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JDD

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

ISSN: 1545 9616 January 2020 • Volume 19 • Issue 1

ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

Nutrition Therapy in Dermatology

Consensus Recommendations for Monopolar RF

Calculating Superficial Fatty Layer Thickness

Topical Agents for the Treatment of AD

Minimally Invasive Procedures for the Millennial Aesthetic Patient

SPECIAL FOCUS:

AESTHETIC TREATMENTS

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The only FDA-approved treatment with a potent-to-superpotent steroid that can be used until control is achieved

The effi cacy and safety of DUOBRII Lotion was investigated in two 8-week clinical trials and an additional 1 year safety study.1,3

Discontinue treatment with DUOBRII Lotion when control is achieved or if atrophy, striae, telangiectasias, or folliculitis occurs.1

Halobetasol (0.01%) Provides powerful

antiinfl ammatory effects and reduces skin irritation, which is

often associated with retinoids1,4,5

The fi rst and only steroid/retinoid therapy, allowing halobetasoland tazarotene to work together in an advanced, once-daily lotion that can be dosed to clearance1-3

American Academy of Dermatology (AAD) Guidelines give the combination of a corticosteroid and a retinoid an A rating with Evidence Level I for the treatment of psoriasis4

®/TM are trademarks of Ortho Dermatologics’ affi liated entities. ©2019 Ortho Dermatologics’ affi liated entities. DUO.0052.USA.18

Please see Brief Summary of full Prescribing Information on the following page.

References 1. DUOBRII Lotion [prescribing information]. Bridgewater, NJ: Bausch Health US, LLC. 2. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. Accessed April 29, 2019. 3. Data on fi le. 4. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60(4):643-659. 5. Orfanos CE, Schmidt HW, Mahrle G, et al. Retinoic acid in psoriasis: its value for topical therapy with and without corticosteroids: clinical, histological and electron microscopical studies on forty-four hospitalized patients with extensive psoriasis. Br J Dermatol. 1973;88(2):167-182. 6. Lesnik RH, Mezick JA, Capetola R, Kligman LH. Topical all-trans-retinoic acid prevents corticosteroid-induced skin atrophy without abrogating the anti-infl ammatory e� ect. J Am Acad Dermatol. 1989;21(2 Pt 1):186-190. 7. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, e� cacy, and duration of therapeutic e� ect. J Am Acad Dermatol. 1997;37(1):85-92.

Learn more at DUOBRII.com

IndicationDUOBRII™ (halobetasol propionate and tazarotene) Lotion, 0.01%/0.045%, is indicated for the topical treatment of plaque psoriasis in adults.

Important Safety InformationContraindication DUOBRII Lotion is contraindicated in pregnancy.

Warnings and Precautions• Women of child-bearing potential should be warned of the

potential risk of fetal harm from DUOBRII and use adequate birth-control. A negative result for pregnancy should be obtained within 2 weeks prior to treatment. If the patient becomes pregnant during treatment, discontinue DUOBRII Lotion and advise patient of the potential hazard to the fetus.

• DUOBRII Lotion has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis during or after treatment and may require that patients be evaluated periodically during treatment.

• Predisposing factors for HPA axis suppression include: use of more potent corticosteroids, use on large areas, use under occlusive dressings, use on altered skin barrier, concomitant use of other steroids, liver failure and young age.

• Systemic e� ects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria.

• Local adverse reactions may include atrophy, striae, telangiectasias, folliculitis and contact dermatitis. If these e� ects occur, discontinue until the integrity of the skin has been restored. Do not resume treatment if contact dermatitis is identifi ed. DUOBRII Lotion should not be used on eczematous skin, as it may cause severe irritation.

• Avoid exposure to sunlight, sunlamps and weather extremes. Patients with sunburn should be advised not to use DUOBRII Lotion until fully recovered. DUOBRII Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers because of the increased potential for photosensitivity.

• Topical corticosteroids may increase the risk of cataracts and glaucoma; advise patients to report any visual symptoms and refer to an ophthalmologist if needed.

Adverse Events • The most common adverse events in clinical trials were contact

dermatitis (7%), application site pain (3%), folliculitis (2%), skin atrophy (2%), and excoriation (2%).

To report SUSPECTED ADVERSE REACTIONS, contact Ortho Dermatologics at 1-800-321-4576 or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

bettertogetherFor adults with plaque psoriasis

Tazarotene (0.045%) Regulates cell growth and specialization to reduce hyperproliferation, increases collagen, and extends remission post treatment4,6,7

The only FDA-approved treatment with a potent-to-superpotent steroid that can be used until control is achieved

Tazarotene (0.045%) Regulates cell growth and specialization to reduce hyperproliferation, increases collagen, and extends remission post treatment

mechanisms of change

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BRIEF SUMMARY OF PRESCRIBING INFORMATIONThis Brief Summary does not include all the information needed to prescribe DUOBRII safely and effectively. See full Prescribing Information for DUOBRII.

DUOBRII™ (halobetasol propionate and tazarotene) Lotion, 0.01%/0.045% for topical useINDICATIONS AND USAGE DUOBRII (halobetasol propionate and tazarotene) Lotion, 0.01%/0.045% is indicated for the topical treatment of plaque psoriasis in adults.CONTRAINDICATIONSPregnancy DUOBRII Lotion is contraindicated in pregnancy [see Warnings and Precautions and Use in Specific Populations].WARNINGS AND PRECAUTIONSEmbryofetal RiskBased on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, DUOBRII Lotion may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Tazarotene is teratogenic, and it is not known what level of exposure is required for teratogenicity in humans [see Contraindications and Clinical Pharmacology]. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits [see Use in Specific Populations]. Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to DUOBRII Lotion therapy. Initiate DUOBRII Lotion therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with DUOBRII Lotion therapy [see Use in Specific Populations]. Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid EffectsDUOBRII Lotion contains halobetasol propionate, a corticosteroid, and 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 of the topical corticosteroid. The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with DUOBRII Lotion was evaluated in a study of 20 adult subjects with moderate to severe plaque psoriasis involving ≥20% of their body surface area. The subjects were treated once daily for 8 weeks and assessed for HPA axis suppression at Weeks 4 and 8. HPA axis suppression occurred in 3 out of 20 (15%) subjects at Week 4 and none (0%) of these 20 subjects had HPA axis suppression at Week 8 [see Clinical Pharmacology in full Prescribing Information]. Because of the potential for systemic absorption, use of topical corticosteroids, including DUOBRII Lotion, 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 or reduce the frequency of application. 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 topical corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids because of their larger surface-to-body mass ratio [see Use in Specific Populations]. Local Adverse ReactionsLocal adverse reactions may include atrophy, striae, telangiectasias, folliculitis and contact dermatitis. Some local adverse reactions may be irreversible. If these adverse reactions occur, discontinue the medication at least until the integrity of the skin is restored; do not resume treatment if allergic contact dermatitis is identified. Avoid use of DUOBRII Lotion on eczematous skin, as it may cause severe irritation. Photosensitivity and Risk for SunburnBecause of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of DUOBRII Lotion. Patients must be instructed to use sunscreens and protective clothing when using DUOBRII Lotion. Patients with sunburn should be advised not to use DUOBRII Lotion until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using DUOBRII Lotion. DUOBRII Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. Ophthalmic Adverse Reactions Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroid products. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation. 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 DUOBRII Lotion until the infection has been adequately treated.

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, 410 adults with plaque psoriasis were treated with DUOBRII Lotion or vehicle lotion and had post-baseline safety data. Subjects applied DUOBRII Lotion or vehicle lotion once daily for up to eight weeks. The adverse reactions occurring in ≥1% of the subjects treated with DUOBRII through Week 8 were contact dermatitis (7%), application site pain (3%), folliculitis (2%), skin atrophy (2%), and excoriation (2%). USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryBased on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, DUOBRII Lotion may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Safety in pregnant females has not been established. The potential risk to the fetus outweighs the potential benefit to the mother from DUOBRII Lotion during pregnancy; therefore, DUOBRII Lotion should be discontinued as soon as pregnancy is recognized [see Contraindications, Warnings and Precautions, Clinical Pharmacology].Observational studies suggest an increased risk of low birthweight in infants with the maternal use of potent or very potent topical corticosteroids (see Data).In animal reproduction studies with pregnant rats, reduced fetal body weights and reduced skeletal ossification were observed after topical administration of a tazarotene gel formulation during the period of organogenesis at a dose 11 times the maximum recommended human dose (MRHD) (based on AUC comparison). In animal reproduction studies with pregnant rabbits, single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were observed after topical administration of a tazarotene gel formulation at 116 times the MRHD (based on AUC comparison) (see Data).In animal reproduction studies with pregnant rats and rabbits, malformations, fetal toxicity, developmental delays, and/or behavioral delays were observed after oral administration of tazarotene during the period of organogenesis at doses 9 and 228 times, respectively, the MRHD (based on AUC comparison). In pregnant rats, decreased litter size, decreased numbers of live fetuses, decreased fetal body weights, and increased malformations were observed after oral administration of tazarotene prior to mating through early gestation at doses 9 times the MRHD (based on AUC comparison) (see Data).In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oral administration of halobetasol propionate during the period of organogenesis to pregnant rats and rabbits (see Data). 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 DUOBRII Lotion.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.DataHuman DataAvailable observational studies in pregnant women did not identify a drug-associated risk of major birth defects, preterm delivery, or fetal mortality with the use of topical corticosteroids of any potency. However, when the dispensed amount of potent or very potent topical corticosteroids exceeded 300 g during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants.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.In an embryofetal development study in rats, a tazarotene gel formulation, 0.5% (0.25 mg/kg/day tazarotene) was topically administered to pregnant rats during gestation days 6 through 17. Reduced fetal body weights and reduced skeletal ossification occurred at this dose (11 times the MRHD based on AUC comparison). In an embryofetal development study in rabbits, a tazarotene gel formulation, 0.5%, 0.25 mg/kg/day tazarotene) was topically administered to pregnant rabbits during gestation days 6 through 18. Single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were noted at this dose (116 times the MRHD based on AUC comparison).When tazarotene was given orally to animals, developmental delays were seen in rats; malformations and post-implantation loss were observed in rats and rabbits at doses producing 9 and 228 times, respectively, the MRHD (based on AUC comparisons).In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, classic developmental effects of retinoids including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights were observed at this dose (16 times the MRHD based on AUC comparison). A low incidence of retinoid-related malformations was observed at that dose.In a pre- and postnatal development toxicity study, topical administration of a tazarotene gel formulation (0.125 mg/kg/day) to pregnant female rats from gestation day 16 through lactation day 20 reduced pup survival but did not affect the reproductive capacity of the offspring. Based on data from another study, the systemic drug exposure in the rat at this dose would be equivalent to 5 times the MRHD (based on AUC comparison).LactationRisk SummaryThere are no data on the presence of tazarotene, halobetasol propionate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production after treatment with DUOBRII Lotion.After single topical doses of a 14C-tazarotene gel formulation to the skin of lactating rats, radioactivity was detected in rat milk.

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 DUOBRII Lotion and any potential adverse effects on the breastfed child from DUOBRII Lotion.Clinical ConsiderationsAdvise breastfeeding women not to apply DUOBRII Lotion directly to the nipple and areola to avoid direct infant exposure.Females and Males of Reproductive PotentialPregnancy TestingDUOBRII Lotion is contraindicated in women who are pregnant. Females of reproductive potential should be warned of the potential risk and use adequate birth-control measures during treatment with DUOBRII Lotion. The possibility that a female of reproductive potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy should be obtained within 2 weeks prior to DUOBRII Lotion therapy, which should begin during menstruation.ContraceptionBased on animal studies, DUOBRII Lotion may cause fetal harm when administered to a pregnant female [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with DUOBRII Lotion. Pediatric UseSafety and effectiveness of DUOBRII Lotion 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 the 270 subjects exposed to DUOBRII Lotion in clinical trials, 39 subjects were 65 years or older. Clinical trials of DUOBRII Lotion 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.A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to 1.4 times the MRHD (based on AUC comparison).A long-term study with topical application of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Tazarotenic acid systemic exposure at the highest dose was 35 times the MRHD (based on AUC comparison).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, and 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.Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in human lymphocytes. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in an in vivo mouse micronucleus test.Studies in rats following oral administration of halobetasol propionate at dose levels up to 0.05 mg/kg/day, approximately 0.53 times the MRHD based on BSA comparisons, indicated no impairment of fertility or general reproductive performance.No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of a tazarotene gel formulation up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat at the highest dose was 5 times the MRHD (based on AUC comparison).No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene, which produced a systemic exposure 17 times the MRHD (based on AUC comparison).No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose, which produced a systemic exposure 30 times the MRHD (based on AUC comparison).Manufactured for:Bausch Health Americas, Inc. Bridgewater, NJ 08807 USABy:Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada U.S. Patent Numbers: 6,517,847; 8,809,307 and 10,251,895 DUOBRII is a trademark of Ortho Dermatologics’ affiliated entities.©2019 Bausch Health Companies Inc. or its affiliates. DUO.0039.USA.18 Based on 9645601

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January 2020 4 Volume 19 • Issue 1

Copyright © 2020 EDITORIAL BOARD Journal of Drugs in Dermatology

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

Impact FactorImpact Factor Score: 1.394*

Normalized Eigenfactor® Score: 0.574*

Article Influence Score: 0.378*

*Clarivate Analytics, Formerly the IP & Science Business of Thomson Reuters, June 2019




Copyright © 2020 TABLE OF CONTENTS Journal of Drugs in Dermatology

ORIGINAL ARTICLES

12 The Role of Medical Nutrition Therapy in Dermatology and Skin Aesthetics: A ReviewMartina M. Cartwright PhD RD, Emmy M. Graber MD MBA, Linda Stein Gold MD

20 Consensus Recommendations for 4th Generation Non-Microneedling Monopolar Radiofrequency for Skin Tightening: A Delphi Consensus Panel Anne Chapas MD, Brian S. Biesman MD, Henry Hin Lee Chan MD, Michael S. Kaminer MD, Suzanne L. Kilmere, Mary P. Lupo MD, Ellen Marmur, Susan Van Dyke MD

28 Ultrasound Evaluation of a Single Treatment With a Temperature Controlled Multi-Frequency Monopolar Radio Frequency Device for the Improvement of Localized Adiposity on the Abdomen and FlanksAmy Taub MD, James Bartholomeusz BS BAppSc

36 Calculating the Thickness of the Superficial Fatty Layer of the Body Using Age, Gender, and Body Mass Index Sebastian Cotofana MD PhD, Doris Hexsel MD, Luiz E.T. Avelar MD, Christine G. Munia MD, Mariana Muniz MD, Gabriela Casabona MD, Thilo L. Schenck MD PhD, Jeremy B. Green MD, Nirusha Lachman PhD, Konstantin Frank MD

46 Demonstration of the Antioxidant Capabilities of a Product Formulated With Antioxidants Stabilized in Their Reduced FormZoe Diana Draelos MD, Catherine J. Pachuk PhD

50 Topical Agents for the Treatment of Atopic DermatitisLawrence F. Eichenfield MD, Thomas Luger MD, Kim Papp MD, Jonathan I. Silverberg MD PhD MPH, Debra Sierka PhD, Chuanbo Zang PhD, Anna M. Tallman PharmD, Michael A. Zielinski PharmD, William C. Ports DVM

66 Q-Switched 1064nm Nd:YAG Laser in Treating Axillary Hyperpigmentation in Filipino Women With Skin Types IV-V Irene Gaile C. Robredo MD FPDS



© RHOFADE is a registered trademark of EPI HEALTH, LLC.[RHO-JA-1119]

References: 1. RHOFADE® cream full Prescribing Information 2018.

INDICATIONRHOFADE cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

IMPORTANT SAFETY INFORMATION AND WARNINGSWARNINGS AND PRECAUTIONS Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. RHOFADE cream should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.

Potentiation of Vascular Insuffi ciency RHOFADE cream should be used with caution in patients with cerebral or coronary insuffi ciency, Raynaud’s phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insuffi ciency develop.

Risk of Angle Closure GlaucomaRHOFADE cream may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop.

CONTRAINDICATIONSThere are no contraindications for RHOFADE cream.

ADVERSE REACTIONSThe most common adverse reactions >1% for RHOFADE cream were: application-site dermatitis 2%, worsening infl ammatory lesions of rosacea 1%, application-site pruritus 1%, application-site erythema 1%, and application-site pain 1%.

For topical use only. Not for oral, ophthalmic, or intravaginal use.Please see full Prescribing Information for RHOFADE cream at rhofadehcp.com and Brief Summary attached.

RHOFADE cream is the #1 prescribed topical treatment for persistent facial erythema associated with rosacea

in adults*At hours 3, 6, 9, and 12 on Day 29 of clinical trials, a >2-grade improvement in per-sistent facial erythema was seen in 12% to 18% of subjects using RHOFADE cream vs 5% to 9% using vehicle. The most common side eff ects at the application site include: dermatitis, worsening of rosacea pimples, itching, redness, and pain.1 These are not all the possible side eff ects of RHOFADE cream. Individual results may vary.

BEFOREDay 1: Predose

AFTERDay 29: Hour 12

Unretouched photos of clinical trial subject. Individual results may vary.

See results with RHOFADE creamNot an actual patient

*Based on Symphony Health PHAST data recording the number of prescriptions written between July 2017and October 2019. Data on fi le. EPI Health, LLC

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BRIEF SUMMARY—PLEASE SEE THE RHOFADE® CREAM PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION.

INDICATIONS AND USAGERHOFADE cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

DOSAGE AND ADMINISTRATIONFor topical use only. Not for oral, ophthalmic, or intravaginal use.Prime the RHOFADE cream pump before using for the first time. To do so, with the pump in the upright position, repeatedly depress the actuator until cream is dispensed and then pump three times. Discard the cream from priming actuations. It is only necessary to prime the pump before the first dose.RHOFADE cream tubes do not require priming.Apply a pea-sized amount of RHOFADE cream, once daily in a thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. Wash hands immediately after applying RHOFADE cream.

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSPotential Impacts on Cardiovascular DiseaseAlpha-adrenergic agonists may impact blood pressure. RHOFADE cream should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.Potentiation of Vascular InsufficiencyRHOFADE cream should be used with caution in patients with cerebral or coronary insufficiency, Raynaud’s phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop.Risk of Angle Closure GlaucomaRHOFADE cream may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop.

ADVERSE REACTIONSClinical Studies ExperienceBecause clinical trials are conducted under 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 practice.A total of 489 subjects with persistent facial erythema associated with rosacea were treated with RHOFADE cream once daily for 4 weeks in 3 controlled clinical trials. An additional 440 subjects with persistent facial erythema associated with rosacea were also treated with RHOFADE cream once daily for up to one year in a long-term (open-label) clinical trial. Adverse reactions that occurred in at least 1% of subjects treated with RHOFADE cream through 4 weeks of treatment are presented in the table below:Adverse Reactions Reported by ≥ 1% of Subjects Through 4 Weeks of Treatment in Controlled Clinical Trials

Adverse ReactionPooled Controlled Clinical Trials

RHOFADE Cream (N = 489)

Vehicle (N = 483)

Application-site dermatitis 9 (2%) 0

Worsening inflammatory lesions of rosacea 7 (1%) 1 (< 1%)

Application-site pruritus 5 (1%) 4 (1%)

Application-site erythema 5 (1%) 2 (< 1%)

Application-site pain 4 (1%) 1 (< 1%)

In the long-term (open-label) clinical trial, the rates of adverse reactions over a one-year treatment period were as follows: worsening inflammatory lesions of rosacea (3%), application-site dermatitis (3%), application-site pruritus (2%), application-site pain (2%), and application-site erythema (2%). Subjects with persistent erythema along with inflammatory lesions were allowed to use additional therapy for the inflammatory lesions of rosacea.

DRUG INTERACTIONSAnti-hypertensives/Cardiac GlycosidesAlpha-adrenergic agonists, as a class, may impact blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised.Caution should also be exercised in patients receiving alpha-1 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynaud’s disease.

Monoamine Oxidase InhibitorsCaution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryThere are no available data on RHOFADE cream use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. A literature article describing intranasal decongestant use in pregnant women identified a potential association between second-trimester exposure to oxymetazoline (with no decongestant exposure in the first trimester) and renal collecting system anomalies. In animal reproduction studies, there were no adverse developmental effects observed after oral administration of oxymetazoline hydrochloride in pregnant rats and rabbits at systemic exposures up to 3 times and 73 times, respectively, the exposure associated with the maximum recommended human dose (MRHD). The estimated background risks of major birth defects and miscarriage for the indicated population 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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsFollowing repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment of nasal congestion at a dose 5 times higher than recommended, one case of fetal distress was reported in a 41-week pregnant patient. The fetal distress resolved hours later, prior to the delivery of the healthy infant. The anticipated exposures for the case are 8- to 18-fold higher than plasma exposures after topical administration of RHOFADE cream.Human DataNo adequate and well-controlled trials of RHOFADE cream have been conducted in pregnant women. Across all clinical trials of RHOFADE cream, two pregnancies were reported. One pregnancy resulted in the delivery of a healthy child. One pregnancy resulted in a spontaneous abortion, which was considered to be unrelated to the trial medication.LactationNo clinical data are available to assess the effects of oxymetazoline on the quantity or rate of breast milk production, or to establish the level of oxymetazoline present in human breast milk post-dose. Oxymetazoline was detected in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RHOFADE cream and any potential adverse effects on the breastfed child from RHOFADE cream or from the underlying maternal condition.Pediatric UseSafety and effectiveness of RHOFADE cream have not been established in pediatric patients below the age of 18 years.Geriatric UseOne hundred and ninety-three subjects aged 65 years and older received treatment with RHOFADE cream (n = 135) or vehicle (n = 58) in clinical trials. No overall differences in safety or effectiveness were observed between subjects ≥ 65 years of age and younger subjects, based on available data. Clinical studies of RHOFADE cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

OVERDOSAGERHOFADE cream is not for oral use. If oral ingestion occurs, seek medical advice. Monitor patient closely and administer appropriate supportive measures as necessary. Accidental ingestion of topical solutions (nasal sprays) containing imidazoline derivatives (e.g., oxymetazoline) in children has resulted in serious adverse events requiring hospitalization, including nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. Keep RHOFADE cream out of reach of children.

RHOFADE is a registered trademark of EPI HEALTH, LLC.Patented. U.S. Patent Numbers: U.S. 7,812,049; U.S. 8,420,688; U.S. 8,815,929; U.S. 8,883,838; U.S. 9,974,773; and U.S. 10,335,391. Made in the U.S.A.

RHOFADE® (oxymetazoline HCI) cream, 1%

RHO-BSUM-1119


https://www.rhofade.com/




ORIGINAL ARTICLES (CONTD)

70 Tazarotene 0.045% Lotion for Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Results from Two Phase 3 TrialsEmil A. Tanghetti MD, William P. Werschler MD, Terry Lain MD, Eric Guenin PharmD PhD MPH, Gina Martin MOT, Radhakrishnan Pillai PhD

78 Tazarotene 0.045% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris in Adult MalesFran E. Cook-Bolden MD, Michael H. Gold MD, Eric Guenin PharmD PhD MPH

CASE REPORTS

86 Rapid and Sustained Improvement in a Patient With Plaque Psoriasis Switched to Brodalumab After Failing Treatment Clearance on Six Other Biologic TherapiesKathleen Haycraft DNP, Linda Cooke MD

89 Clinical Characteristics and Disease Course in Black Patients With Lymphomatoid Papulosis: A Case Series Shamir Geller MD, Sarah J. Noor MD, Patricia L. Myskowski MD

92 Necrobiosis Lipoidica Mimicking Cutaneous Sarcoidosis Finally Treated With an Intralesional Injection of Corticosteroid: A Case ReportMohamad Goldust MD, Ghasem Rahmatpour Rokni MD, Jeffrey M. Weinberg MD, Leon Kircik MD, Martine Bagot MD, Ali Mirabid

BRIEF COMMUNICATION

95 A Closer Look at a Multi-Targeted Approach to Hair Loss in African American WomenCheryl Burgess MD, Wendy Roberts MD, Jeanine Downie MD, Megan Kera PA-C, Sophia Kogan MD, Danamarie Belpulsi MD

100 Minimally Invasive Facial Cosmetic Procedures for the Millennial Aesthetic PatientNisreen Mobayed BS, Julie K. Nguyen MD, Jared Jagdeo MD MS





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104 Growing Patient Education in Dermatology: An Upside-Down Tree Analogy for Immunomodulatory TherapiesSteven R. Madsen MD, Aleksi J. Hendricks BS, Vivian Y. Shi MD

PIPELINE PREVIEWS



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Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology

SPECIAL TOPIC

The Role of Medical Nutrition Therapy in Dermatology and Skin Aesthetics: A Review

Martina M. Cartwright PhD RD,a Emmy M. Graber MD MBA,b Linda Stein Gold MDc

ªDepartment of Nutritional Sciences, The University of Arizona, Tucson, AZ BDermatology Institute of Boston, Boston, MA; Affiliate Northeastern University, Boston, MA

cHenry Ford Health System, Detroit, MI

The field of nutritional sciences has advanced beyond research of the role of individual nutrients, supplements, and diet in disease to the multi-disciplinary practice of adjuvant medical nutrition therapy (MNT). Nutrition research is often that of association rather than cause and effect, yet there are compellingly strong relationships between diet and disease severity and incidence of a number of dermatological conditions. MNT is a tailored, evidence-based, comprehensive nutrition intervention strategy delivered by a physician and registered dietitian to a subset of dermatology patients who may benefit from nutrition intervention. With shorter clinical interac-tion times and patients requesting nutrition information, a collaborative approach may spur clinically meaningful nutritional changes with advice beyond the often quoted “eat better, lose weight, and exercise.” This review provides a comprehensive overview of the latest Dermatology Medical Nutrition Therapy (D-MNT) recommendations and advocates an evidence-based, collaborative approach to dermatological patient care.

J Drugs Dermatol. 2020;19(1):12-18. doi:10.36849/JDD.2020.4745

ABSTRACT

INTRODUCTIONMedical Nutrition TherapyMedical Nutrition Therapy (MNT) is recognized by the Ameri-can Academy of Nutrition and Dietetics, the Centers for Disease Control and the National Institutes of Health (NIH) as essential to the prevention and treatment of certain diseases.1-3 MNT is an evidence-based approach to addressing specific health con-ditions through a tailored nutrition care plan implemented by a registered dietitian or nutrition professional who provides comprehensive diagnostic, therapy, and counseling services based on an individual’s nutritional intervention needs.4 MNT can be a beneficial adjuvant to some dermatology patients with chronic skin conditions, but questions remain as to the strength of the associations between diet or nutrients and skin health.5,6

Confounding interpretation of nutrition data is the lack of level one evidence involving placebo-controlled trials.7 Neverthe-less, strong associations have been observed between dietary components and some skin diseases.5

MNT involves a comprehensive nutrition assessment, planning and implementation of evidence-based nutrition intervention with goal-directed diet counseling and post-implementation progress monitoring.1 Strong MNT protocols exist for diabe-tes, cardiovascular disease, oncology, weight management and food allergy,1-3 with dermatology MNT (D-MNT) an area of evolving interest.5,6

MNT in DermatologyDermatology MNT (D-MNT) recommendations exist for cu-

taneous manifestations of nutrient imbalance, acne, atopic dermatitis (AD), psoriasis and wound management. MNT is meant to complement, not replace, the normal use of thera-pies prescribed by physicians and other licensed healthcare providers and may be appropriate for subsets of dermatology patients, particularly those with inflammatory conditions5 (Fig-ure 1).

Acne, AD, psoriasis and wounds are characterized by inflam-mation.9 Diet, excess nutrient intake and deficiencies and body composition influence inflammation; D-MNT focuses on modu-lation of nutrients affecting inflammatory pathways.5

Obesity is a condition of subclinical inflammation linked to the incidence and severity of AD, psoriasis, and poor wound healing.10 Central adipose tissue is metabolically active, releas-ing cytokines, growth factors and chemokines which regulate appetite, inflammation, and metabolism.11 Waist circumfer-ence rather than body mass index (BMI) is a better indicator of inflammatory disease risk and metabolic syndrome.10 Loss of adipose may improve some inflammatory skin conditions, but loss of lean body mass (LBM) contributes to skin barrier dysfunction.12

Sarcopenia is age-related loss of LBM. Nutrient poor diets and chronic inflammatory conditions accelerate sarcopenic onset and severity leading to compromised skin barrier function and wounds.12 Specific MNT protocols exist to combat sarcopenia

doi:10.36849/JDD.2020.4745



13

Journal of Drugs in DermatologyJanuary 2020 • Volume 19 • Issue 1

M.M. Cartwright, E.M. Graber, L. Stein Gold

FIGURE 1. Dermatology Medical Nutrition Therapy (D-MNT) protocol algorithm.



14



sequala. Optimal nutrient intake varies based on age, gender, and medical conditions.14 Nutrient excess and deficiencies im-pact skin appearance (Table 1 and 2) as do dietary patterns.14-17

In a study of 4,026 middle-aged women, those with wrinkled appearance consumed significantly less dietary protein, potas-sium, vitamin C, and vitamin A.18 Dry skin is associated with lower linoleic acid and vitamin C intake.18 Less wrinkling of sun-exposed skin in older adults was observed in those con-suming eggs, yogurt, legumes, fruits, vegetables, and olive

and may be implemented in some dermatology patients.

Enhanced Recovery After Surgery (ERAS) protocols use MNT to address nutritional status prior to elective surgeries resulting in notable outcome benefits.13 Development of D-MNT ERAS protocols for cosmetic surgeries and melanoma are underway.

Skin Health and Aesthetics Initial D-MNT assessment and diagnosis may reveal nutrient imbalances confirmed by laboratory values and other clinical

TABLE 1.

Recommended Macronutrient Dietary Recommendations for Adults and Potential Symptoms of Deficiency and Excess14,17

NutrientRecommended Intake Levels

Food Sources Normal Deficiency Excess

Protein10-35% of

total calories or 46-56 gm/d

EAA—meat, poultry, eggs, dairy or com-binations of vegan foods

Structure, function of all biological functions

Common in at risk groups (elderly, chronically ill, malnourished). Poor

wound healing, infection, sarcopenia.

Kidney dysfunction, obesity, calcium loss

Fats25-35%

of calories from fat

Fish, dairy, meat, eggs, avocados, oils, nuts

Structure and function; hormones; skin lipids, ceramides; fat soluble

vitamin absorption

RareObesity, heart disease

risk

Essential Fatty Acids (EFA)

5-10% of total

calories

Fatty fish, flaxseeds,

nuts

Structure and function; hormones; membranes

Rare. Low fat diets, extreme vegan-ism, anorexia nervosa, malabsorptive

diseases, and starvation; extremely dry skin, dermatitis and alopecia. Bar-rier function is impaired with greater

transepidermal water loss (TEWL) and poor wound healing.

Possible CV and im-mune dysfunction

Linoleic acid (LA)

11-14 gm/d Flaxseed, nuts -- -- --

Alpha linolenic acid

(ALA)1.1-1.6 gm/d Flaxseed, nuts -- -- --

EPA 250-500 mg/d Fatty fish -- -- Impaired blood clotting

DHA 250-500 mg/d Fatty fish -- -- Impaired blood clotting

Carbohydrates30-65% of total calories

Whole grains, fruits, vegetables,

sweets

Energy to keratinocytes Poor wound healing

High glucose inhibits proliferation of epider-mal keratinocytes and dermal fibroblasts, im-pairing wound healing and causing cross link-ing of collagen (AGEs); IGF-1, hyperinsulinemia

driven acne; obesity

Complex20-55% of total calories

Whole grains, fruits,

vegetables -- --

Potential for excess caloric intake

Simple

Added sugar

<10% of total calories

Fruits, vegetables,

dairy

Sugary foods and beverages

-- -- Hyperinsulinemia



15



TABLE 2.

Nutrients and Associated Dermatological Deficiency and Excess Symptoms. Established RDA and Upper Limit (UL) are shown. UL does not apply to individuals with medical conditions and is defined as the level for which there is an association for an increased risk of adverse ef-fects.14,15

NutrientAdult RDA

Deficiency Causes/Risk FactorsExcess/Toxicity Upper Limit

(UL)Causes/Risk Factors

Riboflavin (B2)1.1-1.3 mg/d

Ariboflavinosis Inflammation of skin and mucous mem-brane--angular stomatitis,

cheilosis, hair loss.

Chronic diarrhea, malabsorption disorders,

thyroid disordersNone reported

n/aNo UL

Niacin (B3)24-16 niacin

equivalents (NE)

Pellegra—diarrhea, dermatitis, dementia

Malabsorption disorders, alcoholism, prolonged

isoniazid treatment Niacin “flush”

Supplements; energy drinks, therapeutic dosing; No UL

B61.3-1.7 mg/d

Scaly dermatitis; seborrheic dermatitis, cheilosis

Malabsorption diseases, alcoholism, poor protein diets;

isoniazid Skin lesions n/a; No UL

Biotin (B7)30 mcg/d

Skin rash, hair lossCrohn’s disease, prolonged

use of anti-seizure mediations; long term antibiotics

None reported n/a; No UL

B122.4 mcg

Psoriasis, wound healing Stomach acid suppressants;

age; strict vegan dietsAcne, rosacea Supplements; No UL

Vitamin C (ascorbic acid)

75-90 mg/dAdded 35 mg for smokers

Scurvy-pinpoint hemor-rhages, poor wound healing, stratum corneum thickening, fragility, photoaging and loss

of collagen

Low produce diets; alcoholism, anorexia;

smoking, dialysis Diarrhea

Supplements; 2,000 mg/d UL

Vitamin A 700-900 mcg

Retinol Activity Equivalents (RAE)

Phrynoderma—dry, hyper-keratotic papules; poor

wound healing Atopic dermatitis

Fat malabsorption, small bowel surgery; bariatric surgery, liver disorders; poor diet

Hypervitaminosis A—joint pain, headaches, loss of hemoglobin

and potassium amenorrhea

Eating animal liver (beef) 3,000 RAE UL

Beta Carotene (pro-vitamin A)

n/a Poor diet; low produce diet; CarotodermaSupplements; high

consumption of orange-yellow produce; No UL

Vitamin D(Dairy,

sunlight)600-800 IU/d

Dry skin; incidence and severity of atopic dermatitis

and psoriasis; skin aging;

Fat malabsorption; limited UV light exposure

(indoors, cloudy/northern cli-mate, SPF >8); older adults

Hypervitaminosis D—100 mcg/day or 4,000 IU for adults; No

dermatology symptoms; kidney stones, kidney failure; arterial

calcification; joint pain; nausea; vomiting

Supplements; overcon-sumption of Vitamin D

fortified foods 4,000 IU UL; Toxicity with 10,000-40,000 IU

Vitamin E15 mg/d

Dry skin; erythrocyte hemoly-sis and bruising; ulcerations

Fat malabsorption

Hypervitaminosis E--100mg--blood clotting issues; stomatitis, cheilosis, urticaria and impaired

wound healing

Supplements; 1,000 mg/d UL

Vitamin K90-120 mcg/d

Bruising, hemorrhage Fat malabsorption, Prolonged antibiotic use; anti-coagulant

drugs

Not common—hemolysis, jaundice and brain damage

Supplements; No UL

Copper 900 mcg/d

Poor wound healing; steely hair syndrome pale skin,

photoaging.

Zinc supplementation, poor diet

Liver dysfunction, GI symptoms, renal failure, weakness

Supplements; 10 mg/d UL 10-20 gm lethal

Iron8-18 mg/d

Spoon shaped nails, pale pal-lor, poor wound healing

Poor diet; strict vegans (no red meat); low vitamin C; children and childbearing aged women

Liver dysfunction; blood clotting abnormalities

Supplements; 45 mg UL

Selenium 55 mcg/d

Heart disease; psoriasis Poor diet1 mg or more vomiting,

diarrhea, brittle hair and nail loss; skin lesions

Supplements; excessive intake of Brazil nuts 400

mcg/d UL

Zinc9-11 mg/d

Hair loss, lesions, rough dry skin, dermatitis, poor wound healing; Epidermolysis bul-losa acquired acrodermatitis

enteropathica, necrolytic migratory erythema.

High phytate diets; children; wound/burn patients;

50-450 mg can cause vomiting headaches –interferes with copper

absorption at 40 mg;

Supplements; storing food in galvanized pots

40 mg/d UL



16



tion of Cutibacterium acnes.25 IGF-1 increases expression of SREBP-1, which in turn may stimulate sebocyte lipogenesis through activation of phosphoinositide 3-kinase/Akt pathways. Cow’s milk is highly insulinemic and increases IGF-1.23,24

The AAD does not advocate specific dietary changes in the management of acne yet, emerging data suggests high GI diets may be associated with limited evidence suggesting that some dairy products influence acne.26 Juhl, et al27 found that “any” dairy was linked to acne severity whereas a 2018 meta-analysis found a positive association between acne and milk but not yogurt or cheese.28 From a nutritional assessment standpoint, “dairy” includes more than cow-derived sources; is unknown if the animal source influences acnegenesis.

MNT-acne recommends limited cow’s milk intake in those with a documented sensitivity.5,6 Probiotics have shown some effi-cacy in small studies. Twenty adults with acne were given oral lactobacillus rhamnosus supplements; acne improved and co-incided with a reduction in IGF-1.29 Therapeutically, probiotic foods and supplements are used to treat antibiotic-associated diarrhea and may benefit acne patients on oral antibiotics.30

Specific recommendations regarding the dose and strain(s) re-main elusive.5

There is no evidence that alcohol, tea, or coffee cause or wors-en acne.23 Small studies suggest chocolate is acnegeneic.23 Fish oil supplements do not improve acne severity31 but may reduce isotretinoin dryness.32 Zinc modulates 5-alpha reductases and affect androgen activity, but specific recommendations are lack-ing.24

A low GI diet containing probiotic foods and an anti-inflamma-tory meal pattern may benefit some acne patients.23 Patients on isotretinoin may require hypertriglyceridemia MNT.33

Atopic DermatitisIg-E mediated food allergies are strongly associated with AD.34

MNT elimination diets are initiated after physician-initiated food challenge testing and documented reactions.24 In children, AD flares are linked to cow’s milk, eggs, wheat, soy, and peanuts.24

In adults tree nuts, peanuts, fish, shellfish, and pollen associ-ated foods like tomatoes, chamomile, bananas, cantaloupe, honeydew, and celery may trigger flares.24 MNT is essential to formulate AD elimination diets that prevent deficiency in grow-ing children and adults with comorbidities.24,34

AAD recommends the following:35 If a patient has a true Ig-E-mediated allergy, practice avoidance to prevent potential serious health sequelae; children < 5 years of age with moder-ate to severe AD should be evaluated for allergies to milk, egg, peanut, wheat, and soy if at least 1 of the following is met: (A) persistent AD in spite of optimized treatment or (B) having a re-

oil.19 Smoother skin and less visible sun damage coincided with intake of vitamin C and lycopene-rich foods.18,20,21 Oral collagen given daily over several weeks may improve skin tone, texture, and hydration but results are inconsistent.22

High Glycemic Index (GI) diets and fried, grilled, and roasted foods are associated with Advanced Glycation End products (AGEs).20 Formed when sugar binds to collagen, fibronectin laminin, and elastin in the skin, AGE renders skin repair mecha-nisms ineffective and contributes to poor wound healing and wrinkles.20

The American Academy of Dermatology (AAD) does not pro-vide recommendations regarding diet and aesthetics. In clinical nutrition practice, D-MNT for skin health includes dietary pat-tern recommendations for optimal essential nutrient intake specific to the patient’s age, gender, and co-morbid condi-tions.14,15 Supplementation is only recommended for deficiency or medical need.15

AcneHigh glycemic index (GI)/glycemic load (GL) and frequent dairy intake are associative factors in acne severity.23 Simple sugars raise blood glucose levels rapidly and with a similarly robust insulin response. Chronic hyperinsulinemia driven by diets rich in high GI foods, elevated GL, and dairy elicits an endocrine response that triggers insulin like growth factor (IGF-1) and suppresses IGFBP-3.24 IGF binding to receptors sets off a mo-lecular cascade of inflammatory events within skin cells and follicles. IGF is a strong mediator of cell growth and enhances bioavailability of androgens.24 During puberty, IGF-1 increases dehydroepiandrosterone sulfate (DHEAS) synthesis, stimulates skin androgen receptors (AR), and induces 5-α-reductase.24

Both IGF-1 and androgens stimulate sebum production.25 An-drogens, like testosterone and dihydrotestosterone, bind to AR in sebocytes promoting localized inflammation and sebum pro-duction. This drives abnormal keratinization and desquamation leading to obstruction of the pilosebaceous duct and prolifera-

TABLE 3.

Recommended Nutrient Intakes for Wound Management43-46

Nutrient Amount Per Day

Protein 1.5-2.0 gm/kg/day

HMB 1.5 gm/d BID

Arginine 4.5 gm/d - 7 gm/d BID

Glutamine 0 - 7 gm/d BID

Zinc17 mg/d40-220 mg BID for 10 -14 days if deficient

Vitamin A 10,000 -15,000 IU for 10 -14 days if deficient

Vitamin C500 – 1000 mg/d in divided doses; 1,000-2,000/d for burns



17



liable history of immediate reaction after ingestion of a specific food; inconsistent evidence precludes specific dietary supple-ments for AD treatment.

PsoriasisCardiovascular disease risk and obesity are associated with psoriasis.36,37 Weight loss and reduced waist circumference improves psoriasis. Established MNT protocols for metabolic syndrome, CVD, and obesity are often implemented for the psoriatic patient. Indeed, the National Psoriasis Foundation (NPF) strongly recommends dietary weight reduction with a hypocaloric diet and a meal pattern that may affect psoriasis such as implementation of a Mediterranean diet (MD).37,38

Some psoriatic patients may benefit from bariatric surgery,36

although micronutrient deficiencies, impaired wound healing and skin infections resistant to traditional dermatological inter-vention have occurred in this patient population.39 Therefore, those with a history of bariatric surgery should be assessed for nutrient deficiencies.39

The AAD-NPF guidelines36 call for weight management and counseling including dietary and exercise recommendations for adults >25 years with type 2 diabetes mellitus, ≥ 3 cardio-vascular risk factors and/or hypertension. Well-established MNT protocols exist for these conditions often with benefit of insurance coverage.1-3

RosaceaRosacea may be exacerbated by spicy and hot foods. Histamine rich foods like cola, soy and processed meats may enhance red-ness24 and both alcohol and caffeine have been implicated in worsening rosacea in some patients.40 It’s postulated that these dietary triggers stimulate neurogenic vasodilation, leading to facial flushing, burning and redness. Avoidance of dietary trig-gers is recommended.40

MelanomaMelanoma patients may benefit from oncology MNT protocols specific to radiation/chemotherapeutic treatment regimens.3

Antioxidant supplementation for melanoma prevention has been inconclusive.24,41 The Skin Cancer Foundation recom-mends an anti-inflammatory, nutrient-dense MD-like meal plan based on previous research.41,42 There are no AAD dietary rec-ommendations for the prevention or treatment of melanoma.

WoundsThe three phases of wound healing are inflammation, prolif-eration and remodeling.43 Non-healing wounds remain in the inflammation phase. Wounds increase dietary protein demand by up to 250% and caloric requirements up to 50%. MNT proto-cols exist for various types of wounds.43

Nutritional management of wounds includes adequate dietary protein, certain vitamins and minerals and consideration of beta-hydroxy-beta methyl butyrate (HMB) oral nutrition supple-ments with arginine and glutamine.43-46

HMB, a metabolite of the amino acid leucine, is found in small amounts in foods and inhibits muscle protein degradation while promoting muscle protein synthesis by modulating inflamma-tion and protecting muscle from stress related damage.43,46

HMB increases LBM in the infirmed, immobile and athletes;46

in head and neck cancer, it reduces radiation dermatitis47 and improves diabetic foot wounds.48

Arginine stimulates protein biosynthesis, mediates growth hormone and facilitates nitric oxide production to improve va-sodilation, vascular permeability and blood flow to wounded areas; it also supports macrophages and T cells to quell infec-tion.43 Glutamine combined with HMB and arginine stimulates collagen synthesis and supports immunity.43

HMB (3 gram/d) with arginine (14 gram/day) and glutamine (14 gram/day) over six weeks significantly increased muscle and collagen synthesis, reduced muscle degradation, and improved wound healing.46 Therapeutic levels of HMB must be supple-mented.

Reducing Inflammation Through DietRich in fruits, vegetables, whole grains, beans, nuts, seeds, legumes, red wine, fish and olive oil, the Mediterranean Diet may reduce risk of metabolic, cardiovascular, and neoplastic diseases.49 This largely plant based, low GI diet is abundant in antioxidants and monounsaturated fats fostering anti-in-flammation. Indeed, C-reactive protein and proinflammatory cytokines decline with habitual consumption.38 The MD may be calorically controlled for weight management and has found favor in modulating inflammatory skin conditions like acne, AD, psoriasis, and rosacea. It may improve skin tone, texture, and appearance of older skin.19,21,49

CONCLUSIONSNutritional science has evolved to a multi-disciplinary, evidence-based medical therapeutic approach to disease prevention and adjuvant treatment for a number of dermatological condi-tions. These conditions share a commonality of inflammation and specific MNT may improve skin health in certain patients. Dermatologists may consider collaboration with a registered dietitian an effective means to improve patient adherence to di-etary interventions.

DISCLOSURESDr. Cartwright is a speaker for Abbott Nutrition. The other au-thors have no relevant disclosures.



18



ACKNOWLEDGMENTSThe authors wish to thank Dr. Scott Going and Trudy Morrow for their review of this manuscript.

REFERENCES1. MNT versus nutrition education. The Academy of Nutrition and Dietetics

Web site. https://www.eatrightpro.org/payment/coding-and-billing/mnt-vs-nutrition-education Published August 2006. Accessed September 19, 2019

2. Centers for Disease Control. Medical Nutrition Therapy. https://www.cdc.gov/diabetes/dsmes-toolkit/reimbursement/medical-nutrition-therapy.html. Updated 2018. Accessed September 12, 2019.

3. National Cancer Institute. Nutrition in cancer care, professional version. https://www.cancer.gov/about-cancer/treatment/side-effects/appetite-loss/nutrition-hp-pdq. Accessed September 10, 2019.

4. Tinker LF, Heins JM, Holler HJ. Commentary and translation: 1994 nutrition recommendations for diabetes. J Am Diet Assoc. 1994;94:507–511.

5. Burris J, Wolfe K. Diet and dermatology. What is the role for Medical Nutri-tion Therapy? American Academy of Nutrition and Dietetics. 2018 National Conference. October 20-23, 2018. Web site. https://www.eatrightstore.org/cpe-opportunities/fnce-sessions/244-diet-and-dermatology-what-is-the-role-for-medical-nutrition-therapy. Accessed September 19, 2019.

6. Burris J, Rietkerk W, Woolf K. Acne: the role of medical nutrition therapy. J Acad Nutr Diet. 2013;113(3):416-30.

7. Laville M, Segrestin B, Alligier M, et al. Evidence-based practice within nutri-tion: what are the barriers for improving the evidence and how can they be dealt with? Trials. 2017;18(1):425.

8. Diseases and Conditions. The Academy of Nutrition and Dietetics. Web site. https://www.eatrightpro.org/news-center/nutrition-trends/diseases-and-con-ditions. Accessed September 1, 2019.

9. Dainichi T, Hanakawa S, Kabashima K. Classification of inflammatory skin diseases: a proposal based on the disorders of the three-layered defense systems, barrier, innate immunity and acquired immunity. J Dermatol Sci. 2014 Nov;76(2):81-9.

10. Stefanadi EC, Dimitrakakis G, Antoniou CK, et al. Metabolic syndrome and the skin: a more than superficial association. Reviewing the association be-tween skin diseases and metabolic syndrome and a clinical decision algo-rithm for high risk patients. Diabetol Metab Syndr. 2018;10:9.

11. Choe SS, Huh JY, Hwang IJ, et al. Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Front Endocrinol. 2016;7:30.

12. Robinson SM, Reginster JY, Rizzoli R, et al. Does nutrition play a role in the prevention and management of sarcopenia? Clin Nutr. 2018;37(4):1121-1132.

13. Nanavati AJ, Prabhakar S. Enhanced recovery after surgery: if you are not implementing it, why not? Pract Gastroenter. 2016;151:46-56.

14. National Institutes of Health. Office of Dietary Supplements. Nutrient rec-ommendations. Dietary reference intakes. https://ods.od.nih.gov/Health_In-formation/Dietary_Reference_Intakes.aspx. Accessed August 26, 2019.

15. Driscoll MS, Kwon EK, Skupsky H, et al. Nutrition and the deleterious side effects of nutritional supplements. Clin Dermatol. 2010;28(4):371-9.

16. Pappas A, Liakou A, Zouboulis CC. Nutrition and skin. Rev Endocr Metab Disord. 2016;17(3):443-448.

17. Demling RH. Nutrition, anabolism and the wound healing process: an over-view. Eplasty. 2009;9:65-94.

18. Cosgrove MC, Franco OH, Granger SP, et al. Dietary nutrient intakes and skin-aging appearance among middle-aged American women. Am J Clin Nutr. 2007;86:1225-1231.

19. Purba MB, Kouris-Blazos A, Wattanapenpaiboon N, et al. Skin wrinkling: can food make a difference? J Am Coll Nutr. 2001;20:71-80.

20. Draelos ZD. Aging skin: the role of diet: facts and controversies. Clin Derma-tol. 2013;31(6):701-6.

21. Darvin M, Patzelt A, Gehse S. Cutaneous concentration of lycopene cor-relates significantly with the roughness of the skin. Eur J Pharm Biopharm. 2008;69(3):943-7.

22. Proksch E, Segger D, Degwert J, et al. Oral supplementation of specific collagen peptides has beneficial effects on human skin physiology: a double-blind, placebo-controlled study. Skin Pharmacol Physiol. 2014;27(1):47-55.

23. Claudel JP, Auffret N, Leccia MT, et al. Acne and nutrition: hypotheses, myths and facts. J Eur Acad Dermatol Venereol. 2018;32(10):1631-1637.

24. McCusker M, Sidbury R. Nutrition and skin: Kids are not just little people. Clin Dermatol. 2016;34(6):698-709.

25. Lai JJ, Chang P, Lai KP, et al. The role of androgen and androgen receptor in skin-related disorders. Arch Dermatol Res. 2012;304(7):499-510.

26. Role of diet in acne: Recommendations. American Academy of Dermatolo-gy. Web site. https://www.aad.org/practicecenter/quality/clinical-guidelines/acne/role-of-diet-in-acne. Accessed September 24, 2019.

27. Juhl CR, Bergholdt HKM, Miller IM, et al. Dairy intake and acne vulgaris: a systematic review and meta-analysis of 78,529 children, adolescents, and young adults. Nutrients. 2018;10(8):1049.

28. Aghasi M, Golzarand M, Shab-Bidar S. Dairy intake and acne development: A meta-analysis of observational studies. Clin Nutr. 2019 Jun;38(3):1067-1075.

29. Fabbrocini G, Bertona M, Picazo Ó, et al. Supplementation with Lactobacil-lus rhamnosus SP1 normalises skin expression of genes implicated in insu-lin signalling and improves adult acne. Benef Microbes. 2016;7(5):625-630.

30. Fuchs-Tarlovsky V, Marquez-Barba MF, Sriram K. Probiotics in dermatologic practice. Nutrition. 2016 Mar;32(3):289-95.

31. Khayef G, Young J, Burns-Whitmore B, Spalding T. Effects of fish oil supple-mentation on inflammatory acne. Lipids Health Dis. 2012;11:165.

32. Mirnezami M, Rahimi H. Is oral omega-3 effective in reducing mucocutane-ous side effects of isotretinoin in patients with acne vulgaris? Dermatol Res Pract. 2018;2018:6974045.

33. Berglund L, Brunzell JD, Goldberg AC, et al. Treatment options for hypertri-glyceridemia: from risk reduction to pancreatitis. Best Pract Res Clin Endo-crinol Metab. 2014;28(3):423–437.

34. Bronsnick T, Murzaku EC, Rao BK. Diet in dermatology: Part I. Atopic derma-titis, acne, and nonmelanoma skin cancer. JAAD. 2014;71(6):1039.e1-1039.e12.

35. Atopic dermatitis: Recommendations for dietary interventions. American Academy of Dermatology. Web site. https://www.aad.org/practicecenter/quality/clinical-guidelines/atopic-dermatitis/disease-flares-and-adjunctive-therapy/recommendations-for-dietary-interventions. Accessed September 21, 2019.

36. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and atten-tion to comorbidities. JAAD. 2019;80(40):1073-1113.

37. Ford AR, Siegel M, Bagel J, et al. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the medical board of the National Pso-riasis Foundation: A systematic review. JAMA Dermatol. 2018;1;154(8):934-950.

38. Korovesi A, Dalamaga M, Kotopouli M, Papadavid E. Adherence to the Mediterranean diet is independently associated with psoriasis risk, sever-ity, and quality of life: a cross-sectional observational study. Int J Dermatol. 2019;58(9):e164-e165.

39. Zouridaki E, Papafragkaki DK, Papafragkakis H, et al. Dermatological compli-cations after bariatric surgery: report of two cases and review of the litera-ture. Dermatology. 2014;228:5-9.

40. Weiss E, Katta R. Diet and rosacea: the role of dietary change in the manage-ment of rosacea. Dermatol Pract Concept. 2017;7(4):31–37.

41. Ombra MN, Paliogiannis P, Stucci LS, et al. Dietary compounds and cutane-ous malignant melanoma: recent advances from a biological perspective. Nutr Metab. 2019;16:33.

42. Sarnoff DS, Gerome D. Can diet help prevent skin cancer? Skin Cancer Foundation Web site. https://www.skincancer.org/blog/can-your-diet-help-prevent-skin-cancer/. Published June 2017. Accessed September 10, 2019.

43. Quain AM, Khardori NM. Nutrition in wound care management: a compre-hensive overview. Wounds. 2015;27(12):327-35.

44. Brown KL, Phillips TJ. Nutrition and wound healing. Clin Dermatol. 2010; 28(4):432-9.

45. Alon T, Bagchi D, Preuss HG. Supplementing with beta-hydroxy-beta-methyl-butyrate (HMB) to build and maintain muscle mass: a review. Res Commun Mol Pathol Pharmacol. 2002;111:139-152.

46. Williams JZ, Abumrad N, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition. Ann Surg. 2002;236:369-375.

47. Imai T, Matsuura K, Asada Y, et al. Effect of HMB/Arg/Gln on the prevention of radiation dermatitis in head and neck cancer patients treated with concur-rent chemoradiotherapy. J Clin Oncol. 2014;44(5):422-7.

48. Jones MS, Rivera M, Puccinelli CL, et al. Targeted amino acid supplementa-tion in diabetic foot wounds: pilot data and a review of the literature. Surg Infect. 2014;15(6):708-12.

49. Katta R, Kramer MJ. Skin and diet: an update on the role of dietary change as a treatment strategy for skin disease. Skin Therapy Lett. 2018 Jan;23(1):1-5.

AUTHOR CORRESPONDENCE

Martina Cartwright PhD RDE-mail:................……............... [email protected]



Brief Summary of Package InsertCloderm® Cream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsivedermatoses. The most common adverse events with Cloderm® Cream include burning, itching, irritation, dryness, andfolliculitis. Cloderm® Cream is contraindicated in patients who are hypersensitive to any of the ingredients of this product.As with all topical corticosteroids, systemic absorption can produce reversible HPA-axis suppression. Full prescribing information is at www.coldermcream.com

References: 1. Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen in corticosteroids influences potency and side effects. J Drugs Dermatol. 2006;5(2):125-130. 2. Del Rosso J, Friedlander SF. Corticosteroids: options in the era of steroid-sparing therapy. J Am Acad Dermatol. 2005;53(1 Suppl 1):S50-58. 3. US Food and Drug Administration NDA 017765. Promius Pharma, LLC, Princeton, NJ: Aug 1977. 4. Rosenthal AL. Clocortolone pivalate: a paired comparison clinical trial of a new topical steroid in eczema/atopic dermatitis. Cutis. 1980;25(1):96-98. J Am Acad Dermatol. 2005;53(1 Suppl 1):S50-58. 3. US Food and Drug Administration NDA 017765. Promius Pharma, LLC, Princeton, NJ: Aug 1977.

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SPECIAL TOPIC

Consensus Recommendations for 4th Generation Non-Microneedling Monopolar Radiofrequency for

Skin Tightening: A Delphi Consensus PanelAnne Chapas MD,ª Brian S. Biesman MD,B Henry Hin Lee Chan MD,c Michael S. Kaminer MD,d

Suzanne L. Kilmer,e Mary P. Lupo MD,f Ellen Marmur,g Susan Van Dyke MDh

aUnion Square Laser Dermatology, New York, NYbBrian S. Biesman PLLC, Nashville, TN

cHong Kong Dermatology and Laser Center, Hong KongDSkin Care Physicians, Chestnut Hill, MA

ELaser & Skin Surgery Center of Northern California, Sacramento, CAfLupo Center for Aesthetic & General Dermatology LLC, New Orleans, LA

gMarmur Medical, New York, NYhVan Dyke Aesthetics, Paradise Valley, AZ

Importance: The demand for non-invasive methods for facial and body rejuvenation has experienced exponential growth over the last two decades. While multiple treatment systems exist, device specific guidelines to help guide clinicians to achieve the best outcomes are lacking.Objective: To develop expert consensus on the use of 4th generation non-microneedling monopolar radiofrequency.Design: In a modified Delphi process, a panel of 8 international experts in aesthetic dermatology participated in 3 rounds of consensus building commencing in April 2019. Initially, 32 consensus statements were developed addressing patient selection, patient outcomes, treatment settings, and practical use of non-microneedling monopolar radiofrequency. By the 3rd round, these had been reduced and refined to a total of 19 statements. The consensus process was completed in June 2019 and the data were analyzed in July 2019.Results: In 3 Delphi rounds, the 8 panelists achieved consensus on 19 recommendations on the use of 4th generation non-micronee-dling monopolar radiofrequency and developed additional explanatory guidance to support 12 of the consensus statements including those related to patient selection, procedural technique, and anticipated treatment outcomes.Conclusions and Relevance: Although guidelines will never replace individual clinical judgment, as the demand for noninvasive tissue tightening increases, so too does the need for positive, reproducible outcomes. Careful patient selection, pre-treatment counseling, treatment planning, and good technique, are all critical for success. These consensus statements should assist clinicians in each of these areas.


ABSTRACT

INTRODUCTION

The increasing demand for safe and effective, non-surgi-cal, skin rejuvenation modalities has resulted in a para-digm shift in the fields of dermatology and aesthetic

medicine. Although surgical procedures and ablative laser tech-nology produce dramatic results, many patients opt for proce-dures with minimal or no downtime, minimal discomfort, and a lower risk of side effects and complications. Several minimally invasive skin rejuvenation procedures help improve skin tex-ture, reducing the appearance of fine lines, wrinkles, and acne scars. The goal of most non-invasive skin rejuvenation proce-dures is to trigger a wound repair response, encouraging the body to replenish or remodel old or damaged tissues. The pro-cess may be mechanical, chemical, or thermal.

Non-surgical thermal skin tightening procedures work by using targeted energy to heat deeper layers of skin, which stimulates collagen and elastin production and gradually improve skin texture. Non-invasive options for skin tightening include fo-cused ultrasound, non-ablative lasers, and radiofrequency (RF).

One such system, a non-microneedling monopolar RF system (Thermage FLX®, Solta Medical) is a capacitively coupled mo-nopolar radiofrequency system that utilizes a reverse thermal gradient that has been in use since 2002. The fourth generation system, approved by the U.S. FDA in 2017, includes enhanced features such as optimized energy delivery, shorter treatment times, uniform energy delivery over the tip, multiple tip sizes, enhanced multi-directional vibration, a universal handpiece for all tips, and a larger 4cm tip size that reduces treatment time

doi:10.36849/JDD.2020.4807



21


A. Chapas., B.S. Biesman, H.H. Lee Chan, et al

Based upon the responses to the Round 0 survey, 32 consensus statements were developed by the independent observer and reviewed by two independent third parties with subject matter expertise to confirm clinical accuracy.

These consensus statements were then distributed and re-viewed by the panel in accordance with a modified Delphi technique1 — a group communication process that aims to achieve a convergence of opinion on a specific real-world is-sue.2 The Delphi technique has been validated and widely used for medical research3-9 and has been shown to be particularly valuable for consensus building2,3 and when there are gaps or contradictions in knowledge.

An iterative approach was employed where sequential surveys were presented to the expert panel of experts to gain consen-sus.10 Participants reviewed and commented on the statements in isolation and all responses were anonymous, ensuring each participant provided their own opinion without influence, peer-pressure, or the potentially coercive effect of dominant in-dividuals within the group.3

For each statement, all eight participants were asked to judge whether the statement was clear (‘yes’ or ‘no’), whether they believed that the statement should be included (1 = ‘definitely do not include’ to 9 = ‘definitely include’), and finally to provide any comments, in the form of free text, that might help clarify the meaning of the statement (Figure 1).

Using the criteria in Table 1, all statements were analyzed to determine whether the statement should be considered for in-

by 25 percent. Its FDA cleared indications include non-invasive treatment of facial and periorbital wrinkles and rhytids, includ-ing lower and upper eyelids, and temporary improvement in the appearance of cellulite.

Given the absence of high-quality evidence or peer-reviewed published practical guidance, the aim of this research was to develop a set of clinician-led consensus statements on the use of this novel 4th generation non-microneedling monopolar RF device.

METHODSA literature review was conducted by an independent observer to obtain published material on the use of non-microneedling monopolar RF. Following completion of the literature review, an on-line survey of 32 open-ended questions was developed. These questions were divided into three sections: background information, clinical information, and other information.

In parallel with development of the online survey, a panel of eight international experts were invited, and agreed, to partici-pate in an online collaboration to develop consensus statements. The experts were all practicing aesthetic dermatologists. Seven were located in the US while one was based in Hong Kong. All had clinical experience treating patients with one or more generations of non-microneedling monopolar RF (mean, 12.7 years) and the 4th generation device (mean, 12 months / 50-100 patients).

The questionnaire was delivered electronically, and complete responses were received from 7 of 8 members of the expert consensus panel.

FIGURE 1. Overview of consensus statement development and the Delphi Technique



22



studies comparing each generation device, these may not be relevant or applicable for the 4th generation of non-micronee-dling monopolar RF.

The Round 0 online questionnaire resulted in the development of 32 statements. These addressed patient selection, patient outcomes, treatment settings and practical use of non-mi-croneedling monopolar RF.

Following Round 1 review of the 32 statements, 12 were un-modified, 7 statements were deleted, and 13 statements were revised based on participants comments. Two statements were added as a result of revisions that split subject matter from one previous statement into two new statements and one statement – Patients who are treated with 4th generation non-microneedling monopolar RF every 1-2 years may experience prolonged, con-sistent skin tightening that helps to prevent future sagging – was added, as one of the panelists felt strongly that this had been omitted from the original list, resulting in a total of 28 state-ments being submitted for review in Round 2.

Round 2 results revealed 19 statements that met the threshold for inclusion; 3 that were classified as maybe include; 2 that could be excluded, and 4 for which revisions were suggested. A conference call was then conducted between all members of the consensus panel and the independent observer to review and discuss the “maybe include” and “revise” statements from Round 2, which resulted in the acceptance of 19 final Consensus Statements.

Final Consensus Statements1. Skin quality, degree of laxity and extent of photoaging are

more important than chronological age when selecting the ideal candidate for 4th generation non-microneedling monopolar RF. Although some clinicians suggest the ideal candidate is between 30-65 years old, patients outside of this age range (ie, over 65 years old) can also benefit. As 4th generation non-microneedling monopolar RF addresses skin laxity through immediate collagen contraction and sec-ondary collagen remodeling, it is possible better results will be achieved in patients without extensive collagen damage (ie, sun damage, acne scarring).

2. The ideal 4th generation non-microneedling monopolar RF patient should have no more than mild-moderate skin lax-ity. People who have mild-to-moderate sagging skin are more likely to benefit from this treatment than people with severe facial sagging. The consensus panel agreed that al-though even severe laxity may improve, the results are less predictable. [It is important to note that there is no FDA or dermatology society agreed definition of mild, moderate, or severe laxity. Thus, these terms are largely subjective and based on physician and patient experience and expec-

clusion, with or without modification. Following the first round of the Delphi technique, participants were provided with the results from the entire panel. Where statements remained un-modified, participants were shown individual ratings and the group ratings. This included the percentage of the group that agreed the statement was clear, median rating for inclusion, percentage of the group who rated the statement as ‘definitely include’, and combined comments. This summation of com-ments made each participant aware of the range of opinions and the reasons underlying those opinions.

Where a statement was modified, participants were shown the same information and asked to re-rate the revised statements. Deleted statements were not presented to the panel in subse-quent rounds. Non-responders were sent weekly follow-up email reminders to complete the online survey.

All online surveys were built and distributed using SurveyMon-key® software. Data collection for all three rounds took place over 3 months; however, data collection per round lasted no longer than two weeks. All eight clinicians participated in Rounds 1 and 2 and the subsequent conference call.

The feedback process allowed and encouraged the participants to reassess their initial judgments about the information pro-vided in previous iterations based on their ability to review and assess the comments and feedback provided by the other con-sensus panelists.

RESULTSThe comprehensive MedlinePlus11 search failed to identify any peer reviewed clinical studies or consensus guidelines on the use of the 4th generation non-microneedling monopolar RF de-vice. Consensus Statements had been published for the first generation device12 but given the technical advances that have occurred over the past 15 years, and the absence of clinical

TABLE 1.

Delphi Technique – Consensus Statement Inclusion Criteria

Statement Result

Threshold Applied

Definitely

Include

(i) >80% of consensus panel rate statement as =9 OR

(ii) Median rating of >8

Maybe

Include

(i) >70% of consensus panel rate statement as =9 OR

(ii) Median rating of >7

Definitely

Exclude

(i) <70% of consensus panel rate statement as =9 AND

100% of consensus panel said statement was clear OR

(ii) Median rating of <6 AND

100% of consensus panel said statement was clear*

Revise

(i) Major revisions suggested OR

(ii) <70% of panel rate statement as =9 AND

<100% of consensus panel said statement was clear*

*suggesting that low scores are not due to lack of understanding of proposed Consensus Statement



23



8. Most appropriately selected patients see visible improve-ments after a single 4th generation non-microneedlingmonopolar RF treatment.

9. Most patients expect to achieve some contouring after 4th

generation non-microneedling monopolar RF treatment.Contouring is a subjective term, but may equate to firming,improved elasticity or “shrink-wrapping.” As applied to thejawline, it may imply more definition or angularity (Figures2A and 2B).

10. Patient feedback on heat sensation scale should be usedto select 4th generation non-microneedling monopolar RFtreatment settings. It should be hot, but easily tolerable.The discomfort of treatment is related to RF energy con-verting to heat energy in the skin. Tissue properties such asdermal thickness, fat thickness, fibrous septae, and adnexalstructures affect local impedance. Additionally, the abilityto tolerate pain varies from patient to patient and by treat-ment location. The expert consensus panel agreed that 4th

generation non-microneedling monopolar RF is more toler-able than previous generations, due to the larger tip size,multi-directional vibration, and cooling cryogen spray. Mostsensitive patient’s discomfort can be mitigated by pre-medi-cating with 800 mg of ibuprofen or 500 mg acetaminophen.For patients with lower pain thresholds, adding low doseoral anxiolytics may be effective. It should be noted that themanufacturer does not recommend the use of sedatives,regional blocks or narcotic pain medications as these mayprevent the patient from providing accurate heat sensationfeedback which could potentially increase the risk of adverse events. The manufacturer recommends starting with cleandry skin and then applying a generous amount of the pro-vided Coupling Fluid to the targeted site before beginningtreatment and reapplying throughout treatment.

tations. While there is a comprehensive grading scale for assessment of rhytides, laxity, and photodamage13 this is mainly used to assess the efficacy of cosmetic treatment modalities in the context of a clinical study rather than in routine clinical practice.]

3. Discussing /managing patient expectations prior to treat-ment with 4th generation non-microneedling monopolarRF is essential. It is always important for patients to haverealistic expectations when undergoing any cosmetic pro-cedure. While 4th generation non-microneedling monopolarradiofrequency may improve overall appearance, it is not asurgical treatment and typically does not result in dramaticchanges. Managing expectations through frank and honestdiscussion prior to treatment will lead to improved patientsatisfaction. Equally important is to prepare patients for thetiming of results. Patients should expect some immediateimprovement with continued tightening and smoothing ofthe skin over the next 2-6 months as new collagen forms.

4. Patients with severe sun damage are not ideal candidatesfor 4th generation non-microneedling monopolar RF. Thepanel noted that patients with poor skin quality and milddyschromia can achieve good results, especially when 4th

generation non-microneedling monopolar radiofrequencyis used in combination with other treatment modalities.

5. Greater than 90% of properly selected patients may achievepositive results with 4th generation non-microneedlingmonopolar RF. Based on their one-two years of clinical ex-perience with 4th generation non-microneedling monopolarRF, the expert panel feels that their patients are achievingresults equivalent or better than with previous generations.The panel recommends repeating the groundbreaking,5,700 patient satisfaction survey study undertaken with thefirst-generation device in 2005 which showed that 87% ofpatients experienced immediate tightening, 92% observedskin tightening 6 months after treatment, and 94% of pa-tients found the treatment results met their expectations.14

6. Patients in whom positive results are seen may benefit fromadditional treatments with 4th generation non-micronee-dling monopolar RF, as results appear to be cumulative. The collagen changes induced by 4th generation non-micronee-dling monopolar RF don't go away but the aging processcontinues, so the skin that was tightened will eventuallyshow signs of laxity again. Repeat treatments will help tokeep skin tightened and may postpone the need for surgery.

7. 4th generation non-microneedling monopolar RF can beused safely and effectively to treat eyes, face, submentumand body.

FIGURE 2. (A) Jaw line before non-microneedling monopoloar RF treatment. (B) Jaw line contouring after non micro-needling monopolar RF treatment.

(A)

(B)



24



11. Energy settings can be titrated up or down based on the pa-tient’s comfort level. Use a 0-4 patient feedback scale with a target goal of 2–2.5 (Figure 3).

12. 4th generation non-microneedling monopolar RF treatments should be repeated approximately every 12 months to main-tain results and to continue to induce further skin tightening and smoothing. Some patients may choose to “touch-up” in 6-months, others may wait up to 2 years to repeat. Treat-ment interval decisions may be based on patient age, what the patient wants to achieve / avoid and financial consider-ations.

13. 4th generation non-microneedling monopolar RF can be used in patients who have, or will, receive neurotoxins, der-mal fillers and fractionated skin resurfacing ablative and/or non-ablative laser modalities, based on medical judgment.

14. When adding therapies, 4th generation non-microneedling monopolar RF may be done before, or after the other treat-ment depending on medical judgment, schedules and convenience for the patient. Should not be done on ery-thematous skin, ie, immediately post fractional laser.

15. The wait period between 4th generation non-microneedling monopolar RF and injecting dermal fillers is based on pa-tient preference and clinician judgment.

16. The wait period between 4th generation non-microneedling monopolar RF and injecting neurotoxins is based on patient preference and clinician judgment.

17. 4th generation non-microneedling monopolar RF treatment-related side effects are very rare and generally mild. To prevent superficial burns or other tissue damage, clinicians are urged to inspect the treatment tip membrane before, and periodically during, treatment to ensure integrity and to regularly apply generous amounts of coupling fluid. Of note, the historical concerns about fat atrophy, associated with earlier generations of the device, have not been observed with the current generation device. Furthermore, since the launch of the 4th generation non-microneedling monopolar radiofrequency device, the overall incidence rate of adverse events reported to the manufacturer, based on their sales of treatment tips equates to less than 0.05%.15

18. Patients who are treated with 4th generation non-micronee-dling monopolar RF every 1-2 years may experience prolonged, consistent skin tightening that could help to pre-vent future sagging.

19. Achieving favorable results with 4th generation non-mi-croneedling monopolar RF is dependent upon following

proper patient selection and treatment guidelines, together with good technique. Good technique constitutes 2-4 passes using moderate treatment levels, using the patient feed-back scale where the treatment goal is hot but tolerable. The multiple passes are followed by 5–10 vector and contouring passes, treating to the clinical endpoint of visible or palpable tightness.

DISCUSSIONSkin laxity and wrinkling are major findings associated with aging. The demand for noninvasive methods to decrease skin laxity and smooth irregular body contours has experienced exponential growth over the last two decades. Non-ablative aesthetic RF treatments have established a good safety record and are associated with minimal to zero downtime. The mech-anism of action is based on an oscillating electrical current, forcing collisions between charged molecules and ions, which are then transformed into heat. RF generated tissue heating has different biologic and clinical effects, depending on the depth of tissue targeted, the frequency used, and specific cooling of the dermis and epidermis. A study that examined the thermo-elastic response of cutaneous and subcutaneous tissues to RF heating demonstrated that there is greater power absorption in the fibrous septa filaments than in fat.16 Heat disrupts hydrogen bonds of collagen molecules resulting in conformational chang-es. The denatured collagen fibrils immediately contract and then act as a tightened scaffold over which new collagen is laid down in the secondary/repair phase of wound healing, giving rise to skin tightening.17 RF device settings and the number of treat-ment passes were shown in one study to have an important effect on collagen fibril change.18 Increases in pass number at the same setting dramatically increased the extent of irrevers-

FIGURE 3. 4th generation non-microneedling monopolar RF treatment– Patient feedback scale.



25



ible collagen fibril change, specifically, increase in diameter, as did increases in energy setting at a standard pass number.18 The depth of penetration of RF energy is inversely proportional to the frequency. Consequently, lower frequencies of RF are able to penetrate more deeply into the dermal layers to stimulate col-lagen contraction and neocollagenesis.19

RF devices may be monopolar, bipolar, tripolar, polypolar, or combination. Monopolar systems deliver current through a single contact point with an accompanying grounding pad that serves as a low resistance path for current flow to complete the electrical circuit. Monopolar electrodes concentrate most of their energy near the point of contact and energy rapidly dimin-ishes as the current flows toward the return pad.

The 4th generation non-microneedling RF system uses a high-frequency generator that produces a 400W, 6.78MHz monopolar current signal. A disposable membrane tip with a treatment area of 0.25, 3.0, 4.0, or 16.0cm2 is used with a disposable adhesive return pad that serves as the passive electrode. The depth of heating is dependent upon the size and geometry of the treat-ment tip being used. A conductive coupling fluid is used during the treatment to enhance the thermal and electrical contact between the treatment tip and the skin. The treatment tip cre-ates an electrical field within the tissue by alternating its charge from positive to negative 6 million times per second with elec-trons and ions simultaneously attracted and repelled from the surface. The movement of these ions generates heat which re-sults in immediate collagen denaturation with resultant fibril contraction and tissue thickening.20 A secondary inflammatory wound healing response follows, resulting in collagen neogen-esis, deposition and remodeling along with gradual reduction in rhytides, tissue tightening, and improvement in skin texture in most patients. Skin surface cooling is maintained through the use of a cryogen gas spray, while comfort is improved by use of vibration and adjusting energy level of the handpiece according to patient feedback.

Recommended treatment algorithms with the RF device have significantly changed since their introduction to the U.S. mar-ketplace nearly 18 years ago. Initially, patients were treated with a single pass of the RF device at high-energy settings, sometimes resulting in mixed clinical results and significant treatment discomfort. Subsequent treatment guidelines used a multiple pass technique with reduced energy settings, resulting in superior clinical results and significant reduction in patient discomfort.12,19,21

In developing these Consensus Statements, we aimed to pro-vide clear, unambiguous practical guidance for clinicians. However, we have steered away from providing numerical rec-ommendations for treatment settings or retreatment intervals. For example, energy level selection is best determined by con-

tinuously evaluating the level of heat tolerance for individual patients during the procedure. Not only do patients have differ-ent pain tolerance but they also vary in skin composition, which in turn affects RF penetration, resistance and thermal deposi-tion within tissues. As such, each patient’s feedback regarding tolerability is vital during treatment to avoid excessive thermal delivery to the skin.

Although there is an extensive body of clinical literature to sup-port non-microneedling monopolar RF, and consensus panel recommendations have been published for previous genera-tions of the device, these consensus statements represent the first, real-world, practical treatment guidelines for the 4th gen-eration non-microneedling monopolar RF. While we recognize that each patient is unique and that guidelines will never replace individual clinical judgment, as the demand for noninvasive tissue tightening increases, so too does the need for positive, reproducible outcomes. Although improvement in skin laxity is not as pronounced as that observed with surgical lifting pro-cedures, the advantages of RF procedures include a virtually nonexistent postoperative recovery period and extraordinarily low risk of serious adverse effects. Careful patient selection, pre-treatment counseling, managing patient expectations regarding potentially modest results, thorough treatment planning and good technique are all critical for success.

Doctors routinely rely on the scientific literature in addition to their own knowledge and experience when optimizing treat-ment for their patients. However, when no such literature exists, and a device is new to the market, additional tools, including these Consensus Statements, will assist clinicians to achieve successful outcomes for their patients.

LimitationsAll guidelines have potential limitations, the most important of which is that recommendations may be incorrect for indi-vidual patients. Although these Consensus Statements were developed by internationally recognized experts in aesthetic dermatology, following a precise and transparent methodology, development of Consensus Statements is less rigorous than for evidence-based Clinical Guidelines. Furthermore, we lacked a systemic review of the literature, simply because the literature did not exist.

Given that patient expectations and outcomes represent an im-portant aspect of this RF treatment modality, it could be argued that we should have diversified our expert to include other con-tributors, including patients.

Other limitations relate to the selected methodology. Although there are many advantages to using the Delphi technique, there are some important drawbacks. First, judgments in the second and subsequent rounds may be influenced by feedback giv-



26



en over the course of the rounds because overall feedback is given to each participant. Second, the lack of face-to-face col-laboration, coupled with the increased potential for participant burnout as the number of rounds increases.

Finally, although these Consensus Statements provide clinicians with recommendations, further work is necessary to gener-ate the data that would be needed to develop evidence-based guidelines. We encourage the manufacturer to support the de-velopment of a patient registry that would allow prospective collection of outcomes data from both patients and treatment data from clinicians.

DISCLOSURESAll authors were financially compensated by Solta Medical, a division of Bausch Health, for their work on the development, editing, review, approval and decision to submit the manuscript for publication, their participation in the consensus statement process and analysis and interpretation of the data.

Solta Medical had no role in the design or conduct of the study nor collection, management, analysis or interpretation of the data; nor in the preparation, review, or approval of the manu-script.

ACKNOWLEDGMENTSDr. Anne Chapas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors would like to thank Jeffrey S. Dover MD, FRCPC, (SkinCare Physicians, Chestnut Hill, MA), for his expert review of the manuscript and Judi Miller (SRxA, McLean, VA) for as-sistance with consensus statement methodology research, questionnaire design and interpretation and manuscript prep-aration. Ms. Miller’s work was financially supported by Solta Medical.

REFERENCES1. Descriptions of Methods and Techniques. Jytte Brender, in Handbook of

Evaluation Methods for Health Informatics. 1st ed. Burlington, MA: Elsevier Academic Press; 2006.

2. Hsu CC. The Delphi technique: making sense of consensus. practical as-sessment, research & evaluation. 2007;12;10:1-8.

3. Jones J, Hunter D. Qualitative research: consensus methods for medical and health services research. BMJ (Clin Res Ed). 1995;311(7001):376–80.

4. Avouac J, Fransen J, Walker UA, Riccieri V, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi consensus study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis. 2011;70(3):476–81.

5. Powell BJ, McMillen JC, Proctor EK, Carpenter CR, et al. A compilation of strategies for implementing clinical innovations in health and mental health. Med Care Res Rev. 2012;69(2):123–57.

6. Ilic D, Nordin RB, Glasziou P, Tilson JK, et al. Development and validation of the ACE tool: assessing medical trainees’ competency in evidence based medicine. BMC Med Educ. 2014;14(1):114.

7. Rosier PF, De Ridder D, Meijlink J, Webb R, et al. Developing evidence-based standards for diagnosis and management of lower urinary tract or pelvic floor dysfunction. Neurourol Urodyn. 2012;31(5):621-4.


Anne Chapas MDE-mail:................……......................... [email protected]

8. Kerr MP, Mensah S, Besag F, de Toffil B, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associ-ated with epilepsy. Epilepsia. 2011;52(11):2133-8.

9. Flume PA, Mogayzel PJ, Robinson KA, Rosenblatt RL, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumo-thorax. Am J Respir Crit Care Med. 2010;182(3):298–306.

10. Linstone HA, Turoff M. The Delphi method: techniques and applications. Reading, MA: Addison-Wesley; 1975.

11. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); https://www.ncbi.nlm.nih.gov/pubmed. Accessed September 4, 2019.

12. Burnes JA. Thermage: Monopolar radiofrequency. Aesthetic Surg J. 2005;25:38-42.

13. Alexiades-Armenakas M.R. A quantitative and comprehensive grading scale for rhytides, laxity and photoaging. J Drugs Dermatol. 2006 Sep; 5 (8): 808-9.

14. Dover JS, Zelickson B; 12-Physician multispecialty consensus panel. Results of a survey of 5,700 patient monopolar radiofrequency facial skin tightening treatments: assessment of a low-energy multiple-pass technique leading to a clinical end point algorithm. Dermatol Surg. 2007;33(8):900-7.

15. Solta Medical; Hayward, CA. Personal communication. June 26, 2019.16. Jiminez-Lozano J, Vacas-Jacques P, Franco W. Thermo-elastic response of

cutaneous and subcutaneous tissues to noninvasive radiofrequency heating. Excerpt from the Proceedings of the 2012 COSMOL Conference in Boston.

17. Kirsch KM, Zelickson BD, Zachary CB, Tope WD. Ultrastructure of collagen thermally denatured by microsecond domain pulsed carbon dioxide laser. Arch Dermatol. 1998; 134(10):1255-1259.

18. Kist D, Burns J, Sanner R, Counters J, et al. Ultrastructural evaluation of multiple pass low energy versus single pass high energy radio-frequency treatment. Lasers Surg Med. 2006;38:150-144.

19. Beasley KL, Weiss RA. Radiofrequency in cosmetic dermatology. Dermatol Clin. 2014;32:79-90

20. Fritz M, Counters JT, Zelickson BD. Radiofrequency treatment for middle and lower face laxity. Arch Facial Plast Surg. 2004;6:370-3.

21. Zelickson BD, Kist D, Bernstein E, Brown DB, et al. Histological and ultra-structural evaluation of the effects of a radiofrequency-based nonablative dermal remodeling device: a pilot study. Arch Dermatol. 2004;140:204-9.




https://skinluma.com/




SPECIAL TOPIC

Ultrasound Evaluation of a Single Treatment With a Temperature Controlled Multi-Frequency Monopolar

Radio Frequency Device for the Improvement of Localized Adiposity on the Abdomen and Flanks

Amy Taub MD,a,b James Bartholomeusz BS BAppScb

aAdvanced Dermatology, LLC, Lincolnshire, IL and Glencoe, IL; Northwestern University Medical School, Chicago, ILbSkinQRI, Lincolnshire, IL

Background and Objectives: Energy modalities used for fat reduction include cryotherapy, focused and unfocused ultrasound, ra-diofrequency, and laser. Two devices have been proven to reduce fat layer thickness using ultrasound as measurement after a single treatment. We hypothesized that a novel, high frequency monopolar radiofrequency device could increase the fat temperature enough to reduce its thickness as measured by ultrasound, without excessively increasing the temperature of the skin, leading to a safe, toler-able, and clinically relevant reduction of fat. Study Design/Materials and Methods: A high frequency monopolar radiofrequency platform was used to treat twelve patients on the abdomen or flanks (truSculpt® 3D, Cutera, Brisbane, CA). Each patient received one treatment session, consisting of 15-minute increments for four areas (60 minutes total). Each area (approximately 144 cm2) was treated with a gliding handpiece technique to a skin temperature of 44-45˚C, correlating to in vivo measurements of the subcutaneous layer of >45˚C. Patients were evaluated at eight- and twelve-weeks following treatment. Clinical efficacy was measured using 360˚ positioned clinical photography. Fat layer reduction was measured with ultrasound. Safety was assessed by the treating physician; patient comfort was assessed during treatment via a 10-point pain scale. Results: All patients responded to treatment. Ultrasound measurements indicated mean fat layer reduction of 4.6 mm, which corre-lated with a 24% reduction in fat layer thickness at 12 weeks. A significant improvement was noted between the 8-week and the 12-week follow up. A high level of inter-patient consistency was achieved with most patients (10/12= 83%) having an average fat thickness reduction of >20%. No adverse events were observed, and pain scores during the treatment session ranged from 2 to 4 out of 10. Conclusion: High frequency monopolar radiofrequency device produced consistent and statistically significant fat thickness reduction from a single 60-minute treatment session, with minimal discomfort and no demonstrated side effects. Results are comparable to other hypo- and hyper-thermic fat treatment technologies.


ABSTRACT

INTRODUCTION

Nearly 170,000 non-surgical fat reduction procedures, or body sculpting procedures, were performed in 2016, a 6% increase over the previous year. The popu-

larity of these non-surgical procedures is growing rapidly, at approximately the rate of liposuction, which was the most pop-ular aesthetic procedure in 2016 for both men and women, with an increase of 5% from 2015 to 2016.1 The 2016 American Soci-ety for Dermatologic Surgery survey of 7,322 consumers ranked body sculpting as the third most popular treatment in the US with 50 percent of respondents considering the procedure.2

Various energy modalities are being used for non-surgical fat reduction including cryotherapy, focused and unfocused ultrasound, radiofrequency (RF), and laser.3 Non-invasive RF technology has a unique advantage of selectively heat-ing relatively large volumes of subcutaneous adipose tissue.4

The biophysics of how this technology achieves this effect has been explained in detail by Franco et al.4,5 The heat induced by RF energy is transferred from the electric field causing move-ment of atoms in the tissue, resulting in friction and collision of the tissue molecules. The RF devices employed for aesthetic

doi:10.36849/JDD.2020.4568



29


A. Taub, J. Bartholomeusz

pieces designed for the treatment of large, small, and anatomi-cally difficult areas.

The treatment protocol was conducted according to a standard-ized protocol. All patients received the truSculpt 3D treatment on their abdomens and/or flanks. Treatment zones were iden-tified using the differently sized truSculpt templates. Medium templates were typically used for patients with BMI of 20-30, with waist circumferences between 30 and 40 inches. The large templates were used in addition to the medium templates for females with BMI of 30-40 and waist circumference between 40 and 44 inches. The templates were placed on the patient’s abdomen or flanks, and the edges traced on the skin with a marker, resulting in treatment areas of approximately 144 cm2

(medium template) and 230cm2 (large template). The treatment areas were cleaned with a warm towel and all lotion or creams were removed prior to the treatment. Areas with significant hair that covered more than 30% of the treatment area were cleanly shaven to avoid damage to the electrode membrane. Enough 100% glycerin liquid (Pure Glycerin, CVS Pharmacy) was applied to the skin on the treatment zones to facilitate applicator glide across the skin surface and to ensure smooth and easy gliding of the truSculpt 3D applicator over the treatment area.

Each zone as defined by the template was treated for 15 minutes by gliding the applicator over the entire area at a speed of ap-proximately 40 cm2 per second. That speed equates to moving the applicator by one applicator length per second. Most pa-tients required two 15-minute treatments on the abdomen and/or one 15-minute treatment on each flank for a total possible treatment time of 60 minutes.

All patients were treated using the same truSculpt 3D settings. The 40 cm2 handpiece was used at a frequency of 2 MHz. Skin temperature was adjusted to accommodate patient comfort but was kept in the range of 44-45˚C by the closed loop temperature sensing software. The temperatures of the skin maintained at the target temperature by the closed loop sensing software are presented in Figure 1.

Data were collected from the patients at baseline, then at eight weeks and twelve weeks following the single truSculpt 3D treatment. Height and waist circumference were measured. Additionally, skin-fold measurements and subcutaneous ul-trasound measurements were made in each treatment area. Digital photographs were taken using 360˚ positioned clinical photography (FotoFinder Body System, Columbia, MD) and re-viewed for efficacy by the investigators. Fat layer reduction was measured by controlled ultrasound measurements (MyLabFIVE, Esaote North America, Inc., Fishers, IN). Safety was assessed by the treating physician and patient comfort was assessed at the time of treatment via a 10-point pain scale.

treatments are delivered to the skin via monopolar, bipolar, or unipolar electrode design. Specific frequencies between 3.4 MHz to 40.68 MHz are selected for skin rejuvenation and tight-ening procedures, while frequencies of 1-4 MHz are used for lipolysis because as the frequency gets lower and the wave-length gets longer, the energy waves penetrate deeper into the tissue. Low frequencies of RF efficiently transmit energy into the adipose tissue without heating the skin or muscle tissue to damaging temperatures. Attenuation by cutaneous tissue, which is proportional to RF, is less at the lower frequencies.5

To date, only two devices (cryolipolysis and hyperthermic laser lipolysis) have shown reductions in fat layer thickness using ultrasound or MRI after a single treatment.6,7 The CoolSculpt-ing System (Allergan, Parsippany, NJ) pulls tissue between two cooling plates at -10˚C using suction for a 60-minute treatment (CoolCore) or gently draws the tissue in a -11˚C cup (CoolCup) for 35 minutes. Both CoolSculpting options have been shown to reduce fat thickness significantly (P<0.000001) measured with subcutaneous ultrasound measurement at twelve weeks following a single treatment.6 Decorato et al.7 evaluated the CoolSculpting method and a hyperthermic treatment using a 1060 nm diode laser (SculpSure, Cynosure, Inc., Westford, MA), and found average fat thickness reductions by ultrasound mea-surement of 17% for the cryolipolysis method and 18% for the hyperthermic method twelve weeks after a single treatment. Corresponding MRI measurements were 22% and 24%, respec-tively.

Our objective was to evaluate a multi-frequency monopolar RF device with subcutaneous ultrasound to determine the amount of fat layer reduction observed after a single treatment. We hy-pothesized that the monopolar RF device would increase the temperature of the fat without increasing the temperature of the skin excessively, resulting in a tolerable treatment yielding reductions of the fat layer thickness measurable by ultrasound after one treatment, which would approximate the reductions demonstrated by other hypo- and hyper-thermic body sculpting technologies. It is important to keep the skin at a lower tem-perature due to patient comfort and to reduce potential side effects.

MATERIALS AND METHODSThis study was a prospective, single-arm, open label evalua-tion conducted at a private dermatologic practice clinic. Patients with BMI between 20 and 40 who desired fat reduction on their abdomen and/or flanks provided consent prior to a single treat-ment with the truSculpt 3D device (Cutera, Inc., Brisbane, CA). The truSculpt 3D platform utilizes a 1 MHz and 2 MHz frequency monopolar radiofrequency. It is designed with a closed-loop temperature feedback mechanism that allows for precise con-trol of temperatures during the treatment and has two hand



30



Skin fold and ultrasound measurements of the treatment areas are summarized in Table 2. Reductions in fat layer thickness were observed for all twelve patients. The average percent reduc-tion across all treatment areas by skin fold measurement was 28.1%. The subcutaneous ultrasound measurements of the fat layer also were reduced in each area for all patients. Across all treatment areas, ultrasound indicated an average fat thickness reduction of 23.7% from baseline. All patients responded to the treatment with no adverse events observed. Patient pain scores during the treatment ranged from 2 to 4 on a 10-point scale.

RESULTSTwelve patients participated in the evaluation. Body mea-surement data collected at baseline and at twelve weeks are summarized in Table 1. At twelve weeks, there was a statistically insignificant increase in weight and BMI, with the mean percent changes for both of 0.14%, and P-values of 0.7602 and 0.8506, respectively. No patient lost or gained more than 5% of their body weight. There was a statistically significant mean decrease in waist circumference of 2.5% (P=0.0003).

FIGURE 1. In vivo subcutaneous tissue temperatures.

TABLE 1.

Summary of Patient Measurements at Baseline and Twelve Weeks after Treatment With the truSculpt 3D Body Sculpting Protocol

BaselineTwelve Weeks

Twelve WeeksMinus

Baseline

Mean (Standard Deviation)(Minimum, Maximum)


TMean (Standard Deviation)(Minimum, Maximum)

Height (cm)164 (7)

(150, 175)164 (7)

(150, 175)No change

Weight (kg)72 (12)

(57, 104)73 (12)

(57, 105)0.12 (1.38)

(-2, 2)

BMI27 (5)

(21, 38)27 (5)

(21, 39)0.03 (0.52)

(-0.89, 0.65)

Waist Circumference (cm)

91 (10)(75, 110)

89 (10)(74, 108)

-2.25 (1.51)(-6, -1)

P=0.0003

TABLE 2.

Skin Fold and Ultrasound Measurements at Baseline and Twelve Weeks after Treatment With truSculpt 3D

BaselineTwelve Weeks

Twelve WeeksMinus

Baseline



TMean (Standard Deviation)(Minimum, Maximum)

Skin Fold (cm)2.61 (0.90)(1.85, 5.25)

1.83 (0.71)(1.00, 3.65)

-0.73 (0.40)(-1.60, -0.20)

P<0.0001

Ultrasound (cm)1.89 (0.72)(0.47, 3.09)

1.32 (0.56)(0.35, 2.30)

-0.46 (0.21)(-0.79, -0.12)

P<0.0001



31



Body measurement changes are summarized and presented for four representative patients (Table 3).

The first patient (03) had a BMI of 28 at baseline and waist cir-cumference of 86 cm, presented in Figure 2. At twelve weeks,

TABLE 3.

Change in Body Measurements from Baseline to Twelve Weeks for Four Representative Patients

PatientWeight

(kg)BMI

Waist (cm)

Change in Skin Fold

Measurements (cm)

Change in Ultrasound

Measurements (cm)

03 -2.0 -0.8 -4.2 -1.1 -0.4

05 0.5 0.2 -1.0 -0.6 -0.4

07 -2.0 -0.7 -6.0 -0.8 -0.6

10 -2.0 -0.9 -1.0 -0.9 -0.2

FIGURE 2. Digital photos (upper) and ultrasound images (lower) of patient 03 at baseline (left) and 12 weeks post-treatment (right).




waist circumference was 82 cm, a 4.9% reduction. Skin fold measurements for this patient had a 53.5% reduction in the thickness of the fat layer, and a 24.4% reduction measured by ultrasound. This patient experienced a 2 kilogram, 2.8%, weight loss during the study period. Patient 05 had a BMI of 29 and waist circumference of 90 cm at baseline. At twelve weeks, waist circumference was 89 cm, a 1.1% change, and the patient gained 0.5 kg (0.72%). Skin fold measurements for this patient showed a 33.3% reduction in the thickness of the fat layer, and a 21.3% reduction measured by ultrasound (Figure 3). The third patient (07) had a BMI of 25 and waist circumference of 85 cm at base-line. At twelve weeks following treatment, waist circumference was 79 cm, a 7.1% reduction, while 2 kg were lost (a 2.7% re-duction). This patient experienced a 46.0% reduction in the fat layer by skin fold measurement and a 34.9% reduction by sub-cutaneous ultrasound (Figure 4). The fourth patient (10) had an initial BMI of 29 and waist circumference of 86 cm at baseline. At



32



FIGURE 6. Variations in thermal heating between 1 MHz and 2 MHz frequencies at two treatment depths.

FIGURE 7. “Heat Inversion” phenomenon where skin temperature remains cooler than internal tissues.

FIGURE 8. The effect of time and temperature variations on adipocyte viability.

twelve weeks, waist circumference was 85 cm, a 1.2% reduction, and 2 kg were lost, which was a 3.0% reduction in weight. Skin fold measurements for this patient showed a 31.0% reduction in the thickness of the fat layer, and a 10.4% reduction measured by ultrasound. Images for this patient are shown in Figure 5.

DISCUSSIONThe monopolar RF device used in this evaluation showed simi-lar reductions in fat layer thickness by subcutaneous ultrasound to other devices on the market that use cryolipolysis and laser-based thermo-lipolysis, when analyzed by ultrasound or MRI. There are two novel features of this device: utilization of a dif-ferent frequency of RF (as well as ability to use two different frequencies where needed) and a temperature stabilization feature (“closed-loop system”) that ensures uniformity of the energy delivered at both 7- and 15-mm depths. These are impor-tant features that improve efficacy and safety. Because it does not depend on suction, this device can be used on smaller ar-eas, or areas that are adjacent to bone. With this device, neither bruising nor the discomfort experienced from suction are ob-served, although both disadvantages of cryolipolysis have been reduced with new generation handpieces. This is also the first time a localized monopolar RF device has proven tolerable to patients when used for fat reduction.

Two additional unique features of this novel technology may be an ability to improve skin quality in patients with concerns over skin laxity and to treat patients with a BMI greater than 30. Al-though it is not a primary indication of this device, we observed an improvement in skin quality that warrants further study. We hypothesize that the combination of extended therapeutic tem-peratures with monopolar RF technology shows demonstrable skin tightening following a single treatment.

Cryolipolysis devices are not recommended for patients with greater than 30 BMI, but in our study, we treated two patients who fell in that category. Following treatment with this device, these patients obtained greater than 20% FTR by skin fold mea-surement and ultrasound, with a notable clinical improvement, making this an additional interesting topic for further study.

We chose ultrasound evaluation of the fat reduction because it also has been used as an objective measure for both cryolipoly-sis and the laser hyperthermic method. Additionally, the laser method of fat reduction was measured with MRI.7 We believe these are the most valid current objective methods to measure non-invasive fat reduction. Although these methods have well-documented flaws,8 more ideal options are not available at this time. The observation that the three measured devices were in the same range of fat reduction is a validation of the consistency of the method.

Dual frequencies of 1 MHz or 2 MHz allows the user to target



33



FIGURE 9. The heating characteristics of bipolar and monopolar radiofrequency electrode designs.

the device to specific fat thicknesses. The higher frequency of 2 MHz produces higher temperatures at both 7 mm and 15 mm subcutaneous tissue depths than does the 1 MHz setting. The av-erage differential amount of in vivo thermal changes from three patients at these two depths were measured using a Luxtron 812 temp probe (Lumasense Technologies, Santa Clara, CA),9,10

which result from a phenomenon known as “heat inversion” (Figure 6). The 1 MHz smaller application has been used for suc-cessful reduction of unwanted facial fat.11

Heat inversion occurs when a waveform of a certain frequency has the properties of heating the adipose layer faster than other frequencies while retaining lower surface temperatures. This al-lows the device to deliver heat very selectively to the targeted fat layer. This phenomenon is illustrated using the 2 MHz setting of the truSculpt 3D device (Figure 7). Cell damage is optimized at greater than 45֯ C in the adipose layer at a 15 mm subcutane-ous depth.5

In seminal basic research published by Franco et al., time and temperature were critical factors to adipocyte viability follow-ing thermal treatment. Exposure of the treatment area to three minutes of sustained 45˚C heat resulted in 60% loss of cell vi-ability (Figure 8).4,5 At the subcutaneous temperatures resulting from this treatment setting, skin surface temperatures are not elevated beyond 44˚C.5 Skin pain threshold to heat is estimated at greater than 43-45˚C, although subcutaneous heating less than 50˚C remains safe for the skin. Patients vary in how they tolerate temperatures of 42-45 ˚C. We have found that tech-niques that slowly increase to the target temperature results in greater patient tolerance of higher temperatures. The closed

loop temperature feedback of this device provides consistent temperature control for both the skin surface and the subcuta-neous adipose layer. Additionally, the fascia acts as a grounding electrode, which acts to reflect heat back toward to the treatment electrode. The adipose tissue that is “sandwiched” between the skin and the fascial layer is then exposed to a higher tempera-ture without any additional heating effect on the skin surface.4,5

We observed uniformity of heat delivery with the current device with average temperatures of 44.2-44.4˚C (standard deviation of 0.3˚C) across each treatment. The monopolar electrode provides more uniform heating into the fat layer than do the bipolar or full field electrodes, without creating hot spots or edge effects on the skin (Figure 9). A bipolar design has two symmetrical, active electrodes that are close to one another where the current flows through the path of least resistance, creating controlled heat within the skin and reaching into the epidermis and the su-perficial dermis.12 The full field approach uses an electrode that creates a focused RF field that hovers above the skin, creating heat that targets the subcutaneous fat layer.13 The monopolar design used in our evaluation has an active electrode and a dispersive grounding pad that are far apart. In this system, the energy passes through the skin to heat the subcutaneous adi-pose tissue before dispersing in the underlying muscle tissue.12

Our evaluation was limited by small sample size and lack of a control group. However, we saw significant differences between baseline and twelve-week results for both skin fold measure-ments and ultrasound measurements with P<0.0001 (Student’s t-test, two-tailed, paired) for fat layer thickness.



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11. Sugawara J, Kou S, Kokubo K, et al. Application for lower facial fat reduction and tightening by static type monopolar 1-MHz radio frequency for body contouring. Lasers Surg Med. 2017;49(8):750-755. doi:10.1002/lsm.22676.

12. Sadick NS, Nassar AH, Dorizas AS, Alexiades-Armenakas M. Bipolar and multipolar radiofrequency. Dermatol Surg. 2014 Dec;40 Suppl 12:S174-9.

13. Nassab R. The evidence behind noninvasive body contouring devices. Aesthetic Surg J. 2015;35(3):279-293. doi:10.1093/asj/sju063.

CONCLUSIONNon-invasive body sculpting is an important and much sought-after aesthetic procedure. Optimized RF platforms, such as the monopolar RF device used in this evaluation, can precisely tar-get adipose tissue without causing overheating and discomfort to the patient’s skin. In this evaluation, the truSculpt 3D device produced consistent and statistically significant reduction in fat thickness from a single 60-minute treatment session. Patients tolerated the procedure well and experienced little to no pain during the procedure with no prolonged discomfort following the procedure. Results at twelve weeks are similar to those demonstrated with other hypo- and hyper-thermic fat treatment technologies. Future evaluations are needed to study monopo-lar RF devices like the truSculpt 3D platform to determine the applicability of our findings to a larger population.

DISCLOSURESkinQRI received research funding from Cutera for this study. Amy Taub and James Bartholomeusz are principals of SkinQRI. Amy Taub was loaned the truSculpt 3D equipment to use for the study.

ACKNOWLEDGMENTWe would like to thank Cutera, Inc., Brisbane, CA for funding and for providing equipment for the study to Dr. Taub. We would also like to thank Dana Fletcher, MA for her assistance with preparing the manuscript. Finally, we would like to thank Elana Cole, RN, for her assistance with this project.

REFERENCES1. 2016 Cosmetic Surgery National Data Bank Statistics. The American Soci-

ety for Aesthetic Plastic Surgery. https://www.surgery.org/sites/default/files/ASAPS-Stats2016.pdf. Published 2016. Accessed January 1, 2017.

2. American Society for Dermatologic Surgery. American Society for Derma-tologic Surgery 2016 Survey. https://www.asds.net/_Media.aspx?id=9576. Accessed January 1, 2017.

3. Friedmann DP. A Review of the Aesthetic Treatment of Abdominal Subcuta-neous Adipose Tissue: Background, Implications, and Therapeutic Options. Dermatol Surg. 2015;41:18-34. doi:10.1097/DSS.0000000000000209.

4. Franco W, Kothare A, Goldberg DJ. Controlled volumetric heating of subcuta-neous adipose tissue using a novel radiofrequency technology. Lasers Surg Med. 2009;41(10):745-750. doi:10.1002/lsm.20876.

5. Franco W, Kothare A, Ronan SJ, Grekin RC, McCalmont TH. Hyperthermic in-jury to adipocyte cells by selective heating of subcutaneous fat with a novel radiofrequency device: Feasibility studies. Lasers Surg Med. 2010;42(5):361-370. doi:10.1002/lsm.20925.

6. Kilmer SL. Prototype CoolCup cryolipolysis applicator with over 40 % re-duced treatment time demonstrates equivalent safety and efficacy with greater patient preference. Lasers Surg Med. 2017;49(1):63-68. doi:10.1002/lsm.22550.

7. Decorato JW, Chen ÃB, Sierra R. Subcutaneous adipose tissue response to a non-invasive hyperthermic treatment using a 1 , 060 nm laser. Lasers Surg Med. 2017;49(5):480-489. doi:10.1002/lsm.22625.

8. Auh S, Iyengar S, Weil A, et al. Quantification of noninvasive fat reduction: A systematic review. Lasers Surg Med. 2017;(Dec 6):[Epub ahead of print]. doi:10.1002/lsm.22761.

9. Franco W, Kothare A, Ronan SJ, Grekin RC, McCalmont TH. Hyperthermic in-jury to adipocyte cells by selective heating of subcutaneous fat with a novel radiofrequency device: feasibility studies. Lasers Surg Med. 2010;42(5):361-370. doi:DOI 10.1002/lsm.20925.

10. Tanaka Y. Three-dimensional volumetric assessment of body sculpting using a uniform heating radio frequency device in Asians. J Cosmet Laser Ther. 2015;17(4):194-199. doi:10.3109/14764172.2015.1007059.


James Bartholomeusz E-mail:................……......................... [email protected]



Copyright © 2019 ALASTIN Skincare®, Inc. All rights reserved.www.Alastin.comReferences: 1. Clinical data on file at ALASTIN Skincare®. 2. Widgerow AD, Fabi SG, Palestine RF, et al. Extracellular matrix modulation: optimizing skin care and rejuvenation procedures. J Drugs Dermatol. 2016;15(4)(suppl):s63-s71.

TransFORM Body Treatment with TriHex Technology® accelerates and enhances body contouring outcomes.

ACCELERATE results: After hot or cold body fat reduction procedures.1 Faster visible results

ENHANCE results: After body-skin tightening procedures or as a daily stand-alone treatment to improve the appearance of skin texture, laxity, and crepiness.2


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SPECIAL TOPIC

Calculating the Thickness of the Superficial Fatty Layer of the Body Using Age, Gender, and Body Mass Index

Sebastian Cotofana MD PhD,a,b Doris Hexsel MD,c Luiz E.T. Avelar MD,D Christine G. Munia MD,E Mariana Muniz MD,f Gabriela Casabona MD,g Thilo L. Schenck MD PhD,h Jeremy B. Green MD,i

Nirusha Lachman PhD,j Konstantin Frank MDh

aDivision of Anatomy, Department of Medical Education, Albany Medical College, Albany, NYBDivision of Plastic Surgery, Department of Surgery, Albany Medical Center, Albany, NY

cBrazilian Centre for Studies in Dermatology, Porto Alegre, BrazildPrivate Practice, Belo Horizonte, Brazil

ePrivate Practice, Sao Paolo, BrazilfPrivate Practice, Sao Paolo, Brazil

gOcean Clinic, Marbella, SpainhDepartment for Hand, Plastic and Aesthetic Surgery, Ludwig – Ludwig Maximilians University of Munich, Germany

iSkin Associates of South Florida, Coral Gables, FLjMayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, MN

Background: Injections of biostimulator agents are increasing in popularity as an alternative to surgical or energy-based skin tightening procedures. The present study was designed to develop a formula that helps to guide health care providers injecting biostimulators into the correct plane to enhance effectiveness and longevity by targeting precisely the superficial fascial system. Methods: 150 Caucasian individuals (75 males and 75 females) were investigated with a balanced distribution of age (n=30 per decade: 20–29, 30–39, 40–49, 50–59, and 60–69 years) and body mass index (n=50 per group: BMI≤24.9kg/m2, BMI between 25.0 and 29.9kg/m2 BMI≥30kg/m2). The distance between skin surface and the superficial fascia was measured via ultrasound in the buccal region, premasseteric region, the lateral neck, posterior arm, abdomen, buttocks, anterior thigh, medial thigh, and posterior thigh.Results: Mean thickness of the superficial fatty layer is variable between the different locations investigated with smallest values for the lateral neck of 3.71mm ± 0.55 [range, 2.00–5.00mm] and greatest values for the gluteal region with 20.52mm±10.07 [range, 6.10–38.40mm]. A formula was developed to estimate the thickness of the superficial fatty layer based on the targeted region, age, gender, and body mass index of the patient: Thickness of superficial fatty layer (mm): Region constant + (XX* BMI) - (YY*Age).Conclusions: Injections of biostimulators deeper than the calculated values might result in reduced efficacy as the superficial fascial system is not targeted and the effected collagen neogenesis does not affect the skin surface.


ABSTRACT

INTRODUCTION

Non-surgical, minimally invasive skin tightening procedures have been shown to provide improve-ments for patients seeking skin-lifting and/or skin-

tightening to overcome the signs of aging.1–10 The annually statistics report by the American Society of Plastic Surgeons, revealed that a total of 500,428 procedures were performed utilizing biostimulators in 2017.11 In 2018, this number increased by 0.5% to 502,687 procedures performed in the US alone.

The subdermal architecture is arranged in layers with the following sequence from superficial to deep: skin, superficial fat, superficial fascia, deep fat, and deep fascia.12,13 This layered arrangement can be found throughout the entire body.14–18 Of those described layers, the skin, the superficial fatty layer

which includes short connective tissue fibers that connect the skin to the superficial fascia and the superficial fascia itself are considered to be a functional biomechanical unit, which has been previously termed the superficial fascial system.17,19–24

The superficial fascial system has been shown to provide major structural support for the skin and the subcutaneous fat as inclusion of this system into suturing techniques increases wound strength resulting in a better aesthetic and functional outcome after surgical procedures.25

The superficial fatty layer and the short connective tissue fibers within it have been previously identified to play a key role in the formation of surface irregularities observed in cellulite.14 This indicates that the subdermal attachment of the short connective

doi:10.36849/JDD.2020.4619



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S. Cotofana, D. Hexsel, L.E.T. Avelar, et al

MATERIALS AND METHODSStudy Sample150 Caucasian individuals (75 males, 75 females) with a mean age of 44.03 ± 14.08 years [range, 20–68 years] and a mean BMI of 26.93 ± 4.49 kg/m2 [range, 19.57–39.18] and Fitzpatrick skin types I–III were investigated applying ultrasound imaging (Table 1). The study was conducted between January and December 2017 at the Vida Skin Surgery and Laser Centre, Clinica Vida, Sao Paulo, Brazil.

The total sample consisted of 15 males and 15 females from each of the following decades: 20–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years. Of the 30 individuals investigated (15 males and 15 females) per decade, 10 individuals (5 males and 5 females) had a BMI ≤24.9 kg/m2, 10 individuals (5 males and 5 females) had a BMI between 25.0, and 29.9 kg/m2, and 10 individuals (5 males and 5 females) had a BMI ≥30 kg/m2 (Table 1).

Written information and verbal explanations about the aims and the scopes of the study as well as about the risks of the procedure (ultrasound imaging) were provided to the participants before the inclusion into this study. Following the Declaration of Helsinki protocols (1996), written informed consent to participate in this study was obtained from all participants. This study was conducted in accordance with regional laws and good clinical practice.27

Ultrasound ImagingUltrasound imaging was performed using a linear 15 MHz transducer (MTurbo portable, Fujifilm SonoSite, Inc., Bothell). Patients were standing upright during the scanning process to account for the effects of gravity. Measurements were performed without application of pressure to the skin as the transducer was placed into the visualization gel only without direct skin contact (Aquasonic® Clear Ultrasound Gel, Parker Laboratories Inc., Fairfield, NJ). Measurements were performed bilaterally in the following locations (Figures 1-3):

tissue fibers influences the position and the tension of the overlying skin.

Agents classified as biostimulators are injected into the subcutaneous tissue to induce neocollagenesis.7,9,26 It can be assumed that placing the product deep to the superficial fascial system may result in a limited skin tightening effect as the short connective tissue fibers or the superficial fascia are not precisely targeted. On the contrary, it can also be assumed that biostimulator agents have their greatest effect on the skin surface if they are positioned inside the superficial fascial system ie, between the skin and the superficial fascia where they can directly affect the subdermal short connective tissue fibers improving skin firmness and the support of subcutaneous structures. Of note, this subdermally located layer of fat has been shown to vary in thickness with age, body mass index (BMI), and gender.15,16,18 This can create challenges in correct product placement and can thus influence the aesthetic outcome of the procedure.

The goal of this ultrasound-based study is to measure the thickness of the superficial fatty layer in a large sample with a balanced distribution of gender, BMI, and age. The measurements will be used to develop mathematical formulas whereby the thickness of the superficial fatty layer can be estimated based on the information of gender, BMI, and the age of the patient. This could potentially guide practitioners to more effective outcomes with biostimulator products as the superficial fatty layer including the short connective tissue fibers can be precisely targeted.

FIGURE 1. Photograph of a female head from the right lateral side. The location in which the ultrasound imaging was performed at the buccal region, the premasseteric region and the lateral neck has been marked by the blue lines.

TABLE 1.

Table Showing the Demographic Data of the Study Sample

n = 150

Gender: n (%)

Women 75 (50)

Men 75 (50)

Mean Age (years; mean ± SD) [range]44.02 ± 14.11

[20-69]

Body Mass Index (kg/m2; mean ± SD) [range]26.93 ± 4.5 [19.6 – 39.2]

Body Mass Index (kg/m2): n (%) 0.3

< 25 50 (33.3%)

25 – 29.9 50 (33.3%)

> 30 50 (33.3%)

Age (years): n (%)

20 – 29 30 (20)

30 – 39 30 (20)

40 – 49 30 (20)

50 – 59 30 (20)

60 – 69 30 (20)



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Thighs: Anterior thigh: Anterior lower third of the thigh, 5 cm superior to the superior border of the patella in the midline of the thigh (when viewed from anterior) (Figure 2 and 8)Medial thigh: Medial upper third of the thigh in the midline of the thigh (when viewed from medial) (Figure 2 and 9)Posterior thigh: Posterior upper third of the thigh in the midline of the leg (when viewed from posterior) (Figure 2 and 10)

All measurements were performed bilaterally. The thickness of the superficial fatty layer was measured at all given areas of interest.

Statistical Analyses Differences between values obtained in males versus females were calculated using independent Student’s t-tests. Correlations between age, gender, and BMI and the measured distances/thicknesses were calculated using Pearson’s correlation coefficient (rp) using bivariate correlations. To identify the influence of age, gender, or BMI, multifactorial linear regression models were calculated, and the R-squared value was used to determine the global fit of the statistical model. All analyses were performed using SPSS Statistics 23 (IBM, Armonk, NY) and results were considered significant at a probability level of ≤ 0.05.

RESULTSGeneral Results Five different layers were consistently and bilaterally identified

Face: Buccal region: In a vertical line 1cm posterior to the modiolus (Figure 1 and 4)Premasseteric Region: In a vertical line 1 cm anterior to the angle of the mandible (Figure 1 and 4)Neck: Lateral neck: In a vertical line 5 cm inferior to the midline of the mandible (Figure 1)Arms: Posterior medial third of the arm in the midline (when viewed from posterior) (Figure 2 and 5)Abdomen: Lateral Abdomen: At the level of the umbilicus in the mid-clavicular line (Figure 2 and 6)Buttock: Gluteal region: 3 cm superior to the infra-gluteal sulcus in the middle of the buttock (Figure 2 and 7)

FIGURE 3. Bar graph showing the mean thickness of the superficial fatty layer in mm independent of age, or BMI for the respective investigated areas of males (blue bars) and females (red bars). Error bars represent a confidence interval of 95%.

FIGURE 2. Processed 3D scan showing a 22-year-old female from anterior. Ultrasound imaging was performed at the locations marked with the blue line (abdomen, gluteal region, posterior arm, anterior thigh, medial thigh, and posterior thigh).



40



in all investigated individuals: skin, superficial fat, superficial fascia, deep fat, and deep fascia. The thickness of the superficial fatty layer varied highly with smallest values for the lateral neck with 3.71mm ± 0.55 [range, 2.00–5.00mm] and greatest values for the gluteal region with 20.52mm ± 10.07 [range, 6.10–38.40mm]. Influence of BMI and age are presented region specific in Table 2.

Face: Buccal Region (Figures 1–4)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 4.75 mm ± 0.72 and in females 4.89mm ± 0.97 with P=0.164. In those with a BMI <24.9 kg/m2

the mean thickness was for males/females 4.24mm ± 0.61/4.46mm ± 1.16, whereas it was in those with a BMI of 25.0–29.9kg/m2

5.12mm ± 0.68/5.25 mm ± 0.80 and for those with a BMI >30.0 kg/m2

it was 4.90mm ± 0.58/4.96mm ± 0.73. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.395, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.295, P<0.001). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:

Male: Thickness of superficial fatty layer in mm:3.619+(0.072*BMI)-(0.018*Age)

Female: Thickness of superficial fatty layer in mm:3.519+(0.079*BMI)-(0.017*Age)

Face: Premasseteric Region (Figures 1–4)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 4.34 mm ± 0.57 and in females 4.14mm ± 0.69 with P=0.009 In those with a BMI <24.9 kg/m2 the mean thickness was for males/females 4.13mm ± 0.64/3.54mm ± 0.56, whereas it was in those with a BMI of 25.0–29.9kg/m2 4.24mm ± 0.52/4.22 mm ± 0.50 and for those with a BMI >30.0kg/m2 it was 4.64mm ± 0.39/4.68mm ± 0.45. Increasing BMI values correlated significantly with an increase in superficial fatty layer

thickness (rp = 0.590, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.426, P<0.001). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:



Lateral Neck (Figure 1 and 3)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 3.71 mm ± 0.55 and in females 3.71 mm ± 0.55 with P=0.925 In those with a BMI <24.9kg/m2 the mean thickness was for males/females 3.25mm ± 0.36/3.21 mm ± 0.38, whereas it was in those with a BMI of 25.0–29.9kg/m2 3.87mm ± 0.44/3.87 mm ± 0.46 and for those with a BMI >30.0 kg/m2 it was 4.01mm ± 0.53/4.05mm ± 0.40. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.615, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp

= -0.424, P<0.001). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:



FIGURE 10. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, biceps femoris muscle) of the posterior thigh and in the right panel the corresponding ultrasound image scanned in the exact same location.

TABLE 2.

Table Showing the Correlation Coefficient (rp) Between the Thick-ness of the Superficial Fatty Layer and BMI/Age, Respectively.

Region

Correlation between thickness of superficial fascial

system and BMI

Correlation between thick-

ness of superficial fascial system and

Age

Buccal Regionrp = 0.395 (P < 0.001)

rp = -0.295 (P < 0.001)

Premasseteric Region

rp = 0.424 (P < 0.001)/ rp = 0.748

(P < 0.001)*

rp = -0.569 (P < 0.001) / rp = -0.325 (P < 0.001)*

Lateral Neckrp = 0.615 (P < 0.001)

rp =-0.424 (P < 0.001)

Posterior Armrp = 0.754 (P < 0.001)

rp = -0.355 (P < 0.001)

Abdomenrp = 0.829 (P < 0.001)

rp = -0.104 (P < 0.001)

Gluteal Regionrp = 0.933 (P < 0.001)

rp = -0.101 (P = 0.013)

*a statistically significant difference (p = 0.009) could be observed between males and females, thus a correlation coefficient was given for males and females.



39



FIGURE 4. Left sided facial cadaveric dissection of a male body donor showing the layers of the lateral face: Skin, superficial fatty layer, superficial musculo-aponeurotic system, deep fatty layer, parotideomasseteric fascia, masseter muscle.

FIGURE 5. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, triceps muscle) of the posterior arm and in the right panel the corresponding ultrasound image scanned in the exact same location.

FIGURE 6. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, abdominal external oblique muscle) of the abdomen and in the right panel the corresponding ultrasound image scanned in the exact same location.

FIGURE 7. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, gluteus maximus muscle) of the gluteal region and in the right panel the corresponding ultrasound image scanned in the exact same location.

FIGURE 8. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, quadriceps muscle) of the anterior thigh and in the right panel the corresponding ultrasound image scanned in the exact same location.

FIGURE 9. Figure showing in the left panel anatomic dissections of the subdermal layers (skin, superficial fatty layer, superficial fascia, deep fatty layer, deep fascia, adductor magnus muscle) of the medial thigh and in the right panel the corresponding ultrasound image scanned in the exact same location.



41



Posterior Arm (Figure 1, 3, and 5)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 4.39 mm ± 0.84 and in females 4.36mm ± 0.97 with P=0.780. In those with a BMI <24.9 kg/m2 the mean thickness was for males/females 3.70mm ± 0.55/3.54mm ± 0.68, whereas it was in those with a BMI of 25.0–29.9kg/m2 4.39mm ± 0.74/4.34mm ± 0.79 and for those with a BMI > 30.0kg/m2 it was 5.09mm ± 0.55/5.21mm ± 0.62. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.754, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.355, P<0.001). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:



Abdomen (Figure 1 ,3, and 6)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 12.81mm ± 2.88 and in females 12.48mm ± 3.44 with P=0.376 In those with a BMI <24.9 kg/m2 the mean thickness was for males/females 9.41mm ± 1.14/8.24mm ± 1.30, whereas it was in those with a BMI of 25.0–29.9 kg/m2 13.97mm ± 1.78/13.72mm ± 1.50 and for those with a BMI >30.0kg/m2 it was 15.03mm ± 1.61/15.48mm ± 1.72. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.829, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.104, rp=0.071). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:


Female: Thickness of superficial fatty layer in mm:-5.059+(0.686*BMI)-(0.020*Age)

Gluteal Region (Figure 1, 3, and 7)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 8.89mm ± 0.73 and in females 11.13mm ± 0.91 with P=0.373. In those with a BMI <24.9kg/m2 the mean thickness was for males/females 12.10mm ± 2.05/7.14mm ± 0.51, whereas it was in those with a BMI of 25.0–29.9kg/m2 18.57mm ±3,64/19.24 mm ± 3.73 and for those with a BMI >30.0kg/m2 it was 32.43mm ± 1.70/33.62mm ± 1.93. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.933, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.101, P=0.080). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:

Male: Thickness of superficial fatty layer in men:-23.484+(1.788*BMI)-(0.086*Age)


Anterior Thigh (Figure 1, 3, and 8)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 7.70mm ± 2.27 and in females 8.10mm ± 2.31 with P=0.131 In those with a BMI <24.9kg/m2 the mean thickness was for males/females 5.36mm ± 0.64/5.78mm ± 0.84, whereas it was in those with a BMI of 25.0–29.9 kg/m2 7.52mm ± 1.33/7.83mm ± 1.32 and for those with a BMI >30.0kg/m2 it was 10.23mm ± 1.16/10.70mm ± 1.11. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.892, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.159, P=0.006). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:

Male: Thickness of superficial fatty layer in mm:-2.981+(0.432*BMI)-(0.023*Age)


Medial Thigh (Figure 1, 3, and 9)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 5.73mm ± 1.05 and in females 5.74mm ± 1.27 with P=0.964. In those with a BMI <24.9kg/m2 the mean thickness was for males/females 4.98mm ± 0.77/4.50mm ± 0.87, whereas it was in those with a BMI of 25.0–29.9kg/m2 5.59mm ± 1.00/5.82mm ± 0.91 and for those with a BMI >30.0kg/m2 it was 6.63mm ± 0.59/6.91mm ± 0.60. Increasing BMI values correlated significantly with an increase in superficial fatty layer thickness (rp = 0.769, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.253, P<0.001). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:



Posterior Thigh (Figure 1, 3, and 10)The mean thickness of the superficial fatty layer independent of age or BMI, was in males 7.71mm ± 3.07 and in females 7.84mm ±3.34 with P=0.721. In those with a BMI <24.9kg/m2 the mean thickness was for males/females 4.75mm ± 0.44/4.53mm ± 0.87, whereas it was in those with a BMI of 25.0–29.9kg/m2 6.83mm ± 1.46/6.96mm ± 1.44 and for those with a BMI >30.0kg/m2 it was 11.54mm ± 1.28/12.03mm ± 1.12. Increasing BMI values



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correlated significantly with an increase in superficial fatty layer thickness (rp = 0.925, P<0.001) whereas increasing age correlated significantly with a decrease in its thickness (rp = -0.172, P=0.003). Multifactorial linear regression revealed the following formula to compute the thickness of the superficial fatty layer based on information of age and BMI:

Male: Thickness of superficial fatty layer in mmn:-7.026+(0.610*BMI)-(0.039*Age)


DISCUSSIONThis ultrasound-based study investigated the thickness of the superficial fatty layer in various regions of the body: face, neck, arms, abdomen, buttock, and thighs. The results reveal that the thickness varies based on location, with smallest mean values for the lateral neck of 3.71mm ± 0.55 [range, 2.00–5.00mm] and greatest values for the gluteal region of 20.52mm ± 10.07 [range, 6.10–38.40mm]. Based on the results obtained we were able to compute a formula whereby the thickness of the superficial fatty layer could be estimated if information on gender, age, and the BMI of the patient is available. The results reveal that the formula computed is different for each body region which accounts for the variation in superficial fatty layer thickness. The strengths of the study are the large sample size (n=150) with equal distribution of males and females (each n=75) and a balanced distribution of age (n=30 per decade: 20–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years) and BMI (n=50 per group: BMI ≤24.9 kg/m2, BMI between 25.0 and 29.9kg/m2 BMI ≥30kg/m2). This unique cohort allows analysis of the thickness of the superficial fatty layer per each anatomic region of clinical interest in individuals 50 years apart, and capability to draw conclusions about the influence of age on the variation in thickness relevant for biostimulator injections. Using three different BMI groups facilitates investigation of the influence of body habitus on superficial fatty layer thickness within and across the different age groups and genders. Another strength of the study is the non-invasive nature of the ultrasound imaging. Real time measurements were obtained without skin contact and applied pressure, ie sound waves were transmitted via the visualization gel, preserving the original tissue thickness.

Limitations of the study are that the ultrasound-based measurements were performed with subjects standing in an upright position. This might potentially limit the applicability of the measurements as some biostimulator injections are performed with the patient in the supine or prone position which can cause a shift in soft tissue proportions and thus a change in the reported thicknesses. Futures studies, however, will need to provide evidence for this potential postural change. Another limitation is that this study investigated Fitzpatrick types I–III

patients. It is unclear whether the results are generalizable to darker skinned patients.

The results of the present study confirm clinical observations where different magnitudes of superficial fatty layer thickness are observed. In the lateral neck, superficial fatty layer thickness is 3.71mm ± 0.55 [range, 2.00–5.00 mm] whereas in the gluteal region the thickness is 20.52mm ± 10.07 [range, 6.10–38.40 mm]. This difference in thickness influences treatment strategies especially when injecting biostimulators. The superficial fatty layer is not a homogenous mass of fat composed of adipocytes exclusively but is rather a highly organized compound structure with honeycomb-like architecture.23,25 This architecture is formed by adipocytes arranged in fat lobules which are surrounded by walls composed of fibrous connective tissue.25 These fibrous connective tissue walls together form a 3D fibrous connective tissue framework which encloses the fat lobules. Together, these fibrous connections form septae which attach to the underside of the dermis25 and expand into deeper layers. The deep attachment of these septal connections is the superficial fascia.16,18 Together, the skin, the superficial fatty layer, the connective tissue fibers that connect the skin to the superficial fascia and the superficial fascia itself are considered to be a functional biomechanical unit which has been previously termed the superficial fascial system.17,19–24 The thickness of the superficial fatty layer which increases in thickness with increasing BMI values15,16,18 influences the status of the superficial fascial system.

In cellulite, an aesthetic condition which predominantly affects post-pubertal females, increasing BMI is a risk factor for its development and its severity.14 It was recently demonstrated that the fibrous connections between the skin and the superficial fascia contribute to the stability of the superficial fascial system and that this stability is primarily influenced by gender with females having less stable subdermal fibrous connective tissue architecture.14 In the same cadaveric investigation, males were shown to have a higher number of fibrous connective tissue septae per area spanning the distance between the dermis and the superficial fascia. This resulted in significantly increased tensile strength values versus females when tested in an experimental load-until-failure study design.14

The results of those previous investigations demonstrate that the subdermal fatty layer, containing the fibrous connective tissue septae, is of crucial importance for maintaining skin tension and position. Alterations to this delicate arrangement influences skin surface appearance of which the most frequent are skin laxity and surface irregularities frequently observed in cellulite and aging. These aesthetic conditions can be explained by alterations in the superficial fascial system: reduced tension of the superficial fascial system can result in skin laxity whereas increased tension of the superficial fascial system and its components (like the superficial fatty layer due to increased



43



BMI) can result in skin surface irregularities.

Understanding and respecting this delicate subdermal architecture may increase the efficacy and the longevity of biostimulator treatment. Biostimulators have been shown to induce collagen synthesis via various pathways.1 Ultimately, those pathways result in an increased content of collagen within the adjacent connective tissues. If the targeted tissue is the superficial fascial system, effects on the skin could be expected including reduction in skin laxity and surface irregularities. Newly formed collagen could result in an increased amount and/or increased thickness of the connective tissue fibers that connect the skin to the superficial fascia. Being anchored to the superficial fascia, the alteration in conformation and/or tension of those septae could reduce skin laxity by bringing the skin closer to the superficial fascia. In dimple-type cellulite, the increase in collagen content in the superficial fascial system could lead to an increase in containment forces that stabilize the skin around depressions. As dimples are the result of soft tissue protrusion next to the subdermal attachment of vascularized “super-septae”, injecting biostimulators around areas with dimples can reduce the difference in skin level between the bottom of the dimple (original skin level) and the wall around the dimple (protruded skin level). This stabilization effect can be induced by the injection of biostimulators especially if the superficial fascial system is targeted.

The present study provides a mathematical formula to compute the thickness of the superficial fatty layer, which is an integral part of the superficial fascial system. With this formula, the maximal depth of biostimulator injections can be estimated if the age, gender, and the BMI of the patient are known. The result of the calculated region-specific formula can guide aesthetic providers towards more effective treatments as the output is the maximal depth of biostimulator injections targeting the superficial fascial system. Injections deeper than the calculated value (results are in millimeters) might result in a reduced efficacy as the superficial fascial system is not targeted and the induced neocollagenesis does not impact the fibrous connective tissue septae that connect the skin to the superficial fascia.

CONCLUSIONThe results of the present study reveal that the thickness of the superficial fatty layer is highly variable in the human body as it depends on the investigated region, age, gender, and BMI. The superficial fatty layer is an integral component of the superficial fascial system which influences skin laxity and skin surface irregularities. The result of the calculated region-specific formula can guide aesthetic providers towards more effective treatments as the output is the maximal depth of biostimulator injections whereby the superficial fascial system is targeted. Injections deeper than the calculated values might result in a reduced effectiveness as the superficial fascial system is not

targeted and the induced collagen formation does not affect the fibrous connective tissue septae and thus ultimately the skin surface.

DISCLOSURESNone of the other authors listed has any commercial associations or financial disclosures that might pose or create a conflict of interest with the methods applied or the results presented in this article.

Funding: This study received funding by Merz North America, Inc., Raleigh, NC, USA (Grant Nr.: 02092018) and by Q-Med Galderma, Uppsala, Sweden (Grant Nr.: 07172019) for statistical financial support for the generation of the formula.

REFERENCES1. Fitzgerald R, Vleggaar D. Facial volume restoration of the aging face with poly-

l-lactic acid. Dermatol Ther. 24(1):2-27. doi:10.1111/j.1529-8019.2010.01375.x2. Lam SM, Azizzadeh B, Graivier M. Injectable poly-L-lactic acid (Sculptra):

technical considerations in soft-tissue contouring. Plast Reconstr Surg. 2006;118(3 Suppl):55S-63S. doi:10.1097/01.prs.0000234612.20611.5a

3. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plast Surg. 27(5):354-366; discussion 367. doi:10.1007/s00266-003-3022-1

4. Lowe NJ. Optimizing poly-L-lactic acid use. J Cosmet Laser Ther. 2008. doi:10.1080/14764170701840074

5. Lowe NJ, Maxwell CA, Lowe P, Shah A, Patnaik R. Injectable poly-L-lactic acid: 3 years of aesthetic experience. Dermatologic Surg. 2009. doi:10.1111/j.1524-4725.2008.01061.x

6. Mazzuco R, Sadick NS. The use of poly-l-lactic acid in the gluteal area. Dermatol Surg. 2016;42(3):441-443. doi:10.1097/DSS.0000000000000632

7. Mazzuco R, Hexsel D. Poly-L-lactic acid for neck and chest rejuvenation. Dermatol Surg. 2009;35(8):1228-1237. doi:10.1111/j.1524-4725.2009.01217.x

8. Peterson JD, Goldman MP. Rejuvenation of the aging chest: a review and our experience. Dermatologic Surg. 2011. doi:10.1111/j.1524-4725.2011.01972.x

9. Redaelli A, Forte R. Cosmetic use of polylactic acid: report of 568 patients. J Cosmet Dermatol. 2009. doi:10.1111/j.1473-2165.2009.00459.x

10. Redaelli A. Cosmetic use of polylactic acid for hand rejuvenation: report on 27 patients. J Cosmet Dermatol. 2006. doi:10.1111/j.1473-2165.2006.00259.x

11. American Society for Dermatologic Surgery. Survey on Dermatologic Procedures. https://www.asds.net/portals/0/PDF/procedure-survey-results-infographic-2017.pdf. Accessed September 18, 2018.

12. Cotofana S, Schenck TL, Trevidic P, et al. Midface: clinical anatomy and regional approaches with injectable fillers. Plast Reconstr Surg. 2015;136:219S-234S. doi:10.1097/PRS.0000000000001837

13. Schenck TL, Koban KC, Schlattau A, et al. The functional anatomy of the su-perficial fat compartments of the face: a detailed imaging study. Plast Re-constr Surg. 2018;141(6):1351-1359. doi:10.1097/PRS.0000000000004364

14. Rudolph C, Hladik C, Hamade H, et al. Structural gender dimorphism and the biomechanics of the gluteal subcutaneous tissue. Plast Reconstr Surg. 2019;143(4):1077-1086. doi:10.1097/PRS.0000000000005407

15. Casabona G, Frank K, Koban KC, et al. Influence of age, sex, and body mass index on the depth of the superficial fascia in the face and neck. Dermatologic Surg. March 2019:1. doi:10.1097/DSS.0000000000001909

16. Frank K, Casabona G, Gotkin RH, et al. Influence of age, gender and body mass index on the thickness of the gluteal subcutaneous fat – implications for safe buttock augmentation procedures. Plast Reconstr Surg. April 2019:1. doi:10.1097/PRS.0000000000005707

17. Lockwood T. High-lateral-tension abdominoplasty with superficial fascial system suspension. Plast Reconstr Surg. 1995;96(3):603-615. http://www.ncbi.nlm.nih.gov/pubmed/7638284. Accessed August 19, 2018.

18. Frank K, Hamade H, Casabona G, et al. Influences of age, gender, and body mass index on the thickness of the abdominal fatty layers and its relevance for abdominal liposuction and abdominoplasty. Aesthetic Surg J. May 2019. doi:10.1093/asj/sjz131

19. Kitzinger HB, Lumenta DB, Schrögendorfer KF, Karle B. Using superficial fascial system suspension for the management of the mons pubis after massive weight loss. Ann Plast Surg. 2014;73(5):578-582. doi:10.1097/SAP.0b013e31827e29e5



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403. doi:10.1016/j.asj.2006.05.00526. Sadick NS, Arruda S. The use of poly-l-lactic acid in the abdominal area.

Dermatol Surg. 2017;43(2):313-315. doi:10.1097/DSS.000000000000088127. WMA Declaration of Helsinki – Ethical Principles for Medical Research

Involving Human Subjects – WMA – The World Medical Association. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed August 5, 2018.


Sebastian Cotofana MD PhD E-mail:................……......................... [email protected]

20. Stecco C, Macchi V, Porzionato A, Duparc F, De Caro R. The fascia: the forgotten structure. Ital J Anat Embryol. 2011;116(3):127-138. http://www.ncbi.nlm.nih.gov/pubmed/22852442. Accessed August 19, 2018.

21. Lockwood T. Brachioplasty with superficial fascial system suspension. Plast Reconstr Surg. 1995;96(4):912-920. http://www.ncbi.nlm.nih.gov/pubmed/7652066. Accessed August 19, 2018.

22. Lockwood T. Lower body lift with superficial fascial system suspension. Plast Reconstr Surg. 1993;92(6):1112-1122; discussion 1123-5. http://www.ncbi.nlm.nih.gov/pubmed/8234509. Accessed August 19, 2018.

23. Lockwood TE. Fascial anchoring technique in medial thigh lifts. Plast Reconstr Surg. 1988;82(2):299-304. http://www.ncbi.nlm.nih.gov/pubmed/3399559. Accessed August 19, 2018.

24. Lockwood TE. Superficial fascial system (SFS) of the trunk and extremities: a new concept. Plast Reconstr Surg. 1991;87(6):1009-1018. http://www.ncbi.nlm.nih.gov/pubmed/2034721. Accessed August 19, 2018.

25. Song A, Askari M, Azemi E, Aalber S, Hurwitz D, Rubin J. Biomechanical properties of the superficial fascial system. Aesthetic Surg J. 2006;26(4):395-

JDDFacial

Skin Tightening W

ith Microfocused

Ultrasound and Dermal Fillers

:

Considerations fo

r Patient Selection and Outcomes

STILL AVAILABLE

Facial Skin Tightening With Microfocused Ultrasound and Dermal Fillers:Considerations for Patient Selection and Outcomes

This continuing education enduring activity is supported by an educational grant provided by Merz North America, Inc.

Available now in the JDD CME Library: www.JDDonline.com/CME


jddonline.com



aerolase.com




SPECIAL TOPIC

Demonstration of the Antioxidant Capabilities of a Product Formulated With Antioxidants Stabilized in Their

Reduced FormZoe Diana Draelos MD,ª Catherine J. Pachuk PhDb

aDermatology Consulting Services, PLLC, High Point, NCBSomahlution, Jupiter, FL

Oxidative damage from reactive oxygen species is instrumental in aging. Topical antioxidants are used in many cosmeceuticals to provide appearance benefits; however, the activity of these antioxidants may be questionable. This research validated the activity of L-ascorbic acid and L-glutathione in the studied facial product and correlated this activity with clinical appearance improvement following 12 weeks of use.


ABSTRACT

INTRODUCTION

The final common pathway for skin damage of all types, including aging, is the production of reactive oxygen species (ROS). Unfortunately, avoiding ROS exposure

is impossible due to their extrinsic environmental abundance and intrinsic production through cellular metabolism.1 The body has developed a variety of antioxidant protective mecha-nisms, which may be augmented through use of exogenous antioxidant materials; however, the antioxidants must be stable and functional in cosmetic formulations. In order to be effec-tive, antioxidants must exist in a reduced or active state since only reduced antioxidants can neutralize an oxidant.2,3 Without special manufacturing or formulation controls to stabilize anti-oxidants in their reduced form, antioxidants are converted to their inactive oxidized form and are no longer functional. This antioxidant capability must be maintained over the shelf life of the product, which is rarely substantiated by cosmetic manu-facturers.

Many currently marketed antioxidant formulations claim to contain stabilized forms of vitamin C, such as ascorbyl-2-glu-coside and magnesium ascorbyl phosphate, or stabilized forms of glutathione, such as acyl-glutathione. While these molecules are stable, they are not antioxidants. They are antioxidant-precursors that must be enzymatically modified following skin application to yield L-ascorbic acid and glutathione respec-tively.4,5 While conversion to functional antioxidants has been demonstrated in cell culture, where it is relatively easy to in-troduce large amounts of these stable precursors, conversion following topical application is an inefficient process.4 Other skin care products claim to contain antioxidant fruit or herb ex-tracts; however, any antioxidant originally present in the fruit or herb is no longer active when the extract is prepared for addi-tion to a cosmetic formulation.

This research examined a novel antioxidant formulation of L-ascorbic acid and L-glutathione manufactured using antioxidant stabilization technology originally developed for organ/tissue preservation products. The primary cause of operating room transplant organ damage is oxidative damage. The organ pres-ervation solution must contain active and stable antioxidants to optimize the viability of the harvested organ. Development of these solutions requires proof of the presence and stabil-ity of antioxidants prior to regulatory clearance. Manufacturing must also occur under GMP conditions. This same preservation technology has been used to stabilize the L-ascorbic acid and L-glutathione in the tested cosmetic formulation.

METHODSVerification of Ascorbate ConcentrationThe total ascorbate in the cosmetic formulation and a com-petitor product labelled as containing 7.5% L-ascorbic acid was measured using a UV spectrophotometric method. Wavelength scans were performed on a PerkinElmer Lambda 35 Spectropho-tometer, (PerkinElmer Corp., Hopkinton, MA) and measurement of ascorbate was taken at 243 nm, the wavelength of maxi-mum absorbance for ascorbic acid under the assay conditions. Ascorbate concentrations in product samples were determined by interpolation; plotting measured values on a concentration curve generated by ascorbic acid standards. The method was verified for all products using ascorbic acid spike recovery as-says.

Functional Antioxidant Assay 10 mLs of an 8.8 µM thionin solution prepared in Hanks Balanced Salt Solution (pH 3) was aliquoted to control and test flasks. 250 µl of the study product or the comparator ascorbic acid-containing cosmetic was added to separate thionin-containing

doi:10.36849/JDD.2020.3947



47


Z.D. Draelos, C.J. Pachuk

A two-tailed Mann Whitney t-test was used to analyze the nonparametric data sets (investigator efficacy and tolerability, subject efficacy and tolerability) with significance set at P<0.05. The noninvasive parametric numerical data (TEWL, corneom-etry, elasticity, colorimetry) were analyzed using Student's t test with significance set at P<0.05. A longitudinal analysis was per-formed for the monadic study with each timepoint compared to baseline.

RESULTSLaboratory Results The functional assay results are shown in Figure 1. The oxidant thionin imparts a purple color to the solution; reduction of thionin converts the color of the solution from purple to clear. From left to right, the following specimens are presented: negative control (no antioxidants added), competitor product, and study product. The purple color indicates antioxidant failure and was observed for both the competitor product and the negative control, but not the study product. This observation verifies the presence of active antioxidants in the study product. Figure 2 presents the analytical UV-vis assay for L-ascorbic acid detection.

flasks, incubated under ambient conditions on bench top, and observed for up to 24 hours. Aliquots of thionin mixed with the products were removed for pH measurement. Thionin solu-tion to which no antioxidants were added served as negative controls. The positive controls included thionin solutions con-taining various concentrations of the L-ascorbic acid standard or L-glutathione standard. The potential inhibitory effect of test ar-ticles was assessed by spiking test articles into positive control solutions and measuring inhibition of L-ascorbic acid standard activity in the assay. No inhibitory effects were observed.

Clinical EvaluationsThis was a single-site monadic study enrolling 30 female sub-jects 35-65 years of age with Fitzpatrick skin type I-V and mild to moderate photoaging who successfully completed informed consent (Allendale Institutional Review Board, Lyme, CT). Subjects used the product twice daily to the entire face (Soma-Ceutica, Somahlution, Jupiter, FL). Assessments consisted of investigator and subject efficacy evaluations on a 5 point ordi-nal scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) including the following criteria: fine lines, wrinkles, skin tone, skin color, tactile smoothness, textural smoothness, firmness, radiance, luminosity, sallowness, dullness, laxity, pigmenta-tion, erythema, desquamation, stinging, burning, and overall appearance. Investigator and subject tolerability assessments were performed on the same 5 point ordinal scale evaluating erythema, desquamation, stinging, and burning. Facial nonin-vasive assessments included transepidermal water loss (TEWL)(Cyberderm, Broomall, PA), corneometry (Dermalab, Cortex Technologies, Hadsund, Denmark), skin elasticity (Dermalab, Cortex Technologies, Hadsund, Denmark), colorimetry (Minolta, Toyko, Japan), and Visia CR4.3 (Canfield Scientific, Parsippany, NJ) photographs of the front, right, and left side of the face. All assessments were performed at baseline, week 2, week 4, week 8, and week 12.

FIGURE 1. Functional assay results. The functional assay results shown from left to right: negative control (no antioxidants added), competitor product, and study product.

FIGURE 2. UV spectra. UV spectra was collected between 200 and 350λ and shown between 200-290λ. Absorbances are shown for the negative control, 7.5%, 10%, and 20% ascorbic acid standards and the study and competitor products.



48



and elasticity did not increase nor did TEWL decrease. Im-provements were seen in facial colorimetry with a statistically significant increase in luminosity (P=0.021) and a decrease in facial redness (P=0.005) and sallowness (P=0.034). The inves-tigator rated statistically significant improvements (P<0.001) at week 12 in textural and tactile smoothness, luminosity, firmness, radiance, dullness, and overall appearance (Figure 3). After 12 weeks of use, there was a statistically significant improvement (P<0.001) in subject assessments relating to fine lines, wrinkles, skin tone, skin color, tactile smoothness, textural smoothness, firmness, pigmentation, radiance, luminosity, and overall ap-pearance (Figure 4).

The UV spectrum is shown over 220-290 nm wavelength range. The x-axis is wavelength (nm) and the y-axis is absorbance. Absorbances are plotted for the negative control, 7.5%, 10%, and 20% ascorbic acid standards and the study and competitor products. The expected wavelength of maximum absorbance for ascorbic acid was observed at 243 nm.

Clinical Results30/30 subjects successfully completed the study without allergic or irritant contact dermatitis or other adverse events yielding an excellent product safety profile. The study product was not placed in a moisturizing vehicle and therefore corneometry

FIGURE 3. Investigator efficacy mean scores. Mean scores for the selected investigator efficacy endpoints of firmness, radiance, textural smoothness, and overall appearance are shown at baseline and weeks 4, 8, and 12. Mean scores are provided with * designating statistical significance.

FIGURE 4. Subject efficacy mean scores. Mean scores for the selected subject efficacy endpoints of firmness, radiance, textural smoothness, and overall appearance are shown at baseline and weeks 4, 8, and 12. Mean scores are provided with * designating statistical significance.



49



DISCUSSIONThe study product contained the antioxidants L-ascorbic acid and L-glutathione, which were stabilized in their active reduced form. The presence of the reduced forms of the molecules was shown in two ways; liquid chromatography mass spectroscopy (LCMS) or spectrophotometry and functional assays to dem-onstrate and quantitate the activity of reduced antioxidants. Ascorbic acid results are shown by way of example for the study product and a competitor product claiming to contain 7.5% ascorbic acid (Figure 1). Only the study product shows activity in the functional ascorbic acid assay. Activity is demonstrated by the ability of the antioxidant to neutralize or reduce thionin, which possesses a purple color when oxidized. Once reduced or neutralized, thionin loses its color and the solution becomes clear. The study product had sufficient ascorbic acid antioxidant activity to neutralize 5.4 x1016 oxidants in 45 seconds. No de-tectable antioxidant activity was seen in the competitor product even after 24 hours.

The UV spectrophotometric assay (Figure 2) was consistent with these results and demonstrated a peak of maximum absorbance at 243 nmλ corresponding to a 17% L-ascorbic acid concentra-tion in the study product. This represents over 75% of labeled concentration still present nine months post-manufacture. No ascorbic acid could be detected in the competitor product, which was tested the day it was purchased. The absorbance was close to that of the negative control. A second sample of competitor product with a different lot number was also tested and yielded similar results.

A separate functional assay conducted prior to this research, based on DTNB (Ellman’s reagent) derivatization to detect thiols, was also positive for the study product, indicating the presence of active and reduced L-glutathione that was subsequently con-firmed by LCMS (data not shown).

The laboratory results were verified by investigator and subject clinical assessments indicating appearance improvement based on the active ingredients, since the vehicle possessed no mois-turizing properties. The presence of active stable ascorbic acid and glutathione were confirmed in the study formulation. This is important as antioxidants are common ingredients in cosme-ceutical formulations and are frequently cited as "containing vitamin C." This is an ingredient disclosure on the packaging and indicates the ingredient was placed in the formulation at the time of manufacture, but the presence and stability of the ingredient are not guaranteed. This has been a challenge when investigating antioxidant-containing cosmeceuticals. This research is unique in that it linked the presence of the active ascorbic acid and glutathione antioxidants to the demonstrated clinical effects.

DISCLOSURESZoe Diana Draelos, MD, received a research grant from Somah-lution to conduct the research. Catherine J Pachuk, PhD, is an employee of Somahlution.

ACKNOWLEDGMENTSCheryl Rosenberger and Matthew P. Cleary provided analytical testing support. Vilas Satishchandran assisted with clinical op-erations.

REFERENCES1. Birben E, Sahiner UM, Sackesen C et al. Oxidative stress and antioxidant

defense. Review Article. World Allergy Organ J. 2012;5(1):9-19.2. Lu J-M, Lin PH, Yao Q et al. Chemical and molecular mechanisms of anti-

oxidants: Experimental approaches and model systems. J Cell Mol Med. 2010;14(4):840-60.

3. Akbari A, Jelodar G, Nazifi A et al. An overview on the characteristics and function of vitamin C in various tissues; relying on its antioxidant function. Zahedan J Res Med Sci. 2016;18(11):4037.

4. Hanada Y, Iomori A, Ishii R et al. Protection of free radical-induced cytotoxic-ity by 2-0-α-D-glucopyranosyl-L-ascorbic acid in human dermal fibroblasts. Biosci Biotechnol Biochem. 2014;78(2):301-306.

5. Fanelli S, Francioso A, Cavallaro RA et al. Oral administration of S-acetyl-glutathione: Impact on the levels of glutathione in plasma and erythrocytes of health volunteers. Int J Clin Nutr Diet. 2018;4:134


Zoe Diana Draelos MDE-mail:................……......................... [email protected]





SPECIAL TOPIC

Topical Agents for the Treatment of Atopic DermatitisLawrence F. Eichenfield MD,a,b Thomas Luger MD,c Kim Papp MD,d Jonathan I. Silverberg MD PhD MPH,e

Debra Sierka PhD,f,* Chuanbo Zang PhD,f Anna M. Tallman PharmD,g,* Michael A. Zielinski PharmD,f

William C. Ports DVMh,*

aUniversity of California, San Diego, San Diego, CA BRady Children’s Hospital-San Diego, San Diego, CA

cWestphalian Wilhelms-University Münster, Münster, GermanyDK Papp Clinical Research and Probity Medical Research, Waterloo, Ontario, Canada

EThe George Washington University School of Medicine and Health Sciences, Washington, DCfPfizer Inc., Collegeville, PAgPfizer Inc., New York, NY

hPfizer Inc., Groton, CT*At the time of this research

Approval of the new topical phosphodiesterase 4 inhibitor crisaborole ointment, 2%, to treat mild-to-moderate atopic dermatitis (AD) warrants careful consideration of available efficacy and safety data for topical therapies to contribute to a better understanding of the role of crisaborole in the treatment of mild-to-moderate AD. A literature review was conducted to identify results of randomized, blinded, vehicle-controlled trials of topical agents for the treatment of AD published from January 1, 1997 to April 30, 2018. This review summarizes the efficacy and safety data of topical therapies including corticosteroids, calcineurin inhibitors, and crisaborole and it shows that comparison among available agents is difficult because of differing methodologies used across clinical trials and that there is considerable variability in safety reporting among AD trials. Published clinical studies for crisaborole demonstrate its efficacy and manageable safety profile.


ABSTRACT

INTRODUCTION

Atopic dermatitis (AD) is a chronic, inflammatory skin disease that follows a chronic and relapsing course.1

Essential features include pruritus and eczematous le-sions that present with a typical morphology and age-associ-ated distribution.2,3 Up to 90% of children with AD have mild or moderate disease.4 Common signs and symptoms include pruritus, erythema, edema, xerosis, erosions/excoriations, ooz-ing and crusting, and lichenification, which vary by age and chronicity of lesions.2 Because of the chronicity, intense symp-tom burden, and visible nature of the disease, patients with AD frequently have reduced quality of life (QoL) and psychological comorbidities, including depression and anxiety.5 Pruritus is responsible for a significant portion of this burden, which in-cludes the associated impact on sleep quality.2,6

According to the American Academy of Dermatology (2014) and joint guidelines of the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology (2013), topical therapies remain stan-dard treatment for AD and provide efficacy while minimizing the potential for systemic adverse events (AEs).7,8 Basic skin care, moisturizers, and trigger avoidance are recommended as

initial treatment and are integral to AD therapy, aiming to treat and prevent xerosis, reduce transepidermal water loss (TEWL), reduce signs of AD, and prevent flares.7,8 When the AD is not suf-ficiently controlled with nonpharmacologic approaches, topical corticosteroids (TCSs) are recommended.7,8 TCSs have been the mainstay of anti-inflammatory therapy for AD for decades and can be used reactively to treat established lesions and proac-tively to prevent relapse.7 However, safety concerns regarding local and systemic AEs can result in treatment hesitancy in care-givers and patients.7,9 Therefore, appropriate selection of TCS potency, correct application (including duration and location of treatment), and patient education are important.7,8 Topical cal-cineurin inhibitors (TCIs) are immunosuppressant agents that are recommended as second-line treatment in areas where skin atrophy is a concern (eg, face, eyelids, skin folds), for steroid-nonresponsive AD, when steroids are not advisable, or when a TCS treatment holiday is necessary.7,8 Transient localized burn-ing and itching can occur with TCIs, which can limit their use in some patients.7,8

Crisaborole ointment is a nonsteroidal, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild-to-moderate AD.

doi:10.36849/JDD.2020.4508



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L.F. Eichenfield, T. Luger, K. Papp, et al

Vehicle Effects“Vehicle effects” are an additional challenge, in that vehicle emollient effects may improve barrier function and reduce TEWL leading to improved outcomes in AD, which are observed frequently in vehicle-controlled RCTs.10,19,26,44 Vehicle composi-tion, which commonly varies from product to product, can also contribute to local application site AEs such as stinging and erythema.45 For example, a number of trials included in this analysis report more AEs and treatment-related AEs (TRAEs) in the vehicle arm than in the active treatment arm (Table 1).

EFFICACY OF TOPICAL TREATMENTSPhosphodiesterase 4 Inhibitors Three vehicle-controlled trials have been conducted to inves-tigate the efficacy of crisaborole ointment, 2%, including 2 identically designed 4 week phase 3 trials10 and a 6-week phase 2a proof-of-concept trial.11 In the phase 3 trials, higher pro-portions of crisaborole-treated patients than vehicle-treated patients achieved the primary endpoint of ISGA of clear (0) or almost clear with ≥2-grade improvement from baseline at day 29 (Study 1: P=0.038; Study 2: P<0.001) (Table 1, Figure 1).10

Higher proportions of crisaborole-treated patients also achieved the type 1 error-controlled key secondary endpoint of ISGA clear (0) or almost clear (1) versus vehicle (Study 1: 51.7% vs 40.6%, P=0.005; Study 2: 48.5% vs 29.7%, P<0.001).10 In a separate analysis of secondary endpoints based on Severity of Pruritus Scale (SPS; 4 point rating scale adapted from the Atopic Derma-titis Severity Index (ADSI) to assess pruritus severity with a 24 hour recall46), higher proportions of crisaborole-treated patients achieved improvement in pruritus (SPS score ≤1 with ≥1 point improvement from baseline) compared with vehicle (Study 1: 37% vs 21%, P<0.0001; Study 2: 34% vs 21%, P=0.0006), and that crisaborole-treated patients achieved pruritus improvement earlier than vehicle-treated patients (median days, Study 1: 4.0 vs 9.0, P=0.0008; Study 2: 5.0 vs 9.0, P=0.0042).47 In the phase 2a intrapatient comparison trial, lesion-specific efficacy was as-sessed by change from baseline in ADSI score (none [0] to most severe [15]).11 More patients experienced a greater decrease in ADSI score for the crisaborole-treated lesion than the vehicle-treated lesion at day 28 (primary end point; P=0.017) (Table 1, Figure 1) as well as at each of the other time points assessed (days 14 and 42).11

Topical CorticosteroidsIn 8 articles summarizing 9 trials, the efficacy of low potency (fluocinolone acetonide in peanut oil, 0.01%; desonide hydrogel, 0.05%),16,17 lower-medium potency (hydrocortisone butyrate ointment and cream, 0.1%),18,19 medium potency (betamethasone valerate cream, 0.1%; triamcinolone acetonide cream, 0.05%),20,21 and very high potency (clobetasol propionate cream and lotion, 0.05%)22,23 TCSs were assessed. Reiterating the importance of vehicle, 7 of these trials explored various vehicles

Multiple clinical trials have evaluated the safety and efficacy of crisaborole in patients with mild-to-moderate AD.10-14 Crisab-orole received its first approval in December 2016 in the United States for the treatment of mild-to-moderate AD in patients aged 2 years and older.

Although results of current head-to-head trials to compare cri-saborole to other available topical therapies are not available (ClinicalTrials.gov, NCT03539601), a review of efficacy and safe-ty data can contribute to a better understanding of the potential role of crisaborole in treating mild-to-moderate AD. Herein, the data published between 1997 and 2018 supporting the effective-ness and safety of available topical therapies (TCSs, TCIs, and crisaborole) will be reviewed.

LITERATURE ANALYSISOur strategy consisted of searching Medline (via PubMed; Table S1) for blinded, vehicle-controlled trials of topical agents pub-lished from January 1, 1997 to April 30, 2018. Identified citations were then selected as shown in Figure S1. In total, 134 publica-tions were identified through the search; publications were hand screened for inclusion. 85 publications were excluded based on the abstract; 21 were excluded based on full text. A total of 28 publications are summarized herein (Table 1).10,11,15-41 The P val-ues represent 2 comparator tests unless otherwise specified.

CONSIDERATIONS FOR COMPARISONSVariety of Assessment ToolsThere is no standardized single assessment tool for measuring the severity of AD and therapy response. A systematic review published in 2003 assessed the heterogeneity of AD severity measures, and it was found that only 27% (23 of 85) of ran-domized controlled trials (RCTs) used a previously published scoring system.42 The most commonly used disease severity scales include different aspects of AD.43 The SCORing of Atopic Dermatitis (SCORAD) assesses representative signs of AD and symptoms of pruritus and sleep loss. The Eczema Area and Severity Index (EASI) assesses lesional extent and intensity for each of 4 body regions, and the Investigator’s Static Global Assessment (ISGA) and the Investigator’s Global Assessment (IGA) assess overall severity by clinical signs.43 Heterogene-ity of severity assessment instruments was also observed for the trials identified in the current search (Table 1): investigators variously used SCORAD, ISGA/IGA, total severity score (TSS), dermatologic sum score, and days on trial without flare (defined by use of TCS). The variety of instruments used to assess the severity of AD, different interpretation of scores, and lack of pre-cise definitions makes comparison of efficacy between clinical trials challenging. The remitting-relapsing course of AD further complicates the interpretation of RCT results because waning disease severity can be misinterpreted as efficacy, especially in clinical trials with small sample sizes.



52



FIGURE 1. Effect of Topical Treatments on Severity of Atopic Dermatitis. Treatment success defined as aPGA 0 or 1 with ≥2-grade change from baseline at day 29 bIGSS 0 or 1 with ≥2-grade change in IGSS from baseline at week 4; cISGA clear (0) or almost clear (1) with ≥2-grade improvement from baseline at day 29; dGSS 0, 0.5, or 1 at week 2; eIGA 0 or 1 at end of treatment (Bangert: week 3; Breuer: day 29; Leung: week 6; Eichenfield: day 43; Schneider: week 14); fIGADA clear or almost clear at week 6; gISGA of clear (0) or almost clear (1) at day 29; h>75% improvement from baseline in PGE at day 22; ipercent reduction in TSS at week 2; j≥1-grade improvement in IGA at day 7; k≥75% in PGE at day 22; lIGA mild or less at week 24; mgreater decrease in ADSI score from baseline at day 28 for active-treated lesion versus vehicle-treated lesion. ADSI, Atopic Dermatitis Severity Index; bid, twice daily; CI, confidence interval; GSS, Global Severity Score; IGA, Investigator’s Global Assessment; IGADA, Investigator’s Global AD, Assessment; IGSS, Investigator’s Global Severity Score; ISGA, Investigator’s Static Global Assessment; ND, not determined; PDE4, phosphodiesterase 4; PGA, Physician’s Global Assessment; PGE, Physician’s Global Evaluation; PGI, Physician Global Improvement; TCI, topical calcineurin inhibitor; TCS topical corticosteroid.

2

FIGURES

Figure 1. Effect of Topical Treatments on Severity of Atopic Dermatitis

Treatment success defined as aPGA 0 or 1 with ≥2-grade change from baseline at day 29 bIGSS 0 or 1 with ≥2-grade

change in IGSS from baseline at week 4; cISGA clear (0) or almost clear (1) with ≥2-grade improvement from

baseline at day 29; dGSS 0, 0.5, or 1 at week 2; eIGA 0 or 1 at end of treatment (Bangert: week 3; Breuer: day 29;

Leung: week 6; Eichenfield: day 43; Schneider: week 14); fIGADA clear or almost clear at week 6; gISGA of clear

(0) or almost clear (1) at day 29; h>75% improvement from baseline in PGE at day 22; ipercent reduction in TSS at

week 2; j≥1-grade improvement in IGA at day 7; k≥75% in PGE at day 22; lIGA mild or less at week 24; mgreater

decrease in ADSI score from baseline at day 28 for active-treated lesion versus vehicle-treated lesion. ADSI, Atopic

Dermatitis Severity Index; bid, twice daily; CI, confidence interval; GSS, Global Severity Score; IGA, Investigator’s

Global Assessment; IGADA, Investigator’s Global AD, Assessment; IGSS, Investigator’s Global Severity Score;

ISGA, Investigator’s Static Global Assessment; ND, not determined; PDE4, phosphodiesterase 4; PGA, Physician’s

Global Assessment; PGE, Physician’s Global Evaluation; PGI, Physician Global Improvement; TCI, topical

calcineurin inhibitor; TCS topical corticosteroid.

Drugclass

Treatmentduration Scale Reference

N(total) P-value



53



TABLE 1.

Multicenter, Randomized, Blinded, Vehicle-Controlled AD/Eczema Trials of Published January 1997-April 2018

Reference and Population Treatment Primary Efficacy Primary Safety

TOPICAL PHOSPHODIESTERASE 4 INHIBITORS

Paller (2016)10 − Age ≥2 years − ISGAc mild (2) or moderate (3)

4 weeks bid

Proportion of patients with ISGAc clear (0) or almost clear (1) with ≥2-grade improvement at day 29

Overall TEAEs, SAEs, TRAEs not reported

Study 1 Study 2

Crisaborole ointment, 2% (N=507 | N=514) 32.8%, P=0.038 vs vehicle 31.4%, P <0.001 vs vehicle

Vehicle (N=256 | N=250) 25.4% 18.0%

Murrell (2015)11 − Age 18-75 years − 2 comparable lesions

~10-500 cm2 − ADSId ≥6 to ≤12 with between-

lesion difference ≤1

6 weeks bid Proportion of patients with greater decrease in ADSId versus other lesion at day 28

AEs SAEs TRAEs

not reported (N=25)b

Crisaborole ointment, 2% 68%, P=0.017 vs vehicle 44% 0%

Vehicle 20%

TOPICAL CORTICOSTEROIDS

Paller (2003)16 − Age 2-12 years − Moderate-to-severe AD − %BSA ≥20

2 weeks bid Improvement in symptomse at week 1

Overall AEs not reported

SAEs

Overall TRAEs

not reported

Fluocinolone acetonide in peanut oil, 0.01% (N=49)

Erythema: P<0.005 vs vehicle Scaling: P<0.005 vs vehicle

Lichenification: P<0.005 vs vehicle Pruritus: P<0.005 vs vehicle

0%

Vehicle (N=45) NR 0%

Hebert (2007)17 − Age 3 months-18 years − IGSSf mild or moderate

4 weeks bid Proportion of patients with IGSSf clear (0) or almost clear (1)

with ≥2-grade change at week 4 AEs SAEs

TRAEs not

reported Study 1 Study 2 Pooled Pooled

Desonide hydrogel, 0.05% (N=289 | N=136) 44%, P<0.001 28%, P<0.001 20% 0.2%

Vehicle (N=136 | N=65) 14% 6% 29% 0%

Gong (2006)18 − Age 2-65 years − Chinese patients with eczema

(N=208) or AD (N=119)

28 days qd ≥50% improvement in symptom and sign scores at day 28

Safety not reported Hydrocortisone butyrate ointment, 0.1% + mupirocin (N=160)

85.0%, NS vs hydrocortisone butyrate + vehicle

Hydrocortisone butyrate ointment, 0.1% + vehicle (N=167)

83.2%

Abramovits (2010)19 − Age 3 months-<18 years − PGAg mild (39%) or

moderate (61%)

1 month bid PGAg clear (0) or almost clear (1) with ≥2-grade reduction at

day 29 AEs SAEs TRAEs

Hydrocortisone butyrate lipocream, 0.1% (N=131) 63%, P<0.001 vs vehicle 21% 0% 2%

Vehicle (N=133) 28% 22% 0% 2%

Cato (2001)20 − Age 18-86 years − ≥3 stable or worsening AD

lesions for ≥1 year with 2 of 3 having total disease sign and symptom scoreh ≥7

2 weeks bid Reduction in total disease sign and symptom scoreh AEs SAEs

TRAEs not

reported

Triamcinolone acetonide, 0.05%i/laurocapram (N=50)

Day 15: P=0.01 vs triamcinolone acetonide Day 3: P<0.01 vs vehicle

6% 0%

Triamcinolone acetonide, 0.05%i (N=50) NR 8% 0%

Vehicle (N=50) NR 20% 0%

TABLE 1.



Larsen (2007)21 − Age ≥6 years − Infected AD − Target lesion ≥4×4 cm2

Betamethasone valerate (1 mg/g)/fusidic acid (20 mg/g), bid for 2 weeks

Percentage reduction in TSSj at week 2 AEs

SAEs, TRAEs not reported

Lipid cream (N=275) 82.9%, P<0.001 vs vehicle 13.5%

Cream (N=264) 82.7% 10.5%

Lipid cream vehicle (N=90) 33% 21.6%

Maloney (1998)22 − Age ≥12 years − Moderate-to-severe AD − %BSA ≥2

4 weeks bid Mean change in lesion TSSk AEs

SAEs not reported

TRAEs

Clobetasol propionate emollient cream, 0.05% (N=41)

Days 4, 8, 15, 29, and 43: P<0.001 vs vehicle 2.4% 2.4%

Vehicle (N=40) NR 5.0% 5.0%

Breneman (2005)23 − Age 12-86 years − DSSl ≥6 in target area +

≥3 signs/symptoms (pruritus, flexural lichenification, linearity in adults, chronic/chronically relapsing dermatitis, history of atopy)

Clobetasol propionate, 0.05%, bid for 2 weeks Proportion of patients with GSSm of 0, 0.5, or 1 at week 2

Overall AEs, SAEs, TRAEs not reported

Lotion (N=96) 72.9%, P=0.001 vs vehicle, NS vs emollient cream

Emollient cream (N=100) 74.0%

Vehicle (N=33) 36.4%

TOPICAL CALCINEURIN INHIBITORS

Ruzicka (1997)24 − Age 13-60 years − Moderate-to-severe AD (Rajka

and Langeland criteria) − Lesion size ≥200-1000 cm2

3 weeks bid Median percentage decrease in TSSn at week 3

AEs


Trunk & extremities Face & neck

Tacrolimus ointment, 0.03% (N=54) 66.7%, P<0.001 vs vehicleo 71.4%, P<0.001 vs vehicleo 59.2%



Vehicle (N=54) 22.5% 25.0% 42.6%

Boguniewicz (1998)25 − Age 7-16 years − Moderate-to-severe AD − %BSA=5-30

22 days bid Proportion of patients with ≥75% improvement

in PGEp at day 22


Tacrolimus ointment, 0.03% (N=43) 69%, P=0.005 vs vehicle



Vehicle (N=44) 38%



54



TABLE 1.





4 weeks bid



Study 1 Study 2


Vehicle (N=256 | N=250) 25.4% 18.0%





AEs SAEs TRAEs



Vehicle 20%





SAEs

Overall TRAEs

not reported




0%





TRAEs not



Vehicle (N=136 | N=65) 14% 6% 29% 0%


(N=208) or AD (N=119)





83.2%


moderate (61%)




Vehicle (N=133) 28% 22% 0% 2%




TRAEs not

reported



6% 0%



TABLE 1.



Schachner (2005)26 − Age 2-15 years − IGADAq mild (1) or moderate (2) − Individual assessment scorer of

mild (1) or moderate (2) for ≥3 signs/symptoms of AD (erythema; edema, induration, papulation; excoriations; oozing, weeping, crusting; scaling; lichenification)

− %BSA=2-30

6 weeks bid Proportion of patients with IGADAq clear or almost clear at week 6

AEs


Tacrolimus ointment, 0.03% (N=158) 50.6%, P<0.0001 vs vehicle 36.7%

Vehicle (N=159) 25.8% 45.3%

Breneman (2008)27 − Age ≥2 years − PSGAs clear (0) or almost clear (1)

Once daily 3× weekly for 40 weeks Mean number of flare-free days over 40 weeks

Overall AEs, AEs, TRAEs not reported

Tacrolimus ointment, 0.03% (ages 2-15 years), 0.1% (ages ≥16 years) (N=125) 177.4 days, P=0.003 vs vehicle

Vehicle (N=72) 134.1 days

Kaufmann (2006)28 − Age 18-81 years − IGA mild (2) or moderate (3) − %BSA ≥5 − Pruritus scoret of moderate (2) or

severe (3)

7 days bid Time to ≥1-point improvement in pruritus scoret

Proportion of patients with ≥1-point improvement in pruritus scoret at day 2

AEs SAEs, TRAEs not

reported Pimecrolimus cream, 1% (N=100) 2 days, P=0.0001 vs vehicle 56%, P=0.003 vs vehicle 20.0%

Vehicle (N=98) 4 days 34% 17.3%

Guttman-Yassky (2017)29 − Age 18-71 years − IGA mild (2) or moderate (3)

2 weeks qd Percentage reduction in TSSu at day 15 AEs SAEs TRAEs

(N=30)b

Pimecrolimus cream, 1% 39.6%, P=0.26 vs vehicle

73.3% 0% 0% Betamethasone dipropionate cream, 0.05%

66.7%, P<0.001 vs vehicle

Clobetasol propionate, 0.05%i 75.5%, P<0.001 vs vehicle

Vehicle 29.8%

Spergel (2007)30 − Age 2-65 years − Symmetrical AD lesions on

2 extremities with severe AD (modified EASIv >7)

2 weeks Change in modified EASIv at week 2 AEs

SAEs not reported

TRAEs

(N=45)b

Pimecrolimus cream, 1% bid + fluticasone propionate cream, 0.05% qd

P=0.262 vs vehicle + fluticasone propionate 21.3% 0%

Vehicle bid + fluticasone propionate cream, 0.05% qd

NR

Bangert (2011)31 − Age ≥20 years − IGA mild (2) or moderate (3) − Acute episode of mild or

moderate AD within 5 days of baseline

− Bilateral arm/leg lesions with local EASI=1-8

3 weeks bid to post-lesion skin to prevent relapse (following open-label run-in with TCS for ≤2 weeks to induce remission [local EASI ≤1])

Proportion of patients with IGA clear (0) or almost clear

(1) at week 3

Proportion of patients with local EASI <2 for any sign of

AD at week 3 Overall AEs, SAEs, TRAEs not

reported Pimecrolimus cream, 1% (N=34) 53.0% 73.5%

Vehicle (N=33) 27.3% 39.4%

TABLE 1.



Breuer (2004)32 − Age 3-23 months − IGA mild (2) to very severe (5) − %BSA ≥5

4 weeks bid Percentage change in EASI at day 29

Safety not reported Pimecrolimus cream, 1% (N=130) -71.5%, P<0.001 vs vehicle


Leung (2009)33 − Age 2-49 years − IGA mild (2) or moderate (3) − %BSA ≥5 − Documented clinical insensitivity

to TCS − Colonization with S aureus

6 weeks bid Mean decrease in EASI

at week 3 Percentage change ± SD

in EASI at week 6

Overall AEs, SAEs, TRAEs not reported Pimecrolimus cream, 1% (N=47) P=0.043 vs vehicle 1.8% ± 81.3%

Vehicle (N=26) NR 26.9% ± 99.8%

Eichenfield (2002)34 − Age 1-17 years − IGA mild (2) or moderate (3) − %BSA ≥5

6 weeks bid (following 7 days of emollient before baseline)

Proportion of patients with IGA clear (0) or almost clear (1) at day 43 Overall AEs, SAEs,

TRAEs not reported Pimecrolimus cream, 1% (N=267) 34.8%, P≤0.05 vs vehicle

Vehicle (N=136) 18.4%

Meurer (2002)35 − Age 18-69 years − IGA moderate (3) or severe (4) − %BSA ≥5

24 weeks bid (TCS as needed after 3 days if AD worsened)

Mean percentage (95% CI) of days with TCS use

over 24 weeks

Proportion of patients with no TCS use over 24 weeks

AEs, SAEs not reported

TRAEs

Pimecrolimus cream, 1% (N=96) 14.2% (8.3%, 21.1%), P<0.001

vs vehicle 49.0% 24.0%

Vehicle (N=96) 37.2% (30.4%, 44.0%) 21.9% 20.8%

Zuberbier (2007)36 − Age 2-17 years − Severe AD (Rajka and Langeland

grade 8/9) − Responded to 7-21 days of

prednicarbate cream, 0.25%, bid for flare in screening phase

24 weeks bid (prednicarbate reinitiated in case of flare)

Mean percentage ± SD of days with TCS use over 24 weeks AEs

SAEs not reported

TRAEs

Pimecrolimus cream, 1% (N=95) 29% ± 25%, P=0.1841 vs vehicle 86% 5.3%

Vehicle (N=89) 35% ± 25% 85% 4.5%

Sigurgeirsson (2008)37 − Age 2-17 years − History of IGA of mild (2) or

moderate (3), IGA clear (0) or almost clear (1) at baseline

26 weeks bid initiated at signs of recurring AD (TCS as needed after 3 days if AD worsened)

Mean number ± SD of days with no TCS use over 26 weeks

Overall AEs, SAEs not reported

TRAEs

Pimecrolimus cream, 1% (N=256) 160.2 ± 36.3 days, P<0.0001 vs vehicle 9.3%

Vehicle (N=265) 137.7 ± 51.9 days 10%

Gollnick (2008)38 − Age ≥18 years − History of IGA mild (2) or



Mean number ± SD of days with no TCS use over 26 weeks Overall AEs not reported

SAEs TRAEs

not reported


Vehicle (N=266) 138.7 ± 53.2 days 2.8%

(CONTINUED)



55



TABLE 1.





4 weeks bid



Study 1 Study 2


Vehicle (N=256 | N=250) 25.4% 18.0%





AEs SAEs TRAEs



Vehicle 20%





SAEs

Overall TRAEs

not reported




0%





TRAEs not



Vehicle (N=136 | N=65) 14% 6% 29% 0%


(N=208) or AD (N=119)





83.2%


moderate (61%)




Vehicle (N=133) 28% 22% 0% 2%




TRAEs not

reported



6% 0%



TABLE 1.



Breuer (2004)32 − Age 3-23 months − IGA mild (2) to very severe (5) − %BSA ≥5

4 weeks bid Percentage change in EASI at day 29

Safety not reported Pimecrolimus cream, 1% (N=130) -71.5%, P<0.001 vs vehicle


Leung (2009)33 − Age 2-49 years − IGA mild (2) or moderate (3) − %BSA ≥5 − Documented clinical insensitivity

to TCS − Colonization with S aureus

6 weeks bid Mean decrease in EASI

at week 3 Percentage change ± SD

in EASI at week 6

Overall AEs, SAEs, TRAEs not reported Pimecrolimus cream, 1% (N=47) P=0.043 vs vehicle 1.8% ± 81.3%

Vehicle (N=26) NR 26.9% ± 99.8%

Eichenfield (2002)34 − Age 1-17 years − IGA mild (2) or moderate (3) − %BSA ≥5

6 weeks bid (following 7 days of emollient before baseline)

Proportion of patients with IGA clear (0) or almost clear (1) at day 43 Overall AEs, SAEs,

TRAEs not reported Pimecrolimus cream, 1% (N=267) 34.8%, P≤0.05 vs vehicle

Vehicle (N=136) 18.4%

Meurer (2002)35 − Age 18-69 years − IGA moderate (3) or severe (4) − %BSA ≥5

24 weeks bid (TCS as needed after 3 days if AD worsened)

Mean percentage (95% CI) of days with TCS use

over 24 weeks

Proportion of patients with no TCS use over 24 weeks

AEs, SAEs not reported

TRAEs

Pimecrolimus cream, 1% (N=96) 14.2% (8.3%, 21.1%), P<0.001

vs vehicle 49.0% 24.0%

Vehicle (N=96) 37.2% (30.4%, 44.0%) 21.9% 20.8%

Zuberbier (2007)36 − Age 2-17 years − Severe AD (Rajka and Langeland

grade 8/9) − Responded to 7-21 days of

prednicarbate cream, 0.25%, bid for flare in screening phase

24 weeks bid (prednicarbate reinitiated in case of flare)

Mean percentage ± SD of days with TCS use over 24 weeks AEs

SAEs not reported

TRAEs

Pimecrolimus cream, 1% (N=95) 29% ± 25%, P=0.1841 vs vehicle 86% 5.3%

Vehicle (N=89) 35% ± 25% 85% 4.5%

Sigurgeirsson (2008)37 − Age 2-17 years − History of IGA of mild (2) or



Mean number ± SD of days with no TCS use over 26 weeks

Overall AEs, SAEs not reported

TRAEs


Vehicle (N=265) 137.7 ± 51.9 days 10%

Gollnick (2008)38 − Age ≥18 years − History of IGA mild (2) or



Mean number ± SD of days with no TCS use over 26 weeks Overall AEs not reported

SAEs TRAEs

not reported


Vehicle (N=266) 138.7 ± 53.2 days 2.8%

TABLE 1.



Kapp (2002)39 − Age 3-23 months − AD diagnosis (Seymour criteria) − IGA at least mild (≥2) − %BSA ≥5

1 year bid initiated at signs of recurring AD (TCS as needed for flares)

Proportion (95% CI) of patients with no flares


Month 6 Month 12

Pimecrolimus cream, 1% (N=204) 67.6% (61.2%, 74.1%),

P<0.001 vs vehiclew 56.9 (50.1%, 63.7%), P<0.001

vs vehiclew

Vehicle (N=46) 30.4% (17.1%, 43.7%) 28.3% (15.2%, 41.3%)

Schneider (2016)40 − Age 3-18 months − IGA at least mild (≥2) − AD for ≤3 months

3 years bid as needed (TCS as needed after 3 days if AD worsened)

Difference vs vehicle in proportion (95% CI) of patients with no TCS use

AEs SAEs TRAEs not

reported

Week 14 (end of investigator-initiated TCS period)

Week 158 (end of double-blind phase)

Pimecrolimus cream, 1% (N=546) –0.088 (–0.123, –0.053), P=0.001 vs vehicle

0.005 (–0.029, 0.038), P=0.79 vs vehicle

89.5% 7.7%

Vehicle (N=545) 87.7% 6.8% AD, atopic dermatitis; ADSI, Atopic Dermatitis Severity Index; AE, adverse event; bid, twice daily; BSA, body surface area; CI, confidence interval; DSS, Dermatologic Sum Score; EASI, Eczema Area and Severity Index; GSS, Global Severity Scale; IGA, Investigator’s Global Assessment; IGADA, Investigator’s Global AD Assessment; IGSS, Investigators Global Severity Score; ISGA, Investigator’s Static Global Assessment; NR, not reported; PGE, Physician’s Global Evaluation; PGA, Physician’s Global Assessment; PSGA, Physician’s Static Global Assessment; qd, once daily; SAE, serious AE; SCORAD, SCORing of Atopic Dermatitis; SD, standard deviation; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid; TRAE, treatment-related AE; TSS, total severity score. aTSS calculated as the sum of severity scores for erythema, edema/papulation, oozing/crusting, excoriations, and lichenification rated from absent (0) to severe (3) bIntrapatient comparison cISGA ranged from clear (0) to severe (4) dADSI ranged from none (0) to most severe (15) eImprovement in erythema, scaling, lichenification, and pruritus severity rated from none (0) to very severe (4) fIGSS rated as clear (0) to very severe (5) for Study 1, and clear (0) to severe (4) for Study 2 gPGA rated as clear (0) to severe (4) hTotal disease sign and symptom score calculated as the sum of severity scores for erythema, induration, and pruritus rated from absent (0) to markedly severe (6) iFormulation not specified jTSS calculated as the sum of severity scores for erythema, edema/papulation, oozing/crusting, and excoriation rated from absent (0) to severe (3) kTSS calculated as the sum of severity scores for erythema, pruritus, induration/papulation, lichenification, erosion/oozing/crusting, and scaling/dryness rated from absent (0) to severe (3) lDSS calculated as the sum of severity scores for erythema, excoriation, and induration/papulation rated from none (0) to severe (4) mGSS ranged from none (0) to severe (4) nTSS calculated as the sum of severity scores for erythema, edema, and pruritus rated from absent (0) to severe (3) oBy Jonckheere test pPGE rated as worse (<0% clinical improvement) to cleared (100% clinical improvement) qIGADA rated as clear, almost clear, mild, moderate, severe, or very severe rIndividual assessment score rated as absent (0) to severe (3) sPSGA rated from clear (0) to very severe (5) tPruritus rated from absent (0) to severe (3) uTSS calculated as the sum of severity scores for erythema, edema/papulation, oozing/crusting, excoriation, lichenification, and dryness rated from absent (0) to severe (3) vModified EASI calculated as the sum of severity scores for erythema, infiltration/papulation, excoriation, and lichenification rated from mild (0) to severe (3) wBy Van Elteren test

(CONTINUED)



56



vehicle (P=0.003 and 0.037, respectively) (Table 1).27

PimecrolimusMultiple studies have substantiated the efficacy of pimecrolimus cream based on primary efficacy endpoints of improvement in pruritus,28 decrease in EASI or local EASI,31-33 proportion of patients achieving IGA clear (0) or almost clear (1),31,34 reduction in the need for TCS,35,37,38 and proportion of patients who remained flare free.39 However, in other studies, significant differences were not reported for the primary efficacy endpoint (Table 1).29,30,36,40

In comparison with vehicle in trials of 3-4 weeks in duration, pimecrolimus treatment resulted in significantly more patients achieving IGA clear (0) or almost clear (1) (Table 1, Figure 1)31,32

and local EASI <2 for any lesion (Table 1)31 as well as greater changes in IGA score (secondary endpoint; P<0.001) (Figure 1)32 and EASI score (P<0.001) (Table 1).32 In identically designed, 6-week trials, 34.8% of pimecrolimus-treated patients achieved IGA clear (0) or almost clear (1) at day 43 (primary endpoint) compared with 18.4% of those treated with vehicle (P≤0.05) (Table 1, Figure 1).34

Another trial assessed the percentage of days that TCS was used. The primary endpoint was the percentage of days with TCS use.35 Secondary endpoints included the number of flares, time-to-first flare, proportion of patients with IGA mild or less (≤2) (Figure 1), and changes in EASI score and pruritus severity. By week 24, pimecrolimus-treated patients had significantly fewer days with TCS use than vehicle-treated patients (P<0.001) and a higher proportion of pimecrolimus-treated than vehicle-treated patients had no TCS use (Table 1).35 Decrease in TCS use was also seen in several subsequent trials,37,38 including in patients with mild-to-moderate AD38,48 and pediatric patients.37

However, 1 study in patients with severe AD did not show a significant decrease in the mean percentage of days with TCS use for pimecrolimus compared with vehicle (Table 1).36 Unlike the other “TCS reduction” studies, this study had a screening phase in which all patients applied prednicarbate cream, 0.25%, twice daily for 7-21 days until flare was under control before enrollment in the double-blind portion of the study. After the study, it was determined that, although study centers enrolled patients with high severity scores according to Rajka and Langeland criteria, some patients did not have active disease, as shown by baseline IGA scores of almost clear (1) and mild (2)). When these patients were excluded in a post hoc analysis, there were significantly fewer days with TCS use in patients who received pimecrolimus than in those who received vehicle.36

In a 1-year study, significantly more pimecrolimus-treated versus vehicle-treated infants aged 3-23 months remained flare-free through month 6 (primary endpoint; P<0.001 Van Elteren test) and month 12 (Table 1), translating into longer flare-free

for established TCS designed to expand indications,16 eliminate alcohol and surfactants,17 improve penetration,20 ease dryness,21 and provide additional formulation options.23

Of these, 8 trials showed significant improvement in AD severity or symptoms in patients who received TCS compared with vehicle by end of treatment (Table 1, Figure 1). In one of the earliest trials captured within the limits of this search, lesion TSS was significantly improved by day 4 for clobetasol propionate compared with vehicle (P≤0.006), and remained significantly improved through end of treatment (day 43; P<0.001) (Table 1).22 In a phase 3 trial investigating the efficacy and safety of hydrocortisone butyrate cream, 0.1%, more hydrocortisone butyrate-treated patients exhibited Physician’s Global Assessment (PGA) success at day 29 (primary endpoint; PGA clear (0) or almost clear (1) with ≥2-grade reduction) compared with vehicle-treated patients (P<0.001) (Table 1, Figure 1).19

One trial explored the benefit of adding the antibiotic mupirocin to hydrocortisone butyrate cream, 0.1%.18 There was no difference in the primary efficacy endpoint (percentage improvement in signs and symptoms) between patients who received hydrocortisone butyrate + mupirocin and those who received hydrocortisone butyrate + vehicle at the end of treatment (day 28) (Table 1); however, differences were observed earlier in treatment (day 7).18

Topical Calcineurin InhibitorsTacrolimusFour tacrolimus ointment publications fit the criteria for this analysis. Significant differences compared with vehicle were reported for the primary endpoint in each (Table 1).24-27

In a phase 2 trial of tacrolimus in patients aged 13-60 years, median decreases in TSS (erythema, edema, and pruritus) at week 3 (primary endpoint) were significantly different between each dosage of tacrolimus and vehicle (P<0.001 via Jonckheere test) (Table 1), with no differences among tacrolimus dosages.24 The efficacy of tacrolimus ointment was further explored in children.25 The primary efficacy endpoint, physician global evaluation (PGE) of clinical response on a scale of worse (<0%) to cleared (100%), was significantly improved for each dosage of tacrolimus compared with vehicle at the end of treatment (day 22; Table 1, Figure 1).25

Additional efficacy endpoints were explored in the remaining 2 tacrolimus trials. In the first trial, significantly more tacrolimus-treated than vehicle-treated patients achieved the primary efficacy endpoint of Investigator’s Global AD Assessment (IGADA) clear or almost clear at week 6 (P<0.0001; Table 1; Figure 1).26 In the second trial, the mean number of flare-free treatment days and the time to first relapse were significantly longer in patients who received tacrolimus compared with



57



periods (P<0.001 via log-rank test), fewer flares per year (1.0 vs 2.2, P<0.001 via Van Elteren test), and greater proportions of patients with no TCS use (63.7% vs 34.8%).39 This reduction in risk of flare was observed regardless of baseline disease severity, including for patients with severe AD.39 Likewise, the proportion of patients achieving IGA clear (0) or almost clear (1) was significantly greater for pimecrolimus versus vehicle at day 8 (44.6% vs 8.7%; P<0.001) and continuing through month 6 (52.9% vs 37.0%, P<0.03); at month 12, differences remained numerically, but not statistically, greater (53.9% vs 47.8%, P>0.05).39 Differences in EASI score and proportion of patients achieving pruritus score of none (0) or mild (1) were also significantly greater for pimecrolimus versus vehicle at day 43 and beyond.39

The Study of the Atopic March (SAM) was a long-term study of pimecrolimus compared with vehicle in patients aged 3-18 months with IGA ≥2 newly diagnosed with AD.40 The trial was designed as a 3-year double-blind, dose-escalation study followed by 3 years of open-label pimecrolimus. Coprimary endpoints included proportion of disease-free days (ie, with no TCS use) and longest duration of remission. The study was prematurely halted after a mean follow-up of 2.8 years after the double-blind phase at the recommendation of the independent study monitoring committee based on protocol-specified criteria.40 TCS could be used for flares; during the first 14 weeks, its use was governed by the investigator, whereas after 14 weeks, TCS could be initiated at the discretion of the caregiver. There was a significant difference between pimecrolimus and vehicle groups in the proportion days with no TCS use at week 14 (P<0.001), but this difference decreased in subsequent weeks and there was no difference at the end of the double-blind phase (week 158) (Table 1).40 Similar trends were observed for the secondary endpoint of proportion of patients achieving IGA clear (0) or almost clear (1) (Figure 1).40 It was concluded that, although the SAM trial replicated the short-term efficacy previously observed with pimecrolimus compared with vehicle, the high discontinuation rate (48%) and empowerment of caregivers to initiate rescue TCS could have impacted the ability to identify the efficacy of pimecrolimus long-term.40

A randomized, double-blind, parallel-group trial was conducted to investigate the efficacy of pimecrolimus in patients with TCS-insensitive AD, defined as a <35% reduction in EASI after at least 12 days treatment with twice-daily prednicarbate cream, 0.25% (Table 1).33 The difference in the primary endpoint (decrease in EASI score) between the pimecrolimus and vehicle arms was only significant at week 3 (P=0.043) (Table 1), with large standard deviations and substantial differences between mean and median values, indicating that there was significant variability in patient response.33 Treatment success, defined as IGA clear (0) or almost clear (1), was achieved by 11% of pimecrolimus-treated patients and zero vehicle-treated patients (Figure 1).33

Change in lesion-specific IGA scores, pruritus scores, and patient assessment of AD were comparable between the pimecrolimus and vehicle arms.33

To evaluate whether TCI plus TCS has a synergistic effect, an exploratory randomized, vehicle-controlled intrapatient comparison trial was conducted to evaluate the efficacy of pimecrolimus twice daily + fluticasone propionate cream, 0.05%, once daily compared with vehicle twice daily + fluticasone propionate cream, 0.05%, once daily in patients with severe AD.30 Secondary efficacy endpoints included IGA score (Figure 1), local IGA score, and patient/caregiver assessment of eczema severity. At end of treatment, there was no statistically significant difference in change from baseline in modified EASI score at week 2 (primary endpoint, P=0.262) (Table 1).30 There were also no differences in secondary efficacy endpoints—proportion of patients achieving global or local IGA clear (0) or almost clear (1).30 Post hoc analyses to explore variables such as age, study site, sex, baseline EASI score, right versus left side, or lesion site found no differences that could predict response.30

SAFETY OF TOPICAL TREATMENTS

Phosphodiesterase 4 InhibitorsIn the phase 3 crisaborole trials, the most frequently reported TRAE was application site pain (burning or stinging), which was reported for 4.4% of crisaborole-treated patients and 1.2% of vehicle-treated patients (Table 2); most patients (77.6%) experienced resolution within 1 day of onset.10 No treatment-related serious AEs (SAEs) were reported. In the long-term (48 weeks), open-label safety extension trial (N=517), no new safety signals were identified, and no evidence of skin atrophy or telangiectasia were reported.49

In the phase 2a intrapatient comparison crisaborole trial, AEs were reported for 44% of patients, and TRAEs were reported for 12% of patients (Table 1).11 These TRAEs included application site events such as erythema, irritation, pain, and pruritus (Table 2).11 There was no evidence of severe AEs or SAEs.11

Topical CorticosteroidsThe occurrence of local AEs with TCS is well known, but the true incidence is poorly characterized because of the lack of clinical trials performed to modern standards and because many trials do not report the incidence of TEAEs.7,8,50 Systemic absorption of TCS also has the potential to lead to systemic AEs, such as hypothalamic-pituitary-adrenal axis suppression7 and decreased serum cortisol (Table 2). To reduce the risk for systemic absorption of TCS, treatment guidelines include cautions for use with occlusive wrappings, coverage of a high percentage of the body, and prolonged use, especially in small children and infants and on sensitive skin areas (eg, facial skin).7,8 Additional concerns include TCS addiction and steroid withdrawal syndrome, which are most often associated with



58



TABLE 2.

Adverse Events of Interest

Reference AEs of interest, n (%)


Paller (2016)10

Crisaborole ointment, 2% (N=1012) Vehicle (N=499)

Application site pain 45 (4.4) 6 (1.2)

Application site pruritus 5 (0.5) 6 (1.2)

Murrell (2015)11

Crisaborole ointment, 2% (N=25) Vehicle (N=25)

Itch and redness 1 (4) 1 (4)

Contact dermatitis, irritant 1 (4) NR

Contact dermatitis, allergic NR 1 (4)

Application site stinging 0 1 (4)


Paller (2003)16

Fluocinolone acetonide in peanut oil, 0.01% (N=49) Vehicle (N=45)

Hypopigmentation 2 (4.1) 0

Rash 1 (2.0) 1 (2.2)

Telangiectasia 0 0

Skin atrophy 0 0

Hebert (2007)17

Desonide hydrogel, 0.05% (N=425) Vehicle (N=157)

Application site burning NR (1) NR

Rash NR (1) NR

Discontinuation because of telangiectasia

1 (<1) 1 (<1)

Application site pruritus NR (<1) 0

Skin atrophy 0 1 (<1)

Discontinuation because of burning and stinging

0 1 (<1)

Abramovits (2010)19

Hydrocortisone butyrate lipocream, 0.1% (N=131) Vehicle (N=133)

Dermatitis 0 2 (2)

Telangiectasia 0 2 (2)

Erythema 0 1 (1)

Urticaria 0 1 (1)

Cato (2001)20

Triamcinolone acetonide, 0.05%a/

laurocapram (N=50)

Triamcinolone acetonide, 0.05%a (N=50)

Vehicle (N=50)

Burning/pruritus/disease exacerbation

3 (6) 2 (4) 6 (12)

Larsen (2007)21

Betamethasone valerate (1 mg/g)/fusidic acid (20 mg/g)

Vehicle (N=88) Lipid cream (N=274) Cream (N=258)

Any lesional or perilesional AE 7 (2.6) 4 (1.6) 12 (13.6)

Pruritus 2 (<1) 0 6 (6.8)

Skin burning 3 (1.1) 3 (1.2) 4 (4.5)

Maloney (1998)22

Clobetasol propionate emollient, 0.05% (N=41) Vehicle (N=40)

Pruritus/burning/stinging 1 (2.4) 0

Skin atrophy/pruritus 0 2 (5.0)

≥50% decrease in serum cortisol NR (15) NR (11)

Serum cortisol below normal range 3 (8) 0

Breneman (2005)23

Clobetasol propionate, 0.05%

Vehicle (N=33) Lotion (N=96) Emollient cream (N=100)

Clinically significant skin atrophy

0 0 0

Telangiectasia 0 0 0



59



TABLE 2.



TOPICAL CALCINEURIN INHIBITORS

Ruzicka (1997)24

Tacrolimus ointment

Vehicle (N=54) 0.03% (N=54) 0.1% (N=54) 0.3% (N=51)

Application site burning 20 (37.0) 25 (46.3) 25 (49.0) 8 (14.8)

Application site pruritus 7 (13.0) 2 (3.7) 7 (13.7) 4 (7.4)

Application site erythema 3 (5.6) 6 (11.1) 6 (11.8) 3 (5.6)

Exacerbation of AD 4 (7.4) 4 (7.4) 2 (3.9) 7 (13.0)

Discontinuation because of application site AE

1 (1.9) 4 (7.4) 3 (5.9) 2 (3.7)

Boguniewicz (1998)25

Tacrolimus ointment

Vehicle (N=44) 0.03% (N=43) 0.1% (N=49) 0.3% (N=44)

Application site pruritus 11 (25.6) 10 (20.4) 13 (29.5) 7 (15.9)

Application site burning 9 (20.9) 5 (10.2) 10 (22.7) 3 (6.8)

Application site erythema 0 1 (2.0) 3 (6.8) 2 (4.5)

Increased serum creatinine 1 (2.3) 0 0 0

Schachner (2005)26

Tacrolimus ointment, 0.03% (N=158) Vehicle (N=159)

Itching 37 (23.4) 53 (33.3)

Erythema 12 (7.6) 30 (18.9)

Burning/stinging 30 (19.0) 27 (17)

Discontinuation because of application site AE

4 (2.5) 12 (7.5)

Eczema herpeticum 0 1 (<1)

Breneman (2008)27

Tacrolimus ointment, 0.03% (N=125) Vehicle (N=71)

Application site burning 2 (1.6) 1 (1.4)

Increased irritation NOS 2 (1.6) 0

Application site pruritus 1 (0.8) 2 (2.8)

Skin infection, other NOS 1 (0.8) 0

Application site reaction NOS 1 (0.8) 0

Skin infection, folliculitis 0 0

Skin infection, molluscum 0 1 (1.4)

Kaufmann (2006)28

Pimecrolimus cream, 1% (N=100) Vehicle (N=98)

Burning sensation 3 (3.0) 1 (1.0)

Discontinuation because of application site burning

0 1 (1.0)

Atopic dermatitis 0 2 (2.0)

Eczema 0 2 (2.0)

Guttman-Yassky (2017)29

Pimecrolimus cream,

1% (N=30)

Betamethasone dipropionate

cream, 0.05% (N=30)

Clobetasol propionate, 0.05%a

(N=30) Vehicle (N=30)

Application site reaction 0 1 (4.6) 0 0

Spergel (2007)30

Specific application site AEs not reported

Bangert (2011)31


Application site reaction 0 1 (3)

Leung (2009)33


Skin infection 8 (17.0) 2 (7.7)

Herpes simplex 2 (4.3) 0

Eichenfield (2002)34


Any local AE NR (28) NR (35)

Application site burning NR (10.4) NR (12.5)

(CONTINUED)



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TABLE 2.



Meurer (2002)35


Local AEs 38 (39.6) 35 (36.5)

Any skin infection 18 (18.8) 9 (9.4)

Herpes 10 (10.4) 5 (5.2)

Bacterial 4 (4.2) 3 (3.1)

Fungal 2 (2.1) 1 (1.0)


Eczema herpeticum 0 2 (2.1)

Zuberbier (2007)36


Treatment-related


Herpes simplex 1 (1.1) NR

Impetigo 1 (1.1) 1 (1.1)

Molluscum contagiosum 1 (1.1) NR

Keratitis NR 1 (1.1)

Blepharitis NR 1 (1.1)

Conjunctivitis NR 1 (1.1)

Herpes virus infection NR 1 (1.1)

Contact dermatitis NR 1 (1.1)

Sigurgeirsson (2008)37


Impetigo 9 (3.7) 6 (2.3)

Varicella 9 (3.7) 8 (3.1)

Urticaria 8 (3.3) 4 (1.5)

Molluscum contagiosum 6 (2.4) 8 (3.1)


Eczema herpeticum 1 (<1) 0

Gollnick (2008)38


Application site burning 11 (4.2) 2 (<1)

Herpes simplex virus infection 9 (3.4) 12 (4.7)

Eczema herpeticum 0 1 (<1)

Kapp (2002)39


Application site reaction NR (6.5) NR (14.7)

Any skin infection NR (27.0) NR (27.6)

Bacterial NR (12.7) NR (9.1)

Viral NR (3.3) NR (6.9)

Schneider (2016)40 Application site AEs not reported

AD, atopic dermatitis; AE, adverse event; NOS, not otherwise specified; NR, not reported; SAE, serious AE; TRAE, treatment-related AE. aFormulation not specified.

(CONTINUED)



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medium- to high-potency TCSs.51 Addiction occurs with TCS misuse, resulting in physical or psychological dependence.52 The most common sign of steroid withdrawal is erythema; other symptoms include burning/stinging, pain, pruritus, facial hot flashes, and exacerbation with heat or sun.51 The recurrence of AD symptoms and/or the signs of steroid withdrawal when TCS use is stopped often leads patients to restart TCS.52 As a consequence of the safety concerns associated with TCS treatment and steroid withdrawal syndrome, many patients develop steroid phobia, which can hinder adherence and can result in undertreatment.53-55

The lack of consistent reporting of AEs makes it difficult to compare AEs among TCSs (Tables 1 and 2). Common local adverse reactions reported by those who received TCS in the trials summarized herein included secondary infections, eczema herpeticum, contact dermatitis, burning, itching, and skin atrophy ranging in incidence from 0% to 12% (Table 2).16,17,19-

23 Skin atrophy and telangiectasia were reported in few trials; incidence was low when reported (maximum reported: <1% for skin atrophy and 2% for telangiectasia) (Table 2).16,17,19,23

Few studies evaluated systemic AEs, likely as a result of the short duration of the trials (2 -4 weeks), reflecting current treatment guidelines.7,8 One study evaluated the effect of TCS on serum cortisol.22 In the clobetasol propionate group, 15% of patients experienced ≥50% decrease in serum cortisol level, compared with 11% in the vehicle group (P=0.737) (Table 2).22

In addition, 3 patients (8%) in the clobetasol propionate arm experienced serum cortisol below the normal range compared with 0 patients in the vehicle arm (P=0.240) (Table 2).22

Topical Calcineurin InhibitorsThe addition of TCIs to the treatment paradigm in the early 2000s provided an alternative for situations in which the safety of TCSs was of concern, such as in patients with steroid-induced atrophy, for those who required long-term uninterrupted topical anti-inflammatory treatment, and for the treatment of sensitive skin areas.7 The most frequently reported local TEAEs associated with TCIs include application site burning or pruritus, which typically improve as lesions resolve.7 The more significant concern with TCIs is the possibility that their use is associated with immune system-mediated malignancy. In 2006, the US Food and Drug Administration required that a boxed warning regarding the theoretical risk for malignancy be included in TCI prescribing information in response to widespread off-label use in children <2 years of age.7,56,57 Even though no causative link between TCI use and malignancy has been established,57-60 the boxed warning remains.

Unlike in the TCS studies, extensive safety data were reported in the TCI trials identified in this search. Tacrolimus was well tolerated when applied once or twice daily at least 3 times

weekly for up to 40 weeks in those aged ≥2 years,24-27 and pimecrolimus was well tolerated in those aged ≥2 years for up to 26 weeks28-31,33-38 and in those aged <2 years for up to 3 years39,40 (and up to 5 years in an open-label study,61 which is outside the scope of this review) (Tables 1 and 2). Application site AEs were most frequently reported for tacrolimus (although causality was not often reported), and incidence ranged from 1.4% to 49% for burning, 0.8% to 29.5% for pruritus, and 0% to 11.8% for erythema (Table 2).24-27 Among those who received pimecrolimus, application site burning was reported by 1.2% to 10.4% of patients; application site pruritus and erythema were less likely to be reported (Table 2).

CONCLUSIONSTopical drugs to treat AD include PDE4 inhibitors, TCSs, and TCIs. In the absence of head-to-head trials, comparison among available agents is difficult because of the different study designs, endpoints, and methodologies used across published clinical studies. A lack of precise outcome definitions and consistent safety reporting further complicate comparison among trials. For example, in the current literature analysis, 12 of 28 publications did not report total AEs (Table 1), and individual AE reporting and causality assessments varied. This is in part because of changes in guidelines for reporting of clinical trial results over the duration of the literature search, including the adoption of guidelines such as the CONSORT statement62 and the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in Medical Journals adopted by the International Committee of Medical Journal Editors.63 The topical PDE4 inhibitor crisaborole represents a novel therapy targeting proinflammatory factors involved in AD pathogenesis. The completed clinical studies for crisaborole demonstrate efficacy and a favorable safety profile, enabling health care providers to include crisaborole among topical therapeutic options available for the treatment of mild-to-moderate AD.

DISCLOSURESLawrence Eichenfield has been a consultant, investigator, data safety monitoring board member, or speaker for Pfizer Inc., Allergan, Anacor, Arcutis, Dermavant, Dermira, Eli Lilly, Galderma, LEO Pharma, Medimetriks, Novartis, Otsuka, Regeneron, Sanofi-Genzyme, OrthoDerm/Valeant, and UCB.

Thomas Luger has no conflicts of interest to disclose.

Kim Papp has been a consultant, scientific adviser, investigator, scientific officer, and/or speaker for Pfizer Inc., AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Bausch Health, Boehringer Ingelheim, BMS, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Gilead, GlaxoSmithKline, Janssen, Kyowa Hakka Kirin, LEO Pharma, Medimmune, Meiji Seika Pharma, Merck Sharp & Dahme, Merck-Serano, Mitsubishi



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Pharma, Novartis, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, UCB, and Valeant.

Jonathan Silverberg has been a consultant, speaker, or data safety monitoring board member and/or received travel support from Pfizer Inc., AbbVie, Anaptysbio, Asana, Boehringer Ingelheim, Eli Lilly, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Menlo, Novartis, Realm Therapeutics, and Regeneron-Sanofi.

Debra Sierka, Anna Tallman, and William Ports were employees and stockholders of Pfizer Inc., at the time of this work.

Chuanbo Zang and Michael Zielinski are employees and stockholders of Pfizer Inc.

ACKNOWLEDGMENTSEditorial/medical writing support under the guidance of authors was provided by Jennifer M. Kulak, PhD, and Corey Mandel, PhD, at ApotheCom, San Francisco, CA, and was funded by Pfizer Inc., New York, NY, USA, in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461-464).

REFERENCES1. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1109-1122. 2. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the manage-

ment of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70:338-351.

3. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;60:44-47.

4. Silverberg JI, Simpson EL. Associations of childhood eczema severity: a US population-based study. Dermatitis. 2014;25:107-114.

5. Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol. 2005;22:192-199.

6. Mollanazar NK, Sethi M, Rodriguez RV, et al. Retrospective analysis of data from an itch center: integrating validated tools in the electronic health re-cord. J Am Acad Dermatol. 2016;75:842-844.

7. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the manage-ment of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116-132.

8. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131:295-299.e227.

9. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in pa-tients with atopic eczema. Br J Dermatol. 2000;142:931-936.

10. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e496.

11. Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2a, vehicle-controlled, proof-of-con-cept study. J Drugs Dermatol. 2015;14:1108-1112.

12. Stein Gold LF, Spelman L, Spellman MC, et al. A phase 2, randomized, con-trolled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol. 2015;14:1394-1399.

13. Tom WL, Van Syoc M, Chanda S, et al. Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study. Pediatr Dermatol. 2016;33:150-159.

14. Zane LT, Kircik L, Call R, et al. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure study. Pediatr Dermatol. 2016;33:380-387.

15. Griffiths CE, Van Leent EJ, Gilbert M, et al; Cipamyflline Study Group. Ran-domized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treat-

ment of atopic dermatitis. Br J Dermatol. 2002;147:299-307. 16. Paller AS, Nimmagadda S, Schachner L, et al. Fluocinolone acetonide 0.01%

in peanut oil: therapy for childhood atopic dermatitis, even in patients who are peanut sensitive. J Am Acad Dermatol. 2003;48:569-577.

17. Hebert AA, Cook-Bolden FE, Basu S, et al; Desonide Hydrogel Study Group. Safety and efficacy of desonide hydrogel 0.05% in pediatric subjects with atopic dermatitis. J Drugs Dermatol. 2007;6:175-181.

18. Gong JQ, Lin L, Lin T, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Derma-tol. 2006;155:680-687.

19. Abramovits W, Oquendo M. Hydrocortisone butyrate 0.1% lipocream in pe-diatric patients with atopic dermatitis. Skinmed. 2010;8:72-79.

20. Cato A, Swinehart JM, Griffin EI, et al. Azone enhances clinical effectiveness of an optimized formulation of triamcinolone acetonide in atopic dermatitis. Int J Dermatol. 2001;40:232-236.

21. Larsen FS, Simonsen L, Melgaard A, et al. An efficient new formulation of fu-sidic acid and betamethasone 17-valerate (fucicort lipid cream) for treatment of clinically infected atopic dermatitis. Acta Derm Venereol. 2007;87:62-68.

22. Maloney JM, Morman MR, Stewart DM, et al. Clobetasol propionate emollient 0.05% in the treatment of atopic dermatitis. Int J Dermatol. 1998;37:142-144.

23. Breneman D, Fleischer AB Jr, Kaplan D, et al. Clobetasol propionate 0.05% lotion in the treatment of moderate to severe atopic dermatitis: a random-ized evaluation versus clobetasol propionate emollient cream. J Drugs Der-matol. 2005;4:330-336.

24. Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N Engl J Med. 1997;337:816-821.

25. Boguniewicz M, Fiedler VC, Raimer S, et al; Pediatric Tacrolimus Study Group. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol. 1998;102:637-644.

26. Schachner LA, Lamerson C, Sheehan MP, et al; US Tacrolimus Ointment Study Group. Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: re-sults from a randomized, double-blind, vehicle-controlled study. Pediatrics. 2005;116:e334-342.

27. Breneman D, Fleischer AB Jr, Abramovits W, et al; Tacrolimus Ointment Study Group. Intermittent therapy for flare prevention and long-term disease control in stabilized atopic dermatitis: a randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle. J Am Acad Der-matol. 2008;58:990-999.

28. Kaufmann R, Bieber T, Helgesen AL, et al; multicentre investigator group. Onset of pruritus relief with pimecrolimus cream 1% in adult patients with atopic dermatitis: a randomized trial. Allergy. 2006;61:375-381.

29. Guttman-Yassky E, Ungar B, Malik K, et al. Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis. J Allergy Clin Immunol. 2017;140:1032-1042.e1013.

30. Spergel JM, Boguniewicz M, Paller AS, et al. Addition of topical pimecrolim-us to once-daily mid-potent steroid confers no short-term therapeutic benefit in the treatment of severe atopic dermatitis; a randomized controlled trial. Br J Dermatol. 2007;157:378-381.

31. Bangert C, Strober BE, Cork M, et al. Clinical and cytological effects of pimecrolimus cream 1% after resolution of active atopic dermatitis le-sions by topical corticosteroids: a randomized controlled trial. Dermatology. 2011;222:36-48.

32. Breuer K, Braeutigam M, Kapp A, et al. Influence of pimecrolimus cream 1% on different morphological signs of eczema in infants with atopic dermatitis. Dermatology. 2004;209:314-320.

33. Leung DY, Hanifin JM, Pariser DM, et al. Effects of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, multicentre vehicle-controlled trial. Br J Dermatol. 2009;161:435-443.

34. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moder-ate atopic dermatitis in children and adolescents. J Am Acad Dermatol. 2002;46:495-504.

35. Meurer M, Folster-Holst R, Wozel G, et al; CASM-DE-01 study group. Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology. 2002;205:271-277.

36. Zuberbier T, Heinzerling L, Bieber T, et al. Steroid-sparing effect of pimecro-limus cream 1% in children with severe atopic dermatitis. Dermatology. 2007;215:325-330.

37. Sigurgeirsson B, Ho V, Ferrandiz C, et al; Pimecrolimus 1% cream in (pae-diatric) Eczema: Prevention of Progression multi-centre investigator study group. Effectiveness and safety of a prevention-of-flare-progression strategy



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with pimecrolimus cream 1% in the management of paediatric atopic der-matitis. J Eur Acad Dermatol Venereol. 2008;22:1290-1301.

38. Gollnick H, Kaufmann R, Stough D, et al; Pimecrolimus Cream 1% in (adult) Eczema: Prevention of Progression Multicentre Investigator Study Group. Pimecrolimus cream 1% in the long-term management of adult atopic der-matitis: prevention of flare progression. A randomized controlled trial. Br J Dermatol. 2008;158:1083-1093.

39. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic dermati-tis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol. 2002;110:277-284.

40. Schneider L, Hanifin J, Boguniewicz M, et al. Study of the Atopic March: development of atopic comorbidities. Pediatr Dermatol. 2016;33:388-398.

41. Tripodi S, Di Rienzo Businco A, Panetta V, et al. Lack of efficacy of topical furfuryl palmitate in pediatric atopic dermatitis: a randomized double-blind study. J Investig Allergol Clin Immunol. 2009;19:204-209.

42. Charman C, Chambers C, Williams H. Measuring atopic dermatitis sever-ity in randomized controlled clinical trials: what exactly are we measuring? J Invest Dermatol. 2003;120:932-941.

43. Rehal B, Armstrong AW. Health outcome measures in atopic dermatitis: a systematic review of trends in disease severity and quality-of-life instru-ments 1985-2010. PLoS One. 2011;6:e17520.

44. Chapman MS, Schachner LA, Breneman D, et al; US Tacrolimus Ointment Study Group. Tacrolimus ointment 0.03% shows efficacy and safety in pedi-atric and adult patients with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2005;53:S177-185.

45. Draelos ZD. Differences in cutaneous irritation of five commonly used topi-cal products. J Drugs Dermatol. 2016;15:870-873.

46. Yosipovitch G, Simpson EL, Bushmakin AG, et al. Assessment of pruritus in atopic dermatitis: validation of the Severity of Pruritus Scale (SPS). Itch. 2018;3:e13.

47. Yosipovitch G, Simpson EL, Tan H, et al. Effect of crisaborole topical oint-ment, 2%, on atopic dermatitis-associated pruritus: an extended analysis of 2 phase 3 clinical trials. Itch. 2018;3:e12.

48. Meurer M, Fartasch M, Albrecht G, et al; CASM-DE-01 Study Group. Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis. Dermatology. 2004;208:365-372.

49. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017;77:641-649.e645.

50. Callen J, Chamlin S, Eichenfield LF, et al. A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol. 2007;156:203-221.

51. Hajar T, Leshem YA, Hanifin JM, et al; Force tNEAT. A systematic review of topical corticosteroid withdrawal ("steroid addiction") in patients with atopic dermatitis and other dermatoses. J Am Acad Dermatol. 2015;72:541-549.e542.

52. Ghosh A, Sengupta S, Coondoo A, et al. Topical corticosteroid addiction and phobia. Indian J Dermatol. 2014;59:465-468.

53. Aubert-Wastiaux H, Moret L, Le Rhun A, et al. Topical corticosteroid phobia in atopic dermatitis: a study of its nature, origins and frequency. Br J Derma-tol. 2011;165:808-814.

54. Muller SM, Tomaschett D, Euler S, et al. Topical corticosteroid concerns in dermatological outpatients: a cross-sectional and interventional study. Der-matology. 2016;232:444-452.

55. Li AW, Yin ES, Antaya RJ. Topical corticosteroid phobia in atopic dermatitis: a systematic review. JAMA Dermatol. 2017;153:1036-1042.

56. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lym-phoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14:163-178.

57. Siegfried EC, Jaworski JC, Kaiser JD, et al. Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin in-hibitors in pediatric patients with atopic dermatitis. BMC Pediatr. 2016;16:75.

58. Arellano FM, Arana A, Wentworth CE, et al. Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom. J Allergy Clin Immunol. 2009;123:1111-1116.e1113.

59. Margolis DJ, Abuabara K, Hoffstad OJ, et al. Association between malig-nancy and topical use of pimecrolimus. JAMA Dermatol. 2015;151:594-599.

60. Luger T, Boguniewicz M, Carr W, et al. Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow use in infants. Pediatr Allergy Immunol. 2015;26:306-315.

61. Sigurgeirsson B, Boznanski A, Todd G, et al. Safety and efficacy of pimecroli-mus in atopic dermatitis: a 5-year randomized trial. Pediatrics. 2015;135:597-606.

62. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 changes and testing blindness in RCTs. Lancet. 2010;375:1144-1146.

63. ICMJE. Recommendations for the conduct, reporting, editing, and publica-tion of scholarly work in medical journals. http://www.icmje.org/. Accessed December 12, 2018.


Lawrence F. Eichenfield MDE-mail:................……......................... [email protected]



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FIGURE S1. Search Results and Exclusions. aReviews included general reviews, systematic reviews, and meta-analyses.

15

Figure S1. Search Results and Exclusions

aReviews included general reviews, systematic reviews, and meta-analyses.

SUPPLEMENTAL MATERIALS

TABLE S1.

Search Parameters

Parameters SearchNumber of

publications

Search topical corticosteroid AND vehicle AND atopic dermatitis

#1 80

Search topical corticosteroid AND vehicle AND eczema

#2 27

Search topical steroid AND vehicle AND atopic dermatitis

#3 67

Search topical steroid AND vehicle AND eczema

#4 19

Search topical crisaborole AND vehicle AND atopic dermatitis

#5 7

Search topical crisaborole AND vehicle AND eczema

#6 2

Search topical pimecrolimus AND vehicle AND atopic dermatitis

#7 52

Search topical pimecrolimus AND vehicle AND eczema

#8 24

Search topical tacrolimus AND vehicle AND atopic dermatitis

#9 78

Search topical tacrolimus AND vehicle AND eczema

#10 31

#1 OR #2 OR #3 OR #4 OR #5 or #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12

#11 134

Search was conducted using PubMed on May 3, 2018. Filters included publica-tion date January 1997 through April 2018.




http://defenage.com/




SPECIAL TOPIC

Q-Switched 1064nm Nd:YAG Laser in Treating Axillary Hyperpigmentation in Filipino Women With Skin Types IV-V

Irene Gaile C. Robredo MD FPDSSt Luke’s Medical Center Global City, Taguig City, Philippines;

Asian Hospital and Medical Center, Muntinlupa City, Philippines;beautiqueMD, Taguig City, Philippines; dermHQ, Makati City, Philippines

Background: Axillary post inflammatory hyperpigmentation (PIH) is one of the most common dermatological complaint in women with darker skin types. Standard of care include mainly topical bleaching agents either alone or combination with other treatments. Lately, laser-based treatments have emerged as potential therapeutic options for the treatment of PIH in patients with darker skin types. Objective: To assess the safety and efficacy of a 1064nm Q-switched Nd:YAG laser in the treatment of axillary hyperpigmentation in Filipino women with Fitzpatrick skin types IV-V. Materials and Methods: Nine women (18 axillae) ages 20-52 years old with axillary PIH were prospectively evaluated for treatment using a nanosecond 1064nm Q-switched Nd:YAG laser. Clinical evaluation included pigmentary changes of PIH lesion compared to non-affected regions and GIAS satisfaction assessment both by the treating physician and patients. Safety parameters included adverse events and pain visual analogue scale (VAS) scoring. Results: All axillae responded to the laser treatment, exhibiting reduction in pigmentation in 85-100% of lesion area. GIAS satisfac-tion results exhibited 22-33% excellent improvement and 55% much improved scores. All patients’ pigmentary improvements were maintained at the final follow-up visit, three months following final treatment. No adverse events were recorded throughout the trial. Treatment related pain was well tolerated, as exhibited by pain VAS scores recorded after each treatment. Conclusion: Use of a low-fluence 1064nm Q-switched Nd:YAG laser in the treatment of axillary hyperpigmentation is safe and effective in patients with darker skin type.


ABSTRACT

INTRODUCTION

Post inflammatory hyperpigmentation (PIH) is an acquired hyper-melanosis typically arising following inflamma-tory lesions. It is one of the most common dermatologic

complaints, which may develop in all skin types, however, high-er prevalence is seen in patients with Fitzpatrick skin types IV-VI. The etiology underlying PIH can either be an exogenous source (allergy, irritation, contact dermatitis, dermabrasion, laser ther-apy, or burns), an endogenous factor (primary inflammatory or bullous dermatosis) or even induced by an infectious agent such as herpes zoster virus infection. Morphologic pattern and degree of pigmentation vary depending on causative factors and melanin distribution in the epidermis, dermis, or both.1,2,3

PIH typically manifests as macules or patches in the same distribution in previous areas of inflammation, which can be classified as two clinical forms: epidermal and/or dermal. In epidermal PIH, melanocytes are activated, and release mela-nin resulting in tan brown or dark brown appearance and may take months to years to resolve. Dermal PIH includes activa-tion of basal keratinocytes, which also release melanin, and present as dark brown to blue-grey discoloration that may ei-ther be permanent or resolve over an extended period of time

if not treated. Differentiating between the two is difficult, and PIH is probably a result of the combination of both epidermal and dermal lesions.4 The degree of PIH varies depending on the etiological factors, skin type or “chromatic tendency” as well as exposure to UV light, certain medications, and cutaneous injuries (trauma or even shaving).1,2,5,6 The discoloration is de-termined by the distribution and depth of pigment within the skin layers.

The pathogenesis of PIH is often related to an increase in mela-nin synthesis and/or irregular pigment dispersion resulting from cutaneous inflammation. It is considered the end result of: melanocyte proliferation, melanin synthesis, and increased activation of tyrosinase coupled with transfer of melanosomes to neighboring keratinocytes. Although the exact mechanism is not yet fully understood, the rise in melanocyte activity and proliferation has been known to be stimulated by inflammatory mediators such as reactive oxygen species, prostaglandins, and leukotrienes.1,5

PIH management is commonly addressed by prevention of the inflammatory dermatosis. A variety of medication and

doi:10.36849/JDD.2020.4623



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I.G.C. Robredo

a 10-week treatment protocol, which consisted of 4 treatment sessions at 2 weeks intervals and a follow-up visit at one and three months following the fourth treatment.

Clinical EvaluationPrimary end point of the study was reduction in axillary hyper-pigmentation. Pigmentary changes were assessed by calculating the L* (luminosity) according to the Von Luschan's Chromatic classification scale (Figure 1). Improvement was assessed by comparing the difference (L*∆) between target treatment area of the axilla and a non PIH affected area (L*∆= axilla–periaxilla), at baseline and at the final follow-up visits. Assessment was car-ried out by the treating physician and by two other objective evaluators. Clinical improvement was assessed by the GIAS score (stages of improvement scoring: 1= very much improved, 2= much improved, 3= improved, 4= no change, or 5= worse outcomes) both by the treating physician and the patients throughout the study. Safety parameters included treatment related adverse events and pain, scored on a 10-point visual as-sessment scale (VAS scale), recorded after each treatment.

procedures in addition to photoprotection have been shown to effectively treat PIH. Topical treatment with depigmenting agents such as hydroquinone, keratolytic agents, retinoids, or corticosteroids has been shown to be effective as a stand-alone treatment or in combination with other topicals, oral medica-tion, or procedures mainly influencing epidermal PIH. Dermal PIH, which is characterized by deeper pigmentation does not respond well to these modalities.2,5,7 Laser and light-based therapies provide alternatives or adjuncts to topical therapy, especially in refractory cases. Typically, short wavelength lasers are efficiently absorbed by epidermal melanin while longer wavelengths penetrate deeper with more selective absorption by dermal chromophores enabling safer treatment options for patients with darker skin type.2,8 In recent years, a variety of la-sers have been studied. Q-Switched Ruby (694nm), Alexandrite (755nm), and Neodymium:yttrium aluminum garnet (Nd:YAG) (1064nm), as well as fractional lasers (various wavelengths) have been clinically studied exhibiting statistically significant improvement in pigmentation up to complete clinical clearance in some cases.7 The Q-Switched (QS) Ruby and Alexandrite lasers have been reported to worsen lesions in dark-skinned patients and generally not recommended for this patient group. The QS Nd:YAG 1064nm laser was shown to be highly effec-tive in darker skin type patients with various PIH etiologies.9

Picosecond lasers have also been reported in the treatment of pigmentation and PIH that proved difficult to treat with conven-tional QS lasers.10

Axillary hyperpigmentation is a frequent dermatological com-plaint, characterized by dermal and epidermal PIH mainly associated with women of darker skin types. Etiological theory associates axillary hyperpigmentation of a form of post inflam-matory hyperpigmentation due to continuous irritation due to hair removal, cleansing, tight cloths, or innate darkening from genetic related factors.11 The purpose of this case study was to evaluate the efficacy of a 1064nm nanosecond QS Nd:YAG laser in the treatment of axillary PIH in Filipino women with Fitzpat-rick skin types IV-V.

MATERIALS AND METHODSStudy DesignNine (9) female patients, aged 20 to 52 years (mean age, 39 ± 10 years), with skin types IV-V and bi-lateral underarm hyper-pigmentation (18 axillae) were included in this prospective study. Verbal and written informed consent were obtained. The patients were in good health and were not treated with concom-itant whitening or depigmenting agents.

All 18 axillae were treated with a QS Nd:YAG (1064nm) laser (Alma Q, Alma Lasers GmbH, Nürnberg, Germany). Treatment was carried out according to the following treatment pro-tocol: four (4) passes over the treatment area with a focused handpiece, 7 mm spot size, fluence of 2.6mJ/cm2 until total en-ergy accumulation reached 800kJ. Case study design included

FIGURE 1. Von Luschan's Chromaticclassification scale.

FIGURE 2.



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I.G.C. Robredo

DISCUSSIONPost inflammatory hyperpigmentation (PIH) is a common ac-quired pigmentary disorder. Melanocytes of darker skin types are hyperactive and thus release more melanin, which may ac-count for the high frequency of PIH in Fitzpatrick skin types IV-VI populations.2 Recently, laser-based treatments have emerged as safe and effective therapeutic options for PIH, specifically tar-geting melanin. The Q-Switched photoacoustic effect promotes chromophore shattering with subsequent evacuation by im-munologic associated cells. These treatments have produced variable results when treating PIH.

Near-infrared lasers such as 1064nm QS Nd:YAG laser are less absorbed by melanin compared with the green and red light la-sers thus are considered safer for the treatment of patient with darker skin types. This is due to the fact that the 1064nm wave-length targets not only melanin but also hemoglobin and water. In addition, the 1064nm wavelength is known for its deeper penetration into the skin and thus can effectively target dermal pigmented lesions.8,12 A study using low-fluence 1064nm QS Nd:YAG laser was shown to be a safe and effective treatment for PIH as a single or combined therapy, however, with recur-rence after several weeks.7 To date there are limited studies on the 1064nm QS Nd:YAG laser for PIH treatment, with most clini-cal data collected from melasma studies.12

Recently, the efficacy of low-fluence 1064nm- QS Nd:YAG laser was evaluated for the treatment of the axillary hyperpigmenta-tion with satisfactory results. This was the first observational study clinically testing axillary PIH treatment using laser, which exhibited good-to-excellent improvement after a minimum of 3 treatments with lasting results for at least 6 months.4 Our study followed a similar treatment protocol and laser to be done on Filipino women with skin types IV-V.

RESULTSReduction in hyperpigmentation of the axillae was apparent in all patients, affecting 85-100% of pigmented lesion. At the one-month follow-up visit, the mean L*∆ values were 0.4±0.05 compared to 3.5±1.58 at baseline, presenting major pigmentary improvement following laser treatment (Table 1). At the three months follow-up visit, all patients maintained their improved state in PIH reduction. Clinical improvement by GIAS scores rated laser treatment for axillary PIH by the physician and the patients as excellent in 33.3% and 22.2%, very much improved in 55.5% (by both physician and patients), and improved in 22.2% and 11%, respectively (Table 2).

The VAS pain rating was scored after each treatment and report-ed as 3.8, 2.7, 1.4, and 1, respectively. No adverse events were reported during the trial or at the follow-up visits.

TABLE 2.

Clinical Improvement by GIAS Scale

Clinical Improvement (GAIS) 1 Month

Patient # Physician Patient

1 Much improved Much improved


3 Much improved Improved


5 Very much improved Very much improved

6 Much improved Improved

7 Improved Much improved

8 Very much improved Much improved

9 Very much improved Very much improved

TABLE 1.

Axillary Pigmentary Changes (L*∆) Following Q-Switched Laser Treatment

Von Luschan’s Chromatic Classification of Skin Color Scale Score

Axillary PeriaxillaryBaseline (L*∆)

(Axillary-Periaxillary)1 Month (L*∆)

(Axillary-Periaxillary)

Patient # Right Left Right Left Right Left Right Left

1 28 27 25 25 3 2 0 1

2 29 27 24 24 5 3 1 0

3 31 29 26 26 5 3 1 1

4 28 28 25 25 3 3 0 0

5 31 31 25 25 6 6 0 0

6 28 30 25 25 3 5 0 1

7 27 27 25 25 2 2 0 0

8 26 27 25 25 1 2 0 0

9 29 29 24 24 5 5 1 1

Mean 28.6 + 0.6 28.3 + 0.5 24.9 + 0.6 24.9 + 0.2 3.7 + 0.6 3.4 + 0.5 0.3 + 0.2 0.4 + 0.2

Note: Data are expressed as color scale score by Von Luschan’s chromatic scale and summarized as mean ± standard error of mean.



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I.G.C. Robredo

Since axillary hyperpigmentation is considered a common dis-order associated mainly with darker skin types and poses a major influence on quality of life, we focused on Filipino women with skin types IV-V with axillary hyperpigmentation. Objective analysis of pigmentation showed a marked reduction in after 4 laser treatments. Paired clinical improvement scoring both by the treating physician and patients proved that following 4 treatments, all lesions reported pigment reduction compared to baseline. Previous studies have shown that pigments treated with QS Nd:YAG exhibited recurrence of pigment after a few months or even cases in which the laser treatment itself pro-duced PIH.7 We found that the low-fluence treatment protocol spaced 2 weeks apart did not induce additional PIH in any of the patients and that reduction in pigmentation was sustained for at least 3 months after the final treatment session. Furthermore, none of the major adverse events of traditional laser treat-ments such as pain, burning, or edema were noted. Pain scored throughout the trial was tolerable as shown by the consistent reduction in VAS scores after each treatment session.

CONCLUSIONAxillary hyperpigmentation is a common and problematic aes-thetic condition that has not been extensively studied, although presenting high prevalence among females of dark skin types. Our study supports previous preliminary data that showed a minimum 3 laser treatments for PIH in the axillary area. We found that low fluence QS 1064nm Nd:YAG nanosecond la-ser treatment is a safe and effective treatment option for PIH associated axillary pigmentation. Our data show marked im-provement in pigmentation, which was sustained for as long as three months after the final treatment with no related adverse events or treatment related PIH.

Further investigation and large-scale clinical studies are nec-essary to substantiate clinical significance of low0fluence QS 1064nm Nd:YAG laser in the treatment of PIH.

DISCLOSURESThe author has no conflicts of interest to declare.

REFERENCES1. Lamel SA, Rahvar M, Maibach HI. Postinflammatory hyperpigmentation sec-

ondary to external insult: an overview of the quantitative analysis of pigmen-tation. Cutan Ocul Toxicol. 2013;32(1):67-71.

2. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20-31.

3. Nouveau S, Agrawal D, Kohli M, Bernerd F, Misra N, Nayak CS. Skin hyperpig-mentation in indian population: insights and best practice. Indian J Dermatol. 2016;61(5):487-95.

4. Ghannam S, Al Otabi FK, Frank K, Cotofana S. Efficacy of low-fluence Nd:YAG 1064nm laser for the treatment of post-inflammatory hyperpigmentation in the axillary area. J Drugs Dermatol. 2017;16(11):1118-1123.

5. Lacz NL, Vafaie J, Kihiczak NI, Schwartz RA. Postinflammatory hyperpigmen-tation: a common but troubling condition. Int J Dermatol. 2004;43(5):362-5.

6. Silpa-Archa N, Kohli I, Chaowattanapanit S, Lim HW, Hamzavi I. Postinflam-matory hyperpigmentation: A comprehensive overview: epidemiology, pathogenesis, clinical presentation, and noninvasive assessment technique.

J Am Acad Dermatol. 2017;77(4):591-605.7. Chaowattanapanit S, Silpa-Archa N, Kohli I, Lim HW, Hamzavi I. Postinflam-

matory hyperpigmentation: a comprehensive overview: treatment options and prevention. J Am Acad Dermatol. 2017;77(4):607-621.

8. Battle EF, Hobbs LM., Laser surgery on darker ethnic skin. Dermatol Clin. 2003;21(4):713-23.

9. Agbai O, Hamzavi I, Jagdeo J. Laser treatments for postinflammatory hyper-pigmentation: a systematic review. JAMA Dermatol. 2017;153(2):199-206.

10. Lee YJ, Shin HJ, Noh TK, Choi KH, Chang SE. Treatment of melasma and post-inflammatory hyperpigmentation by a picosecond 755-nm alexandrite laser in Asian Patients. Ann Dermatol. 2017;29(6):779-781.

11. Castanedo-Cazares JP, Lárraga-Piñones G, Ehnis-Pérez A, Fuentes-Ahumada C, Oros-Ovalle C, Smoller BR, Torres-Álvarez B. Topical niacinamide 4% and desonide 0.05% for treatment of axillary hyperpigmentation: a random-ized, double-blind, placebo-controlled study. Clin Cosmet Investig Dermatol. 2013;6:29-36.

12. Pooja A, Sarkar R, Garg VK, Arya L. Lasers for treatment of melasma and post-inflammatory hyperpigmentation. J Cutan Aesthet Surg. 2012;5(2):93-103.

13. Cho SB, Park SJ, Kim JS, Kim MJ, Bu TS. Treatment of post-inflammatory hy-perpigmentation using 1064nm Q-switched Nd:YAG laser with low fluence: report of three cases. J Eur Acad Dermatol Venereol. 2009;23(10):1206-7.


Irene Gaile C. Robredo MD FPDSE-mail:................……......................... [email protected]





SPECIAL TOPIC

Tazarotene 0.045% Lotion for Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Results from Two

Phase 3 TrialsEmil A. Tanghetti MD,ª William P. Werschler MD,B Terry Lain MD,c Eric Guenin PharmD PhD MPH,d

Gina Martin MOT,E Radhakrishnan Pillai PhDe

ªCenter for Dermatology and Laser Surgery, Sacramento, CABUniversity of Washington, School of Medicine, Seattle, WA

cUniversity of Texas MD Anderson Cancer Center, Houston, TXdOrtho Dermatologics, Bridgewater, NJ

eBausch Health Americas, Inc., Petaluma, CA

Background: Tazarotene has been extensively studied in clinical trials and is widely used to treat acne vulgaris (acne), with data sug-gesting that is one of the most potent topical retinoids. Irritation from the cream, foam, and gel formulations has limited its use in clinical practice. Objective: To assess the efficacy, safety, and tolerability of a unique tazarotene 0.045% lotion formulation based on polymeric emul-sion technology in subjects with moderate or severe acne.Methods: A total of 1614 subjects, 9 years and older were randomized to receive tazarotene 0.045% lotion or vehicle in two identical double-blind, randomized, vehicle-controlled 12-week studies evaluating safety and efficacy (inflammatory [papules and pustules] and noninflammatory [comedonal] lesion counts and using Evaluator Global Severity Scores [EGSS]). Treatment success was defined as at least a 2-grade improvement in EGSS and ‘clear’/’almost clear’ and efficacy assessed through reduction in lesion counts. In addition, patients completed a validated Acne-Specific Quality of Life (Acne-QoL) questionnaire. Safety, adverse events (AEs), and cutaneous tolerability were assessed throughout.Results: Tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflam-matory lesion counts at week 12. Mean percent reductions in inflammatory and noninflammatory lesions were 55.5% and 51.4% (Study 1, both P<0.001 versus vehicle [45.7% and 41.5%, respectively]) and 59.5% and 60.0% (Study 2, both P<0.001 versus vehicle [49.0% and 41.6%, respectively]), with tazarotene 0.1% cream at week 12. Treatment success was achieved by 25.5% (Study 1) and 29.6% (Study 2) of subjects treated with tazarotene 0.045% lotion (both P<0.001 versus vehicle [13.0% and 17.3%, respectively]). Im-provements in QoL domain scores were consistently greater with tazarotene. Tazarotene 0.045% lotion was well-tolerated. The most common treatment-related AEs were application site pain (5.3%), dryness (3.6%), and exfoliation (2.1%).Conclusions: Tazarotene 0.045% lotion provides statistically significant greater efficacy than vehicle in terms of lesion reduction and treatment success, with a highly favorable safety and tolerability profile in moderate-to-severe acne patients.


ABSTRACT

INTRODUCTION

Topical tazarotene 0.1% gel, foam and cream have been shown to be highly effective for the treatment of acne vulgaris (acne), both as monotherapy and in combina-

tion with other agents. Several studies have shown tazarotene to markedly reduce both comedonal and inflammatory facial acne lesions.1-13

All topical retinoids can produce irritant contact dermatitis during the first few weeks of application; with many patients experiencing erythema, scaling, dryness, burning, and pruritus that can vary in severity, that appear to be compound, quan-

tity applied and vehicle dependent, and can be sufficiently symptomatic to reduce adherence with treatment.14 Although tazarotene is an effective topical retinoid to treat acne, as true with all retinoids, skin irritation can limit its usefulness.14

A new approach utilizing polymeric emulsion technology has been applied to the development of dermatological prod-ucts. Upon topical application, the polymeric emulsion helps a uniform release of humectants, moisturizing/hydrating in-gredients, and uniform distribution of micronized oil droplets containing active ingredient which helps control the delivery

doi:10.36849/JDD.2020.3977



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E.A. Tanghetti, W.P. Werschler, T. Lain

A washout period of up to 1 month was required for patients who used previous prescription and over-the-counter acne treatments longer for systemic retinoids. Specifically, the fol-lowing mandatory washout periods and restrictions applied to these topical and systemic treatments: topical astringents and abrasives (1 week); topical anti-acne products, including soaps containing antimicrobials, and known comedogenic products (2 weeks); topical retinoids, retinol, and systemic acne treatments, such as hormonal or antibiotic treatments (4 weeks); and sys-temic retinoids (6 months). Approximately 1600 subjects (800 in each study) were planned for enrollment.

Study drug kits were assigned based on a randomization code. Subjects were randomized (1:1) to receive tazarotene 0.045% lotion or vehicle applied topically to the face once daily for 12 weeks. The initial topical application was made at the investiga-tional center. Subjects were asked to apply their daily treatment in the evening at home. During the studies, each subject was permitted to use only approved cleansers, moisturizers, and sun-screens, and noncomedogenic makeup and shaving products. Investigators were trained thoroughly to ensure consistency in the evaluation of the subjects for lesion count and EGSS. As-sessments were carried out at screening, baseline, weeks 2, 4, 8, and 12 (end of treatment). The EGSS was determined prior to performing lesion counts. Subjects also completed an Ac-ne-Specific Quality of Life (Acne-QoL) questionnaire and were asked to answer questions pertaining to their QoL as it related to their facial acne at baseline and at week 12.

Study OversightSubjects provided written informed consent before study-re-lated procedures were performed; protocol and consent were approved by institutional review boards (IRBs) or ethics com-mittees at all investigational sites. The studies were conducted in accordance with the principles of Good Clinical Practice (GCP) and Declaration of Helsinki.

Statistical and Analytical PlanThe intent-to-treat (ITT) population comprised all subjects ran-domized and provided with study drug. The safety population comprised all randomized subjects who were presumed to have used the study medication or vehicle at least once and who had at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov Chain Monte Carlo multiple im-putation method. For analyses of the changes from baseline in noninflammatory and inflammatory lesion counts in both pivotal phase 3 studies, significant skewness was observed, and a nonparametric method used in which the changes in le-sion counts were rank-transformed prior to being submitted to the ANCOVA. Values were adjusted for multiple imputations. Significance of EGSS reductions were obtained from logistic regression (using Firth’s Penalized Likelihood) with factors of

into skin, thus resulting in an efficient and clinically effective delivery system. This formulation approach has been used to develop tazarotene 0.045% lotion, providing uniform distribu-tion of tazarotene onto the skin and providing a more efficient delivery into the epidermis; which may afford similar efficacy to the higher concentrations of tazarotene formulations currently available (gel, foam, and cream) while reducing the irritation potential.

In a phase 2 comparative study with tazarotene 0.045% lo-tion versus tazarotene 0.1% cream, tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts (P=0.013 and P<.001) at week 12.15 At less than half the con-centration, tazarotene 0.045% lotion was numerically more effective than tazarotene 0.1% cream in terms of reduction in lesion counts and treatment success. Treatment Emergent Ad-verse Events (TEAEs) were twice as common with tazarotene 0.1% cream (26.8% versus 14.7% with tazarotene 0.045% lotion and 13.4% with vehicle) and there were also more treatment-related AEs with tazarotene 0.1% cream (5.6% versus 2.9%); most common being application site pain (4.2%) which is likely a manifestation of irritation.

Here we present data from two large multicentred, double-blind vehicle-controlled studies of tazarotene 0.045% lotion in subjects with moderate or severe acne.

METHODSStudy DesignTwo multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies to assess safety, tolerability, and efficacy of tazarotene 0.045% lotion in subjects with moder-ate or severe acne (with an Evaluator’s Global Severity Score [EGSS] of 3 [moderate] or 4 [severe]). Treatment was topically applied once-daily to the face, excluding mouth, eyes, inside the nose, and lips. Power calculations were computed using the results from the phase 2 study.15 Active and vehicle were identi-cal formulations, with the absence of tazarotene in the vehicle comparator, with identical physical appearance and packaging to ensure blinding.

Studies were registered on clinicaltrials.gov NCT03168334 and NCT03168321, conducted at 89 clinical sites in the United States and Canada from June 2017 to July 2018.

Subjects and RandomizationKey inclusion criteria included subjects of either gender, 9 years or older with moderate (EGSS=3) or severe (EGSS=4) acne. Spe-cifically, subjects had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones) and two or less facial nodules.



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postscreening study visits using a 4-point scale, where 0=none and 3=severe. Tolerability (individual assessments of itch-ing, burning, and stinging) was reported by the subjects at all postscreening study visits. Subjects were asked to provide an average evaluation of each parameter over the period since the previous study visit using a 4-point scale, where 0=none and 3=severe.

Vital sign measurements were recorded, blood samples col-lected, and an abbreviated physical examination performed at baseline and week 12. A medical history was taken at screening, and confirmed and revised at baseline, if necessary.

RESULTSSubject DispositionOverall, 1614 subjects were randomized to tazarotene 0.045% lo-tion or vehicle lotion and included in the ITT population (Figure 1). Across the two studies, 86.6% (N=799) and 88.6% (N=815) of subjects treated with tazarotene 0.045% lotion or vehicle completed. Main reasons for study discontinuation with tazaro-tene 0.045% lotion were lost to follow-up (5.6%, N=45), subject request (4.3%, N=34), or adverse events (2.4%, N=19). Lost to follow-up (6.9%, N=56) and subject request (2.8%, N=23) were also the main reasons for discontinuation in the vehicle arms.A total of 1570 subjects were included in the safety population, (44 subjects were not included due to no post baseline safety evaluation).

Demographics and Baseline CharacteristicsDemographic data were comparable across the two studies (Ta-ble 1). Mean age was 20.6 (SD 7.11) in Study 1 and 20.3 (SD 6.65) in Study 2. Overall, the majority of subjects were female (65.9%, N=1064) and Caucasian (73.8%, N=1191).

treatment group and analysis center. Values were adjusted for multiple imputations. Descriptive statistics were used to sum-marize the results of the Acne-QoL questionnaire. In subjects who discontinued treatment before Week 12 or missed visits between baseline and final evaluation, the last observation was carried forward. 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. All AEs occurring during the studies were recorded and classified on the basis of medical dictionary for drug regulatory activities terminology (MedDRA) for the safety population.

Study AssessmentEfficacy Co-primary endpoints were EGSS and absolute reduction in in-flammatory lesion and noninflammatory lesion counts. Percent of subjects who had at least a 2-grade reduction from baseline EGSS at week 12, and an EGSS of ‘clear’ or ‘almost clear’ were considered a treatment success. Additional assessments includ-ed percent change in inflammatory and noninflammatory lesion counts from baseline at each study visit and absolute change in Acne-QoL domain scores.

Safety Safety evaluations, including AEs, cutaneous safety evaluations and tolerability, vital signs, laboratory evaluations, and physi-cal examinations were performed; information on reported and observed AEs obtained at each visit, cutaneous safety, and toler-ability at each study visit.

Cutaneous safety (individual assessments of scaling, erythema, hypopigmentation, and hyperpigmentation at the drug ap-plication site) was reported by the investigator/evaluator at all

FIGURE 1. Patient disposition showing percent completion and reasons for discontinuation (All Randomized Subjects Study 1 and Study 2).



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Baseline disease characteristics were comparable (Table 1). Subjects had a baseline EGSS of 3 - moderate (90.9%, N=1467) or 4 - severe (9.1%, N=147). Mean (SD) inflammatory and nonin-flammatory lesion counts were 28.1 (7.12) and 41.1 (16.54).

Efficacy EvaluationEvaluator’s Global Severity Score (EGSS)

Tazarotene 0.045% lotion was significantly more effective than vehicle in achieving treatment success (Figure 2), defined as at least a 2-grade improvement in EGSS and ‘clear’/’almost clear’. By week 12, 25.5%, and 29.6% (Study 1 and 2) of subjects in the tazarotene 0.045% lotion groups achieved this co-primary efficacy outcome compared with 13.0% and 17.3% with vehicle (both P<0.001). In addition, 28.3% and 34.5% (Study 1 and 2)

TABLE 1.

Demographics and Baseline Characteristics (ITT population Study 1 and Study 2)

Study 1 Study 2

Tazarotene 0.04%

(N=402)

Vehicle(N=411)

Total(N=813)

Tazarotene 0.04%

(N=397)

Vehicle(N=404)

Total(N=801)

Age- Mean years (SD) 20.8 (7.29) 20.4 (6.94) 20.6 (7.11) 20.1 (6.48) 20.5 (6.81) 20.3 (6.65)

Range 10-50 10-65 10-65 10-54 10-53 10-54

Sex N (%)

Male Female

122 (30.3%)280 (69.7%)

140 (34.1%)271 (65.9%)

262 (32.2%)551 (67.8%)

146 (36.8%)251 (63.2%)

142 (35.1%)262 (64.9%)

288 (36.0%)513 (64.0%)

Ethnicity N (%)

Hispanic or Latino Not Hispanic or Latino

67 (16.7%)335 (83.3%)

76 (18.5%)335 (81.5%)

143 (17.6%)670 (82.4%)

101 (25.4%)296 (74.6%)

108 (26.7%)296 (73.3%)

209 (26.1%)592 (73.9%)

Race N (%)

American Indian or Alaska Native Asian Black or African American Native Hawaiian or Other Pacific Islander White Other

3 (0.7%)15 (3.7%)76 (18.9%)0 (0.0%)

293 (72.9%)15 (3.7%)

3 (0.7%)13 (3.2%)

83 (20.2%)2 (0.5%)

297 (72.3%)13 (3.2%)

6 (0.7%)28 (3.4%)

159 (19.6%)2 (0.2%)

590 (72.6%)28 (3.4%)

6 (1.5%)27 (6.8%)49 (12.3%)0 (0.0%)

298 (75.1%)17 (4.3%)

3 (0.7%)23 (5.7%)54 (13.4%)2 (0.5%)

303 (75.0%)19 (4.7%)

9 (1.1%)50 (6.2%)

103 (12.9%)2 (0.2%)

601 (75.0%)36 (4.5%)

Evaluator’s Global Severity Score N (%)

3 – Moderate 4 – Severe

368 (91.5%)34 (8.5%)

384 (93.4%)27 (6.6%)

752 (92.5%)61 (7.5%)

358 (90.2%)39 (9.8%)

357 (88.4%)47 (11.6%)

715 (89.3%)86 (10.7%)

Inflammatory Lesion Count- Mean (SD) 28.5 (7.04) 28.1 (7.04) 28.3 (7.04) 28.0 (7.32) 27.9 (7.10) 28.0 (7.21)

FIGURE 2. Treatment success. Subjects with at least a 2-grade improvement and ‘clear’ or ‘almost clear at each study visit (ITT population, Study 1 and Study 2).



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of subjects in the tazarotene 0.045% lotion groups achieved at least a 2-grade improvement in EGSS at week 12 compared with 15.2% and 20.9% with vehicle (both P<0.001).

Lesion CountsTazarotene 0.045% lotion was significantly more effective than

vehicle in achieving a reduction in lesion counts (Figure 3 and 4). At week 12, the absolute reduction (15.6, Study 1 and 16.7, Study 2) in inflammatory lesion count relative to baseline for the tazarotene 0.045% lotion group was significantly greater than for vehicle (12.4, Study 1 and 13.4, Study 2, P<0.001 both studies). Correspondingly, the absolute reduction (21.0, Study 1 and 24.6, Study 2) in noninflammatory lesion count relative to baseline for the tazarotene 0.045% lotion group was signifi-cantly greater than for vehicle (16.4, Study 1 and 16.6, Study 2, P<0.001 both studies).

By week 12, there was a 55.5% and 51.4% (Study 1) change in in-flammatory and noninflammatory lesion counts from baseline (LS mean), and a 59.5% and 60.0% change in Study 2, respec-tively, compared with 45.7% and 41.5% (Study 1, both P<0.001) and 49.0% and 41.6% (Study 2, both P<0.001) with vehicle.

Percent changes in noninflammatory lesions were statisti-cally significant compared with vehicle from week 2 (Study 2, P=0.018) or week 4 (Study 1, P=0.004) and changes in inflamma-tory lesions statistically significantly greater at week 8 (P≤0.006)Acne-Specific QoL

At baseline, the mean scores for each domain were similar. By Week 12 improvements in QoL (mean absolute changes) were consistently greater in the groups treated with tazarotene 0.045% lotion. Absolute change from baseline in Self-Percep-tion, Role-Emotional, Role-Social and Acne Symptom domains were 7.5, 6.0, 4.7, and 6.4, respectively, compared with 6.7, 5.5, 4.1, and 5.3 for subjects treated with vehicle.

Safety EvaluationOverall, 26.8% (N=209) of subjects treated with tazarotene 0.045% lotion reported AEs compared with 19.1% (N=151) with

TABLE 2.

Treatment-Emergent and Related Adverse Event (AE) Characteristics through Week 12 (Safety population, pooled data)

Pooled Data (Study 1 and Study 2)

Tazarotene 0.045% Lo-

tion (N=779)

Vehicle Lotion

(N=791)

Subjects reporting any TEAE 209 (26.8%) 151 (19.1%)

Subjects reporting any SAE 4 (0.5%) 4 (0.5%)

Subjects who died 0 (0.0%) 0 (0.0%)

Subjects who discontinued due to TEAE

22 (2.8%) 4 (0.5%)

Severity of AEs reported

Mild 136 (17.5%) 83 (10.5%)

Moderate 63 (8.1%) 64 (8.1%)

Severe 10 (1.3%) 4 (0.5%)

Relationship to study drug

Related 88 (11.3%) 9 (1.1%)

Unrelated 121 (15.5%) 142(18.0%)

Treatment Related AEs reported by ≥1% subjects

Application site pain 41 (5.3%) 2 (0.3%)

Application site dryness 28 (3.6%) 1 (0.1%)

Application site erythema 14 (1.8%) 0 (0.0%)

Application site exfoliation 16 (2.1%) 0 (0.0%)

FIGURE 3. Percent change in inflammatory lesions from baseline to week 12 (ITT population, Study 1 and Study 2, LS Mean).



75



creases in these reports following treatment, peaking at week 2 (N=137, 18.1%; N=165, 21.7%; and N=114, 15.0%).

The severity of itching, burning and stinging was very low over the course of the studies (Figure 5). Mean scores for itching, burning and stinging at baseline (0.11, 0.02, and 0.02, respec-tively) increased slightly all peaking at week 2 (0.21, 0.29, and 0.20, respectively, where 1=mild) following tazarotene 0.045% lotion treatment, returning to below, or similar to baseline levels by week 12.

Reports of scaling (N=71, 9.1%) or erythema (N=207, 26.6%) were more common at baseline, although in most instances these were mild. Again, following treatment with tazarotene 0.045% lotion there were transient increases in mean scores,

vehicle; the majority (98.7%) were mild or moderate (Table 2). There were an equal number of SAEs with tazarotene 0.045% lotion and vehicle (N=4). Less than half of the tazarotene 0.045% lotion AEs were treatment-related AEs (88/209). Most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Only four subjects reported serious AEs (SAEs) following tazarotene 0.045% lotion treatment; none were treatment-related (abortion induced [2], abortion sponta-neous, suicidal ideation). There was no death reported in either study.

Cutaneous Safety and TolerabilityAt baseline, there were few reports of itching (N=75, 9.6%), burning (N=14, 1.8%), or stinging (N=13, 1.7%) in the tazarotene 0.045% lotion treatment groups. There were slight transient in-

FIGURE 4. Percent change in noninflammatory lesions from baseline to week 12 (ITT population, Study 1 and Study 2, LS Mean).

FIGURE 5. Cutaneous safety and tolerability assessment from baseline to week 12 (Safety population, pooled data).



76



from baseline (0.09 and 0.34) peaking at week 2 (0.38 and 0.41, respectively, where 1=mild), returning to below, or similar to baseline levels by week 12. Again, mean scores were low (where 1=mild) over the course of the studies.

Hyperpigmentation (N=145, 18.6%) was more commonly report-ed than hypopigmentation (N=26, 3.4%) at baseline. There were no increases in severity (mean scores) with treatment.

DISCUSSIONTopical retinoids provide the mainstay of acne treatment. While they have been shown to be very effective either as monothera-py or in combination, they are capable of producing cutaneous irritancy during the first few weeks of application. These side effects vary in severity and duration, appear to be compound and vehicle dependent, and can both limit treatment and reduce patient adherence. Studies suggest tazarotene 0.1% (gel, foam, or cream) may be the most effective retinoid, but its potential for cutaneous irritation is also the greatest. While tazarotene 0.1% foam may overcome some of the aesthetic disadvantages of gels and creams (they have been reported to leave a greasy, sticky residue and can be difficult to apply evenly16), no data are available on patient preferences and clinical benefits17 are simi-lar to those reported in other randomized, double-blind studies of tazarotene 0.1% cream2 and gel.18 Treatment-emergent AEs such as application site irritation (18% and 11%, study 1 and 2 respectively), dryness (6% and 8%), and erythema (9% and 4%) were still common, especially over the first four weeks treat-ment.

The rationale behind the novel formulation of tazarotene 0.045% lotion was to develop a topical treatment for moderate or severe acne; providing optimal efficacy and minimizing the tazarotene irritant effects in a light and aesthetically pleasing lotion for-mulation, where lotion is the preferred formulation for facial application. The formulation process utilized new polymeric emulsion technology to ensure uniform distribution of tazaro-tene and moisturizing ingredients onto the skin surface and efficient delivery into the epidermal layers. A comparative study of tazarotene 0.045% lotion and tazarotene 0.1% cream in mod-erate-to-severe acne reported numerically greater efficacy with tazarotene 0.045% lotion at 12 weeks despite half the concentra-tion of tazarotene and fewer treatment-related AEs.15

Following the promising phase 2 results, we further investigat-ed the safety and efficacy of tazarotene 0.045% lotion, reporting on two phase 3 clinical studies in moderate-to-severe acne in subjects 9 years and older. Treatment success was achieved in close to 30% of subjects by week 12; with significant reductions in both inflammatory and comedonal lesions, compared with vehicle (P<0.001). Tazarotene 0.045% lotion was also well-toler-ated. Most common treatment-related AEs were application site pain (5.3%), dryness (3.6%), and exfoliation (2.1%). Application

site reactions were less common than those reported previously with tazarotene 0.1% gel, cream or foam and may be as a result of formulation benefits as well as the lower concentration of taz-arotene. Overall cutaneous tolerability and safety scores were also low. There were slight transient increases peaking at week 2 with scores returning to below or similar to baseline levels by week 12.

CONCLUSIONSTazarotene 0.045% lotion utilizes new polymeric emulsion technology with moisturizing excipients to provide a topical treatment for moderate-to-severe acne that is effective and well-tolerated. With half the concentration of other marketed formulation (gel, foam, or cream) it appears to be at least as ef-fective and demonstrates a better safety and tolerability profile.

DISCLOSURESDrs Tanghetti, Werschler, and Lain are investigators and/or ad-visors to Ortho Dermatologics. Drs Guenin and Pillai and Ms Martin are employees of Bausch Health.

ACKNOWLEDGMENTSWe thank Brian Bulley, MSc (Konic Limited, UK) for assistance with the preparation of the manuscript. Valeant Pharmaceuti-cals, funded Konic’s activities pertaining to this manuscript.

REFERENCES1. Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory

acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther. 2005;27(2):216-224.

2. 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(11):1865-1873.

3. Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, double-blind, randomized, parallel-group study. Arch Dermatol. 2006;142(5):605-612

4. Draelos ZD, Tanghetti EA. Optimizing the use of tazarotene for the treat-ment of facial acne vulgaris through combination therapy. Cutis. 2002;69(2 Suppl):20-29.

5. Tanghetti E, Abramovits W, Solomon B, et al. Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a mul-ticenter, double-blind, randomized parallel-group trial. J Drugs Dermatol. 2006;5(3):256-261

6. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1 % gel versus once-daily tretinoin 0.1 % microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis. 2002;69(2 Suppl):12-19.

7. Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind,randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris. Cutis. 2002;69(2 Suppl):4-11.

8. 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(6 Suppl):4-9.

9. Leyden J, Lowe N, Kakita L, et al. Comparison of treatment of acne vul-garis with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis. 2001;67(6 Suppl):10-16.

10. 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(2):153-158.

11. Tanghetti E, 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 treat-



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ment of patients with at least moderate facial acne vulgaris. J Drugs Derma-tol. 2010;9(5):549-558.

12. Tanghetti E, Dhawan S, Green L, et al. Clinical evidence for the role of a topi-cal anti-inflammatory agent in comedonal acne: findings from a randomized study of dapsone gel 5% in combination with tazarotene cream 0.1% in patients with acne vulgaris. J Drugs Dermatol. 2011;10(7):783-792.

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. Del Rosso JQ, Tanghetti E. A status report on topical tazarotene in the man-agement of acne vulgaris. J Drugs Dermatol. 2013;12(3):S53-S58.

15. Tanghetti EA, Kircik LH, Green LJ, et al. 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 (Tazorac®) in the Treatment of Moderate-to-Severe Acne Vulgaris. J Drugs Dermatol. 2019 in press.

16. Zhao Y, Jones SA , Brown MB. Dynamic foams in topical drug delivery. J Pharm Pharmacol. 2010;62:678-684

17. 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.

18. Feldman SR, Werner CP, Alio Saenz, AB. The Efficacy and Tolerability of Taz-arotene 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.


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Tazarotene 0.045% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris in Adult Males

Fran E. Cook-Bolden MD,ª Michael H. Gold MD,B Eric Guenin PharmD PhD MPHc

ªMount Sinai Health System, New York, NYBTennnessee Clinical Research Center, Nashville, TN

cOrtho Dermatologics, Bridgewater, NJ

Background: There has been an increasing interest in gender differences both in the pathogenesis and treatment of acne vulgaris (acne). However, while acne prevalence among adolescents is comparable across sexes, acne is much more common in adult women than in adult men which has been largely ignored. Acne is likely less common in adult men because of the declining rate of sebum se-cretion observed with increasing age, and yet it can be more severe than in adult women. In addition, adherence to topical medications is especially poor in adult men where tactile and sensory perceptions are low. The first lotion formulation of tazarotene was developed using polymeric emulsion technology to provide an important alternative option to treat these acne patients, especially those who may be sensitive to the irritant effects of other tazarotene formulations. Objective: To evaluate the efficacy and safety of a new tazarotene 0.045% lotion formulation based on polymeric emulsion technology in treating adult male subjects with moderate or severe acne, in comparison with adolescent males treated with the same tazarotene 0.045% lotion.Methods: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies in moderate-or-severe acne. Subjects (aged 10 and older, N=1614) were randomized (1:1) to receive tazarotene 0.045% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory and noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator’s Global Severity Score [EGSS] and clear or almost clear). Quality of Life was assessed using the validated Acne-QoL scale. Safety, adverse events (AEs) were evaluated throughout; cutaneous tolerability (using a 4-point scale where 0=none and 3=severe) at each study visit.Results: A total of 268 male subjects (85≥18 years old and 183<18 years old) were treated with tazarotene 0.045% lotion once-daily for 12 weeks. At week 12, percent reductions in inflammatory and noninflammatory lesions with tazarotene 0.045% lotion were 62.3% and 59.5% in the adult male population, compared with 49.4% (P=0.001) and 49.5% (P=0.016) in the adolescent male population. Treatment success was achieved by 33.0% of adult male subjects treated with tazarotene 0.045% lotion, compared with 21.6% in the adolescent male population (P=0.059). Quality of life (as assessed by Acne-QoL domain scores) was better in adolescent males at baseline. Improvements in QoL domain scores were similar to those seen in the overall study population, with greater absolute change in domain scores in the adult males. Improvement in acne symptom scores was significantly greater in adult males (P=0.029). Tazaro-tene 0.045% lotion was well-tolerated. The number of subjects reporting any AE in the adult male population was 11 (13.6%) compared with 39 (21.4%) in the adolescent male population. There was only one (1.2%) treatment-related AE (application site pain) reported in the adult males compared with 11 (6.0%) in the adolescent males, where the most common treatment-related AEs were application site pain (3.3%), dryness (1.1%), and erythema (1.1%). Mean scores for hyper- and hypopigmentation were very low at baseline in both groups with no appreciable change with treatment.Conclusions: Tazarotene 0.045% lotion provides greater efficacy and better tolerability in adult males (above 18 years old) than the adolescent male population with moderate-to-severe acne patients.


ABSTRACT

INTRODUCTION

Although acne prevalence is comparable among ado-lescents of both genders,1 it is much more common in adult females than adult males.2,3 While there has been

increased interest in adult female acne,4 acne in adult males has largely been ignored and data specifically looking at their management sparse.

The mechanisms behind the development of acne lesions are multifactorial. Increased sebum production has been shown to play an important role,5,6 and it has been suggested that acne may be less common in adult males because of the declining rate of sebum secretion observed with increasing age.7 If acne pathogenesis in men is more dependent on sebum production, treatments that can reduce sebum such as retinoids may be beneficial.8-10

doi:10.36849/JDD.2020.3979



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F.E. Cook-Bolden, M.H. Gold, E. Guenin

METHODS Study Design and OversightTwo multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies to assess safety, tolerability, and efficacy of tazarotene 0.045% lotion in subjects with moder-ate or severe acne (with an Evaluator’s Global Severity Score [EGSS] of 3 [moderate] or 4 [severe]). Tazarotene 0.045% lotion or vehicle (randomized 1:1) was topically applied once-daily to the face (excluding mouth, eyes, inside the nose, and lips) for 12 weeks.

Subjects provided written informed consent before study-re-lated procedures were performed; protocol and consent were approved by institutional review boards (IRBs) or ethics com-mittees at all investigational sites. The studies were conducted in accordance with the principles of Good Clinical Practice (GCP) and Declaration of Helsinki.

Study PopulationApproximately 1600 subjects (800 in each study) were planned for enrollment. The initial topical applications were made at the investigational center. Subsequently, subjects were asked to apply their daily treatment in the evening at home. They were permitted to use only approved cleansers, moisturizers, and sunscreens, and noncomedogenic makeup and shaving prod-ucts. The post hoc analysis was in adult (≥18 years of age) and adolescent (<18 years) male subjects with moderate or severe acne.

Key inclusion criteria included subjects with moderate (EGSS=3) or severe (EGSS=4) acne. Specifically, subjects had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones) and two or less facial nodules. Mandatory washout periods and restrictions applied to subjects who had used previous prescrip-tion of over-the-counter acne treatments: topical astringents and abrasives (1 week); topical anti-acne products, including soaps containing antimicrobials, and known comedogenic products (2 weeks); topical retinoids, retinol, and systemic acne treatments, such as hormonal or antibiotic treatments (4 weeks); and sys-temic retinoids (6 months).

Efficacy assessments were carried out at screening, baseline, weeks 4, 8, and 12 (end of treatment). The EGSS was determined prior to performing lesion counts. Subjects also completed a validated Acne-Specific Quality of Life (Acne-QoL) question-naire that asked questions pertaining to their QoL as it related to their facial acne, at baseline and week 12. Adverse events (AEs) were recorded throughout the study and cutaneous tolerability at weeks 2, 4, 8, and 12.

Other gender differences may be important. Women with acne were significantly more embarrassed than their male counter-parts about their skin disease and sought medical care more frequently. Also, the psychological impact caused by the pres-ence of acne seems to affect more female patients than male patients.11 In addition, adherence to medication can play an important role in acne treatment; male patients being less com-pliant than females,12 with side effects being the main reason for non-adherence, especially in older patients. The poor adher-ence of males to topical medications may also be due to their limited experience with using topical products generally.

There are no clinical studies that have specifically looked at the treatment of acne in the adult male population. There are a few studies that have reported post hoc analyses of gender as a clinically relevant outcome variable.13-16 Only one study has pre-sented data specifically on adult males.16 A study with dapsone 5% gel in moderate acne suggested that females experienced a significantly greater reduction in acne lesions compared to male acne patients after 12 weeks treatment.13 The data were not analysed to look at age differences. A post hoc analysis re-ported at the same time with clindamycin phosphate 1.2%/BP 2.5% gel also looked at gender differences, as well as stratify-ing by age.16 The net reduction in lesion counts (active minus vehicle) was much greater in the adolescent population; and treatment success (at least a 2-grade improvement in acne severity) favored adult males and adolescent females. A sub-sequent study with clindamycin phosphate 1.2%/BP 3.75% gel appeared to demonstrate greater efficacy in females, but the data were only stratified by age for the females.15 One study, with adapalene 0.3% /benzoyl peroxide 2.5% gel reported com-parable efficacy by gender and by age.11 No specific data on adult males was presented.

Topical retinoids have played an important role in the manage-ment of acne, supported by extensive clinical data. Tazarotene has generally been considered to be the most effective, but the less well tolerated.17-26 Recently, data on a novel formulation of tazarotene have been published.27 Tazarotene 0.045% lotion uti-lizes polymeric emulsion technology to provide more efficient delivery into the dermal layers, and less irritancy on application to the skin. Tazarotene 0.045% lotion was significantly more ef-fective than vehicle in reducing lesion counts, and comparable to tazarotene 0.1% cream despite the two-fold difference in tazarotene concentrations. Tazarotene 0.045% lotion was also better tolerated.

Here we present a post hoc analysis of the two phase 3 studies looking at the efficacy of tazarotene in adult males with moder-ate or severe acne and comparing the data to the adolescent male population.



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postscreening study visits. Subjects were asked to provide an average evaluation of each parameter over the period since the previous study visit using a 4-point scale, where 0=none and 3=severe.

Vital sign measurements were recorded, blood samples col-lected, and an abbreviated physical examination performed at baseline and week 12. A medical history was taken at screening, and confirmed and revised at baseline, if necessary.

RESULTSSubject DispositionOverall, 550 male subjects were randomized to tazarotene 0.045% lotion (N=268) or vehicle lotion (N=282) and included in the ITT population. In the two studies, there were 186 adult males (≥18 years old) and 364 adolescent males (>18 years old).

Demographics and Baseline CharacteristicsComparing the two male subject populations treated with taz-arotene 0.045% lotion, there were a few differences between the two groups (Table 1). There were more Caucasian adolescent

Statistical and Analytical PlanThe intent-to-treat (ITT) population comprised all subjects ran-domized and provided with study drug. The safety population comprised all randomized subjects who were presumed to have used the study medication or vehicle at least once and who had at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov Chain Monte Carlo multiple im-putation method. For analyses of the changes from baseline in noninflammatory and inflammatory lesion counts in both pivotal phase 3 studies, significant skewness was observed, and a nonparametric method used in which the changes in le-sion counts were rank-transformed prior to being submitted to the ANCOVA. Values were adjusted for multiple imputations. Significance of EGSS reductions were obtained from logistic regression (using Firth’s Penalized Likelihood) with factors of treatment group and analysis center. Values were adjusted for multiple imputations. Descriptive statistics were used to sum-marize the results of the Acne-QoL questionnaire. In subjects who discontinued treatment before week 12 or missed visits between baseline and final evaluation, the last observation was carried forward. 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. All AEs occurring during the studies were recorded and classified on the basis of medical dictionary for drug regulatory activities terminology (MedDRA) for the safety population.

Study AssessmentEfficacy Co-primary endpoints were EGSS and absolute reduction in inflammatory lesion and noninflammatory lesion counts. Sub-jects who had at least a 2-grade reduction from baseline EGSS at week 12, and an EGSS of ‘clear’ or ‘almost clear’ were con-sidered a treatment success. Additional assessments included percent change in inflammatory and noninflammatory lesion counts from baseline at each study visit, percent of subjects who achieved treatment success, and absolute change in Acne-QoL domain scores.

Safety Safety evaluations, including AEs, cutaneous safety evaluations and tolerability, vital signs, laboratory evaluations, and physi-cal examinations were performed; information on reported and observed AEs obtained at each visit, cutaneous safety and toler-ability at each study visit.

Cutaneous safety (individual assessments of scaling, erythema, hypopigmentation, and hyperpigmentation at the drug ap-plication site) was reported by the investigator/evaluator at all postscreening study visits using a 4-point scale, where 0=none and 3=severe. Tolerability (individual assessments of itch-ing, burning, and stinging) was reported by the subjects at all

TABLE 1.

Demographics and Baseline Characteristics (ITT Population Adult [≥18 years old] and Adolescent [<18 years old] Males, Pooled Data, Subjects Treated With Tazarotene 0.045% Lotion)

Adult Males (≥18 years)

(N=85)

Adolescent Males

(<18 years)(N=183)

Total(N=268)

Age (years), mean (SD) 22.9 (5.76) 15.1 (1.46) 17.6 (4.99)

Range 18-44 10-17 10-44

Ethnicity (N/%)

Hispanic 28 (32.9%) 28 (15.3%) 56 (20.9%)

Non-Hispanic 57 (67.1%) 155 (84.7%) 212 (79.1%)

Race (N/%)

American Indian or Alaska Native

1 (1.2%) 1 (0.5%) 2 (0.7%)

Asian 12 (14.1%) 6 (3.3%) 18 (6.7%)

Black or African Ameri-can

14 (16.5%) 11 (6.0%) 25 (9.3%)

Native Hawaiian or Other Pacific Islander

0 (0.0%) 0 (0.0%) 0 (0.0%)

White 54 (63.5%) 155 (84.7%) 209 (78.0%)

Other/Multiple 4 (4.7%) 10 (5.5%) 14 (5.2%)

Inflammatory Lesion Count (mean [SD])

30.8 (7.40) 29.3 (7.78) 29.8 (7.68)

Noninflammatory Lesion Count (mean [SD])

39.8 (15.12) 45.5 (18.91) 43.7 (17.97)

Evaluator Global Severity Score (EGSS), N/%

3=Moderate 74 (87.1%) 162 (88.5%) 236 (88.1%)

4=Severe 11 (12.9%) 21 (11.5%) 32 (11.9%)



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males (84.7% versus 63.5%) and the mean baseline noninflam-matory lesion count was a little higher than that noted in the adult males (45.5 versus 39.8), although the proportion of sub-jects classified as severe (EGSS=4) was slightly lower in the adolescent male population (11.5% versus 12.9%). In the overall study populations, efficacy of tazarotene 0.045% lotion in Cau-casian or Black subjects was similar, so it is unlikely that these differences would have influenced efficacy in the two male pop-ulations.

Efficacy EvaluationEvaluator’s Global Severity Score (EGSS) Significantly more adult male subjects achieved at least a 2-grade

improvement in EGSS with tazarotene 0.045% lotion compared with adolescent male subjects at week 12 (42.1% versus 24.6%, P=0.006); see Figure 1. Differences were significant from week 8. In addition, 33.0% of adult males were considered ‘treatment successes’ (defined as at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’) compared with 21.6% of adolescent subjects treated with tazarotene 0.045% lotion (P=0.059).

Lesion CountsTazarotene 0.045% lotion was more effective in achieving an absolute reduction in lesion counts in adult males. At week 12, the absolute reduction in inflammatory and noninflammatory lesion count relative to baseline for the adult male group was

FIGURE 1. Treatment success. Patients with at least a 2-grade improvement at each study visit (ITT population pooled data). Adult male subjects (≥18 years old) and adolescent males (<18 years old) treated with tazarotene 0.045% lotion.

FIGURE 2. Percent change in inflammatory lesions from baseline to week 12 (ITT population, pooled data, LS mean). Adult male subjects (≥18 years old) and adolescent male subjects (<18 years old) treated with tazarotene 0.045% lotion.



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19.1 and 24.2, compared with 14.4 and 21.5, respectively, in the adolescent males.

By week 12, in the adult males there was a 62.3% and 59.5% change in inflammatory and noninflammatory lesion counts from baseline (LS mean) with tazarotene 0.045% lotion, compared with 49.4% (P=0.001) and 49.5% (P=0.016) in the ado-lescent males (Figures 2 and 3). Efficacy differences between the adult and adolescent males were significant from week 4.

Acne-Specific QoL At baseline, the mean scores for Self-Perception, Role-Emo-tional, Role-Social, and Acne Symptoms in those subjects subsequently treated with tazarotene 0.045% lotion were high-er (ie, better QoL) in the adolescent males: 27.2, 27.0, 23.8, and 22.5 compared with 20.1, 21.3, 18.1, and 19.2, respectively, in the adult males. By week 12 the absolute change from base-line in Self-Perception, Role-Emotional, Role-Social and Acne Symptom domains were 3.0, 1.7, 1.8, and 3.9, respectively, in

FIGURE 3. Percent change in noninflammatory lesions from baseline to week 12 (ITT population, pooled data, LS mean). Adult male subjects (≥18 years old) and adolescent male subjects (<18 years old) treated with tazarotene 0.045% lotion.

FIGURE 4. Absolute change from baseline in Acne-QoL domain scores by age (ITT population, pooled data). Adult male subjects (≥18 years old) and adolescent males (<18 years old) treated with tazarotene 0.045% lotion.



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the adolescent males were much lower than those seen in the adult male population (7.3, 5.8, 5.7, and 7.6) treated with tazaro-tene 0.045% lotion (Figure 4). Only the change in acne symptom score was statistically significant (P=0.029).

FIGURE 5. Cutaneous safety and tolerability assessment from baseline to week 12 (safety population, pooled data). Adult male subjects (≥18 years old) and adolescent male subjects (<18 years old) treated with tazarotene 0.045% lotion. Adult males in sold lines and adolescent males in dotted lines.

TABLE 2.

Treatment-Emergent Adverse Event (AE) Characteristics through Week 12 (Safety population, pooled data) Adult male subjects (≥18 years old) and Adolescent Male Subjects (<18 years old) Treated With Tazarotene 0.045% Lotion.

Adult Males (N=81)

Adolescent Males

(N=182)

Subjects reporting and AE 11 (13.6%) 39 (21.4%)

Subjects reporting any SAE 0 (0.0%) 1 (0.5%)

Subjects who prematurely discontinued study/drug due to AE

1 (1.2%) 2 (1.1%)

Severity of AE

Severe 0 (0.0%) 2 (1.1%)

Moderate 4 (4.9%) 11 (6.0%)

Mild 7 (8.6%) 26 (14.3%)

Strongest relationship to study drug

Related 1 (1.2%) 11 (6.0%)

Not Related 10 (12.3%) 28 (15.4%)

Treatment Related AEs

Application site pain 1 (1.2%) 6 (3.3%)

Application site dryness 0 (0.0%) 2 (1.1%)

Application site erythema 0 (0.0%) 2 (1.1%)

Application site dermatitis 0 (0.0%) 1 (0.5%)

Application site exfoliation 0 (0.0%) 1 (0.5%)

Application site pruritus 0 (0.0%) 1 (0.5%)

Safety EvaluationOverall, 13.6% (N=11) of adult male subjects and 21.4% (N=39) adolescent male subjects treated with tazarotene 0.045% lotion reported AEs (Table 2). The majority were mild and there were no severe or serious AEs reported in the adult male popula-tion. There was one serious AE reported in the adolescent male population. Only one AE (1.2%) with tazarotene 0.045% lotion in adult males was considered treatment-related AEs (application site pain), compared with 11 (8.0%) in the adolescent males.

Cutaneous Safety and TolerabilityThere were slight transient increases in mean severity scores for scaling (from week 2 in both groups) and erythema (from week 2 in the adolescent males). Over the 12-week treatment period, no score was greater than 0.4 (where 1=mild), with similar se-verity at the end of the study compared with baseline (Figure 5).Hyper- and hypopigmentation was rare at baseline, and through-out the study period.

DISCUSSIONAcne is a very common skin disorder that is predominantly seen in adolescence. However, data suggest that the preva-lence in adults is increasing, especially in females.2 While the prevalence of adolescent acne is similar between genders, post-adolescent acne appears to affect more women than men, with a prevalence of three percent in men and 12% in women in a population of randomly selected individuals with similar demo-graphic characteristics.2 Although there has been a significant increase in interest in adult female acne as a result, data on the treatment of adult males with moderate or severe disease re-mains sparse.

A post hoc analysis on the treatment of moderate-to-severe acne with the fixed combination clindamycin (1.2%)/benzoyl peroxide



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(2.5%) gel provided data in adult (≥18 years old) and adolescent (<18 years old) males.16 Reduction in inflammatory (56.7%) and noninflammatory (44.0%) lesion counts at week 12 was great-er in the adult males; but the differences between adult and adolescent males were not significant (P=0.308 and P=0.761). Treatment success was also greater in the adult males (32.6% versus 23.0%), however again differences were not significant (P=0.089). In our analysis we were able to show greater efficacy of tazarotene 0.045% lotion in adult males, whereby changes in both lesion counts and achievement of treatment success were statistically significant compared to adolescent males. The effi-cacy of tazarotene 0.045% lotion in adult males was also greater than that reported in the overall study populations.28

The psychological impact caused by the presence of acne seems to affect more female patients than male patients.11 In our study, QoL at baseline was much better in the adolescent males compared with the adult males. As a result, absolute increases in mean domain scores following treatment with tazarotene 0.045% lotion were greatest in adult males, however only in terms of acne symptoms was the difference significant in favor of the adult males.

Evidence-based guidelines for acne have shown retinoids to have an essential role in the management of acne.17,29 Limita-tions to their widespread use have included a perception of poor efficacy in inflammatory lesions and cutaneous irritation.29 Our data show tazarotene 0.045% lotion to have a comparable effect on both inflammatory and comedonal lesions, confirming other clinical data that have shown retinoids to both reduce visible le-sions and inhibit the development of microcomedones and new lesions.30-32

Local skin reactions, such as erythema, scaling, dryness, burn-ing, and stinging are well-known with retinoids. In adult males treated with tazarotene 0.045% lotion, there was a transient in-crease in mean scaling and burning scores at week 2, otherwise cutaneous tolerability was similar to that reported at baseline. Treatment-related AEs with tazarotene 0.045% lotion were rare, with only one report of application site pain. In contrast, AEs in the adolescent male population were similar to those reported in the overall study population.

A common complication of acne is residual postinflammatory hyperpigmentation (PIH), which causes further psychological and social distress in affected patients. Tazarotene has also been shown to significantly decrease post-inflammatory hyperpig-mentation (PIH) and be more effective than other retinoids.33,34 In our study, PIH was relatively rare both at baseline and through-out treatment, perhaps in part due to the high proportion of Caucasian male subjects enrolled (78%), with no increase in mean scores over the 12-week treatment period. A longer-term study in subjects more prone to PIH is warranted.

CONCLUSIONSTazarotene 0.045% lotion is more effective and better tolerated in adult male acne than in adolescent males, with better results than those reported in the overall study populations.

DISCLOSURESDr Cook-Bolden and Dr Gold are advisors and/or investigators with Ortho Dermatologics. Dr Guenin is an employee of Bausch Health.

ACKNOWLEDGMENTSWe thank Brian Bulley, MSc (Konic Limited, UK) for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

REFERENCES1. Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about

acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol. 2001;145:274-279.

2. Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol. 1997;136(1):66–70.

3. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58(1):56-59.

4. Zeichner JA, Baldwin HE, Cook-Bolden FE, et al. Emerging issues in adult female acne. J Clin Aesthet Dermatol. 2017;10(1):37-46.

5. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol. 2004; 22:360–366.

6. Janicek-Dolphin N, Cook J, Thiboutot D, et al. Can sebum reduction predict acne outcome? Br J Dermatol. 2010;163:683-688.

7. Jacobsen E, Billings JK, Frantz RA, et al. Age-related changes in seba-ceous wax ester secretion rates in men and women. J Invest Dermatol. 1985;85:483-485.

8. Gollnick H, Cunliffe W, Berson D, et al. Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(suppl 1):S1-S37.

9. Roh M, Han M, kim D, et al. Sebum output as a factor contributing to the size of facial pores. Br J Dermatol. 2006;155:890–894.

10. Baron JM, Heise R, Blaner W, et al. retinoic acid and its 4-oxo metabo-lites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005;125:143–153.

11. Dumont-Wallon G, Dréno B. Acné de la femme de plus de 25 ans: spécifique par sa clinique et les facteurs favorisants [Specificity of acne in women older than 25 years] Presse Med. 2008;37(4):585–591.

12. Jones-Caballero M, Pedrosa E, Penas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309-314.

13. Tanghetti EA, Harper J, Baldwin HE, et al. Once-Daily Topical Dapsone Gel, 7.5%: Effective for Acne Vulgaris Regardless of Baseline Lesion Count, With Superior Efficacy in Females. J Drugs Dermatol. 2018;17(11):1192-1198.

14. Gold LS, Werschler WP, Mohawk J. Adapalene/Benzoyl Peroxide Gel 0.3%/2.5%: Effective Acne Therapy Regardless of Age or Gender. J Drugs Dermatol. 2017;16(6):582-589.

15. Harper JC. The efficacy and tolerability of a fixed combination clindamycin (1.2%) and benzoyl peroxide (3.75%) aqueous gel in patients with facial acne vulgaris: gender as a clinically relevant outcome variable. J Drugs Dermatol. 2015;14(4):381-384.

16. Harper JC. Gender as a clinically relevant outcome variable in acne: benefits of a fixed combination clindamycin phosphate (1.2%) and benzoyl peroxide (2.5%) aqueous gel. J Drugs Dermatol. 2012;11(12):1440-1445.

17. 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.

18. 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.

19. 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.

20. 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.



85



21. 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.

22. 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.

23. 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.

24. 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

25. 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.

26. 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):49-558.

27. Kerdel FA, Draelos ZD, Tyring SK, et al. A phase 2, multicenter, double-blind, randomized, vehicle-controlled clinical study to compare the safety and ef-ficacy of a halobetasol propionate 0.01% lotion and halobetasol propionate 0.05% cream in the treatment of plaque psoriasis. J Dermatolog Treat. 2019;30(4):333-339.


Fran E. Cook-Bolden MDE-mail:................……................... [email protected]

Written for Physicians by Physicians.

@JDDonline

28. Tanghetti AE, Werschler WP, Lain T, et al. Tazarotene 0.045% Lotion for Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Results from two Phase 3 Trials. J Drugs Dermatol. 2019; in press.

29. Leyden J, Gold LS, Weiss J. Why topical retinoids are the mainstay of thera-py for acne. Dermatol Ther. 2017;7(3):293-304.

30. 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.

31. 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.

32. 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.

33. Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmen-tation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45–50.

34. Tanghetti E, 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 treat-ment of patients with at least moderate facial acne vulgaris. J Drugs Derma-tol. 2010;9:549–558.




Copyright © 2020 CASE REPORT Journal of Drugs in Dermatology

SPECIAL TOPIC

Psoriasis is a chronic, inflammatory, remitting/relapsing autoimmune condition involving a dysregulated inflammatory response of the interleukin (IL) 23/T-helper (Th)-17 pathway. Greater understanding of the immune-mediated pathology of the disease has led to the development of numerous biological therapies and biosimilars that target the various inflammatory pathways. Each biologic has a unique mechanism of action, pharmacodynamics, and pharmacokinetics resulting in different clinical efficacy and tolerability. This case describes a 64-year-old female with a nine-year history of plaque psoriasis, predominantly affecting her feet, who was successfully treated with brodalumab having previously failed multiple topical and systemic therapies including six other biologicals.

To date, there are few guidelines to help physicians select the optimal biology agent and none that have looked specifically at plantar psoriasis. For this patient, finding a biologic that worked and was tolerable was a process of trial and error that took four years. The results achieved in this previously refractory patient with difficult-to-treat psoriasis may be due to the unique mechanism of action of brodalumab, though this will need to be confirmed in larger studies.


ABSTRACT

INTRODUCTION

Psoriasis is a T-cell meditated disease involving a dysregu-lated IL-23/Th-17 inflammatory response. With greater understanding of the pathogenesis of the disease, bio-

logic agents that target specific cytokines have been developed. To date, 10 monoclonal antibody drugs and 6 biosimilars that target 3 main pathways: tumor necrosis factor α, IL-23, and IL-17 have been approved for the treatment of plaque psoriasis.1 While most of these biologics demonstrate similar efficacy in clinical trials, patient response in real-world settings is unpre-dictable and highly variable.2

Psoriasis involving the hands and feet affects only about 30% of patients with plaque psoriasis but is a uniquely problemat-ic form of the disease.3 Although the total body surface area (BSA) may be small, the impact of hand or foot psoriasis on a patients' quality of life can be significant. The location of the lesions often prevents patients from participating in activities of daily living. Patients with hand and foot involvement are af-fected to a greater degree by physical aspects of the disease, such as pain, discomfort, cracking, and bleeding of the skin.4 Furthermore, as this case demonstrates, hand and foot psoria-sis is difficult to treat and often refractory to multiple therapies. The toll that hand and foot involvement can take on a patient physically, psychosocially, and even economically requires that the bar for treatment success be raised when treating this spe-cific subpopulation.

CASEA 64-year-old Caucasian female was first seen in our office in October 2014 for evaluation of bilateral plantar psoriasis. Other than psoriasis for the past five years, she had no past medical or surgical history, no known allergies, and was a former smoker.Prior psoriasis treatments included calcipotriene cream, fluci-nonide cream, calcipotriene and betamethasone dipropionate (Taclonex®, Leo Pharma) topical suspension 0.005%/ 0.064%, Tazarotene (Tazorac®) cream, clobetasol propionate cream and lotion, methotrexate 20 mg once a week for a total life time dose of 1120 mg, adalimumab (Humira®, Abbvie) 40 mg subcutane-ous every other week, and flurandrenolide tape.

At her initial consult, inspection of both feet revealed ery-thematous plaques with thick adherent silvery scale (Figure 1).

Inspection of skin outside of affected area showed no abnor-malities. The patient was being treated with subcutaneous ustekinumab (Stelara®, Janssen) injections every 12 weeks and advised to perform twice weekly bleach water soaks to decrease

Rapid and Sustained Improvement in a Patient With Plaque Psoriasis Switched to Brodalumab After Failing Treatment

Clearance on Six Other Biologic Therapies Kathleen Haycraft DNP, Linda Cooke MD

ªRiverside Dermatology, Hannibal, MO

FIGURE 1. Plantar plaque psoriasis initial consult.

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K. Haycraft, L. Cooke

process to switch her from guselkumab to brodalumab (Siliq®, Ortho Dermatologics). Brodalumab injections were started in March 2018 and she was seen for follow-up in August at which time her plantar psoriasis showed significant improvement. The patient indicated that her psoriasis was the best it had been in years, despite increased emotional stress due to the sudden death of her husband. On examination both feet showed im-proving, erythematous plaque with thick adherent silvery scale with decreased cracking of the plantar foot. Inspection of skin outside of affected area revealed no abnormalities (Figure 2).

At the time of writing, the patient has been on brodalumab 210 mg subcutaneous injections every other week for 15 months and her condition continues to improve. We will follow her ev-ery three months.

DISCUSSIONDifficult-to-treat areas of plaque psoriasis, such as the palms and feet, may not respond well to traditional treatment algo-rithms and may be associated with disproportionately high physical and psychosocial burdens.5-7 Additionally, the manage-ment of patients with recalcitrant disease is a challenge for even the most experienced dermatologists. While the availability of biologic medications for psoriasis has reduced the challenge considerably, as this case shows, they have not eliminated it.

And although emerging evidence from head-to-head random-ized clinical trials provides pertinent information regarding the safety and efficacy of biologic agents in the treatment of moderate-to-severe psoriasis, and clues as to which agents may work best for patients with certain disease related factors and comorbid conditions, this case underscores the importance of providing personalized therapy for each patient based on indi-vidual clinical outcomes and tolerance of specific treatments.

To date, there are few guidelines to help physicians select the optimal biology agent for their patient and none that have looked specifically at plantar psoriasis. For this patient, finding a biologic that proved to have both efficacy and safety was a process of trial and error that took four years. Prior to starting treatment with brodalumab, the patient had previously tried and failed treatment clearance with adalimumab, apremilast, gusel-

infection risk. Over time, the duration of efficacy of ustekinum-ab waned and the patient began to experience flare ups in her feet between injections and the development of new psoriasis plaques on her hands and elbows, despite doubling the dose, and decreasing the injection interval to 10 weeks. In July 2015, apremilast (Otezla®, Celgene) 30 mg twice daily was added to her treatment regimen. At 3-month follow-up, although there was improvement in her feet and right palm, she had developed new erythematous plaque with thick adherent silvery scale on her right and left elbows and right and left legs. Despite ongoing treatment with ustekinumab and apreminlast, she continued to have intermittent flares and was advised to apply calcipotriene and betamethasone dipropionate (Enstilar®, Leo Pharma) foam, 0.005%/0.064% twice daily when flared.

In March 2016, she developed culture proven methicillin-resis-tant staphylococcus aureus (MRSA) on both feet which was treated with doxycycline.

In May 2016, she was switched from ustekinumab to secukinum-ab (Cosentyx®, Novartis) 300 mg subcutaneous injections weekly for 5 weeks and then every 4 weeks and advised to use UVB at least twice weekly. Apremilast was discontinued as patient did not feel it was helping. At this time, she was also diagnosed with psoriasiform dermatitis on the right lower leg and was com-plaining of flaring, tingling in her feet and pain when walking.

In June 2016, she developed another persistent MRSA infection in her feet, which was treated with multiple 30-day courses of doxycycline. In July, she was switched from secukinumab to ix-ekizumab (Taltz®, Lilly) due to constant flaring and increased foot itch and pain. She returned for follow-up after three ixekizumab injections, complaining of worsening symptoms and foot pain. Inspection of left lower leg, right lower leg, right plantar foot, and left plantar foot showed deep, seated vesicles with overly-ing erythematic, fissures, scaling, and honey crusting.

In June 2017, apremilast was added to ixekizumab due to con-tinued worsening symptoms and the patient was advised to use betamethasone cream and flurandrenolide tape daily. At two-month follow-up, the patient stated that she had seen minimal improvement since adding apremilast and that she did not like ixekizumab injections because they caused "stabbing pain, red-ness, and a baseball-size knot at the injection site."

Both biologics were discontinued, and she was started on gusel-kumab (Tremfya®, Janssen). At 1 and 3-month follow-up of the first injection, the patient stated that her symptoms were no bet-ter and that her feet hurt continuously, and that she would flare five days before injections became due.

In February 2018, she presented in our office with severe foot pain and a recurrence of culture proven MRSA, which was treated with bleach baths and doxycycline and we initiated the

FIGURE 2. After treatment with brodalumab



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K. Haycraft, L. Cooke

Given that brodalumab is the only licensed agent that can block IL-17 C and F, this may also account for the clinical improve-ments seen in this patient.

The results observed in this single patient need to be confirmed in larger Phase 4 studies of recalcitrant patients.

DISCLOSURESKathleen Haycraft has participated in Advisory Boards for Pfizer, Lilly, Celgene, Abbvie, Valeant, Sanofi Aventis/ Regeneron, Maui Dermatology Conferences, and Johnson and Johnson; addi-tionally, she has received Consultancy Payments from Bausch Health.

Dr. Cooke has no relevant disclosures or conflicts of interest.

REFERENCES1. von Csiky-Sessoms S, Lebwohl M. What's New in Psoriasis. Dermatol Clin.

2019;37(2):129-136.2. Amin M, No DJ, Egeberg A et al. Choosing First-Line Biologic Treatment for

Moderate-to-Severe Psoriasis: What Does the Evidence Say? Am J Clin Der-matol. 2018;19:1-13.

3. Fretzin S, Crowley J, Jones L, Young, M, Sobell, J. Successful treatment of hand and foot psoriasis with efalizumab therapy. J Drugs Dermatol. 2006;5(9):838-846.

4. Pettey AA, Balkrishnan R, Rapp SR, Fleischer AB, Feldman SR. Patients with palmoplantar psoriasis have more physical disability and discomfort than pa-tients with other forms of psoriasis: Implications for clinical practice. J Am Acad Dermatol. 2003;49(2):271-275.

5. Menter A, Griffiths CE. Current and future management of psoriasis. Lancet. 2007;370(9583):272.

6. Pettey A.A, Balkrishnan R, Rapp SR, Fleischer AB, Feldman SR. Patients with palmoplantar psoriasis have more physical disability and discomfort than pa-tients with other forms of psoriasis: Implications for clinical practice. J Am Acad Dermatol. 2003;49(2):271-275.

7. Rapp SR, Exum ML, Reboussin DM, Feldman SR, Fleischer A, Clark A. The physical, psychological and social impact of psoriasis. Journal of Health Psy-chology. 1997;2(4):525-537.

8. Ixekizumab injection Prescribing Information. Eli Lilly and Company, India-napolis, IN. April 2018.

9. Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L et al. Charac-terization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160(2):319-324.

10. Soderstrom C, Berstein G, Zhang W, Valdez H, Fitz L, et al. Ultra-sensitive measurement of IL-17A and IL-17F in psoriasis patient serum and skin. AAPS J. 2017;19(4):1218-22.

11. Park YA, Kim YH, Sol IS, Yoon SH, Hong JY et al. Relationship between serum interleukin-17F level and severity of atopic dermatitis in children. Pediatr Al-lergy Immunol Pulmonol. 2015;28(2):112-6.

12. Johansen C, Vinter H, Soegaard-Madsen L, Olsen LR, Steiniche T, et al. Pref-erential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFalpha therapy. Br J Dermatol. 2010;163(6):1194-1204.

13. Johnston A, Fritz Y, Dawes SM, Diaconu D, Al-Attar PM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immu-nol. 2013;190(5):2252–62.

kumab, ixekizumab, secukinumab, and ustekinumab.

Additionally, she had experienced severe injection site reactions to ixelizumab. This is consistent with the adverse events report-ed in the plaque psoriasis pivotal clinical trials through week 12. According to the ixekizumab prescribing information,8 injection site reactions occurred in 17% of patients and were the most frequently reported adverse event. The worsening symptoms our patient experienced while on ixekizumab could have been due to immunogenicity. Data from clinical studies showed that 22% of subjects, treated at the recommended dosing regimen developed antibodies to ixekizumab during a 60-week treatment period, which was associated with reduced clinical response and 10% of these were classified as neutralizing antibodies which was associated with loss of efficacy.8

Could immunogenicity have been the problem with other agents and could immunotolerance to brodalumab be the rea-son why is she responding to one biologic when so many others failed? We may never know with absolute certainty, but in the meantime, we speculate that it could also be due to differences in the mechanism of action of these agents.

In psoriatic skin, immune triggers activate a signaling cascade. At the beginning of the cascade, dendritic cells create the in-flammatory cytokines IL-12and IL-23. IL-12 activates Th1 cells, while IL-23 activates Th17 cells. Th1 has long been linked with immunological conditions, but the Th17 pathway has only re-cently been identified as one of the key culprits in psoriasis; since it’s a source of IL-17 cytokines, including IL-17A. Further downstream, on the surface of the keratinocyte, these cytokines bind to, and activate, signaling through the IL-17 receptor. IL-17 receptor activation results in the release of pro-inflammatory factors and additional IL-17 cytokines driving further inflamma-tory processes in the skin.

Several of the biologics approved for plaque psoriasis inhibit upstream cytokines such as TNF-α, IL-12, and IL-23, which can re-duce production of IL-17 cytokines. Other biologics inhibit IL-17 downstream, by essentially gathering up cytokines and slowing the process before they bind with the receptor, whereas broda-lumab is the only biologic that blocks the signaling of the IL-17 Receptor A (IL-17RA), thus inhibiting further downstream pro-inflammatory effects. Doing so affects several IL-17 cytokines including IL17A, IL-17F, IL-17C, IL-17A/F, and IL-25, interfering with transmission of the pro-inflammatory signs that lead to psoriasis.

Studies have shown that IL-17F contributes to skin manifesta-tions and comorbidities of psoriasis in a tissue-specific fashion and is increased in both psoriatic lesional skin and the sera of psoriatic patients.9-11 IL-17C has been linked to skin inflammation and is also over-expressed in lesional skin of psoriatic pa-tients.12-13 In murine models, IL-17C injections leads to epidermal thickening and psoriasiform dermatitis.


Kathleen Haycraft DNPE-mail:................……...................... [email protected]




Copyright © 2020 BRIEF COMMUNICATION Journal of Drugs in Dermatology

SPECIAL TOPIC

Clinical Characteristics and Disease Course in Black Patients With Lymphomatoid Papulosis: A Case Series

Shamir Geller MD,a,b Sarah J. Noor MD,ª Patricia L. Myskowski MDa

ªDermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medicine, New York, NYBDepartment of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Introduction: Lymphomatoid papulosis (LyP) is a CD30+ T-cell lymphoproliferative disorder (LPD) presenting as a recurrent eruption of papules and nodules which resolve spontaneously. CD30+ LPD prevalence in African American (AA)/Black patients is lower compared to White patients. CD30+ LPD has been recently reported to have worse outcomes in AA patients compared to White patients.

Methods: A retrospective chart review identified eight AA patients with LyP. We describe our experience with these eight patients and review the literature on similar cases.

Results: In half of the eight included patients, lesions occurred 1-4 years before they were diagnosed. In six patients (75%), resolution of the lesions resulted in hyperpigmented macules and scars. Five patients (63%) had also mycosis fungoides. Most of the patients who were followed (4/7, 57%) did not have complete resolution at their last visit, despite different treatment approaches.

Discussion: Our results highlight that although LyP has an indolent course in AA/Black patients, residual hyperpigmentation and scars frequently occur, highlighting the need for better treatments of this lymphoproliferative disorder in this specific population.


ABSTRACT

INTRODUCTION

Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) comprise a dis-ease spectrum known as primary cutaneous CD30+ T-cell

lymphoproliferative disorders (CD30+ LPD).1 CD30+ LPD is the second most common group of cutaneous T-cell lymphomas (CTCL) after mycosis fungoides (MF) and is regarded as an in-dolent lymphoproliferative disorder1 LyP typically manifests clinically as a recurrent eruption of papules and nodules with variable central ulceration, scale or crust that resolve spontane-ously within several weeks and may result in hyperpigmenta-tion, hypopigmentation, and scarring. LyP histology is usually characterized by wedge-shaped cellular infiltrate that contains atypical large CD30+ lymphocytes.1 LyP is uncommon in Black patients and have been described in a few case reports.2 Analy-sis of two separate collaborative cancer databases in the united states showed that CD30+ LPD is mainly diagnosed in Cauca-sian patients and only rarely in African American (AA)/Black patients. AA/Blacks comprised only 7%-8%3,4 and 10%5 of all CD30+ LPD patients included in these two large databases. A re-cent study of prognostic factors in CD30+ LPD patients with an emphasis on outcomes among ethnic groups, showed that AA patients have a significantly poorer overall survival than Cauca-sians.5 These studies did not differentiate LyP from other CD30+ LPD cases and did not elaborate on the symptoms and clinical

features. Therefore, these findings and recommendations are difficult to interpret in routine clinical practice. We herein report on the clinical characteristics and disease course of LyP in a series of eight AA/Black patients from our institution and three previously published case reports.

REPORTEight AA/Black patients with a confirmed diagnosis of LyP were identified in a retrospective search of the tumor registry and pathology database at Memorial Sloan Kettering Cancer (Table 1). Five males and three females presented to us be-tween the years 2000-2017 with a median age of 42 (range of 28-75 years). Six patients were non-hispanic, one hispanic and ethnicity was unknown in one patient. Five patients (63%) were also diagnosed with MF either before, at the same time, or after their LyP diagnosis. In half of the patients, lesions had occurred 1-4 years before the patients were diagnosed and presented to us. In one case, a diagnosis of LyP was made three years earlier; and the rest of the patients had an onset of less than one year prior to diagnosis. On physical examination at presentation, all patients had multiple lesions; however, one patient presented with one active lesion and few scars from past lesions, and one patient had only hyperpigment-ed macules and scars. In six (75%) of the patients, resolution

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S. Geller, S.J. Noor, P.L. Myskowski

TABLE 1.

Clinical Characteristics and Disease Outcomes in Black Patients With Lymphomatoid Papulosis (LyP) Seen At Our Center (cases 1 to 8) and Described in the Literature (cases 9 to 11).

Pt.Age/Sex

Race/Ethnicity

Associated Hematologic Malignancy

History Clinical presentation Treatment

Status at last follow

up

1 57/MBlack, non-

HispanicHypopigmented

MF, stage IB+

1-year history of papules appear in crops, resolve

spontaneously within weeks

Scattered hyperpigmented papules, some with central erosion or hyperkeratosis.

NBUVB and topical

corticosteroids

AWD, 6.5

years

2 28/MBlack, non-

HispanicMF, stage IB+

3-4-year history of papules, resolve spontaneously within a month leaving

hyperpigmentation

Hyperpigmented and erythematous to violaceous

papules. NBUVB

AWD, 5 years

3 45/F Black MF, stage IA*

3-4-year history of papular rash, some lesions resolve

spontaneously within weeks.

Hyperkeratotic papule and scars.Topical

corticosteroidsAWD,

8 years

4 36/MBlack, non-

HispanicNone

New onset, painful papules, some resolve

spontaneously.

Erythematous papules, some hyperpigmented and/or with

scale. (Fig 1-A) None

AWD, 2 years

5 59/FBlack, non-

HispanicMF, stage IIIA*

Diagnosed with LyP three years before presentation.

Ulcerating nodules that responded to doxorubicin

and to methotrexate.

Few erythematous papules with central crust.

Bexarotene, gemcitabine, methotrexate, brentuximab vedotin, light

therapy

AWOD, 4 years(active

MF)

6 35/MBlack, non-

Hispanic

None (chronic lichenoid rash, not diagnostic

for MF)

3-year history of papules appear in crops, scab and

resolve spontaneously within 6-8 weeks leaving

hyperpigmentation

Scattered hyperpigmented scars None

AWD, 2.5

years

7 75/FBlack, non-

HispanicMF, stage IA^

New onset, red and itchy/painful papules, appear in crops, scale and resolve spontaneously leaving

hyperpigmentation.

Diffuse erythematous to violaceous papules, some with

central scale or crust.(Fig 1-B, 1-C)

--Lost to

F/U

8 39/MBlack,

HispanicNone

New onset, ulcerated nodule and papules

resolving spontaneously

Erythematous papules and hyperpigmented macules with

central scale.Methotrexate

AWOD, 1 year

9 24/M2 Black, Afro-Caribbean

None1-year history of multiple relapsing pruritic macules

Numeroushyperpigmented and

erythematous, 3-to 5-mm macules

NBUVBAWOD,

N/M

10 47/M2 BlackGranulomatous

MFN/M N/M

Topical carmustine

N/M

11 50/F2 Black None N/M N/M N/M N/M

Abbreviations: AWD, alive with disease; AWOD, alive without disease; F, female; M, male; MF, mycosis fungoides; NBUVB, narrow band ultra-violet B, N/M, not mentioned. +diagnosed concomitantly*LyP diagnosis preceded other diagnosis^other diagnosis preceded LyP diagnosis



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rected therapies (including topical steroids and phototherapy), and low-dose methotrexate are the best documented therapies for LyP.8 Our patients demonstrated heterogenous responses to different therapies used, with most of the patients still suf-fering from active disease after a follow-up periods of up to 8 years, highlighting that there is currently no curative therapy for LyP. The efficacy and safety of brentuximab vedotin, an anti-body-drug conjugate directed against CD30, has recently been assessed for the treatment of LyP in 12 patients, including 2 AAs.9 Brentuximab vedotin was reported to be effective in treat-ing LyP and has been suggested as a possible therapy in severe and refractory cases. Further studies are ongoing to optimize its dosing and to minimize adverse events.9,10

In conclusion, a diagnosis of LyP should be considered in Black patients who present with recurring eruption of papules or nod-ules that resolve spontaneously. Patients with LyP should be carefully examined for concurrent or later development of MF. Although an indolent course may be expected in Black patients, residual hyperpigmentation and scars following resolution of the LyP lesions are common in this population, highlighting the need for better treatments of this disorder in the Black population. DISCLOSURESThe authors have no conflicts of interest to declare.This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

REFERENCES1. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus

recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutane-ous anaplastic large-cell lymphoma. Blood. 2011;118(15):4024-4035.

2. Angra K, Kennedy LJ, Rodney IJ. Lymphomatoid papulosis in a young adult of African descent. JAAD Case Rep. 2015;1(4):212-214.

3. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma in-cidence patterns in the United States: a population-based study of 3884 cases. Blood. 2009;113(21):5064-5073.

4. Yu JB, Blitzblau RC, Decker RH, Housman DM, Wilson LD. Analysis of primary CD30+ cutaneous lymphoproliferative disease and survival from the Surveillance, Epidemiology, and End Results database. J Clin Oncol. 2008;26(9):1483-1488.

5. Su C, Nguyen KA, Bai HX, et al. Ethnic disparity in primary cutaneous CD30(+) T-cell lymphoproliferative disorders: an analysis of 1496 cases from the US National Cancer Database. Br J Haematol. 2018;181(6):752-759.

6. Geller S, Pulitzer M, Myskowski P, Kheterpal M. Low-G rade cutaneous b-cell lym-phoma in African American Patients. J Drugs Dermatol. 2018;17(12):1334 - 1337.

7. Su C, Nguyen KA, Bai HX, et al. Racial disparity in mycosis fungoides: An analysis of 4495 cases from the US National Cancer Database. J Am Acad Dermatol. 2017;77(3):497-502.e492.

8. Fernandez-de-Misa R, Hernandez-Machin B, Servitje O, et al. First-line treat-ment in lymphomatoid papulosis: a retrospective multicentre study. Clin Exp Dermatol. 2018;43(2):137-143.

9. Lewis DJ, Talpur R, Huen AO, Tetzlaff MT, Duvic M. Brentuximab vedotin for patients with refractory lymphomatoid papulosis: an analysis of phase 2 results. JAMA Dermatol. 2017;153(12):1302-1306.

10. Geller S, Myskowski PL, Kim YH, Moskowitz A, Horwitz S. The optimal regimen of brentuximab vedotin for CD30(+) cutaneous lymphoma: are we there yet? Br J Dermatol. 2018;178(2):571.


Shamir Geller MD E-mail:................……......................... [email protected]

of the LyP lesions resulted in hyperpigmented macules and scars (Figure 1A-C). Seven patients were followed for 1 to 8 years, and most the patients (4/7, 57%) had documentation of active disease on their last visit despite different treatment ap-proaches.

DISCUSSIONMajor racial differences in incidence among cutaneous lympho-ma subtypes have been reported.3,6 AA/Blacks have statistically higher incidence ratios of CTCL and MF than other races and a trend towards lower incidence of CD30+ LPD was found in a national US database, which included 31 AAs with CD30+ LPD.3 A more recent study of another database included 153 AA patients with CD30+ LPD who had a significantly shorter overall survival compared to Caucasians after adjusting for patient disease characteristics, socioeconomic factors and types of treatment.5 Our case series and three additional case reports suggest an indolent disease course of LyP in AA/Black patients. There are several possible explanations for the previ-ous findings on poor survival in AA patients with CD30+ LPD. These results might be due to inclusion of ALCL and borderline cases with poorer prognosis compared to LyP. Another possi-bility is that patients with more aggressive CTCL variants (eg, transformed tumor-stage MF) might have been misdiagnosed or miscoded as CD30+ LPD. Our case series highlights the need for additional studies before clinical recommendations can be made regarding prognosis and treatment of LyP and CD30+ LPD in the different race groups. Our results support previous reports on an earlier-onset of disease seen in AA/Black patients with LyP5 as well as with other CTCL subtypes, such as MF.7 A de-lay in diagnosis of LyP is not uncommon since the self-healing crops of papules and nodules can be easily misdiagnosed as other malignant or inflammatory skin conditions (eg, arthropod bites). Most of the Black patients in our series had concurrent MF. The diagnosis of early-stage patch stage MF may be more difficult in Black skin where erythema is less pronounced com-pared to lighter skin types. Careful physical examination should be performed in Black patients who are diagnosed with LyP and no known history of MF. Once the diagnosis of LyP is made, several treatment approaches are possible. Noninterventional (“wait-and-see”) strategy is a legitimate approach, especially in patients with a limited number of lesions. Topical and skin-di-

FIGURE 1. Clinical presentation in Black patients with lymphomatoid papulosis (A, patient 4; B-C, patient 7). (A) Erythematous papules and a hyper pigmented macule on the posterior forearm. (B) Erythematous to violaceous papules on the back and posterior forearm, some have central scale and crust. (C) Hyperpigmented macules on the chest and violaceous papules on the anterior arm.




Copyright © 2020 CASE REPORT Journal of Drugs in Dermatology

SPECIAL TOPIC

Background: Necrobiosis lipoidica (NL) and sarcoidosis are granulomatous disorders with an unknown pathogenesis. They may coexist in the same patient, which suggests a possible overlap between these diseases among shared granulomatous inflammatory pathways.Case Presentation: This study presents the case of a non-diabetic 52-year-old woman who presented with red-yellowish border plaques on the face and upper extremities previously diagnosed as sarcoidosis. After 13 years of inappropriate treatment, histopathological findings consistent with the clinical and para-clinical examination suggested the diagnosis of NL. After treatment with an intralesional injection of steroids, significant improvement was observed, and no recurrent lesions were found. Conclusion: Necrobiosis lipoidica may mimic cutaneous sarcoidosis. Prompt recognition and treatment of NL can be helpful for manag-ing the disease.


ABSTRACT

INTRODUCTION

Necrobiosis lipoidica (NL) and cutaneous sarcoidosis are rare granulomatous diseases. Sarcoidosis is a chronic multisystem inflammatory disease, which can

involve any part of the body. The cutaneous form of sarcoidosis was observed in 25% to 30% of NL patients and has a varying clinical morphology.1,2 In the histopathology, cutaneous sar-coidosis is characterized as clusters of epithelioid histiocytes without significant necrosis or surrounding lymphocytic infil-trates. NL can develop in any patient, but approximately 60% occurs in type 1 diabetic patients.3-5

Herein we report the case of a 52-year-old non-diabetic wom-an who was misdiagnosed with cutaneous sarcoidosis for 13 years. Clinically she presented with painless red-yellowish plaques with an erythematous border on the upper extremities. She was treated with an intralesional injection of steroids, and improvement was observed within 3 weeks.

CASE PRESENTATIONA 52-year-old woman presented to a dermatologist with annular painless red-yellowish plaques with an erythematous border on the face and upper extremities. The patient described a 13-year

history of cutaneous sarcoidosis, which was treated with pred-nisolone 10 mg to 15 mg/daily for 5 years and calcium 400 mg/daily. When symptoms continued after 5 years, she looked for a second opinion. A clinical eye examination revealed intact disc, macula, and vessels. Additional laboratory tests were negative -- including blood biochemistry tests, complete blood count, erythrocyte sedimentation rate, blood urea nitrogen, creatinine, alkaline phosphatase, calcium, C-reactive protein, and purified protein derivative tests. Antinuclear antibody, anti-DNA, and angiotensin-converting-enzyme tests were also negative. Urinal-ysis was normal. Chest X-ray and spiral multidetector computed tomography showed no fibrosis or interstitial lesions; but a few small nodules were present at the peripheral middle zone on both lungs. In addition, high-resolution computed tomography showed no pleural effusion, lymph node enlargement, sor me-diastinal masses; however, fibrotic changes in the parenchymal view of the inferior lung area were observed, potentially caused by an infectious lesion.

The following diagnoses were proposed: necrobiosis lipoidica, lupus vulgaris, sarcoidosis, and granuloma annulare. A biopsy of the lesions was taken. A histopathological examination of the

Necrobiosis Lipoidica Mimicking Cutaneous Sarcoidosis Finally Treated With an Intralesional Injection of Corticosteroid:

A Case ReportMohamad Goldust MD,a,b,c Ghasem Rahmatpour Rokni MD,d Jeffrey M. Weinberg MD,E Leon Kircik MD,e

Martine Bagot MD,f Ali MirabidªUniversity of Rome G. Marconi, Rome, Italy; Department of Dermatology,

BUniversity Medical Center Mainz, Mainz, Germany; Department of Dermatology, cUniversity Hospital Basel, Basel, Switzerland

DMazandaran University of Medical Sciences, Sari, IraneIcahn School of Medicine at Mount Sinai, New York, NY

fDepartment of Dermatology, Hopital Saint-Louis, Paris, France

doi:10.36849/JDD.2020.4675



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M.Goldust, G.R.Rokni, J.Weinberg, et al

The incidence of NL and sarcoidosis occurring in the same non-diabetic patient has been reported in a few studies.7 This occurrence may be incidental or due to an association between the 2 disorders with unclear pathophysiology. Chiba et al evalu-ated a 70-year-old woman with a 8-year systemic sarcoidosis history concomitant with NL, and stated that although necrobio-sis was present, there were non-necrotizing granulomas in the dermis with histological diagnosis of cutaneous sarcoidosis.8

Mendoza et al evaluated 3 patients with confirmed diagnosis of sarcoidosis who developed NL skin lesions, reporting that the relationship of NL-like skin lesions with sarcoidosis is not widely appreciated.9 Igawa et al evaluated a 62-year-old woman with systemic sarcoidosis and lower leg erythematous plaques and reported that because cutaneous involvement of sarcoidosis may mimic NL clinically and/or histologically, her skin lesions were necrobiosis-like skin sarcoids.

NL is typically located on the lower extremities. In our case, giv-en the atypical locations on the face and upper extremities, the diagnosis of NL was very difficult, explaining why the lesions were misdiagnosed as sarcoidosis. More studies are needed to explore the pathogenesis of granulomatous disorders and the associations between these disorders.

CONCLUSIONIn summary, we report a rare case of non-diabetic necrobiosis lipoidica. Our case is novel since after being misdiagnosed with cutaneous sarcoidosis for 13 years, our patient then improved with just one intralesional injection of corticosteroid after the new diagnosis of necrobiosis lipoidica.

There is a probable relationship between the occurrence of NL and sarcoidosis. They may represent different stages of the same granulomatous process linked through yet unknown patho-mechanisms, but at the same time they may be quite different diseases with an overlapping clinical and pathologic history. Diagnosis at the appropriate time can help in prevent-ing unnecessary or incorrect treatment. NL may present with lesions localized in atypical sites, in which cases it may be mis-diagnosed and managed

DISCLOSURESThe authors have reported no conflicts.

REFERENCES1. Katta R. Cutaneous sarcoidosis: a dermatologic masquerader. Am Fam Phy-

sician. 2002;65(8):1581-1588.2. Peckruhn M, Tittelbach J, Elsner P. Update: Treatment of necrobiosis lipoidi-

ca. J Deutschen Dermatologischen Gesellschaft. 2017;15(2):151-158.3. Schulman JM, LeBoit PE. Adipophilin expression in necrobiosis lipoidica,

granuloma annulare, and sarcoidosis. Am J Dermatopathol. 2015;37(3):203-209.

4. Patsatsi A, Kyriakou A, Sotiriadis D. Necrobiosis lipoidica: early diagnosis and treatment with tacrolimus. Case Rep Dermatol. 2011;3(1):89-93.

5. Wee E, Kelly R. Pentoxifylline: An effective therapy for necrobiosis lipoidica. Australas J Dermatol. 2017;58(1):65-68.

biopsy revealed collagen degeneration and vascular changes within the entire dermis, as well as extra-cellular lipid and giant cells. Overall, these findings were consistent with necrobiosis li-poidica and treatment for NL was started. The patient was treated with a one-time intralesional injection of corticosteroid. Lesions were significantly improved after 3 weeks. At one-year follow-up, no further lesions or recurrent plaques were observed.

DISCUSSIONSarcoidosis is a multisystem disorder and can involve any or-gan of the body. Approximately 30% of systemic sarcoidosis appears with skin involvement.6 NL did not come to mind in the first differential diagnosis of the annular lesions of the face. Our case subject was undergoing treatment with an oral corticoste-roid (prednisolone 15-10 mg/daily) for about 8 years because of suspected sarcoidosis, without improvement. After the diagno-sis of NL and a one-time intralesional injection of corticosteroid, significant improvement was observed.

FIGURE 1. Involvement of the full thickness of the dermis with extension into the subcutis, collagen degeneration. and vascular damage. Extracellular lipid and giant cell are seen.

FIGURE 2. Red-yellowish erythematous border plaques on the face and upper extremities.

FIGURE 3. Three weeks after treatment with an intralesional corticosteroid injection. Do Not Copy

Penalties Apply


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6. Mishra AK, George AA, Peter D. Annular cutaneous sarcoidosis with sys-temic involvement. J Family Med Prim Care. 2017;6(3):660.

7. Valecha N, Bennett G, Yip L. A granulomatous conundrum: Concurrent nec-robiosis lipoidica, cutaneous sarcoidosis and erythema nodosum in a nondia-betic patient. Australas J Dermatol. 2017;58(4).

8. Chiba T, Takahara M, Nakahara T, et al. Cutaneous sarcoidosis clinically mim-icking necrobiosis lipoidica in a patient with systemic sarcoidosis. Annals Dermatol. 2012;24(1):74-76.

9. Mendoza V, Vahid B, Kozic H, Weibel S. Clinical and pathologic manifesta-tions of necrobiosis lipoidica-like skin involvement insarcoidosis. Joint Bone Spine. 2007;74(6):647-649.

10. Igawa K, Maruyama R, Satoh T, Yokozeki H, Katayama I, Nishioka K. Nec-robiosis lipoidica-like skin lesions in systemic sarcoidosis. J Dermatol. 1998;25(10):653-656.


Mohamad Goldust MD DOE-mail:................……...................... [email protected]

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SPECIAL TOPIC

A Closer Look at a Multi-Targeted Approach to Hair Loss in African American Women

Cheryl Burgess MD,ª Wendy Roberts MD,b Jeanine Downie MD,c Megan Kera PA-C,c Sophia Kogan MD,d Danamarie Belpulsi MDd

ªCenter for Dermatology and Dermatologic Surgery, Washington, DCbGenerational and Cosmetic Dermatology, Rancho Mirage, CA

cImage Dermatology P.C., Montclair, NJdNutraceutical Wellness, Inc., New York, NY

INTRODUCTION

Hair loss is a common problem that spares no gender or ethnic group. As we know, there are differences in straight and curly hair including follicle shape, growth

rate, and density.¹ Similarly, there are also differences epidemi-ologically in what types of hair loss are more commonly seen in different ethnic groups, as well as how it’s diagnosed and treated.2

However, hair loss among the various groups can result in the same psychosocial distress leading to depression, anxiety, and frustration often further precipitated by the limited availability of treatment options that traditionally produce variable results with a chance for side effects. According to the American Acad-emy of Dermatology, a 2016 survey showed that almost half of African American women experience hair loss, while only few bring it to the attention of a physician.2,3 In fact, African Ameri-can women are prone to hair loss, which can be compounded by certain styling practices. Most importantly, this population has the highest risk of central centrifugal cicatricial alopecia (CCCA), marked by inflammation and progressive destruction of follicles through scarring – limiting treatment options further when diagnosed late or not at all.2,3,4

While the presentation, morphology, and prevalence of hair loss vary within different ethnic groups, science shows that etiological factors are still numerous regardless of ethnicity. They include genetics, hormones, psycho-emotional stress, environmental factors, inflammation, oxidative damage, as well as lifestyle and styling habits, to name a few.5,6 Sadick et al describes the research behind the ever-growing number of pathways involved in the undermining of a healthy follicle. He and colleagues call for a paradigm shift in therapeutic approach to hair loss from mono-targeting to multi-targeting interven-tions, to reflect the multi-factorial nature of all types of hair disorders.5,6 The multi-targeting nature of these interventions supports their use in any patient population, regardless of age, ethnicity, gender, etc.

In this case series, attempting to highlight one particular hair type- African American, which has the slowest growth rate and is more affected by breakage with easily observed fragility in vivo,7 we present four African American female patients who

consistently ingested a nutraceutical for 2 months, 3 months, 10 months, and 2 years after experiencing significant hair loss and failed previous treatments. The addition of the nutraceu-tical therapy to these patients’ regimens showed significant improvement, as seen by both patients and their treating physicians. The carefully formulated ingredients found in this supplement have resulted in positive outcomes for all four pa-tients as evidenced below with photographic documentation before and after. Further, we will discuss the multi-targeted ap-proach and the mechanisms of action that support the success of this nutraceutical.

CASE 1 A 41-year-old healthy African American female (Fitzpatrick V) presented with a history of wearing wigs, extensions, and hair weaves for >20 years. Gradually, the hair enhancements caused thinning of the frontal and temporal hairline with sewn in and adhesive weave attachments. There was no past medical or family history of hair loss. She takes Vitamin D supplements; otherwise, is not on any medications. She routinely gets chemi-cal relaxers and color treatments every 6-8 weeks along with a touch up of the hair weave.

She was advised to alter her hair care practices and not com-bine color with chemical relaxers at the same hair appointment to prevent hair fragility and breakage. This can be cumbersome when expensive hair weave touch ups are also scheduled at each hair treatment. She was likewise advised to wear a natu-ral hairstyle to strengthen the hairline. The patient was placed on Nutrafol® hair supplements, four capsules daily, with food. Within 2 years, she had healthy hair regrowth along the hairline, and she continues to take Nutrafol daily along with additional Vitamin D supplementation (Figure 1).

doi:10.36849/JDD.2020.4754

FIGURE 1. A 41-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 2 years of treatment. Photo courtesy of Cheryl Burgess, MD.

4

8. Loussouarn G, Lozano I, Panhard S, Collaudin C, El Rawadi C, Genain G. Diversity in human hair growth, diameter, colour and shape. An in vivo study on young adults from 24 different ethnic groups observed in the five continents. Eur J Dermatol. 2016;26(2):144-54

9. Rodgers, N.E, Avram, M.R. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008;59(4):547-555

10. Farris PK, Rodgers N, McMichael A, Kogan S. A novel multi-targeting approach to treating hair loss, using standardized nutraceuticals. J Drugs in Dermatol. 2017;16:141-148

11. Ablon G, Kogan, S. A six-month, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of a nutraceutical supplement for promoting hair growth in women with self-perceived thinning hair. J Drugs Dermatol. 2018;17:58-565

FIGURES:

Figure 1. A 41-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 2 years of treatment. Photo courtesy of Cheryl Burgess, MD.

Figure 2. 63-year-old female with Fitzpatrick Skin Type V, before (top row) and (bottom row) at 3 months of treatment. Photos courtesy of Jeanine Downie, MD, M. Kera, PA-C.



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using OTC shampoo, conditioner, and keratin strengthening products, as well as color-treating her hair every 4-6 weeks, and no history of new styling practices. The patient reported extreme stress due to massive shedding of scalp hair. Patient was on topical minoxidil and spironolactone 50 mg daily for hair loss, in addition to fluocinolone acetonide 0.05% as needed for itching and tender scalp.

On physical exam, the patient was noted to have color-treated thinning hair and mild erythema of the scalp, with a positive hair pull test. Microscopic examination revealed normal appear-ing telogen follicles. The hair shafts were without fractures and tensile strength was normal in recoil. The patient was placed on Nutrafol supplement 4 capsules daily for 3 months after expe-riencing the recent massive hair shedding, melatonin 3 mg at bedtime, and oral antibiotics for mild folliculitis symptoms for 1 week. The pain, itching, and shedding ceased and 2 months following the start of therapy the “after” photograph was taken. During the interim, she color treated her hair 1 month prior and had noted significant hair regrowth from the time of her previ-ous coloring treatment. No side effects were experienced with the prescribed therapies. She is delighted at the results of ac-celerated hair growth (Figure 3).

CASE 4 A 55-year-old African American female (Fitzpatrick V) presented with a painful throbbing sensation and thinning in the bilateral temple area. Previous interventions included hair strengthening shampoos, minoxidil, and Vitalize hair serum, without improve-ment. On physical examination, there was distinct alopecia with thinning and tenderness to palpation at bilateral temple areas with a positive hair pull test. Differential diagnoses considered were possible early central centrifugal cicatricial alopecia or traction alopecia. Previous therapies were discontinued, and she was started on a 4-week course of doxycycline 100 mg and

CASE 2 A 63-year-old African American female (Fitzpatrick V) present-ed with a twenty-year history of hair loss. Patient had a long history of hypothyroidism – stabilized on levothyroxine for twenty years, as well as congestive heart failure and hyper-tension, for which she had been taking spironolactone 25mg daily, also for many years, without change in her hair loss patterns. The remaining medical history includes atrial fibril-lation and hypercholesterolemia and additional medications include carvedilol, ramipril, and pravastatin. She had no his-tory of itching or pain in the scalp and no family history of hair loss. Patient denied any history of prior medical, surgi-cal, procedural, or supplement interventions for hair loss and wore weaves for coverage of affected areas. On clinical exam, she was found to have thinning encompassing the frontal and occipital areas, and most notably patchy alopecia of bilateral temporal line. No scarring, scaling, or redness were noted. Dermoscopy exam revealed thick and thin variability of hair shaft diameter, indicating miniaturization. Diagnosis of an-drogenetic alopecia was given. The patient was interested in a non-invasive approach with little side effects. A multi-targeted approach using a combination of standardized botanical in-gredients found in Nutrafol supplement was the suggested treatment course. Photographs show before treatment and 3-months after taking 4 capsules daily result. There was marked improvement with new growth seen on bilateral temporal ar-eas, and some regrowth on frontal and occipital areas on exam. The patient also reported a noticeable improvement (Figure 2).

CASE 3 A 50-year-old postmenopausal African American female (Fitz-patrick IV) presented with mild pain, moderate itching, and massive shedding of scalp hair for 3 months. She had been

FIGURE 2. 63-year-old female with Fitzpatrick Skin Type V, before (top row) and (bottom row) at 3 months of treatment. Photos courtesy of Jeanine Downie, MD, M. Kera, PA-C.

FIGURE 3. A 50-year-old female with Fitzpatrick Skin Type IV, before (left) and (right) at 2 months of treatment. Photos courtesy of Cheryl Burgess, MD.

4

8. Loussouarn G, Lozano I, Panhard S, Collaudin C, El Rawadi C, Genain G. Diversity in human hair growth, diameter, colour and shape. An in vivo study on young adults from 24 different ethnic groups observed in the five continents. Eur J Dermatol. 2016;26(2):144-54


10. Farris PK, Rodgers N, McMichael A, Kogan S. A novel multi-targeting approach to treating hair loss, using standardized nutraceuticals. J Drugs in Dermatol. 2017;16:141-148

11. Ablon G, Kogan, S. A six-month, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of a nutraceutical supplement for promoting hair growth in women with self-perceived thinning hair. J Drugs Dermatol. 2018;17:58-565

FIGURES:

Figure 1. A 41-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 2 years of treatment. Photo courtesy of Cheryl Burgess, MD.

Figure 2. 63-year-old female with Fitzpatrick Skin Type V, before (top row) and (bottom row) at 3 months of treatment. Photos courtesy of Jeanine Downie, MD, M. Kera, PA-C.

5

Figure 3. A 50-year-old female with Fitzpatrick Skin Type IV, before (left) and (right) at 2 months of treatment. Photos courtesy of Cheryl Burgess, MD.

Figure 4. A 55-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 10 months of treatment. Photo courtesy of Wendy Roberts, MD.



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Treatments to date are limited and have relied mainly on mod-ern medicine’s reductionist approach—narrowly focusing on singular targets and pathways.10 Among the few FDA approved solutions available, many carry associated side effects, appli-cation and compliance issues, and provide variable success. Efficacy is improved with use of multiple therapies at the same time, requiring a multi-modal, multi-targeted approach, espe-cially in African American patients.

New research has revealed that a multitude of signaling path-ways, as well as internal and external triggers underlie all hair loss pathophysiology.5 Nutrafol supplements leverage the pow-er of standardized nutraceuticals to multi-target the numerous triggers and pathways that compromise hair health and contrib-ute to hair loss: inflammation, cortisol, and mediators of stress, dihydrotestosterone (DHT), and hormonal imbalances, environ-mental insults, and oxidative damage.6 The mechanisms behind these standardized nutraceutical botanicals was described in detail by Farris et al in 2017.6 In a 2018 double-blind, placebo-con-trolled, randomized clinical study published in Journal of Drugs in Dermatology, the women’s formulation was demonstrated to safely and effectively promote hair growth in female subjects with hair loss and thinning with skin types I-IV.11 The case studies reviewed here suggest that the efficacy of this multi-targeting nutraceutical alone or in combination with other therapies is showing success without ethnic barriers, specifically in darker skin types of African descent.

We have demonstrated four successful cases of improved hair growth in African American women. The thought process and treatment regimens for acquiring healthy hair are moving to-wards a multi-targeted approach, addressing many of the possible ‘stressors’ that can affect one’s hair biology within any ethnic background.

DISCLOSURESDr. Burgess, Dr. Roberts, Dr. Downie, and Megan Kera PA-C have not received payments or services for any aspect of the submit-ted work including grants, personal fees, non-financial support, or patents, and have no conflicts of interest to disclose. Drs. Kogan and Belpulsi are medical researchers at Nutraceutical Wellness Inc.

REFERENCES1. Tanus A, Oliveira CC, Villarreal DJ, Sanchez FA, Dias MF. Black women's hair:

the main scalp dermatoses and aesthetic practices in women in African eth-nicity. An Bras Dermatol. 2015;90(4):450-465

2. McMichael A.J. Hair and scalp disorders in ethnic populations. Dermatol Clin. 2003;21(4):629–644.

3. American Academy of Dermatology Association. 2016. Survey: Almost Half of African-American Women Have Experienced Hair Loss. Retrieved from: https://www.newswise.com/articles/survey-almost-half-of-african-american-women-have-experienced-hair-loss.

4. Okereke U, Simmons A, Callender VD. Current and emerging treatment strat-egies for hair loss in women of color. Int J Womens Dermatol. 2019;5(1):37-45.

5. Sadick NS, Callender VD, Kircik LH, Kogan S. New insight into the patho-

Nutrafol. The patient continued on Nutrafol 4 capsules daily and occasional Vitalize hair serum (she ran out). At follow up exam after 10 months on Nutrafol, clinical evaluation revealed posi-tive hair growth in bilateral temporal areas. Patient reported less shedding, less pain and overall positive results (Figure 4).

DISCUSSIONHair loss is an increasingly common condition that will impact over 50% of both men and women at some point in their lives. Although not life-threatening, it is frequently seen as destructive to self-image and emotional well-being, leading to significant psychological impact. Differences in straight and curly hair can be seen in the follicle’s shape, in the density of the hair and in the growth rate.8 Follicle shape is what determines the hair’s shape. Round to slightly oval-shaped follicles produce straight to wavy hair in Asians. The oval shaped follicles in Caucasians form straight to curly hair. The curly to coiled hair is produced by oval to elliptical follicles.

Growth rates also vary between races. Caucasian hair grows at a rate of about 1.2cm a month and has the greatest density of all three hair types. Blondes have about 146,000 hairs on their heads, black hair about 110,000 hairs, brunettes 100,000 hairs, and redheads roughly 86,000 hairs. African American hair is predominantly black, and a healthy person possesses about 50,000 to 100,000 hairs on their head. This population has the slowest growth rate of about 0.9cm per month. Asian hair – the most dominant hair type in the world – out speeds the rest with a growth rate of 1.3cm per month, and despite an estimated 80,000 to 140,000 scalp hairs, it usually has the least density.9

Likewise, the manifestation, presentation, morphology, and prevalence of hair loss varies amongst ethnic groups as well. In African American women specifically, scarring, and inflam-mation can be contributing factors in hair loss, commonly presenting in CCCA, making diagnosis and early treatment im-perative.2,3,4 However, differential diagnosis with androgenetic alopecia (AGA) can be challenging due to mixed presentation, assisted with clinical evaluation, dermoscopy, and biopsy. It is not uncommon, nevertheless, to see a combination of both of these and/or other types like traction alopecia in this population.2

FIGURE 4. A 55-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 10 months of treatment. Photo courtesy of Wendy Roberts, MD.

5

Figure 3. A 50-year-old female with Fitzpatrick Skin Type IV, before (left) and (right) at 2 months of treatment. Photos courtesy of Cheryl Burgess, MD.

Figure 4. A 55-year-old with Fitzpatrick Skin Type V, before (left) and (right) at 10 months of treatment. Photo courtesy of Wendy Roberts, MD.



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physiology of hair loss trigger a paradigm shift in the treatment approach. J Drugs Dermatol. 2017;16(11): s135-s140

6. McMichael, Amy J. Hair breakage in normal and weathered hair: focus on the black patient. J Investig Dermatol Symp Proc. 2007;12:6–9

7. Franbourg A, Hallegot P, Baltenneck F, Toutaina C, Leroy F. Current research on ethnic hair. J Am Acad Dermatol. 2003;48(6):S115-S11

8. Loussouarn G, Lozano I, Panhard S, Collaudin C, El Rawadi C, Genain G. Di-versity in human hair growth, diameter, colour and shape. An in vivo study on young adults from 24 different ethnic groups observed in the five continents. Eur J Dermatol. 2016;26(2):144-54


10. Farris PK, Rodgers N, McMichael A, Kogan S. A novel multi-targeting ap-proach to treating hair loss, using standardized nutraceuticals. J Drugs in Dermatol. 2017;16:141-148

11. Ablon G, Kogan, S. A six-month, randomized, double-blind, placebo-con-trolled study evaluating the safety and efficacy of a nutraceutical supple-ment for promoting hair growth in women with self-perceived thinning hair. J Drugs Dermatol. 2018;17:58-565


Sophia Kogan MD E-mail:................……...................................... [email protected]

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Clinical Evidence of the Anti-Aging Effects of a Collagen Peptide Nutraceutical Drink on the Skin

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SPECIAL TOPIC

Minimally Invasive Facial Cosmetic Procedures for the Millennial Aesthetic Patient

Nisreen Mobayed BS,ª Julie K. Nguyen MD,a,b Jared Jagdeo MD MSa,b

ªDepartment of Dermatology, SUNY Downstate Medical Center, Brooklyn, NYbDermatology Service, VA New York Harbor Healthcare System – Brooklyn Campus, Brooklyn, NY

INTRODUCTION

In aesthetic medicine, millennials have emerged as one of the leading patient demographics seeking minimally in-vasive cosmetic procedures.1-3 Millennials, defined as the

generation of individuals born between 1981 and 1996, have surpassed baby boomers as the largest living generation in the United States.4,5 Extending between the ages of 23 and 39, this group is comprised of individuals with varying experiences and priorities; millennials have also been reported to be the most diverse adult generation in American history.6 With their transi-tion into adulthood, millennials have become crucial, informed decision-makers of their health, shaping the culture of medi-cine with their unique perspectives and priorities.7 Given their impact on the expanding aesthetic medicine market and their favorable disposition towards cosmetic procedures, it is neces-sary for dermatologists and cosmetic providers to understand their motivations and perspectives.

We have conducted a review of the literature pertaining to minimally invasive facial aesthetic procedures in the millennial demographic. While popular media has accumulated abundant information on millennials and the aesthetics industry, schol-arly research on millennials and minimally invasive facial cosmetic procedures remains lacking. A PubMed.gov search on August 6, 2019 of the keyword “millennial” produced 878 results. Review of these titles and abstracts revealed zero publi-cations exploring millennials and facial aesthetics preferences; this demonstrates the lack of scholarly literature in this domain.

doi:10.36849/JDD.2020.4641

Millennials, defined as the generation of individuals born between 1981 and 1996, have emerged as one of the leading patient demo-graphics seeking minimally invasive cosmetic procedures. Worldwide, millennials are more likely to consider preventative treatments compared to any other age-group. The three most popular minimally invasive facial procedures in this demographic include botulinum toxin, dermal fillers (eg, hyaluronic acid, calcium hydroxylapatite, facial fat-fillers), and microdermabrasion. Given their impact on the ex-panding aesthetic medicine market and their favorable disposition towards cosmetic procedures, it is necessary for dermatologists and cosmetic providers to understand their motivations and perspectives. While some research studies have elicited the opinions of millen-nials on social issues, education, and technology, there is a paucity of literature on millennials’ impressions, opinions, and perceptions of aesthetic procedures. As a generation that has been reshaping the culture of healthcare delivery and encouraging the innovation of products and procedures with their unique values and perspectives, accounting for their beliefs, and fostering a better understanding of their experiences will promote an elevation in the quality of their care.


ABSTRACT

This review serves as an exploratory effort to begin to fill this gap.

Understanding Millennials In order to understand the surge of minimally invasive cosmet-ic procedures in this population, it is necessary to contextualize the socioeconomic background of this demographic.

A generation raised amidst a technological revolution, millenni-als stand apart as true digital natives.8 In particular, social media has emerged as a leading platform for this generation’s social and commercial experiences.9 Millennials reportedly spend over six hours a week on social media, demonstrating it to be an integral component of the millennial lifestyle.10 Their affinity for the digital world has become a target of advertising efforts; digital marketing and personalized advertising have been uti-lized as prominent commercial strategies to target millennial consumers.11,12 Rising to the forefront of the advertising plat-form is social media, with the emergence of plastic surgeons and other medical doctors as “social media influencers” as well as the use of plastic surgery-related hashtags.13-15 An example of the utilization of social media in aesthetic medicine is Re-alSelf, an online marketplace whereby consumers of cosmetic procedures can connect on a social platform to review and rate their experiences, supported by photographs and personal tes-timonies.16,17



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exposure and preventing skin damage by avoiding smoking.22

Regardless of the evidence or lack thereof to support prejuve-nation as an effective preventative measure of skin aging, it remains a popular trend particular to millennials.

The Rise of Minimally Invasive Cosmetic ProceduresWith the destigmatization of cosmetic procedures, minimally invasive procedures have become incorporated into the aes-thetic tool-box of the modern-day millennial. Per Allergan’s 360° Aesthetics Report, “82% of millennial consumers believe injectable treatments to be socially acceptable,” with a reported 52% having considered dermal fillers and 60% having consid-ered neuromodulating agents.1 Worldwide, millennials are also more likely to consider preventative treatments compared to any other age-group.1 The American Society for Dermatologic Surgery’s 2017 Procedures survey reports that use of facial in-jectables has nearly doubled in those under 30 years in the last 6 years.27 In this demographic, the three most popular minimal-ly invasive facial procedures are botulinum toxin, dermal fillers (eg, hyaluronic acid, calcium hydroxylapatite, facial fat-fillers), and microdermabrasion.3

These reported findings reveal a notable trend in young adults seeking to enhance their physical appearance via cosmetic pro-cedures as adjunct tools to accompany non-invasive cosmetic products.1-3 While botulinum toxin injections and dermal fillers have traditionally been used by older demographics seeking facial rejuvenation, millennials comprise a fast-growing con-sumer demographic of these products.28

There is a lack of scholarly literature exploring the motivation behind this trend; several hypotheses include the influence of social media, celebrities, and selfie-culture promoting a sense of perfectionism.2 The rise of minimally invasive procedures, particularly injectables, is likely multifactorial in nature. Owing to the affordability of these procedures relative to more inva-sive plastic surgery, the subtle, yet appreciable results, as well as reasonable recovery times, patients are seeking convenient approaches to achieve their aesthetic goals. Injectables rep-resent a popular option for patients interested in achieving a more youthful appearance but are not ready to commit to more invasive or irreversible options to attain these results.29

Botulinum ToxinBotulinum toxin injections are the most common nonsurgical cosmetic procedure worldwide.30 According to the American Society for Aesthetic Plastic Surgery (ASAPS), over 2.5 million injectable procedures were performed in 2018, with 67% of these procedures consisting of botulinum toxin injections.29,31

Botulinum injections have increased by 36% since 2014, dem-onstrating a steady uptrend in the popularity of this procedure.31

Cosmetic injectables, such as neuromodulators, have become

In general, millennials are considered economically disadvan-taged as the generation encumbered with more student debt and lower incomes than other age-group.18 Lower earnings coupled with debt have contributed to lower credit supply, ulti-mately leading this generation to have fewer assets compared to preceding generations.18,19 With less disposable income, millennials have delayed social commitments like marriage and parenthood, choosing instead to focus on their individual growth through higher education, careers, experiences, and personal fulfillment.20 Yet, even with relatively less money to spend, millennials have invested in self-care and personal well-ness, reportedly outspending baby boomers 2:1 in the self-care industry.21 With aesthetic medicine falling in the realm of these self-care services, millennials have become avid consumers of this market, seeking cosmetic procedures to improve the overall quality of their life. Particularly, the volume of minimally inva-sive cosmetic procedures performed annually has increased tremendously in this demographic.2,3 These procedures are fiscally advantageous given their capacity to provide notable results at a fraction of the cost of more invasive cosmetic sur-geries. Thus, millennials have identified the most cost-effective solution to maintaining youthfulness and delaying the aging process: starting preventative treatment at a young age.22,23

PrejuvenationAmong the latest cosmetic trends in the millennial consumer group is prejuvenation, a portmanteau combining the words prevention and rejuvenation.24 Prejuvenation refers to the use of minimally invasive procedures to maintain a youthful appearance and ideally delay the onset of visible signs of ag-ing.22,24 This trend highlights the focus of millennials on early maintenance treatments to produce natural-appearing results in order to avoid or delay more invasive procedures down the line. Injectables, specifically neuromodulators and dermal fill-ers, are the leading products utilized to achieve these results.3

A long-term twin study seeking to evaluate the prevention of wrinkles with neuromodulating agents concluded that long-term onabotulinumtoxinA treatment can effectively prevent facial lines present at rest.25 This study, although limited by de-sign, suggests that long-term treatment with neuromodulating agents can lead to the prevention of future wrinkles, providing supporting evidence for prejuventation. An additional study demonstrated similar results with long-term treatment of gla-bellar rhytids with onabotulinumtoxinA, further supporting the use of neuromodulators for prejuventation.24

Yet, the efficacy of utilizing cosmetic procedures to prevent facial aging is still highly debated given the relative paucity of long-term, compelling research to support the anti-aging effects. Some physicians believe that providers should not pre-treat younger patients prior to any visible signs of aging.22

Rather, these physicians advocate for skin protection from sun



102



the leading products utilized to achieve subtle, yet notable im-provement in facial aesthetics.3 Neuromodulating agents have been used cosmetically to reduce the appearance of dynamic rhytids and fine lines.32-34 By inhibiting muscles from contract-ing, neuromodulating agents decrease facial movement and in theory may be used preventatively to suspend the develop-ment of wrinkles.32,33

While neuromodulator injections have been widely used by older generations to achieve a more youthful appearance by treating fine lines and wrinkles, their popularity has been steadily growing in the millennial generation. According to the American Academy of Facial Plastic and Reconstructive Sur-gery, botulinum toxin injections have increased by 22% among millennials in the past five years; members of this organization have attributed this in part to the prejuvenation trend.2 Aller-gan, the maker of Botox® Cosmetic, has targeted millennials in its latest advertising campaign; this campaign seeks to empha-size the ability of Botox to produce natural and subtle results in this demographic, promising consumers to “look like you with fewer lines.”35

Dermal FillersDermal fillers comprise the second most popular minimally invasive procedure in facial aesthetics in the millennial popula-tion.3 Within the dermal fillers category, hyaluronic acid fillers remain the most popular, followed by calcium hydroxylapa-tite (e.g. Radiesse), and facial fat-fillers.3 Per the ASAPS’s 2018 Procedure Report, hyaluronic acid injections are up 58% since 2014.31 Of all injectable procedures performed in 2018, 30% con-sisted of hyaluronic acid injections.29 Given their lasting effects and lower potential to induce allergic reactions relative to other classes of fillers,36,37 hyaluronic acid fillers have become the preferred filler by cosmetic providers.

Dermal fillers have been utilized to improve volume distribu-tion and ultimately achieve balanced facial contouring.34 Similar to neuromodulator injections, the subtle, yet notable results coupled with little to no down-time has made this procedure popular in millennials. The Global Aesthetics Consensus Group has devised consensus recommendations, advocating for an integrative approach to injectables by endorsing combination treatment of neuromodulators and hyaluronic acid fillers.30

Allergan has also tailored advertisement of Juvéderm, the com-pany’s family of hyaluronic acid fillers, to millennial women in the advertisement montage titled “Juvéderm It”; in this mon-tage, a diverse group of women pose as a backdrop to bolded pink messages directed at younger consumers: “Live it, work it, pose it, boss it.”38

Microdermabrasion Microdermabrasion, a popular method of superficial skin resur-facing, utilizes microcrystals or diamond tips, as exfoliants to

remove the outermost layer of skin.39 Microdermabrasion has been studied for its effects on acne, pigmentation disorders, and scarring disorders.40 This rejuvenating cosmetic treatment has risen in popularity amongst millennials, coming in as the third most popular minimally invasive procedure in facial aes-thetics.3

Like fillers and neuromodulators, microdermabrasion provides subtle, natural, and rejuvenating results that are appealing to the millennial population. By smoothing and buffing the skin’s surface, microdermabrasion brightens the face,41 producing a natural glow that many patients are seeking. Furthermore, giv-en that it is believed to stimulate dermal collagen and elastic fiber production, microdermabrasion serves as an additional tool utilized in the prejuvenation trend targeting millennials.40

CONCLUSIONThe ASAPS reports that Americans spent more than 15 billion dollars on surgical and nonsurgical aesthetic procedures in 2016, with nonsurgical procedures accounting for 44% of this total.42 Given that millennials command a significant spend-ing influence in the aesthetics sector and represent the leading age-group most likely to consider preventative treatments,1

it is important to explore and document their motivations and perspectives. While some research studies have elicited the opinions of millennials on social issues, education, and technology, there is a paucity of literature on millennials’ im-pressions, opinions, and perceptions of aesthetic procedures. With millennials serving as a target of several advertising campaigns in the cosmetic dermatology and aesthetic medi-cine markets, it is worthwhile to produce reliable studies of their experiences with cosmetic procedures. As a generation that has been reshaping the culture of healthcare delivery and encouraging the innovation of products and procedures with their unique values and perspectives, accounting for their beliefs and fostering a better understanding of their experi-ences will promote an elevation in the quality of their care. DISCLOSURESNM and JKN have no conflicts of interest to disclose. JJ is a scientific consultant for Allergan and Galderma and received a Merz product grant for educational training purposes.

REFERENCES1. Allergan plc. Allergan 360°: Aesthetics Report. Available at:

https://360aestheticsreport.com/view-report/. Published April 8, 2018. Ac-cessed July 22, 2019.

2. American Academy of Facial Plastic and Reconstructive Surgery: AAFPRS 2018 Annual Survey. Available at: https://www.aafprs.org/media/stats_polls/m_stats.html. Published January 23, 2019. Accessed July 22, 2019.

3. American Society of Plastic Surgeons: 2018 National Plastic Surgery Sta-tistics. Available at: https://www.plasticsurgery.org/documents/News/Sta-tistics/2018/plastic-surgery-statistics-full-report-2018.pdf. Accessed August 11, 2019.

4. Fry R. Millennials projected to overtake baby boomers as America’s larg-est generation. Pew Research Center. http://pewrsr.ch/2FgVPwv. Published March 1, 2018. Accessed August 6, 2019.

5. Sherber NS. The millennial mindset. J Drugs Dermatol. 2018; 17 (12):1340-1342.



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6. Frey WH. The millennial generation: a demographic bridge to America’s diverse future. Available at: https://www.brookings.edu/wp-content/uploads/2018/01/2018-jan_brookings-metro_millennials-a-demographic-bridge-to-americas-diverse-future.pdf. Published: January 2018. Accessed: August 14, 2019.

7. How millennials are redefining healthcare today: are you behind? Mobile Smith Health. Available at: https://www.mobilesmith.com/resources/white-papers/millennials-redefining-healthcare/ Published March 9, 2018. Ac-cessed August 9, 2019.

8. The evolution of technology across generations. Nordic IT. Available at: https://nordic-it.com/evolution-technology-throughout-generations/. Pub-lished November 10, 2016. Accessed August 8, 2019.

9. Barnes NG, Lescault AM. Millennials transform social commerce. Center for Marketing Research, University of Massachusetts Dartmouth. Available at: https://www.umassd.edu/cmr/social-media-research/millennials-transform-social-commerce/. Published December 1, 2014. Accessed August 8, 2019.

10. Casey S. 2016 Nielsen Social Media Report. Nielsen Social. Available at: https://www.nielsen.com/us/en/insights/report/2017/2016-nielsen-social-media-report/. Published January 17, 2017. Accessed August 8, 2019.

11. Serazio M. Selling (Digital) Millennials: The social construction and tech-nological bias of a consumer generation. Television & New Media. 2013; 16(7):599–615. doi:10.1177/1527476413491015.

12. Smith KT. Longitudinal study of digital marketing strategies targeting millen-nials. J Consum Mark. 2012; 29(2):86-92. doi:10.1108/07363761211206339.

13. Chandawarkar AA, Gould DJ, Stevens WG. The top 100 social media influ-encers in plastic surgery on Twitter: who should you be following? Aesthet Surg J. 2018; 38(8);913-917. doi:10.1093/asj/sjy024.

14. Dorfman RG, Vaca EE, Mahmood E, Fine NA, Schierle CF. Plastic surgery-related hashtag utilization on Instagram: implications for education and mar-keting. Aesthet Surg J. 2017; 38(3):332-338. doi:10.1093/asj/sjx120.

15. Reissis D, Shiatis A, Nikkhah D. Advertising on social media: the plastic sur-geon’s prerogative. Aesthet Surg J. 2017; 37(1):NP1-NP2. doi:10.1093/asj/sjw174

16. Real Self – Reviews of cosmetic treatments, surgery, doctors. 2014. http://realself.com/. Accessed August 8, 2019.

17. Schlichte MJ, Karimkhani C, Jones T, Trikha R, Dellavalle RP. Patient use of social media to evaluate cosmetic treatments and procedures. Dermatol On-line J. 2015; 21(4):13.

18. Kurz C, Li G, Vine DJ. Are Millennials Different? Finance and Economics Dis-cussion Series 2018-080. Washington: Board of Governors of the Federal Reserve System. doi:10.17016/FEDS.2018.080.

19. Boone G. The Kids are Alright: Millennials and the Economy. Bureau of Labor Statistics. Available at: https://www.bls.gov/opub/mlr/2019/beyond-bls/the-kids-are-alright-millennials-and-the-economy.htm. Published February 2019. Accessed August 5, 2019.

20. Goldman Sachs. Millennials: coming of age. Available at: https://www.gold-mansachs.com/insights/archive/millennials/. Accessed August 5, 2019.

21. Field Agent. Millennials, Boomers, & 2015 resolutions: 5 key generational differences. Available at: https://blog.fieldagent.net/millennials-boomers-new-years-resolutions-5-key-generational-differences. Published January 13, 2015. Accessed August 9, 2019.

22. Hilton L. Examining the prejuvenation trend. Available at: https://www.der-matologytimes.com/facial-aesthetics/examining-prejuvenation-trend. Pub-lished April 12, 2019. Accessed August 10, 2019.

23. Rabimov S. The millennial approach to remaining young and beautiful. Avail-able at: https://www.forbes.com/sites/stephanrabimov/2018/02/27/the-mil-lennial-approach-to-remaining-young-beautiful/#3ced60312c6a. Published February 27, 2018. Accessed August 7, 2019.

24. Campbell C. What is prejuvenation? preventative Botox and injectables. Available at: https://prejuvenation.com/article/prejuvenation-botox-inject-ables-antiaging. Published June 23, 2019. Accessed August 10, 2019.

25. Rivkin A, Binder W. Long-term effects of onabotulinumtoxinA on facial lines: a 19-year experience of identical twins. Dermatologic Surgery. 2015; 41, S64-S66. doi:10.1097/DSS.0000000000000193.

26. Dailey R, Philip A, Tardie G. Long-term treatment of glabellar rhytides us-ing onabotulinumtoxinA. Derm Surg. 2011; 37:918-28. doi:10.1111/j.1524-4725.2011.02024.x.

27. American Society for Dermatologic Survey: 2017 Procedure Results Infograph-ic. Available at: https://www.asds.net/portals/0/PDF/procedure-survey-re-sults-infographic-2017.pdf. Published May 17, 2018. Accessed August 9, 2019.

28. Stahl D. Botox for millennials? Center for Ethics and Humanities in the Life Sciences at Michigan State University. Available at: https://msubioethics.com/2019/01/24/botox-for-millennials-stahl/. Published January 24, 2019. Ac-cessed August 9, 2019.

29. American Society for Aesthetic Plastic Surgery: New data shows that Ameri-cans spent more than $2 billion on silicone gel breast implants and inject-ables in 2018. Available at: https://www.surgery.org/media/news-releases/new-data-shows-that-americans-spent-more-than-2-billion-on-silicone-gel-breast-implants-and-injectables-in-2. Published May 1, 2019. Accessed Au-gust 10, 2019.

30. Sundaram H, Massimo S, Liew S, et al. Global Aesthetics Consensus: Botulinum toxin type A—evidence-based review, emerging concepts, and consensus recommendations for aesthetic use, including updates on complications. Plast Reconstr Surg. 2016; 137(3):518–529. doi:10.1097/01.prs.0000475758.63709.23.

31. American Society for Aesthetic Plastic Surgery: 2018 Cosmetic (Aesthetic) Surgery National Data Bank Statistics. Available at: https://www.surgery.org/sites/default/files/ASAPS-Stats2018_0.pdf. Accessed August 10, 2019.

32. Carruthers A, Carruthers J. Botulinum toxin type A: history and current cosmetic use in the upper face. Semin Cutan Med Surg. 2001; 20:71-84. doi:10.1053/sder.2001.25138.

33. Humphrey S. Neurotoxins: Evidence for prevention. J Drugs Dermatol. 2017; 16(6 Suppl):s87-90.

34. Anand C. Facial contouring with fillers, neuromodulators, and lipolysis to achieve a natural look in patients with facial fullness. J Drugs Dermatol. 2016; 15(12):1536-1542.

35. Bulik BS. Ready for Botox, millennials? Allergan has launched its first cam-paign targeting you. Available at: https://www.fiercepharma.com/marketing/get-ready-millennials-allergan-launches-its-first-botox-campaign-targeting-younger-20s Published January 30, 2019. Accessed August 10, 2019.

36. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers: a comprehensive review. Facial Plast Surg. 2009; 25(2):086-094. doi:10.1055/s-0029-1220647.

37. Kim JE, Sykes JM. Hyaluronic acid fillers: history and overview. Facial Plast Surg. 2011; 27(06):523-528. doi:10.1055/s-0031-1298785.

38. PR Newswire. Allergan launches new Juvéderm It campaign designed to reach the next generation of consumers. Available at: https://www.prnewswire.com/news-releases/allergan-launches-new-juvederm-it-campaign-designed-to-reach-the-next-generation-of-consumers-300723447.html Published October 3, 2018. Accessed August 9, 2019.

39. Grimes PE. Microdermabrasion. Derm Surg. 2006; 31(s3):1160–1165. doi:10.1111/j.1524-4725.2005.319.

40. Meaike JD, Agrawal N, Chang D, Lee EI, Nigro MG. Noninvasive facial reju-venation. part 3: physician-directed—lasers, chemical peels and other non-invasive modalities. Semin Plast Surg. 2016; 30(3):143-150. doi:10.1055/s -0036-1584818.

41. Dessy LA. Noninvasive physical treatments in facial rejuvenation. In: Scuderi N., Toth B. (eds) International Textbook of Aesthetic Surgery. Springer, Berlin, Heidelberg; 2016. doi: 10.1007/978-3-662-46599-8_79.

42. American Society for Aesthetic Plastic Surgery: Americans spend more than $15 billion on aesthetic procedures for the first time ever. Available at: https://www.surgery.org/media/news-releases/americans-spend-more-than-15-billion-on-aesthetic-procedures-for-the-first-time-ever. Published March 15, 2017. Accessed August 10, 2019.


Jared Jagdeo MD MSE-mail:................……......................... [email protected]




Copyright © 2020 LETTERS TO THE EDITOR Journal of Drugs in Dermatology

In an age of increasing respect for the ethical principle of autonomy, patient education is growing exponentially. Abundant medical information is readily available online,

emboldening patients to play a more active role in their health-care. Meanwhile, physicians are gaining greater appreciation for patient education and informed consent, and the role of physician as educator is now more important than ever before.

In 2003, alefacept became the first Food and Drug Admin-istration (FDA)-approved biologic for psoriasis.1 Dozens of immune-targeting therapies have since been approved for myriad dermatologic conditions from psoriasis, atopic dermati-tis and hidradenitis suppurativa to cutaneous malignancy, with novel agents continuously in development. The advent of these immunomodulators, such as monoclonal antibodies and small molecule inhibitors, introduces the corresponding need for im-proved patient education. The burden on the dermatologist to distill the complexities of the immune system, and mechanisms of drugs which target it, is steadily increasing as more patients transition from traditional immunosuppressive medications to newer immunomodulator therapies. Many have been treated with traditional immunosuppressives such as cyclosporine, mycophenolate mofetil, or methotrexate for years, and are nat-urally curious about the mechanisms of their new treatments.

In the 2016 “Voice of the Patient” forum hosted by the FDA, psoriasis patients expressed concerns about potential side ef-fects and “compromising the immune system” as significant deterrents to initiating biologics.2 Studies of non-dermatologic

diseases have demonstrated similar patient concerns regard-ing side effects and immunocompromise,3,4 suggesting that enhanced patient education on immunomodulators’ mecha-nism of action may improve willingness to use and compliance with biologics over traditional immunosuppressives.

Psoriasis serves as the archetype for immunomodulatory ther-apy, but given the increasing number of dermatoses treated via these agents, a broad and understandable approach to ex-plaining the mechanism of action of targeted therapies may be valuable to augment patient understanding, reduce fears associated with treatment regimens, improve willingness to transition to or begin immunomodulators, and bolster medica-tion adherence. We propose the following educational aid to help clinicians explain the immune system and mechanisms of immune targeting therapies in a succinct, relatable fashion (Figure 1).

When counseling patients, the complex immune system can be simplified and compared to an upside-down tree. The trunk represents the immune system as a whole. Large branches aris-ing from the trunk are analogous to upstream immune pathway targets, ie, various cell types and physical barriers. Each large branch further divides into smaller branches, which represent more specific downstream immunological pathways. Finally, the leaves represent effectors of the immune system which characterize both immunocompetence and immune-mediated disease.

Growing Patient Education in Dermatology: An Upside-Down Tree Analogy for Immunomodulatory Therapies

Steven R. Madsen MD,ª Aleksi J. Hendricks BS,B Vivian Y. Shi MDc ªUniversity of Connecticut Department of Dermatology, Farmington, CT

bUniversity of Arizona College of Medicine, Tucson, AZ cUniversity of Arizona Department of Medicine, Division of Dermatology, Tucson, AZ

As patient autonomy gains momentum in the era of readily accessible health information, dermatologists bear a growing responsibility in patient education. With the rapid evolution and development of targeted therapies for dermatologic conditions, clinicians are faced with questions from patients regarding the mechanisms of action and side effects of novel therapeutic agents. We present an educa-tional aid to be used in patient counseling to describe and compare the mechanisms of traditional immunosuppressive medications and targeted agents such as biologics and small molecule inhibitors. Using an upside-down tree as an analogy for the immune system, traditional immunosuppressives can be represented by an axe, chopping at large branches (ie, upstream immune pathways), while tar-geted immunomodulators can be represented by pruning shears, trimming select small branches and leaves (ie, specific downstream effectors). This approachable visual aid can guide practitioners in explaining the complexities of the immune system and immunomodu-latory therapies with the goal of augmenting patient understanding and addressing patient concerns regarding new medications.


ABSTRACT

doi:10.36849/JDD.2020.4574




Copyright © 2020 LETTERS TO THE EDITOR Journal of Drugs in Dermatology

targeted treatments, our counseling methods must expand and evolve in parallel to new therapeutic options. Simplified, relatable, and visually engaging instruments such as this upside-down tree will aid clinicians in their responsibilities as patient educators.

DISCLOSURESVivian Shi is a stock shareholder of LearnHealth and has served as a consultant or investigator for or has received research funding from Sanofi/Regeneron, Eli Lilly, Dermira, Novartis, AbbVie, SUN Pharma, Pfizer, Leo, Menlo Therapeutics, Burt’s Bees, GpSkin, and Skin Actives Scientific.

Steven Madsen and Aleksi Hendricks have no conflicts of inter-est to declare relevant to this manuscript.

References1. Jenneck C, Novak N. The safety and efficacy of alefacept in the treatment of

chronic plaque psoriasis. Ther Clin Risk Manag.. 2007;3(3):411-420.2. Center for Drug Evaluation and Research (CDER). The Voice of the Patient:

Psoriasis. U.S. Food and Drug Administration; March 17, 2016 2016.3. Dzubur E, Khalil C, Almario CV, et al. Patient concerns and perceptions regard-

ing biologic therapies in ankylosing spondylitis: insights from a large-scale survey of social media platforms. Arthritis Care Res. 2019;71(2):323-330.

4. Martinez B, Dailey F, Almario CV, et al. Patient understanding of the risks and benefits of biologic therapies in inflammatory bowel disease: insights from a large-scale analysis of social media platforms. Inflamm Bowel Dis. 2017;23(7):1057-1064.


Vivian Y. Shi MD E-mail:................……[email protected]

Traditional immunosuppressive therapies inhibit upstream targets within the immune pathway, analogous to an axe chopping large branches. In inhibiting upstream targets, the immunological component responsible for a certain disease may be cut off, but the axe may have also chopped off a branch that fights infection or guards against cancer. Just as with an axe to a tree, the closer to the trunk that these medications take action, the more of the tree (the components of the immune system) will be affected. Targeted therapies are analogous to pruning shears, clipping off small branches in hopes of inhibiting only the parts of the immune system responsible for a disease. Directed use of pruning shears rather than an axe targets specific derangements in the immune pathway while leaving others intact, with the goal of maximizing treatment efficacy while minimizing side effects.

Two medications commonly used in psoriasis treatment, methotrexate and rizankizumab, can be compared using this model. Methotrexate is a traditional immunosuppressive that interferes with DNA replication. As all cells must synthesize new DNA, methotrexate can potentially act on many immune cell types in addition to the overactive lymphocytes causing inflammatory disease. Therefore, methotrexate is analogous to an axe, chopping at large branches of the tree. Rizankizumab is an immunomodulator specifically targeting IL-23, a prominent cytokine in psoriasis pathogenesis. Consequently, rizankizumab acts as pruning shears, cutting off smaller branches of the immune system “tree”.

The wealth of therapeutic options available to dermatologists is rapidly expanding. As we move forward in this era of emerging

FIGURE 1. Upside-down tree analogy for traditional immunosuppressive vs. targeted immunomodulatory agents.Figure 1. Upside-down tree analogy for traditional immunosuppressive vs. targeted immunomodulatory agents



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