoraria or fees related to the development of this article. Funding Disclosures: Research for this manuscript was funded by Allergan plc. Medi-cal writing and editorial assistance was provided to the authors by Adrienne Drinkwater, PhD, of Peloton Advantage, an OPEN Health company, and funded by Allergan plc.

ACKNOWLEDGMENTSWriting and editorial assistance was provided to the authors by Peloton Advantage, an OPEN Health company, and funded by Allergan plc, Dublin, Ireland.

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64. Harvey VM, Ozoemena U, Paul J, et al. Patient-provider communication, con-cordance, and ratings of care in dermatology: Results of a cross-sectional study. Dermatol Online J. 2016;22(11).

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66. Geria AN, Lawson CN, Halder RM. Topical retinoids for pigmented skin. J Drugs Dermatol. 2011;10(5):483-489.

67. Sarkar R, Bansal S, Garg VK. Chemical peels for melasma in dark-skinned patients. J Cutan Aesthet Surg. 2012;5(4):247-253.

68. Callender VD, St Surin-Lord S, Davis EC, et al. Postinflammatory hyperpig-mentation: etiologic and therapeutic considerations. Am J Clin Dermatol. 2011;12(2):87-99.

69. Taylor CT, Kelly AP, Lim HW, et al. Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. Columbus, OH: McGraw-Hill Education; 2016.

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18. Alexis AF. Lasers and light-based therapies in ethnic skin: treatment options and recommendations for Fitzpatrick skin types V and VI. Br J Dermatol. 2013;169(suppl 3):91-97.

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Andrew F. Alexis MD MPH E-mail:................……................................. [email protected]





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, CABJosé Raúl Montes Eyes & Facial Rejuvenation, San Juan, Puerto Rico

cSHINO BAY Cosmetic Dermatology & Laser Institute, Fort Lauderdale, FLdBucay Center for Dermatology and Aesthetics, San Antonio, TX

EAllergan plc, Marlow, UKfAllergan plc, Madison, NJ

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 condi-tions, 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 concerns and treatment priorities specific to Hispanic/Latino women will enhance the practitioner’s patient-centric treatment approach.

J Drugs Dermatol. 2019;18(7):623-632.

ABSTRACT

INTRODUCTION

T he growing popularity of cosmetic procedures has in-creased the racial and ethnic diversity of the aesthetic practitioner's patient population. This growing diversity

is reflected by a 52% increase in the total number of Hispanic patients who received cosmetic procedures within the past decade in the USA.1,2 Minimally-invasive facial aesthetic treat-ments are also an increasing trend and accounted for 90% of all procedures performed in the USA in 2017 with neuromod-ulators and dermal fillers representing mainstay treatment modalities.2 Among the growing aesthetic patient population, Hispanic/Latinos have represented the largest proportion of non-Caucasian patients (versus African Americans and Asian Americans) receiving neuromodulators and dermal fillers for the last 5 years in a row.3

The descriptors “Hispanic” and “Latino” (also known as Mes-tizo) define an ethnic group which includes individuals of Mexican, Central-to-South American descent, and those of Spanish-Caribbean descent (eg, Cuban, Puerto Rican, and Do-

minican). Hispanic/Latino Americans are also represented by a range of cultures, languages, and biological ancestry which in-clude Asian, African, European, and native North, Central, and South American.4 As facial structure and skin type contribute to the characteristic and the progression of facial aging, it must be appreciated that the diversity within the Hispanic/Latino popu-lation makes this facial aesthetic patient also potentially the most diverse to treat.5-8 The practitioner will need to evaluate and sort out the patient’s predominant phenotype with respect to skin type and baseline facial structure to determine the best treatment approach.

While there is much published on the treatment approaches suitable for non-Hispanic white patients, there are far fewer that address the specific aesthetic needs of the Hispanic/Latino patient. An individual’s racial and ethnic identity also imbues a cultural influence on standards of beauty, attitudes toward ap-pearance, and priorities in the management of facial aging.9-11 For the culturally-competent practitioner, an awareness of not



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S. Fabi, J.R. Montes, S.B. Aguilera, et al

disagree) to 6 (completely agree)?” Existing concerns were identified from a list of options paired with the following question: “Would you consider talking to a physician about a treatment for any of the following within the next 2 years?”

Most Bothersome Facial Areas and Treatment Priorities QuestionnairesA 15-point facial diagram and a 6-point Likert scale (1, “not at all bothered” to 6, “very bothered”) were used to assess how bothersome each area was if at all (Figure 1). A Maximum Dif-ference (MaxDiff) ranking methodology, also referred to as “Best/Worst scaling” was then used to generate a rank order of each area as it related to treatment priority.16 Nine different iterations of the facial diagram were shown, each consisting of 3 facial areas at a time until all 15 features were presented. With 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”. MaxDiff ranking scores were represented by a “relative impor-tance value”. An average ranking of importance was established among all areas combined. Areas ranking above average repre-sented greater importance and priority relative to those areas ranking close to or below the average.

Awareness of Aesthetic Procedures and Future Treatment Considerations QuestionnairesTreatment procedure awareness and future treatment con-siderations were identified from a list of options paired with the questions: “Which treatments that are administered in a physician's office have you ever heard of?” and “Which facial treatments that are administered in a physician's office would you consider within the next 2 years?”

Motives and Barriers Impacting Consideration Rate of In-jectable Treatment QuestionnairesMotives and barriers were identified from a list of options paired with the questions: “Which of the following describes why you would consider a facial injectable treatment for facial lines, wrinkles, and folds in the next 2 years?” and “Which of

only the structural and cutaneous signs of aging but also the patient’s attitudes toward aging are integral in a patient-centric 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) atti-tudes 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-ticipants.12

METHODS Participants and Study DesignParticipants were recruited through online river sampling (banner ads, pop-up ads, instant capture promotions) by the Lieberman Research Worldwide (LRW) agency between March and April 2016. Primary inclusion criteria were: 1) females ages 30 to 65 years old living in the USA; 2) aesthetically-oriented, qualified by level of agreement on an aesthetic orientation screening questionnaire; 3) household annual income >$50,000 with some discretionary spending flexibility; 4) naïve to facial injectable treatments; 5) aware of BOTOX® Cosmetic; and 6) considering a medical facial aesthetic treatment within the next 2 years.

Participants identified their ethnic background as one of the following: Mexican, Mexican American, Puerto Rican, Cu-ban, or “Other Spanish, Hispanic, or Latino”. A questionnaire adapted from the Skin Cancer Foundation website was used to categorize participants by Fitzpatrick Skin Phototype (FSP) I through VI.13,14 The questionnaire took into account eye color, natural hair color, skin color (non-exposed areas, presence/absence of freckles (non-exposed areas), and skin response to ultraviolet radiation (UVR), including the susceptibility of facial and body skin to burn or turn brown (tan) following exposure. Participants also identified their pigmentary characteristics by selecting a color most representative of their natural skin tone from a range of 11 skin codes (colors).15

MEASURES AND ANALYSIS Attitudes Toward Facial Aesthetics and Existing Facial Con-cerns QuestionnairesAttitudes toward improving facial aesthetics were assessed by the aesthetic orientation screening questionnaire which in-cluded a list of options paired with the question “How strongly do you agree with each statement on a scale of 1 (completely

FIGURE 1. Diagram used to select most bothersome facial areas and treatment priorities.



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treatment (59%; Table 1). The majority were categorized as FSP III or IV (71%) and a large proportion (46%) self-identified with a Mexican ethnic background (Table 2).

Attitudes Toward Improving Facial Aesthetics and Existing Facial ConcernsMost participants agreed with the statement that they wanted their face to look good for their age (84%). A large propor-tion was interested in treatments that could make them look less tired (72%), and that would address facial lines/wrinkles/signs of aging (68%) as well as hyper/hypo-pigmentation (63%) (Figure 2). Facial wrinkles (56%), dark under-eye circles (55%), uneven skin tone/color (47%), and bags under the eyes (45%) were among the most frequently-reported conditions (Figure 3).

Most Bothersome Facial AreasThe most bothersome areas included sagging underneath the chin/double chin (41%), under-eye/tear trough area (37%), crow’s feet lines (CFLs) (37%), and forehead lines (FHLs) (36%). These were followed by glabellar lines (GLs) (31%) and areas of the mid-to-lower face, including nasolabial folds (NLFs) (34%), oral commissures (OCs) (32%), chin (27%), and marionette lines (MLs) (27%; Figure 4). Perioral lines (25%), jawline (23%), lips (22%), cheeks (20%), and temples (16%) were the least bother-some areas.

the following are the top 3 reasons why you would consider a facial injectable treatment for facial lines, wrinkles, and folds but have never tried it before?”

Data AnalysisMax Diff analyses and analysis for correlation between bother-some facial areas and their treatment priorities were conducted by the LRW agency and presented descriptively by percent or by average.

RESULTS ParticipantsThe majority of the 401 participants included in the study were 30 to 44 years old (57%), born in the USA (83%), married (83%), with household income > $75,000 (71%), an average spending of < $250/month on facial aesthetic products/services (70%), and had previously spent ≥ $250 on a single medical facial

TABLE 1.

Participant Demographics

Characteristic, Statistic% Total Respondents

(N = 401)

Age

30 - 44 57

45 - 65 43

USA Region of Current Residence

Northeast 20

South 35

Midwest 13

West 32

Born in the USA 83

Marital Status

Married 83

Single (Never Married) 9

Separated/Divorced/Widowed 8

Education

High school or Less 8

Some College or College Graduate 64

Post Graduate 28

Household Income

Less than $ 75,000 29

$ 75,000 - $ 150,000 56

$ 150,000 or More 15

Monthly Spend on Products and Services for Facial Aesthetics*

Less than $ 250 70

$ 250 or More 29

Maximum Spend on a Single Medical Facial Treatment

Less than $ 250 41

$ 250 or More 59*1% preferred not to answer

Fitzpatrick Skin Phototype Among Different Ethnic Backgrounds

% Fitzpatrick Skin Phototype

Ethnic Background I - II III - IV V - VI

Mexican (n = 183) 23 72 5

Puerto Rican (n = 75) 22 76 2

Cuban (n = 42) 37 58 5

Other Hispanic (n = 101) 23 71 6*Includes Mexican American and Chicano**Includes all other Spanish, Hispanic, or Latino origins

TABLE 2.

Proportions of Fitzpatrick Skin Phototypes (FSPs) and Ethnicities


(N = 401)

Fitzpatrick Skin Phototype

I - II 24

III - IV 71

V - VI 5

Ethnic Background

Mexican* 46

Puerto Rican 19

Cuban 10

Other Hispanic** 25



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FIGURE 2. Attitudes toward improving facial aesthetics.

FIGURE 3. Existing facial concerns.

FIGURE 4. Most bothersome facial areas.



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Treatment PrioritiesThe treatment priorities of each facial area (represented by rela-tive importance scores) ranged from 27 to 77 with treatment priorities tending to correlate with bothersome facial areas (R2 =.81, data not shown). In younger participants (ages 30 to 44), areas of the upper face had the highest priorities and in-cluded the under-eye/tear trough area (77) and CFLs (75; Figure 5a). Other areas of high importance were FHLs (64), sagging underneath the chin/double chin (64), GLs (56), OCs (55), and NLFs (54). Mid-to-lower facial areas such as chin (44), MLs (43), jawline (38), and cheeks (35) were lower priorities, and perioral lines (32), temples (31), and lips (27) were the least likely to be prioritized for treatment.

For the older participants (ages 45 to 65), under-eye/tear trough area (70) and CFLs (68) remained a top priority but sagging underneath the chin/double chin had increased importance (67; Figure 5b).

Subsequent priorities were NLFs (61), OCs (59), FHLs (59), and GLs (56), followed by MLs (49), jawline (44), and chin (42). Mid-to-lower facial areas such as perioral lines (36) and cheeks (33) were lower priorities, and lips (27) and temples (27) were the lowest priorities.

Awareness of Treatments Options and Future Treatment Consideration RatesMost participants were aware of the treatments or procedures used to enhance skin quality such as microdermabrasion (89%), laser skin resurfacing (88%), skin tightening procedures (83%), and chemical peels (79%; Figure 6a), and high consideration rates were observed for those treatments within the next 2 years (43 - 64%; Figure 6b). Furthermore, all were aware of neuromodulators (100%), most were aware of un der chin fat reduction (79%) and dermal fillers (70%) products, with 69%, 32%, and 35% consideration rates, respectively.

Motives and Barriers Impacting Consideration Rate of Injectable TreatmentsAmong the 84% (341/401) who would consider an injectable treatment, the most common motives were wanting their face to look good for their age (64%) and to look more youthful (52%; Figure 7). Interestingly, a much smaller proportion agreed with wanting to maintain a competitive edge in the workforce (15%) and to improve dating prospects or relationship prospects (10%). The top 3 most common barriers cited for not having tried injectable treatments yet were cost (49%), concerns about safety and side effects (37%), and concerns about injecting a foreign substance into their body (36%; Figure 8). In alignment with this, among the 16% of participants who would not con-sider injectables, the primary barriers included concerns about safety and side effects (66%), injecting a foreign substance into their body (52%), and concern that their face would not look natural (34%) (data not shown).

DISCUSSIONThe rate of onset, severity, and pattern of facial aging is influenced by race and ethnicity, while the motives that prompt an individ-ual to seek treatment may be based more on social and cultural ideals of beauty and attitudes about improving their facial aes-thetics.9-11 In this survey of 401 Hispanic/Latino American women aged 30 to 65, the predominant aesthetic concerns and goals were reported, which may help familiarize practitioners with this patient population and help guide relevant treatment plans.

Attitudes Toward Improving Facial AestheticsParticipant attitudes about facial aesthetic treatments suggested that attitudes and treatment interests may stem from current skin and facial conditions, which are also influenced by an in-dividual’s ethnic background. A high proportion of responders considered treatments that would make them look less tired (72%) and address facial wrinkles and lines (68%) and hyper/hypo-pigmentation (63%); correspondingly, a majority also re-ported having facial wrinkles (56%), dark circles under the eyes (55%), uneven skin tone/color (47%), and bags under eyes (45%). Although the greater melanin content in more darkly pigmented skin types affords some protection against the immediate ef-fects of UV exposure (eg, sun burn), photodamage still occurs and results in pigmentary changes (eg, freckling, solar lentigo, and melasma) and increases an individual’s risk factor for post-inflammatory hyperpigmentation (PIH) following inflammation or injury.17,18 Melasma and hyperpigmentation are believed to occur more frequently in Hispanic and Latino ethnicities, with as many as half of all Mexican women reporting melasma as-sociated with pregnancy.19

Most Bothersome Facial Areas and Treatment PrioritiesBothersome facial areas correlated somewhat with treatment priorities (R2 =.81, data not shown), and any discrepancy (ie, low-er importance for short, thinning lashes) might represent areas more easily enhanced by the application of cosmetics versus those that are not. The most bothersome facial areas reported by all were sagging underneath the chin/double chin, under-eye/tear trough, CFLs, and FHLs. While these all translated to areas with high treatment priority, differences between the younger and older age groups were observable. Among the more ad-vanced age group (45 to 65-year-olds) sagging underneath the chin/double chin and areas of the lower face (OCs and NLFs) increased in relative importance in comparison to the younger age group (30 to 44-year-olds). This result is expected since in-creasing midface ptosis, which accompanies facial aging, can exacerbate grooves and folds in the lower face and displace the importance assigned to areas of the upper face (under-eye/tear trough, CFLs, and FHLs) at a younger age. Also aligned with that reasoning is the change in the importance of the marionette lines (MLs) and the jawline, which were scored as lower priori-ties by the younger group but increased in importance in the older group.



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

FIGURE 6A AND 6B. Awareness of treatments and treatments considered within the next two years.



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Overall, areas of the upper face (under-eye/tear trough and CFLs) were assigned greater relative importance than the lower face. Although this is expected as areas of the upper face tend to reveal more of the initial signs of aging, it is important to note that participants were not given the option to differentiate between under-eye and tear trough. The cause of dark under-eye circles are multifactorial and could be attributable to periocular inflammation, blood stasis, uneven pigmentation, or may be the result of shadowing caused by tear trough deformity.20,21 With aging, the orbital bone resorption, loss of midface volume, and

increasing skin laxity can be associated with increased severity of tear troughs, which are characterized by a concavity sepa-rating the lower eyelid from the cheek.22,23 Therefore, this may imply that dark circles under the eyes is a common phenom-enon in the Hispanic/Latino population, and may represent key aesthetic concerns for this patient population.

Mestizo or Hispanic individuals with Native American origins share greater craniofacial similarity with Asians than with whites.24 In this light, it should be considered that some His-

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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panic/Latino patients may also share some of the facial aging patterns observed with the Asian ethnicities.25 While both His-panic and Asian facial shape can be characterized as broad (wide bizygomatic and bigonial distance) with heavier malar fat pads, certain Asian ethnicities also tend to have less anteromedial midface projection, which may contribute to the gravitational descent that exposes the tear trough.26,27 In another similarity with Asians, aging of the Mestizo face may include an increase in the forehead-glabella supraorbital prominence contributing to superior concavity and shadowing of the forehead.28 Orbital 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

The high importance level and priority assigned to sagging underneath the chin/double chin in both older and younger participants may reflect gravity-induced changes associated with a heavier, thicker skin type in the Hispanic/Latino popula-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.” Body mass index (BMI) can contribute more significantly to the appearance of submental fullness than skin laxity or sagging. As BMI was 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 differenc-es in the BMI in this group.

Consideration Rates for Future Treatments Including Inject-ablesAlthough there appeared to be a high awareness of injectable treatments involving under chin fat reduction and dermal fill-ers, they corresponded with lower consideration rates than other minimally-invasive treatments such as microdermabra-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 obser-vation 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 neuromodula-tors.3

The strengths of this study include a large participant population, a cross-sectional design, and the use of MaxDiff methodology to minimize scale bias, as compare to using paired compari-sons. The data collected and presented here characterizes the priorities and treatment awareness among a diverse popula-tion of Hispanic/Latino Americans naïve to facial injectable use and helps clinicians to understand this population and to plan treatments accordingly. Two case examples of Hispanic/Latino patients treated by the authors are presented in Figure 9 and Figure 10.

FIGURE 9. Facial rejuvenation using injectable treatments with a patient representative of a 30 to 44-year-old age range. Left, pre-treatment. Center, treatment diagram showing placement of hyaluronic acid filler (yellow) (2.1 mL total) for upper and lower eyelids, midface, and onabotulinumtoxinA (45 U total) for glabellar and crow’s feet lines, masseter, depressor anguli oris (DAO), and chin. Right, approximately 2 weeks post-treatment. Patient photos courtesy of Dr. JR Montes.

FIGURE 10. Facial rejuvenation using injectable treatment with a patient representative of a 45 to 65-year-old age range. Left, pre-treatment. Center, treatment diagram showing placement of hyaluronic acid filler (yellow) (4 mL total) for upper and lower eyelids, temples, midface, marionette lines, and jawline; deoxycholic acid (orange) (2 mL total) for submental region; and onabotulinumtoxinA (52.5 U total) for forehead, glabellar, and crow’s feet lines, oral commissures, depressor anguli oris (DAO), and mentum. Right, approximately 2 months post-treatment. Patient photos courtesy of Dr. JR Montes.



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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: spe-

cial considerations. Facial Plast Surg. 2010;26(2):164-713.27. Liew S, Wu WT, Chan HH, Ho WW, et al. Consensus on changing trends, atti-

tudes, 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.


Sabrina Fabi MDE-mail:................……...................................... [email protected]

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CONCLUSIONSHispanic/Latino Americans are a growing patient population for aesthetic practitioners. As much of the literature pertaining to facial aesthetic rejuvenation is focused on Caucasian women, there is a need to explore the facial aging process among His-panic/Latino women and identify the attitudes that factor into their consideration of the different treatments. Compared to other racial/ethnic groups, Hispanic/Latino women comprise a diverse racial and ethnic background with signs of facial aging that may share common patterns and characteristic of other racial/ethnic groups, but the practitioner will need to keenly identify them.

This survey highlighted key aesthetic concerns common among the Hispanic/Latino American women and revealed the most bothersome areas for this population as the under-eye/tear trough area, CFLs, FHLs, and the submental area. With ad-vancing age, priorities shifted slightly from upper facial areas to include more of the mid and lower facial areas. In addition, the discrepancy between the high level of aesthetic concern for underneath the chin area and low consideration rate for the injectable treatments for this suggest there may be opportuni-ties to educate patients regarding available treatments that may help them achieve aesthetic goals.

Among participants who would not consider injectables, the main reasons cited were concerns about safety/side effects, concerns about putting a foreign substance into their body, and concern that their face will not look natural. Educating and counseling patients on these barriers may increase patient ac-ceptability of a broader range of treatment options and comfort them in knowing there is a reinforcement on “naturalness” in medical aesthetic treatments. By lessening the barriers to in-jectables, patients may ultimately achieve a more impactful and longer lasting treatment results. Also, discussing treatment strategies that address existing pigmentary issues and mini-mize the risk of PIH may help strengthen the patient-practitioner bond.

With the observations presented here, this study hopes to con-tribute to a first step in providing practitioners with a more patient-centric and culturally-competent approach to their treat-ment of Hispanic/Latino facial aesthetic patients.

DISCLOSURESS Fabi serves as a consultant, researcher, and advisory board member for Allergan plc. JR Montes serves as a speaker and trainer for Allergan plc. SB Aguilera serves as a speaker and trainer for Allergan plc. V Bucay serves as a speaker and con-sultant for Allergan plc. S Manson Brown and N Ashourian are employees of Allergan plc and may own stock/options in the company. The opinions expressed in this article are those of the authors. The authors received no honoraria related to the

development of this article. This study was funded by Allergan, Inc. Writing and editorial support for this article was provided by Erika von Grote, PhD, Allergan plc, Irvine, CA. The authors would like to thank Garrett T. Shumate of Allergan plc for his invaluable assistance in the interpretation of data and in the development of this manuscript

REFERENCES1. 2008 ASAPS Statistics: Complete Plastic Surgery Statistics Report. Ameri-

can Society for Aesthetic Plastic Surgery. Available from: http://www.sur-gery.org/sites/default/files/2008stats.pdf. Accessed October 2018.

2. 2017 ASAPS Statistics: Complete Plastic Surgery Statistics Report. American 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 October 2018.

4. Bertoni B, Budowle B, Sans M, Barton SA, et al. Admixture in Hispanics: distribution of ancestral population contributions in the continental United States. Hum. Biol. 2003;75:1-11.

5. Talakoub L, Wesley NO. Differences in perceptions of beauty and cos-metic procedures performed in ethnic patients. Semin Cutan Med Surg. 2009;28(2):115-129.


7. Alexis AF, Alam M. Racial and ethnic differences in skin aging: implications for treatment with soft tissue fillers. J Drugs Dermatol. 2012;11(8):s30-s32; discussion s2.

8. Vashi NA, de Castro Maymone MB, Kundu RV. Aging differences in ethnic skin. J Clin Aesthet Dermatol. 2016;9(1):31-38.

9. Cobo R. Trends in facial plastic surgery in Latin America. Facial Plast Surg. 2013;29(3):149-53.

10. Broer PN, Juran S, Liu YJ, Weichman K, et al. The impact of geographic, eth-nic, and demographic dynamics on the perception of beauty. J Craniofac Surg. 2014;25(2):e157-161.

11. Montes JR. Ethnic and Gender Considerations in the Use of Facial Inject-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 treatment considerations for skin of color populations: African American, Asian and Hispanic. Poster presented at: The Skin of Color Seminar Series; May, 2018; New York, NY.

13. Fitzpatrick TB. The validity and practicality of sun reactive skin types I-VI. Arch Dermatol. 1988;124:869-871.

14. https://blog.skincancer.org/2018/09/13/are-you-at-risk-for-skin-cancer/As-sessed February 2019.

15. Ho BK, Robinson JK. Color bar tool for skin type self-identification: A cross-sectional study. J Am Acad Dermatol. 2015;73(2):312-3.e1.

16. The MaxDiff System Technical Paper, Version 8. Sawtooth Software 2015;Available at: URL: http://www.sawtoothsoftware.com/support/techni-cal-papers/maxdiff-best-worst-scaling/maxdiff-technical-paper-2013.

17. Del Bino S, Duval C, Bernerd F. Clinical and biological characterization of skin pigmentation diversity and its consequences on UV impact. Int J Mol Sci. 2018;19(9). pii: E2668.

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. 2010;16(2):168-178.

19. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2003; 21:689-697.

20. Friedmann DP, Goldman MP. Dark circles: etiology and management options. Clin Plast Surg. 2015;42(1):33-50.

21. 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 the Brazilian population. An Bras Dermatol. 2015;90(4):494-503.

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.

23. Glaser DA, Lambros V, Kolodziejczyk J, et al. Relationship between midface volume deficits and the appearance of tear troughs and nasolabial folds. Der-matol Surg. 2018;44(12):1547-1554.

24. Dudzik B, Jantz RL. Misclassifications of Hispanics Using Fordisc 3.1: com-paring cranial morphology in Asian and Hispanic populations. J Forensic Sci. 2016;61(5):1311-1318.

25. Oranges CM, Gohritz A, Haug M, Harder Y, Schaefer DJ. Universal and eth-nic-specific considerations on facial rejuvenation: where do you inject your





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, CADBay Area Laser Institute, San Francisco, CA †Deceased prior to journal submission

EAllergan plc, Marlow, UK

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 mo-tives/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 and priorities specific to Asian American women may help guide treatment plans more aligned with the goals and expectations of this patient population.

J Drugs Dermatol. 2019;18(7):633-641.

ABSTRACT

INTRODUCTION

As the number of aesthetic procedures increases, it is important for physicians to understand who comprises the expanding population seeking such treatments. In

recent years it is clear that as procedures become more widely accepted and commonplace, the patient population seeking them has also grown in terms of its racial, ethnic, and cultural diversity. While many published treatment algorithms in the US are suitable for Caucasian patients, there are far fewer that fo-cus on the aesthetic concerns and needs specific to the Asian patient. In addition, very little data exists focusing on Asian Americans which is a broad community of people representing several countries.

Over the past decade, the total number of Asian patients who received cosmetic procedures in the US increased by 33% with a growing number of younger patients (ie, 18 to 40 years of age) among them.1-3 A predominance of minimally-invasive fa-cial aesthetic treatments has grown to represent at least 90% of

all cosmetic procedures performed in the US in 2017.1 Similar to this trend in aesthetics, Asian patients primarily seek non-surgical, minimally-invasive treatment modalities, and express concerns for maintaining a natural appearance.3

The descriptor “Asian American” encompasses a diverse population with ethnic origins in East Asia (eg, China, Korea, Japan, Taiwan), South Asia (eg, Bangladesh, Nepal, Pakistan, Sri Lanka), and Southeast Asia (eg, Thailand, Singapore, In-donesia, Philippines). Among this diverse population, there is also a wide range of facial morphologies and Fitzpatrick Skin Phototypes (FSPs).4 Importantly, variations in skin type and underlying structural anatomy impact the rate, pattern, and severity of facial aging among different ethnicities.5-8 How-ever, social and cultural influences ultimately have a defining influence in perceptions of beauty and motivations for seek-ing treatment.9-11 For the aesthetic physician, understanding not only the structural and cutaneous components of aging



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A. Chiu, K. Mariwalla, A. Hui-Austin, et al

considered a higher treatment priority relative to those areas ranked below the average. Awareness of aesthetic procedures, future treatment considerations, and motives and barriers im-pacting the consideration rate of injectable treatments were assessed by questionnaire.

Data AnalysisMax Diff analyses and analysis for correlation between bother-some facial areas and their treatment priorities were conducted by the LRW agency and presented descriptively by percent or by average.

RESULTS ParticipantsThe majority of the 403 participants included in the study were 30 to 44 years old (57%), born outside of the US (55%), married (82%), with household incomes > $75,000 (74%), an average spending of < $250/month on products or services for facial aesthetics (79%), and had spent ≥ $250 on a single medical fa-cial treatment (55%) (Table 1). The majority were categorized as FSP III or IV (89%) and a large proportion identified with a Southeast Asian (Asian Indian, Filipino, Vietnamese, n = 147) or Chinese (n = 119) ethnic background (Table 2).

Attitudes Toward Improving Facial Aesthetics and Existing Facial ConcernsMost agreed with wanting their face to look good for their age (86%), cared about improving their facial appearance (78%), were interested in treatments that addressed hyper/hypo-pig-mentation (72%), facial wrinkles and lines (64%) and treatments that would make them look less tired (63%) (Figure 2). Uneven skin tone/color (64%), facial wrinkles (50%), and sun damage (48%) were the most frequently-reported facial concerns (Fig-ure 3).

Most Bothersome Facial AreasAreas of the upper face were the most bothersome and includ-ed the under-eye/tear trough area (32%), crow’s feet lines (CFLs)

but also the treatment preferences and motivations relevant to Asian American women may help guide treatment plans more aligned with the goals and expectations of this patient popula-tion.

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 to-ward signs of facial aging and existing facial concerns; 2) facial areas that are most bothersome; 3) facial areas most/least like-ly to represent a priority in a future aesthetic treatment plan; 4) awareness of available aesthetic treatments and their con-sideration 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 also included African American and Hispanic/Latino American participants.12

METHODS Participants and Study DesignParticipants living in the US were recruited through online river sampling (banner ads, pop-up ads, instant capture promotions) by the Lieberman Research Worldwide (LRW) agency between March and April 2016. Primary inclusion criteria were 1) females ages 30 to 65 years living in the US; 2) aesthetically-oriented, as determined by level of agreement on an aesthetic orienta-tion questionnaire; 3) household annual income >$50,000 with some discretionary spending flexibility; 4) naïve to facial injectable treatments; 5) aware of BOTOX® Cosmetic; and 6) considering having a medical facial aesthetic treatment within the next 2 years.

Participants identified their most predominant ethnic back-ground as one of the following: Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, American Indian/Alaskan Na-tive, Native Hawaiian, or other Pacific Islander (ie, Samoan, Guamanian, or Chamorro). Participant’s FSP was categorized as I through VI using a questionnaire adapted from the Skin Cancer Foundation website in combination with their selection of a color that most represented their natural skin tone from a range of 11 skin codes (colors).13-15

Measures and AnalysisThe study design and questionnaire format have been previ-ously described.16 Briefly, attitudes toward improving facial aesthetics and existing concerns were assessed by question-naire. Most bothersome facial areas and treatment priorities were assessed using a 15-point facial diagram (Figure 1) and a Maximum Difference (MaxDiff) ranking methodology was used to identify the relative importance of each area.17 MaxDiff scores were represented by a “relative importance value”. Areas ranked above average indicated greater importance and were

FIGURE 1. Diagram used to select most bothersome facial areas and treatment priorities.



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TABLE 1.

Participant Demographics


(N = 403)

Age

30 - 44 57

45 - 65 43

US Region of Current Residence

Northeast 21

South 20

Midwest 13

West 46

Born in the US 45

Marital Status

Married 82

Single (Never Married) 14

Separated/Divorced/Widowed 4

Education

Highschool or Less 1

Some College or College Graduate 64

Post Graduate 35

Household Income

Less than $ 75,000 26

$ 75,000 - $ 150,000 47

$ 150,000 or More 27

Monthly Spend on Products and Services for Facial Aesthetics*

Less than $ 250 79

$ 250 or More 20

Maximum Spend on a Single Medical Facial Treatment

Less than $ 250 45

$ 250 or More 55*1% preferred not to answer

% Fitzpatrick Skin Phototype Among Different Ethnic Backgrounds


Ethnic Background I - II III - IV V - VI

Chinese 5 90 5

Japanese 5 85 10

Asian Indian -- 86 14

Filipino -- 89 11

Korean 5 90 5

Vietnamese -- 100 --

Other Asian* 5 92 3*Includes American Indian, Alaskan Native, Native Hawaiian or other Pacific Islander (including Samoan, Guamanian, or Chamorro)

TABLE 2.

Proportions of Fitzpatrick Skin Phototypes (FSPs) and Ethnicities


(N = 403)


I - II 3

III - IV 89

V - VI 8

Ethnic Background

Chinese 30

Japanese 16

Asian Indian 16

Filipino 14

Korean 10

Vietnamese 7

Other Asian* 7

FIGURE 2. Attitudes toward improving facial aesthetics.



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(61), and GLs (59), followed by NLFs (55), and OCs (54). Areas of lower relative importance included MLs (42), chin (37), jawline (36), and cheeks (35). Perioral lines (32), temples (31), and lips (26) were among the least important. Among the older group (ages 45 to 65) (Figure 5b), the under-eye/tear trough area (77) and CFLs (70) were also selected as highest priorities followed by sagging underneath the chin/double chin (62), FHLs (62), and NLFs (61), GLs (56), OCs (56), and MLs (52). Areas of lower relative importance included jawline (39), chin (38), cheeks (34). Perioral lines (29), temples (27), and lips (19).

Awareness of Treatments Options and Future Treatment Consideration RatesA high proportion of participants were aware of surgical pro-cedures (facial plastic surgery and liposuction, 93-95%) (Figure 6a) which corresponded with lower consideration rates com-pared to minimally-invasive treatments (Figure 6b). A high

(29%), and forehead lines (FHLs) (29%) (Figure 4). These were followed by sagging underneath the chin/double chin (26%), nasolabial folds (NLFs) (23%), glabellar lines (GLs) (21%), mari-onette lines (MLs) (20%), and oral commissures (OCs) (18%). Areas selected with less frequency were the chin (16%), cheeks (14%), jawline (13%), perioral lines (12%), temples (11%), and lips (10%).

Treatment PrioritiesThe relative importance ranking of each area ranged from 19 to 77 across the 15 facial areas; overall bothersome facial areas tended to correlate with the treatment priorities (R2 =.82, data not shown). Among the younger group (ages 30 to 44) (Figure 5a), the facial areas of highest priority (represented by relative importance values above the average) included the under-eye/tear trough area (75) and CFLs (75). Other areas of high impor-tance were FHLs (66), sagging underneath the chin/double chin

FIGURE 3. Existing facial concerns.

FIGURE 4. Most bothersome facial areas.



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

FIGURE 6A AND 6B. Awareness of treatments and treatments considered within the next two years.Do Not CopyPenalties Apply


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proportion were aware of treatments to enhance skin quality such as skin tightening procedures (88%), laser skin resurfacing (87%), microdermabrasion (85%), and chemical peels (84%), which also corresponded with high treatment consideration rates for those kinds of procedures (37 - 64%). Regarding inject-able treatments, all or most were aware of neuromodulators (100%), under chin fat reduction (76%) and dermal fillers (72%), and were reflected by future consideration rates of 33%, 20%, and 18%, respectively.

Motives and Barriers Impacting Consideration Rate of In-jectable TreatmentsAmong participants who would consider injectables (74%, 300/403), a high proportion wanted to look good for their age (68%) and look more youthful (55%) (Figure 7). Twenty-three percent agreed that they would consider injectables because they have seen, read, or heard positives things about them and there is more information now available about those treat-ments (22%). A smaller proportion was motivated by wanting

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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to maintain a competitive edge in the workforce (12%) or im-prove dating prospects or relationships (7%).

The top 3 barriers for not having tried injectable treatments yet cited concerns about safety and side effects (57%), cost (43%), and concerns about their face not looking natural (38%) (Figure 8). Among the 26% who would not consider injectables, the top 3 reasons included 1) concerns about injecting a foreign sub-stance into their body (60%), 2) concerns about safety and side effects (55%), and 3) dislike of needles (32%) (data not shown).

DISCUSSIONAs 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 ag-ing affect everyone, it is important to keep anatomic differences between races/ethnicities intact so that when corrections are discussed with patients, they are not being made to appear ho-mogenous within the general population. Whether or not signs of facial aging are bothersome to an individual and prompts them to seek treatment is heavily dependent on their social and cultural ideals of beauty and how motivated they are to main-tain or improve their facial aesthetics.

Attitudes Toward Improving Facial AestheticsNot surprisingly, the data showed that attitudes toward facial aesthetics were aligned with facial concerns. Notably, a high proportion would consider treatments for hyper/hypo-pigmenta-tion (72%) which reflected a high incidence of uneven skin tone/color (64%) and facial sun damage (48%). This data is expected given that dyschromia has may be more apparent in FSPs III through VI, and the majority of these participants (89%) were in the FSP III and IV categories. An advantage that comes with greater melanin content (primary determinant of pigmentation) is added protection against the immediate effects of UV expo-sure (eg, sunburn), but photodamage still occurs and is more obvious over time after it has caused pigmentary disorders (eg, freckling, solar lentigo, melasma, and seborrheic keratosis).18,19 Greater melanin content also increases an individual’s predis-position toward a post-inflammatory hyperpigmentation (PIH) reaction following inflammation or injury.19 While correcting un-even skin tone may represent a concern for many individuals, a high level of interest among Asian participants, although pre-dominantly younger (57% ages 30 - 44) may also reflect a strong cultural aesthetic standard to preserve and maintain clear and even-toned facial skin.9,11,20

Most Bothersome Facial Areas and Treatment PrioritiesBothersome facial areas tended to correlate with treatment pri-orities (R2 =.82, data not shown) although some bothersome areas translated to lower priorities (eg, short, thinning lashes). Discrepancies between bothersome areas and treatment priori-ties might reflect the difference between areas amendable with

the application of cosmetics versus those that are more struc-tural. Regardless of age, Asian participants were most bothered by areas of the upper face which included the under-eye/tear trough area, CFLs, and FHLs. While under-eye/tear trough, CFLs, and FHLs were also ranked among the highest treatment priority for both age groups, areas of the mid and lower face (NLFs, OCs, and MLs) were ranked with higher relative importance among the older group. This shift in importance is also expected as it re-flects the increasing structural changes and midface ptosis that accompanies facial aging. Furthermore, anatomical characteris-tics shared by many Asian ethnicities, which include a weaker skeletal facial framework, a wide zygomaticomalar region, less projection of the anteromedial midface, and heavier malar fat pads, provide no support or resistance to the midface ptosis that exposes the tear trough and accentuate redundant skin (folds) in the lower face.3,21-23

It is important to note that while these observations highlight this as a key treatment area for this patient population, par-ticipants were not given the option to differentiate this area specifically as “under-eye”, under-eye bags, and/or “tear trough”. The under-eye area may involve dark circles which includes a vascular or pigmentary basis, distinct from a tear trough.24 Ma-lar ptosis can contribute to formation of under-eye bags (orbital

FIGURE 9. Facial rejuvenation using injectable treatments with a patient representative of a 30 to 44-year-old age range. Left, pre-treatment. Center, treatment diagram showing placement of hyaluronic 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), nasal bridge (0.5 mL total), jawline and mentum (1.0 mL total). Right, immediately post-treatment. Patient photos courtesy of Dr. A Chiu.

FIGURE 10. Festoon correction using injectable treatment with a patient representative of a 45 to 65-year-old age range. Left, pre-treatment. Center, treatment diagram showing placement of hyaluronic acid filler (yellow) (1.0 mL total) for medial midface and tear troughs. Right, immediately post-treatment. Patient photos courtesy of Dr. A Hui Austin.



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ate between “sagging underneath the chin” and “double chin”. Body mass index likely plays more of a role in the appearance of submental fullness than laxity or sagging. Regardless of the contributing factors, these observations highlight that softening of the cervicomental angle is a strong enough aesthetic concern among Asian women to motivate a desire for treatment and may represent another key treatment area.

The strengths of the study included such factors as a large participant population, a cross-sectional design, and use of the MaxDiff methodology to minimize scale bias versus using paired comparisons. The value in these data is the Asian aes-thetic perspective with the potential influence of US or Western cultural standards, as 45% were US-born. As the Asian Ameri-can population becomes more multicultural, such perspectives may be more relevant than those reporting on traditional aes-thetic standards observed by Asians residing in their country of origin. Two case examples of Asian American patients treated by the authors are presented in Figure 9 and Figure 10.

The study questionnaires were designed to suit a racially/eth-nically diverse group participants which limited the number of facial areas evaluated to those most common among all. In doing so, several key treatment areas that are predominant in Asia (ie, nose and masseters) where not evaluated in this study. Future studies should include evaluation of these 2 areas in ad-dition to a more granular evaluation of the key treatment areas, under-eye and submental area, highlighted here.

CONCLUSIONSAsian Americans are a growing segment of the patient popula-tion for aesthetic physicians. Since much of the literature and instructional training in injectables has been focused on the ag-ing patterns of Caucasian women, there is a need to evaluate how this process occurs among Asian women of varying eth-nicities and in what way it may motivate them to seek treatment. In this survey of 403 Asian American women, aged 30 to 65, the facial areas ranked with the highest importance and priority in-cluded the under-eye/tear trough, CFLs, FHLs, and the submental areas with priorities shifting slightly from upper facial lines to mid and lower facial folds and creases with advancing age.

Although awareness of injectable treatments was high, and the majority would consider having them, they were secondary to the skin-focused treatments (eg, skin tightening procedures, la-ser skin resurfacing, microdermabrasion, and chemical peels). Among participants who would consider injectable treatments but haven’t tried them yet, the greatest barriers were concerns about safety and side effects, cost, and unnatural appearance. Among participants who would not consider injectables, the main reasons cited were concerns about putting a foreign sub-stance into their body, safety and side effects, and a dislike of needles.

fat pad pseudo-herniation) and tear trough depression; a result which is further exacerbated by increasing infraorbital skin lax-ity and orbital bone loss.24,25 Because these fat compartments are no longer forming a smooth plane, surface shadowing be-comes more obvious.

Surprisingly, the treatment priority for CFLs was high among the younger group and declined in importance for the older group, although this decline may be the result of shifting priori-ties as age-related changes in the mid and lower face become increasingly more bothersome. Another reason suggested for this, observed in practice by contributing authors, is that their Asian patients associate a minimal amount of CFLs with a more natural expressive appearance. The initial appearance and se-verity of CFLs result from dynamic movement of the orbicularis oculi muscle which can also be exacerbated by accumulated photodamage. A classification of CFLs delineates them as up-per, lower, and bidirectional, with the bidirectional type usually only becoming more common as people age.26,27 However, in comparisons with a Caucasian population, the presence of bidi-rectional CFLs has been observed in a higher proportion among Asians beginning at a younger age.26 The high priority for CFLs among the younger group of participants may be aligned with such a predisposition, but more so highlights that CFLs may represent another key treatment area among Asian women re-gardless of age. Similar to CFLs, a decline in the importance of FHLs among the older group may simply indicate a shift in prior-ities, as they are displaced by areas of the mid (NLFs) and lower (MLs) facial areas which increased in importance. However, the forehead area is an important aesthetic unit by East Asian beau-ty standards, and the impact of aging may include an increase in forehead-glabella supraorbital prominence which contributes to superior concavity and shadowing of the forehead.28

A high priority was also given to the treatment of sagging un-derneath the chin/double chin and was of similar importance among both age groups. While aging of the submental area isn’t defined by race or ethnicity, the effects of aging on the submen-tal area have been suggested to be more pronounced in more heavily pigmented skin types. This is proposed to be due to the gravity-induced descent of a thicker and heavier skin type op-posed to descent due to increased skin laxity (accompanied by more jowling) in thinner, less pigmented skin types.29 It may also may be due to the fact that initial signs aging for photo-protect-ed skin types are volumetric and structural versus those that are more cutaneous (eg, fine lines and wrinkles) for less pigmented, less protected skin types. Other anatomical contributors may include a more recessed chin position with greater posterior angulation of the lower mentum, a characteristic observable in varying degrees among some Asian ethnicities.7,30 This lack of skeletal support against tissue descent may exacerbate the appearance of submental fat.30,31 However, it is important to note that participants were not given the option to differenti-



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12. Boyd C, Chui A, Montes JR, Narurkar V, et al. Differential facial aesthetic treatment considerations for skin of color populations: African American, Asian and Hispanic. Poster presented at: The Skin of Color Seminar Series; May, 2018; New York, NY.

13. Fitzpatrick TB. The validity and practicality of sun reactive skin types I-VI. Arch Dermatol. 1988;124:869-871.

14. https://blog.skincancer.org/2018/09/13/are-you-at-risk-for-skin-cancer/As-sessed February 2019.

15. Ho BK, Robinson JK. Color bar tool for skin type self-identification: A cross-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-standing the female Hispanic/Latino American facial aesthetic patient. J Drugs Dermatol. 2019;18(7):623.

17. The MaxDiff System Technical Paper, Version 8. Sawtooth Software 2015;Available at: URL: http://www.sawtoothsoftware.com/support/techni-cal-papers/maxdiff-best-worst-scaling/maxdiff-technical-paper-2013.

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. 2010;16(2):168-78.

19. Yu SS, Grekin RC. Aesthetic analysis of Asian skin. Facial Plast Surg Clin North Am. 2007;15(3):361-5.

20. Galzote C, Estanislao R, Suero MO, Khaiat A, et al. Characterization of fa-cial skin of various Asian populations through visual and non-invasive instru-mental evaluations: influence of age and skincare habits. Skin Res Technol. 2013;19(4):454-65.

21. Sykes JM. Management of the aging face in the Asian patient. Facial Plast Surg Clin North Am. 2007;15(3):353-360.

22. Oranges CM, Gohritz A, Haug M, Harder Y, Schaefer DJ. Universal and eth-nic-specific considerations on facial rejuvenation: where do you inject your fillers? Plast Reconstr Surg Glob Open. 2016;4:e842.

23. Kapoor KM, Chatrath V, Anand C, Shetty R, et al. Consensus recommenda-tions for treatment strategies in indians using botulinum toxin and hyaluronic acid fillers. Plast Reconstr Surg Glob Open. 2017;5(12):e1574.

24. Friedmann DP, Goldman MP. Dark circles: etiology and management options. Clin Plast Surg. 2015;42(1):33-50.

25. Glaser DA, Lambros V, Kolodziejczyk J, Magyar A, et al. Relationship be-tween midface volume deficits and the appearance of tear troughs and na-solabial folds. Dermatol Surg. 2018;44(12):1547-54.

26. Kane MA. Classification of crow’s feet patterns among Caucasian women: the key to individualizing treatment. Plast Reconstr Surg. 2003;112(Suppl 5):33S.

27. Park DH, Han DG, Shim JS, Lee YJ, et al. Analysis of the patterns of lateral 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 contouring in Asians with fat grafting and botulinum toxin. Ann Plast Surg. 2019;82(1S Suppl 1):S59-65.

29. Alexis AF, Alam M. Racial and ethnic differences in skin aging: implications for treatment with soft tissue fillers. J Drugs Dermatol. 2012;11(8):s30-s32; discussion s2.

30. Shirakabe Y, Suzuki Y, Lam SM. A new paradigm for the aging Asian face. Aesthetic Plast Surg. 2003;27(5):397-402.

31. Shaw RB, Jr., Katzel EB, Koltz PF, Yaremchuk MJ, et al. Aging of the facial skeleton: aesthetic implications and rejuvenation strategies. Plast Recon-struct Surg. 2011;127(1):374-83.


Annie Chiu MD E-mail:................……........................ [email protected]

Educating and counseling patients with these barriers in mind may increase patient acceptability of a broader range of treat-ment options, which will help them achieve more impactful and longer lasting treatment results, and comfort them in expressing there is a growing reinforcement of maintaining “naturalness” with all medical aesthetic treatments. Ultimately, the practitio-ner’s best approach for introducing new aesthetic treatments may be by starting with primary skin quality concerns using treatment strategies that minimize the risk of PIH and address existing dyschromia and sun damage. This strategy may help strengthen the patient-practitioner bond and overcome barriers with their Asian American patients. This study intends to pro-vide physicians with advice for achieving a more patient-centric approach in their treatment of Asian American facial aesthetic patients.

DISCLOSUREA Chiu serves as a consultant and clinical investigator for Al-lergan plc. K Mariwalla has served on an advisory board for Allergan plc. A Hui-Austin serves as a consultant for Allergan plc. V Narurkar has served as a consultant and clinical investiga-tor for Allergan plc. C de la Guardia is an employee of Allergan plc and may own stock/options in the company. The opinions expressed in this article are those of the authors. The authors received no honoraria related to the development of this article.This study was funded by Allergan, Inc. Writing and editorial support for this article was provided by Erika von Grote, PhD, Allergan plc, Irvine, CA. The authors would like to thank Garrett T. Shumate of Allergan plc for his invaluable assistance in the interpretation of data and in the development of this manuscript

REFERENCES1. 2017 ASAPS Statistics: Complete Plastic Surgery Statistics Report. Ameri-

can Society for Aesthetic Plastic Surgery. Available from: http://www.sur-gery.org/sites/default/files/2017stats.pdf. Accessed October 2018.

2. 2008 ASAPS Statistics: Procedures by ethnicity. American Society for Aes-thetic Plastic Surgery. Available from: http://www.surgery.org/sites/default/files/2008stats.pdf. Accessed October 2018.

3. Liew S, Wu WTL, Chan HH, Ho WWS, et al. Consensus on changing trends, attitudes, and concepts of asian beauty. Aesth Plast Surg. 2016. 40:193-201.

4. Sundaram H, Huang PH, Hsu NJ, Huh CH, et al. Aesthetic applications of botulinum toxin A in Asians: An international, multidisciplinary, Pan-Asian consensus. Plast Reconstr Surg Glob Open. 2016;4(12):e872.

5. Talakoub L, Wesley NO. Differences in perceptions of beauty and cos-metic procedures performed in ethnic patients. Semin Cutan Med Surg. 2009;28(2):115-129.


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.



June 2019 542 Volume 18 • Issue 6


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, CAbIndiana University School of Medicine, Indianapolis, IN, Physicians Skin Care, PLLC, Louisville, KY,

Icahn School of Medicine at Mount Sinai, New York, NYcDepartment of Dermatology, George Washington University School of Medicine, Washington, DC

dOrtho Dermatologics, Bridgewater, NJ eBausch Health, Bridgewater, NJ

fBausch Health Americas, Inc., Petaluma, CA

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 Global Severity Scores [EGSS]). In addition, patients completed a patient satisfac-tion survey (PSS), and acne-specific quality of life (QoL) questionnaire. Safety and cutaneous tolerability were assessed throughout.Results: A novel tazarotene 0.045% lotion demonstrated statistically significant 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 reduc-tion, 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.

ABSTRACT

INTRODUCTION

Topical retinoids (eg, tazarotene, tretinoin, adapalene) have played an important role in the management of acne vulgaris (acne). They reduce visible lesions and in-

hibit the development of microcomedones and new lesions.1-3

Retinoids normalize the abnormal desquamation process by reducing keratinocyte proliferation and promoting differen-tiation,4 as well as modulating several important inflammatory pathways.4-10 Extensive clinical data have shown retinoids to

be highly effective in acne, and they are recommended as the cornerstone of topical therapy.11 Comparative studies between tazarotene, tretinoin and adapalene have generally reported greater efficacy with tazarotene, but more irritation.12-20

A key aspect of acne management has been the ongoing evolu-tion of topical treatments that use innovative delivery solutions and optimal formulations to help minimize irritation, without



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Journal of Drugs in DermatologyJune 2019 • Volume 18 • Issue 6

E.A. Tanghetti, L.H. Kircik, L.J. Green, et al

vestigator. Primary efficacy endpoints included mean absolute change from baseline to week 12 in inflammatory and nonin-flammatory lesion counts, and the proportion of patients who achieved at least a 2-grade reduction from baseline to week 12 in EGSS and were ‘clear’ or ‘almost clear’. Other efficacy end-points included mean percent change from baseline to week 12 in inflammatory and noninflammatory lesion counts. Data for vehicle lotion and cream were pooled for the efficacy analysis.

Additional analyses were performed to evaluate the impact of treatment on other patient outcomes. These included a Patient Satisfaction Survey (PSS) with scores ranging from 1-10 (where 10 was the most satisfied); a validated Acne-Specific Quality of Life (Acne-QoL) questionnaire (Merck & Co, Inc. Whitehouse, NJ); and a Subject Self-Assessment (SSA) scale (using a 7-point scale, where 0=worse and 6=clear). The SSA was assessed at baseline and weeks 2, 4, 8, and 12; PSS and Acne-QoL were completed at baseline and week 12.

Safety EvaluationCutaneous safety (erythema, scaling, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) were assessed using a 4-point scale where 0=none, 1=mild, 2=moderate and 3=severe. The investigator assessed erythema, scaling, and hyper-/hypopigmentation at the time of the study visit. Itching, burning, and stinging were solicited from the patient and recorded as an average of the patient’s symptoms during the period since the previous visit.

Safety was also evaluated through reported adverse events (AEs), which were summarized by treatment group, severity, and relationship to study medication.

Statistical AnalysisThe intent-to-treat (ITT) population comprised all patients ran-domized and provided with study drug and vehicle. The safety population comprised all randomized patients who were pre-sumed to have used the study medication or vehicle at least once and who provided at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was last observation carried forward (LOCF). No imputations were made for missing safety data.

Reductions in lesion counts are presented as means and con-trast p-values are from a ranked analysis of covariance with factor of treatment and the respective baseline lesion count as covariate. Significance of EGSS reductions were obtained from a Cochran-Mantel-Haenszel (CMH) test.

All statistical analyses were conducted using SAS® version 9.3 or later. Statistical significance was based on 2-tailed tests of the null hypothesis resulting in P values of 0.05 or less.

compromising efficacy. A novel lotion formulation was devel-oped using a polymeric emulsion, with the aim of improving both efficacy and tolerability. This polymeric emulsion tech-nology provides a more uniform distribution of active and moisturizing excipients at the surface of the skin, which should enhance efficacy and minimize irritation.

In this report data from a comparative phase 2 clinical study where patients with moderate-to-severe acne were treated with tazarotene 0.045% lotion, tazarotene 0.1% cream, or vehicle are presented.

METHODS Study DesignThis was a multicenter, randomized, double-blind, vehicle-controlled, clinical study in patients with moderate-to-severe acne who met specific inclusion/exclusion criteria as described below. Protocol received approval from the appropriate in-stitutional review board (IRB) for each center before patient enrollment and were conducted in accordance with the Dec-laration of Helsinki and Good Clinical Practices (GCP) and in compliance with local regulatory requirements. All patients were informed of the study details and provided written con-sent.

Patients were enrolled with an Evaluator Global Severity Score [EGSS] score of 3 (moderate) or 4 (severe). Treatments were randomized (2:2:1:1) to tazarotene 0.045% lotion, tazarotene 0.1% cream, and vehicle lotion or cream (to ensure blinding). Data on vehicle are combined in the result presented here. All patients applied study medication to the face once-daily in the evening for 12 weeks; after being instructed to gently washing their face with a non-medicated cleanser.

Study PopulationApproximately 210 patients were planned for enrollment. Eli-gible patients were of any gender, race and ethnicity aged 12 years and older who presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflam-matory lesions (open and closed comedones), and two nodules or less. Women of childbearing potential were required to have a negative urine pregnancy test result and to agree to use an effective form of contraception for the duration of the study. A washout period of up to 1 month was required for patients who used previous prescription and over-the-counter acne treatments (and six months for systemic retinoids). Investiga-tor approved non-mediated facial cleanser, moisturizer, and sunscreen was allowed.

Efficacy EvaluationEfficacy evaluations comprised inflammatory, and noninflam-matory lesion counts and an EGSS at screening, baseline, and during treatment (at weeks 2,4, 8, and 12) performed by the in-



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All AEs occurring during the studies were recorded and clas-sified on the basis of medical dictionary for drug regulatory 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 CharacteristicsTotal 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, in-cluding 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 dis-continuation were ‘lost to follow-up (N=12)’ or ‘subject request (N=5)’. One patient treated with tazarotene 0.1% cream discon-tinued due to adverse event. Four patients were excluded from the safety population due to no post-baseline safety assess-ment.

Demographic data (Table 1) was similar across the treatment groups. The mean age was 21.2 to 23.3 years. There was a slightly higher proportion of female patients overall (55.2%); 61.4% were Caucasian, with 28.6% Black or African American. There were no noticeable differences between treatment groups in regard to baseline lesion counts, or EGSS. At base-line, the mean number of inflammatory and noninflammatory lesions ranged from 27.2 to 28.3 and 36.6 to 37.6, respectively. At baseline, 92.4% of patients had moderate acne (EGSS=3).

EfficacyLesion CountsTazarotene 0.045% lotion resulted in statistically significant reductions in both inflammatory and noninflammatory lesion reductions compared to combined vehicle at week 12. Mean percentage change from baseline to week 12 in inflammatory lesion counts was 63.8% versus 51.4% with the combined ve-hicle (P=.006), and in noninflammatory lesion counts 56.9% versus 35.2% with vehicle (P<.001), see Figures 2 and 3. Tazaro-tene 0.045% lotion showed a greater reduction from baseline to week 12 in inflammatory and noninflammatory lesions when compared with tazarotene 0.1% cream, but differences were not significant (P=.680 and .612).

Median percent change from baseline to week 12 in inflam-matory and noninflammatory lesion counts with tazarotene 0.045% lotion was 72.4% and 62.5% versus 66.7% and 56.4% with tazarotene 0.1% cream and 60.0% and 42.3% with vehicle, respectively.

FIGURE 1. Patient disposition ITT population (all randomized subjects, N=210).

TABLE 1.

Demographics and Baseline Characteristics (ITT population)

Tazarotene 0.045% Lotion

(N=69)

Tazarotene 0.1% Cream

(N=72)

CombinedVehicle(N=69)

Age

Mean years (SD) 23.3 (10.20) 22.0 (8.96) 21.2 (8.44)

Sex N (%)

Male 32 (46.4%) 31 (43.1%) 31 (44.9%)

Female 37 (53.6%) 41 (56.9%) 38 (55.1%)

Ethnicity N (%)

Hispanic or Latino 27 (39.1%) 29 (40.8%) 25 (36.2%)

Not Hispanic or Latino

42 (60.9%) 42 (59.2%) 44 (63.8%)

Race N (%)

American Indian or Alaska Native

1 (1.4%) 0 (0.0%) 2 (2.9%)

Asian 4 (5.8%) 4 (5.6%) 2 (2.9%)

Black or African American

21 (30.4%) 16 (22.2%) 23 (33.3%)

Native Hawaiian or Other Pacific Islander

1 (1.4%) 0 (0.0%) 1 (1.4%)

White 41 (59.4%) 50 (69.4%) 38 (55.1%)

Other 1 (1.4%) 2 (2.8%) 3 (4.3%)

Evaluator’s Global Severity Score N (%)

3 – Moderate 64 (92.8%) 66 (91.7%) 64 (92.8%)

4 – Severe 5 (7.2%) 6 (8.3%) 5 (7.2%)

Inflammatory Lesion Count

Mean (SD) 28.3 (6.00) 27.3 (5.95) 27.2 (5.49)

Noninflammatory Lesion Count

Mean (SD) 37.6 (14.70) 36.6 (13.31) 36.6 (13.17)



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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.

Treatment SuccessTreatment success was defined as at least a 2-grade improve-ment in global severity by EGSS and ‘clear’ or ‘almost clear’. At week 12, 18.8% of patients achieved treatment success with tazarotene 0.045% lotion compared to 10.1% with combined vehicle (P=.148; Figure 4). Tazarotene 0.045% lotion showed a greater treatment success at week 12 when compared with tazarotene 0.1% cream (16.7%), but differences were not sig-nificant.

Subject Self-Assessment (SSA)Tazarotene 0.045% lotion showed a greater numerical treatment success (‘clear’ or ‘almost clear’) at week 12 in terms of SSA when compared with tazarotene 0.1% cream (P=.768). Treat-ment success was achieved in 38.5% of patients, compared with 35.9% and 24.6% (tazarotene 0.01% cream and combined ve-hicle [P=.096], respectively).



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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.

Patient Satisfaction (PSS) and Quality of LifeThere were no significant differences in PSS mean scores at week 12 between tazarotene 0.045% lotion and tazarotene 0.1% cream (P=.372) or combined vehicle (P=.242). Overall, patients treated with tazarotene 0.045% lotion assessed their treatment satisfaction higher than tazarotene 0.1% cream (mean score of 7.7 versus 7.4).

There were also no statistically significant differences in the improvement between treatment groups based on the mean

Acne-QoL assessments in each of the 4 evaluated domains. Im-provements in self-perception, role-emotional, and role-social were similar with tazarotene 0.045% lotion and tazarotene 0.1% cream, and markedly greater than those achieved in the com-bined vehicle groups. In terms of acne symptoms improvement, the absolute change from baseline with tazarotene 0.045% lo-tion was again greater than that achieved with the combined vehicle, however tazarotene 0.1% cream only demonstrated an improvement similar to that achieved with vehicle.



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TABLE 2.

Treatment-Emergent and Related Adverse Event (AE) Characteristics through Week 12 (Safety population, N=206)

Tazarotene Lotion (N=68)

Tazarotene Cream(N=71)

Combined Vehicle(N=67)

Patients reporting any TEAE 10 (14.7%) 19 (26.8%) 9 (13.4%)

Patients reporting any SAE 0 (0.0%) 0 (0.0%) 0 (0.0%)

Patients who died 0 (0.0%) 0 (0.0%) 0 (0.0%)

Patients who discontinued due to TEAE

0 (0.0%) 1 (1.4%) 0 (0.0%)

Severity of AEs reported

Mild 6 (8.8%) 12 (16.9%) 9 (13.4%)

Moderate 2 (2.9%) 7 (9.9%) 0 (0.0%)

Severe 2 (2.9%) 0 (0.0%) 0 (0.0%)

Relationship to study drug

Related 2 (2.9%) 4 (5.6%) 0 (0.0%)

Unrelated 8 (11.8%) 15 (21.1%) 9 (13.4%)

Treatment Related AEs reported by ≥1% patients

Application site pain 2 (2.9%) 3 (4.2%) 0.(0.0%)

Application site erythema 0 (0.0%) 1 (1.4%) 0 (0.0%)

Application site exfoliation

0 (0.0%) 1 (1.4%) 0 (0.0%)

Application site dryness 0 (0.0%) 1 (1.4%) 0 (0.0%)

Erythema 0 (0.0%) 1 (1.4%) 0 (0.0%)

SafetyA higher proportion of patients treated with tazarotene 0.1% cream (26.8%) reported treatment-emergent AEs compared with tazarotene 0.045% lotion (14.7%) or combined vehicle (13.4%). TEAEs were mostly mild or moderate and unrelated to study drug (Table 2). Treatment-related AEs were more common with tazarotene 0.1% cream. There were two reports of applica-tion site pain (2.9%) with tazarotene 0.045% lotion; compared with three reports with tazarotene 0.1% cream (4.2%).

Cutaneous Safety and Tolerability Each of the signs and symptoms of cutaneous safety and tolerability (scaling, erythema, hypopigmentation, hyperpigmentation, itching, burning, and stinging) showed improvements from baseline to week 12. There were slight increases in mean scores for scaling, burning and stinging at week 4, consistent with tazarotene’s safety profile, but these reduced at subsequent study visits. All mean scores were ≤0.6 (where a score of 1=mild); scores being similar or slightly lower at interim study visits with tazarotene 0.045% lotion compared with tazarotene 0.1% cream, especially in terms of scaling, itch-ing, burning, and stinging at weeks 2 and 4.

DISCUSSIONDespite recommendations to use retinoids as first-line acne treatment,11,21 they remain underutilized.22-24The slow onset of action in the treatment of inflammatory lesions,25 and the widely recognized irritation potential of these agents have somewhat limited their use. Consequently, several attempts have been made to alleviate these efficacy and tolerability issue using new delivery technology. The clinical benefits observed with tazaro-tene 0.1% foam,26,27 0.1% cream,28 and 0.1% gel29 appear similar, although no direct comparisons exist in the literature.

The rationale behind the development of a novel lotion formula-tion of tazarotene stemmed from its proven efficacy in acne and the fact that a lotion formulation is the easiest and most accept-able formulation for application to the face; but also the potential for tazarotene cream (and to a lesser extent foam26) to cause concentration dependent skin irritation and dryness, which had been shown to be both bothersome in many patients and may impact adherence and successful acne treatment. For example, pooled results from several clinical studies showed that 14% of patients treated with tazarotene 0.1% foam reported irrita-tion and 7% dryness, compared with only 1% using vehicle.30

Tazarotene 0.045% lotion is a novel topical treatment for mod-erate-to-severe acne leveraging polymeric emulsion technology with the aim to improve both efficacy and tolerability. The poly-meric emulsion technology affords more uniform deposition of active, excipients and moisturizers onto the skin surface. This phase 2 study is the first to compare a novel formulation of tazarotene 0.045% lotion with commercially available taz-

arotene 0.1% cream in patients with moderate-to-severe acne. Tazarotene 0.045% lotion was significantly superior to vehicle in reducing both inflammatory and noninflammatory lesions; and numerically more effective than tazarotene 0.1% cream despite the two-fold difference in tazarotene concentration. Median re-ductions in inflammatory and noninflammatory lesions with tazarotene 0.045% lotion were 72% and 63%, respectively, at 12 weeks.

The only treatment-related AE with tazarotene 0.045% lotion observed was application site pain (2.9%). Skin reactions (such as scaling, burning, and stinging) were infrequent, had onsets early in the treatment period, were mostly mild and appeared transient. Erythema and itching noted at baseline improved pro-gressively with daily tazarotene 0.045% lotion treatment. Again, these data concur with those in other clinical trials of retinoids where the peak of cutaneous irritation typically occurs within the first 1-2 weeks and subsides.31

CONCLUSIONSTazarotene 0.045% lotion was developed using a polymeric emulsion technology. In this phase 2 study of patients with mod-erate-to-severe acne, tazarotene 0.045% lotion was as effective as the higher concentration tazarotene 0.1% cream, with fewer treatment-emergent adverse events.



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non-dermatologists in the management of acne vulgaris. J Am Acad Derma-tol 2016;74:1252–1254.

23. Balkrishnan R, Fleischer AB Jr, Paruthi S, Feldman SR. Physicians under-utilize topical retinoids in the management of acne vulgaris: analysis of US National Practice Data. J Dermatolog Treat 2003;14:172–176.

24. Balkrishnan R, Bhosle MJ, Camacho F, at al. Prescribing patterns for topical 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 therapy for acne. Dermatol Ther 2017;7:293-304.

26. Jarratt M, Werner CP, Alió Saenz AB. Tazarotene foam versus tazarotene gel: a randomized relative bioavailability study in acne vulgaris. Clin Drug Investig 2013;33:283–289.

27. Feldman SR, Werner CP, Alió AS. The efficacy and tolerability of tazarotene foam, 0.1%, in the treatment of acne vulgaris in 2 multicenter, randomized, vehicle-controlled, double-blind studies. J Drugs Dermatol 2013;12(4):438-446.

28. Shalita AR, Berson DS, Thiboutot DM, et al. Effects of tazarotene 0.1 % cream in the treatment of facial acne vulgaris: pooled results from two mul-ticenter, double-blind, randomized, vehicle-controlled, parallel-group trials. Clin Ther 2004;26:1865-1873.

29. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effec-tive in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis 1999;63:349-354.

30. Epstein EL, Stein Gold L. Safety and efficacy of tazarotene foam for the treatment of acne vulgaris. Clin Cosmet Investig Dermatol 2013;6:123-125.

31. Leyden J, Grove G, Zerweck C. Facial tolerability of topical retinoid therapy. J Drugs Dermatol 2004;3:641–651.


Emil Tanghetti MDE-mail:................……........ [email protected]

DISCLOSURESDrs Tanghetti, Kircik and Green were study investigators. Dr Kir-cik and Green are advisors to Ortho Dermatologics. Dr Guenin, Pillai, and Ms Harris and Martin are employees of Bausch Health Americas, Inc.

ACKNOWLEDGMENTThe authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Ortho Dermatologics funded Kon-ic’s activities pertaining to this manuscript.

REFERENCES1. Thielitz A, Abdel-Naser MB, Fluhr JW, et al. Topical retinoids in acne–an evi-

dence-based overview. J Dtsch Dermatol Ges 2008;6:1023–1031. 2. Thielitz A, Helmdach M, Ropke EM, et al. Lipid analysis of follicular casts

from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J Dermatol 2001;145:19–27.

3. Del Rosso JQ. Pharmacotherapy review: topical tazarotene, a composite review of clinical and research experience with focus on optimal use and safety. J Am Osteopath Coll Dermatol 2004;1(2):55–59.

4. Czernielewski J, Michel S, Bouclier M, et al. Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne. J Eur Acad Derma-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.

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 2003;49:S1–37.

7. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy 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.

10. Thiboutot DM, Gollnick HP.Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies. J Drugs Der-matol 2006;5(8):785–794.

11. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the man-agement 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 com-pared 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 ver-sus 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% ver-sus tazarotene cream 0.05% in subjects with healthy skin. J Drugs Dermatol 2007;6(6):632-638.

17. 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, ran-domized comparison study of the efficacy and tolerability of once-daily taz-arotene 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.

21. 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





SPECIAL TOPIC

A Survey-Based Comparison of Sun Safety Practices in a Representative Cohort of the General Public Versus Attendees

of a Skin Cancer ScreeningEmily 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

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 preven-tion 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 sunscreen and sun-protective 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 be better popularized among non-white and younger populations or more effective educational vehicles are needed.

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

ABSTRACT

INTRODUCTION

Proper photoprotective practices are critical for the pre-vention of melanoma and non-melanoma skin cancers. A significant proportion of data on these practices is yield-

ed from intake forms for free skin cancer screenings, such as through the American Academy of Dermatology’s SPOTme pro-gram. This program was started in 1985 and is one of the largest cancer screening programs.1 The risk profile, care access, and examination results of SPOTme’s screening population from 1986 to 2014 was recently examined by Okhovat et al.1 Nearly two million screenings were reviewed, which showed that the SPOTme program detected thousands of skin cancers that may have gone undetected given 52% of those screened would not have seen a doctor otherwise.1 Compared to the general United States (US) population, the screening sample was older (only 8.9% of participants were 15 to 29 years old) and included more white individuals (90.3% of the sample was Caucasian). The screening population also included only 37.7% men, and the

percentage of men attending screenings decreased over time. Given melanoma deaths are higher among men than women,2 the authors stated that men, especially white men, are a critical group to screen for skin cancer.1

However, it is possible that the knowledge and perceptions of populations who seek skin cancer screenings may differ from the general public, leading to different photoprotective prac-tices among these populations. This is especially relevant in the US where the demographics of our largest skin cancer screen-ing program was not representative of the general population.1

The SPOTme program is clearly valuable as it has identified over 20,000 melanomas, 32,000 squamous cell carcinomas, and 129,000 basal cell carcinomas,1 but the data gathered from this program includes only patients who self-select to attend free screenings.



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E.C. Murphy, S. Kao, H. Wang, et al

Due to the limited number of survey responses for some races (Hispanic, Asian, mixed, and other races), race was compared dichotomously by white versus non-white (including Black, His-panic, Asian, and Mixed/Other) participants. A P-value of less than or equal to 0.05 was considered statistically significant.

We sought to examine the differences between the population who chooses to attend screenings and the general population by surveying pedestrians in a major city and attendees of a free skin cancer screening. By examining differences in demograph-ics, photoprotective practices, and skin cancer risk factors, this study highlights future directions needed for skin cancer pre-vention efforts.

METHODSAn IRB-approved survey was randomly administered at six loca-tions in Washington, DC (public group, n=285) and to attendees of a free skin cancer screening at George Washington Univer-sity School of Medicine and Health Sciences (screening group, n=144). The survey included eight questions on demographics (Table 1) as well as sun protective practices and risk factors for skin cancer (Table 2). Based on the Centers for Disease Control and Prevention (CDC) definition of sun-protective behaviors, the participants were asked about their sunscreen use, shade-seeking practices to avoid peak sun, and use of sun-protective clothing to cover up from sun exposure.3 Further, the survey as-sessed 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-sion 7.0 (GraphPad Software Inc.). Chi-square tests were used to compare answers between the public group and survey group. Additionally, survey answers from the public and screening groups were combined to compare answers by age and race.

TABLE 1.

Demographics of Survey Respondents in the Screening Group and Public Group

DemographicScreening Group

% of RespondentsPublic Group

% of Respondents

Gender

Female 69.8 64.5

Male 30.2 35.5

Age

<31 years 15.5 47.0

31 – 60 years 40.4 40.0

>60 years 44.1 13.0

Race

White 73.0 48.2

Black 13.9 28.7

Hispanic 7.3 5.7

Asian 2.9 12.4

Mixed/Other 2.9 5.0

TABLE 2.

Responses to Survey Questions Regarding Photoprotective Practices and Skin Cancer Risk Factors for the Screening (n=144) and Public (n=285) Groups

QuestionAnswer

% 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 17.3

2. Do you seek shade when possible?* Always Sometimes Rarely Never


Public Group 32.3 52.8 12.4 2.5

3. Do you wear sun-protective clothing?* Always Sometimes Rarely Never


Public Group 9.2 48.1 28.3 14.5

4. How many blistering sunburns did you have prior to age 20?

0 to 3 4 to 6 7 to 10 11 or more


Public Group 73.2 14.3 5.4 7.1

5. Approximately how many times over your lifetime have you used indoor tanning equipment?

0 1 to 10 11 to 20 21 or more


Public Group 79.9 14.5 1.4 2.1

*Indicates significant differences between the screening and public groups (P<0.05).



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not vary by race. Patients over 60 years old were more likely to always seek shade (53.2% for >60 years versus 24.0% for <31 years; P<0.0001) and wear sun-protective clothing (17.0% for >60 years versus 9.7% for <31 years; P=0.018) than those younger than 31 years (Figure 2). Sunscreen use did not vary by age. These age- and race-based relationships reinforce the need to target non-white and younger populations for sun safety educa-tion, who were less likely to attend our skin cancer screening.

Alternatively, white participants reported more blistering sun-burns than non-white participants (40.3% with ≥4 sunburns for white versus 12.0% with ≥4 sunburns for non-white; P<0.0001). Therefore, sun sensitivity in fair-skinned individuals may en-courage proper sun safety practices. White respondents also reported more indoor tanning uses (18.7% ≥5 uses for white versus 3.8% ≥5 uses for non-white; P<0.0001) than non-white respondents. The number of blistering sunburns and indoor tan-ning uses did not differ by age.

DISCUSSIONTogether, these data show that those who attend skin cancer screenings are more likely to wear sunscreen, seek shade, and wear sun-protective clothing than a randomly sampled popula-tion. These photoprotective behaviors defined by the CDC3 can reduce patients’ sun exposure and therefore, their risk of squa-mous cell carcinoma, basal cell carcinoma, and melanoma.6–8

For melanoma specifically, exposure to ultraviolet radiation accounts for more than 90% of the cases in the US.7,8 Indoor

RESULTSTable 1 presents the demographics for the screening group and public group. The gender distribution did not significantly differ between the two groups, although there was a larger percent-age of female participants in both groups (69.8% female for screening group, 64.5% female for public group). The screening group was older with 44.1% being over 60 years old compared to 13.0% of the public group (P<0.0001). A higher percentage of the screening group was white compared to the public group (73.0% white in screening group versus 48.2% white in public group; P<0.0001).

The survey responses for the screening and public groups re-garding sun safety practices and risk factors are presented in Table 2. More respondents from the screening group always wear sunscreen (P=0.001), always seeks shade (P=0.002), and always or sometimes wear sun-protective clothing (P=0.002) compared to the public group. Responses between the groups did not differ for the number of blistering sunburns prior to age 20 and the number of indoor tanning uses, suggesting equal risk for both groups.

Given the screening group was older and included more white participants than the public group, these demographic popula-tions may have superior photoprotective practices compared to younger and non-white populations, respectively. To examine this, we combined all the survey responses for the screening and public groups and compared the answers by white versus non-white participants and for three age groups (<31 years, 31-60 years, and >60 years). White participants were more likely to always or sometimes wear sunscreen (84.2% for white ver-sus 52.2% for non-white; P<0.0001) and sun-protective clothing (67.5% for white versus 55.4% for non-white; P=0.012) than 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).

FIGURE 2. Responses to survey questions for all participants (screening and public groups combined) regarding photoprotective practices, separated by age: <31 years (n=154), 31-60 years (n=165), and >60 (n=94). *Indicates significant differences between age groups (P<0.05).



652



tanning use was equal among the screening and public groups, meaning that all patients need to be educated on indoor tanning risks,4 especially fair-skinned individuals who reported higher use in this survey.

The screening group was older and included more individu-als with fair skin, highlighting the need to target younger and non-white populations for sun safety education. Despite the US Preventive Services Task Force (USPSTF) recommendation to target fair-skinned individuals for skin cancer prevention counsuling,9 survival from melanoma is significantly lower for non-white groups, making these critical populations to reach.10

Prior research has demonstrated that many individuals with darker skin types believe that they are not at risk for skin can-cer and that their dark skin provides more sun protection than lighter skin.11,12 Tailored sun safety education may be useful for individuals with dark skin to alter their perceptions that skin cancer is not a risk and to encourage good photoprotective practices among patients of all skin colors.11,13 In terms of age, while the incidence of melanoma increases with age,2 sunburns at an early age are associated with a later risk of melanoma.14

Therefore, encouraging sun safety in younger populations will decrease the risk of skin cancer for patients now and later in their lives.

That said, educating populations who seek skin cancer screen-ings is still important given 22% of our screening cohort reported rarely or never wearing sunscreen, underscoring this program’s value. However, a comprehensive skin cancer prevention program should offer more than total body skin ex-aminations. To prevent skin cancer though increased sunscreen use and reduced sunburns, the Community Preventative Servic-es Task Force recommends multicomponent, community-wide interventions, including school-based interventions.15–17 An ex-ample of such a program is Australia’s SunSmart skin cancer prevention program.18 This comprehensive campaign includes school- and workplace-based programs, practitioner education, media campaigns, and resource dissemination. From 1988 to 2003, SunSmart was estimated to prevent 9,000 new melanoma cases and 1,000 melanoma deaths in the state of Victoria. Fur-thermore, the program saved $2.30 for every $1 spent.18 Based on this program and the doubling of the incidence of melanoma in the US from 1982 to 2011, the CDC estimated that a compre-hensive skin cancer program could prevent 20% of melanoma cases and reduce spending on new melanomas by $2.7 billion from 2020 to 2030.2 A multicomponent, multiple-setting program in the US would likely reach broader demographic populations than skin cancer screenings alone.

Limitations of this study include a small sample size and pos-sible selection bias given the sampling for the public group was done near a university, which may include a more educated population. Thus, it is unknown whether our public group is

truly representative of the general public. In addition, the dichot-omous categorization of race (white versus non-white) could have overlooked other race-based mediators of sun-protective behaviors, such as differences in cultural practices. Future larger studies should delve further into race-based differences in pho-toprotective behaviors.

Despite these limitations, this survey-study highlights the need to tailor future skin cancer prevention programs to younger and non-white populations, who we are missing with free skin cancer screenings, which comprise the majority of our current efforts. A more comprehensive skin cancer prevention program could reach a more diverse population, with the goal of reduc-ing new skin cancers among all patient populations.

DISCLOSURESThe authors have no conflict of interest to declare.

REFERENCES1. Okhovat J-P, Beaulieu D, Tsao H, et al. The first 30 years of the American

Academy of Dermatology skin cancer screening program: 1985-2014. J Am Acad Dermatol. 2018;79(5):884-891. doi:10.1016/j.jaad.2018.05.1242

2. Guy GP, Thomas CC, Thompson T, et al. Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030. MMWR Morb Mortal Wkly Rep. 2015;64(21):591-596.

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.

4. Wehner MR, Shive ML, Chren M-M, Han J, Qureshi AA, Linos E. Indoor tan-ning and non-melanoma skin cancer: systematic review and meta-analysis. BMJ. 2012;345:e5909. doi:10.1136/bmj.e5909

5. Dennis LK, Vanbeek MJ, Beane Freeman LE, Smith BJ, Dawson DV, Cough-lin JA. Sunburns and risk of cutaneous melanoma: does age matter? A com-prehensive meta-analysis. Ann Epidemiol. 2008;18(8):614-627. doi:10.1016/j.annepidem.2008.04.006

6. Iannacone MR, Wang W, Stockwell HG, et al. Patterns and timing of sunlight 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

7. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med. 1999;340(17):1341-1348. doi:10.1056/NEJM199904293401707

8. Armstrong BK, Kricker A. How much melanoma is caused by sun exposure? Melanoma Res. 1993;3(6):395-401.

9. Behavioral Counseling to Prevent Skin Cancer: Recommendation Statement - U.S. Preventive Services Task Force - American Family Physician. https://www.aafp.org/afp/2012/1015/od3.html. Accessed October 15, 2018.

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. doi:10.1016/j.jaad.2016.06.006

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. doi:10.1111/pde.13433

12. Kim M, Boone SL, West DP, Rademaker AW, Liu D, Kundu RV. Perception of Skin Cancer Risk by Those With Ethnic Skin. Arch Dermatol. 2009;145(2):207-208. doi:10.1001/archdermatol.2008.566

13. Gloster HM, Neal K. Skin cancer in skin of color. J Am Acad Dermatol. 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-sure and risk of melanoma. Arch Dis Child. 2006;91(2):131-138. doi:10.1136/adc.2005.086918

15. Skin Cancer: Multicomponent Community-Wide Interventions. The Guide to Community Preventive Services (The Community Guide). https://www.thecommunityguide.org/findings/skin-cancer-multicomponent-community-wide-interventions. Published April 16, 2014. Accessed February 17, 2019.

16. Skin Cancer: Interventions in Outdoor Recreational and Tourism Settings. The Guide to Community Preventive Services (The Community Guide). https://www.thecommunityguide.org/findings/skin-cancer-interventions-outdoor-recreational-and-tourism-settings. Published October 14, 2016. Ac-



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cessed February 17, 2019.17. Skin Cancer: Primary and Middle School-Based Interventions. The Guide to

Community Preventive Services (The Community Guide). https://www.the-communityguide.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


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Managing Seborrheic Keratoses: Real World Experience Using a Novel Treatment Solution

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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 PateleaDivision 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 NetherlandscDSB Consulting LLC, Del Mar, CA

DDepartment of Dermatology, Boston University School of Medicine, Boston, MAEBiochemistry and Cell Biology, UC San Diego, Class of 2017, San Diego, CA

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 chal-lenges 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 im-petigo, 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 MRSA isolates. Ozenoxacin 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 of pathogens against 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.

ABSTRACT

INTRODUCTION

Impetigo is a highly contagious bacterial infection involv-ing the superficial skin, primarily due to S. aureus, less fre-quently S. pyogenes, or both. It occurs most frequently in

children ages two to six year but may affect younger and older children and adults as well. Self-inoculation and small family or communities outbreaks are common. There are more than 3 million cases of impetigo in the United States every year.1 Impetigo may be classified as a primary (direct bacterial inva-sion of an intact skin) or secondary infection of pre-existing skin disease or traumatized skin (atopic dermatitis, scabies, cuts, abrasions, insect bites, and chickenpox)2,3 Secondary impetigo is sometimes referred to as "impetiginization."

Two clinical forms of impetigo are recognized: (1) nonbullous and (2) bullous. The nonbullous type (also known as impetigo

contagiosa) is the most common and accounts for around 70% of cases and in the industrialized world is caused by mainly by S. aureus.2 However, S. pyogenes remains a common cause of nonbullous impetigo in developing nations. Clinically, nonbul-lous impetigo presents as erythematous pustules or vesicles (red sores) that quickly evolve into superficial erosions with a characteristic "honey-colored" crusts. Lesions usually in-volve the face, around the nose and mouth, but can be seen on extremities and trunk. The lesions are often smaller than 2 cm, not or minimally painful and without erythema or con-stitutional symptoms, although regional adenopathy may be present.1,2 More severe forms of impetigo may be associated with pruritus, erythema, crusted erosions, fissures, and odor. Bullous impetigo is less common, usually intertriginous areas, and is caused by strains of S. aureus that produce exfoliative



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L. Schachner, A. Andriessen, N. Bhatia, et al

cline, trimethoprim/ sulfamethoxazole, and macrolides (Table 2).3,7-10 Second line therapies comprise among others intrave-nous antibiotics and topical antiseptics, and third line therapies include systemic antibiotics, topical antibiotics, plus a treatment addressing S aureus to reduce nasal and pharyngeal coloniza-tion to prevent cross infection.3,7-10 In case of a suspected MRSA infection, oral antibiotics such as vancomycin, tetracycline, or linezolid are considered.7-10 For additional treatment and/or maintenance bleach baths with hypochlorites twice a week for 10 minutes may be used.7-10

Antibiotic and Antiseptic Resistance in Skin Infections The World Health Organization (WHO) recognizes antimicrobial resistance (AR) as a “rapidly evolving health issue extending far beyond the human health sector”. 11,12 Antimicrobial stew-ardship is critical to optimizing the use of antibiotics while preventing the development of resistance and improving pa-tient outcomes.11 Antimicrobial stewardship has been defined

toxin A, a toxin that causes cleavage of very superficial epider-mal layers by targeting the protein desmoglein.1 Lesions are usually large, transparent superficial flaccid bullae before rup-turing, leaving round erosions that become crusted often with erythematous plaques. Bullous impetigo occurs frequently in intertriginous areas and is exclusively caused by S. aureus which is often colonized from the nose.2 The skin infection does not penetrate below the epidermal-dermal junction and is to be distinguished from eg herpes simplex infections, Pseudomo-nas aeruginosa infections, scabies, thermal injury, and allergic contact dermatitis.2,4 Impetigo typically resolves within two to three weeks without scarring and complications.5 Complica-tions of non-bullous impetigo are rare but local and systemic spread of infection can occur that may result in cellulitis, lym-phangitis, or septicemia. Non-infectious complications of S. pyogenes infection include scarlet fever, guttate psoriasis, and post-streptococcal glomerulonephritis.5

Treatment options include topical antibiotics such as mupi-rocin, retapamulin or oral antibiotic therapy eg, amoxicillin/clavulanate, dicloxacillin, cephalexin, clindamycin, doxycycline, minocycline, trimethoprim/ sulfamethoxazole, and macrolides. There are increasing concerns about antibiotic and antiseptic resistance, especially those that are applied topically.6

METHODSThe target group of this review included dermatologists, pe-diatricians and general practitioners involved in impetigo treatment. To explore challenges in treating impetigo, particular-ly in a pediatric population, and to review the role of ozenoxacin 1% cream, we performed PubMed and Google Scholar searches of the English-language literature (2010-2018) using the terms impetigo, bullous impetigo, non-bullous impetigo, antimicrobi-al resistance, antibiotic resistance, mupirocin, retapamulin, and ozenoxacin. Relevant publications were manually reviewed for additional resources.

Therapeutic Options for ImpetigoBoth mild- to- moderate non-bullous and bullous types of impe-tigo typically resolve within two to three weeks without scarring and complications.5 Severe disease, however, can result in cel-lulitis, osteomyelitis, or septicemia.5

Therapeutics recommended in guidelines7-10 and from a meta-analysis have been updated9 regularly but did not change much since 2014.9,10 Cleansing and crust removal is a part of the treatment of impetigo.3, 7-10 Previously FDA-approved topical therapies included mupirocin and retapamulin.3,7-10 Other topical therapies for treating impetigo include bacitracin, polymyxin, erythromycin, neomycin, gentamycin, mupirocin, retapamu-lin, and more recently, ozenoxacin (Table 1).3,7-10 Oral treatment options for antibiotic therapy include amoxicillin/clavulanate, dicloxacillin, cephalexin, clindamycin, doxycycline, minocy-

TABLE 1.

Current Topical Antibiotics for Impetigo

Type of Treatment

Ozenoxacin 1% Cream28

Mupirocin 2% Ointment30

Retapamulin 1% Ointment29

Indication Impetigo due to S. aureus, including MRSA, or S. pyogenes in patients 2 months of age and older.

Impetigo due to S. aureus or S. pyogenes in patients 2 months of age and older.

S. aureus (methicillin-susceptible isolates only) or S. pyogenes in patients aged 9 months and older.

Frequency and period of application

Twice daily for 5 days

3 Times daily for 7-10 days

Twice daily for 5 days

Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes (S. pyogenes)

TABLE 2.

Current Oral Antibiotics for Impetigo

Extensive Infection: Oral Antibiotics

Not MRSA infection MRSA Infection

Dicloxacillin 250 mg 4 times daily for 1 week

Vancomycin +/- Rifampin 300 mg 3 times a day for 10 days

Cephalexin 250 mg 4 times daily for 1 week

Clindamycin 300 to 600 mg 4 times daily for 7 days

*Erythromycin 250 mg 4 times daily for 1 week

Trimethoprim-Sulfamethoxazole 160/800 mg twice daily for 7 days

Amoxicillin/Clavulanate 875 mg/125 mg PO BID for 7 days

Tetracycline 500 mg 4 times daily for 7 days

Telavancin

Linezolid

Daptomycin

Methicillin-resistant Staphylococcus aureus (MRSA)



657



medications. Therefore, these topical treatments are preferred for localized mild-to-moderate impetigo.3,7-10

Ozenoxacin Cream 1%: Efficacy and Safety Ozenoxacin (XepiTM, Cutanea Life Sciences) 1% cream is the only FDA approved non-fluorinated quinolone for the topical treat-ment of impetigo in adults and children 2 months or older.19,20

Ozenoxacin acts as a potent selective inhibitor of DNA replica-tion, blocking the bacterial DNA gyrase A and the topoisomerase IV enzymes, which are critical enzymes for the transcription and replication processes of bacterial DNA.21-23,24 The 1% cream has been shown to have potent bactericidal activity against Gram-positive pathogens associated with skin infections.19-23, 25 A multicenter, randomized, placebo-controlled, parallel, blinded study20 compared ozenoxacin 1% cream with its vehicle (place-bo) and retapamulin 1% ointment. In this trial, retapamulin was included as an internal validity control. Treatments were applied 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 included pediatric patients of 2 years of age and older had non-bullous (368 (79.3%) and bullous (96 (20.7%) impetigo. 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. The clinical success rate de-fined as clinical cure for ozenoxacin 1% cream was significantly superior to placebo (success rate 54 (34.8%) versus 30 (19.2%); P=0.003.20 Expanded criteria for clinical success including clini-cal cure and improvement were also assessed as a post hoc analysis. (Figure 1). Microbiological success after 3-4 days was 109 (70.8%) for ozenoxacin 1% cream and 58 (38.2%) for placebo and 122 (79.2%) for ozenoxacin 1% cream versus 86 (56.6%) for placebo after 6-7 days (Figure 2).20 Moreover, ozenoxacin 1% cream application resulted in a more rapid microbiological clearance than retapamulin.20

Rosen et al conducted a randomized clinical trial19 evaluating and comparing clinical efficacy and safety of ozenoxacin 1% cream and placebo in 139 adults and 272 children with non-bullous and bullous impetigo. Ozenoxacin 1% cream or placebo was applied twice daily for 5 days. Cure/clinical success was de-fined 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 af-fected areas necessary.19 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.

The clinical cure rate for ozenoxacin 1% cream at the 6-7 days assessment was significantly superior to placebo 112 (54.4%)

as “the optimal selection, dosage, and duration of antimicro-bial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance”.13

The authors of the current review noted that dermatologists are among the most frequent prescribers of topical antibiot-ics. Resistance patterns in a wide range of pathogens against oral or topical antibiotics and antiseptics used for the treatment of dermatological conditions, such as atopic dermatitis, acne, and impetigo have been observed.14-16 AR such as in methicil-lin-resistant Staphylococcus aureus (MRSA) is threatening to compromise the effectiveness of crucial medical treatments.12 S. aureus resistance against erythromycin and cloxacillin treatment has moved therapy towards first-generation cepha-losporins and/or topical antimicrobials.14-16 Moreover, there is an increase in resistance against clindamycin, its susceptibility decreased from 90% to 83%.17

Retapamulin is indicated for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes in patients aged 9 months or older.7-10

Topical mupirocin was frequently used for the treatment of impetigo and has been an important component in MRSA pre-vention, however; reports of increasing mupirocin resistance are of serious concern.14,16 A retrospective study evaluated 358 S. aureus isolates taken between May 2012 and September 2013, from 249 children who visited an outpatient dermatology clinic.18 At the time of the first culture, 19.3% had mupirocin-re-sistant S. aureus isolates, 22.1% of subjects presenting with an S. aureus infection had a mupirocin-resistant isolate and 31.3% of all collected S. aureus isolates showed resistance to mupi-rocin.18 Prior mupirocin impetigo treatment the children had received was strongly correlated (odds ratio [OR]26.5; P<0.001) with mupirocin resistance.18

A cross-sectional study of children and adults evaluated samples of those diagnosed with atopic dermatitis and S. aureus coloni-zation.6 A total of 91 subjects were included and 100 S. aureus isolates were analyzed.6 All strains were methicillin-susceptible S. aureus.6 The study showed a prevalence of mupirocin resis-tance of 5.9%, fusidic acid resistance of 1.1%, and high levels of neomycin and bacitracin resistance (42.6% and 100%, respec-tively).6 Fusidic acid resistance was found to be associated with more severe atopic dermatitis.6

Topical agents that are effective in treating skin infections caused by resistant strains are developed that may help to avoid resistance and adverse effects from the use of antibiotics. Moreover, topical formulations deliver treatment directly to the site of infection with low systemic absorption compared to oral



658



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.

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.

34.80%

85.20%

19.20%

73.70%

37.70%

83.10%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

Clinical Success (primary end point) Clinical Success with expanded criteria (post-hocanalysis)

Ozenoaxacin Placebo Retapamulin

n = 54

P=0.001

P=0.0276 P=0.085

P=0.003

n =30 n = 58 n = 132 n = 115 n = 128

FIGURE 2. Bacteriological response at day 3-4 and at day 6-7 (end of therapy). Eradication/microbiological success was defined as: The absence of the original pathogen(s) from visit 1 in specimen taken from the baseline affected area (with or without the presence 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; ozenoxacin vs retapamulin, P=1.0000.26

Figure 2: Bacteriological response at day 3-4 and at day 6-7 (end of therapy).

Eradication/microbiological success was defined as: The absence of the original

pathogen(s) from visit 1 in specimen taken from the baseline affected area (with

or without the presence 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;

ozenoxacin vs retapamulin, P=1.0000.26

70.80%

79.20%

38.20%

56.60%56.90%

81.70%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

Visit 2 (day 3-4) Visit 3 (day 6-7)

Ozenoxacin Placebo Retapamulin

P<0.0001

n = 109 n = 58 n = 87 n = 122 n = 86 n = 86



659



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. No additional antimicrobial therapy of the baseline affected areas necessary.19 For 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.

Fig 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. No additional antimicrobial therapy of

the baseline affected areas necessary.19 For 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.

54.4%

88.8%

38%

78%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Clinical Success (primary endpoint) Clinical Success with expanded criteria (secondaryendpoint)

Ozenoxacin Placebo

P < 0.001

P = 0.003

Clin

ical s

ucce

ss (%

)

n = 122 n = 78 n = 183 n = 161

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

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

87.20%92.00%

63.90%

73.10%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

Visit 2 (day 3-4) Visit 3 (day 6-7)

Ozenoxacin Placebo

P<0.002P<0.005

n = 109 n = 76 n = 115 n = 87



660



versus 78 (37.9%); P<0.001 (Figure 3). Expanded criteria for clini-cal success which included clinical cure and improvement were also assessed as a secondary outcome (Figure 3).19 Microbio-logical success after 3-4 days was 109 (87.2%) for ozenoxacin 1% cream and 76 (63.9%) for placebo (P<0.002) and 115 (92.0%) for ozenoxacin 1% cream versus 87 (73.1%) for placebo (P<0.005) after 6-7 days (Figure 4).19

Overall, the rate of selection of resistant mutants of ozenoxa-cin is lower than the observed with ciprofloxacin and similar or lower than the observed with levofloxacin in methicillin‐sen-sitive S. aureus (MSSA), methicillin‐sensitive S. epidermidis (MSSE) and MRSA organisms.23 Ozenoxacin has demonstrated efficacy versus S. aureus (including MRSA, Mupirocin-resistant Staph aureus, Ciprofloxacin resistant Staph aureus) and S. pyo-genes.19,20,23

Ozenoxacin demonstrated clinical and microbiological success in pediatric and adult subjects treated for impetigo.19,20 The faster microbiological success of the ozenoxacin 1% cream compared to retapamulin could lead to a more rapid resolution of infectiv-ity for the individual and their contacts.

The in vitro activity of ozenoxacin against Pseudomonas aeru-ginosa has been shown to be greater than that of nadifloxacin, clindamycin, erythromycin, and gentamicin, but less than that of ofloxacin and levofloxacin. However, the therapeutic efficacy of ozenoxacin against Pseudomonas aeruginosa has not been evaluated.24

Dermal application studies measuring ozenoxacin levels dem-onstrated negligible systemic absorption suggesting a safety advantage versus oral antibiotics.26 Moreover, ozenoxacin 1% cream offers a safe and effective alternative for existing topical therapies such as fusidic acid27 and mupirocin4 that have shown resistance patterns in a wide range of pathogens, used for the treatment of dermatological conditions such as impetigo.

CONCLUSIONSEmerging antimicrobial resistance is a growing concern in der-matology. Treatment decisions for impetigo should consider resistance pattern of S. aureus. Ozenoxacin 1% cream is a novel prescription medicine, FDA-approved for the topical treatment of impetigo in adults and children 2 months or older. Efficacy and safety of ozenoxacin cream 1% for the treatment of impeti-go has been demonstrated in two adequate and well-controlled Phase 3 trials. Ozenoxacin has demonstrated potent bactericidal activity and has shown to be active against MRSA isolates and has a low probability of selecting spontaneous resistant mu-tants in quinolone-susceptible or quinolone-resistant bacterial strains. Ozenoxacin 1% cream offers a lower dosing frequen-cy and shorter treatment regimen. Dermal application studies measuring ozenoxacin levels demonstrate negligible systemic

absorption suggesting a favorable safety profile.

DISCLOSURESThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by an unrestricted educational grant from Cutanea Life Sciences.

REFERENCES1. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048837.htm2. Bacterial Diseases. In: Bolognia J, Jorizzo JL, Schaffer JV, ed. Dermatology.

3rd ed. Elsevier Saunders; 2012:1187-1189.3. Simkin DJ, Grossberg AL, Cohen BA. Bullous impetigo rapid diagnostic and

therapeutic quiz: a model for assessing basic dermatology knowledge of primary care providers. Pediatr Dermatol. 2016 Nov;33(6):627-631.

4. Bowen AC, Mahé A, Hay RJ, Andrews RM, Steer AC, Tong SYC, et al. The global epidemiology of impetigo: a systematic review of the popula-tion prevalence of impetigo and pyoderma. Reid SD, editor. PLoS One. 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.

6. Bessa GR, Quinto VP, Machado DC, et al. Staphylococcus aureus resistance to topical antimicrobials in atopic dermatitis. Anais Brasileiros de Dermato-logia. 2016;91(5):604-610.

7. Stevens BL, Bisno AL, Chambers HF, et al. Practice guidelines for the diag-nosis and management of skin and soft skin infections; 2014 update by the 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. European J Gen Practice. 2014;20:294-300.

9. Lebwohl, Heymann WR, Berth-Jones J, et al. Treatment of Skin Disease: Comprehensive Therapeutic Strategies, 4th ed. Elsevier. 2014. 332-334.

10. Lebwohl MG, Heymann WR, Berth-Jones J, et al, Treatment of skin disease comprehensive therapeutic strategies 5th Edition Elsevier 2018 369-371.

11. Palmer GH, Call DR. Antimicrobial resistance: a global public health chal-lenge requiring a global One Health strategy [commentary]. Washington, DC: Institute of Medicine of the National Academies; 2013. http://www.iom.edu/Global/ Perspectives/2013/AntimicrobialResistance. Accessed Septem-ber 3, 2018.

12. Wernli D, Jørgensen PS, Harbarth S, et al. Antimicrobial resistance: The com-plex challenge of measurement to inform policy and the public. PLOS Med. 2017; (8):1-9. https://doi.org/10.1371/journal.pmed.1002378

13. Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc. 2011;86(11):1113-1123

14. Thum D, Seidl HP, Hein R, et al. Current resistance patterns of Staphylo-coccus aureus towards topical antibiotics and relevant antiseptics in pa-tients with atopic dermatitis and impetigo. J Dtsch Dermatol Ges. 2013 Sep;11(9):875-8. doi: 10.1111/ddg.12111.

15. Bangert S, Levy M, Hebert AA. Bacterial resistance and impetigo treatment trends: a review. Pediatr Dermatol. 2012;29(3):243–248.

16. Poovelikunnel T, Gethin G, Humphreys H. Mupirocin resistance: clinical impli-cations and potential alternatives for the eradication of MRSA. J Antimicrob Chemother. 2015; 70: 2681–2692

17. Sutter DE, Milburn E, Chukwuma U, et al. Changing susceptibility of Staphy-lococcus aureus in a US pediatric population. Pediatrics. 2016 April;137(4) e20153099; DOI: 10.1542/peds.2015-3099.

18. Antonov NK, Garzon MC, Morel KD, Whittier S, Planet PJ, Lauren CT. High prevalence of mupirocin resistance in Staphylococcus aureus iso-lates from a pediatric population. Antimicrobial Agents and Chemotherapy. 2015;59(6):3350-3356.

19. Rosen T, Albareda N, Rosenberg N, et al. Efficacy and safety of ozenoxacin cream for treatment of adult and pediatric patients with impetigo a random-ized clinical trial. JAMA Dermatol. 2018;154(7):806-813. doi:10.1001/jamader-matol.2018.1103

20. Gropper S, Albareda N, Chelius K, et al. Ozenoxacin 1% cream in the treat-ment of impetigo: a multicenter, randomized, placebo- and retapamulin-controlled clinical trial. Future Microbiol. 2014;9(9):1013-23. doi: 10.2217/fmb.14.78.

21. López Y, Tato M, Espinal P et al. In vitro activity of ozenoxacin against qui-nolone-susceptible and quinolone-resistant Gram-positive bacteria. Antimi-crob. Agents Chemother. 2013;57:6389–6392.

22. Sissi C., Palumbo M. In front of and behind the replication fork: bacterial type



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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.

27. Alsterholm M, Fytström I, Bergbrant JM, Faergemann J. Fusidic acid resis-tant S aureus in impetigo contagiosa and secondarily infected atopic derma-titis. 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.access-data.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

31. 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.


Anneke Andriessen PhDE-mail:................……....................................... [email protected]

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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, NCbDuke University Medical Center, Durham, NC

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.

ABSTRACT

INTRODUCTION

The treatment of plantar warts is challenging and current therapies often do not result in satisfactory clearance of verrucae.1 A large number of plantar warts, particularly

those that are large and hyperkeratotic, are recalcitrant to first-line treatments. For instance, cryotherapy and salicylic acid have not demonstrated superiority compared to a wait-and-see approach.2

Numerous therapeutic modalities have been utilized in the treatment of plantar warts, including topical cantharidin-podo-phyllotoxin-salicylic acid,3 topical trichloroacetic acid,4 topical 5% imiquimod,5 intralesional mumps, Candida, or Trichophyton antigen,6 and intralesional 5-fluorouracil.7 Cidofovir, a nucleo-tide analogue, is a potent inhibitor of viral DNA polymerase but is nephrotoxic when administered systemically.8 Local adminis-tration of this medication shows significant promise for treating HPV-related verrucous neoplasms. Treatment with intralesional cidofovir has demonstrated complete clearance of plantar warts in up to 98% of patients.9 Despite recent advances in therapeu-tic options for plantar warts, patients with symptomatic, large verrucous nodules and tumors remain a therapeutic challenge.

Ablative fractional lasers (AFLs) can be utilized to facilitate drug delivery beyond the stratum corneum and target lesions located within the deeper epidermis and dermis. This technique, known as laser-assisted drug delivery (LAD), has been utilized for various cutaneous applications in treating actinic keratoses,10

non-melanoma skin cancers,11,12 and hypertrophic scars.13 Sev-eral AFLs, including erbium:yttrium-aluminum-garnet (Er:YAG) and carbon dioxide (CO2), are emerging as new treatment

options for recalcitrant warts, with clearance rates reported be-tween 47% and 100%.14 For example, one study showed that treatment with Er:YAG followed by topical podophyllotoxin resulted in complete lesion clearance in 89% of patients with plantar warts.15 In this report, we describe two cases of refrac-tory plantar verrucae treated with Er:YAG and topical cidofovir.

CASE REPORTSPatient 1A 59-year-old male presented with an eight-year history of a gradually enlarging painful verrucous tumor on the right heel that made it difficult to wear closed footwear. A biopsy was consistent with verruca. This lesion had been previously treated with excision, salicylic acid, and cantharidin. He then received three treatments with pulsed dye laser and 40% urea cream; ini-tial improvement was noted, but the lesions exhibited recurrent growth within weeks. A trial of AFL-assisted delivery of topical cidofovir 75mg/mL was proposed. Pre-treatment examination demonstrated a 5.5 x 4 cm yellow hyperkeratotic verrucous tumor on the right posterior heel (Figure 1A). Treatment was ini-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 each laser treatment, 1 mL of cidofovir 75mg/mL was applied topically to the treated area and was covered with an occlusive transparent medical dressing for 1 hour (Figure 1B). Following nine serial treatments every two to six weeks, the lesion demon-strated approximately 60% decrease in tumor size with islands of complete clearance and markedly decreased hyperkeratosis; furthermore, the patient was able to resume wearing closed footwear (Figure 1C).



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M. Coates, J. Patel, C. Powers, C. Burton

Techniques such as paring down the verruca with a scalpel have been used to improve drug delivery.17 A new approach to in-creasing drug absorption beyond the stratum corneum is the use of AFLs. AFLs are able to create microthermal zones: mul-tiple 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-dofovir has shown promising clearance rates in multiple case studies.9,20,21 Local delivery of this antiviral via intralesional injec-tions has shown complete clearance in both immunocompetent and immunocompromised patients.9 Padilla et al. have reported 80% of patients demonstrating improvement with topical cido-fovir alone.21 We extended this therapeutic concept by utilizing an AFL to further enhance delivery of cidofovir to the target tis-sue. Our two patients with recalcitrant verruca treated with AFL and topical cidofovir demonstrated a modest to significant re-duction in lesion size and improvement in symptoms.

CONCLUSIONPlantar warts, particularly large, hyperkeratotic nodules and tu-mors, are challenging to treat effectively and most conventional treatments yield unsatisfactory results. The use of AFLs to cre-ate microthermal zones has been utilized in drug delivery for various dermatological applications. We described two cases of Er:YAG-assisted delivery of topical cidofovir for the treatment of 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.

DISCLOSURESThe authors declare no disclosures.

REFERENCES1. Vlahovic TC, Khan MT. The human papillomavirus and its role in plantar warts:

a comprehensive review of diagnosis and management. Clin Podiatr Med Surg. 2016;33(3):337-353.

2. Bruggink SC, Gussekloo J, Berger MY, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010;182(15):1624-1630.

3. Lopez Lopez D, Vilar Fernandez JM, Losa Iglesias ME, et al. Safety and ef-fectiveness of cantharidin-podophylotoxin-salicylic acid in the treatment of recalcitrant plantar warts. Dermatol Ther. 2016;29(4):269-273.

4. Pezeshkpoor F, Banihashemi M, Yazdanpanah MJ, Yousefzadeh H, Sharghi M, Hoseinzadeh H. Comparative study of topical 80% trichloroacetic acid with 35% trichloroacetic acid in the treatment of the common wart. J Drugs Dermatol. 2012;11(11):e66-69.

5. Stefanaki C, Lagogiani I, Kouris A, Kontochristopoulos G, Antoniou C, Kat-sarou A. Cryotherapy versus imiquimod 5% cream combined with a kerato-lytic lotion in cutaneous warts in children: A randomized study. J Dermatolog Treat. 2016;27(1):80-82.

6. Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: a single-blinded, randomized, and controlled trial. Arch Dermatol. 2005;141(5):589-594.

Patient 2A 44-year-old male presented with a two-year history of plantar warts on the right forefoot and right medial fourth toe associated with pain on ambulation. He had previously received treatment with liquid nitrogen every two weeks for six months without im-provement. He then underwent four treatments with a pulsed dye laser without any improvement in lesion size or symptoms. Pre-treatment examination demonstrated numerous verrucous papules coalescing into a plaque on the right plantar forefoot and a six mm verrucous papule on the right plantar fourth toe (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 the same protocol described above. After five treatments, the right forefoot demonstrated 80% clearance and the right fourth toe demonstrated 100% clearance (Figure 2B).

Both patients demonstrated a substantial decrease in the size of their verrucous lesions. Furthermore, there was a significant improvement in symptoms. There was mild localized erythema and edema following each treatment that resolved within 24 hours.

DISCUSSIONAFLs are a promising therapeutic option for difficult-to-treat cutaneous lesions, including plantar warts. Topical medications are often ineffective in treating these keratotic neoplasms in large part due to impaired drug delivery to deeper zones of viral replication.1 The stratum corneum serves as a physical barrier to environmental insults and exposures, including medications; absorption of topical medications is generally less than 5%.16

FIGURE 1. (A) Patient 1 pre-treatment. (B) Application of topical cidofovir after treatment with AFL. (C) Patient 1 after 9 treatments.

(A) (B) (C)

FIGURE 2. (A) Patient 2 pre-treatment. (B) Patient 2 after 5 treatments.

(A) (B)



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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 treat-ment 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 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 frac-tional CO2 laser: a randomized clinical trial. Br J Dermatol. 2012;166(6):1262-1269.

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 us-ing 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.

17. 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: a preliminary study. Lasers Surg Med. 2013;45(8):503-508.

19. Vora SB, Brothers AW, Englund JA. Renal toxicity in pediatric patients receiv-ing cidofovir for the treatment of adenovirus infection. J Pediatric Infect Dis Soc. 2017;6(4):399-402.

20. Gupta M, Bayliss SJ, Berk DR. Topical cidofovir for refractory verrucae in children. Pediatr Dermatol. 2013;30(1):131-134.

21. Padilla Espana L, Del Boz J, Fernandez Morano T, Arenas Villafranca J, de Troya Martin M. Topical cidofovir for plantar warts. Dermatol Ther. 2014;27(2):89-93.


Margaret Coates BAE-mail:................……......................... [email protected]

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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 StudyAzam 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, MDBGeorge Washington University School of Medicine and Health Sciences, Washington, DC

cGeorgetown University School of Medicine, Washington, DC dGeorge Washington Medical Faculty Associates, Washington, DC

Background: Collagen-based products have been implemented in wound healing due to collagen’s hemostatic properties, low antige-nicity, 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.Conclusion: These data suggest that collagen powder is non-inferior to 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.

ABSTRACT

INTRODUCTION

Collagen, an essential component of the extracellular matrix (ECM), is a triple helical structure composed of three polypeptide chains.1–3 During normal wound heal-

ing, collagen acts as a scaffold for cellular ingrowth and orga-nized deposition of new collagen.2,4 Proteases degrade native collagen, releasing polypeptide fragments that act as chemo-tactic molecules to recruit inflammatory mediators, promote keratinocyte migration, and stimulate the proliferation of fibro-blasts and subsequent collagen deposition.2,4,5 Collagen-based dressings and fractionated collagen powders have been devel-oped for wound therapy as they are thought to replace degrad-ed collagen by bypassing enzymatic breakdown.2,4,6 Further-more, powdered collagen supports ECM production and acts as a signaling molecule, recruiting inflammatory cells, fibroblasts, and keratinocytes.7,8 Collagen has low antigenicity and can be left in wounds without causing irritation or enhancing bacte-

rial growth.9,10 Additionally, collagen promotes thrombosis and hemostasis and has hydrophilic properties useful for absorb-ing fluid in exuding wounds.11,12 These factors make collagen an ideal wound therapy agent.

Punch biopsies are frequently performed for diagnostic purpos-es and are often closed primarily with non-absorbable sutures, but may also be left to heal by secondary intention. In a recent survey distributed by the present authors to providers on the Orlando Dermatology Aesthetic and Clinical Conference email-ing list, 877 (29.6% response rate) providers completed a survey in which only 5.13% of respondents indicated that they leave a 4mm punch biopsy wound open to heal by secondary intention (data not published). Most respondents were MD/DOs (98.6%), with many being in practice for more than 10 years (38.4%, data not published). While clearly commonly used, it is important



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A. Qureshi, E. Murphy, R. Milando, et al

Biopsy and TreatmentEach patient received a single 4 mm punch biopsy on the same level of each mid-anterior thigh to provide for internalized con-trols. One wound was managed with PC, while the other was treated with daily topical collagen powder for up to four weeks. Prior to each biopsy, the areas were cleansed with an alcohol swab and anesthetized using 1 mL of 2% lidocaine with epi-nephrine. An Integra Miltex 4.0 mm Standard Biopsy Punch instrument was used to create full-thickness wounds and pres-sure was applied with gauze until hemostasis.

Up to one gram of type 1, 100% bovine collagen powder (Nu-vagenTM, CPN Biosciences, Inc., Largo, FL) was placed on one wound before covering it with a non-adherent sterile dressing. The other wound underwent PC with two epidermal sutures (4-0 Ethilon Nylon Sutures, Ethicon, Somerville, NJ) and was similarly covered with a sterile dressing after application of petroleum jelly. At the four week follow-up, wounds were re-biopsied following the same procedures.

For home treatment, patients were provided with collagen powder in one-gram containers and dressings along with the following instructions: 1) Irrigate the wound with tap water or saline solution, 2) Dry the wound gently with dry gauze, 3) Ap-ply up to one gram of collagen powder to the wound, and 4) Apply a sterile dressing. This procedure was repeated daily for four weeks after the first biopsy and until wound closure after the second biopsy. For wounds closed primarily, patients were instructed to apply petroleum jelly before covering the wounds with sterile dressings once daily until suture removal (two weeks after placement).

to note that primary closure (PC) with non-absorbable sutures requires patients to return to clinic in 1-2 weeks for suture re-moval, which is associated with approximately $250,000 in direct and indirect costs per year based on findings from a sin-gle academic center.13 Furthermore, potential adverse effects of primary closure include skin allergies to suture materials and infections, with the suture serving as a nidus for infection by promoting microbial adherence and wound contamination.14–18

Mechanical irritation from the suture can also result in pruritus.

Given collagen powder can support ECM development at the wound site without increasing the risk of allergy or infection, management of biopsy wounds with collagen powder may lead to similar or improved healing outcomes compared to PC. Collagen powder also eliminates the need for suture removal, which reduces costs associated with a subsequent clinic visit. This pilot study is the first to compare the utility of topical col-lagen powder on the rate and quality of full-thickness wound healing compared to the gold standard, PC, through histopath-ological analysis of healing, and comparison of symptoms and early cosmetic outcomes.

METHODS

Patient SelectionApproval for this study (Clinical Trials Registration: NCT03481907) was obtained from the George Washington University Institu-tional Review Board (Protocol #121745). Eight healthy volunteers 18-75 years old were enrolled after providing informed consent. Inclusion and exclusion criteria are presented in Table 1.

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



669



are reported ± the standard error of the mean (SEM). P-values were calculated using the two-sample t-test for equal variances with P-values ≤ 0.05 considered significant.

RESULTSPatient PopulationAll eight subjects (mean age: 37, range: 23-59 years) completed the study. Two subjects were female and six were male. One subject was Fitzpatrick Skin Type (FST) I, three were FST II, one was FST III, two were FST III/IV, and one was FST V. All subjects reported no, occasional, or moderate alcohol consumption (1 drink per day for women, 2 drinks per day for men).

Process of Collagen Treatment Collagen powder was applied daily for four weeks after the first biopsy and for an average of 25.38±3.46 days after the second biopsy until subjective wound closure. In addition to application of pressure and collagen powder after the biopsy, one out of eight patients required hyfrecation for hemostasis, which did not impact the patient’s overall outcome. Three out of eight patients reported that the collagen powder treatment was “annoying” but no patients thought it was “difficult.” Overall, patients felt that treatment with collagen powder was more time intensive than PC, requiring careful placement of powder and dressings over the wounds to prevent spillage.

Wound ClosureWound size reduced by 28.95±5.09%, 55.76±6.29%, and 95.94±3.53% after 1, 2, and 4 weeks of collagen powder treat-ment following the initial biopsy, respectively (Figure 1). After the second biopsy, wound size reduced by 75.71±5.63% after 2 weeks (Figure 1). Interestingly, this reduction in wound size was significantly greater than the reduction 2 weeks after the first biopsy (P<0.04). Six out of eight collagen-treated sites were completely healed 4 weeks after the first biopsy, and all wounds were completely healed 8 weeks after the second biopsy. Com-parisons of collagen powder- and PC-treated wounds at each study visit are shown in Figure 1 for two representative patients.

HistopathologyHistopathology revealed a well-formed epidermis with some artefactual epidermal/dermal separation for collagen- and PC-treated wounds. However, collagen-treated wounds displayed less inflammatory granulation tissue, and more organized and well-formed collagen bundles on H&E (Figure 2A) and Mas-son trichrome staining (Figure 2B) compared to PC. Collagen staining intensity was significantly greater in collagen-treated wounds, with a mean staining intensity of 173.40+9.33 versus 125.8+7.31 for PC (Figure 3A; P<0.0001). CD31 staining (Figure 2C) revealed increased neoangiogenesis for collagen-treated wounds compared to PC-treated wounds (Figure 3B) (8.55±0.25 versus 4.10±0.17, respectively; P<0.0001).

Histopathology and Outcome AssessmentsImmunohistochemical and histopathological processing was performed by HistoWiz, Inc. (Brooklyn, NY) on one baseline sample and both four-week samples, including hematoxylin and eosin (H&E), CD31 (platelet-derived endothelial cell adhe-sion molecule-1), and Masson trichrome staining. H&E staining was used to examine the quality of the epidermis and colla-gen bundles as well as to observe the amount of inflammatory granulation tissue. CD31 antibody staining was performed to as-sess the level of angiogenesis. Staining identified to be artifact, related to large vessels, and outside the wound bed, was ex-cluded. Masson trichrome staining was used to assess collagen deposition. To determine the percent area stained by Masson trichrome, the number of pixels staining above a threshold in-tensity on images of histopathology slides was calculated using ImageJ 1.48v (National Institutes of Health, Bethesda, MD) and normalized to the total number of pixels. Forty high-power fields (HPF) were reviewed per treatment arm (5 per wound) to tabu-late CD31-positive cells.

Photographs of the wounds were taken at 0, 1, 2, 4, 6, and 12 weeks with a ruler in frame to allow ImageJ size calibration. Wound edges were traced and surface areas were calculated using ImageJ. Measurements were performed by two observ-ers and averaged.

Subjects rated itch at 1, 2, 4, 6, and 12 weeks using the Pru-ritus Numerical Rating Scale (PNRS), a validated and reliable instrument with scores ranging from 1-10 with higher num-bers indicating worse itch.19 Itch and pain improvement were also measured using the Patient Overall Assessment Scale, a scale developed for this study which ranges from 1-4 for each symptom with 1 = excellent improvement, 2 = moderate improvement, 3 = no change, and 4 = worsening. After suture re-moval at weeks 2 and 6, patients rated pain with suture removal on a scale from 0-10, with higher numbers indicating worse pain. Subjects also reported overall wound treatment prefer-ence and cosmetic preference at each visit. At the conclusion of the study, subjects were asked about their overall opinions of collagen powder treatment and whether the application process was “annoying” or “difficult.”

Using photographs, three faculty dermatologists blinded to treatment method reported their cosmetic preferences for each wound four weeks after the first biopsy and eight weeks after the second biopsy.

Statistical AnalysisStatistical analysis was performed with Microsoft Excel 2013 and GraphPad Prism, version 7.0. Pain, pruritus, and preference measures were analyzed using data from a single visit or data summed for several visits. Mean values of continuous variables



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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.

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.

(A) (B) (C)



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Pain and PruritusNo significant differences in pain and pruritus improvement or mean PNRS scores were noted between PC- and collagen-treat-ed sites at visit 2, visits 2-4 combined, or visits 5-6 combined (Table 2). Of note, six out of eight patients commented that re-ported itch was actually sensed in areas around the adhesive dressings rather than areas treated with collagen powder. Pain with suture removal was reported as an average of 1.06±0.29 out of 10 for all patients.

Cosmetic and Overall OutcomesPatients significantly preferred the cosmetic outcomes of wounds treated with collagen powder compared to PC, with 4.19±0.23 total cumulative responses preferring collagen pow-der and only 0.69±0.25 total cumulative responses favoring PC over the course of study (Table 2; P<0.001). Dermatologist evaluation of the cosmetic appearances of wounds also sup-ported 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 col-lagen powder itself. Three patients reported minor pain after the biopsies, and one patient felt the pain was worse with re-wounding at 4 weeks. No wound dehiscence or infection was noted at either of the treated sites in any subject.

DISCUSSIONResults of this internally-controlled pilot study demonstrate that acute full-thickness wounds treated with collagen powder heal at least as well as those treated with the standard of care, PC, and that collagen powder can be applied safely for at least four weeks. Furthermore, collagen powder treatment leads to

FIGURE 3. Quantification of collagen intensity and CD31+ vessels per HPF. (A) Mean collagen staining intensity was significantly greater in collagen-treated wounds (173.40+9.33) compared to PC-treated wounds (125.80+7.31). *P<0.0001. (B) CD31 staining revealed increased neoangiogenesis for collagen-treated wounds compared to wounds treated with PC based on HPF vessel counts (8.55±0.25 versus 4.10±0.17, respectively). *P<0.0001.

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.

Assessment Scale VisitsPrimary Closure

(N=8)Collagen Powder

(N=8)P-value

Pain Improvement POAS

2 1.50±0.27 1.38±0.18 0.71

2-4 4.50±0.65 4.25±0.53 0.77

5-6 4.00±0.69 3.63±0.73 0.72

Pruritus Improvement POAS

2 1.88±0.40 1.63±0.32 0.63

2-4 5.75±0.67 5.00±0.60 0.42

5-6 4.38±0.73 4.25±0.82 0.91

Pruritus PNRS

2 3.00±1.12 2.38±0.92 0.69

2-4 4.63±1.31 3.50±1.07 0.52

5-6 1.88±0.95 2.56±1.41 0.69

Overall Preference Votes2-4 1.44±0.48 1.56±0.48 0.86

2-6 1.88±0.69 3.13±0.69 0.22

Cosmetic Preference Votes2-4 0.69±0.25 2.19±0.23 <0.001

2-6 0.69±0.25 4.19±0.23 <0.001



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significantly improved early cosmetic outcomes eight weeks post-wounding.

Overall, patient-reported pain and itch were similar for colla-gen-treated and primarily closed wounds, with most patients reporting that the itching was due to the adhesive dressings rather than the wounds. Four weeks after the first biopsy, 75% of collagen-treated wounds were completely healed and wounds treated with collagen powder healed significantly faster after the second biopsy in comparison to the first biopsy. Although an untreated control is not available for comparison, the presence of collagen powder in the wound bed may have enabled faster healing after the second biopsy. Indeed, accelerated maturation was visualized histologically for collagen-treated wounds com-pared to primarily-closed wounds.

Histopathology also demonstrated that collagen treatment in-creased neoangiogenesis, which may create a stronger, more vascularized wound bed that enhances healing. In vitro stud-ies have shown that type I collagen increases endothelial cell proliferation and migration and that fragmented collagen may be more effective at doing so than its intact form.20–22 Collagen can also support the development of capillary-like structures in vitro, possibly due to its ability to suppress cyclic AMP and pro-tein kinase A, leading to the formation of necessary actin stress fibers.20,23 Clinical trials have also demonstrated that collagen can promote angiogenesis.24–26 Compared to untreated wounds, modified collagen gel treatment was shown to contribute to acute inflammatory cell and fibroblast recruitment, collagen I deposition, increased endothelial cells, upregulated vascular endothelial growth factor, and improved blood flow.24,25

Our results suggest that collagen powder may be used as an alternative to PC for 4mm punch biopsy wounds. Based on a cost analysis by Christenson et al, the average medical cost per suture placement and removal is $15.13, which amounts to an annual cost of $99,858 for all punch biopsies performed at an academic center.13 This includes both the suture costs as well as physicians’ and nurses’ time for placement and removal. Notably, this does not include the cost to procure, maintain, and sterilize instruments. Indirect costs to the patient, includ-ing transportation and sacrificed work time, adds an additional $145,332 to the annual cost of punch biopsies.13 Using collagen powder to manage punch biopsies instead of PC will save time for physicians and nurses and has the potential to increase net reimbursements to clinics. Practitioners can purchase 1 gram packages of collagen powder to assist with hemostasis and to demonstrate the application process to patients following the biopsy. In our study, hemostasis was achieved with pressure and collagen powder in 7 of 8 participants. Daily 1 gram doses of collagen powder can be ordered for patients for up to 30 days. Based on the 2019 published fee schedule, Medicare will reim-burse $35.66/gram of collagen powder, generally resulting in a

net reimbursement of $15-20/gram. Reimbursement rates from private insurances vary. Given its potential reimbursement, the use of collagen powder may be an inexpensive means to close a punch biopsy site.

Limitations of this study include a small sample size and lack of negative control group. Although underpowered, this pilot study provides foundational evidence that collagen powder can be an effective treatment for punch biopsies and supports fur-ther study with larger trials. We chose PC with sutures as our comparison given a recent survey performed in which only 5.13% of resident and practicing dermatologist respondents indicated preference for leaving a 4mm punch biopsy open to heal by secondary intention (data not published). Further, we had ethical concerns about excessively wounding patients, while only treating one out of three wounds with the standard of care. Previous work compared PC to secondary intention for 4mm punch biopsy wounds and found that physician-rated cos-metic appearances were similar for both treatments.13 Given our data conveying that collagen powder-treatment leads to signifi-cantly better early cosmetic outcomes than PC, we hypothesize that early cosmetic outcomes of collagen powder treatment are likely better than early outcomes from healing by secondary in-tention.

Future research elucidating the optimal duration of collagen therapy is needed, as less than four weeks may be sufficient. Shortened treatment courses would decrease the cost and ef-fort required by patients. Future studies should also investigate the efficacy of collagen powder in healing larger wounds and in comparison to healing by secondary intention.

CONCLUSIONThis is the first study to compare the use of collagen powder and PC to heal punch biopsy wounds in humans. Using an in-ternally-controlled design, results show that collagen powder is safe when applied daily for four weeks, confers healing ca-pability that is at a minimum non-inferior to PC, may enhance the strength and maturity of the healing wound/scar based on histopathology, and provides superior early cosmetic outcomes compared to PC. Future work should aim to ease the delivery of topical collagen powder while elucidating additional pa-rameters for administration including duration of therapy and candidate wound sizes.

DISCLOSURESThe authors have no relevant conflicts of interest to declare. CPN Biosciences, Inc. provided the support to carry out the study.

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2000;26(1):54-62. doi:10.1016/S0305-4179(99)00103-5.2. Fleck CA, Simman R. Modern collagen wound dressings: Function and

purpose. J Am Col Certif Wound Spec. 2010;2(3):50-54. doi:10.1016/j.



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26. Seandel M, Noack-Kunnmann K, Zhu D, Aimes RT, Quigley JP. Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen. Blood. 2001;97(8):2323-2332. http://www.ncbi.nlm.nih.gov/pubmed/11290594. Accessed November 27, 2018.


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acid on the proline, hydroxyproline, glycine, and collagen content of regener-ating guinea pig skin. J Biol Chem. 1957;226(1):289-300.

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 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 collagen fragments as revealed by atomic force microscopy and diffusion-ordered NMR spectroscopy. ChemPhysChem. 2012;13(13):3117-3125. 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 col-lagen, 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 en-hance 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 immuno-histochemical 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 sec-ond-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):431-434. http://www.ncbi.nlm.nih.gov/pubmed/539325. Accessed November 12, 2018.

16. Katz S, Izhar M, Mirelman D. Bacterial adherence to surgical sutures. A pos-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.

17. Chu CC, Williams DF. Effects of physical configuration and chemical struc-ture 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: prospec-tive 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.

21. Kirkpatrick CJ, Kampe M, Rixen H, Fischer EG, Ruchatz D, Mittermayer C. In vitro studies on the expansion of endothelial cell monolayers on compo-nents 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.

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24. Elgharably H, Ganesh K, Dickerson J, et al. A modified collagen gel dress-ing promotes angiogenesis in a preclinical swine model of chronic ischemic wounds. Wound Repair Regen. 2014. doi:10.1111/wrr.12229.

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

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

JDDPatient-focused Solutions in

Rosacea Management: Treatment Challenges in Special

Patient Groups

NOWAVAILABLE






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, CABUniversity of California, Irvine, Department of Dermatology, Irvine, CA

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.

ABSTRACT

INTRODUCTION

Injectable deoxycholic acid (DCA) is currently United States Federal Drug Association (FDA) indicated for treatment of moderate-to-severe submental fat (SMF), typically present-

ing as excessive inferior jawline fullness, or colloquially, “dou-ble chin.”1 Prior to the discovery and use of DCA, phosphatidyl-choline (PC), a naturally occurring phospholipid that emulsifies fat, was used as a lipolytic agent to prevent or treat venous fat embolism. Eventually, its use evolved to include local reduction of adipose tissue for aesthetic purposes.

DCA is the lipolytic component of human bile acid that disrupts adipocyte cell membranes, which results in cell death while sparing protein-rich skin and muscle tissue remains unaffect-ed.2 Necrosis following lipolysis reduces adipocyte size through inflammatory, cell-mediated fibroblast activation and collagen deposition, while simultaneously strengthening structural in-tegrity of underlying tissue.3 Histologically, inflammation is localized to the pannus. Several preclinical and clinical studies have established a favorable safety profile for injectable DCA and efficacy for SMF reduction.1 This manuscript will system-atically review and discuss pertinent findings from all available literature regarding off-label injectable DCA application for li-polysis in non-submental regions of the body.

MATERIALS AND METHODSLiterature SearchThis systematic review was done in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).4 A primary literature search was conducted using PubMed, Cochrane, Web of Science and CINAHL. Two authors (CS/FC) independently screened the above-mentioned databas-es using the search term, “ATX-101 OR Kybella OR deoxycholic OR deoxycholate NOT amphotericin NOT bile,” utilizing Medi-cal Subject Headings (MeSH®) controlled vocabulary and text words. Systematic literature search was conducted on Novem-ber 26, 2018.

Study Selection and AppraisalTwo reviewers (CS/FC) independently screened all article titles and abstracts to include clinical trials, cohort studies, case-con-trol studies, case series, cross-sectional studies, or case reports, written in English, on off-label use of deoxycholic acid or deoxy-cholate in human subjects apart from its approved indication of submental fat reduction. Animal studies and articles not avail-able in English were excluded. There were no date exclusions applied to this search. Subsequently identified studies were subjected to full-text review. Authors were contacted for miss-ing data. Bias risk and methodological quality were assessed



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C.T. Sung, A. Lee, F. Choi, M. Juhasz , N. A. Mesinkovska

enced improvement of bra line adiposity and decreased skin thickness.10,11 The first case series described two middle-aged fe-male patients receiving injectable DCA (10mg/ml). One patient received bilateral 2ml (4ml total) injections in the upper back, just above the horizontal bra line, while the other patient re-ceived bilateral 1ml (2ml total) injections lateral to both breasts at the axillary tail of Spence. Injections were given in 0.15ml volumes spaced 0.5-1.0cm apart in each treatment area. Both patients required only one treatment session and reported high satisfaction with the gradual reduction of fat bulging based on patient-reported visual self-assessment over a three to nine-month period.

The second case series included five patients treated with DCA injections, over a 12-week period, for persistent posterior-supe-rior bra line liposis.11 Each patient received a total dose of 2mg/cm2 bilaterally in 0.2ml injection intervals every four weeks and patients experienced an average 5.2mm reduction in skin pinch thickness of the posterior back and 17-percent reduction in their posterior bra-bulge, similar to Jegasothy’s experience.

Gluteotrochanteric/Trochanteric Region Two larger-scale studies (n=63) reported on the use of DCA-containing injections for aesthetic reduction of the gluteo-trochanteric regions.12 One controlled study (n=26) using 10ml 5% PC/4.3% DCA/ethanol subcutaneous injections into the right posterior trochanteric area twice, three weeks apart. Reduction of adipose tissue was evaluated by ultrasound and an optical device (Lipometer®; Moeller Messtechnik, Graz, Styria, Austria) at baseline, 8 weeks, and 20 weeks, and photography at baseline and 20 weeks. At week 20, there was no statistically significant difference between the right and left areas using Lipometer, ul-trasound nor qualitative photographic. No patients evaluated the procedure positively, and only two patients (7.7%) opted to receive contralateral injections.

according to the Cochrane Handbook for Systematic Reviews 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 exclud-ed studies were reviewed for potential studies not identified through initial search strategy.

Data Extraction and AnalysisIncluded studies were summarized using a data extraction form. Studies were graded using the Oxford Center for Evidence-Based Medicine 2011 Levels of Evidence.5

RESULTSInitially, 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 flow diagram (Figure 1).4 Results of included studies are sum-marized in Table 1.

FaceTwo case reports described single-patient experiences with in-jectable PC/DCA in the jowl and lower face, in conjunction with hyaluronic acid (HA) and botulinum toxin type A (BTX-A), as an alternative to surgery.6,7 In one case, a young Asian woman desired non-operative lower facial contouring and underwent 11 injection-only treatments over a 26-month period with PC/DCA lipolysis of the lower jowl, face, and chin, HA augmenta-tion of the chin, cheek, and nose, and BTX-A contouring of the 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-tial treatment. Her non-operative transformation produced the desired heart-shaped face by slimming the lower cheeks and improving jawline definition.

The second case reported a one-stage, combination jowl rejuve-nation procedure in a middle-aged female with BTX-A, HA, and DCA injections to the depressor anguli oris, marionette lines, and the subcutaneous-fat-rich jowl area, respectively.7 Results of the Face-Q, a validated patient-reported outcome instrument, completed 3-months post-treatment indicated significant im-provement in facial appearance from baseline (84.5% vs 44%), and an independent standardized wrinkle assessment scale (WAS) assessment (0=no wrinkle, 5=very deep wrinkle) per-formed by five independent plastic surgeons were consistent, with an average of 2-point improvement from baseline.8,9

Brassiere Line Two case series (n=7) explored off-label use of DCA injections to the brassiere (bra) line using one to three treatments per site. Six patients received injections to the posterior bra line, and one patient received anterior injections. All seven patients experi-

FIGURE 1. PRISMA flow diagram summarizing literature search.

FIGURES Figure 1: PRISMA flow diagram summarizing literature search.



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TABLE 1.

Summary of Included Studies

Authors; Year

Study Type (Level of Evidence)

Off-label Use Subjects Intervention Outcomes Adverse Events

Face

Wong et al. 20186

Case report (LOE 5)

Lower face and jaw remodeling

20-year-oldhealthyAsianfemale

Eleven treatments using (1) botulinum toxin, (2) HA, and (3) PC/DCA (50mg/ml PC, 42mg/ml DCA).

A total of four PC/DCA treatments were given at: - 10 weeks (750mg)- 5 months (875mg)- 9 months (937.5mg)- 22.5 months (593mg)- 3155.5mg PCA/DCA total.

Aesthetic enhance-ment of face shape, jaw contour, and jowl definition. Patient was satisfied with cosmetic result.

None reported.

Mess 20177 Case report (LOE 5)

Marionette lines and jowls

55-year-oldfemale

Sequential treatment using (1) botulinum toxin, (2) HA, (3) DCA.

Satisfaction with facial appearance at 3 months: 84.5% compared to 44% at baseline (FaceQ).

Self-limited injection-site bruising and edema.

Brassiere Line

Jegasothy 201810

Case series (LOE 4)

Bra-line lipolysis

Case A: 46-year-oldhealthyCaucasianfemaleCase B:47-year-oldhealthyEast Indianfemale

1 injection of Kybella treatment seated upright: - Case A: 2 ml (20mg) DCAon each side (upper back)- Case B: 1 ml (10mg) DCAon each side (lateral breasts).

Both subjects reported gradual bra line fat decrease beginning at 1 month and continuing until 3- and 9-months post-treatment, respectively; no re-accumulation of fat in treated areas.

Self-limited injection site edema, tender-ness, and itching; resolved within 7 days.

Verma et al. 201811

Case series (LOE 4)

Bra-line lipolysis

5 healthy females

20 mg DCA every 4 weeks. Average 5.2 mm re-duction (4-9 mm) in skin pinch thickness and 17% (10-24%) reduction in poste-rior bra-bulge from baseline.

Self-resolving injection site pain, swelling/edema, and bruising.

Gluteotrochanteric/Trochanteric Region

Salti et al. 200713

Double-blind random-ized trial (LOE 2)

Gynoid lipodystrophy

37 healthy females

Treatments randomized per side: - One side: 50/25mg/ml PC/NaDC(1000/500mg total)- Other side: 47.5mg/ml NaDC(475mg total)

Given 4 treatments per side, every 8 weeks.

Overall reduction of local fat in 91.9% of patients without sig-nificant differences between the treated sides.

Self-resolving pain, bruising, and palpable subcutaneous nodule with both treatments; pain and bruising were more intense with NaDC.

Systemic cholinergic effects: dizziness/lightheadedness (n=2, 5.4%), nausea/malaise (n=4, 10.6%), and diar-rhea/steatorrhea (n=6, 16.2%) of unknown etiology; resolved within 24 hours.



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TABLE 1. (CONTINUED)

Summary of Included Studies

Authors; Year

Study Type (Level of Evidence)

Off-label Use

Subjects Intervention Outcomes Adverse Events

Gluteotrochanteric/Trochanteric Region

Kopera 200712

Cohort study (LOE 3)

Trochanteric bulges

26 healthy females

3 treatments with 10ml of 5%PC/4.3%NaDC/ethanol to the right posterior trochanteric region.

No significant de-crease in trochan-teric bulge between sides. Zero patients evaluated treatment positively.

Not reported.

Feet

Turkmani 201814

Case report (LOE 5)

Piezogenic pedal pap-ules

34-year-oldobese (121kg) womanwith in-tense heelpain for 10months

0.05ml to 0.1ml of 1% DCA. Nodules completely disappeared after 2 weeks; no more pain with walking or standing.

None reported.

Paradoxical Adipose Hyperplasia

Ward et al. 201815

Case report (LOE 5)

Paradoxi-cal adipose hyperplasia secondary to cryolipol-ysis at lower abdomen

58-year-oldhealthyCaucasianfemale

4 ml 1% DCA 3 times: - Initial: 1.7ml (left), 2.3ml (right)- Remaining: 2ml per side.

Waist circumference decreased from 30.5 inches to 29.5 inches after 3 treatments.

Self-resolving erythema, swelling, and mild tenderness around the injection site within 2-3 days.

Highly Active Antiretroviral Therapy (HAART)-Associated Lipodystrophy of the Buccal Fat Pad

Rotunda et al. 201116

Case report (LOE 5)

HIV/HAART-related lipohyper-trophy

48-year-oldHIV-posi-tive maleon HAARTwith bilat-eral buccallipoma-likegrowthsoverprevious 2years

1 ml 1% NaDC and 0.25 ml 2% lidocaine; given 3 times.

Both lesions de-creased in size and became asymptom-atic.

Not reported.

Lipoma

Rotunda et al. 200517

Cohort study (LOE 3)

Lipoma 6 patients; 12 lipomas

1%, 2.5% or 5% NaDC at intervals of 2-20 weeks.

Injection volumes (ml) equaled half the largest lipoma dimensions.

All lipomas de-creased in size (mean area reduction 75% [37-100%]) after an average of 2.2 treatments. Several lipomas fragmented or became softer in addition to decreas-ing in volume.

2 and 5% DCA associ-ated with burning and prolonged swelling; took up to 6 weeks to resolve. Two patients experi-enced injection-site cutaneous paresthesia with 5% DCA; took up to 6 weeks to resolve.



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A double-blind, self-controlled, randomized study (n=37 females) investigated the use of PC/DCA (50/25mg/ml) versus DCA alone (47.5mg/ml) in patients with localized gynoid lipodystrophy. Four treatments were administered to the gluteotrochanteric region every eight weeks to allow for post-infiltrative nodular resolu-tion.13 Each patient received 1000/500mg of PC/DCA on one side and 475mg DCA alone on the contralateral side. After both solu-tions were diluted in saline, a total of 80 infiltrations (40ml) per side were administered over 1cm intervals during each treat-ment. Outcome was assessed using thigh circumference at the level of the sub-gluteal fold, ultrasonographic measurement of trochanteric fat pad thickness, and photographs at baseline and eight weeks after the last treatment. Thirty-four patients (91.9%) achieved reduction in thigh circumference and trochanteric fat pad thickness without significant difference bilaterally; three pa-tients (8.1%) were non-responders.13

Feet One case report described treatment of symptomatic piezogenic pedal papules (pressure-induced papules) on the foot and heel in a 34-year-old obese woman using 0.05-0.1ml (based on pap-ule size) of 1% DCA solution. The patient achieved complete resolution of papules and bilateral heel pain in two weeks.14

Treatment of Paradoxical Adipose Hyperplasia One 58-year-old Caucasian female was treated with injectable DCA (10mg/ml) for abdominal paradoxical adipose hyperplasia (PAH) after two prior cryolipolysis treatments.15 A total of three, 4ml treatments were given at 0, 6, and 16 weeks resulting in gradual reduction of lower abdominal fullness. Positive results were maintained five months after the third treatment despite no change in caloric intake or expenditure. The patient was highly satisfied decreased waist circumference from 30.5 to 29.5 inches.

Treatment of HIV-Associated Lipodystrophy of the Buccal Fat Pad One case of highly active antiretroviral therapy (HAART)-asso-ciated buccal fat pad lipodystrophy in a 48-year old male was treated with three bilateral injections of DCA at baseline, 14 days and 24 days.16 Each 4cm mass was treated with four intralesion-al injections of 1ml 1% DCA. Clinical reduction and magnetic resonance imaging (MRI) assessment three-months after initial treatment confirmed a decrease in maximum buccal fat pad depth from 12-14 to 10mm. At six months, the lesions measured ap-proximately 1cm and regrowth to 1.5cm after one year, and they were reinjected with 1ml of 1% DCA with no further follow-up.

Treatment of Lipoma A small prospective study (n=6) detailed the use of isolated DCA in the treatment of 12 lipomas, ranging from 1cm to 3.5cm in largest dimension, at intervals of 2 to 20 weeks. Patients were injected with DCA at concentrations of 10, 25, or 50mg/ml at volumes equaling half the largest lipoma dimension in centi-meters until satisfactory tumor reduction was achieved (one to

four treatments). All lipomatous tumors decreased in size with a mean area reduction of 75% (37-100%) after an average 2.2 treat-ments, while some tumors fragmented and/or became softer after injection. Most importantly, change in lipoma size did not correlate with DCA concentration as patients treated with the lowest dose achieved similar clinical response to those receiv-ing higher doses.17

DISCUSSIONMinimally invasive cosmetic procedures continue to gain pop-ularity over time, evidenced by a 186% increase in national utilization between 2000 and 2017 (versus a six-percent drop in cosmetic surgical procedures over the same period).18 Injectable DCA is among several minimally invasive cosmetic procedures popularized by social media, alongside botulinum toxin injec-tions and soft tissue fillers, which prompts further investigation into safety and efficacy as popular interest and indications continue to expand. Cosmetic and medical outcomes of DCA lipolysis injections achieved desirable results according to pa-tients and providers. The overall high patient satisfaction and minimal side effects associated with non-submental DCA injec-tions mirrors the level of success associated with submental DCA injections and further highlights the potential of less-inva-sive alternatives to aggressive surgical treatments for adipose tissue removal. For example, combination therapies using in-jectable DCA in conjunction with HA and BTX-A for lower face contouring may spare future patients from undergoing genio-plasty or mandibuloplasty.19,20 DCA injections of the jowls and lower face provides an alternative to traditional rhytidectomy or facelift for facial rejuvenation.21 Notably, patient and physi-cian/evaluator-reported assessments of aesthetic outcomes were concordant in studies on the face, brassiere line, feet, PAH, lipodystrophy and lipomas reported in this article. Future studies may be strengthened by incorporating more patients, utilizing standardized treatments, and using validated tools to measure treatment outcomes, such as the Face-Q or Body-Q, or quantitative measurements with high-resolution ultrasound or MRI.8,22 Although DCA injection has unanimously demonstrated superior efficacy in smaller anatomic areas, conflicting evidence reported for DCA injections in reducing gluteotrochanteric and trochanteric fat suggests the need for further research on the efficacy of DCA on larger anatomic areas.12,13

Side effects associated with injectable DCA ranged from no side effects, as seen in treatment of piezogenic pedal pap-ules, to systemic side effects (nausea, dizziness, and diarrhea) potentially associated with large-volume gluteotrochanteric DCA injections.13,14 High-volume DCA injections may have sev-eral volume-related local effects not seen with smaller-volume DCA injections may cause compression of local structures or increased hydrostatic pressure at the injection site. On a simi-lar note, patients experienced less pain and inflammatory response, without a significant difference in fat reduction using



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REFERENCES1. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, random-

ized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an inject-able drug for submental fat reduction. Dermatol Surg. 2016;42(1):38-49.

2. Rotunda AM, Suzuki H, Moy RL, Kolodney MS. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formu-lation used for localized fat dissolution. Dermatol Surg. 2004;30(7):1001-1008.

3. Young VL. Lipostabil: the effect of phosphatidylcholine on subcutaneous fat. Aesthet Surg J. 2003;23(5):413-417.

4. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.

5. Howick J, Chalmers I, Glasziou P, et al. The Oxford 2011 Levels of Evidence. In:2011.

6. Wong GR, Chen WP. Phosphatidylcholine/deoxycholate lipolysis and hyal-uronic acid augmentation to enhance nonsurgical lower facial contouring us-ing botulinum toxin type A. J Cosmet Dermatol. 2011;10(2):159-162.

7. Mess SA. Lower Face Rejuvenation with Injections: Botox, Juvederm, and Kybella for Marionette Lines and Jowls. Plast Reconstr Surg Glob Open. 2017;5(11):e1551.

8. Kappos EA, Temp M, Schaefer DJ, Haug M, Kalbermatten DF, Toth BA. Vali-dating Facial Aesthetic Surgery Results with the FACE-Q. Plast Reconstr Surg. 2017;139(4):839-845.

9. Buchner L, Vamvakias G, Rom D. Validation of a photonumeric wrinkle as-sessment scale for assessing nasolabial fold wrinkles. Plast Reconstr Surg. 2010;126(2):596-601.

10. Jegasothy SM. Deoxycholic acid injections for bra-line lipolysis. Dermatol Surg. 2018;44(5):757-760.

11. Verma KD, Somenek MT. Deoxycholic acid injection as an effective treatment for reduction of posterior upper torso brassiere strap adiposity. Plast Recon-str Surg. 2018;141(1):200e-202e.

12. Kopera D, Horejsi R, Werner S, Moeller R. Injection lipolysis for reduction of saddlebag trochanteric bulges--half-side controlled pilot study. J Dtsch Der-matol Ges. 2008;6(4):287-290.

13. Salti G, Ghersetich I, Tantussi F, Bovani B, Lotti T. Phosphatidylcholine and so-dium deoxycholate in the treatment of localized fat: a double-blind, random-ized study. Dermatol Surg. 2008;34(1):60-66; discussion 66.

14. Turkmani MG. Piezogenic pedal papules treated successfully with deoxycho-lic acid injection. JAAD Case Rep. 2018;4(6):582-583.

15. Ward CE, Li JY, Friedman PM. ATX-101 (deoxycholic acid injection) for para-doxical adipose hyperplasia secondary to cryolipolysis. Dermatol Surg. 2018;44(5):752-754.

16. Rotunda AM, Jones DH. Human immunodeficiency virus-associated lipohy-pertrophy (buccal fat pad lipoma-like lesions) reduced with subcutaneously injected sodium deoxycholate. Dermatol Surg. 2010;36(8):1348-1354.

17. Rotunda AM, Ablon G, Kolodney MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol. 2005;53(6):973-978.

18. American Society of Plastic Surgeons National Clearinghouse of Plastic Sur-gery Procedural Statistics. Published 2017. Accessed January 7, 2019.

19. Kantor J. Synergistic effect of combination deoxycholic acid and botulinum toxin (the Bellatox technique) for the treatment of submental fullness. J Am Acad Dermatol. 2017;76(6):e209-e211.

20. Lee J, Lee S. Facial contouring surgery-mandibuloplasty: genioplasty and mandible angle correction. Plast Reconstr Surg Glob Open. 2017;5(10):e1296.

21. Derby BM, Codner MA. Evidence-Based Medicine: Face Lift. Plast Reconstr Surg. 2017;139(1):151e-167e.

22. Poulsen L, McEvenue G, Klassen A, Hoogbergen M, Sorensen JA, Pusic A. Pa-tient-reported outcome measures: BODY-Q. Clin Plast Surg. 2019;46(1):15-24.

23. Walker PS, Monheit GD, Smith SR, et al. Multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the safety and efficacy of ATX-101 (sodium deoxycholate for injection) intralipomal injections for the treatment of superficial lipomas. In:2015.

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.

25. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as car-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 orphan nuclear receptor. Science. 1999;284(5418):1365-1368.

a combination PC/DCA.13 This therapy may be utilized in areas that experience friction and pressure from functional move-ments, such as the brassiere line.11 Higher concentrations of DCA does not equate to greater clinical fat reduction according to Rotunda et al.’s study which achieved statistically compara-ble efficacy in terms of lipoma reduction even when using the lowest 1% DCA concentration.17 This phenomenon is further supported by findings from Walker et al.’s recent clinical trial.23 Further work remains to determine different effects of DCA in neoplastic versus native fat cells and ideal dosing for minimiz-ing side effects in different anatomic areas.

Economic burden associated with DCA injections was found to be a major factor of consideration for patients according to a pooled analysis of four clinical trials of injectable DCA. Patel and Kridel estimated that clinical trial patients receiving injectable DCA incurred an average $6,426 in expenses (186mg of drug per patient), compared to $2,976 as the average cost incurred by pa-tients for liposuction. However, these values may not accurately reflect the charges incurred in clinical practice, as the amount of DCA required can vary drastically based on treated anatomi-cal location. Evaluation of the average number of injections per patient in clinical practice, in addition to characterizing primary payor, is needed to determine the true economic burden of each procedure in the clinical setting.24

Off-label use of injectable DCA is not limited to aesthetic pur-poses as injectable DCA treats painful piezogenic pedal papules, lipomas, and HAART-associated-lipodystrophy.14,16 Given DCA’s potential to cause DNA damage through production of reactive oxygen species and modulation of interactions between steroid ligands and their receptors, DCA may possess anti-tumor prop-erties warranting further translational research for treatment of malignant fatty tissue.25,26 Despite promising results, the limited literature and number of patients who have undergone non-sub-mental DCA injections should prompt further experimentation of new anatomical applications, indications, and dosages, in ad-dition to establishing safety profiles.

CONCLUSIONMost non-submental applications of injectable DCA appear to demonstrate a similar safety profile, efficacy, and patient sat-isfaction comparable to FDA-approved use for persistent SMF. Current experiences of off-label DCA injection demonstrate favorable cosmetic results and may be a viable alternative to sur-gical adipose tissue removal, cryolipolysis in PAH-prone patients or patients that cannot receive cryolipolysis, or other non-inva-sive methods of lipolysis. Larger-scale studies are warranted to explore further cosmetic and potential medical applications. DISCLOSURESThe authors have no conflicts of interest to disclose.The authors received no financial funding for this research.


Calvin T. Sung MD E-mail:................……........................ [email protected]



Atopic Dermatitis: A Review of Topical Treatment

An overview of recent advances in AD, specifically topical corticosteroids, which remain a fundamental component of treatment algorithms

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

A SUPPLEMENT TO

JDDAtopic Dermatitis:

A Review of Topical Treatment

STILLAVAILABLE






SPECIAL TOPIC

Effective and Safe Repeated Full-Face Treatments With AbobotulinumtoxinA, Hyaluronic Acid Filler,

and Skin Boosting Hyaluronic AcidPer 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

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, and RSB was 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 indications was well tolerated. 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.

ABSTRACT

INTRODUCTION

Aesthetic treatment with either botulinum toxin type A (BoNT-A) or hyaluronic acid (HA) filler(s) is generally more common than combination treatment1-4; approxi-

mately one-third of patients receive a combination of injectable treatments.5

Upper facial aesthetic indications of BoNT-A include glabel-lar lines, lateral canthal lines, and horizontal forehead lines.6-10 The marketing authorization for abobotulinumtoxinA (ABO) includes treatment of hyperfunctional facial lines in Brazil and moderate-to-severe glabellar lines and lateral canthal lines in many European countries including France and Sweden.

HA fillers are most commonly used for aesthetic soft-tissue augmentation of the mid and lower face.11-16 Restylane® Skin-boosters (RSB [Galderma Aesthetics, Sweden])17-19 are used for skin rejuvenation and improved skin quality.

The objective of this study was to collect data on subjects re-ceiving monotherapy with either ABO or HA filler followed by repeated combination treatment with ABO, HA filler, and RSB to provide guidance to practitioners for individual treatment plans. BoNT-A in up to three upper facial indications has not previously been studied in combination with HA filler and RSB.

METHODSStudy DesignThis was an 18-month study conducted at four sites in Sweden, France, and Brazil (Figure 1). ABO cohort data up to 6 months have been published.20 The study protocol was approved by in-dependent Ethics Committees and conformed to the Declaration of Helsinki, Good Clinical Practice, and local regulations.

Eligibility CriteriaSubjects between 35 and 50 years who provided signed in-



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P. Hedén, D. Hexsel, H. Cartier, et al

Aesthetics, Sweden). OBT fillers were Restylane Refyne and/or Restylane Defyne; NASHA fillers were Restylane Lidocaine and/or Restylane Lyft Lidocaine. Needle/cannula and injection method were at the Investigator’s discretion. No touch-up was allowed.

Combination TreatmentAt months 6 and 12, subjects in both cohorts received up to 125 s.U ABO in at least two upper facial indications, ≤2 mL HA filler in nasolabial folds and/or cheeks (and other areas as applicable), and ≤1 mL Restylane Skinboosters Vital Lidocaine (Europe)/Re-stylane Skinboosters Vital (Brazil) (Figure 1). Touch-up with ABO was allowed after 2 weeks. Each subject received either OBT or NASHA filler during the study. A second RSB treatment (≤1 mL) was given at month 7. Efficacy AssessmentsSubject photographs were taken one month after each treat-ment (months 1, 7, and 13). Global aesthetic facial appearance was assessed by blinded evaluators by comparing photographs from months 1 and 7, as well as from month 13.

Subject photographs were also used for blinded evaluation of perceived age and first impression regarding social skills, academic performance, dating success, occupational success, attractiveness, financial success, relationship success, and ath-letic success, using a 10-grade scale. Overall first impression was the sum of the scores from all categories, with a maximum score of 80.

Aesthetic improvement compared to baseline was assessed us-ing the 5-grade Global Aesthetic Improvement Scale (GAIS).23

formed consent and had mild-to-moderate nasolabial folds21

and moderate-to-severe upper facial lines at maximum contrac-tion22 were eligible for the study.

Key exclusion criteria included (1) apparent facial sagging, (2) facial procedures eliciting an active dermal response during the preceding 6 months, or BoNT-A, HA or collagen treatment with-in the preceding 12 months, (3) treatment with non-collagen or non-HA product, or facial surgery, (4) history of dysphagia, neuromuscular junctional disorders, signs of compensatory frontalis muscle activity or eyelid ptosis, known hypersensitivity to BoNT-A, HA, lidocaine hydrochloride or other amide-type an-esthetics, or history of autoimmune disease, (5) inflammation, active skin disease, scarred, or damaged facial skin.

Treatment ProcedureInjections were performed in accordance with the Instructions for Use (HA fillers and RSB) and Summary of Product Charac-teristics (ABO) that were valid at the time. Local anesthesia was used by decision of the Investigators.

MonotherapyABO cohort: Subjects received up to 125 s.U ABO (Azzalure®/Dysport® [Ipsen Biopharm Limited, UK]) intramuscularly in at least two upper facial indications. Recommended doses were 50 s.U in 5 injection points for glabellar lines, 60 s.U (30 s.U/side) in 3 injection points/side for lateral canthal lines, and 20-60 s.U in 4-6 injection points for forehead lines. Optional touch-up was allowed after 2 weeks.

HA cohort: Subjects were injected in nasolabial folds and/or cheeks with ≤1 mL of either OBT™ or NASHA™ fillers (Galderma

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

M1 M6 M7 M9D1 M3 M12 M13 M15

2W: optional t-u; ≤125 s.U ABO

Monotherapy 1st combination treatment

2nd combination treatment

ABO cohort: ≤125 s.U ABO in at least

2 of GL, LCL + FL

HA cohort: ≤1 mL HA

in NLFs/cheeks

Both cohorts: • ≤125 s.U ABO in at least

2 of GL, LCL + FL• ≤2 mL HA in NLFs/cheeks

+ other areas• ≤1 mL RSB

Both cohorts: • ≤125 s.U ABO in at least

2 of GL, LCL + FL • ≤2 mL HA in NLFs/cheeks

+ other areas• ≤1 mL RSB

Both cohorts: ≤1 mL RSB

2W: optional t-u;≤125 s.U ABO

2W: optional t-u; ≤125 s.U ABO



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intervals. The aim was to show that global facial aesthetic ap-pearance was superior at month 7 compared to month 1, with the 95% confidence interval above 50%. First impression was presented descriptively and using Wilcoxon signed-rank test. Perceived age assessments were presented descriptively and with paired t-test. Satisfaction questionnaires were analyzed de-scriptively.

RESULTSFigure 2 shows subject disposition. Sixty-five subjects were randomized to monotherapy with either ABO (n=32) or HA filler (n=33). Table 1 and Table 2 show demographic and baseline data. Injection data are presented in Table 3 to Table 5.

EfficacyGlobal Facial Aesthetic Appearance One month after first combination treatment (month 7), most subjects (ABO cohort: 67%; HA cohort: 94%) had a superior global facial aesthetic appearance compared with after mono-therapy (month 1; Figure 3). When the evaluators compared photographs from months 1, 7, and 13, the best result was ob-tained at month 13 (one month after the second combination treatment [60% of subjects]), followed by first combination treatment (36%) and monotherapy (4%), both cohorts combined (Figure 4).

Blinded evaluators used photographs, while subjects and Inves-tigators did the assessment during the medical appointment. Wrinkle severity assessment of upper facial indications at rest and at maximum contraction was assessed by Investigators us-ing a validated 5-grade scale.22

Subject and Investigator satisfaction was assessed using ques-tionnaires.

Safety AssessmentMethods for collecting safety data included assessment of ad-verse events (AEs).

Statistical MethodsTwo analysis populations were defined for the study. The safety population included all subjects who were injected in at least one nasolabial fold/cheek (HA cohort) or one injection point (ABO cohort). The intention-to-treat population was the primary population for efficacy analyses and included all subjects who were injected in both nasolabial folds/cheeks or at least two up-per facial indications.

Statistical analyses and the randomization list were done using SAS® version 9.4. Analyses of global facial aesthetic appearance, wrinkle severity, and GAIS were done using 95% confidence

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, or related conditions (n=1). bAE (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.



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TABLE 2.

Wrinkle Severity22 at Baseline

ABO cohort (N=32)

HA cohort (N=33)

At restn (%)

At max contraction

n (%)

At restn (%)

At max contraction

n (%)

GL

No GL 2 (6.3) -- 1 (3.0) --

Mild GL 21 (65.6) -- 21 (63.6) --

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 -- -- -- --

LCL

No LCL 2 (6.3) -- 1 (3.0) --

Mild LCL 21 (65.6) -- 21 (63.6) --

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 -- -- -- --

FL

No FL 2 (6.3) -- 1 (3.0) --

Mild FL 21 (65.6) -- 21 (63.6) --

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

GAISAccording to blinded evaluators, 70% of subjects in the ABO cohort and 61% in the HA cohort were improved on the GAIS after monotherapy. After first and second combination treat-ment, 90% and 88% of subjects were improved, respectively, both cohorts combined. GAIS assessments by subjects and In-vestigators showed improvement for 88-100% of subjects after monotherapy and for 94-100% of subjects after both combina-tion treatments (Figure 5).

Wrinkle SeverityResponders to treatment were defined as subjects with at least 1-grade improvement of upper facial lines. In general, more subjects were responders at maximum contraction than at rest, except forehead lines, for which more subjects were responders at rest than at maximum contraction. A majority of subjects were responders at 1 month after each treatment (month 1, month 7, and month 13). Six months after the treatments (month 6, month 12, and month 18), the effect had generally subsided. However, more subjects were responders at month 12 than at month 6, and also at month 18 than at month 12, except for lateral canthal lines at rest (Figure 6).

First Impression Overall first impression was similar between monotherapy and combination treatments; mean scores ranged from 42.4 to 44.6 during the study, both cohorts combined.

Perceived AgeSubjects were perceived to look younger after first and second combination treatment compared to after monotherapy, mean difference was -1.3 years (P-0.007) and -2.0 years (P<0.001), re-spectively, both cohorts combined. Also, most subjects were assessed as looking younger after the second combination treatment than after the first; mean difference was -0.9 years with P=0.043, both cohorts combined.

TABLE 1.

Demographic and Baseline Data

ABO cohort (N=32)

HA cohort (N=33)

Age, mean (range) 43.9 (35-50) 44.8 (36-50)

Sex, n (%)

Female 31 (96.9) 32 (97.0)

Male 1 (3.1) 1 (3.0)

Fitzpatrick skin type24, n (%)

I 1 (3.1) 1 (3.0)

II 10 (31.3) 8 (24.2)

III 14 (43.8) 19 (57.6)

IV 3 (9.4) 3 (9.1)

V 4 (12.5) 2 (6.1)

VI -- --

%=(n/N)*100



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TABLE 3.

Injection Information Baseline

ABO cohort (N=32)

HA cohort (N=33)

ABO dose (s.U), mean (range)

GLBaseline (n=32) 47.5 (30.0-58.0)

Touch-up (n=11) 16.4 (6.00-26.0)

LCLBaseline (n=32) 33.9 (20.0-50.0)

Touch-up (n=13) 14.5 (1.50-22.0)

FLBaseline (n=27) 29.2 (7.50-60.0)

Touch-up (n=4) 10.6 (1.00-20.0)

HA filler volume mL, mean (range)

NLFs (n=33) 0.87 (0.40-1.00)

Cheeks (n=9) 0.44 (0.20-0.60)

GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead lines

TABLE 4.

Injection Information: First Combined Treatment (Month 6)

ABO cohort (N=31)

HA cohort (N=31)

Both (N=62)


GL

Month 6 (n=31a/31b)

49.3 (32.0-64.0)

51.5 (40.0-64.0)

50.4 (32.0-64.0)

Touch-up (n=12a/9b)

19.6 (6.0-30.0)

30.2 (18.0-50.0)

24.1 (6.0-50.0)

LCL

Month 6 (n=30a/31b)

38.1 (20.0-56.0)

37.7 (24.0-58.0)

37.9 (20.0-58.0)

Touch-up (n=10a/9b)

17.7 (12.0-30.0)

19.0 (8.0-40.0)

18.3 (8.0-40.0)

FL

Month 6 (n=28a/23b)

28.8 (9.0-54.0)

30.3 (8.0-46.0)

29.5 (8.0-54.0)

Touch-up (n=6a/5b)

23.0 (10.0-40.0)

23.4 (2.0-40.0)

23.2 (2.0-40.0)


NLFs (n=31a/29b)0.71

(0.40-1.30)0.61

(0.20-1.20)0.66

(0.20-1.30)

Cheeks (n=24a/24b)0.77

(0.20-1.30)0.73

(0.40-1.20)0.75

(0.20-1.30)

Otherc (n=29a/31b)0.67

(0.20-1.60)0.78

(0.10-2.00)0.72

(0.10-2.00)


Month 6 (n=31a/31b)0.95

(0.50-1.00)0.95

(0.50-1.00)0.95

(0.50-1.00)

Month 7 (n=29a/31b)0.94

(0.50-1.00)0.97

(0.50-1.00)0.96

(0.50-1.00)

GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead linesaABO cohortbHA cohortcMarionette lines, oral commissures, tear troughs, lips, jaw line, nose area, chin, eye area, forehead, perioral lines, mental crease, glabella, mouth corners, pre-jowls.

TABLE 5.

Injection Information: Second Combined Treatment (Month 12)

ABO cohort (N=31)

HA cohort (N=29)

Both (N=60)


GL

Month 12 (n=30a/29b)

46.0 (25.0-64.0)

49.2 (32.0-58.0)

47.6 (25.0-64.0)

Touch-up (n=11a/7b)

20.3 (3.0-40.0)

17.1 (10.0-24.0)

19.1 (3.0-40.0)

LCL


41.0 (25.0-60.0)

38.7 (28.0-60.0)

39.8 (25.0-60.0)

Touch-up (n=9a/7b)

14.6 (3.0-16.0)

21.4 (16.0-30.0)

17.6 (3.0-30.0)

FL


29.1 (10.0-40.0)

28.0 (8.0-40.0)

28.7 (8.0-40.0)

Touch-up (n=5a/5b)

24.0 (10.0-40.0)

31.6 (18-60.0)

27.8 (10.0-60.0)


NLFs (n=28a/26b)0.51

(0.20-1.00)0.50

(0.20-1.00)0.51

(0.20-1.00)

Cheeks (n=29a/25b)0.82

(0.30-1.60)0.89

(0.30-2.00)0.85

(0.30-2.00)

Otherc (n=27a/22b)0.73

(0.20-1.80)0.63

(0.20-1.50)0.69

(0.20-1.80)

RSB volume mL, mean (range)

Month 12 (n=30a/29b)0.95

(0.50-1.00)0.94

(0.40-1.00)0.94

(0.40-1.00)

FIGURE 3. Subjects with superior global facial aesthetic appearance after first combination treatment than after monotherapy. Since the confidence interval was above the predetermined limit (50%; dashed line) in the HA cohort and in both cohorts combined, it was shown that with 95% confidence, the majority of subjects in the underlying populations had a superior facial aesthetic appearance after combination treatment than after monotherapy.

ABOco

hort

HAfill

erco

hort

All subjec

ts0

100

%su

bjec

ts(w

ith95

%C

I)

GL: Glabellar lines; LCL: Lateral canthal lines; FL: Forehead linesaABO cohortbHA cohortcOral commissures, marionette lines, mouth corners, lips, jaw line, chin, tear troughs, perioral lines, forehead, eye area, nose area, glabella, mental crease, pre-jowl, medium cheek, low cheek, mid face.



687



FIGURE 5. GAIS score improvement compared to baseline. *Somewhat, much, or very much improved.

FIGURE 4. Subject photographs. Female subject, age 45, with no previous facial procedures. The subject provided signed consent 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)

(B)

Subject and Investigator Satisfaction Questionnaire At baseline, approximately one-third of subjects were satisfied with their facial appearance. The proportion of satisfied subjects increased from baseline/month 1 to month 7 and month 13 (Fig-ure 7a). Satisfaction with skin quality parameters improved from 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).

SafetyMonotherapyTen 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 treatmentTwenty-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 in-jection was most commonly reported, affecting 13 subjects. Headache was most common in the ABO cohort, reported for 2 subjects.



688



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

Second combination treatmentNineteen subjects (31%) had 36 treatment-related AEs of mild or moderate intensity, most resolved within two weeks; none were serious. All but one treatment-related AE were related to HA filler and/or RSB injection. Injection-site bruising was most commonly reported, affecting 14 subjects.

DISCUSSIONWe previously conducted a study where ABO was administered in glabellar lines only (Cartier et al, accepted for publication Dermatologic Surgery 2019). The present study was designed similarly, but with ABO administered also in lateral canthal lines and forehead lines.

As in our previous study (Cartier et al, accepted for publication Dermatologic Surgery 2019), overall aesthetic outcomes were more beneficial after combination treatment than after mono-therapy. The first combination treatment achieved a superior global facial aesthetic appearance over monotherapy in most subjects. Global aesthetic appearance increased further with the second combination treatment. Thus, cumulative treatments over time resulted in better aesthetic outcomes.

Most subjects had GAIS score improvement throughout the study (61-90%) according to blinded evaluators. Subject/In-vestigator assessments showed improvement for 94-100% of subjects after both combination treatments and after monother-apy with ABO, and for 88-91% of subjects after monotherapy with HA filler.

Combination treatments achieved higher subject and Investi-

gator satisfaction than monotherapy. This is in line with results after combination treatment in another study where higher mean ABO doses and HA filler volumes were injected.1 It should be noted though, that combination treatments were adminis-tered after monotherapy in our study.

The volume of HA filler at monotherapy was restricted to maximum 1 mL to reflect what was considered feasible for the majority of new aesthetic patients. Although the Investigators assessed that most subjects (76%) would have benefited from having additional filler volume, most subjects (64%) in the HA filler cohort were satisfied with the treatment results after mono-therapy and Investigators were satisfied with the overall facial aesthetic outcome for 67% of the subjects.

Subject satisfaction with treatment and skin quality improved over time, suggesting that the addition of Skinbooster was effec-tive for improving skin quality, although the assessment could be influenced by all products included in the combination treat-ments.

The wrinkle severity of upper facial lines improved at least 1-grade 1 month after treatment for a majority of subjects, both at rest and at maximum contraction. Improvement was gen-erally higher at maximum contraction than at rest, except for forehead lines for which improvement at rest was comparative-ly high, also at six months after treatment. By reducing muscle movement while maintaining some muscle activity, botulinum toxins have potential to reduce also static wrinkles with natural looking results. Wrinkle severity improvement data for glabellar lines were in line with previous results (Cartier et al, accepted for publication Dermatologic Surgery 2019).

Hydrat

ion

Elastic

ity

Softne

ssGlow

Freshn

ess

Structu

re

Firmne

ss0

100

%sa

tisfie

d*su

bjec

ts

Baseline

Month 7

Month 1325

15

37

17 17

9

2

74

83 8276

7376

73

82

9085 85

888382

(A) (B)



689



Both single and combination treatments were well tolerated. Most treatment-related AEs resolved spontaneously, and all were of mild-to-moderate intensity. The most frequently report-ed AE was injection-site bruising, an anticipated reaction to the study treatments.

This study was limited by the restricted volumes of HA filler, set to reflect a real-life scenario where subjects often have limited resources. Also, since combination treatments were administered in sequence following monotherapy, potential confounding effects on clinical outcome should be considered.

Efficacy results from this and from our previous study (Cartier et al, accepted for publication Dermatologic Surgery 2019) un-derline the benefit of establishing treatment plans based on patients’ individual treatment goals.

CONCLUSIONSTreatment of several indications with HA products and ABO was effective and well tolerated. Combination treatment with ABO, HA filler, and RSB, administered in sequence after mono-therapy, resulted in more beneficial aesthetic outcomes than monotherapy alone.

DISCLOSURESGalderma funded the study and provided the study products. H. Cartier, P. Bergentz, C. Siega, and F. Camozzato have no other conflicts of interest to declare; P. Hedén is a consultant for Al-lergan, Galderma, and Teoxane; D. Hexsel is a consultant for Galderma and Merz; C. Skoglund, C. Edwartz, and M. Norberg are employed by Galderma; P. Kestemont is a consultant for Al-lergan, Filorga, Galderma, Teoxane, Universkin, and Vivacy.

REFERENCES1. 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 acid filler. Dermatol Surg. 2015;41 Suppl 1:S325-332.

2. Fabi SG, Goldman MP, Mills DC, et al. Combining microfocused ultrasound 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 multi-modal facial aesthetic treatment: injection techniques and treatment charac-teristics from the HARMONY study. Dermatol Surg. 2016;42 Suppl 2:S177-191.

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 recommenda-tions 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,

dose-ranging study. Dermatol Surg. 2009;35(10):1478-1486.10. Rzany B, Dill-Müller D, Grablowitz D, et al. Repeated botulinum toxin

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 No.):S18-25.

11. Rzany B, Cartier H, Kestemont P, et al. Full-face rejuvenation using a range 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-ticle hyaluronic acid with lidocaine for correction of midface volume deficit or contour deficiency. Dermatol Surg. 2016;42(6):699-709.

13. Narins RS, Dayan SH, Brandt FS, Baldwin EK. Persistence and improve-ment of nasolabial fold correction with nonanimal-stabilized hyaluronic acid 100,000 gel particles/mL filler on two retreatment schedules: results up to 18 months on two retreatment schedules. Dermatol Surg. 2008;34 Suppl 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 18-month extension study. Dermatol Surg. 2011;37(5):644-650.

15. Carruthers J, Klein AW, Carruthers A, et al. Safety and efficacy of nonanimal stabilized hyaluronic acid for improvement of mouth corners. Dermatol Surg. 2005;31(3):276-280.

16. Rzany B, Bayerl C, Bodokh I, et al. An 18-month follow-up, randomized com-parison of effectiveness and safety of two hyaluronic acid fillers for treat-ment of moderate nasolabial folds. Dermatol Surg. 2016.

17. 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 1:389-393; discussion 394.

18. Williams S, Tamburic S, Stensvik H, Weber M. Changes in skin physiology and clinical appearance after microdroplet placement of hyaluronic acid in aging hands. J Cosmet Dermatol. 2009;8(3):216-225.

19. Kerscher M, Bayrhammer J, Reuther T. Rejuvenating influence of a stabilized 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-tion after abobotulinumtoxina treatment of upper facial lines. Dermatol Surg. 2018.

21. Narins RS, Carruthers J, Flynn TC, et al. Validated assessment scales for the lower face. Dermatol Surg. 2012;38(2 Spec No.):333-342.

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.

23. Narins RS, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29(6):588-595.

24. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124(6):869-871.


Philippe Kestemont MDE-mail:................…….................................... [email protected]




Copyright © 2019 CASE REPORT Journal of Drugs in Dermatology

SPECIAL TOPIC

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.

ABSTRACT

REPORT OF A CASE

A62-year-old woman presented for evaluation of recur-rent itchy lesions distributed over her upper and lower extremities including her hands and feet. She reported

that the rash had been present for several months, but that she 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 re-vealed 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-mented papules on the dorsal feet and ankles. Oral lesions were absent. Two 4 mm punch biopsy specimens were obtained from the left palm and right wrist.

Histopathologic examination revealed parakeratosis and a brisk lichenoid inflammation with scattered dyskeratotic ke-ratinocytes and erythrocyte extravasation. These histologic findings were consistent with pityriasis lichenoides et varioli-formis acuta (PLEVA). The patient tested negatively for syphilis and antinuclear antibody laboratory results were within normal limits.

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, GABWake Forest University School of Medicine, Winston-Salem, NC

cDepartment of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC

FIGURE 1. Clinical Image Multiple erythematous and hyperpigmented scaling papules and plaques on both palms and forearms.

FIGURE 2. Histopathologic Image Punch biopsy specimen from the center of a papule on the left palm (hematoxylin-eosin, original magnification ×10).



691


C. Ediale, K. Felix, K. Anderson, C. Ahn, A.J. McMichael

DISCLOSURESAmy J. McMichael MD is a consultant for Aclaris, Allergan, Bion-iz, Cassiopea, Covance, eResearch Technology, Inc., Galderma, Guthey Renker, Incyte, Johnson & Johnson, Keranetics, Merck & Co., Inc., Merz Pharmaceuticals, Pfizer, Proctor & Gamble, Sa-mumed, and received Royalties from Informa Healthcare and UpToDate. Dr. McMichael performed researche for Cassiopea, Proctor & Gamble, and Samumed. All other authors do not have conflicts of interest.

REFERENCES1. Fernandes NF, Rozdeba PJ, Schwartz RA, Kihiczak G, Lambert WC. Pityriasis

lichenoides et varioliformis acuta: a disease spectrum. International Journal of Dermatology. 49(3):257-261. doi:10.1111/j.1365-4632.2008.03915.x

2. Patel DG, Kihiczak G, Schwartz RA, Janniger CK, Lambert WC. Pityriasis li-chenoides. Cutis. 2000;65(1):17-20, 23.

3. Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol. 2006;55(4):557-572; quiz 573-576. doi:10.1016/j.jaad.2005.07.058

4. Longley J, Demar L, Feinstein RP, Miller RL, Silvers DN. Clinical and histo-logic features of pityriasis lichenoides et varioliformis acuta in children. Arch Dermatol. 1987;123(10):1335-1339.

5. Ersoy-Evans S, Greco MF, Mancini AJ, Subaşi N, Paller AS. Pityriasis lichenoi-des in childhood: a retrospective review of 124 patients. J Am Acad Derma-tol. 2007;56(2):205-210. doi:10.1016/j.jaad.2006.08.023

6. Nair PS. A clinical and histopathological study of pityriasis lichenoides. Indian J Dermatol Venereol Leprol. 2007;73(2):100-102.

DISCUSSIONPityriasis lichenoides is a cutaneous inflammatory disease with unknown etiology. It is considered to be on a spectrum, with both acute and chronic forms.1 The acute type, called Pit-yriasis lichenoides et varioliformis acuta (PLEVA), also known as Mucha-Habermann disease, can be found in patients of all ages but is most commonly seen in individuals in their second or third decade of life.2 Currently, there is no established etiol-ogy, though proposed theories include lymphoproliferation, an inflammatory reaction to a viral infection, and possible immune-complex-mediated vasculitis.3

Patients with PLEVA often present with erythematous pap-ules, with a light micaceous scale and a central punctum, that progress into necrotic papules.4 Papules are usually present in several different stages of development, which is a hallmark of diagnosis. Lesions are typically concentrated proximally, with heaviest involvement of the trunk, proximal limbs, and flexor surfaces and are often asymptomatic but can be pruritic or associated with a burning sensation.3 Involvement of distal ap-pendages is not common, especially as the only location for the disease process.2

Previously, the patient was diagnosed with coxsackie virus because of the positive coxsackie titers, though it is not clear if they were germane to the skin eruption. While there were papular lesions in the mouth as well as on the palms, soles of the feet, and gluteal area and biopsy results showed confluent necrosis, parakeratosis and hyperkeratosis, a specific histopath-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 dis-ease. Methotrexate is reserved for the treatment of patients who have failed oral antibiotics and phototherapy. Topical corticoste-roids 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.


Constance Ediale MS E-mail:................……............................ [email protected]



Implications of Treatment Vehicles in Effective Topical Therapy

To provide dermatology providers with an educational reference tool exploring the important role ofvehicle technology, the advancements in vehicle formulation and the role of vehicles in optimizingtherapeutic outcomes in cutaneous diseases including acne vulgaris and plaque psoriasis.

This supplement is funded by an educational grant provided by Mayne Pharma Group Limited.

A SUPPLEMENT TO

JDDImplications of Treatment Vehicles

in Effective Topical Therapy

STILLAVAILABLE






SPECIAL TOPIC

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.

ABSTRACT

INTRODUCTION

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. Clinically, ag-gressive SCC may present similarly to KA with rapid growth over weeks. Furthermore, it is often challenging, histologically, to distinguish between KA and SCC without an excisional biop-sy.1-3 While some KAs have shown the ability to spontaneously 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

We report a patient with a solitary KA of the skin of the right ala successfully treated with intralesional (IL) injections of meth-otrexate (MTX). We also provide a review of the literature on IL-MTX as a treatment modality for KA.

REPORT OF A CASEA 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 carcino-ma, keratoacanthoma type, with lesional tissue extending to the base of the biopsy. The lesion was injected with 1cc of metho-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).

DISCUSSIONThere is a great deal still unknown of the etiology and patho-

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, NCbLaser and Skin Surgery Center of Indiana, Indianapolis, IN

FIGURE 1. 53-year-old woman developed a 1cm keratoacanthoma on the nasal ala.

FIGURE 2. The keratoacanthoma demonstrated necrosis one week following intralesional methotrexate injection.

FIGURE 3. The keratoacanthoma has undergone considerable shrinkage two weeks post intralesional methotrexate injection.



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L. Doerfler, C.W. Hanke

chitecture of the tumor shows a central keratin-filled crater surrounded by symmetrical, cup-shaped invaginations of thin 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 transects the base of the lesion. Though it may appear to be a KA, without the base, an invasive SCC cannot be ruled out. Thus, biopsies that are fully representative of the lesion are helpful though not always practical for a large KA or KAs in cosmetical-ly sensitive areas.2,21 There are no reliable immunohistochemical staining markers used in differentiating KA from SCC.22

Treatment for Solitary KAsThe ambiguity between a KA and SCC creates a dilemma with regard to the management of KAs. Though there is a tendency for spontaneous involution, most do not recommend waiting for the tumor to self-resolve due to the uncertainty of behavior.25 In addition, therapeutic intervention may hasten resolution, limit damage to vital structures and provide an improved cosmetic result. Many treatment modalities have been reported with vari-ous success rates and side effects.

Surgical removal is the gold standard regimen when possible. Standard surgical excision with 5 mm margins, Mohs surgery or curettage and electrodessication is commonly used in small (<1 cm), solitary KAs.22

Intralesional (IL) chemotherapy may be warranted for solitary large KAs or those adjacent to vital structures that may often re-quire extensive reconstruction. Methotrexate (MTX) is preferred as an intralesional drug, with 5-fluorouracil (5-FU), bleomycin or interferons being other options.23 MTX has an appealing mecha-nism of action for a rapidly growing KA. It is a folic acid analog that inhibits DNA synthesis in actively dividing cells. KAs treat-ed with IL-MTX show high cure rates of 71-92%.21,23-27

There is no standard protocol for administering IL-MTX injec-tions. Current data show 1-4 injections are generally required with many resolving in 2 injections. Injections are separated by 2 to 3 weeks. The concentrations used per injection show ex-treme variation from 0.3 to 2.0 mL in a concentration of 25 mg/mL or 12.5 mg/mL.21,23-27 Annest and colleagues showed a 92% cure rate among 38 KAs treated with a mean cumulative dose 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 quadrants at the central base of the lesion. MTX is injected until an end point of uniform tumor blanching is achieved. Though

physiology of KA. Even classifying it as a malignant versus benign tumor is controversial. With so much uncertainty, there are no clear guidelines to follow in management of KAs.

EtiologyKA is assumed to originate from the hair follicle as it exhib-its markers consistent with those in the follicular isthmus and infundibulum.1 The classic KA evolves in 3 clinical stages: prolif-erative, stabilization, and regression. There are several variants of KA including solitary sporadic, solitary iatrogenic, multiple iatrogenic, multiple familial, and centifugum et marginatum. Ul-traviolet exposure is a predominant risk factor for most of these variants.7-9

Clinical ManifestationsSolitary sporadic KA is a rapidly enlarging neoplasm appear-ing mainly on sun-exposed areas of the skin. Men are affected up to 3 times more frequently than women. The classic lesion presents as a dome-shaped nodule with a central hyperkeratotic plug. There may be associated pain or tenderness. KAs usually enlarge rapidly to full size within 6 to 10 weeks. Most KAs grow 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-volution tends to begin around 8-12 weeks and can take up to 4 to 6 months to fully resolve. The resulting scar is often hypopig-mented and atrophic.3

Iatrogenic KA can be induced by medical procedures that create trauma to the skin or in response to systemic chemotherapy. They can be solitary or multiple. Solitary KA along prior exci-sion areas can mimic tumor regrowth.10 Multiple/Eruptive KAs are rapidly growing nodules that can also occur along prior ex-cision areas. Multiple KAs may also be associated with prurigo nodularis, usually on the lower limbs of elderly women with sun-damaged skin.11 There are reports of KAs following esthet-ic procedures on sun damaged skin including chemical peels, dermabrasion, and resurfacing laser procedures.13-17 Systemic chemotherapy notably BRAF inhibitors and Hedgehog pathway inhibitors are associated with KAs.18,19

HistologyKAs have a distinct histologic appearance. The distinctive ar-

FIGURE 4. The tumor has totally resolved 6 months following intralesional methotrexate injection. The skin appears clinically normal without scarring.



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excisions and reconstructions that may compromise functional and esthetic outcome. A poor response to IL-MTX indicates a more aggressive entity and must be re-evaluated.

REFERENCES1. Schwartz RA. Keratoacanthoma: a clinico-pathologic enigma. Dermatol Surg.

2004;30:326-333.2. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from

keratocanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology. 1999;199:208-12.

3. Savage JA, Maize JC Sr. Keratoacanthoma clinical behavior: a systematic review. Am J Dermatopathol. 2014;36:422-429.

4. Ramselaar CG, Ruitenberg EJ, Kruizinga W. Regression of induced kerato-acanthomas in anagen (hair growth phase) skin grafts in mice. Cancer Res. 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. 1993;15:332-42.

6. Misago N, Inoue T, Nagase K, et al. Crater/ulcerated form of infundibular squamous cell carcinoma: a possible distinct entity as a malignant (or high-grade) counterpart to keratoacanthoma. J Dermatol. 2015;42:667-673.

7. Sullivan JJ. Keratoacanthoma: the Australian experience. Australas J Derma-tol. 1997;38(Suppl 1):S36-S39.

8. Sina B, Adrian RM. Multiple keratoacanthomas possibly induced by psoralens and ultraviolet A photochemotherapy. J Am Acad Dermatol. 1983;9:686-688.

9. Craddock KJ, Rao J, Lauzon GJ, Tron VA. Multiple keratoacanthomas arising post-UVB therapy. J Cutan Med Surg. 2004; 8:239-243.

10. Pattee SF, Silvis NG. Keratoacanthoma developing in sites of previous trau-ma: a report of two cases and review of the literature. J Am Acad Dermatol. 2003;48(Suppl):S35-S38.

11. Goldberg LH, Silapunt S, Beyrau KK, Peterson SR, Friedman PM, Alam M. Keratoacanthoma as a postoperative complication of skin cancer excision. J Am Acad Dermatol. 2004;50:753-758.

12. Wu TP, Miller K, Cohen DE, Stein JA. Keratoacanthomas arising in associa-tion with prurigo nodules in pruritic, actinically damaged skin. J Am Acad Dermatol. 2013;69:426-430.

13. Mohr B III, Fernandez MP, Krejci-Manwaring J. Eruptive keratoacanthomas after Jessners and trichloroacetic acid peel for actinic keratosis. Dermatol Surg. 2013;39:331-333.

14. Cox S. Rapid development of keratoacanthomas after a body peel. Dermatol Surg. 2003;29:201-203.

15. Mamelak AJ, Goldberg LH, Marquez D, Hosler GA, Hinckley MR, Friedman PM. Eruptive keratoacanthomas on the legs after fractional photothermoly-sis: report of two cases. Dermatol Surg. 2009;35:513-518.

16. Gewirtzman A, Meirson DH, Rabinovitz H. Eruptive keratoacanthomas fol-lowing carbon dioxide laser resurfacing. Dermatol Surg. 1999;25:666-668.

17. Gogia R, Grekin RC, Shinkai K. Eruptive self-resolving keratoacanthomas developing after treatment with photodynamic therapy and microdermabra-sion. Dermatol Surg. 2013;39:1717-1720.

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.

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. 2012;366:207-215.

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.

21. Rossi AM1, Park B, Qi B, Lee EH, Busam KJ, Nehal KS. Solitary Large Kerato-acanthomas of the Head and Neck: An Observational Study. Dermatol Surg. 2017 Jun;43(6):810-816.

22. Kwiek B, Schwartz RA. Keratoacanthoma (KA): An update and review. J Am Acad Dermatol. 2016 Jun;74(6):1220-33. doi: 10.1016/j.jaad.2015.11.033. Epub 2016, Feb 4.

23. Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin can-cer: a practical review. J Am Acad Dermatol. 2010;63:689-702.

24. Moss M, Weber E, Hoverson K, Montemarano AD. Management of kera-toacanthoma: 157 tumors managed with surgery or intralesional methotrex-ate. Dermatol Surg. Epub 2019, Jan 2.

25. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrex-ate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol. 2007;56:989-993.

26. Aubut N, Alain J, Claveau J. Intralesional methotrexate treatment for kera-toacanthoma tumors: a retrospective case series. J Cutan Med Surg.

rare, there are reports of pancytopenia following a single 25 mg dose of IL-MTX.28,29 Both cases occurred in patients with hemo-dialysis-dependent renal failure. Thus, obtaining a baseline and 1-week post injection complete blood cell count is reasonable, particularly in patients with kidney disease.

IL-5FU has also shown success in treating KAs.23,30 Many prefer IL-MTX compared to IL-5FU for practical reasons. IL-5FU often requires pretreatment with local anesthesia while IL-MTX is gen-erally well tolerated without the use of local anesthesia. IL-5FU also requires weekly injections while IL-MTX requires injections performed at 2 to 3-week intervals.25

While cure rates are high, factors that predict when a KA will not respond to IL-MTX are not well established. Rossi and col-leagues studied response rates of IL-MTX in solitary KAs of the head and neck.21 Potential factors were identified that may be associated with treatment failures. They found that persistent pain and sustained growth post two treatments of IL-MTX may suggest an underlying aggressive SCC. In addition, immu-nosuppression may also raise concern for a more aggressive SCC tumor. Some Larger KAs have also shown to have poor response. Annest et al found the average tumor diameter for nonresponding lesions was larger than the average tumor for responsive lesions (2.8 vs 1.9 cm).25

IL-MTX is an attractive treatment modality for KA. It is relatively noninvasive, inexpensive, quickly administered, safe, relatively painless, tissue sparing with good cosmetic outcomes. In sum-mary, if the clinical and diagnostic biopsy suggest a diagnosis of KA, approximately 1 mL of MTX in a concentration of either 12.5 or 25 mg/mL is injected directly in the base of the tumor. This should be repeated at 2 week intervals until tumor resolution. If the tumor does not respond after two treatments, surgical treat-ment should be considered as the diagnosis may be invasive SCC. Monitor for MTX-induced cytopenias in renal failure pa-tients.

Treatment for Multiple KAsMultiple KAs have been managed with systemic retinoids.31,32

Patients have a marked response while on the retinoid. When the medication is discontinued however there is frequently regrowth. The dosage varies from 0.5 to 1.0 mg/kg of acitretin at the beginning of treatment and tapered as needed. Smaller doses of 20 to 20 mg/day are often necessary to sustain clinical response. IL corticosteroids are occasionally used with good re-sponse either as monotherapy or with systemic retinoids.33

CONCLUSIONWhile the majority of KAs are benign acting, the diagnostic ambiguity has led to treatment standards toward that used for well-differentiated SCC. The increasing data on the effectiveness of IL-MTX is promising and prevents overtreatment with large



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2012;16:212-217.27. Yoo M, Kim I. Intralesional methotrexate for the treatment of keratoacanth-

oam. retrospective study and review of the Korean literature. Ann Dermatol. 2014;26(2)172-176.

28. Goebeler M, Lurz C, Kolve-Goebeler ME, Brocker EB. Pancytopenia after treatment of keratoacanthoma by single lesional methotrexate infiltration. Arch Dermatol. 2001;137:1104-5.

29. Cohen PR, Schulze KE, Nelson BR. Pancytopenia after a single intradermal infiltration of methotrexate. J Drugs Dermatol. 2005;4:648-51.

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.

31. LaPresto L, Cranmer L, Morrison L, Erickson CP, Curiel-Lewandrowski C. A novel therapeutic combination approach for treating multiple vemurafenib-induced keratoacanthomas: systemic acitretin and intralesional fluorouracil. JAMA Dermatol. 2013;149:279-281.


Laura Doerfler MDE-mail:................……............................ [email protected]

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32. Robertson SJ, Bashir SJ, Pichert G, Robson A, Whittaker S. Severe exacerba-tion of multiple self-healing squamous epithelioma (Ferguson-Smith disease) with radiotherapy, which was successfully treated with acitretin. Clin Exp Dermatol. 2010;35:e100-e102.

33. Sanders S, Busam KJ, Halpern AC, Nehal KS. Intralesional corticosteroid treatment of multiple eruptive keratoacanthomas: case report and review of a controversial therapy. Dermatol Surg. 2002;28:954-958.





SPECIAL TOPIC

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 ver-rucous 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.

ABSTRACT

MANUSCRIPT

A65-year-old African American female presented to an outpatient dermatology clinic with an occasionally pru-ritic and painful “abnormal skin growth” on her back

for 22 years. On the mid back was a 22-centimeter tan-brown, horn shaped growth, with a well vascularized base, attached to a pedunculated flesh colored plaque. A shave biopsy was performed below the base of the lesion. Pathology revealed an 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 bi-opsy specimen were negative/clear and the patient has yet to return with recurrence.

A literature search of various synonyms of the words “giant cutaneous horn” suggests that this reported case of a 22-cen-timeter 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 ver-rucae that may have a genetic predilection in their viral DNA to tremendous angiogenic and proliferative abilities. Cutane-ous horns secondary to malignant neoplasms tend to grow in

a much more disordered pattern, as would be expected with malignant cells, compared to horns secondary to verrucae.

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

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 back.

FIGURE 1B. 22cm giant cutaneous horn with a large well vascularized base hanging from a pedunculated flesh colored plaque.



698


D. Nussbaum, J. Schwartz, A. Friedman

Cutaneous horns, or “cornu cutaneum” in Latin, are described first in the 16th century, those with horns at the time were used for show. Horns are common among various animals; the main distinction of animal horns and cutaneous horns are animal horns tend to grow off bones giving them strength and cutane-ous horns have no bony structure. Similarly, animal horns tend to be common among a species and the same cannot be said for cutaneous horns in humans.4 All human cutaneous horns are pathologic in nature and require a diagnostic biopsy. Again, the differential diagnosis consists of a cutaneous horn second-ary to a verruca, squamous or basal cell carcinoma, or actinic keratosis. Further treatment may be required if the origin is ma-lignant and extending to the margins of the biopsy or if the initial biopsy does not resolve an underlying verruca or actinic keratosis. Previous literature may indicate that the larger and more structured a cutaneous horn appears may point to a ver-rucous, rather than malignant origin but more inquiry needs to be conducted to affirm such an association.

DISCLOSURESThe authors have no conflicts of interest to declare.

REFERENCES1. Gould JW, Brodell RT. Giant cutaneous horn associated with verruca vul-

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.

3. Chen W, Wei W, Yan-Jun L, et al. Multiple huge cutaneous horns overlying 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.

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


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

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BRIEF SUMMARY OF PRESCRIBING INFORMATIONThis brief summary does not include all the information needed to use BRYHALI safely and effectively. See full prescribing information for BRYHALI.BRYHALI™ (halobetasol propionate) lotion, 0.01% for topical use Initial U.S. Approval: 1990INDICATIONS AND USAGEBRYHALI™ (halobetasol propionate) Lotion, 0.01% is indicated for the topical treatment of plaque psoriasis in adults.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSHypothalamic-Pituitary-Adrenal (HPA) Axis SuppressionBRYHALI has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.Systemic effects of topical corticosteroids may include reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment with the topical corticosteroid.The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with BRYHALI was evaluated in a study of 19 adult subjects with moderate to severe plaque psoriasis involving ≥20% of their body surface area (BSA). HPA axis suppression was reported for 1 (5.6%) subject at Week 4 and for 3 (15.8%) subjects at Week 8. All 3 subjects had normal HPA axis suppression test with discontinuation of treatment [see Clinical Pharmacology in full Prescribing Information]. Because of the potential for systemic absorption, use of topical corticosteroids, including BRYHALI, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surface areas, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) stimulation test may be helpful in evaluating patients for HPA axis suppression.If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the frequency of application, or substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids due to their larger surface-to-body mass ratios [see Use in Specific Populations].Local Adverse ReactionsLocal adverse reactions from topical corticosteroids may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. These may be more likely with occlusive use, prolonged use, or use of higher potency corticosteroids, including BRYHALI. Some local adverse reactions may be irreversible.Concomitant Skin Infections Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable response does not occur promptly, discontinue use of BRYHALI until the infection has been adequately treated.Allergic Contact Dermatitis Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis of allergic contact dermatitis by appropriate patch testing. Discontinue BRYHALI if allergic contact dermatitis occurs.ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In randomized, double-blind, multicenter, vehicle-controlled clinical trials, 426 adults with plaque psoriasis were treated with BRYHALI and had post-baseline safety data. Subjects applied BRYHALI once daily for up to eight weeks. Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with BRYHALI and more frequently than in vehicle-treated patients.Table 1: Adverse Reactions Occurring in ≥1% of the Subjects Treated with BRYHALI through Week 8

BRYHALI (N=284)

Vehicle (N=142)

Adverse Reaction % %

Upper Respiratory Tract Infection 2% 1%

Application Site Dermatitis 1% 0

Hyperglycemia 1% 0

USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryThere are no available data on BRYHALI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oral administration of halobetasol propionate during organogenesis to pregnant rats and rabbits. The available data do not support relevant comparisons of systemic halobetasol propionate exposures achieved in the animal studies to exposures observed in humans after topical use of BRYHALI. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data

Animal DataHalobetasol propionate has been shown to cause malformations in rats and rabbits when given orally during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats but not in rabbits.LactationRisk SummaryThere are no data on the presence of halobetasol propionate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production after treatment with BRYHALI.Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BRYHALI and any potential adverse effects on the breastfed child from BRYHALI. Clinical ConsiderationsAdvise breastfeeding women not to apply BRYHALI directly to the nipple and areola to avoid direct infant exposure.Pediatric UseSafety and effectiveness of BRYHALI in pediatric patients under the age of 18 years have not been evaluated.Because of higher skin surface area to body mass ratios, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse reactions including striae have been reported with use of topical corticosteroids in infants and children [see Warnings and Precautions].HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema [see Warnings and Precautions].Geriatric UseOf 284 subjects exposed to BRYHALI in clinical trials, 61 subjects were 65 years or older. Clinical trials of BRYHALI did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate.Halobetasol propionate was not genotoxic in the Ames assay, in the sister chromatid exchange test in Chinese hamster somatic cells, in chromosome aberration studies of germinal and somatic cells of rodents, or in a mammalian spot test. Positive mutagenicity effects were observed in a mouse lymphoma gene mutation assay in vitro and in a Chinese hamster micronucleus test. Studies in rats following oral administration of halobetasol propionate at dose levels up to 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance.PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).Manufactured for:Dow Pharmaceutical Sciences, a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USABy:Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada U.S. Patent Numbers: 6,517,847 and 8,809,307BRYHALI is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.© 2018 Valeant Pharmaceuticals North America LLCBased on 9652102 November 2018 BRY.0032.USA.18

VALE5034 BRYHALIJournalAd JDD B/WPage Live: .125"fromTrim Fileformat:PDF/X-1A CarlingCommunications 3/14/19 Trim: 8.25"x10.875" Bleed: 8.50"x11.125”


https://www.bryhali.com


CHART A COURSE

SYMPTOMATIC RELIEF

FOR ADULTS WITH PLAQUE PSORIASIS

TO

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

BRYHALIandthecheckmarkdesignaretrademarksofOrthoDermatologics’affiliatedentities.©2018AllRightsReserved.BRY.0025.USA.18 DISCOVER MORE AT BRYHALI.COM

STUDY RESULTS: 36.5%ofpatientsintrial1and38.4%intrial2achievedtreatmentsuccess*atweek8(primaryendpoint)vs8.1%and12.0%ofpatientswithvehicle,respectively(P<0.001inbothtrials).2

STUDY DESIGN: ThesafetyandefficacyofBRYHALILotionwereassessedin2prospective,multicenter,randomized,double-blind,phase3clinicaltrialsin430adultpatientswithmoderate-to-severeplaquepsoriasis.PatientsweretreatedwithBRYHALILotionorvehiclelotion,appliedoncedaily.Primaryefficacyendpointwastreatmentsuccessevaluatedatweek8.Secondaryefficacyendpointwastreatmentsuccessevaluatedatweeks2,4,6,and12(4 weeksposttreatment).Tertiaryefficacyendpointwasa2-gradeimprovementfrombaselineateachtimepointfortheindividualsignsofpsoriasis(erythema,plaqueelevation,andscaling).2

*Treatmentsuccesswasdefinedasatleasta2-gradeimprovementfrombaselineintheInvestigator’sGlobalAssessmentscore,andascoreof“clear”or“almostclear”(primaryendpointatweek8).2

References: 1.BRYHALILotion[prescribinginformation].Bridgewater,NJ.ValeantPharmaceuticalsNorthAmericaLLC.2.Dataonfile.

A NEW POTENCY CLASS OF STEROID LOTION

IndicationBRYHALI™(halobetasolpropionate)Lotion,0.01%isacorticosteroidindicatedforthetopicaltreatmentofplaquepsoriasisinadults.

Important Safety Information Warnings and Precautions

• BRYHALILotionhasbeenshowntosuppressthehypothalamic-pituitary-adrenal(HPA)axisduringtreatmentoruponcessationoftreatment;periodicevaluationmayberequired.

• SystemiceffectsoftopicalcorticosteroidsmayalsoincludeCushing’ssyndrome,hyperglycemia,andglucosuria.

• Childrenmaybemoresusceptibletosystemictoxicitywhentreatedwithtopicalcorticosteroids.

• Localadversereactionsmayincludeatrophy,striae,telangiectasias,hypopigmentation,andallergiccontactdermatitis.Somelocaladversereactionsmaybeirreversible.

• Useoftopicalcorticosteroidsmayincreasetheriskofposteriorsubcapsularcataractsandglaucoma.Ifvisualsymptomsoccur,considerreferraltoanophthalmologist.

• Useanappropriateantimicrobialagentifaskininfectionispresentoroccurs,andifpromptresponseisnotseen,discontinueuseuntilinfectionhasbeenadequatelytreated.

• DiscontinueBRYHALILotionifallergiccontactdermatitisoccurs.

Adverse Reactions

• Themostcommonadversereactions(≥1%)wereupperrespiratorytractinfection,applicationsitedermatitis,andhyperglycemia.

ToreportSUSPECTEDADVERSEREACTIONS,contactCustomerServiceat1-800-321-4576orFDAat1-800-FDA-1088.

Please see Brief Summary of full Prescribing Information on following page.

2 PIVOTAL PHASE 3 TRIALS

Continued results 4weeksposttreatment1

Signifi cant symptomatic relief asearlyasweek22

No increased epidermal atrophyobservedthrough8weeksoftreatment2

Localadversereactionsfromtopicalcorticosteroidsmayincludeatrophy,striae,telangiectasias,hypopigmentationandallergiccontact

dermatitis.Somelocaladversereactionsmaybeirreversible.

POTENT TO SUPERPOTENT CLEARANCE1:

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