17-9 eJDD Final

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ISSN: 1545 9616 September 2018 • Volume 17 • Issue 9
JDD
SPECIAL FOCUS:
AESTHETICS
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Image credit page 936
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CME ARTICLE: Managing Seborrheic Keratosis
Men’s Trends in Aesthetic Treatment
Scar Treatment With Botulinum Toxin
Vacuum-Assisted Subcision of Cellulite
Topical Melatonin
A I for Evaluation of Acne
RESIDENT ROUNDS NEWS, VIEWS, & REVIEWS PIPELINE PREVIEWS CLINICAL TRIAL REVIEW
ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

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ALL ABOARD ONEXTON GEL

Efficacy and tolerability matter when it comes to treating acne. In the pivotal trial, ONEXTON GEL was shown
to treat both inflammatory and noninflammatory acne, and no patients discontinued due to an adverse event.1,2
INSTANT SAVINGS FOR ELIGIBLE PATIENTS AT ORTHORXACCESS.COM

TERMS AND CONDITIONS APPLY
INDICATION Do Not Copy

ONEXTON (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/3.75% is indicated • ONEXTON Gel should not be used in combination with erythromycin-containing products
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for the topical treatment of acne vulgaris in patients 12 years of age or older. because of its clindamycin component.
• ONEXTON Gel should be used during pregnancy only if the potential benefit justifies the
IMPORTANT SAFETY INFORMATION potential risk to the fetus. A decision should be made whether to use ONEXTON Gel while
• ONEXTON Gel is contraindicated in patients with a known hypersensitivity to nursing, taking into account the importance of the drug to the mother.
clindamycin, benzoyl peroxide, any component of the formulation, or lincomycin. • Patients should be advised to avoid contact with the eyes or mucous membranes.
• ONEXTON Gel is contraindicated in patients with a history of regional enteritis, • Patients should minimize exposure to natural and avoid artificial sunlight (tanning beds
ulcerative colitis, or antibiotic-associated colitis. or UVA/B treatment) while using ONEXTON Gel. To minimize exposure to sunlight,
• Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have protective clothing should be worn and a sunscreen with SPF 15 rating or higher should
been reported with the use of topical and systemic clindamycin. ONEXTON Gel should be used.
be discontinued if significant diarrhea occurs.
• Orally and parenterally administered clindamycin has been associated with severe To report SUSPECTED ADVERSE REACTIONS, contact Ortho Dermatologics at
colitis, which may result in death. 1-800-321-4576 or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.
• Anaphylaxis, as well as other allergic reactions leading to hospitalizations, has been Please see Brief Summary of full Prescribing Information on the following page.
reported in postmarketing use of products containing clindamycin/benzoyl peroxide.
If a patient develops symptoms of an allergic reaction such as swelling and shortness References: 1. ONEXTON [prescribing information]. Bridgewater, NJ: Valeant
of breath, they should be instructed to discontinue use and contact a physician Pharmaceuticals North America LLC. 2. Pariser DM, Rich P, Cook-Bolden FE,
Korotzer A. An aqueous gel fixed combination of clindamycin phosphate 1.2%
immediately. and benzoyl peroxide 3.75% for the once-daily treatment of moderate to
• The most common local adverse reactions experienced by patients in clinical trials severe acne vulgaris. J Drugs Dermatol. 2014;13(9):1083-1089.
were mild and moderate erythema, scaling, itching, burning and stinging.
LEARN MORE AT ONEXTON.COM

ONEXTON is a trademark of Ortho Dermatologics’ affiliated entities.
© All Rights Reserved. ONX.0037.USA.18
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION Neuromuscular Blocking Agents

This Brief Summary does not include all the information needed to use ONEXTON Gel Clindamycin has been shown to have neuromuscular blocking properties that may enhance
safely and effectively. See full prescribing information for ONEXTON Gel. the action of other neuromuscular blocking agents. ONEXTON Gel should be used with
caution in patients receiving such agents.
ONEXTON® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/3.75%, for
topical use USE IN SPECIFIC POPULATIONS
Pregnancy
Initial U.S. Approval: 2000
Pregnancy Category C.
CONTRAINDICATIONS There are no adequate and well-controlled studies in pregnant women treated with
ONEXTON Gel. ONEXTON Gel should be used during pregnancy only if the potential benefit
Hypersensitivity
justifies the potential risk to the fetus.
ONEXTON Gel is contraindicated in those individuals who have shown hypersensitivity
Animal reproductive/developmental toxicity studies have not been conducted with
to clindamycin, benzoyl peroxide, any components of the formulation, or lincomycin.
ONEXTON Gel or benzoyl peroxide. Developmental toxicity studies of clindamycin performed
Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in
in rats and mice using oral doses of up to 600 mg/kg/day (240 and 120 times amount of
postmarketing use with ONEXTON Gel [see Adverse Reactions].
clindamycin in the highest recommended adult human dose based on mg/m2, respectively)
Colitis/Enteritis or subcutaneous doses of up to 200 mg/kg/day (80 and 40 times the amount of
ONEXTON Gel is contraindicated in patients with a history of regional enteritis, ulcerative clindamycin in the highest recommended adult human dose based on mg/m2, respectively)
colitis, or antibiotic-associated colitis [see Warnings and Precautions]. revealed no evidence of teratogenicity.
WARNINGS AND PRECAUTIONS Nursing Mothers
Colitis It is not known whether clindamycin is excreted in human milk after topical application of
Systemic absorption of clindamycin has been demonstrated following topical use of ONEXTON Gel. However, orally and parenterally administered clindamycin has been reported
clindamycin. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) to appear in breast milk. Because of the potential for serious adverse reactions in nursing
have been reported with the use of topical and systemic clindamycin. If significant diarrhea infants, a decision should be made whether to use ONEXTON Gel while nursing, taking into
occurs, ONEXTON Gel should be discontinued. account the importance of the drug to the mother.
Severe colitis has occurred following oral and parenteral administration of clindamycin Pediatric Use
with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents Safety and effectiveness of ONEXTON Gel in pediatric patients under the age of 12 have not
such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. been evaluated.
Severe colitis may result in death.
Geriatric Use
Studies indicate toxin(s) produced by Clostridia is one primary cause of antibiotic-associated colitis.
Clinical trials of ONEXTON Gel did not include sufficient numbers of subjects aged 65 and
The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and
older to determine whether they respond differently from younger subjects.
may be associated with the passage of blood and mucus. Stool cultures for Clostridium difficile and
stool assay for C. difficile toxin may be helpful diagnostically. NONCLINICAL TOXICOLOGY
Ultraviolet Light and Environmental Exposure Carcinogenesis, Mutagenesis, Impairment of Fertility
Minimize sun exposure (including use of tanning beds or sun lamps) following drug Carcinogenicity, mutagenicity and impairment of fertility testing of ONEXTON Gel have not
application [see Nonclinical Toxicology]. been performed.
Benzoyl peroxide has been shown to be a tumor promoter and progression agent in
ADVERSE REACTIONS
a number of animal studies. Benzoyl peroxide in acetone at doses of 5 and 10 mg
The following adverse reaction is described in more detail in the Warnings and Precautions administered topically twice per week for 20 weeks induced skin tumors in transgenic
section of the label: Tg.AC mice. The clinical significance of this is unknown.
Colitis [see Warnings and Precautions]. Carcinogenicity studies have been conducted with a gel formulation containing
Clinical Trials Experience 1% clindamycin and 5% benzoyl peroxide. In a 2-year dermal carcinogenicity study in mice,
Because clinical trials are conducted under widely varying conditions, adverse reaction rates treatment with the gel formulation at doses of 900, 2700, and 15000 mg/kg/day (1.8, 5.4, and
observed in clinical trials of a drug cannot be directly compared to rates observed in the clinical 30 times amount of clindamycin and 2.4, 7.2, and 40 times amount of benzoyl peroxide in the
trials of another drug and may not reflect the rates observed in clinical practice. highest recommended adult human dose of 2.5 g ONEXTON Gel based on mg/m2, respectively)
did not cause any increase in tumors. However, topical treatment with a different gel formulation
These adverse reactions occurred in less than 0.5% of subjects treated with ONEXTON
containing 1% clindamycin and 5% benzoyl peroxide at doses of 100, 500, and 2000 mg/kg/
Gel: burning sensation (0.4%); contact dermatitis (0.4%); pruritus (0.4%); and rash (0.4%).
day caused a dose-dependent increase in the incidence of keratoacanthoma at the treated
During the clinical trial, subjects were assessed for local cutaneous signs and symptoms of skin site of male rats in a 2-year dermal carcinogenicity study in rats. In an oral (gavage)
erythema, scaling, itching, burning and stinging. Most local skin reactions either were the carcinogenicity study in rats, treatment with the gel formulation at doses of 300, 900 and 3000
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same as baseline or increased and peaked around week 4 and were near or improved from mg/kg/day (1.2, 3.6, and 12 times amount of clindamycin and 1.6, 4.8, and 16 times amount of
baseline levels by week 12. The percentage of subjects that had symptoms present before benzoyl peroxide in the highest recommended adult human dose of 2.5 g ONEXTON Gel based
treatment (at baseline), during treatment, and the percent with symptoms present at week 12 on mg/m2, respectively) for up to 97 weeks did not cause any increase in tumors. In a 52-week
are shown in Table 1. dermal photocarcinogenicity study in hairless mice, (40 weeks of treatment followed by 12
Table 1: Local Skin Reactions - Percent of Subjects with Symptoms Present. Results weeks of observation), the median time to onset of skin tumor formation decreased and the
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from the Phase 3 Trial of ONEXTON Gel 1.2%/3.75% (N = 243) number of tumors per mouse increased relative to controls following chronic concurrent topical
administration of the higher concentration benzoyl peroxide formulation (5000 and 10000 mg/
Before Treatment Maximum During End of Treatment kg/day, 5 days/week) and exposure to ultraviolet radiation.
(Baseline) Treatment (Week 12) Clindamycin phosphate was not genotoxic in the human lymphocyte chromosome aberration
Mild Mod.* Severe Mild Mod.* Severe Mild Mod.* Severe assay. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian
cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to
Erythema 20 6 0 28 5 <1 15 2 0 cause sister chromatid exchanges in Chinese hamster ovary cells.
Scaling 10 1 0 19 3 0 10 <1 0 Fertility studies have not been performed with ONEXTON Gel or benzoyl peroxide, but
fertility and mating ability have been studied with clindamycin. Fertility studies in rats
Itching 14 3 <1 15 3 0 7 2 0 treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the
Burning 5 <1 <1 7 1 <1 3 <1 0 amount of clindamycin in the highest recommended adult human dose of 2.5 g ONEXTON
Gel, based on mg/m2) revealed no effects on fertility or mating ability.
Stinging 5 <1 0 7 0 <1 3 0 <1
PATIENT COUNSELING INFORMATION
*Mod. = Moderate
See FDA-approved patient labeling (Patient Information).
Postmarketing Experience
Because postmarketing adverse reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a Manufactured for:
causal relationship to drug exposure. Valeant Pharmaceuticals North America LLC
Anaphylaxis, as well as allergic reactions leading to hospitalizations, has been reported in Bridgewater, NJ 08807 USA
postmarketing use of products containing clindamycin phosphate/benzoyl peroxide.
By:
DRUG INTERACTIONS Valeant Pharmaceuticals International, Inc.
Erythromycin Laval, Quebec H7L 4A8, Canada
Avoid using ONEXTON Gel in combination with topical or oral erythromycin-containing U.S. Patent 8,288,434
products due to its clindamycin component. In vitro studies have shown antagonism Onexton is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.
between erythromycin and clindamycin. The clinical significance of this in vitro antagonism
©Valeant Pharmaceuticals North America LLC
is not known.
Rev 04/2018
Concomitant Topical Medications
9432703
Concomitant topical acne therapy should be used with caution since a possible cumulative
ONX.0081.USA.18
irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive
agents. If irritancy or dermatitis occurs, reduce frequency of application or temporarily
interrupt treatment and resume once the irritation subsides. Treatment should be
discontinued if the irritation persists.
September 2018 924 Volume 17 • Issue 9

Copyright © 2018 EDITORIAL BOARD Journal of Drugs in Dermatology
EDITOR-IN-CHIEF
Perry Robins MD
CO-EDITOR-IN-CHIEF
Deborah S. Sarnoff MD
SENIOR EDITORS
Macrene Alexiades MD PhD Dee Anna Glaser MD Ronald L. Moy MD Gerhard Sattler MD
Robert Baran MD C. William Hanke MD Keyvan Nouri MD James M. Spencer MD
Joseph B. Bikowski MD William Levis MD Neil S. Sadick MD Susan H. Weinkle MD
SENIOR ASSOCIATE ASSOCIATE EDITORS Neil Alan Fenske MD Ariel Ostad MD

EDITORS Dale M. Abadir MD Rebecca Fitzgerald MD Cleire Paniago-Pereira MD
Kenneth Beer MD William Abramovits MD Alina A. Fratila MD Anna C. Pavlick MD
Martin Braun MD Andrew F. Alexis MD MPH Alejandro Camps Fresnada MD Christopher R. Payne MD
Jeffrey Phillip Callen MD Shawn Allen MD Ellen C. Gendler MD António Picoto MD
Jean Carruthers MD Rex A. Amonette MD Dore Gilbert MD Sheldon V. Pollack MD
James Q. Del Rosso DO Robert Anolik MD David J. Goldberg MD Babar K. Rao MD
Lawrence F. Eichenfield MD Martha P. Arroyo MD Leonard H. Goldberg MD Wendy E. Roberts MD
Patricia Farris MD Robin Ashinoff MD Robert H. Gotkin MD Amy E. Rose MD
Norman Goldstein MD Marc R. Avram MD Gloria F. Graham MD Steven Rosenberg MD
Aditya K. Gupta MD PhD David E. Bank MD John Hawk MD Lidia Rudnicka MD
Elizabeth Hale MD Jay G. Barnett MD Michael P. Heffernan MD Bijan Safai MD
Sherry H. Hsiung MD Eliot F. Battle Jr. MD William L. Heimer II MD Eli R. Saleeby MD
Leon Kircik MD Richard G. Bennett MD N. Patrick Hennessey MD Fitzgeraldo A. Sanchez-Negron MD
Mark Lebwohl MD Diane S. Berson MD Alysa R. Herman MD Miguel Sanchez-Viera MD
Henry W. Lim MD Ronald R. Branacaccio MD George J. Hruza MD Julie Schaffer MD
Flor Mayoral MD Rana Anadolu Brasie MD Shasa Hu MD Bryan C. Schultz MD
Maurizio Podda MD PhD Jeremy A. Brauer MD Mark J. Jaffe MD Daniel Mark Siegel MD
Jeffrey Orringer MD Gary Brauner MD Jared Jagdeo MD Arthur J. Sober MD
Maritza Perez MD Neil Brody MD PhD S. Brian Jiang MD Nicholas A. Soter MD
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Kevin Pinski MD Lance H. Brown MD Bruce E. Katz MD Jennifer Stein MD
Luigi Rusciani Scorza MD Isaac Brownell MD PhD Mark D. Kaufmann MD Fernando Stengel MD
Ritu Saini MD Karen E. Burke MD PhD Amor Khachemoune MD Hema Sundaram MD
Noah S. Scheinfeld MD Mariano Busso MD Poong Myung Kim MD Susan C. Taylor MD
Jerome l. Shupack MD
Amy Taub MD
Danny Vleggaar MD
Brian Zelickson MD
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Francisco M. Camacho-Martinez MD Christine Ko MD
Marian Cantisano-Zilkha MD
Alastair Carruthers MD
Roger I. Ceilley MD
David Kriegel MD
Pearon G. Lang MD
Albert M. Lefkovits MD
Emily Tierney MD
George-Sorin Tiplica MD PhD
Ella L. Toombs MD
Irene J. Vergilis-Kalner MD
Clay J. Cockerell MD Aimee Leonard MD Steven Wang MD
David E. Cohen MD Mary P. Lupo MD Ken Washenik MD PhD
Julian S. Conejo-Mir MD Alan Matarasso MD Jeffrey Weinberg MD
Elizabeth Alvarez Connelly MD Alan Menter MD Robert A. Weiss MD
Ira Davis MD Warwick L. Morison MD W. Phillip Werschler MD
FEATURE EDITORS Calvin Day MD Rhoda S. Narins MD Ronald G. Wheeland MD
Kendra G. Bergstrom MD Doris Day MD Mark Naylor MD Jai Il Youn MD
Joel L. Cohen MD Jeffrey S. Dover MD Kishwer S. Nehal MD John Zic MD
Adam Friedman MD Zoe Diana Draelos MD Martino Neumann MD John A. Zitelli MD
James L. Griffith MD Madeleine D. Duvic MD Nelson Lee Novick MD
Marissa Heller MD Mohamed L. Elsaie MD Jorge J. Ocampo Candiani MD
Isaac Zilinsky MD Joseph C. English III MD Philip Orbuch MD
PAST CO-EDITORS-IN-CHIEF
Elizabeth Hale MD (2004) Impact Factor
Susan H. Weinkle MD (2005-2008) Impact Factor Score: 1.527*
Normalized Eigenfactor® Score: 0.660*
Keyvan Nouri MD (2005-2008)
Article Influence Score: 0.409*
Sherry H. Hsiung MD (2008) *Clarivate Analytics, Formerly the IP & Science Business of
James M. Spencer MD (2009-2013) Thomson Reuters, June 2018
Making
college dreams
come true
As part of its commitment to
the dermatology community,
Ortho Dermatologics created the
Aspire Higher scholarship program.
The program sponsors scholarships
for new college students, graduate
students, and mothers returning to
college. Patients who have been treated
for skin conditions are eligible to apply.
Dr. Linda Stein Gold began serving as one of

several judges for Aspire Higher in 2016.
She also performs clinical research and cares
for patients at the Henry Ford Health System.
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How did you become involved as a judge for
the Aspire Higher program? It’s so satisfying to see how
I was approached by Ortho Dermatologics, and I thought the Aspire Higher scholarship
it was a wonderful opportunity. I really liked that they
Penalties Apply
were giving back to the community and that I could
help people who want to further their education.
can change somebody’s life
by helping them further
What is your favorite part about being
a judge for Aspire Higher?
their education.
I really enjoy the whole experience, but two things come to What are your thoughts about Ortho Dermatologics’
mind: Seeing the impact the scholarships have on the lives commitment to the dermatology community through
of the people who win, and reading their stories. this scholarship program?
One of last year’s winners left a voicemail for the judges. I’m thrilled to be part of it. I’m thrilled to have had the
I was in the middle of grocery shopping when I heard it, opportunity to hear the patients’ stories, to understand their
and I started crying because it was so touching. Also, journey, and to be part of making their educational dreams
reading about how a problem with a person’s skin impacts come true. I think this is a major gift that Ortho Dermatologics
each aspect of their life urges us to seek the best possible gives back to the community, and it’s important to get
treatment for our patients even more. I think that what the word out to our patients that this is available. Ortho
Ortho Dermatologics is doing is exceptionally worthwhile. Dermatologics really does care about our specialty.
Hear from 2017 winner Robby Ruffolo at aspirehigherscholarships.com
Ortho Dermatologics is a trademark of Ortho Dermatologics’ affiliated entities.

© All Rights Reserved. NPR.0521.USA.17

Copyright © 2018 TABLE OF CONTENTS Journal of Drugs in Dermatology
Special FocuS: aeStheticS

CME ARTICLE
931 Managing Seborrheic Keratosis: Evolving Strategies and Optimal Therapeutic
Outcomes
Stephanie Kao BA, Alexi Kiss MD, Tatiana Efimova PhD, Adam J. Friedman MD
ORIGINAL ARTICLES
941 Evaluation of Men’s Trends and Experiences in Aesthetic Treatment
Jose Raúl Montes MD FACS FACCS and Elizabeth Santos DrPH
948
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Rheological Properties of Several Hyaluronic Acid-Based Gels:
A Comparative Study
Patrick Micheels MD and Martinien Obamba Eng
956 Penalties Apply

The Potential Role of Botulinum Toxin in Improving Superficial Cutaneous
Scarring: A Review
Akash Dhawan, Sunil Dhawan MD, Domenico Vitarella PhD
960 Three-Dimensional Analysis of Minimally Invasive Vacuum-Assisted Subcision

Treatment of Cellulite
Jeremy A. Brauer MD, Mitalee P. Christman MD, Yoon Soo C. Bae MD, Leonard J. Bernstein MD,
Robert Anolik MD, Ron Shelton MD, Roy G. Geronemus MD
966 Assessing the Potential Role for Topical Melatonin in an Antiaging Skin Regimen
Doris Day MD, Cheryl M. Burgess MD, and Leon H. Kircik MD
970 A Randomized, Double-Blind, Placebo-Controlled, Split-Face Study of the Efficacy

of Topical Epidermal Growth Factor for the Treatment of Melasma
Alexis Lyons MD, Joseph Stoll BS, and Ronald Moy MD FAAD
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Use Heliocare daily to promote more

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Heliocare’s improved
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This product is not intended to diagnose, treat, cure, or prevent any disease.

ORIGINAL ARTICLES (CONTD)

975 Clinical Efficacy of a Novel Two-Part Skincare System on Pollution-Induced
Skin Damage
Elizabeth T. Makino BS MBA, Annie Jain MD, Priscilla Tan BA, Audrey Nguyen BS, Alain Moga MSc,
Cécile Charmel, Kuniko Kadoya PhD, Tsing Cheng PhD, and Rahul C. Mehta PhD
982 Using a New Photo Scale to Compare Product Integration of Different

Hyaluronan-Based Fillers After Injection in Human Ex Vivo Skin
Björn Lundgren PhD, Ulrika Sandkvist MSc, Nicole Bordier MSc, Beatrice Gauthier DVM
987 Once-Daily Oral Sarecycline 1.5 mg/kg/day Is Effective for Moderate to Severe
Acne Vulgaris: Results from Two Identically Designed, Phase 3, Randomized,
Double-Blind Clinical Trials
Angela Moore MD, Lawrence J. Green MD, Suzanne Bruce MD, Neil Sadick MD, Eduardo Tschen
MD MBA, Philip Werschler MD FAAD FAACS, Fran E. Cook-Bolden MD, Sunil S. Dhawan MD, Dou-
glass Forsha MD, Michael H. Gold MD FAAD, Scott Guenthner MD, Steven E. Kempers MD, Leon
H. Kircik MD, Jennifer L. Parish MD, Marta I. Rendon MD, Phoebe Rich MD, Linda Stein-Gold MD,
Stephen K. Tyring MD PhD, Robert A. Weiss MD FAAD, Adnan Nasir MD, Carsten Schmitz MD PhD,
Terry I. Boodhoo MS, Alexandre Kaoukhov MD, and David R. Berk MD
999 A Single Site, Open Label Clinical Trial, Evaluating the Duration, Efficacy, and
Safety of a Novel Lip Plumper
Monica Boen MD, Marwan Alhaddad MD, Isabella Guiha BSc, Douglas P. Wu MD PhD,
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Mitchel P. Goldman MD
1006 Artificial Intelligence for the Objective Evaluation of Acne Investigator Global
Assessment
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Antonella Melina MSc, Nhan Ngo Dinh MSc, Benedetta Tafuri MSc, Giusy Schipani MD,
Steven Nisticò MD, Carlo Cosentino PhD, Francesco Amato PhD, Diane Thiboutot MD,
Andrea Cherubini PhD
BRIEF COMMUNICATIONS
1010 A Comparative Analysis of Electric and Radiofrequency Microneedling Devices
on the Market
Tudor Puiu BS, Tasneem F Mohammad MD, David M. Ozog MD, Pranita V. Rambhatla MD
1015 Facial Volumetric Structural Rejuvenation: A Natural Approach to Restoring

Youthfulness and Preventing Aging
Neil Sadick MD
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Penalties Apply

LETTER TO THE EDITOR

1017 Erratum
1018 Approach to Skin Lightening in Patients With Melasma

Philip R. Cohen MD
Publishers Associate Publisher

OFFICIAL PARTNER OF Shelley N.Tanner Nick Gillespie
Lawrence E. Robins
Executive Editor Scientific Publications Liaison
Karin Beehler Luz Figueroa
Associate Editor Design

Kathleen Leary RN Karen Rebbe
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© 2018 Journal of Drugs in Dermatology


Copyright © 2018 CME Journal of Drugs in Dermatology
MANAGING SEBORRHEIC KERATOSIS: EVOLVING STRATEGIES AND OPTIMAL THERAPEUTIC OUTCOMES

Release Date: September 1, 2018
Termination Date: August 31, 2019
Estimated Time to Complete This CE Activity: 1 hour
Medium or Combination of Media Used: Written article
Method of Physical Participation: Journal article, Journal post-test, web-based post-test, and evaluation
Hardware/Software Requirements: High speed internet connection, any web browser
Review Date: August 1, 2018
Statement of Need
Seborrheic keratoses are the most common benign tumors pathophysiology, and etiology.
found in older patients affecting approximately 83 million
Americans. A genetic predisposition to develop a high number Credit Designation
of SKs has been identified and the role of epidermal growth Category 1: Creighton University Health Sciences Education
factors and their receptors have been the focus of recent study. designates this live activity for a maximum of 1.0 AMA PRA
Variants to the presentation of SK exist; differential diagnosis Category 1 Credit(s)™. Physicians should claim only the credit
includes a variety of benign and malignant conditions and commensurate with the extent of their participation in the ac-
inflammatory eruptions. SK treatments include cryosurgery, tivity.
electrodessication, curettage, shave biopsy, lasers, and chemi-
cal peels that may result in cosmetic challenges including AAPA accepts AMA category 1 credit for the PRA from
pigmentary issues, scarring, chance for wound infection, and organizations accredited by ACCME.
high cost to patient. Dermatology HCPs require expanded clini-
cal skill for understanding the features, benefits, and cost of Nurse CE: Creighton University Health Sciences Continuing
existing surgical and medical interventions offering better cos- Education designates this activity for 1.0 contact hours for
metic outcome and patient satisfaction. nurses. Nurses should claim only credit commensurate with
the extent of their participation in this activity.
Educational Objectives
The educational goal for this series of journal-based continu- Accreditation Statement
Do Not Copy
ing education activities is to summarize key issues associated In support of improving patient care, this activity has been
with managing seborrheic keratoses (SK) in patients of all skin planned and implemented by Creighton University Health
types; Optimize SK treatment approach utilizing newer topical Sciences Continuing Education (HSCE) and Physicians
treatments; Develop clinician-patient dialogues addressing Continuing Education Corporation. Creighton University Health
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positive SK treatment in areas with critical cosmetic concerns. Sciences Continuing Education (HSCE) is jointly accredited by
Upon completion of the CE activity, learners should be able to: the Accreditation Council for Continuing Medical Education
(ACCME), the Accreditation Council for Pharmacy Education
• Summarize current strategies used in the management of (ACPE), and the American Nurses Credentialing Center (ANCC),
seborrheic keratoses to provide continuing education for the healthcare team.
• Discuss developments in topical treatment options for SK
• Develop a new clinical approach to SK management
• Formulate effective and cost-efficient SK treatment plans

for all patient types presenting to the dermatology setting
How to Obtain CE Credit
Target Audience You can earn one (1.0) AMA PRA Category 1 Credit™ by reading
This activity is intended for dermatologists, residents, and the article contained in this issue and completing a Journal
fellows in dermatology, and physician assistants and nurses, post-test, web-based post-test, and evaluation.
and to provide the dermatology healthcare practitioners with
the latest clinical, scientific, and evidence-based information on Test is valid through August 31, 2019 (no credit will be given after
advances in the understanding of seborrheic keratosis including this date).
scope of disease and clinical presentation, issues relating to
effective diagnosis, and advances in the understanding of the SK To receive credit for this activity, please go to www.JDDonline.com

and click on CME Activities under “Library.” You will find instructions are those of the faculty and do not necessarily represent the
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Research, Department of Dermatology, The George Washington is committed to providing whatever special assistance its users
University School of Medicine & Health Sciences, Washington, require to complete this educational activity.
DC.
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Copyright © 2018 ORIGINAL ARTICLES Journal of Drugs in Dermatology
SPECIAL TOPIC
Managing Seborrheic Keratosis: Evolving Strategies and

Optimal Therapeutic Outcomes
Stephanie Kao BA,a Alexi Kiss MD,b Tatiana Efimova PhD,b,c Adam J. Friedman MDc,d
The George Washington University School of Medicine & Health Sciences, Washington, DC
a
b
Department of Anatomy and Cell Biology, The George Washington University School of Medicine & Health Sciences, Washington, DC
c
Department of Dermatology, The George Washington University School of Medicine & Health Sciences, Washington, DC
d
Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY
ABSTRACT
Seborrheic keratosis (SK) is the most common skin tumor seen by dermatologists in everyday practice. Although the lesions are mostly
benign, many patients still elect to have asymptomatic SK removed. The historical standards of treatment are cryosurgery and electro-
cautery, two surgical options that are effective at lesion removal but have high rates of postoperative adverse events such as treatment-
site scarring and pigmentary alterations. The cosmetic outcomes of SK treatment modalities are of keen interest to dermatologists, as
the American population becomes increasingly more diverse. In this article, the inclusion of darker Fitzpatrick skin types into clinical
studies investigating post-treatment side effects of SK therapy is reviewed. The recent approval of a 40% hydrogen peroxide topical
formulation is discussed in light of these issues, and several non-invasive topical treatments that optimize cosmetic outcomes of SK
lesion removal are highlighted. Finally, treatment strategies aimed at reducing cost and minimizing the burden of adverse sequelae are
provided.
J Drugs Dermatol. 2018;17(9):933-940.
INTRODUCTION
S
eborrheic keratosis (SK) is one of the most common derma- Furthermore, the data revealed that patients most frequently
tologic lesions and is therefore the most common skin tu- elected to have asymptomatic SKs removed due to concerns that
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mor seen by dermatologists in everyday practice.1 They are they may be something serious (57%), not liking their appearance
mostly benign, and are most frequently removed for cosmetic rea- (53%), or not liking how they feel when touched (44%).5 Common
sons.2 SK lesions can occur anywhere on the body, but are most reasons that spur patients to decline treatment are the risks of
commonly located on the face, neck, and trunk while sparing the scarring or pigment changes.6 Darker skinned patients, in particu-
Penalties Apply
palms and soles. They present as round or oval, sharply demar- lar, are more prone to post-inflammatory hypo or hyperpigmenta-
cated papules and plaques that appear “stuck” on the surface of tion after SK treatment. Post-inflammatory hyperpigmentation oc-
skin. SK surface texture is highly variable exhibiting a range of curs when post-inflammatory cytokine secretion causes increased
appearances from rough and keratotic to smooth and waxy and melanin production. Consequently, melanin is abnormally trans-
even flat and macular, the latter presentation occurring especially ported into the dermis where it is trapped by macrophages in the
in SKs that appear initially as a lentigo.3 Despite the frequency papillary dermis leading to superficial hyperpigmentation.7 The
with which patients pursue dermatology visits for evaluation and pathophysiology of post-inflammatory hypopigmentation is more
often cosmetic removal, both the literature on this condition and nebulous and has been proposed to be controlled by autosomal
armament of effective treatment options are surprisingly limited.4 dominant genetic endogenous pigmentary factors that follow “in-
dividual chromatic tendency”.8 The “individual chromatic tenden-
Although the majority of SKs are benign, many patients elect to cy” posits that people with weak melanocytes, which are highly
have them removed due to a possibility of malignancy, itching, susceptible to damage, are more likely to develop hypopigmen-
irritation, and/or cosmetic reasons. The number of SKs generally tation, and that dark-skinned people with weak melanocytes are
increases with age, and the lesions have colloquially come to be prone to develop hypopigmentation.8,9 These factors may explain
termed “age spots”. As such, dermatologists frequently hear from why certain individuals develop hyperpigmentation and others hy-
patients that they desire removal of SK lesions in order to main- popigmentation. Repigmentation may occur but is not predictable.
tain a more youthful appearance and improve their quality of life.4
An observational study conducted across 10 dermatology practic- Treatment Options
es by Del Rosso et al highlighted how SKs affect quality of life and Currently, cryosurgery and electrocautery are the two most
treatment concerns. 61% of patients, primarily women, reported commonly employed techniques to physically resolve an
covering their SKs with makeup, specific hairstyles, or clothing.5 SK.10,11 Cryosurgery destroys SK lesions by inducing ice crys-
934
Journal of Drugs in Dermatology S. Kao, A. Kiss, T. Efimova, A.J. Friedman
September 2018 • Volume 17 • Issue 9
tal formation, which leads to physical damage of cells, or via Korean males (88.1%) as in the general Caucasian population
inflammatory processes that are not fully understood.12,13 Suc- (81-100%).3,22 Furthermore, this study concluded that SK preva-
cess with cryosurgery is dependent on a number of factors, lence increased with advancing age, a finding consistent with
such as depth and vascularity of the lesion, duration of freezing, prevalence trends in the Caucasian population. These findings
and number of freeze/thaw cycles performed by the dermatolo- demonstrate that SK is a medical concern not solely limited to
gist.14 Electrocautery destroys SK lesions via electrodessication Caucasians, but a condition that affects people of diverse skin
or electrofulguration with or without curettage. Electrodessica- types.
tion is applied directly to the surface of the lesion and removes
tissue using active electrodes; during electrofulguration, the Dermatosis papulosa nigra (DPN), an SK variant, occurs pre-
electrode is held away from the skin, produces sparking at the dominantly in darker-skinned people with a reported incidence
surface, and induces more superficial tissue damage.4,15 Unlike of 70% in African Americans and 40% in Asians.23 It is consid-
cryosurgery, electrocautery softens SKs at the dermoepidermal ered especially challenging to treat given the increased risk
junction and is more effective for small lesions. of post-inflammatory hypo- or hyperpigmentation in people
with darker skin types.24 Currently, DPN lesions are removed
The adverse events associated with both cryosurgery and elec- via scissor excision, laser therapy, electrodessication, curet-
trocautery include treatment site pain, erythema, local edema tage, cryotherapy, and microdermabrasion. In a 2009 study
and crusting, blister/bulla formation, and bleeding at treatment comparing the post-therapeutic side effects of electrodesicca-
sites.4 All patients are susceptible to some degree of bleed- tion versus potassium-titanyl-phosphate (KTP) laser, Kundu
ing, blistering, infection, scarring, recurrence, and pigmentary et al enrolled 14 patients with dermatologist-diagnosed DPN
changes post-treatment, but darker-skinned individuals are par- who had Fitzpatrick skin phototype IV-VI. The study reported
ticularly vulnerable to the last three adverse events.16-18 Patients that KTP laser treatment led to hyperpigmentation in 5/14 and
with darker skin types have melanocytes with increased sensi- hypopigmentation in 4/14, while electrodessication resulted in
tivity to cutaneous stimulation and, importantly, inflammation hyperpigmentation in 5/14 and hypopigmentation in 2/14 pa-
that can result in either post-inflammatory hypo- or hyperpig- tients.25 These results revealed that destructive therapies, such
mentation.4 Melanocytes are also the most sensitive epidermal as electrocautery and lasers, commonly resulted in pigmentary
cells to severe thermal changes, and are susceptible to tem- alterations in patients with darker skin types. Furthermore, 3/14
peratures less than -5 C.19 This is pertinent to cryosurgery, which subjects reported scarring, a post-treatment adverse event that
utilizes -196 C freezing liquid nitrogen. Therefore, melanocytes increases the risk of keloids. African American patients are par-
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are the first of any superficial cells to succumb to cryosurgery, ticularly susceptible to keloid formation after dermal trauma
resulting in disfiguring and often permanent depigmentation. with an estimated keloid incidence of ~1/30.26 These adverse
As such, patients with darker skin tones are more prone to ex- events present a paradoxical dilemma for patients with darker
perience transient pigmentary changes and are at higher risk skin types for whom pigment alteration and keloid formation
Penalties Apply
to develop permanent depigmentation. Lesions on the trunk, post-cosmetic SK removal could create greater psychosocial
tip of the nose, and helix of the ear are most susceptible to burdens than the initial SK lesion.27 Therefore, care must be
hypopigmentation.11 taken to avoid hyperpigmentation, hypopigmentation, or scar-
ring after treatment.
The considerations of ethnicity and Fitzpatrick skin type have
only recently been incorporated into literature on the cosmetic Topical Therapies
impact of SK therapy. Most clinical investigations have only en- With the number of postoperative adverse events associated
rolled Caucasian patients in studies that explored the effects of with surgical treatment, there has been a push for topical SK
SK treatment. An example includes a study by Wood et al exam- therapy based on patient preference for non-invasive man-
ining the effectiveness of cryosurgery versus curettage where agement options.28 Previous reports have shown moderate
64% of patients preferred cryotherapy over curettage citing effectiveness of topical vitamin D analogues with application
decreased postoperative wound care. The study demonstrated once or twice daily for 3-12 months. Only 1/3 of lesions re-
that neither surgical option showed statistically significant dif- solved completely while other lesions showed a decrease in
ferences in subject ratings for cosmetic improvement at either volume.29 Tazarotene 0.1% cream applied twice daily has also
6-week or 12-month follow up. Additionally, both treatment achieved lesion resolution confirmed by histology, but caused
modalities were found to produce highly satisfactory cosmetic significant burning, pruritus, and redness.28 In December 2017,
outcomes, yet investigators noted that the study only enrolled A-101 (Eskata®) became the first topical drug to be granted FDA
subjects that had Fitzpatrick skin types 1-3.20 In 2003, Kwon et approval for SK therapy.6 A-101 is a stabilized, high concentra-
al evaluated the prevalence and clinical features of SKs in 303 tion hydrogen peroxide (40%) topical solution that capitalizes
Korean males aged 40-70, Fitzpatrick skin types I-V.21 Their re- upon the oxidizing potential of hydrogen peroxide (H2O2 ). Nor-
sults demonstrated that SKs were as common in this cohort of mal physiologic concentrations of H2O2 are tightly regulated
935
as highly reactive hydroxyl radicals (OH.) and other reactive the A-101 treated samples without dermal pigmentary incon-
oxygen species (ROS) produced by H2O2 may be toxic to cells. tinence, though this increased pigment in the epidermis was
The local destructive effects of hydroxyl radicals and ROS are not overtly noted on hematoxylin and eosin staining (Figure 3E,
countered by a complex antioxidant defense system that in- F). Additionally, MRHE tissues treated with A-101 were found to
cludes both enzymatic and nonenzymatic components. Thus, have more intact melanocytes than those treated with cryosur-
when topically applied to SK cells, the supraphysiologic con- gery (Figure 3G, H, I, J).
centration of H2O2 in A-101 overwhelms the antioxidant defense
systems leading to the generation of ROS, direct oxidative Together, these results suggest that A-101 could reduce the risk
damage to the keratinocytes, and eventually apoptosis of SK of post-treatment pigmentary alterations especially in African
cells.6 Phase three clinical trials demonstrated that A-101 was American patients. A-101 treated samples importantly showed
effective at removing SK lesions with very low occurrences of no dermal pigmentary incontinence, a process that underlies
hypopigmentation and/or scarring in predominantly Caucasian post-inflammatory hyperpigmentation. To elucidate the safety
patients (2.3% and 0.6% of patients, respectively).30 Addition- and efficacy of A-101 on darker skin types, a current phase 2
ally, a recent ex-vivo study comparing the toxicologic impact of clinical trial is being conducted to evaluate the risk for hypopig-
A-101 versus cryosurgery on Fitzpatrick V Melanoderm® recon- mentation or hyperpigmentation after treatment of DPN lesions
stituted human epidermal equivalents (MRHE) derived from an on subjects with Fitzpatrick V-VI skin (ClinicalTrials.gov Identi-
African American donor showed that A-101 promotes greater fier: NCT03224598).
melanocyte preservation than does cryosurgery.31 Further data
demonstrating that cryosurgery causes greater epidermal An additional topical therapy that is being explored is BL-5010,
damage than A-101 treatment elaborates on this suggestion; a novel combination of aqueous trichloroacetic acid and formic
MRHE were treated with 5 seconds of cryosurgery (Cryo5), 10 acid. It is suggested that the combined effects of TCA and for-
seconds of cryosurgery (Cryo10), 1L of A-101, or 2L of A-101 mic acid may lead to in situ SK lesion fixation and preservation
compound in vehicle. Histologic evaluation of untreated and which results in cell death and ultimate lesion detachment from
A-101 vehicle treated tissues revealed a regular, basket-weaved skin.32 Results from a phase I/II open-label, single-arm study
stratum corneum, normal spinous and basal cell layers overly- in which a single topical application of BL-5010 was applied to
ing a well organized dermis with scattered fibroblasts (Figures 60 patients with SK demonstrated lesion detachment from the
1A/B). MRHE treated with both cryosurgery for 5 and 10 sec- skin in 97% of patients at the 30 day post-BL5010 application
onds demonstrated overall thinning and increased pallor of the follow-up evaluation.32 The investigators reported cosmetic
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epidermis, with more pyknotic cells noted in the deeper spi- assessment on a subjective scale and it is unknown if investiga-
nous layer of the 10 seconds specimens (Figures 1C/D). In both tors included post-application pigmentary changes or skin type
cryosurgery groups, dermal-epidermal junction separation was in their assessments.
noted, though more prominent in the 10 seconds group. In both
Penalties Apply
A-101 treated groups, acanthosis of the epidermis and mild Therapeutic Selection
pallor was noted though not to the extent of the cryosurgery Together, topical therapies can be included in the arsenal of
treated specimens, and no epidermal clefting was observed in SK treatment options at disposal to dermatologists. Given the
these specimens (Figure 1E/F). most common concern regarding these benign lesions is cos-
metic, appropriate treatments should not provide an alternative
Further TUNEL staining to support the cell viability assays cosmetic disfigurement in the wake of these lesions. Topical
performed by Kao et al was completed on MRHE treated therapies fill this gap by providing non-invasive management
with either cryosurgery or A-101: stains of MRHE treated with options. Therapies must be used cautiously in individuals with
cryosurgery exhibited the most TUNEL positive cells, most numerous SKs or darker Fitzpatrick skin types who are at risk
notably at the basal epidermal layer, as compared to MRHE for pigmentary alterations related to destructive treatments.
treatment with A-101 (Figure 2A-E). These results quantified the Because adverse events associated with treatment can be sig-
greater epidermal cell apoptosis incurred by treatment with nificant, careful matching of treatment to the patient’s skin type,
cryosurgery. Given the sensitivity of melanocytes to decreased lesion location and expectations ultimately determine a suc-
temperatures and the well described hypo- or depigmentation cessful outcome as defined by both the physician and patient.
following cryosurgery treatment of seborrheic keratosis, the Clinicians should consider utilizing multiple treatment modali-
impacts of cryosurgery and A-101 on melanocyte number, me- ties on a few lesions first, and then allow the patient to choose
lanosome dispersion in the epidermis, and dermal pigmentary which method they prefer for the subsequent treatment of the
incontinence were evaluated. Using Fontana-Masson staining, remaining lesions.20 For example, thicker and larger SKs may
decreased melanin was visualized throughout the epidermis benefit from combination therapy whereas thinner and smaller
of those MRHEs treated with cryosurgery (Figure 3A-D). Inter- SKs may be satisfactorily removed with monotherapy. Lesions
estingly, increased melanosome dispersion was visualized in in cosmetically-sensitive areas, such as the face, and patients
936
FIGURE 1. Immunohistochemical stains of MRHE treated with cryosurgery or A-101. 9-millimeter diameter MRHE tissues were fixed in 10%
formaldehyde and paraffin-embedded. Stained sections were taken from the center of the cryosurgery or A-101 application area. Hematoxylin
and eosin stains of untreated control (A), A-101 vehicle control (B), cryosurgery 5 seconds (C), cryosurgery 10 seconds, with inset showing
representative pyknotic nuclei marked by arrows (D), A-101 1 L (E), and A-101 2 L (F). Data is representative of four independent experiments
from four different MRHE tissues. Scale bars represent 200 m.
(A) (B)
(C) (D)
(E) (F)
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with darker skin types may benefit from topical therapies which pair). This is in contrast to non-dermatologists who treated 51%
Penalties Apply
are less cytotoxic to the surrounding epidermis and less dam- of histologically identified SK lesions with low-intensity man-
aging to melanocytes. agement and 49% with high intensity management.34 In sum,
dermatologists had the highest diagnostic accuracy for SKs
Because SKs can mimic several cutaneous malignancies, and were more likely to use low-intensity management options
diagnostic accuracy and cost-efficient treatment plans are im- that both protected patients from undue risks of higher inten-
portant to reducing wasteful healthcare expenditure. Bickers sity procedures and were less costly to Medicare. These results
et al determined that the directed healthcare cost due to SKs underscore the importance of seeing a dermatologist for suspi-
was approximately $1.1 billion with an additional indirect cost cious SK not only for diagnostic accuracy but also to reduce
of $113 million due to lost productivity, and a further intangible costs and wasteful medical expenditures. Moreover, lesion
cost of $6.7 billion caused by negative QOL impact.33 In an- evaluations by dermatologists could spare patients of darker
other study that evaluated the intensity of care (low and high) skin types from paradoxical post-treatment cosmetic sequelae.
and cost of SK treatment biopsied by either dermatologists
or non-dermatologists in a representative sample of the U.S. CONCLUSION
Medicare population, Duque et al found a significant difference Seborrheic keratoses are benign lesions that are most frequent-
in the surgical management of SK between dermatologists ly removed for cosmetic reasons. Current therapeutic options,
and non-dermatologists.34 Specifically, dermatologists treated while effective in lesion removal, often result in post-treatment
89% of histologically identified SK lesions with low-intensity sequelae such as pigmentary alterations and scarring that affect
approaches (biopsy, shaving of epidermal or dermal lesions) darker skinned patients more significantly. Additionally, more
and 11% with high-intensity management (excision of benign research needs to be done on the effectiveness of current SK
lesions, excision of malignant lesions, destruction of malignant management options on patients with darker skin types. Topi-
lesion by any method, simple intermediate repair, complex re- cal agents provide an exciting, new avenue for non-invasive
937
FIGURE 2. Cell viability was assessed via TUNEL immunohistochemical staining. 9-millimeter diameter MRHE tissues were fixed in 10%
formaldehyde and paraffin embedded. Stained sections were taken from the center of the cryosurgery or A-101 application area. TUNEL
stains of untreated control (A), cryosurgery 5 seconds, with inset showing representative TUNEL-positive nuclei marked by arrows (B),
cryosurgery 10 seconds (C), A-101 1 L (D), and A-101 2 L (E). Data is representative of four independent experiments from four different MRHE
tissues. Scale bars represent 200 m.
(A) (B) (C) (D) (E)
FIGURE 3. Fontana-Masson and S100 immunohistochemistry stains of MRHEs treated with cryosurgery or A-101 were used to assess
melanosome dispersion and number of melanocytes, respectively. 9-millimeter diameter MRHE tissues were fixed in 10% formaldehyde and
paraffin embedded. Stained sections were taken from the center of the cryosurgery or A-101 application area. Melanosome dispersion was
visualized using Fontana-Masson staining of cryosurgery 5 seconds (A), cryosurgery 10 seconds (B), A-101 1 L (C), A-101 2 L (D). Increased
melanosome dispersion was observed in the A-101 treated samples (C and D), but was weakly visible on hematoxylin and eosin staining,
A-101 1 L (E), A-101 2 L (F). Melanocyte number was measured using S100 staining of cryosurgery 5 seconds (G), cryosurgery 10 seconds (H),
A-101 1 L (I), A-101 2 L, with inset showing representative S100-positive cells marked by arrows (J). Data is representative of four independent
experiments from four different MRHE tissues. Scale bars represent 200 m.
(A) (B) (C) (D) (E)
(F) (G) Do Not Copy (H) (I) (J)
Penalties Apply
3. Yeatman JM, Kilkenny M, Marks R. The prevalence of seborrhoeic keratoses
SK management that minimize the potential for post-treatment in an Australian population: does exposure to sunlight play a part in their
cosmetic adverse events. A-101, in particular, shows promise frequency? Br J Dermatol. 1997;137(3):411-414.
4. Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current un-
as a therapy that produces better cosmetic outcomes and could
derstanding of seborrheic keratosis: Prevalence, etiology, clinical presenta-
be pivotal in addressing the concerns of patients who elect to tion, diagnosis, and management. J Drugs Dermatol. 2015;14(10):1119-1125.
cosmetically remove their SK lesions. 5. Del Rosso JQ. A closer look at seborrheic keratoses: Patient perspectives,
clinical relevance, medical necessity, and implications for management. J
Clin Aesthet Dermatol. 2017;10(3):16-25.
DISCLOSURE 6. DuBois JC, Jarratt M, Beger BB, Bradshaw M, Powala CV, Shanler SD. A-101,
a proprietary topical formulation of high-concentration hydrogen peroxide
Adam Friedman is a consultant for Aclaris Therapeutics. solution: A randomized, double-blind, vehicle-controlled, parallel group study
of the dose-response profile in subjects with seborrheic keratosis of the
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tassium-titanyl-phosphate laser for treatment of dermatosis papulosa nigra.
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Dermatol Surg. 2009;35(7):1079-1083.
26. Bergsma D, Bergsma D, National Foundation. Birth defects compendium.
2d ed. New York: Published for the National Foundation-March of Dimes by
A. R. Liss; 1979.
27. Stratigos AJ, Katsambas AD. Optimal management of recalcitrant disor-
Penalties Apply
ders of hyperpigmentation in dark-skinned patients. Am J Clin Dermatol.
2004;5(3):161-168.
28. Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: a study compar-
ing the standard cryosurgery with topical calcipotriene, topical tazarotene,
and topical imiquimod. Int J Dermatol. 2004;43(4):300-302.
29. Mitsuhashi Y, Kawaguchi M, Hozumi Y, Kondo S. Topical vitamin D3 is ef-
fective in treating senile warts possibly by inducing apoptosis. J Dermatol.
2005;32(6):420-423.
30. Draelos ZD KS, Smith SR, Wilson DC, Powala CV, Bradshaw M, Estes E,
Shanler SD. Safety and efficacy of A-101 hydrogen peroxide topical solution
in adults with seborrheic keratosis: Results from the phase 3, randomized,
double-blind, vehicle-controlled, parallel-group study. SKIN The Journal of Cu-
taneous Medicine. 2017;1:s119.
31. Kao S, Kiss A, Efimova T, Friedman A. An ex-vivo evaluation of cytotoxic-
ity and melanocyte viability after A-101 hydrogen peroxide topical solution
40% or cryosurgery treatment in seborrheic keratosis lesions. J Am Acad
Dermatol. 2018.
32. Levy-Nissenbaum E, Thio HB, Burstein P, Thaci D. Seborrhoeic keratosis re-
moval in a multicentre phase I/II clinical trial using a novel topical formulation
(BL-5010). Br J Dermatol. 2015;173(1):247-249.
33. Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004 a
joint project of the American Academy of Dermatology Association and the
Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-
500.
34. Duque MI, Jordan JR, Fleischer AB, Jr., et al. Frequency of seborrheic kera-
tosis biopsies in the United States: a benchmark of skin lesion care quality
and cost effectiveness. Dermatol Surg. 2003;29(8):796-801; discussion 801.

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1. What is the most common therapy currently used to 4. What is the direct healthcare cost due to SK?
treat SK?
a. $1,092,000,000
a. Tazarotene 0.1%
b. $113,000,000
b. Vitamin D analogues
c. $6,700,000,000
c. Cryosurgery
d. $540,000,000
d. Laser
5. What are the most sensitive epidermal cells to severe

2. What is the major chemical compound in A-101? thermal changes?
a. Trichloroacetic acid a. Keratinocytes
b.
c.
Hydrogen peroxide
Formic acid
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c.
Melanocytes
Desmosomes
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d. Potassium-titanyl-phosphate d. Hemidesmosomes
3. What is a well-documented adverse event associated

with cryosurgery?
a. Pigmentary alterations
b. Chelitis
c. Thermal burn
d. Acanthosis

Journal of Drugs in DermatologyCMES. Kao, A. Kiss, T. Efimova,
Copyright © 2018 A.J. Friedman
Journal of Drugs in Dermatology
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september 2018 941 Volume 17 • Issue 9

SPECIAL TOPIC
Evaluation of Men’s Trends and Experiences

in Aesthetic Treatment
Jose Raúl Montes MD FACS FACCS and Elizabeth Santos DrPH
Jose Raúl Montes Eyes & Facial Rejuvenation, San Juan, Puerto Rico
ABSTRACT
Men’s interest and participation in cosmetic procedures has increased in recent years; however, the factors that motivate or discourage
men from undergoing these procedures is not well understood. To evaluate which factors impact men’s decisions towards cosmetic
procedures, an observational, single-site, cross-sectional study utilizing a voluntary questionnaire was executed in a target population
size of 209 men ≥21 years old who visited the study site from 2015 to 2017. A majority of the male respondents incorporate a basic
skincare regimen into their daily routine (90%), have had experience with neurotoxin treatments (54%), and expressed interest in either
neurotoxin or dermal filler treatments (77% and 83%, respectively). The main motivating reason to undergo a cosmetic procedure was
pursuit of a youthful appearance and the main discouraging reasons were cost and time for appointments or recovery. This study sug-
gests that a majority of our male patients have either embraced or are interested in cosmetic treatments, but the cost and time play
a big role in their decision. As cosmetic providers, we should reflect a commitment to the male population through marketing efforts
and offerings to increase participation in minimally invasive aesthetic procedures.
J Drugs Dermatol. 2018;17(9):941-946.
INTRODUCTION
T
he number of men undergoing nonsurgical and surgi- surgery (the other 2 were nose and eyelid surgery).1 The top
cal procedures has increased in recent years. Accord- 2 nonsurgical procedures for men reported by ASAPS in 2016
ing to the American Society for Aesthetic Plastic Sur- were botulinum toxin injections and hyaluronic acid filler injec-
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gery (ASAPS), nearly 1 in 10 cosmetic procedures in the United tions.
States are performed in men.1 Men are equally pursuing surgi-
cal and nonsurgical procedures and are open to a variety of Research in cosmetic and non-surgical aesthetic procedures
tactics to maintain and enhance their appearance. In 2016, men has typically focused on the female face and aging. However,
Penalties Apply
had nearly 185,000 surgical procedures (9% of the total) and physicians need to recognize gender differences in anatomy,
more than 1 million nonsurgical procedures (9% of the total). skin biology, skin aging, behavior, and rejuvenation goals to
This rise in male patients’ interest to undergo cosmetic pro- allow the male cosmetic market to reach its potential4-5. From
cedures is related to many social factors: (1) a desire to look 2000-2016, the total amount of minimally-invasive cosmetic
youthful and be more competitive at work, (2) the growing procedures in the US grew by 180%, and the growing mar-
availability of non-surgical options, and (3) the society’s accept- ket between female and male differed by 90% (164% increase
ability of men undergoing cosmetic procedures.2 in female vs. 74% increase in male non-invasive cosmetic
procedures).6 Despite men’s increased interest in cosmetic
According to a survey of 1,000 adults aged 18 years and older treatments, they still only represent a small portion (8%) of
in the US and the U.K. from April 29-May 2, 2013 conducted by the patients undergoing cosmetic procedures.6 As the number
J. Walter Thompson Intelligence, men today feel more pressure of men seeking cosmetic treatment increases, practitioners
to look polished than they did in the past (76%), and a majority should reflect a commitment to the male patient through avail-
agree they have as much pressure as women to have a good able treatments, marketing, clinic design, and staff.7 Thus, there
body (78%) and to be well-groomed (73%).3 According to the is a need for practitioners to understand men’s concerns and
male survey respondents, some of the areas causing them to trends in cosmetic and aesthetic procedures.8 This study aims
have anxiety about their appearance include wrinkles (28%), to inquire about which factors impact men’s decisions towards
beer belly (40%), love handles (33%), lack of abs/six pack (32%), cosmetic procedures, including motivating or discouraging
and gynecomastia/man boobs (30%). These areas are in accor- factors, demographic data, and aspects of appearance that are
dance with 3 of the top 5 surgical procedures for men reported concerning to them.
by ASAPS in 2016: liposuction, breast reduction, and facelift
942
Journal of Drugs in Dermatology J.R. Montes and E. Santos
TABLE 1.
METHODS AND PATIENT POPULATION
Respondent Demographics
This was an observational, single-site, cross-sectional study
which utilized a voluntary questionnaire designed to evalu- Variable, Statistic or Category Total (N = 101)
ate the male patient’s experience with and attitudes toward
aesthetic procedures. The objective of the study was to iden- Average Age (SD; Min, Max) 52.5 (10.7; 28, 82)
tify common factors which motivate or discourage the male Age Distribution, n (%) 0
patient’s pursuit of aesthetic enhancements. The 36-item ques-
25 - 35 years 3 (0.6)a
tionnaire included domains related to skincare routines, history
of aesthetic procedures, existing concerns with appearance, 36 - 45 years 141 (29.3)
and interest in future aesthetic treatments with a specific fo- 46 - 55 years
cus on neurotoxins and dermal fillers. Questions regarding 56 - 65 years 22 (4.6)
relationship status and sexual orientation were also included,
66 + years 10 (2.1)
as these characteristics might influence the level of motivation
regarding an individual’s desire to maintain or enhance their Highest Educational Level, n (%) 13 (2.7)
personal appearance. High school 22 (4.6)

Undergraduate 10 (2.1)
The questionnaire was administered either in-office or by email
Post-Graduate 41 (40.6)
via Blind Carbon Copy. A target population size of 209 eligible
Occupation*, n (%)
male patients were identified ≥21 years old who visited the of-
fice from 2015 to 2017 (Oculoplastic Surgery practice in San Operatives 3 (3.0)
Juan, Puerto Rico). A descriptive analysis of all data was con- Technician 4 (4.0)
ducted. Service 7 (6.9)
RESULTS Unemployed/Retired 9 (8.9)
Respondent Demographics, Skincare Practices, and Concerns Officials/Managers 11 (10.9)

With Appearance Sales 22 (21.8)
A population of 101 male respondents were included in the Professionals 45 (44.6)
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study (Table 1). Respondents were between the ages of 28 and
82 years (mean age, 52.5) and most had achieved an educa- Relationship Status, n (%)
tional level of graduate school or higher (90.1%, graduate and
Single 44 (43.6)
postgraduate levels combined), and were employed in profes-
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sional level occupations (76.2%, officials/managers, sales, and Divorced 13 (12.9)
professionals categories combined). A little more than half of Widowed 1 (1.0)
the respondents (57.4%) were single, (single, divorced, and wid- In a Relationship 6 (5.9)
owed) and 42.6% were married or in a relationship. More than
Married 37 (36.6)
half of respondents (64.4%) were heterosexual, while 31.7%
were homosexual and 4.0% bisexual. Sexual Orientation, n (%)
Heterosexual 65 (64.4)
Medical Conditions Homosexual 32 (31.7)
While 62.4%, (63/101) of respondents reported no medical con-
Bisexual 4 (4)
ditions at all, the most commonly reported conditions in order
of frequency were high blood pressure (19.8 %, 20/101), thy- Note: % = n/101*100; *Categorized using EEO-1 Job Classification Guide 2010
roid condition (5.9%, 6/101) heart condition or HIV (4.0% each, Note: % may not total 100% due to rounding.
4/101), diabetes (3.0%, 3/101), arthritis, cholesterol, glaucoma,
or skin condition (2.0% each, 2/101), and asthma or COPD (1.0% including those who use only sunscreen. Additionally, 60.4%
each, 1/101; data not shown). use a combination up to 2 products and 40.0% (36/91) use a
combination of more than 2 products (data not shown). The
Male Respondent Experiences With Varying Skincare Regimens majority (83.5%, 76/91) of respondents who practiced a form of
The majority of male respondents practiced some form of sk- skincare reported buying their own products (data not shown).
incare routine (90.1%) (n=91; Figure 1). As not all sunscreen Of the 16.5%, (15/91) who did not buy their own products, their
products are moisturizing, the proportion of those respondents wives (76.9%, 10/13), family members (15.4%, 2/13), and signifi-
using moisturizer (49.5%; Figure1) may be conservative by not cant others (7.7%, 1/13) made their purchases for them.
943
FIGURE 1. Skincare practices and use of specialized products. FIGURE 2. Respondent rankings of importance concerning aspects
Abbrev: n, number of respondents. Note: % = n/91*100. of appearance. Abbrev: N, number of respondents. Note: Ranking
goes from highest (1, Most Important) to lowest (10, Least Impor-
tant); % = n/101*100.
FIGURE 3. Respondent experience with dermatological treatments. FIGURE 4. Respondent experience and attitude toward treatment
Abbrev: N/n, number of respondents. Note: Excludes injectable with neurotoxin injectables. Abbrev: N/n, number of respondents.
treatments (eg, dermal fillers, neurotoxins); % = n/101*100 (panel Note: % = n/101*100 (panel 4a); % = n/53*100 (panel 4b); One “yes”
3a); % = n/60*100 (panel 3b). responder did not answer question for panel 4b.
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Male Respondent Rankings of Importance Regarding Aspects Male Respondent Experience With Neurotoxin and Dermal Filler
of Appearance Aesthetic Treatments
Male respondents ranked looking old, feeling old, and tired In terms of neurotoxin aesthetic treatments, half of respon-
eyes as the 3 most important aspects of their appearance that dents (53.5%) had neurotoxin treatments in the past and the
concerned them (Figure 2). majority (77.2%) would consider having neurotoxin treatments
(Figure 4a). The three most commonly treated areas for those
Male Respondent Experience With Dermatologic respondents who had neurotoxin treatments in the past were
“Aesthetic” Treatments glabella (83.0%), forehead (73.6%), and crow’s feet (73.6%; Fig-
A little over half of the male respondents (59.4%) had an aes- ure 4b).
thetic dermatological treatment in the past and of those, the
large majority had a past facial (81.7%; Figure 3a). The 2 other In terms of dermal filler aesthetic treatments, a little less than
most common procedures were silk peel microdermabrasion half (38.6%) had dermal filler aesthetic treatments in the past,
(40.0%) and chemical peel (30.0%; Figure 3b). and the large majority (83.2%) would consider having dermal
filler treatments (Figure 5a). Interestingly, more respondents
944
FIGURE 5. Respondent experience and attitude toward treatment FIGURE 6. Respondent experience with cosmetic surgery. Abbrev:
with dermal filler injectables. Abbrev: N/n, number of respondents. N/n, number of respondents. Note: % = n/101*100 (panel 6a); % =
Note: % = n/101*100 (panel 5a); % = n/38*100 (panel 5b); One “yes” n/34*100 (panel 6b); Four “yes” respondents did not answer ques-
responder did not answer question for panel 5b. tion for panel 6b.
FIGURE 7. Respondent Rankings of Importance Regarding Factors FIGURE 8. Respondent interest in learning more about treatments
that Motivate or Prevent Them from Seeking Neurotoxin or Dermal with neurotoxin or dermal filler injectables. Abbrev: N, number of re-
Filler Treatments. Abbrev: N, number of respondents. Note: Ranking spondents. Note: % = n/41*100 (neurotoxins); % = n/42*100 (dermal
goes from highest (1, Most Important) to lowest (4/5, Least Impor- fillers; panel 8b).
tant); % = n/101*100.
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Penalties Apply
stated they would consider dermal filler aesthetic treatments reasons that respondents stated would prevent them from hav-
than neurotoxin treatments. The three most commonly treated ing either treatment (Figure 7b).
areas for those respondents who had dermal filler aesthetic
treatments in the past were cheeks (65.8%), NLFs (44.7%), and In terms of what treatments respondents were interested in
eyes (13.2%; Figure 5b). learning more about (neurotoxin vs. dermal fillers), more were
interested in learning about dermal filler treatments (60.4%)
Male Respondent Experience With Cosmetic Surgery vs. neurotoxin treatment (53.5%; Figure 8a). These numbers
Less than half of the male respondents (37.6%) had cosmetic agree with what male respondents would consider in the future
surgery in the past (Figure 6a). Blepharoplasty (47.1%) and rhi- (more respondents would consider treatments with dermal fill-
noplasty (26.5%) were the top 2 procedures performed on these ers compared to neurotoxins; Figure 4-5).
respondents (Figure 6b).
Respondents were most interested in learning about how neu-
Male Respondent Attitudes and Interest Regarding Neurotoxin rotoxins work vs. learning general information about dermal
and Dermal Filler Aesthetic Treatments fillers (34.1% vs. 33.3%, respectively). Interestingly, 4 times
The top reason or motivating factor for interest in having a neu- more respondents were interested in details on the possible
rotoxin and/or dermal filler aesthetic treatment was youthful side effects of neurotoxins vs. dermal fillers (24.4% vs. 4.8%,
appearance (84.2%; Figure 7a). Cost and time were the top 2 respectively).
945
Also of note, more than twice as many respondents were in- FIGURE 9. Respondent attitude towards disclosing their neurotoxin
terested in details on treatment results with dermal fillers than or dermal filler treatments. Abbrev: N, number of respondents. Note:
they were with neurotoxins (23.8% vs. 9.8%, respectively; Fig- % = n/101*100 (panel 9a); % = n/84*100 (panel 9b).
ure 8b).
Male Respondent Attitudes Towards Treatment Disclosure

Interestingly, 83.2% of respondents reported that they would be
willing to disclose that they had an aesthetic procedure done
(Figure 9a). However, when asked who they would be willing
to admit it to, only 35.7% stated they would be willing to admit
it to everyone and 36.9% stated they would be willing to admit
it to their spouse/significant other (Figure 9b).
DISCUSSION
As the male population demands for cosmetic procedures An overwhelming majority of the respondents expressed in-
grow, it is increasingly important to understand men’s concerns terest in neurotoxin and filler treatments in the future: 77%
and trends in this field. The purpose of this study was to inquire would consider neurotoxin and 83% would consider filler injec-
about which factors impact men’s decisions towards cosmetic tions. In this study, the main motivating reason to undergo a
procedures, including motivating or discouraging factors, de- cosmetic procedure was the pursuit of a youthful appearance
mographic data, and aspects of appearance that are concerning for their sense of well-being. Work competition and pleasing
them. a significant other were listed as other factors, to a lesser de-
gree. These data are consistent with earlier studies.2 In terms
The typical male respondent in this study was middle-age, of factors that prevent men from seeking aesthetic treatments,
achieved a graduate school education or higher, and employed men weighed the cost before embracing cosmetic procedures,
in a professional level occupation. Interestingly, there was an consistent with their female counterpart.10 Time is also a major
almost equal distribution between single men and those in a concern for men; thus, they have less flexibility to accommo-
relationship, and about two-thirds described themselves as be- date appointments, or set aside periods for recovering.
ing heterosexual.
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Overall, men are very interested in knowing how neurotoxins
A majority of respondents (90%) incorporate a basic skincare and dermal fillers work, and the side effects and general infor-
regimen into their daily routine, with facial cleanser, moistur- mation about each product. They also prefer the idea of coping
izer, and sunscreen being the most popular. Interestingly, a with aging through filler injection rather than neurotoxin treat-
Penalties Apply
majority of those who have a daily regimen reported buying ment (60% vs. 54%). A majority (83%) of respondents said they
their own skincare products. This is a significant finding com- were willing to disclose having undergone a cosmetic treat-
pared to a previous study in which men rarely incorporated ment, and most said they would disclose to either everyone or
skincare products into their daily routine.9 On the referenced only their spouse or significant other.
publication, more than half of the men never used facial mois-
turizer. We explored whether sexual orientation played a role in
respondents experience with specific procedures. The ho-
In terms of what aspects of appearance men are most con- mosexual men embraced earlier cosmetic procedures, such
cerned with, our data showed that male respondents ranked as fillers, neurotoxins, as well as surgery, compared to their
looking and feeling old at the top and “tired eyes” as a top heterosexual counterparts (data not shown). Additionally, we
area of concern. Almost sixty percent of respondents had ex- learned that in general, homosexual men are more open to
perience with some type of aesthetic treatment, such as facials, disclose their experience with cosmetic procedures (data not
microdermabrasion, and peels. Over half (54%) of respondents shown).
had experience with neurotoxin, with glabella, forehead, and Our Hispanic practice is mostly cosmetic, with a gender distri-
crow’s feet being the most popular areas treated. Thirty-nine bution of 90% women and 10% men. We believe this gender
percent of responders had experience with dermal fillers, with distribution will change towards an increase of that percentage
cheeks and nasolabial folds being the most popular areas treat- in male patients, as long as our assessments and discussions
ed. Thirty eight percent of respondents had experience with become tailored to their aspirations:
cosmetic surgery, with eyelid and nose surgery being the two
most popular procedures. (a) Men believe that the focus of rejuvenation should be around
the periocular area and upper face.
946
surgery-statistics-full-report-2016.pdf. Published in 2017. Accessed on Sep-

(b) Although cost is a consideration, lacking information about tember 19,2017.
how the products work and their side effects is a major barrier. 7. Keaney TC. Cornering the Male Aesthetic Market. Modern Aesthetics. 2014;
July/August: 34-37.
Perhaps physician’s discussions with male patients should be 8. Wat, H., Wu, D. C., Goldman, M. P. Noninvasive Body Contouring: A Male
more extensive and include anatomy explanations, since it is Perspective. Dermatologic Clinics. 2018; 36(1): 49-55.
9. Rossi AM, Eviatar J, Green JB, et al. Signs of Facial Aging in Men in a Di-
difficult for the patients to identify specific aging changes, es- verse, Multinational Study: Timing and Preventative Behaviors. Dermatol
pecially in the midface area. Surg. 2017; 43 Suppl 2:S210-S220.
10. Singh C, Dulku A, Haq A, et al. Why Do Females use Botulinum Toxin Injec-
tions? J Cutan Aesthet Surg. 2015; 8(4): 236-238.
(c) Because time is a concerning factor, less invasive rejuvena-
tion treatments with injectables is appealing to men. As a result, AUTHOR CORRESPONDENCE
facial shaping with fillers has a strong potential for growth, es-
pecially around the orbit, midface and nasolabial folds. Jose Raúl Montes
E-mail:................….............. jrmontes@jrmontes.com
(d) Skincare is no longer taboo for men. A majority of our pa-
tients have already embraced the use of sunscreen and facial
moisturizers. If the conversation is directed towards a health
and hygiene perspective, their opinion could be switched into
one in which incorporating a daily workout to fight the most
visible aging changes becomes a priority.
CONCLUSION
Our study suggests that a majority of men have either em-
braced or are interested in facial restoration, but they need
more information about the products and how each of them
work. Cost and time are two factors that play a big role in their
decision. As Cosmetic providers, we should switch gears in
order to attract and accommodate this growing cosmetic pop-
ulation through appropriately tailored marketing efforts and
offerings according to their interests.
DISCLOSURES
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Dr. Montes has served as a consultant for Galderma Laborato-
ries, L.P., Fort Worth, TX
ACKNOWLEDGMENTS
Penalties Apply
Galderma Laboratories, L.P. would like to acknowledge Erika
von Grote, PhD and Jessica Hicks, PhD for providing profes-
sional writing assistance and figure design in preparation of
this manuscript. The authors would like to thank Jessica Brown,
PharmD for her editorial assistance. Medical writing services
funded by Galderma Laboratories, L.P.
REFERENCES
1. 2016 Cosmetic Surgery National Data Bank Statistics by the American So-
ciety for Aesthetic Plastic Surgery (ASAPS). https://www.surgery.org/sites/
default/files/ASAPS-Stats2016.pdf. Accessed September 19, 2017.
2. Cohen BE, Bashey S, Wysong A. Literature review of cosmetic procedures
in men: approaches and techniques are gender specific. Am J Clin Derma-
tol. 2017; 18(1): 87-96.
3. J. Walter Thompson Intelligence; The State of Men. https://www.slideshare.
net/jwtintelligence/the-state-of-men. Updated on June 5, 2013. Accessed
September 19 2017.
4. Rossi AM. Men’s aesthetic dermatology. Semin Cutan Surg. 2014; 33(4):
188-97.
5. Keaney TC. Aging in the Male Face: Intrinsic and Extrinsic Factors. Dermatol
Surg. 2016; 42(7): 797-803.
6. American Society of Plastic Surgeons .Plastic Surgery Statistic Report 2016.
https://www.plasticsurgery.org/documents/News/Statistics/2016/plastic-
Do Not Copy
Penalties Apply

SPECIAL TOPIC
Rheological Properties of Several Hyaluronic Acid-Based Gels:

A Comparative Study
Patrick Micheels MDa and Martinien Obamba Engb
a
Private practice, Geneva, Switzerland
b
Company Rheonova, Saint-Martin-d'Hères, France
ABSTRACT
Background: Adding lidocaine to hyaluronic acid (HA)-based gels appeared to modify their rheological properties, in the view of the
first author.
Objective: This paper sought to compare the rheological properties of three CE-marked and FDA-approved gels, administered with and
without lidocaine, along with two other newly FDA-approved gels.
Methods: The tested gels were as follows: NASHA® Restylane® with and without lidocaine; CPM®; Belotero® Balance with and without
lidocaine; 3-D Matrix®; Surgiderm® 30XP (without lidocaine) and Juvederm® Ultra 3- Juvederm® Ultra Plus XC (with lidocaine); Preserved
Network® RHA®2 (with lidocaine); Vycross® Volbella® (with lidocaine). For rheological analyses, viscoelastic data were collected with
plate-plate geometry of 25mm, temperature regulated by a Peltier-effect plate, and the following assessed: Strain sweep from 0.01%
to 3000% strain at 1Hz over frequency sweep from 0.1 to 100 Hz.
Results: NASHA Restylane gels with and without lidocaine exhibited similar viscoelastic characteristics, with very similar tan δ values,
but the elastic modulus G’ proved significantly higher when the gel was injected with lidocaine vs without. 3D-Matrix Surgiderm 30XP
gel without lidocaine and Juvéderm Ultra 3 with lidocaine exhibited similar viscoelastic characteristics, as well as tan δ values, yet the
elastic modulus G’ of Surgiderm 30XP proved significantly higher than that of Juvederm Ultra 3-Juvederm Ultra Plus XC. CPM Belotero
Balance gels with and without lidocaine exhibited similar G’ and G’’ values. tan δ was somewhat higher when the gel was administered
without lidocaine. VYCROSS Volbella gel exhibited a higher elastic modulus G’ than the other Allergan gels, roughly nearing the NASHA
gel values. Preserved Network RHA 2 gel exhibited values that were close to its partially cohesive "competitors", except for Vycross.
Conclusion: Adding lidocaine to HA gels does modify their rheological properties yet this, to a variable extent depending on the
product.
J Drugs Dermatol. 2018;17(9):948-954.

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INTRODUCTION
F
or over 23 years, hyaluronic acid (HA)-based gels have linked, HA is no longer a natural product and may thus be rec-
found application in esthetic medicine across the world as ognized as a foreign body by our organism, notably the der-
an optimal product to provide soft tissue augmentation, mis, this specific layer that houses our innate host defenses.5
improve facial rejuvenation and wrinkles, and correct tissue de-
fects.1,2 This ubiquitous use of HA gels is primarily accounted Over the past decades, numerous HA fillers have been devel-
for by its specific features, such as its lacking organ or species oped and are now available on the EU market, with most of
specificity prior to cross-linking, in addition to being non-immu- them likewise FDA-approved and also available on the US mar-
nological, highly biocompatible, and able to bind 1,000 times its ket. Features that differentiate the various HA fillers are particle
volume in water. Therefore, there are no significant risks of al- size, crosslinking agent used, type and degree of crosslinking,
lergic reactions when exogenous HA is directly injected into the gel viscosity, percentage of cross-linked HA, amount of unmod-
skin, nor have there been reports of other major adverse events.3 ified HA, extrusion force, as well as elastic modulus termed G’,
the latter being a measure of the gel hardness. These physical
Whereas most complications are mild and self-limiting, late and chemical attributes have been demonstrated to influence
reactions to HA-based fillers have been reported to occur the filler’s clinical characteristics, thereby reflecting the gel’s
at a rate of 0.02%, and according to the authors, their inci- clinical indication, ease of injection, degree of tissue filling,
dence appears to vary depending on the product applied.4 It longevity, clinical appearance, as well as undesirable effects.
may, however, be assumed that in daily practice, the rate of
adverse events encountered following HA injections likely ex- This paper sought to compare the rheological properties of
ceeds the figures reported in scientific literature. But what are three CE-marked and FDA-approved gels, given with and with-
the reasons for this assumption? The point is that once cross- out lidocaine, along with two other newly FDA-approved gels.
949
Journal of Drugs in Dermatology P. Micheels and M. Obamba Eng
Of note is that these latter two are only available with lidocaine structure of HA gels according to the manufacturers, this pub-
in the US. The clinical indications of these HA fillers are similar, lication’s first author had for some time the impression during
and they are all applied for fine lines or filling in wrinkles and his daily practice that some gels, after lidocaine added to them
folds and for volume restoration. By attracting water, HA helps upon the manufacturing process, proved less easily injectable,
maintain fullness in the treated area, and the areas that are pop- more viscous, and less fluid as compared to the same gels
ularly treated with HA fillers include lips and nasolabial folds. without lidocaine. This impression had become even more evi-
dent in the course of a large-scale European multicenter study
This comparative study primarily sought to prove by means in which the first author participated, designed to prepare the
of scientific measurements a series of personal experiences approaching launch of a partially cohesive HA gel incorporating
we have made over time. These personal experiences often lidocaine.
proved contradictory to the messages conveyed by the sales
representatives or manufacturers themselves of the various To confirm this impression that adding lidocaine to HA gels
HA fillers. To avoid any biases, the rheological measurements does actually modify the rheological properties of the respec-
were thus performed by an independent company specialized tive gels, the same rheological tests were performed with the
in rheology, namely Rheonova, Saint-Martin-d'Hères, France. respective gels, with and without lidocaine.
METHODS 1) Non-cohesive gels without lidocaine

Gels Examined - NASHA (Non Animal Stabilized Hyaluronic Acid;
For all the HA gels tested, the crosslinking agent used was Galderma, Sweden: Batch No. 14015-1 2018-05-31)
1,4-butanediol diglycidyl ether (BDDE), and their clinical indi- - Restylane (Rest; FDA approved)
cations were thus similar. Likewise, these gels were usually
injected in the mid-dermis or deep dermis to fill face wrinkles 2) Partially-cohesive gels without lidocaine
and expression lines. For some of these HA-fillers, injection - Hylacross Matrix-3D (Allergan, Pringy, France: Batch No.
into the superficial dermis was likewise possible.6-10 In the fol- XP30A60071 2018-01)
lowing, these gels have been classified depending on their - Surgiderm 30XP (SurJ 30)
cohesiveness feature into non-cohesive, partially cohesive, and
cohesive, as reported in the literature and personally commu- 3) Cohesive gel with lidocaine
nicated by Galderma’s Dr. Albarano in 2016.11-14 - CPM (Merz, Geneva, Switzerland: Batch No. 321210/3
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2017-01)
1) Non-cohesive gels with lidocaine - Belotero Balance (Bel B; FDA approved)
- NASHA (Non Animal Stabilized Hyaluronic Acid gel©;
Galderma, Sweden: Batch No. 14066-1 2018-05-31) Measurements Performed at Rheonova
Penalties Apply
- Restylane-L Lidocaïn Injectable Gel with 0.3% Lidocain Shear stresses were assessed via a DHR-3 rheometer from TA
(FDA approved) Instruments (New Castle, DE), with measurements made us-
ing rough plate-plate geometry, 25mm in diameter, and the
2) Partially-cohesive gels with lidocaine temperature regulated by a Peltier-effect plate. Each test was
- Vycross® (Allergan, Pringy, France: Batch No. carried out at least twice on different samples in order to assess
V15LA60047-2017-12) and ensure reproducibility.
- Volbella® (VyX-VB; FDA approved)
- Hylacross® Matrix-3D® (Allergan, Pringy, France: Batch No. Methodology for Rheological Measurements
X30LA50370 2017.07) Prior to any measurement, the gel sample was placed on a
- Juvéderm® Ultra 3 (Juv U 3) plate, then spread using the upper plate, and the excess prod-
- Juvederm Ultra Plus XC (FDA approved) uct removed using a spatula. The gap was then adjusted and the
- Preserved Network® (Teoxane, Geneva, Switzerland: Batch sample conditioned at the measurement temperature, namely
No. TP30L-153804B6540 2017-09) 25°C, with an accuracy of 0.5°C.
- RHA® 2 (P-Net 2; FDA approved)
The following tests were conducted:
3) Cohesive gel with lidocaine 1) Strain sweeps with oscillations from 0.01 to 3000%, at 1Hz, in
- CPM® (Merz, Geneva, Switzerland: Batch No. 34606073 order to confirm the gel’s visco-elastic behavior and define the
2017-06) elastic modulus (G’), viscous modulus (G’’), and tangent delta
- Belotero® Balance Lido (Bel B-L) [tan (δ) =G’’/G’], as well as deformation, stress, and modulus
values at the crossover point.
While adding lidocaine does not modify the ultramicroscopic 2) Frequency sweeps with oscillations from 0.1 to 100Hz to ac-
950
quire the values of the elastic modules G' and viscous G’’, under gels, these two partially-cohesive gels were revealed to be less
a deformation forming part of the linear domain. elastic, with higher tan δ and weaker G’ values.
Reminder The elastic modulus and viscosity modulus of the last two gels
Linear field of viscoelasticity represents the area where the were very similar, the tan δ value being somewhat higher for
viscoelastic module values (G’ and G”) do not depend on the CPM without lidocaine. At the cross-over point, the deforma-
stress or deformation applied. tion strain and stress values were no longer similar.
G’ represents the component / elastic contribution of the com-
plex shear modulus. For CPM Belotero Balance with lidocaine, there was 74.6% aug-
G’’ represents the component / viscous contribution of the mentation for stress value and 142% augmentation for strain
complex shear modulus. values observed, as illustrated in Figure 3. Of the three gels, the
Tan δ represents the product’s viscoelasticity. If tan δ is close CPM gel was revealed to be modified to the largest extent when
to 0, the fluid is elastic and near to a solid; the closer tan δ is lidocaine was added.
to 1, the more the product behaves like a fluid.
Stress represents the stress applied to the gel and is ex- As based on these rheological data, CPM Belotero lidocaine
pressed in Pascal (Pa). In theory, the greater its value at the would be the HA gel the most difficult to inject, in line with the
cross-over point, the greater the difficulty to inject the gel. author's impression over several months. Likewise, this latter
Strain represents the gel deformation and is expressed in formulation would exert longer-lasting effects compared to the
percentage (%). The higher the deformation value at the cross- same gel without lidocaine.
over point, the greater the gel’s likelihood to exert long-lasting
effects. Reminder
Cross-over point represents the moment when the curves G’ Heat is one of the degradation factors of HA. Adding lidocaine
and G” intersect, which is also the point of flow. In theory, the during the manufacturing process of the HA gels for esthetic in-
higher the stress value at the crossover point, the higher the dications may be compared to a sleeve surrounding the HA gel
difficulty to inject the product. Likewise, the higher the defor- fibers. By this means, lidocaine could modify the rheological
mation value at the crossover point, the greater the product’s properties of the HA gels, thus rendering the gel more resistant
theoretical likelihood to exert long-lasting effects. to degradation by heat during the sterilization process. The gels
G’=G’’ corresponds to the cross-over point mentioned above could by this means be rendered more viscous upon the manu-
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where viscosity equals elasticity. After this point, often called facturing process.
the gel point, the product’s elastic component is no longer
superior to its viscous component, thus resembling a kind of Non-cohesive gel with and without lidocaine
flow. Rest-L
Penalties Apply
For these two non-cohesive gels, our research revealed a dis-
RESULTS crepancy between the stress and strain values at the crossover
The FDA-approved gels were investigated first, both with and point: The stress values at the crossover point were slightly
without lidocaine, and the other HA-gels tested thereafter. In higher for Restylane lidocaine versus the gel without lidocaine
the following, we present and comment on the results. (Table 1). From a theoretical point of view, this gel with lidocaine
should be more difficult to inject and exhibit longer long-lasting
NASHA gels (Restylane) with and without lidocaine were effects than the gel without lidocaine. However, in his clinical
shown to exhibit close viscoelastic characteristics, with very practice, the first author never had this impression.
similar tan δ values. Of note is that for Restylane with lidocaine,
the elastic modulus G’ was proven significantly higher than The strain values at the cross-over point were slightly lower of
modulus G’ when the gel was administered without lidocaine, Restylane lidocaine versus the gel without lidocaine (Table 1).
as shown in Figure 1. Adding lidocaine to NASHA gel would not be of much inter-
est in this case, as this would enhance the theoretical difficulty
Surgiderm 30XP gels without lidocaine and Juvéderm Ultra 3 of injection without gaining on the durability site. However, in
with lidocaine were found to exhibit close viscoelastic charac- order to confirm this hypothesis, a larger dataset would be re-
teristics, with very similar tan δ values. quired.
Nevertheless, Surgiderm 30XP’s elastic modulus G’ was proven The two NASHA gels, with or without lidocaine, were shown
significantly higher as compared to Juvéderm Ultra 3, as shown comparable in their rheological properties. Adding lidocaine to
in Figure 2. The stress values at crossover point were lower for the gel did not change the gel’s rheological properties to a large
Juvéderm Ultra 3. Compared with a gold standard like NASHA extent.
951
FIGURE 1. (A) Strain sweep curves with Restylane® without lidocaïne FIGURE 2. (A) Strain sweep curves with Surgiderm®30XP without
(left) and Restylane® with lidocaïne (right); (B) Comparative plateau lidocaine, Juvéderm, and Juvéderm® Volbella®; (B) Strain sweep
values with Restylane® without lidocaine (blue) and with lidocaine curves with Surgiderm®30XP without lidocaine, Juvéderm®Ultra 3,
(orange). and Juvéderm® Volbella®.
(A) (A)
(B)
(B)
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Partially-cohesive gels with and without lidocaine
We herein describe first the HA gels that are available with and
VyX-VB
This gel using Vycross crosslinking technology displays
without lidocaine, which will be followed by the new genera- rheological characteristics that totally differ from its two pre-
tion gel from this manufacturer, namely Allergan, this new gel decessors. Its crosslinking technology is not identical to SurJ
with lidocaine being FDA-approved. This allows for the three 30 and Juv U 3 (3D Matrix and Vycross), given the inversed
gels from the same manufacturer, with the same treatment in- proportions between high and low molecular weight fibers. The
dication, to be compared. We will then briefly report on another elastic modulus (G’) of VyX-VB was found higher than that of
partially-cohesive HA gels with lidocaine, having recently re- the other Allergan gels, roughly approaching the NASHA gels
ceived FDA-approval. values. This could imply that VyX-VB’s crosslinking technology
proves more effective compared to that of Juv U 3 and SurJ 30,
SurJ 30 and Juv U 3 in line with the laboratory’s claims: more compact mesh, more
SurJ 30 and Juv U 3 were shown to display very close rheo- resistant to shear forces, and closer to a solid, proportionately
logical values, and we could thus consider them equivalent, as guarded.
shown in Table 2. This, however, seems to contradict the first
author’s general impression. A possible explanation may be Of all gels tested, this gel’s G”/G’ (tan δ) proved the lowest, and
that the rheological qualities of Juvéderm Ultra 3 have been this gel thus appears more elastic, being closer to NASHA®.
meanwhile improved since its launch. It would, therefore, be At the cross-over point, Volbella exhibited a 79.80% decrease in
interesting to carry out the same measurements with the 2007- stress value compared to the other two Allergan HA gels tested,
2008 gels. along with an 89.20% decrease in deformation value.
952
FIGURE 3. (A) Strain sweep curves with CPM® Balance without For the CPM gel with lidocaine, the stress values at the cross-
lidocaïne (left) and with lidocaine (right); (B) Comparative plateau over point proved to be 74.60% higher, whereas the strain
values with CPM® Balance without lidocaine (left) and with values at the crossover point were 142.00%, compared to those
lidocaine (right). of the gel applied without lidocaine (Table 3).
(A) These clear differences between the CPM gel with or without
lidocaine suggest that CPM lidocaine would be harder to in-
ject, perfectly in line with the first author’s past experience.
Likewise, from a theoretical point of view, the gel’s lidocaine
formulation would be longer lasting in time than its formula-
tion without lidocaine. Comparative studies would be required
to confirm this last hypothesis, as previously conducted with
other gels.15
DISCUSSION
While the overall study results seem to be reproducible, two
products stand out owing to the stress and strain values
(B) obtained at the cross-over point and thus deserve further dis-
cussion: NASHA gel and CPM gel. On account of their differing
cross-linking technology, these two gels exhibit totally-oppo-
site features, with NASHA being a completely non-cohesive gel
and CPM a fully-cohesive gel. The other gels can be classified
as partially-cohesive, exhibiting intermediate values compared
to these two.13
For NASHA gel, adding lidocaine to the preparation resulted

in a 16.30% increase in stress values, along with a 7.18% de-
crease in deformation values. When applied with lidocaine,
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NASHA gel should thus be more fluid and easier to inject than
its equivalent without lidocaine. It would be difficult for us to
give our opinion on this issue, given that the differences were
rather small and likewise hardly felt, even by expert hands.
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This low stress value at the cross-over point would mean that
this is quite easy to inject, which is perfectly in line with our
practice experience.
For CPM gel, adding lidocaine to the preparation resulted in a
74.60% increase in stress values, along with a 142.00% increase
in strain values obtained at crossover point. These two gels thus
behave quite differently in rheological terms. Adding lidocaine
On the other hand, due to its low deformation value at the cross- made CPM-Belotero more viscous and more difficult to inject.
over point, this would suggest that Volbella gel’s stability over This analysis data thus confirms the clinical impression that the
time may be lower than that of Juv U3 and SurJ 30, which has, first author had had since the gels’ launch on the market. These
however, not be confirmed by our experience. In the following, properties should normally translate into longer-lasting effects
we present the properties of another gel pertaining to this class. as compared to the product applied without lidocaine. To con-
firm this assertion, comparative studies would be required.
P-Net 2 (RHA 2)
This gel may be considered to have values close to its partially Within the Allergan product line, rheological variations were
cohesive "competitors", except for the VyX-VB gel. likewise found between the Hylacross 3D-Matrix formulations
with and without lidocaine. When the Hylacross 3D-Matrix
Cohesive gel with and without lidocaine range with lidocaine, namely Juvéderm Ultra 3 (Juvederm
Adding lidocaine to the CPM gel provoked significant changes Ultra Plus XC), was launched on the market, this product was
as to its rheological properties, as compared to the original presented by Allergan as being similar to its predecessor (Sur-
CPM gel administered without lidocaine. The G’ and G” values, giderm 30XP) with lidocaine "simply" added to the product,
as well as tan δ, were very similar for the two preparations, in- associated with strictly the same injectability for both products.
dicating the gel’s viscoelastic properties being well controlled.
953
TABLE 1.
Non-cohesive Gels With and Without Lidocaine
Strain Sweep
Plateau Cross-over Point
G’ G’’
Sample Tan δ Stress Strain G’=G’’
(Elasticity) (Viscosity)
Pa Pa - Pa % Pa
Restylane® 461.0 83.5 0.18 141.0 90.5 110.0
Standard Deviation (%) 5.52 3.64 0.00 11.0 5.78 5.14

Restylane® lidocaïne 619.0 101.0 0.17 164.0 84 138.0
TABLE 2.
Partially-cohesive Gels With and Without Lidocaine
Strain Sweep
G’ G’’
Pa Pa - Pa % Pa
Surgiderm®30XP 133.0 34.9 0.27 576.0 1009 40.3

Juvéderm® Ultra 3 99.6 27.6 0.28 528.0 1155 32.2
Standard Deviation (%) 0.64
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TABLE 3.
Cohesive Gels With and Without Lidocaine
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Strain Sweep
G’ G’’
Pa Pa - Pa % Pa
Belotero® Balance 57.2 33.2 0.58 185.0 498 26.4

Belotero® Balance
56.0 30.6 0.55 323.0 1203 18.9
lidocaine
954
During the product’s post-marketing study, however, we im- DISCLOSURE

mediately had a quite different impression and have notified Dr. Micheels has worked as a consultant or trainer for Merz,
the manufacturer about this issue. As a matter of fact, to us Antéis, IBSA Pharma, Q-Med, Galderma, Teoxane, and Allergan.
it seemed that when injecting this gel with lidocaine, the gel He has documented having nothing else to disclose that would
proved viscous, at least at that time, as compared with other represent a conflict of interest. M. Obamba has no financial in-
Allergan gels without lidocaine, ie, Hylacross 3D-Matrix gel terests to disclose.
without lidocaine.
REFERENCES
Based on this research comparing the rheological properties 1. Olenius M. The first clinical study using a new biodegradable implant for the
treatment of lips, wrinkles, and folds. Aesthetic Plast Surg. 1998;22:97–101.
of three HA gels with or without lidocaine, it becomes obvious 2. Piacquadio D, Jarcho M, Goltz R. Evaluation of hylan b gel as a soft-tissue
to us that Juvéderm Ultra 3 gel depicts values that are fairly augmentation implant material. J Am Acad Dermatol. 1997;36:544–549.
3. Wahl G. European evaluation of a new hyaluronic acid filler incorporating
close to those of Surgiderm 30 XP, contrarily to our clinical lidocaine. J Cosmet Dermatol. 2008;7:298–303.
impression. The cross-over strain value of Juvederm Ultra 3 4. Artzi O, Loizides C, Verner I, Landau M. Resistant and recurrent late reaction
(Juvéderm Ultra Plus XC), however, proved superior to that of to hyaluronic acid-based gel. Dermatol Surg. 2016;42:31–37.
5. Micheels P. Human Anti-Hyaluronic Acid Antibodies: is it possible? Dermatol
Surgiderm 30XP, which seemed to be more in line with the first Surg. 2001;27:185–191.
author’s clinical impression who, when injecting Juvéderm Ul- 6. Allergan. Package information leaflet. Surgiderm® 30 XP, Juvéderm® Ultra 3
and Volbella®.
tra 3 (Juvederm Ultra Plus XC) for wrinkle filling treatments in 7. Merz. Package information leaflet Belotero® Balance with and without lido-
his daily practice, could, in all cases feel, a stronger resistance caine.
8. Q-Med-Galderma. Package information leaflet Restylane®, Restylane® with
to injection. lidocain.
9. Teoxane. Package information leaflet RHA®2 with lidocaine.
Among the Allergan gels, Volbella gel proved to be totally differ- 10. Vivacy. Package information leaflet Stylage® M.
11. Flynn TC, Thompson DH, Hyun SH, Howell DJ. Ultrastructural analysis of 3
ent, with a 79.80% decrease in cross-over stress and an 89.20% hyaluronic acid soft-tissue fillers using scanning electron microscopy. Der-
decrease in cross-over deformation compared to other Allergan matol Surg. 2015;41:143–152.
12. Sundaram H, Rohrich RJ, Liew S, et al. Cohesivity of hyaluronic acid fillers:
gels tested herein. This gel would therefore be particularly easy Development and clinical implications of a novel assay, pilot validation with a
to inject, entirely in line with both the author’s daily practice five-point grading scale, and evaluation of six U.S. food and drug administra-
tion-approved fillers. Plast Reconstr Surg. 2015;136:678–686.
experience and the manufacturer’s "claims". 13. Gavard Molliard S, Albert S, Mondon K. Key importance of compression
properties in the biophysical characteristics of hyaluronic acid soft-tissue fill-
Concerning the other partially-cohesive gel tested herein, while ers. J Mech Behav Biomed Mater. 2016;61:290–298.
14. Mondon K, Dadras M, Tillier J, Gavard Molliard S. Influence of the macro-
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the rheological characterization of "Preserved Network" (RHA and/or microstructure of crosslinked hyaluronic acid hydrogels on the release
2) hyaluronic acid gel is well known (Teoxane Laboratories, of two model drugs. Clin Cosmet Investig Dermatol. 2017;10:239–247.
15. Prager W, Micheels P. A prospective, comparative survey to investigate
internal data), there exist no comparative data pertaining to a practitioners’ satisfaction with a cohesive, polydensified-matrix®, hyaluronic
gel using the same cross-linking technology and being applied acid-based filler gel with and without lidocaine for the treatment of facial
Penalties Apply
wrinkles. Cosmet Dermatol. 2015;14:124–129.
without lidocaine.
CONCLUSION AUTHOR CORRESPONDENCE

Based on the rheological tests performed by an independent
Patrick Micheels MD
company specialized in rheology, adding lidocaine to a series
E-mail:................……............................. patrickscab@bluewin.ch
of well-established HA gels resulted in a modification of the
gels’ rheological properties, yet to a variable extent depending
on the gel, as compared to the tests results obtained with no
lidocaine added. The higher the stress value at the cross-over
point, the greater the difficulty to inject these gels. Another ex-
planation may be that HA gels that exhibit deformation at high
cross-over may display higher remanence as compared to HA
gels without lidocaine.
As of note, we are presently implementing another study de-

signed to assess the results observed in daily practice and
compare them with the current study’s theoretical data. This
would prove that gels with high stress values at the cross-over
point are not systematically more difficult to inject. This study
would also confirm the correlation between increased stress at
the cross-over point and lidocaine being added to the HA gel.
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Penalties Apply

SPECIAL TOPIC
The Potential Role of Botulinum Toxin in Improving

Superficial Cutaneous Scarring: A Review
Akash Dhawan,a Sunil Dhawan MD,b,c Domenico Vitarella PhDd
Department of Bioengineering, Rice University, Houston, TX
a
Center for Dermatology Clinical Research, Inc., Fremont, CA

b
c
Department of Dermatology, Stanford University School of Medicine, Stanford, CA
d
Bonti, Inc., Newport Beach, CA
ABSTRACT
Botulinum toxins have been utilized in a number of cosmetic and therapeutic applications. One of the more novel uses of botulinum
toxin involves its use to mitigate the effects of superficial cutaneous scarring. This is accomplished by decreasing the dynamic ten-
sion of a wound by denervating the underlying muscle. Studies have indicated that botulinum toxin serotypes A and B have a positive
effect on wound healing and scar appearance. However, larger prospective, blinded, randomized, placebo-controlled clinical trials are
required to refine this concept and target optimum toxin dose placement, timing, and concentration. The delayed onset of effect of
available botulinum toxins is likely not taking full advantage of the scar improvement capabilities of the toxin, considering the time to
immobilization of the muscle is a key factor in the improvement of wound healing with this technique. Furthermore, it has been noted
in studies that the use of botulinum toxin can result in significant, yet temporary functional issues, due to prolonged paralysis of the
muscle. In this paper, we review the role of botulinum toxin in improving scar appearance, evaluate animal and human studies to date
demonstrating its effect on scarring, and highlight an opportunity for continued research in this application.
J Drugs Dermatol. 2018;17(9):956-958.
BACKGROUND procedures in the United States with 4.6 million injections per-
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he Clostridium botulinum bacteria secretes 8 different formed in 2016, exceeding other well-known procedures such as
exotoxins, called serotypes A-H.1,2 Serotype A is the most filler injections and blepharoplasty.7 This high rate of usage has
potent and is marketed under the brand name Botox® led to its application in expanded indications such as hyperhi-
(Allergan, Inc., Irvine, CA). Serotype A consists of a 1295 amino drosis, migraines, and other possible novel uses.8,9 Among these
Penalties Apply
acid chain with a 97 kDa heavy chain and a 57 kDA light chain.The novel uses, studies have shown that botulinum toxins may be
binding domain on the heavy chain attaches to the receptor on used to mitigate the effects of superficial cutaneous scarring.10
the presynaptic terminal. The light and heavy chains are internal-
ized via receptor mediated endocytosis into the endosome of the Wound Repair and Scarring
nerve terminal that contains the acetylcholine neurotransmitter. Cosmetic results of wound repairs are dependent on many fac-
In the acidic environment of the endosome, the light chain can tors, including the quality of the closure, infection, and suture
cross the membrane via translocation into the cytosol and acti- quality. A key factor is the tension on the wound edges, which
vate the metalloprotease enzymatic domain. This domain then tends to increase inflammation, leading to fibrosis and erythe-
disables the synaptosomal-associated protein 25 by cleaving 9 ma. Tension is composed of static tension (the result of wound
amino acids on the C-terminus. When this protein is cleaved, location, size, closure techniques, etc.) and dynamic tension. Dy-
there is no vesicle-membrane fusion and no release of acetyl- namic tension is caused by the action of the muscles underlying
choline in the synapse. This neural blockade results in flaccid pa- the wound. Specifically, the relaxed skin tension lines of Borges
ralysis of the affected muscle.3,4 and Langer are perpendicular to the tension vectors of the un-
derlying muscle, and wounds that are repaired parallel to these
Scott et al (1980) first proposed the use of botulinum toxin in hu- relaxed skin tension lines (RSTL) have less dynamic tension and
mans to immobilize extraocular muscles as an alternate therapy heal with a better cosmetic result. Scars that are perpendicular
for strabismus surgery.5 Carruthers et al (1992) determined that to these RSTL have increased tension, which results in increased
the toxin could be applied in cosmetic uses to correct for glabellar inflammation, increased deposition of collagen and glycos-
rhytids.6 Since then, botulinum toxin has been used to treat rhy- aminoglycans, increased fibroblastic response, and poor wound
tids on other facial areas, including the forehead and periorbital healing and increased scarring.11 Decreasing dynamic tension by
area. Botulinum toxin injections are the most common cosmetic denervating the underlying muscle with botulinum toxin offers
957
Journal of Drugs in Dermatology A. Dhawan, S. Dhawan, and D.Vitarella
an intriguing way to potentially improve scars. was published by Gassner et al (2006).18 Thirty-one patients with
forehead laceration repairs or excisions showed a Visual Analog
Animal Studies Scar Score (VASS) of 8.9 in the toxin treated arm versus 7.2 in
Gassner et al (2000) first proposed using botulinum toxin in the the placebo arm. The toxin or placebo was injected on day after
improvement of scars and demonstrated this in a study using the procedure, with the number of units based on the size of the
forehead wounds in Macaque monkeys.10 Excisions in these repaired wound (between 15 to 45 U). It has been noted that any
monkeys were randomized to receive either 21 units of botuli- VASS score difference of greater than 1.5 is significant.19 Another
num toxin A or placebo (saline) into the frontalis muscle. After 3 study utilized 24 facial wound patients that were randomized to
months the scars were evaluated using a visual analogue scale botulinum toxin A or placebo.20 Results showed a VASS score
conducted by three blinded surgeons. Superior cosmetic results of 8.25 for the toxin group versus 6.25 for the placebo group.
were achieved in the toxin treatment group versus placebo. His- Finally, a retrospective study of Mohs surgery patients injected
tologic examination also revealed less fibrosis and inflammation intraoperatively with botulinum toxin type A or B showed prom-
in toxin-treated wounds. ising and similar cosmetic results.21 A small sub-study of the use
of toxin type A in these subjects undergoing laser resurfacing
Lee et al (2009) conducted a study in rats to determine the ef- showed no treatment effect. This indicates that the effect of tox-
fects of botulinum toxin A on wound healing.12 They proposed ins is via reduction of wound tension, and not from any effect on
that underlying muscle paralysis caused by the toxin would re- re-epithelialization.
duce wound edge tension and the inflammation and fibroblastic
response. Two identical wounds were created on the backs of 15 While the majority of these studies used forehead wounds, low-
rats to observe the effect of the toxin versus saline on the four er face repairs (lip, cheek, chin, etc.) have also been reported
phases of wound healing: coagulation, inflammation, prolifera- to benefit from improved cosmetic appearance with the use of
tion, and maturation. Histological examination was performed at botulinum toxin.11,22 It should be noted that one case demonstrat-
2, 4, and 8 weeks. This showed a statistically significant decrease ed significant, albeit temporary functional issues, due to local
in the acute inflammatory response at 2 weeks, and decreased fi- muscle immobilization. This brings to light the need for a shorter
brosis and fibroblast proliferation at 4 weeks. There was no effect acting toxin as the effect on wound healing is only needed for
on vessel proliferation, wound thickness, or re-epithelialization. 1 to 2 months. Flynn21 suggested that a toxin with faster onset
of action would lead to a more immediate relaxation of the un-
Human Studies derlying musculature to aid healing and suggested that a long
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The first reports in humans for the use of botulinum toxin duration of action is unnecessary. A shorter duration of action
appeared with Choi et al (1997) with its use in eyelid reconstruc- may be of practical benefit, to assure patients that their muscles
tion.13 Favorable results were reported with the use of toxin in will not be immobilized for long periods of time.
patients undergoing laser resurfacing,14 and as well in infant cleft
Penalties Apply
lip repair at 12 U/kg.15 Gassner and Sherris (2003) reported 2 cas- A meta-analysis of the use of botulinum toxin type A in the
es. One case was with a 1.5 cm forehead scar revision, where prevention of hypertrophic scars on the lower face and neck
intraoperative injection of botulinum toxin at 17.5 U improved showed a statistically significant improvement in scar width, pa-
the scar versus its appearance from a prior repair.16 The second tient satisfaction, and VASS scores in the toxin treated group.23
case was a repair of a traumatic forehead wound in a 17-year- Furthermore, a small report indicated some benefit in the use of
old female using an intraoperative botulinum toxin injection at botulinum toxin type A in improving the appearance of keloids.24
a total dose of 40 U. This technique showed superior cosmetic It was proposed that this effect is due to a reduction in the scar
results versus another repair in the same patient on the upper by inhibition of the fibroblast cell cycle by the toxin.
eyelid, where no toxin was used. An interesting concept was
proposed whereby lidocaine was used to reconstitute the toxin, With regard to botulinum toxin dosing, Jablonka et al (2012)
giving an immediate paralyzing effect of the underlying fronta- and Gassner et al (2009) suggested that the maximal dose of
lis muscle complex. This ultimately gave the physician an idea toxin is 25 U into one muscle (at one site), 25 to 50 U for the
of the eventual treatment effect once the toxin had achieved forehead-glabellar complex, and 1 to 5 U in the lower face;
muscle immobilization. The onset of effect for the toxin can be these doses will help minimize the temporary functional defects
1 to 2 weeks. that can occur with toxin injections.11,22 Again, both studies
concluded that botulinum toxin is safe and effective in chemo
Subsequently, a report by Wilson (2006) showed that botulinum immobilization of underlying musculature to improve scars and
toxin could be used with success in 40 patients with facial scar re- enhance appearance.
visions.17 This study was unblinded, but did show improvement
in 90% of patients, using both subjective and objective meas-
ures. The first blinded, placebo-controlled, randomized study
958
Journal of Drugs in Dermatology A. Dhawan, S. Dhawan, and D.Vitarella
improve treatment of facial wounds: a prospective randomized study. J Plast

CONCLUSION Reconstr Aesthetic Surg. 2013;66:209-214.
Both the histologic and clinical evidence indicates that botu- 21. Flynn TC. Use of intraoperative botulinum toxin in facial reconstruction. Der-
matol Surg. 2009;35:182-188.
linum toxin has a positive effect on wound healing and scar 22. Gassner HG, Sherris DA, Friedman O. Botulinum toxin-induced immobiliza-
appearance. Larger, prospective, blinded, randomized, place- tion of lower facial wounds. Arch Facial Plast Surg. 2009;11:140-142.
23. Zhang D, Liu X, Xiao W, et al. Botulinum toxin type A and the prevention of
bo-controlled trials are warranted to refine this concept and hypertrophic scars on the maxillofacial area and neck: a meta-analysis of
determine optimal dosing area, timing (before, during, or after randomized controlled trials. PLOS One. 2016; 1-10.
surgery), and concentration of toxin. An intriguing concept is 24. Robinson AJ, Khan K. Keloid scars and treatment with botulinum toxin type
A: the Belfast experience. Br J Plast Surg. 2012;48:439-440.
the use of a rapid onset and shorter duration of action toxin, 25. Abushkara S, Jarpe M, Ahmad W,et al. Pharmacological Efficacy of EB-001
which would reduce some of the aforementioned issues of pro- Compared to Botox In A Mouse Digit Abduction Assay. Poster presentation.
Abdominal Wall Reconstruction. 6/8/17-6/10/17.
longed reversible functional defects. This would also perhaps
improve scar appearance, as it has been suggested that the
earlier the muscle is immobilized, the better the scar outcome. AUTHOR CORRESPONDENCE
Recent development of such a toxin has been reported and tri-
als with this new entity would be useful.25 Domenico Vitarella PhD DABT
E-mail:................……......................................... dom@bonti.com
DISCLOSURES
Dr. Domenico Vitarella is an employee of Bonti, Inc., a pharma-
ceutical company researching the application of a botulinum
toxin for the improvement of scarring. Dr. Sunil S. Dhawan is a
principal investigator in clinical trials for Bonti, Inc.
REFERENCES
1. Barash JR, Arnon, SS. A novel strain of clostridium botulinum that produces
type B and type H botulinum toxins. J Infect Dis. 2014;209:183-191.
2. Keller JE. Recovery from botulinum neurotoxin poisoning in vivo. Neurosci.
2006;139:629-637.
3. Rossetto O, Pirazzini M, Montecucco C. Botulinum neurotoxins: genetic,
structural and mechanistic insights. Nat Rev Microbiol. 2014;12(8):535-549.
4. Dolly J, Aoki K. The structure and mode of action of different botulinum tox-
ins. Eur J Neurol. 2006;13(s4):1-9.
5. Scott A. Botulinum toxin injection into extraocular muscles as an alternative
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to strabismus surgery. J Pediatr Ophthalmol Strabismus. 1980;17(1):21-25.
6. Carruthers JDA, Carruthers JA. Treatment of glabellar frown lines with C.
botulinum-a exotoxin. J Dermatol Surg Oncol. 1992;18(1):17-21.
7. The American Society for Aesthetic Plastic Surgery. Statistics. Available at:
https://www.surgery.org/media/statistics. Accessed November 23, 2017.
Penalties Apply
8. Heckmann M, Ceballos-Baumann A, Plewig G. Botulinum toxin A for axil-
lary hyperhidrosis (excessive sweating). N Engl J Med. 2001;344(7):488-493.
9. Silberstein S, Mathew N, Saper J, et al. Botulinum toxin type A as a migraine
preventive treatment. Headache: J Head Face Pain. 2000;40(6):445-450.
10. Gassner H, Sherris D, Otley C. Treatment of facial wounds with botulinum
toxin A improves cosmetic outcome in primates. Plast Reconstr Surg.
2000;105(6):1948-1953.
11. Jablonka EM, Sherris DA, Gassner HG. Botulinum toxin to minimize facial
scarring. Facial Plast Surg. 2012;28(5):525-535.
12. Lee BJ, Jeong JH, Wang SG, et al. Effect of botulinum toxin type A on a rat
surgical wound model. Clin Exp Otorhinolaryngol. 2009;2:20-27.
13. Choi JC, Lucarelli MJ, Shore JW. Use of botulinum toxin A toxin in patients
at risk of wound complications following eyelid reconstruction. Ophthalmic
Plast Reconstr Surg. 1997;13259-264.
14. Zimbler MS, Holds JB, Kokoska MS, et al. Effect of botulinum toxin pretreat-
ment on laser resurfacing results: a prospective, randomized, blinded trial.
Arch Facial Plast Surg. 2001;3:165-169.
15. Tollefson TT, Senders CM, Sykes JM, et al. Botulinum toxin to improve re-
sults in cleft lip repair. Arch Facial Plast Surg. 2006;8:221-222.
16. Gassner HG, Sherris DA. Chemoimmobilization: improving predictability in
the treatment of facial scars. Plast Reconstr Surg. 2003;112:1464-1466.
17. Wilson AM. Use of botulinum toxin type A to prevent widening of facial
scars. Plast Reconstr Surg. 2006;117:1758-1768.
18. Gassner HG, Brissett AE, Otley CC, et.al. Botulinum toxin to improve facial
wound healing: a prospective, blinded, placebo-controlled study. Mayo Clin
Proc. 2006;812:1023-1028.
19. Quinn J, Wells G, Sutcliffe T, et al. Tissue adhesive versus suture wound re-
pair at 1 year: randomized clinical trial correlating early, 3 month, and 1-year
cosmetic outcome. Ann Emerg Med. 1998;32:645-649.
20. Ziade M, Domergue S, Batifol D, et al. Use of botulinum toxin type A to
JDDONLINE.COM/PODCAST
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SPECIAL TOPIC
Three-Dimensional Analysis of Minimally Invasive

Vacuum-Assisted Subcision Treatment of Cellulite
Jeremy A. Brauer MD,a,b Mitalee P. Christman MD,b Yoon Soo C. Bae MD,a,b Leonard J. Bernstein MD,a,c
Robert Anolik MD,a,b Ron Shelton MD,a,d Roy G. Geronemus MDa,b
Laser & Skin Surgery Center of New York, New York, NY
a
b
Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY
c
Department of Dermatology, New York Weill Cornell Medical College, New York, NY
d
Department of Dermatology, Mount Sinai School of Medicine, New York, NY
ABSTRACT
Introduction: This was a prospective non-randomized observational study of female subjects seeking treatment for cellulite who were
consecutively enrolled into a registry. The objective was to evaluate the efficacy and safety of a tissue stabilized-guided subcision de-
vice for the treatment of cellulite using three-dimensional (3D) imaging analysis.
Methods: Subjects received a single treatment to the buttocks and/or posterolateral thighs with the study device. Follow-up telephone
evaluations were conducted at 3 and 14 days to evaluate safety and 30 and 90 days to evaluate efficacy. Subjects returned to clinic at
three months to obtain follow-up two dimensional and 3D imaging.
Results: Sixteen women of average age 44.1 years with a total of 291 lesions of cellulite were treated. Thirteen subjects presented
for all follow up visits. Physicians graded results an average of 2.23/5 or “much improved” to “improved” with 9 subjects as much or
very much improved (69.2%). Blinded assessors graded overall improvement an average of 2.8 (26-75% improvement) with 8 subjects
having greater than 50% improvement overall (61.6%). Improvement in dimple depth was graded an average of 2.9, with 9 subjects
having greater than 50% improvement (69.2%). Analysis of 3D imaging yielded 67.4% average improvement in negative volume and
58.4% improvement in minimum height of dimples. Most expected treatment effects resolved within three months after treatment.
Conclusion: Utilizing three-dimensional imaging analysis, investigators quantitatively and objectively demonstrated efficacy of a tissue
stabilized-guided subcision device in the treatment of cellulite of the buttocks and thighs.
J Drugs Dermatol. 2018;17(9):960-965.
INTRODUCTION
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C Penalties Apply
ellulite is commonly observed as a rippling or dimpling (Cellfina® System, Merz North America, Inc., Raleigh, NC). TS-
of the skin on the thighs and buttocks in as many as 80- GS is approved by the United States Food and Drug Administra-
90% of post-pubertal women.1 Although multiple eti- tion for the long-term treatment of cellulite on the buttocks and
ologies may exist, an understanding of the anatomy of cellulite thighs, with no reduction in benefits for 3 years of follow-up.4
is crucial to guiding treatment.2 Normal skin has a support net-
work of fibrous septae running through the subcutis, separating Kaminer et al.5 recently reported the three-year results from
the adipose tissue into chambers resembling a quilt. Magnetic treating 45 patients with a single treatment of the study device,
resonance imaging demonstrates that in cellulite, these fibrous demonstrating the safety and effectiveness of the device. Our
septae are contracted and sclerosed, tethering the skin at a fixed goal was to augment these results with additional data from
length.3 Simultaneously, adipose cells expand with weight gain three-dimensional (3D) imaging analysis.
or water absorption, and in doing so herniate into the dermis,
creating skin dimpling and the characteristic appearance of cel- MATERIALS AND METHODS
lulite. Two distinct morphologies of cellulite may be identified, As part of a larger registry study,6 we conducted a prospective
sometimes in the same patient. The first is diffuse rippling in pa- non-randomized single center observational study of female
tients with increased adipose tissue and/or increased skin lax- subjects seeking treatment for cellulite. These subjects were
ity – these patients may stand to benefit from lipolytic and skin consecutively enrolled into a registry within a multicenter
tightening modalities. The second is dimpling, with discrete el- study. The study was approved by the Asentral institutional re-
lipsoid or linear depressions representing tethering by fibrous view board (Protocol ULT-500). Subjects with unwanted cellulite
septae in patients with good skin tone – these patients stand to of the buttocks and posterolateral thighs who met inclusion and
improve from subcision of fibrous septae by minimally invasive exclusion criteria (Table 1) were enrolled in the study. Informed
techniques such as tissue stabilized-guided subcision (TS-GS) consent was obtained.
961
Journal of Drugs in Dermatology J.A. Brauer, M.P. Christman,Y.C. Bae, et al
FIGURE 1. Description of study device. Image reproduced with FIGURE 2A. Three-dimensional imaging analysis: Five randomly
permission from: Cellfina System (Instructions for use). Mesa, AZ; selected representative dimples were identified with a number
Ulthera, Inc.; 2017. landmark. A broad area selection was placed over each identified
dimple.
FIGURE 2B. Three-dimensional imaging analysis: An analysis script

Standardized two-dimensional (2D) photographs and 3D pho-
was then run after all dimples were identified. A reference surface
tographs (Vectra imaging system (Canfield, NJ) were obtained was created for each dimple based upon the area selection.
prior to subjects receiving treatment. The depressed areas of
cellulite were identified and circled with a marker. The treat-
ment areas were treated with betadine solution and a sterile
drape was placed. TS-GS was applied to the treatment areas for
a single treatment session.
The TS-GS device includes a vacuum chamber that first lifts the
target area, allowing for stabilization and greater control during
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the next two steps, which may be performed at a pre-select-
ed depth of 6 mm or 10 mm. The device infiltrates tumescent
anesthetic solution for local anesthesia, and then inserts a mo-
torized 0.45 mm microblade that moves forward and backward
Penalties Apply
to subcise the fibrous septum underlying the cellulite depres-
sion. The device may be moved manually from side to side to
ensure complete subcision of the fibrous septum underlying FIGURE 2C. Three-dimensional imaging analysis: The distance
the depression (Figure 1).5 between the reference surface and image was calculated. The
threshold was adjusted so that the maximum height was set to 0
Follow-up evaluations were conducted by telephone at 3 days mm (blue) and the minimum height was set to the deepest dimple
and 14 days after treatment to evaluate safety and at 30 days measurement (red).
and 90 days after treatment to evaluate efficacy. Subjects re-
turned to clinic at 180 days (6 months) after treatment to obtain
follow-up 2D and 3D photographs.
As part of the larger registry protocol, improvement was sub-

jectively assessed by both a physician and the subject using
the Global Aesthetic Improvement Scale (GAIS), a 5-point scale
that rates global aesthetic improvement from pre-treatment
appearance. The rating choices included: worse, no change,
improved, much improved, and very much improved. An ad-
ditional efficacy analysis was conducted at our individual site
using 3 physician evaluators who were blinded to the order (ie,
before and after status) of the 2D photographs; these evalua-
tors rated the degree of improvement using a graded 4-point
962
FIGURE 3A. Patient baseline. FIGURE 3B. Baseline with FIGURE 3C. Baseline 3D. FIGURE 3D. Baseline 3D
markings. with depth.
FIGURE 3E. 180 day FIGURE 3F. 180 day FIGURE 3G. 180 day
follow up. follow up 3D. follow up 3D with depth.
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scale (1: 0–25% improvement; 2: 26–50% improvement; 3:
51–75% improvement; 4: 76–100% improvement). Separate as-
sessments were provided for both overall improvement and
a smaller number of thigh lesions were treated (62 total; average
2.8 per patient per thigh). Thirteen subjects presented for follow
up, and their images were graded and analyzed. All subjects
Penalties Apply
dimple depth improvement. were noted to have improvement in the overall appearance and
depth of cellulite lesions by both physician and subject GAIS
Vectra 3D imaging analysis was also performed on patients who ratings (Table 4). Treating physicians graded results an average
completed the follow-up visit as described in Figure 2. Each of 2.23/5 or “much improved to improved”, with 9 subjects as
dimple was outlined following the edge of the 0 mm border. much improved or very much improved (69.2%).
Follow-up images from the 180-day visit were then registered
to the initial baseline image. The area selections and landmarks The additional blinded assessment conducted at this regis-
from the baseline images were projected to the follow-up imag- try site supported the treating physician GAIS ratings. The
es. The analysis script was then run on all marked images. The blinded assessors graded overall improvement an average of
3D analysis script creates volume models by comparing the 2.8 (corresponding to 26-75% improvement), with 8 subjects
outlined dimples to adjacent reference areas. The mean depth (61.6%) assessed as having greater than 50% improvement
and volume of the dimples at both baseline and at the 180-day overall. When assessing depth of dimpling, an average score
follow-up provided as output by the analysis script were used of 2.9 was assigned, with 9 subjects having greater than 50%
to quantitatively assess the efficacy of dimple release by TS-GS. improvement (69.2%; Table 5).
RESULTS Analysis of 3D imaging of dimples and surrounding skin yield-

Sixteen women with a mean age of 44.1 years and mean BMI ed a 67.4% average improvement in negative volume and a
of 22.8 were treated. Seven individuals were of Fitzpatrick skin 58.4% improvement in minimum height (ie, dimple depth; Table
type II (43.8%), five skin type III (31.2%), and two skin types IV 6). Expected treatment effects including post-procedural ecchy-
and VI (12.5%; Table 2). Most subjects had dimpling of the but- moses and soreness resolved by the three-month follow up,
tocks treated (229 total; average 7.2 per patient per buttock), and with one patient experiencing persistent hyperpigmentation
963
TABLE 1.
Inclusion and Exclusion Criteria
• Female subjects ≥ 18years of age.

• Subject is a reasonable candidate and has been scheduled for a study device treatment (no
contraindications, areas to be treated are FDA-cleared) and will receive a single study device treatment
to improve the appearance of cellulite.
• Willingness and ability to comply with protocol requirements, including returning for follow-up visits
and abstaining from exclusionary procedures for the duration of the study.
Inclusion Criteria:
• Subjects of childbearing potential must have a negative urine pregnancy test result
• Absence of psychological conditions unacceptable to the investigator.
• Willingness and ability to provide written consent for study-required photography and adherence to
photography procedures.
• Willingness and ability to provide written informed consent and HIPAA authorization prior to
performance of any study-related activities.
• Pregnant or breastfeeding.
• Actively trying to lose or gain weight or planning to lose or gain weight over the study period.
• Presence of an active systemic or local skin disease that may affect wound healing.
• History of chronic drug or alcohol abuse.
• History of keloid or hypertrophic scarring.
• Concurrent therapy that, in the investigator’s opinion, would interfere with the evaluation of the safety or
efficacy of the study device, such as, but not limited to chemotherapeutic medications.
• Subjects who anticipate the need for surgery or overnight hospitalization during the study.
• Subjects who, in the investigator’s opinion, have a history of poor cooperation, noncompliance with
medical treatment, or unreliability.
• Concurrent enrollment in any study involving the use of investigational devices or drugs.
Exclusion Criteria: • History of the following treatments in the area(s) to be treated:
• Skin tightening procedure within the past 6 months;
• Liposuction in the past year;
• Energy-based body sculpting, fat reduction or cellulite treatment in the past 6 months;
• Needle subcision in the past year;
• Injectable collagenase or deoxycholic acid for fat reduction, body contouring, or cellulite in the past year.
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• History of using the following medications:
• Antiplatelet agents/Anticoagulants (such as Coumadin, Aspirin, Heparin, Plavix, etc);
• Psychiatric drugs that in the investigators opinion would impair the subject from understanding the
protocol requirements, understanding and signing the informed consent, or would confound their
Penalties Apply
responses to subject assessments.
(Table 7). Before and after images of a representative patient described as “much improved” or “very much improved.” Side
are depicted in Figure 3. effects included bruising, edema, and areas of palpable firm-
ness or softness that generally resolved within a month.7 No
DISCUSSION pain or adverse effects were reported at three-year follow-up.
Cellulite is a common condition, with several available treat- Patient satisfaction was high at 85% at 3 months, 94% at 1 year,
ment options of varying efficacy. Appropriate patient selection, 96% at 2 years, and 93% at 3 years.5,7,8
careful evaluation of the anatomy of the patient and the mor-
phology of the cellulite can help identify the best therapeutic The data presented in our study support and extend the previ-
strategy. Diffuse rippling represents increased adiposity and/or ous findings in the TS-GS pivotal studies.5,7,8 Patient registries
increased skin laxity which may stand to benefit from lipolytic provide a unique opportunity to explore the real-world effec-
and skin tightening modalities. Dimpling represents tethering tiveness of a given treatment. In this TS-GS registry, subjects
by fibrous septae, which can be treated directly using TS-GS. were treated according to each individual site’s standard of
care, and subsequently followed for 6 months to assess safety,
Kaminer et al.5 recently reported three-year results from treat- efficacy (subject- and physician-assessed), and subject satis-
ing 45 patients with a single treatment of the study device, faction.6 In addition to the evaluations conducted at all registry
demonstrating its safety and efficacy. Pretreatment cellulite sites, 2 unique assessments were conducted at our individual
severity scale scores were decreased by a mean of 2 points site. First, a blinded panel of physicians rated the degree of
on a 5-point scale at three years. GAIS assessments showed cellulite improvement (both overall and specific dimple depth
noticeable improvement in all patients, with 56% of patients improvement). At 6 months, a majority subjects were assessed
964
TABLE 2. TABLE 3.
Demographics Number of Treatment Areas
Gender: Female n (%) Treatment area n (average)
Average age (yrs) 16 (100) Left buttock 117 (7.3)
Average BMI: 44.1 Right buttock 112 (7.0)
Fitzpatrick types: 22.8 Left thigh* 32 (2.9)
I 0 (0.0%) Right thigh* 30 (2.7)
II 7 (43.8%) *Posterolateral thigh only.
III 5 (31.2%)
IV 2 (12.5%)
V 0 (0.0%)
VI 2 (12.5%)
TABLE 4. TABLE 5.
Global Aesthetic Improvement Scale Results at Blinded Physician Assessment at 180-day Follow-up
180-day Follow-up
Blinded physician
Blinded physician assessment at 180
Improvement Improvement
assessment at 180 days Improvement Improvement days (Degree of
Overall Depth
(Degree of improvement Overall Depth improvement)
(n=13) (n=13)
1: Very much improved 1 (7.7%) 2 (15.4%) 4 (76-100%) 4 (30.8%) 4 (30.8%)
2: Much improved 8 (61.5%) 3 (23.1%) 3 (51-75%) 4 (30.8%) 5 (38.4%)
3: Improved 4 (30.8%) 7 (53.8%) 2 (26-50%) 5 (38.4%) 4 (30.8%)
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4: No change - 1 (7.7%) 1 (0-25%)
- -
5: Worse - -
Mean 2.8 2.9
Mean 2.23 3.0
Penalties Apply
by blinded physician to have >50% improvement in dimple The literature has established that TS-GS provides long-lasting
depth and appearance overall. This finding is highly consistent results as assessed by patients and physicians, with a favorable
with the treating physician GAIS scores, in which all subjects tolerability profile.5,7,8 Together, the safety and efficacy findings
were rated as having some improvement, and 69% were rated from this real-world registry study are highly supportive of this
as “much improved” or “very much improved.” Subject GAIS growing body of clinical evidence and add an important new
scores were similarly favorable. element: an objective, quantitative demonstration that dimple
depth and volume are markedly improved by TS-GS.
The 3D image analysis represented the second unique assess-
ment conducted at this specific registry site; to the best of the CONCLUSION
authors’ knowledge, this study represents the first in which the Our center’s experience with a tissue stabilized-guided subcision
efficacy of TS-GS was objectively and quantitatively assessed device and objective analysis of results further demonstrates
using image analysis. We found that dimple volume was re- that the study device is safe and effective in the treatment of
duced by an average of 67.4%, and dimple depth was improved unwanted dimpled cellulite of the buttocks and thighs.
by 58.4% on average. Direct observation of improvement in
these 2 parameters is consistent with the proposed mechanism
of TS-GS, which involves the release of fibrous septae (ie, teth-
ers) that underlie the dimples.
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TABLE 6.
Vectra 3D Imaging Results
Baseline Day 180 Baseline Day 180 Average
3D Data Point (n=145)
(mean) (mean) (median) (median) Improvement (%)
Negative Volume (mm3)
(Volume between two surfaces, where the
-70.9 -34.5 -21.3 -4.2 67.4%
select measurement surface is negative
relative to the reference surface)
Minimum Height (mm)
(Greatest negative distance between selected -0.34 -0.17 -0.24 -0.09 58.4%
target region and reference surface)
TABLE 7.
Side Effects
Expected Treatment Effects
3 days 14 days 30 days 90 days 180 days
(number of events)
Bleeding / fluid extravasation 3
Ecchymosis/bruising 15 11 10 4
Fluid accumulation 10 1
Hematoma 2 7 9 4
Hyperpigmentation 1 1 1
Induration 1 1 1 1
Numbness 1
Petechia/purpura 8 3 1
Puncture site / red spots 12 5 1
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Soreness 13 12 5
DISCLOSURE Penalties Apply

JB is a consultant with Merz and has received honoraria from 6. Green JB, Geronemus RG, Cohen JL, et al. An Observational Study of the
Safety and Efficacy of Tissue Stabilized Guided Subcision: Final Data. Poster
Merz. YB is a consultant for and has received honoraria from presented at: American Academy of Dermatology Annual Meeting; March
Merz. MC, LB, RA, RS, and RG have no conflicts. Source of 3-7, 2017; Orlando, FL.
7. Kaminer MS, Coleman WP, Weiss RA et al. Multicenter pivotal study of vac-
funding: Merz North America, Inc.
uum-assisted precise tissue release for the treatment of cellulite. Dermatol
Surg. 2015; 41:336-47
REFERENCES 8. Kaminer MS, Coleman WP, Weiss RA et al. Tissue stabilized-guided subci-
sion for the treatment of cellulite: a multicenter pivotal study with two-year
1. Muller G, Nurnberger F. Anatomic principles of the so-called “cellulitis”. Arch
follow-up. Dermatol Surg. 2016; 42:1213-16.
Dermatol Forsch. 1972; 244:171-2.
2. Christman MP, Belkin D, Geronemus RG et al. An anatomical approach to
evaluating and treating cellulite. J Drugs Dermatol. 2017; 16(1):58-61
3. Hexsel D, Abreu M, Rodrigues T et al. Side-by-side comparison of areas with
and without cellulite depressions using magnetic resonance imaging. Der- AUTHOR CORRESPONDENCE
matol Surg. 2009; 35:1471-7.
4. Cellfina System [Instructions for Use]. Mesa, AZ: Ulthera, Inc.; 2017.
5. Kaminer MS, Coleman WP 3rd, Weiss RA, et al. A Multicenter Pivotal Study
Mitalee P. Christman MD
to Evaluate Tissue Stabilized-Guided Subcision Using the Cellfina Device E-mail:................….............. mchristman@laserskinsurgery.com
for the Treatment of Cellulite With 3-Year Follow-Up. Dermatol Surg. 2017;
43(10):1240-1248.

SPECIAL TOPIC
Assessing the Potential Role for Topical Melatonin

in an Antiaging Skin Regimen
Doris Day MD,a Cheryl M. Burgess MD,b Leon H. Kircik MDc
a
NYU Langone Medical Center, New York, NY
b
Center for Dermatology and Dermatologic Surgery; George Washington University School of Medicine and Health Sciences;
Department of Internal Medicine/Dermatology, Georgetown University Medical Hospital, Washington, DC
c
Icahn School of Medicine at Mount Sinai, New York, NY; Indiana Medical Center, Indianapolis, IN;
Physicians Skin Care, PLLC, Louisville, KY; DermResearch, PLLC, Louisville, KY
ABSTRACT
Background: Melatonin is an endogenous hormone commonly associated with regulation of sleep. However, over the last two de-
cades, research has elucidated a range of effects associated with the compound, including anti-inflammatory, both direct and indirect
antioxidant activity, tissue regenerative benefits, and preservation of mitochondrial function. Melatonin’s anti-inflammatory and anti-
oxidant support, coupled with its mitochondrial support, make it an intriguing target for use to support skin health. Human skin and
hair follicles express functional melatonin receptors. They also engage in substantial melatonin synthesis. By supporting cutaneous
homeostasis, melatonin and its metabolites are thought to attenuate carcinogenesis and possibly other pathological processes, includ-
ing hyperproliferative/inflammatory conditions.
The primary extrinsic driver of aging has been considered to be exposure to ultraviolet (UV) light, which is well-established to contribute
to sunburn, immunosuppression, skin aging, and carcinogenesis. Topically applied melatonin has been shown to reduce markers of
reactive oxygen species formation and to reverse signs of skin aging.
As the global population continues to age, photo-damage remains a significant cutaneous concern. While use of sunscreens and UV
avoidance strategies are essential to mitigate skin cancer risks, the potential to protect the skin and improve the appearance of photo-
damage through the use of topical antioxidant support is appealing. The evidence suggests that melatonin deserves consideration for
topical use as an anti-aging and skin protective agent. It is shown to be both safe and effective when topically applied.
J Drugs Dermatol. 2018;17(8):966-969.

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INTRODUCTION
Penalties Apply
M
elatonin, the main neuroendocrine product of the pi- One area of research has focused on the use of melatonin
neal gland, is an endogenous hormone commonly systemically for its anti-aging benefits via preservation of mito-
associated with regulation of the sleep cycle. Exoge- chondrial function. As mitochondrial function declines with age,
nous melatonin, in the form of oral supplements, has been used impairment leads to damage to mitochondrial proteins, lipids,
for many years to help regulate the sleep cycle. Research over and DNA. One way that melatonin may preserve mitochondrial
the last two decades supports a range of additional benefits as- physiopathology and prevent aging is by preserving cardiolipin,
sociated with melatonin, including anti-inflammatory and both a phospholipid that plays an important role in several biochemi-
direct and indirect antioxidant activity. Melatonin also has been cal processes of the mitochondrial function, from ROS mediated
shown to induce tissue regeneration.1 Specifically, research has oxidation.4
elucidated regenerative effects of melatonin on tissues of the
nervous system, liver, bone, kidney, bladder, muscle, and skin.1 Of particular interest, melatonin and its metabolites have been
The combined antioxidant, anti-inflammatory, and regenerative identified as integral to physiological skin functions.5 Such
effects of melatonin are sufficiently potent that melatonin has functions are known to decrease with age and cumulative skin
been investigated as a protective agent for ischemia-reperfu- damage. In the skin, melatonin functions largely as a direct and
sion (IR) injury in brain, heart, and liver.2 The degree of myo- an indirect antioxidant.
cardial protection from melatonin following myocardial IR has
been characterized as “substantial.”3 The range of potential cutaneous benefits associated with
melatonin extend beyond signs of skin aging. By supporting cu-
taneous homeostasis, melatonin and its metabolites are thought
967
Journal of Drugs in Dermatology D. Day, C.M. Burgess, and L.H. Kircik
to attenuate carcinogenesis and possibly other pathological pro- as such shown to stimulate the transcription factor, NRF2 and
cesses, including hyperproliferative/inflammatory conditions.2 up-regulate gene expression and activity of several antioxida-
Reduced melatonin levels have been linked to inflammation in tive enzymes, such as Cu⁄ Zn-superoxide dismutase (CuZn-SOD),
psoriasis, suggesting a possible therapeutic role for melatonin Mn-superoxide dismutase (Mn-SOD), catalase and glutathione
supplementation.6 Topically applied melatonin has demonstrat- peroxidase (GPx) in human skin explants8,21 supporting an in-
ed positive effects for the management of androgenetic alopecia direct antioxidant action of melatonin. The levels of antioxidant
with a reduction in hair loss among women and a maintenance enzymes have been reported to stay upregulated for several
of current hair among men.7 The benefit has been attributed to hours21 suggesting a sustained, long-lasting antioxidant protec-
melatonin’s indirect antioxidant and regenerative capacities.8 tion in the skin whose benefits last through the night.21 Its effects
Melatonin may also have a role in barrier function and enhance in supporting antioxidant activity are potent enough to inspire
wound healing by increasing proliferative activity of keratino- one group of researchers to suggest that melatonin “would
cytes.9 improve the therapeutic ratio in radiation oncology and amelio-
rate skin damage more effectively when administered in optimal
The range of proposed cutaneous benefits associated with mel- and non-toxic doses.”22
atonin are certainly intriguing. However, its role as an anti-aging
agent for topical application may have both greatest promise and While multiple antioxidants have been variously recommend-
potential utility. A careful assessment of the indirect or direct an- ed—either via oral supplementation or topical application for skin
tioxidant and anti-inflammatory effects of melatonin is therefore protection—melatonin presents distinct potential benefits for
warranted. Additionally, it is worthwhile to review the evidence addressing oxidative stress in the skin. Melatonin is associated
for benefit attributed to topical application of melatonin. with stronger antioxidant effects than vitamins C and E. Mela-
tonin is highly lipophilic and penetrates organic membranes to
Skin Aging and Antioxidants protect mitochondria and DNA from oxidative damage. Mamma-
Visible signs of skin aging are the result of various intrinsic and lian skin boasts high concentrations of precursor molecules that
extrinsic factors. Genetic factors may direct the rate and extent facilitate melatonin synthesis. Therefore, topical application of
of cell senescence, the depletion of collagen stores, and structur- melatonin is expected to provide antioxidant benefits directly at
al changes, including the shifting of fat and bone.10,11 However, the site where ROS form in response to exposure to UV light and
extrinsic factors may significantly accelerate aging. The primary pollution. Melatonin applied to the skin has been shown to ele-
extrinsic driver of aging has been considered to be exposure to vate antioxidant enzymes mRNA levels for at least 24 hours. This
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ultraviolet (UV) light. The predominant effects of UV exposure, suggests that the upregulation of gene expression and activity
such as sunburn, immunosuppression, skin aging, and carcino- of the above-mentioned antioxidative enzymes and down-regu-
genesis have been well-documented in the literature.12 Exposure lation of interstitial collagenase (MMP-1), stromelysin 1 (MMP-3),
to UVA has been directly correlated to a reduction of collagen stromelysin 2 (MMP-10), and aldehyde dehydrogenase 3 type A1
Penalties Apply
in human dermal extracellular matrix.13 Relevant to both skin would provide important activity for protecting and repairing the
aging and photocarcinogenesis, the effects of UV exposure on skin.21
the skin encompass DNA alterations, including induction of thy-
mine-thymine dimers and loss of tumor suppressor gene p53.14 In a randomized, split-face, assessor-blinded, prospective three-
More recently, focus has shifted to other extrinsic contributors month study, involving 22 women (mean age, 55 years) with
to skin aging, including visible and infrared (IR) light, as well as moderate-to-severe skin aging, topical application of a mela-
atmospheric pollutants, such as ozone.15-17 tonin cream was associated with a significant 15% reduction in
the appearance of crow's feet, compared with non-treatment, at
The oxidative stress theory of aging is relevant to skin ag- three months. Skin tone and skin dryness were also improved.23
ing, as evidence shows that irrespective of the extrinsic
agent, either solar radiation (at multiple wavelengths) or at- Melatonin absorbs UV light at a wavelength of 225-275 nm,
mospheric pollutants, oxidative stress mediated formation which is below the UVA and UVB wavelengths of 290-390 nm.24
of reactive oxygen species (ROS)18 produces inflammation This has led researchers to speculate that the photoprotective
and cytotoxicity with resultant cell damage.19 Ozone induces benefits of melatonin are actually a direct consequence of its
oxidative stress on the skin's surface via formation of lipid per- strong capacity to quench ROS produced as a result of radiation
oxidation (LPO) products.17 Of note, research has shown that and of its ability to stimulate antioxidant enzymes in the skin.
the mitochondria are responsible for producing 90% of ROS.
In order to show Melatonin’s impact as a direct and indirect an-
Melatonin is shown to function as an indirect antioxidant in the tioxidant, researchers undertook a systematic database review,
skin, with several of its metabolites described as potent antioxi- with 20 studies evaluating melatonin's protective effect against
dants.20 In addition, melatonin is also an indirect antioxidant and UVR-induced erythema in humans, with results indicating a
968
protective effect against UVR-induced erythema when topical As the global population continues to age, photodamage
melatonin was applied before exposure rather than after. All the remains a significant cutaneous concern. In fact, the $46.93 Bil-
studies used artificial UVR-sources and did not investigate pos- lion (USD) global cosmeceuticals market is driven primarily by
sible side effects.25 demand for anti-aging skincare.28 While use of sunscreens and
UV avoidance strategies are essential to mitigating skin cancer
Most recently, an in-vitro study was performed to evaluate the risks as well as photoaging, the potential of topical melatonin
relative expression of genes associated with antioxidant activ- to provide anti-aging benefits through an indirect and direct an-
ity for a melatonin-containing topical night-time formulation. tioxidant effect is appealing.
The formulation was evaluated undiluted and topically applied
on medaka eleutheroembryos (ME). Topical application of me- With its unique antioxidant effects, melatonin should be consid-
latonin-containing formulation significantly increased gene ered for topical use as an anti-aging and skin protective agent.
expression of SOD1, CAT, Nrf2 and GPx1, as demonstrated Although the available in-vitro and in-vivo studies have demon-
via real-time quantitative PCR (Polymerase Chain Reaction) to strated that topical melatonin is an effective anti-aging option
quantify mRNA levels. Findings confirm that topically applied for night-time application, more clinical studies are needed to
melatonin behaves as an indirect antioxidant by up-regulating understand the full potential of topical melatonin.
the gene expression of Nrf2 and antioxidant enzymes.26
DISCLOSURES
Considerations for Topical Application Doris Day MD has been a consultant for ISDIN.
Although oral melatonin supplements are widely available, top-
ical formulations are far less common. Oral administration is Cheryl M. Burgess MD FAAD has served on the advisory board
thought to deliver the active compound to the bloodstream via for Aclaris Therapeutics, Inc, Revance Therapeutics, Inc., The
the gut. But what is the mechanism for topical delivery? Topical- Merz Institute of Advanced Aesthetics, Merz Pharmaceuticals,
ly applied melatonin is a practical option for topical application and ISDIN.
only if it can be safely and effectively delivered to the skin with
minimal systemic effect. Human skin and hair follicles express Leon H. Kircik MD is a consultant and advisory board member
functional melatonin receptors in addition to being engaged in for ISDIN.
substantial melatonin synthesis.27 Topically applied melatonin
has been shown to be safe, even with full body application, REFERENCES
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showing no effect on cognition, including measures of sleepi- 1. Gudjonsson JE, Elder JT. Psoriasis: epidemiology. Clin Dermatol Majidinia
M, Reiter RJ, Shakouri SK, Mohebbi I, Rasteghar M, Kaviani M, Darband SG,
ness. 25 Jahanban-Esfahlan R, Nabavi SM, Yousefik B. The multiple functions of mela-
tonin in regenerative medicine. Ageing Res Rev. 2018 Apr 6. E-pub
2. Ma Z, Xin Z, Di W, Yan X, Li X, Reiter RJ, Yang Y. Melatonin and mito-
Melatonin synthesis in the human body peaks in the evening chondrial function during ischemia/reperfusion injury. Cell Mol Life Sci.
Penalties Apply
hours,21 perhaps not surprising, given its association with reg- 2017;74(21):3989-3998.
ulating circadian rhythms. Since cutaneous repair processes are 3. Yang Y, Sun Y, Yi W, Li Y, Fan C, Xin Z, Jiang S, Di S, Qu Y, Reiter RJ, Yi D. A
review of melatonin as a suitable antioxidant against myocardial ischemia-re-
also thought to take place overnight, and skin permeability is at perfusion injury and clinical heart diseases. J Pineal Res. 2014;57(4):357-66.
its highest at night, topical application of melatonin at nighttime 4. Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Mitochondrial bioen-
ergetics decay in aging: beneficial effect of melatonin. Cell Mol Life Sci.
may optimize the wound healing and anti-aging benefits of the 2017;74(21):3897-3911.
compound while mimicking its endogenous effects. 5. Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM,
Zmijewski JW. Melatonin, mitochondria, and the skin. Cell Mol Life Sci.
2017;74(21):3913-3925.
CONCLUSION 6. Tohid H, Aleem D, Jackson C. Major Depression and Psoriasis: A Psychoder-
There is now substantial evidence that topical melatonin, a matological Phenomenon. Skin Pharmacol Physiol. 2016;29(4):220-30.
7. Garre A, Piquero J, Trullàs C, Martinez M. Efficacy and safety of a new topi-
naturally occurring hormone long used as an oral supple- cal hair loss-lotion containing oleanolic acid, apigenin, biotinyl tripeptide-1,
ment to support sleep, may have important benefits for the diaminopyrimidine oxide, adenosine, biotin and ginkgo biloba in patients
with androgenetic alopecia and telogen effluvium: A six-month open-label
skin. The compound is a strong direct antioxidant as well as prospective clinical study. J Cosmo Trichol. 2018;4:1.
an indirect antioxidant with demonstrated anti-aging benefits. 8. Fischer TW, Trüeb RM, Hänggi G, Innocenti M, Elsner P. Topical melatonin for
treatment of androgenetic alopecia. Int J Trichology. 2012;4(4):236-45.
Within the skin, melatonin behaves as an indirect antioxidant 9. Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ, Paus
by upregulating the gene expression of antioxidant enzymes. R. Melatonin: A cutaneous perspective on its production, metabolism, and
It accomplishes this by upregulating the transcription factor, functions. J Invest Dermatol. 2018;138(3):490-499.
10. Weinkle S, Saco M. Approach to the mature cosmetic patient: Aging grace-
NRF2, which after translocating to the nucleus can induce the fully. J Drugs Dermatol. 2017;16(6):s84-s86.
transcription of antioxidant enzymes, such as SOD1, GPX-1, 11. Cotofana S, Fratila AA, Schenck TL, Redka-Swoboda W, Zilinsky I, Pavicic T.
The anatomy of the aging face: A review. Facial Plast Surg. 2016;32(3):253-
and CAT by binding to the antioxidant response element (ARE) 60.
promoter region. 12. Christensen L, Suggs A, Baron E. Ultraviolet photobiology in dermatology.
Adv Exp Med Biol. 2017;996:89-104.
13. Yamaba H, Haba M, Kunita M, Sakaida T, Tanaka H, Yashiro Y, Nakata S. Mor-
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phological change of skin fibroblasts induced by UV Irradiation is involved in 23. Milani M, Sparavigna A. Antiaging efficacy of melatonin-based day and night
photoaging. Exp Dermatol. 2016;25 Suppl 3:45-51. creams: a randomized, split-face, assessor-blinded proof-of-concept trial.
14. Bosch R, Philips N, Suárez-Pérez JA, Juarranz A, Devmurari A, Chalensouk- Clin Cosmet Investig Dermatol. 2018;11:51-57.
Khaosaat J, González S. Mechanisms of photoaging and cutaneous photo- 24. Fischer T, Bangha E, Elsner P, Kistler GS. Suppression of UV-induced ery-
carcinogenesis, and photoprotective strategies with phytochemicals. Anti- thema by topical treatment with melatonin. Influence of the application time
oxidants (Basel). 2015;4(2):248-68. point. Biol Signals Recept. 1999;8(1-2):132-5.
15. McDaniel D, Farris P, Valacchi G. Atmospheric skin aging-contributors and 25. Scheuer C. Melatonin for prevention of erythema and oxidative stress in
inhibitors. J Cosmet Dermatol. 2018 Apr;17(2):124-137. response to ultraviolet radiation. Dan Med J. 2017;64(6).
16. Liebel F, Kaur S, Ruvolo E, Kollias N, Southall MD. Irradiation of skin with vis- 26. Narda M, Granger C. Anti-aging facial serum containing melatonin, bakuchiol
ible light induces reactive oxygen species and matrix-degrading enzymes. J and ascorbyl tetraisopalmitate upregulates antioxidant gene expression in
Invest Dermatol. 2012;132(7):1901-7. medaka embryos. Poster 7439 presented at the Annual Meeting of the AAD,
17. Burke KE. Mechanisms of aging and development-A new understanding of February 2018.
environmental damage to the skin and prevention with topical antioxidants. 27. Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ, Paus
Mech Ageing Dev. 2018;172:123-130. R. Melatonin: A cutaneous perspective on its production, metabolism, and
18. Dreher F, Maibach H. Protective effects of topical antioxidants in humans. functions. J Invest Dermatol. 2018;138(3):490-499.
Curr Probl Dermatol. 2001;29:157-64. 28. Mordor Intelligence: https://www.mordorintelligence.com/industry-reports/
19. Kandola K, Bowman A, Birch-Machin MA. Oxidative stress--a key emerging global-cosmeceuticals-market-industry, Accessed April 27, 2018.
impact factor in health, ageing, lifestyle and aesthetics. Int J Cosmet Sci.
2015;37:1-8.
20. Kleszczynski K, Fischer TW. Melatonin and human skin aging. Dermatoendo-
crinol. 2012;4(3):245-52.
AUTHOR CORRESPONDENCE
21. Fischer TW, Slominski A, Zmijewski MA, Reiter RJ, Paus R. Melatonin as a
major skin protectant: from free radical scavenging to DNA damage repair. Leon H. Kircik MD
Exp Dermatol. 2008;17(9):713-30.
E-mail:................……............................. wedoderm@yahoo.com
22. Abbaszadeh A, Haddadi GH, Haddadi Z. Melatonin role in ameliorating radia-
tion-induced skin damage: From theory to practice (A review of literature). J
Biomed Phys Eng. 2017;7(2):127-136.
August 201
8 • Volum
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Lifting the Veil on Suicidal Ideation
and Behavior in Psoriasis
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E
YING ACN Guest Editor, Leon H. Kircik MD
DEMYSTIF
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ALGORITH
IEW S
NE PREV
Lifting thCAeL TRVIAL REVIEW
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This activity is supported by an educational grant provided by
Ortho Dermatologics, a division of Valeant Pharmaceuticals North America LLC.
ISSN: 1545 9616

August 2018
• Volume 17
• Issue 8 ( SU
PPLEMENT)

SPECIAL TOPIC
A Randomized, Double-Blind, Placebo-Controlled,

Split-Face Study of the Efficacy of Topical Epidermal
Growth Factor for the Treatment of Melasma
Alexis Lyons MD,a Joseph Stoll BS,a and Ronald Moy MD FAADa
a
Moy, Fincher, Chipps Facial Plastics & Dermatology, Beverly Hills, CA
ABSTRACT
Introduction: Melasma is a condition in which patients develop symmetric, reticulated, hyperpigmented macules and patches on the
face which is thought to be the result of ultraviolet (UV) exposure and hormonal influences, although the pathogenesis is not com-
pletely understood. The topical application of epidermal growth factor has been used as a whitening agent, moisturizer, and an aid for
wound healing. In this study, we explore the efficacy of topical EGF in the treatment of melasma.
Materials and Methods: This was a randomized, double-blind, placebo-controlled, split-face study to determine the efficacy of a topical
EGF serum in the treatment of melasma. Fifteen women with a mean age of 44 were randomized to treatment side of the face and
applied a topical EGF serum and a placebo twice daily to each designated side of the face for eight weeks. Patient satisfaction was
assessed by use of the MelasQoL Questionnaire as well as a patient outcome survey. Subjects were evaluated using the Physician
Global Aesthetic Improvement Scale (GAIS) by two board-certified dermatologists.
Results: GAIS scores showed an improvement in the melasma in 73.4% of subjects vs 13% improvement for the placebo side. The
average MelasQoL questionnaire score decreased from 42 to 33 with 73% of subjects having an improvement in their score. In ad-
dition, 73% of subjects reported an improvement in their melasma. No adverse events or side effects were reported with use of the
topical serum or placebo.
Conclusions: This study suggests that topical EGF is a safe, noninvasive, and effective treatment for melasma.
J Drugs Dermatol. 2018;17(6):970-973.
INTRODUCTION Do Not Copy MATERIALS AND METHODS
M
elasma is a pigmentary condition in which patients de- This was a randomized, double-blind, placebo-controlled,
Penalties Apply
velop symmetric, reticulated, hyperpigmented mac- split-face study to determine the efficacy of topical EGF in the
ules and patches on the face. The disorder is thought treatment of melasma. Fifteen women between the ages of 28
to be the result of ultraviolet (UV) exposure and hormonal influ- and 57 (mean age, 44) were recruited from a private dermatol-
ences, although the pathogenesis is not completely understood. ogy office in Beverly Hills, CA. Informed consent was obtained
It occurs most commonly in women and is more prevalent in from all subjects. Subjects were excluded if they were under
darker skinned individuals, but it can occur in all skin types.1 the age of 18, taking oral contraceptive pills, pregnant, breast-
Melasma is a clinical diagnosis and typically falls under three feeding, or using any lightening creams within the past month.
patterns: centrofacial, malar, and mandibular.2 The centrofacial
pattern is the most common presentation and occurs in 50-80% Subjects who fulfilled the eligibility criteria were randomized
of patients.1 Extrafacial melasma has also been described with to treatment and placebo side of the face and applied a topical
hyperpigmentation occurring on the arms, neck, chest, or back.3 EGF serum and placebo twice daily to the designated side of
Melasma is a common reason for dermatology appointments as the face for eight weeks. Subjects returned for a follow-up visit
it can negatively impact patient quality of life. The treatment of at 4 weeks and a final appointment at 8 weeks. Photographs
melasma has remained a challenge despite its wide prevalence. were taken at each visit.
Epidermal Growth Factor (EGF) promotes cell growth by bind- Results were reviewed at baseline and at the final visit at eight
ing to the EGF receptor (EGFR) on the cell surface. EGF has been weeks (Figure 1A, 1B, 1C, 1D, and Figure 2A, 2B, 2C, 2D). Overall
used in cosmeceuticals as a whitening agent, moisturizer, and improvement was assessed by two board-certified dermatolo-
to accelerate wound healing.4-7 In this study, we explore the ef- gists using the Physician Global Aesthetic Improvement Scale
ficacy of topical EGF serum in the treatment of melasma.
971
Journal of Drugs in Dermatology A. Lyons, J. Stoll, and R. Moy
FIGURE 1A AND 1B. 45-year-old female at baseline and eight week FIGURE 2A AND 2B. 39-year-old female at baseline and eight week
follow-up appointment. follow-up appointment.
FIGURE 1C AND 1D. Placebo side at baseline and eight week FIGURE 2C AND 2D. Placebo side at baseline and eight week
follow-up. follow-up.
(1A) (1B) (2A) (2B)
(1C) (1D) (2C) (2D)
TABLE 1. TABLE 2.
Global Aesthetic Improvement Scale (GAIS) GAIS Outcomes
(3) Very Much Improved Optimal cosmetic result Score Treatment Side Placebo Side
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Marked improvement in appearance 3 6.7% (n=1) 0% (n=0)
(2) Much Improved from the initial condition but not
2 40% (n=6) 0% (n=0)
completely optimal
Obvious improvement in appearance 1 26.7 % (n=4) 13% (n=2)
Penalties Apply
(1) Improved from the initial condition, but a touch
0 26.7 % (n=4) 67% (n=10)
up is indicated
-1 0% (n=0) 20% (n=3)
The appearance is essentially the
(0) No Change
same as the original condition
The appearance is worse than the

(-1) Worse
original condition
(GAIS) where a score of -1 = the appearance is worse than the TABLE 3.

original condition; 0 = the appearance is essentially the same Patient Satisfaction Outcomes
as the original condition; 1 = appreciable improvement in the 2=greatly improved 0% (n=0)
appearance from the original condition; 2 = marked improve-
1=slightly improved 73.3% (n=11)
ment in the appearance from the original condition; 3 = optimal
cosmetic results in the patient (Table 1).8 Patients filled out the 0= no change 20% (n=3)
MelasQoL questionnaire at their initial and final visit (Figure -1=condition worsened 6.7% (n=1)
3).9 A patient outcome survey was also given to the patients
at the final visit to assess subject outcome opinions and was
graded on a scale of -1 to 2 where: -1=condition worsened, 0=
no change, 1=slightly improved, 2=greatly improved.
972
FIGURE 3. MelasQol questionnaire.

DISCUSSION
Melasma is a common and chronic skin condition that is dif-
ficult to treat. The frequency of melasma varies between skin
types and ethnicities. One study found that 15-35% of Brazilian
women were affected by the condition.10 Another study of field
workers in India revealed a prevalence of 41%.11 There is also
a genetic predisposition with 40% of patients having relatives
with the disease.12 The challenges of treatment are attributed to
the unclear pathogenesis, the chronicity of the disease, and the
recurrence rate.
Topical EGF application has been shown to help moisturize, act

as a whitening agent, and promote wound healing.4-7 Studies
have also found that application of EGF after laser treatments
help to decrease post inflammatory hyperpigmentation.13,14 In a
study by Schouest et al, 29 women who applied an EGF- con-
taining serum for three months had improvement in wrinkles,
brown spots, red spots, and skin texture.15 Melanocytes express
EGFR and respond to EGF by activating downstream extracel-
lular signal-regulated kinases which reduce melanin synthesis
through downregulation of microphthalmia-associated tran-
scription factor.16 A study by Yun found that EGF significantly
suppresses tyrosinase activity in melanocytes in a dose depen-
dent manner by up to 63% when compared with controls.13
The topical EGF used in this study was bioengineered from

barley, and unlike other topical EGF products derived from E.
Do Not Copy
coli bacteria, it does not lose potency with exposure to UV light
or room temperature. This same barley-derived EGF has been
shown in additional studies to be effective in treating acne
scars, under eye bags, and senile purpura.17-19
Penalties Apply
A validated Melasma Quality of Life Scale (MelasQoL) was de-
veloped by Balkrishnan et al to assess the effect of melasma
on patient quality of life.9 Our patients had an average im-
provement in their MelasQoL score of nine points and 73% of
subjects reported an improvement in their melasma. There was
also an improvement in GAIS scores in 73.4% of subjects for DISCLOSURE
the treatment side vs 13% for the placebo side. Ronald Moy is the founder of DNARenewal, which provided
the topical epidermal growth factor serum for this study. Alexis
There were some limitations to this study including a rela- Lyons and Joseph Stoll have no financial disclosures or con-
tively short follow-up time of eight weeks, and a small sample flicts of interest.
size. Further studies on a larger patient population with longer
follow-up time are needed to assess for lasting results among REFERENCES
patients. Studies with men are also required to evaluate for 1. Tamega Ade A, Miot LD, Bonfietti C, Gige TC, Marques ME, Miot HA. Clinical
patterns and epidemiological characteristics of facial melasma in Brazilian
generalizability to both sexes. In conclusion, topical EGF is a women. J Eur Acad Dermatol Venereol. 2013;27(2):151–6 (PubMed PMID:
safe, noninvasive, and effective treatment for treatment of me- 22212073).
2. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC Jr. Me-
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• The growing impact of seborrheic keratosis on the
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Dermatol. 2015 Oct;14(10):1147-50. • SK treatment strategies offering optimal outcomes
including patient satisfaction leading to enhanced
AUTHOR CORRESPONDENCE quality of life
Alexis Lyons MD
E-mail:................……............................. alexisblyons@gmail.com
VISIT JDDONLINE.COM/CME
This activity is supported by an educational grant from

Aclaris Therapeutics, Inc.
Jointly provided by:

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SPECIAL TOPIC
Clinical Efficacy of a Novel Two-Part Skincare System

on Pollution-Induced Skin Damage
Elizabeth T. Makino BS MBA,a Annie Jain MD,b Priscilla Tan BA,a Audrey Nguyen BS,a Alain Moga MSc,c
Cécile Charmel,d Kuniko Kadoya PhD,a Tsing Cheng PhD,a and Rahul C. Mehta PhDa
SkinMedica, Inc., an Allergan Company, Irvine, CA
a
b
CIDP Biotech India Pvt. Ltd, New Delhi, India
c
Synelvia S.A.S., Labège, France
d
DermScan Group,Villeurbanne, France
ABSTRACT
Introduction: Air pollution continues to be a global health concern and recent studies have shown that air pollutants can cause skin
damage and skin aging through several pathways that induce oxidative stress, inflammation, apoptosis, and skin barrier dysfunction.
Preventive measures need to be considered to retain optimal skin health, and topical skincare products may be able to alleviate the
negative effects of air pollution on skin. A randomized, double-blind, placebo-controlled clinical usage study was conducted to assess
the efficacy and tolerability of a novel two-part skincare system (LVS) that was developed to provide protection against environmental
skin aggressors including air pollution. After 8 weeks of use in subjects exposed to extremely high levels of pollution, LVS provided
significant improvements compared to placebo in all clinical efficacy parameters including crow’s feet wrinkles, overall skin damage,
skin tone evenness, tactile roughness, and visible redness. Subject self-assessment questionnaires showed that the treatment product
was highly rated in self-perceived efficacy. Decreased SQOOH and MDA content in skin swab samples suggest that LVS helped to
reduce oxidative stress in patients’ skin. Histological analyses of biopsy samples using biomarkers related to skin structure, damage
and function (collagen IV, MMP1, CPD, and CD1a) further support the clinical benefits of LVS. Altogether, the presented study is among
the first to show that topical skincare products can help to reduce pollution-induced skin damage and improve skin quality, especially
when specifically formulated with active ingredients that combat the harmful effects of air pollutants.
J Drugs Dermatol. 2018;17(9):975-981.
INTRODUCTION Do Not Copy In 2010, an epidemiological cohort study following 400 women
I
ncreased awareness of the hazardous consequences of air revealed a significant correlation between air pollution exposure
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pollution has led to global efforts to reduce air pollution and and signs of skin aging, specifically pigment spots and wrinkles.6
improve air quality. Air pollution is a serious issue for overall A multicenter clinical study in Mexico, including subjects from
public health as it has been linked to ~7 million deaths annually, a high pollution area and from a low pollution area, described
primarily through cardiovascular and pulmonary diseases. As a higher frequency of certain skin conditions in the population
such, it is the world’s largest environmental health risk putting exposed to more pollution. Interestingly, skin swab and corneo-
it in the same league with other health risks including smoking, adhesive disc samples taken in this study also revealed several
high cholesterol and obesity.1 Air pollution also has aggravating changes in biochemical parameters including decreased squa-
effects on skin conditions and diseases such as atopic dermati- lene and ATP levels as well as an increase in carbonylated pro-
tis.2-4 Various organic and inorganic matter make up air pollution teins suggesting increased oxidative stress due to pollution.7
including fine particulate matter (defined by a diameter ≤2.5 µm
or ≤10µm as PM2.5 or PM10, respectively) that can penetrate the Several mechanisms through which air pollutants cause skin
skin, gases (such as nitrogen dioxide, carbon monoxide, and damage and aging have been proposed including generation
ground-level ozone), and toxic chemicals (for example, polycy- of free radicals and reactive oxygen species (ROS) resulting
clic aromatic hydrocarbons (PAH) and dioxins). While the cur- in oxidative damage to lipids, proteins and DNA. For exam-
rent understanding is that various environmental factors con- ple, ozone is highly reactive with skin surface lipids causing
tribute to extrinsic skin damage and aging, the primary research lipid peroxidation, which results in cascading inflammatory
focus has historically been on solar radiation, especially UV ex- and oxidative effects in the deeper skin layers, and depletion
posure.5 However, the past decade has seen increased research of surface antioxidants such as squalene.8,9 Squalene is the
efforts to determine the mechanisms through which pollution major scavenger of ozone in the skin and oxidized squalene
could cause skin damage as well as its effects on skin aging. (squalene monohydroperoxide; SQOOH) is a biomarker for
environmental pollution.10,11 Particulate matter (PM) was found
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Journal of Drugs in Dermatology E. Makino, A. Jain, P. Tan, et al
to increase skin tissue cytotoxicity and to trigger apoptosis pollution-induced skin damage, the placebo-controlled clinical
through oxidative stress and inflammation in a reconstructed study was performed in subjects living and/or working in a se-
human skin tissue model.12 An in vitro study further elucidated verely polluted urban environment.
the mechanisms of PM2.5-induced apoptosis. HaCaT keratino-
cytes demonstrated a significant dose-dependent decrease in MATERIALS AN DMETHODS
cell viability with exposure to PM2.5 along with dose-dependent Clinical Study Design: Efficacy and Tolerability
increases in ROS generation and malondialdehyde produc- A randomized, double-blind, placebo-controlled clinical usage
tion (MDA; marker for lipid peroxidation) as well as decrease study was conducted to assess the efficacy and tolerability of
in activity of antioxidant enzyme superoxide dismutase (SOD), a new two-product system, LumiVive System, (LVS), SkinMed-
indicating oxidative stress in the exposed cells. The observed ica®, An Allergan Company, consisting of a DAY product (LVD)
cytotoxic effects were attributed to mitochondria-mediated and a NIGHT product (LVN), on pollution-induced skin damage
apoptosis as expression of cytochrome-c, caspase-9, and cas- compared to placebo when used for 8 weeks. The study was
pase-3 also increased proportionally with PM2.5 dosing.13 Re- conducted between October-December 2017 in New Delhi, In-
lease of cytochrome-c from the mitochondrial membrane trig- dia, which had an average Air Quality Index (AQI) greater than
gers activation of caspases that eventually results in apoptosis. 300 (considered as “Hazardous”) when the study was initi-
ated.18. The Delhi metropolis ranks among the most polluted
Various air pollutants including ozone, PM, PAH, and dioxins cities in the world with annual average PM2.5 and PM10 concen-
can activate the aryl hydrocarbon receptor (AhR), which in- trations of 122 and 229 µg/m3, respectively.19 Since WHO safety
creases pigmentation by inducing tyrosinase activity as the levels of PM2.5 and PM10 are set at an annual mean of 10 and
AhR regulates genes involved in melanogenesis.8,14,15 A recent 20 µg/m3, respectively, Delhi exceeds these levels 11-fold.18
study showed that PM-mediated activation of AhR also nega- Subjects were required to have lived in this severe air pollution
tively impacts skin barrier function, since it downregulated area for at least the past 2 years, or subjects must have been
expression of filaggrin, a protein that is incorporated into the occupationally exposed to the air pollution for the past 2 years,
cornified envelope of keratinocytes providing physical strength for example as an outdoor worker. Subjects were randomized
and barrier function. This study also demonstrated that the PM- to receive LVS or the placebo system and were instructed to ap-
mediated AhR activation increased generation of ROS which ply the designated DAY and NIGHT products once daily on the
in turn upregulated expression of the pro-inflammatory cyto- entire face after cleansing in the morning and evening, respec-
kines cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) tively. Study visits occurred at baseline, week 4, and week 8.
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leading to inflammation. The combination of oxidative dam-
age and inflammation may further impair the skin barrier.16 Re- This study is registered with the Clinical Trials Registry India
cently, proteomic analysis of primary keratinocytes as well as (CTRI) as CTRI/2017/08/009383. Independent Ethics Committee
a 3D skin model exposed to diesel particulate extract revealed (IEC) approval was obtained prior to conduct of any study pro-
Penalties Apply
downregulation of numerous proteins involved in epidermal cedures. All subjects provided informed consent prior to study
differentiation and barrier formation including filaggrin, in- participation.
volucrin, and transglutaminases. Extracellular matrix may be
impacted as matrix metalloproteinase-14 was overexpressed, Clinical Efficacy Assessments
while expression of tissue inhibitor of metalloproteinases 2 Clinical efficacy was assessed at all visits. Crow’s Feet Wrinkles
(TIMP2) was downregulated upon exposure to diesel particu- were assessed by the investigator on a 0-5 scale using Skin
late extract. The proteomic analysis also showed dysregula- Aging Atlas, Volume IV Indian Skin Type. Assessments for the
tion of proteins involved in mitochondrial oxidative phos- following parameters were performed by the investigator using
phorylation, which could lead to increased ROS production.17 a modified Griffiths’ 10-point grading scale, where 0=none (best
possible condition), 1-3=mild, 4-6=moderate, and 7-9=severe:
These recent insights show that it is imperative to protect skin • Overall Skin Damage
against the detrimental effects of air pollution. Since it is nearly • Skin Tone Evenness
impossible to avoid exposure to air pollution, application of • Tactile Roughness
topical skincare products that are specifically designed to re- • Visible Redness
duce damage from air pollution may help to support healthy
skin and to mitigate against the signs of aging.The current study Tolerability was monitored via adverse event reporting.
presents the clinical efficacy and tolerability of a novel two-part
skincare system (LVS) consisting of a DAY product (LVD) and a Standardized Digital Photography
NIGHT product (LVN), that was developed to provide protection Standardized digital photographs of the full face were taken
against environmental skin aggressors including air pollution. at all visits using the VISIA-CR photo station (Canfield Imaging
To specifically assess the benefits of this skincare system on Systems, Fairfield, NJ).
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FIGURE 1. Significantly greater improvements with LVS compared to placebo in crow’s feet wrinkles, overall skin damage, and skin tone
evenness at week 4 (âll P≤0.01; Mann Whitney-U test) and in all parameters compared to placebo at week 8 (âll P≤0.04; Mann Whitney-U test).
Significant improvements with LVS compared to baseline in all parameters at weeks 4 and 8 (*all P≤0.001; Wilcoxon signed rank test). Significant
improvements with placebo compared to baseline in crow’s feet wrinkles at weeks 4 and in tactile roughness at weeks 4 and 8 (*all P≤0.03;
Wilcoxon signed rank test).
Subject Self-Assessment Questionnaire group at baseline (right side of the face) and week 8 (left side
Subjects completed a self-assessment questionnaire at all of the face). Samples were fixed with 10% neutral buffered
follow-up visits (weeks 4, 8, and 12) regarding self-perceived formalin (NBF) and embedded into paraffin blocks. Samples
efficacy and overall satisfaction. were stained with haemotoxylin and eosin (H&E) and immu-
nohistochemistry (IHC) using antibodies against collagen IV
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Skin Swab Analysis (Rockland, Limerick, PA), matrix metalloproteinase-1 (MMP1;
Sebum samples were taken from the forehead with a swab- Abcam, Cambridge, MA), cyclobutane pyrimidine dimer (CPD;
bing method at baseline, week 4 and week 8 from all subjects. Cosmo Bio USA, Carlsbad, CA) and CD1a (Thermo Scientific,
Swab homogenates were centrifuged at 10,000 g for 5 minutes Waltham, MA). IHC was performed using Leica automated
Penalties Apply
and subsequently analyzed for squalene monohydroperoxide stainer BONDIII (Leica, Buffalo Grove, IL) followed by image
(SQOOH) and malondialdehyde (MDA) content. For SQOOH capture with digital image scanner Nanozoomer (Hamamatsu,
analysis, samples were extracted using double liquid/liquid Bridgewater NJ).
extraction method, evaporated under nitrogen at 60°C, and
the residue was dissolved in 50 µl of ethanol. SQOOH was Clinical Study Design: Evaluation of Particulate Matter Deposits
detected using an UltiMate 3000 (Dionex, Sunnyvale, CA) A separate study in human volunteers was conducted to eval-
liquid chromatography system coupled to a MSQ Plus detec- uate the protective effect of LVD against particulate matter
tor (Fisher Scientific, Waltman, MA). Atmospheric pressure deposits on the skin after a single standardized application. The
chemical ionization was used as the ion source for mass spec- polluting agent is made up of pigment micro-particles mod-
trometry (MS) detection. Positive ion spectra were recorded in eling atmospheric pollution (average particle size was 1 μm).
the range 50–450m/z. For MDA analysis, samples were treated Randomized zones on the volar forearm were either treated
by an acid hydrolysis and PFB derivation was performed, fol- with LVD or untreated. Twenty minutes after the application
lowed by liquid/liquid extraction with the organic phase dried of LVD, both zones were exposed to the polluting agent. Five
under nitrogen at 60°C. Residues were dissolved in 50µl of hex- minutes after the particulate matter deposits, both zones un-
ane. For MS detection, a negative ion chemical ionization with derwent standardized rinsing of the skin. The protective effect
methane reagent gas was performed using Selected Ion Moni- is evaluated by measuring the quantity of particles removed
toring (SIM). from the skin by standardized rinsing. Standardized images
were taken from both zones with a Hirox video-microscope and
Skin Biopsy Analysis image analysis was performed to measure and compare the
Two-millimeter skin biopsy samples from the forehead close quantity of particles remaining on the skin of the two zones.
to hair line were collected from subjects in each treatment
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FIGURE 2. Improvement in the appearance of skin tone evenness, FIGURE 3. Improvement in the appearance of skin tone evenness and
tactile roughness, and crow’s feet wrinkles in a 48-year-old female tactile roughness, and crow’s feet wrinkles in a 41-year-old female
with Fitzpatrick Skin Type IV in standard lighting at baseline, week 4, with Fitzpatrick Skin Type V in standard lighting at baseline, week 4,
and week 8. and week 8.
resentative standardized digital photographs that support the

RESULTS improvements observed by the investigator in subjects treated
Clinical Efficacy of LVS with LVS.
Thirty-six female subjects aged 40-50 with Fitzpatrick Skin Types
IV-V completed the 8-week randomized, double-blind, placebo- Subjects highly rated LVS over placebo in self-perceived effi-
controlled clinical study (LVS: n=24, placebo: n=12). Daily use of cacy with 100% of subjects agreeing with statements including
LVS provided statistically significant improvements compared LVS “make my skin look and feel rejuvenated”, “make my skin
to placebo for crow’s feet wrinkles, overall skin damage, and feel energized”, “brightened my skin’s complexion” and “made
skin tone evenness at weeks 4 and 8 (all P≤0.01; Mann Whit- my skin look like it did when I was younger” (Figure 4). At the
ney-U test; Figure 1). Significant improvements compared to end of the study all subjects were “satisfied with the (LVS) prod-
placebo in tactile roughness and in visible redness were ob- ucts”.
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served at week 8 (all P≤0.04; Mann Whitney-U test; Figure 1).
Furthermore, all parameters were significantly improved com- Biochemical Analysis of Skin Swabs
pared to baseline at weeks 4 and 8 with LVS treatment, while Skin swab samples were analyzed for biomarkers of pollution-
the placebo group did not reach statistical significance against induced skin damage (SQOOH) and lipid peroxidation (MDA).
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baseline at any time point for overall skin damage, skin tone Subjects treated with LVS showed greater reductions in both
evenness, and visible redness. LVS was well-tolerated with one SQOOH and MDA compared to baseline (both P<0.0001; Wil-
case of transient pruritus upon application that was considered coxon signed rank test) than subjects treated with placebo
treatment-related. The patient continued to use the treatment compared to baseline (both P≤0.005; Wilcoxon signed rank test)
product and completed the study. Figures 2 and 3 show rep- (Figure 5).
FIGURE 4. Subject self-assessment questionnaire of the test products FIGURE 5. LVS showed significantly greater reductions compared to
at week 8: LVS was highly-rated in self-perceived efficacy. baseline in SQOOH and MDA content at weeks 4 and 8 (âll P<0.0001,
*all P<0.005, Wilcoxon signed rank test).
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Histological Analysis of Skin Biopsies FIGURE 6. Histological analysis of biopsy samples at baseline and
H&E staining of skin biopsies showed no significant structural after 8 weeks of LVS treatment. (A-B) H&E staining; (C-D) collagen IV;
change between LVS-treated samples compared to placebo (E-F) MMP1; (G-H) CPD; (I-J) CD1a. Scale bar: 100 µm
treated samples (Figure 6-A, B). However, significant improve-
ments were observed by IHC analysis of collagen IV, MMP1, (A-B)
CPD and CD1a biomarkers for tissue structure, damage and
function. Collagen IV is a major component of the basement
membrane underneath the epidermis, which is known to de- (C-D)
grade with intrinsic aging and is susceptible to accelerated
degradation by extrinsic factors. Biopsy samples treated with
LVS showed induced expression of collagen IV demonstrating (E-F)
improvement of basement membrane structure (Figure 6-C, D).
LVS treatment also resulted in reduced expression of MMP1
and CPD. MMP1 is a major enzyme responsible for collagen (G-H)
degradation contributing to skin aging. Epidermal MMP1 ex-
pression reflects to dermal events. IHC analysis showed high
epidermal expression of MMP1 in the baseline sample, which (I-J)
was reduced after 8 weeks of LVS treatment (Figure 6-E, F) in-
dicating prevention of skin damage and aging. CPD is a direct
form of DNA damage induced by ultraviolet irradiation, that in-
terferes with transcription and DNA replication. CPD positive
cells were abundant in baseline samples, whereas samples at ing of two products that each contain a specific blend of active
week 8 showed great reduction of CPD suggesting that LVS ingredients including antioxidants and peptides that provide
helps to prevent DNA damage and to repair previous damage targeted protective and reparative benefits: LVD is specifically
of the skin (Figure 6-G, H). Furthermore, LVS treatment induced formulated to provide protection against environmental skin
expression of CD1a, which visualizes antigen-presenting Lang- aggressors including air pollution, while LVN is developed to
erhans cells, speculating improvement of Langerhans cell support cellular recovery and mitochondrial function for en-
function (Figure 6-I, J). Recent studies indicate that Langerhans hanced repair, detoxification and energy levels.
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cells have multiple functions in skin such as surveillance of the
local environment at the skin barrier site and maintenance of To critically assess the performance of this dual-product system,
immune homeostasis.20 the clinical study location of New Delhi, India was specifically
selected for its extreme air pollution conditions. The inclusion
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Particulate Matter Deposits criteria required subjects to have lived in the New Delhi area
Twenty-One Caucasian females aged 21-45 years old with for at least the past 2 years, or they must have been working
Fitzpatrick Skin Types II-IV enrolled and completed the study. outdoors in this area for the past 2 years to ensure long-term
After exposure to the polluting agent followed by standardized exposure to severe pollution. Most notably, in November 2017,
rinsing the LVD treated zone showed a significantly greater re-
moval of particulate matter compared to the non-treated zone FIGURE 7. (A) Quantity of particulate matter removed after rinsing
(P<0.0001; Student t-test; Figure 7-A). Figure 7-B shows repre- is significantly higher on the LVD-treated zone than the non-treated
sentative digital images of LVS treated and non-treated zones zone (P<0.0001; Student t-test). (B) Representative digital images of
after standardized rinsing from two different subjects. LVS treated and non-treated zones after standardized rinsing from
two different subjects.
DISCUSSION
While the damaging effects of UV exposure as an environmen- (A) (B)
tal aggressor to skin have been well-characterized, research has
more recently revealed that air pollution also plays an impor-
tant role in human skin damage and aging. Thus, developing
measures that protect against the damaging effects of air pol-
lutants would greatly benefit patients seeking to mitigate the
signs of aging. The current clinical study suggests that topical
skincare can help protect skin from pollution-induced dam-
age but can also reverse signs of existing damage to support
healthy skin. LVS is a novel two-part skincare system consist-
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during the conduct of the clinical study, a public health emer- study is among the first clinical studies to show that topical
gency was declared for New Delhi as the city endured extreme, skincare products can be used to combat the negative effects
toxic smog conditions with PM2.5 concentrations >700 µg/m3 of air pollution on skin and can effectively reduce skin dam-
and air quality monitoring stations reporting the maximum age and signs of skin aging. These skincare products should
AQI of 999 (AQI >300 qualifies as hazardous air quality con- be specifically formulated with active ingredients that optimize
ditions). Given these circumstances, LVS was able to further benefits for users, especially those in severely polluted areas.
improve skin quality as significant improvements compared to The results show that LVS is able to reduce pollution-induced
placebo were observed for all clinical parameters after 8 weeks oxidative stress resulting in clinically improved skin quality.
of use. In fact, all clinical parameters showed significant im-
provements compared to baseline at weeks 4 and 8 with LVS, DISCLOSURE
whereas the placebo group had no significant improvements Ms. Makino, Ms. Tan, Ms. Nguyen, Dr. Kadoya, Dr. Cheng, and
compared to baseline for overall skin damage, skin tone even- Dr. Mehta are employees of Allergan plc, Irvine, CA.
ness, and visible redness. The marked clinical improvements
in skin quality achieved by LVS despite such extreme environ- REFERENCES
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a novel regulator of human melanogenesis. Pigment Cell Melanoma Res.
incare products may also be able to provide protection against 2010; 23(6):828-33
pollutants on a physical level (ie, by preventing penetration of 15. Mancebo SE, Wang SQ. Recognizing the impact of ambient air pollution on
pollutants into the skin). LVD left less particulate matter depos- skin health. J Eur Acad Dermatol Venereol. 2015; 29(12):2326-32
16. Lee CW, Lin ZC, Hu SC, et al. Urban particulate matter downregulates filag-
its on the skin after rinsing compared to the non-treated zone grin via COX2 expression/PGE2 production leading to skin barrier dysfunc-
suggesting LVD acts as a semi-physical barrier or “fly-trap” tion. Sci Rep. 2016; 6:27995
17. Rajagopalan P, Jain AP, Nanjappa V, et al. Proteome-wide changes in pri-
that minimizes deeper penetration of pollutants allowing for mary skin keratinocytes exposed to diesel particulate extract - A role for
increased removal during skin cleansing thereby minimizing antioxidants in skin health. J Dermatol Sci. 2018 May 21. pii: S0923-
1811(18)30215-9
exposure and skin damage. Since the placebo products in the 18. World Health Organization (WHO) India update of WHO SEARO fact sheets,
clinical study have similar product formulation bases to LVD 9 Nov 2017. http://www.searo.who.int/india/topics/air_pollution/air_pollu-
and LVN, this may explain the observed improvements in the tion_health_impacts.pdf
19. World Health Organization (WHO) Global Urban Ambient Air Pollution Da-
placebo group. tabase; update 2016. http://www.who.int/phe/health_topics/outdoorair/data-
bases/cities/en/
20. West HC, Bennett CL. Redefining the role of Langerhans cells as immune
As air pollution continues to be a global health concern for the regulators within the skin. Front Immunol. 2017; 8:1941
next decades, it is important to take preventive measures to 21. Valacchi G, Muresan XM, Sticozzi C, et al. Ozone-induced damage in 3D-Skin
Model is prevented by topical vitamin C and vitamin E compound mixtures
protect oneself and one’s skin against pollutants. The presented application. J Dermatol Sci. 2016; 82(3):209-12
981
22. Jin SP, Li Z, Choi EK, et al. Urban particulate matter in air pollution pen-
etrates into the barrier-disrupted skin and produces ROS-dependent cutane-
ous inflammatory response in vivo. J Dermatol Sci. 2018 Apr 30. pii: S0923-
1811(18)30202-0
Rahul C. Mehta PhD

E-mail:................……........................ Rahul.Mehta@Allergan.com
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SPECIAL TOPIC
Using a New Photo Scale to Compare Product Integration of

Different Hyaluronan-Based Fillers After Injection in Human
Ex Vivo Skin
Björn Lundgren PhD,a Ulrika Sandkvist MSc,a Nicole Bordier MSc,b Beatrice Gauthier DVMb
a
Galderma, Uppsala, Sweden
b
Galderma, Sophia-Antipolis, France
ABSTRACT
Background: The rheological properties of HA products have been investigated thoroughly, and these properties have been used to
predict the clinical performance of HA fillers. It has been suggested that firm gels have a better ability to withstand deformation, and
softer gels have been claimed to integrate and spread more into the tissue since they are perceived to deform more easily. However,
the scientific published data regarding product integration of filler products with different physicochemical properties is limited. Thus,
there is a need to improve the understanding regarding links between rheological properties of the gel material and the clinical perfor-
mance.
Objective: The objectives of this study were: to develop and validate a photo scale for assessment of product distribution after in-
tradermal injection, and to evaluate if product differences, such as overall rheological properties, gel particle size, swelling factor, and
cohesivity effect the product distribution into the tissue after intradermal injections.
Material and Methods: Intradermal injections of HA fillers were performed in ex vivo human abdominal skin samples. The skin
samples were processed for histological evaluation. In order to evaluate the product integration after intradermal injection and compare
the results between different products a 5-grade product integration scale (from 0 to 4) was developed based on representative micro-
photographs. The scale was validated and used for the evaluation of integration of the different products used in the study. The results
were correlated with the rheological properties of the different products.
Results: G’, the elastic modulus, is one important rheological parameter. Strong and firm gels have higher G’ than weak and soft gels.
When plotting the G’ to mean product integration score in human skin obtained in the study, there was a statistically significant correla-
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tion with products with lowest G’ having the highest integration score and products with high G’ having the lowest integration scores.
No statistical correlation could be seen when analyzing the score versus particle size, swelling factor, and cohesivity.
Conclusion: The degree of product integration can be assessed and scored according to a 5-grade visual scale based on representative
Penalties Apply
microphotographs. Products with different rheological properties distribute differently when injected into the skin. Firmer gel texture
resulted in more targeted product integration whiles softer gel texture resulted in distributed product integration.
J Drugs Dermatol. 2018;17(9):982-986.
INTRODUCTION
T
he gel-based dermal filler market sees new products en- firm gels have a better ability to withstand deformation, and
tering the market each year.The most common type of fill- softer gels have been claimed to integrate and spread more
ers is the hyaluronan (HA) cross-linked gels. For instance, into the tissue since they are perceived to deform more eas-
the European market consists of more than a hundred different ily.1,2 However, the scientific published data regarding product
hyaluronic acid (HA) fillers. With the increased number of fillers integration of filler products with different physicochemical
on the market, there is a need for understanding the differences properties is limited3,4 and there is a need to further improve
regarding biological effects in vivo and how these differences the understanding regarding possible links between rheo-
are linked to the clinical experience of the different products. logical properties of the gel material and the clinical outcome.
The rheological properties of HA products have been investi- Following intradermal injection, HA-based fillers tend to spread
gated thoroughly, and these properties together with certain within the reticular dermis and distribute between dermal fi-
postulations have been used to predict the clinical performance bres. In this context, the term integration is used to describe
of HA fillers. For instance, several authors have suggested that the pattern of distribution within the tissue and, specifically,
983
Journal of Drugs in Dermatology B. Lundgren, U. Sandkvist, N. Bordier, B. Gauthier
FIGURE 1. Galderma Product Integration Scale (ex vivo human skin no measurable difference in product integration between fresh
using a modified haematoxylin-eosin staining). and frozen skin (unpublished results on file at Galderma).
The following marketed products were tested: Restylane Lyft,

Restylane Vital, Restylane Skinbooster Vital light, Restylane
Refyne, Restylane Defyne, Restylane Kysse, and Restylane Fy-
nesse. For each marketed product one batch within expiry date
was tested and each product was injected in six different sites.
As a non-cross-linked control, a sodium hyaluronate solution
(20 mg/ml) was used. The mean molecular mass of the sodium
hyaluronate was 2 million.
The skin was mounted onto a cork plate and the test products
(100 µl) were injected intradermally. For each product six rep-
licates were injected. The product specific needle was used for
respective product. Immediately after injection the injection
sites were carefully dissected and placed into buffered formalin
solution for fixation (10 %).
The skin samples were dehydrated, embedded in paraffin,

and processed for histological analysis. Sections were cut at
a thickness of 5 µm, mounted onto glass slides, and stained
with a slightly modified (in order to visualise the HA filler bet-
ter, Galderma data on file) haematoxylin-eosin staining using a
Ventana Symphony stainer (Roche Diagnostics, USA). All slides
were scanned using the Nanozoomer® from Hamamtsu, Japan
and stored in an internal image database. Product integration
evaluation was done on the virtual slides.
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the way the filler material entangled itself in dermal fillers.
In order to evaluate the product integration after intradermal
injection and compare the results between different products a
5-grade product integration scale (from 0 to 4) was developed
Penalties Apply
based on representative microphotographs (Figure 1). The five
The objectives of this study were: (1) to develop and vali- different categories were:
date a photo scale for assessment of product distribution
after intradermal injection, and (2) evaluate if product dif- Grade 0: No integration. Rounded shape of the implant and one
ferences, such as overall rheological properties, gel par- unique region with absence of collagen fibres. Signs of tissue
ticle size, swelling factor, and cohesivity effect the prod- compression may be seen in the periphery.
uct distribution into the tissue after intradermal injections.
Grade 1: Very low integration. Rounded shape of the implant
and 2–6 regions of low degree of integration separated by thin
septa of tissue.
MATERIAL AND METHODS
The skin sample was human abdominal skin obtained from a Grade 2: Moderate integration. Rounded to elongated shape
female donor (born 1956) who had completed abdominal skin of the implant, >7 regions separated by thin septa of tissue. In
reduction surgery. case of uneven distribution pattern of the filler: <25 % of im-
plant with high degree of integration.
The skin was stored at -18° C prior use in the study. At the day
of the experiment the skin samples were allowed to thaw and Grade 3: High integration- Rounded to elongated shape of the
achieve room temperature before any injections were per- implant. Presence of coarse and thin collagen bundles within
formed. The use of skins that have been frozen prior use has the injected area delimiting numerous islets. In case of uneven
been investigated. Although cytological alterations were seen distribution of the filler: 25–50% of the implant with high degree
in the section from frozen/thawed ex vivo skin samples, there is of integration.
984
FIGURE 2. HA solution. Grade 4: Very high integration. Flattened shape of the implant.
Filler entangled closely with collagen fibers. In case of uneven
distribution pattern of the filler: >50% of the implant with high
degree of integration.
The scale was named the Galderma Product Integration Scale.

After a first evaluation by a trained pathologist, all samples were
reassessed blindly by four persons with experience of evaluat-
ing histological samples in order to ensure the robustness of
the scale. Representative images from the histological samples
were obtained and the four evaluators scored the product inte-
gration from each sample in a masked way. One to two images
(10 X magnification) from each injection site were used for the
scale validation. In order to obtain both intra-observer and
inter-observer reliability data the scoring of the samples were
performed twice by each person. The results were statistically
evaluated using the Kappa coefficient analysis for both inter-
and intra-observer reliability.
FIGURE 3a. Restylane Lyft. FIGURE 3b. Restylane Vital.
After completion of the development of the product integration
scale, all images were sorted according to product injected. The
score from all 4 evaluators for all images per product were col-
lected and the mean score was calculated. The scores for the
different products were compared using the non-parametric
Kruskal Wallis one-way ANOVA analysis. Correlation analyses
between different product characteristsics (G’, particle size,
FIGURE 3c. Restylane Vital Light. FIGURE 3d. Restylane Refyne. swelling factor, and cohesivity) and scores were performed
using the non-parametric Spearman Rank Correlation test. Sig-
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nificance level was set to 0.05.
RESULTS
For the intra-observer reliability, the overall weighted kappa
Penalties Apply
was 0.88 (95% CI 0.85 – 0.90). The kappa coefficient was well
above 0.70 and the lower confidence limit was well above 0.60
FIGURE 3e. Restylane Defyne. FIGURE 3f. Restylane Kysse. indicating a very good agreement within the evaluators.5
FIGURE 4. Mean product integration score for all products.
FIGURE 3g. Restylane Fynesse.

985
FIGURE 5. Correlation between product integration score and G´. FIGURE 6. Correlation between product integration score
and cohesivity.
The ability of the evaluators to rate the injection sites in the to mean product integration score in human skin, there was a
same way was assessed by inter-observer reliability. The statistically significant correlation with products with lowest G´
weighted kappa coefficient ranged from 0.65 to 0.80, indicating having the highest integration score and products with high G´
good agreement between the evaluators. having the lowest integration scores (P=0.0238; Figure 5). No
statistical correlation could be seen when analyzing the score
Based on the results of intra- and inter observer ratings us- versus particle size, swelling factor, and cohesivity, (P values of
ing weighted kappa coefficients, it can be concluded that the 0.531, 0.8397, and 0.6159, respectively). The graph for cohesiv-
5-point scale is considered suitable to assess the level of prod- ity is shown in Figure 6.
uct integration in the tissue.
DISCUSSION
The HA solution integrated completely into the tissue (Figure We have developed and validated an original product integra-
2). tion photo-scale based on representative microphotographs.
The intra-observer and inter-observer results of the scale vali-
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Figures 3a-g show representative images from skin for each of dation were good to very good according to the Kappa analysis.
the products tested. The differences between tested products Thus, the validation shows that the scale should be a robust
spanned from high integration, mean grade 3.8 (Vital Light)) to tool for future product integration assessments of human skin
low integration, mean grade 1.5 (Restylane Lyft), with the rest of samples injected intradermally with fillers. Our intention is to
Penalties Apply
the products fell showed mean integration scores between 2.1 use this scale for future studies dealing with intradermal prod-
and 3.0 (Figure 4). Despite rather high variability in the scores uct integration as a standalone tool or together with image
within respective product the differences were statistically analysis. The advantage with the scale is that it can be used by
significant (P<0.0001, Kruskal-Wallis One-Way ANOVA). When all research teams interested in this matter without purchasing
using the Dunn´s multiple comparison test Restylane Vital Light and validating image analysis systems.
had a significantly higher score than the others products, while
Restylane Lyft had a significantly lower score compared to the The integration results for the different products tested indi-
other products except for Restylane Vital. cates that weaker and softer gels cannot resist the mechanical
forces obtained within the dermis when injected, but rather
These results lead to further statistical correlation analysis be- spread where the least resistance exist. The opposite occurs
tween product characteristics (rheology, particle size, swelling when firmer gels are injected. They have a higher possibility
factor, cohesivity; for product data, see Table 1) and product to withstand the mechanical forces. Consequently, they will
tissue distribution scores. The rheological properties of the spread and distribute less in the tissue. This finding is also sup-
product capture the sum of inherent chemical and physical ported by the complete integration of a non-cross-linked HA
properties such as HA concentration, HA molecular weight, solution.
and degree of cross-linking. The viscoelastic properties of a gel
can be measured using rheometry. When the gel undergoes Our findings are in accordance with the scarce earlier published
an oscillatory small-amplitude deformation, the viscoelastic results. Flynn et al3 shows that Restylane, a firm gel shows less
properties of the material can be determined. G´, the elastic product integration than a soft gel, such as Juvederm Ultra.
modulus, is one important parameter.6 Strong and firm gels The differences seen were explained by the fact that the two
have higher G´ than weak and soft gels. When plotting the G´ products are either biphasic or monophasic. However, the
986
terminology of biphasic and monophasic for dermal fillers is 9. Edsman KLM, Öhrlund JÅ. Correlation between cohesion and other physico-
chemical properties. Dermatol Surg. (In Press).
conceptually wrong7 since most marketed HA filler products
contain both observable gel particles and extractable HA and AUTHOR CORRESPONDENCE
have the ability to absorb added water. Tran et al shows4 the
same results with the explanation that cohesive gels distrib- Björn Lundgren PhD
E-mail:................….............. bjorn.lundgren@galderma.com
ute more in the tissue than less cohesive gels. Cohesion is the
force between particles of the same substance that acts to unite
them. Edsman et al8 has shown that the cohesion of HA filler
products is inversely correlated to G´ of the product. This means
that a soft gel has higher cohesion than a firm gel. Consequent-
ly, it may be the softness of the product that allows them to
deform more easily to be able to squeeze into smaller cavities
in the tissue, rather than the cohesivity of the product. This is
also emphasized in this study where no correlation between
cohesion and product distribution was observed (Figure 6).
In summary, the results indicate that the rheology of the prod- CHOOSE DERMATOLOGY
uct, especially the firmness of the products has an influence
on the overall product integration when injected intradermally. AUTHORITY TO HELP
Furthermore, the long-term clinical implication of the findings
observed directly after injection needs to be further investigated,
YOUR CAREER AND
as well as injections in other planes, such as the subcutaneous
and supraperiosteal planes due to the clinical use of HA fillers.
PRACTICE GROW!
CONCLUSION Here are just a few of the
The degree of product integration can be assessed and scored ways we can assist you:
according to a 5-grade visual scale based on representative mi-
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crophotographs. Products with different rheological properties
distribute differently when injected into the skin. Firmer gel tex-
• The Dermatology Authority Job
ture resulted in more targeted product integration whiles softer Board
gel texture resulted in distributed product integration with a • Consultative Recruiting Services
Penalties Apply
lower lifting capacity. • Career Building and Licensing
Advice
DISCLOSURES
• Medical Licensing and Creden-
All authors are Galderma employees.
tialing Services
REFERENCES • Branding, Marketing, and Social
1. Sundaram H, Voigts B, Beer K, Meland M. Comparison of the rheological Media
properties of viscosity and elasticity in two categories of soft tissue fillers:
Calcium hydroxylapatite and hyaluronic acid. Dermatol Surg. 2010;36:1859- • Practice Startup
2.
1865.
Borrell M, Leslie DB, Tezel A. Lift capabilities of hyaluronic acid fillers. J Cos-
• Existing Practice Growth
met Laser Ther. 2011;13:21-27.
3. Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology
of intradermal implantation of mono and biphasic hyaluronic acid fillers. Der-
matol Surg. 2011;37:1-7.
4. Tran C, Carraux, Micheels P Kaya G; Salomon D. In vivo bio-integration of
three hyaluronic acid fillers in human skin: A histological study. Dermatology.
2014; 228:47-54.
5. Altman DG. Practical statistics for medical research. Chapman & Hall, Lon- Visit us at
don. Oct, 1991.
6. Edsman K, Nord LI, Öhrlund Å, Lärkner H, Helander Kenne A. Gel properties DermatologyAuthority.com
of hyaluronic acid dermal fillers. Dermatol Surg. 2012;38:1170-1179.
7. Öhrlund JÅ, Edsman KLM. The myth of the “biphasic” hyaluronic acid filler. for more information
Dermatol Surg. 2015;S358-S364.
8. Edsman KLM, Wiebensjö ÅM, Risberg AM, Öhrlund JÅ. Is there a method
1-800-577-0125 | Info@DermatologyAuthority.com
that can measure cohesivity? Cohesion by sensory evaluation compared
with other test methods. Dermatol Surg. 2015;S365-S372.

SPECIAL TOPIC
Once-Daily Oral Sarecycline 1.5 mg/kg/day

Is Effective for Moderate to Severe Acne Vulgaris:
Results from Two Identically Designed, Phase 3,
Randomized, Double-Blind Clinical Trials
Angela Moore MD,a Lawrence J. Green MD,b Suzanne Bruce MD,c Neil Sadick MD,d
Eduardo Tschen MD MBA,e Philip Werschler MD FAAD FAACS,f Fran E. Cook-Bolden, MD,g
Sunil S. Dhawan MD,h Douglass Forsha MD,i Michael H. Gold MD FAAD,j Scott Guenthner MD,k
Steven E. Kempers MD,l Leon H. Kircik MD,m Jennifer L. Parish MD,n Marta I. Rendon MD,o
Phoebe Rich MD,p Linda Stein-Gold MD,q Stephen K. Tyring MD PhD,r Robert A. Weiss MD FAAD,s
Adnan Nasir MD,t Carsten Schmitz MD PhD,u* Terry I. Boodhoo MS,u Alexandre Kaoukhov MD,u,*
and David R. Berk MDu
a
Arlington Research Center, Inc., Arlington, TX
b
Lawrence J. Green, MD, LLC, George Washington University School of Medicine, Washington, DC
c
Suzanne Bruce and Associates, PA, Houston, TX
d
Sadick Research Group, New York, NY
e
Academic Dermatology Associates, Albuquerque, NM
f
Premier Clinical Research, Spokane, WA
g
Skin Specialty Dermatology, New York, NY
h
Center for Dermatology Clinical Research, Inc, Fremont, CA
i
Jordan Valley Dermatology Center, Jordan, UT
j
Tennessee Clinical Research Center, Nashville, TN
k
The Dermatology Center of Indiana, PC, Plainfield, IN
l
Associated Skin Care Specialists, Fridley, MN
m
DermResearch, PLLC, Louisville, KY
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n
Parish Dermatology, Philadelphia, PA
o
Rendon Center, Boca Raton, FL
p
Oregon Dermatology and Research Center, Portland, OR
q
Henry Ford Health System, West Bloomfield, MI
r
Penalties Apply
University of Texas Health Science Center, Department of Dermatology, Houston, TX
s
Laser Skin & Vein Institute, Hunt Valley, MD
t
Wake Research Associates, Raleigh, NC
u
Allergan plc, Irvine, CA
*
Former employee
ABSTRACT
Background: Side effects may limit the use of current tetracycline-class antibiotics for acne.
Objective: Evaluate the efficacy and safety of once-daily sarecycline, a novel, narrow-spectrum tetracycline-class antibiotic, in moder-
ate to severe acne.
Methods: Patients 9–45 years with moderate to severe facial acne (Investigator’s Global Assessment [IGA] score ≥3, 20–50 inflamma-
tory and ≤100 noninflammatory lesions, and ≤2 nodules) were randomized 1:1 to sarecycline 1.5 mg/kg/day or placebo for 12 weeks in
identically designed phase 3 studies (SC1401 and SC1402).
Results: In SC1401 (sarecycline n=483, placebo n=485) and SC1402 (sarecycline n=519, placebo n=515), at week 12, IGA success
(≥2-grade improvement and score 0 [clear] or 1 [almost clear]) rates were 21.9% and 22.6% (sarecycline), respectively, versus 10.5%
and 15.3% (placebo; P<0.0001 and P=0.0038). Onset of efficacy in inflammatory lesions occurred by the first visit (week 3), with mean
percentage reduction in inflammatory lesions at week 12 in SC1401 and SC1402 of −51.8% and −49.9% (sarecycline), respectively,
versus −35.1% and −35.4% (placebo; P<0.0001). Onset of efficacy for absolute reduction of noninflammatory lesion count occurred
at week 6 in SC1401 (P<0.05) and week 9 in SC1402 (P<0.01). In SC1401, the most common TEAEs (in ≥2% of either sarecycline or
988
Journal of Drugs in Dermatology A. Moore, L.J. Green, S. Bruce, et al
placebo group) were nausea (4.6% [sarecycline]; 2.5% [placebo]), nasopharyngitis (3.1%; 1.7%), headache (2.7%; 2.7%), and vomiting
(2.1%; 1.4%) and, in SC1402, nasopharyngitis (2.5%; 2.9%) and headache (2.9%; 4.9%). Most were not considered treatment-related.
Vestibular (dizziness, tinnitus, vertigo) and phototoxic (sunburn, photosensitivity) TEAEs both occurred in ≤1% of sarecycline patients.
Gastrointestinal TEAE rates for sarecycline were low. Among females, vulvovaginal candidiasis (SC1401: 1.1% [sarecycline] and 0 [pla-
cebo]; SC1402: 0.3% and 0) and mycotic infection (0.7% and 0; 1.0% and 0) rates were low.
Conclusion: The narrow-spectrum antibiotic sarecycline was safe, well tolerated, and effective for moderate to severe acne, with low
rates of side effects common with tetracycline antibiotics.
J Drugs Dermatol. 2018;17(9):987-996.
INTRODUCTION
B
road-spectrum tetracycline-class antibiotics, such as in patients 12 to 45 years of age with moderate to severe facial
minocycline and doxycycline, are considered first-line acne.9
therapy in the management of moderate to severe
acne.1 In addition to their antimicrobial activity, tetracycline- This report describes the results of 2 identically designed,
class antibiotics have anti-inflammatory properties.2 However, phase 3 pivotal trials, SC1401 and SC1402, to evaluate the ef-
currently available agents may be associated with gastrointes- ficacy and safety of once-daily sarecycline 1.5 mg/kg for 12
tinal (GI) side effects, including nausea, diarrhea, and vomit- weeks in patients aged 9 to 45 years with moderate to severe
ing; other potential side effects include skin photosensitivity facial acne vulgaris.
with doxycycline and vestibular events (eg, dizziness, vertigo)
with minocycline.1,3 Additionally, given their broad spectrum of METHODS
antibacterial activity, oral tetracycline therapies for acne may Study Design
negatively impact the microbiome, potentially leading to an- Two identically designed, randomized, double-blind, placebo-
timicrobial resistance, which may limit the efficacy of tetracy- controlled, parallel-group, phase 3 studies (Figure 1) were
cline antibiotics for the treatment of infectious diseases and, conducted in the United States: study SC1401 (Clinicaltrials.gov
more broadly, promote multidrug resistant bacteria.3-8 These identifier NCT02320149), conducted at 56 centers, and study
limitations demonstrate a need for tetracycline-class antibiotics SC1402 (NCT02322866), conducted at 54 centers. After screen-
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for acne with improved safety profiles and a targeted, narrow ing and baseline assessments, study visits occurred at weeks 3,
spectrum of antibacterial activity.1,3 6, 9, and 12 of treatment.
Sarecycline is a once-daily, novel, tetracycline-class antibiotic The studies were conducted in compliance with Good Clinical
Penalties Apply
for the treatment of moderate to severe acne. Sarecycline has Practice guidelines and approved by an Institutional Review
a narrow antibacterial spectrum with limited activity against Board. All patients provided written informed consent or as-
enteric gram-negative bacteria compared with minocycline, sent.
doxycycline, and tetracycline, which may confer less disruption
of the GI microbiome at doses recommended for acne treat- Patients
ment. A 12-week, phase 2, dose-ranging trial demonstrated that Eligible patients were aged 9 to 45 years, weighed 33 to 136 kg,
sarecycline 1.5 mg/kg/day is well tolerated, safe, and effective and had 20 to 50 inflammatory lesions, ≤100 noninflammatory
lesions, ≤2 nodules, and a score of 3 (moderate) or 4 (severe)
FIGURE 1. Study design for SC1401 and SC1402. IGA, Investigator’s on the Investigator’s Global Assessment (IGA) scale for inflam-
Global Assessment. aAfter enrollment began, a protocol amendment matory lesions of acne.
removed the lower limit for noninflammatory lesion count at baseline.
Individuals were excluded from the studies if they had a der-
No-drug Double-blind matologic condition or facial hair, any chronic illness interfering
Enrollment screening period treatment with study evaluations, allergy or resistance to tetracyclines,
Male or female patients
aged 9–45 years and
Up to 5 weeks 12 weeks drug-induced acne, hormonal contraceptive initiation, systemic
weighing 33–136 kg
Sarecycline retinoids, systemic corticosteroids, androgens, or anti-andro-
Lesions
− 20–50 inflammatory
1.5 mg/kg/day gens within 12 weeks prior to randomization.
− ≤100 noninflammatorya
Nodules ≤2
IGA score 3 (moderate) Placebo All randomized patients composed the intent-to-treat (ITT) pop-
or 4 (severe)
ulations.
989
Treatment skin disease on patients’ quality of life using 3 scales (symp-

Patients were randomized 1:1 to receive sarecycline (1.5 mg/ toms, emotions, and functioning), with scores standardized
kg) or placebo tablets administered orally once daily as 60 mg, from 0 (never bothered) to 100 (always bothered),10 was admin-
100 mg, or 150 mg of sarecycline or matching placebo tablets istered to patients at baseline and week 12.
for 12 weeks.
Safety and Tolerability Assessments
Efficacy Assessments Treatment-emergent adverse events (TEAEs) were assessed at
At baseline and each study visit, facial acne was evaluated using every visit. Vital signs were recorded at screening, baseline, and
the IGA and inflammatory and noninflammatory lesion counts. each study visit. Clinical laboratory evaluations were conducted
IGA scores ranged from 0 (clear) to 4 (severe) and reflected the at screening, baseline, week 3, and week 12 visits. Electrocar-
investigator’s overall general assessment of the quantity and diograms (ECGs) were conducted at screening and at week 12
quality of inflammatory lesions. Counts of inflammatory le- visits, and physical examinations were conducted at screening,
sions (papules, pustules, and nodules) and noninflammatory baseline, and week 12 visits.
lesions (open and closed comedones) on the forehead, cheeks,
nose, and chin were recorded at each visit. Acne severity on the Statistical Analyses
back and chest also was evaluated using IGA scores. Efficacy analyses were conducted in the ITT populations. IGA
success at week 12 was calculated using the Cochran-Man-
Efficacy analyses included IGA success for facial acne at week tel-Haenszel test, with adjustment for pooled site. The same
12, defined as a ≥2-point decrease (improvement) from baseline methodology was used for nonfacial (chest and back) IGA as-
and a score of 0 (clear) or 1 (almost clear), percentage change sessments (≥2-point decrease in patients with IGA score ≥2 at
from baseline in facial inflammatory lesion counts at week 12, baseline). An analysis of covariance model (ANCOVA), with
and absolute change from baseline in facial noninflammatory baseline value as a covariate, treatment and pooled site effects
lesion counts at week 12. A post hoc analysis to determine the as factors, and significance level set at P≤0.05, was used to cal-
percentage change from baseline in noninflammatory lesion culate mean percentage changes from baseline in inflammatory
counts was also performed for each study in ITT patients who lesion counts. This ANCOVA model was also used to calculate
had ≥10 noninflammatory lesions at baseline. The percentages mean absolute changes from baseline in noninflammatory le-
of patients in the ITT population with IGA success for back and sion counts in the entire ITT population and mean absolute
chest acne (defined as a ≥2-point improvement in IGA score in and percentage changes from baseline in noninflammatory
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those areas following a baseline IGA score ≥2) at week 12 were lesion counts in patients with ≥10 baseline noninflammatory le-
also assessed as post hoc analyses. sions. Missing data were handled using a multiple imputation
approach, except for nonfacial IGA assessments, which used
Patient-Reported Outcome Measure observed data.
Penalties Apply
The Skindex-16, a 16-item questionnaire measuring effects of
FIGURE 2. Patient disposition in SC1401 and SC1402. AEs, adverse events; ITT, intent-to-treat. aSafety population included all patients who
received ≥1 dose of study medication after randomization.
SC1401 SC1402
Randomized (ITT) (N=968) Randomized (ITT) (N=1034)
Sarecycline n=483 Sarecycline n=519
Placebo n=485 Placebo n=515
Discontinued (n=143) Safetya (n=964) Safetya (n=1026) Discontinued (n=157)

Sarecycline (n=63) Sarecycline n=481 Sarecycline n=513 Sarecycline (n=86)
• 3 AEs Placebo n=483 Placebo n=513 • 11 AEs
• 28 consent withdrawals • 25 consent withdrawals
• 21 loss to follow-up • 39 loss to follow-up
• 7 treatment noncompliance • 4 treatment noncompliance
• 4 other • 1 lack of efficacy
• 6 other
Placebo (n=80)
• 7 AEs Placebo (n=71)
• 32 consent withdrawals • 6 AEs
• 34 loss to follow-up • 16 consent withdrawals
• 2 treatment noncompliance • 36 loss to follow-up
• 1 lack of efficacy Completed (n=825) Completed (n=877) • 3 treatment noncompliance
• 4 other • 3 lack of efficacy
Sarecycline n=420 Sarecycline n=433 • 7 other
Placebo n=405 Placebo n=444
990
TABLE 1.
Patient Demographics and Baseline Characteristics (ITT population)
SC1401 SC1402
Characteristic Sarecycline Placebo Sarecycline Placebo
(n=483) (n=485) (n=519) (n=515)
Age, years - - - -
Mean 19.6 19.8 20.4 19.7
Range 10, 45 10, 45 9, 44 10, 44
Sex, % male 44.5 44.1 39.3 43.3
Race, n (%) - - - -
White 377 (78.1) 377 (77.7) 407 (78.4) 391 (75.9)
Black 80 (16.6) 79 (16.3) 66 (12.7) 76 (14.8)
Other 26 (5.4) 29 (6.0) 45 (8.7) 48 (9.3)
Mean BMI, kg/m2 25.5 (5.8) 25.3 (5.5) 25.9 (6.4) 25.4 (6.2)
Facial - - - -
Mean facial inflammatory lesions, n 29.7 30.2 30.3 30.2
Mean facial noninflammatory lesions, n 42.4 43.7 42.3 43.9
Mean IGA score (SD) 3.1 (0.4) 3.2 (0.4) 3.2 (0.4) 3.1 (0.4)
IGA score, n (%)
3 (moderate) 413 (85.5) 410 (84.5) 440 (84.8) 439 (85.2)
4 (severe) 70 (14.5) 75 (15.5) 79 (15.2) 76 (14.8)
Back - - - -
Mean IGA score (SD) 1.6 (1.2) 1.6 (1.1) 1.8 (1.1) 1.8 (1.2)
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IGA score, n (%) - - - -
0 (clear) 116 (24.0) 103 (21.2) 91 (17.5) 101 (19.6)
1 (almost clear) 96 (19.9) 121 (24.9) 103 (19.8) 97 (18.8)
Penalties Apply
2 (mild) 152 (31.5) 148 (30.5) 177 (34.1) 154 (29.9)
3 (moderate) 100 (20.7) 92 (19.0) 136 (26.2) 132 (25.6)
4 (severe) 19 (3.9) 21 (4.3) 12 (2.3) 31 (6.0)
Chest - - - -
Mean IGA score (SD) 1.2 (1.1) 1.2 (1.1) 1.4 (1.1) 1.4 (1.1)
IGA score, n (%) - - - -
0 (clear) a
178 (36.9) 152 (31.3) 140 (27.0) 141 (27.4)
1 (almost clear)b 115 (23.8) 145 (29.9) 132 (25.4) 128 (24.9)
2 (mild)c 137 (28.4) 126 (26.0) 156 (30.1) 150 (29.1)
3 (moderate) d
44 (9.1) 46 (9.5) 86 (16.6) 87 (16.9)
4 (severe)e 9 (1.9) 16 (3.3) 5 (1.0) 9 (1.7)
BMI, body mass index; IGA, Investigator’s Global Assessment; ITT, intent-to-treat; SD, standard deviation.
a
No evidence of papules or pustules.
b
Rare inflammatory papules (must be resolving and may be hyperpigmented, though not pink-red).
c
Few inflammatory lesions (papules/pustules only; no nodulocytic lesions).
d
Multiple inflammatory lesions present; many papules/pustules; there may or may not be a few nodulocytic lesions.
e
Inflammatory lesions more apparent; many papules/pustules; there may or may not be a few nodulocytic lesions.
991
Skindex-16 questionnaire scale scores and total scores were FIGURE 3. Percentage of patients with facial IGA success at week
summarized by treatment and visit in the ITT population. 12 (ITT population). Facial IGA success was defined as a ≥2-point
Change from baseline in these scores was calculated for each decrease (improvement) in facial IGA score from baseline and a score
treatment and analyzed using the ANCOVA model. Adjusted of clear/almost clear. IGA, Investigator’s Global Assessment; ITT,
least squares means with associated 95% confidence intervals intent-to-treat. *P<0.0001 vs placebo; †P=0.0038 vs placebo.
(CIs) from the ANCOVA model were analyzed for each treat- 40
Baseline to Week 12 and With IGA Score ≤1, %

ment and difference between treatments.
Patients With ≥2-Point IGA Decrease From

SC1401 SC1402
Safety evaluations were conducted in all patients who received 30
≥1 dose of study drug. TEAEs were summarized by the number
and percentage of patients reporting a TEAE by treatment. 21.9* 22.6†
20
RESULTS 15.3
Patient Demographics and Baseline
10.5
Disease Characteristics 10
Demographic variables were similar across treatment groups in
both studies (Table 1). Baseline disease characteristics, includ-
ing facial inflammatory and noninflammatory lesion counts 0
Sarecycline Placebo Sarecycline Placebo
and facial IGA scores, were similar across treatment groups in (n=483) (n=485) (n=519) (n=515)
both studies.
The majority of patients (SC1401: 85.2%; SC1402: 84.8%) com- than the placebo group at the first follow-up visit at week 3 and
pleted the studies (Figure 2). continued through week 12 in both studies (Figure 4). In study
SC1401, the mean percentage change from baseline in inflam-
Efficacy matory lesion count at week 12 was −51.8% in the sarecycline
IGA success rate was significantly greater in the sarecycline group versus −35.1% in the placebo group (P<0.0001). In study
group than in the placebo group in the ITT population begin- SC1402, the mean percentage change from baseline in inflam-
ning at week 6 in study SC1402 and at week 9 in study SC1401 matory lesion count at week 12 was −49.9% for sarecycline
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and continuing through week 12 in both studies. In study versus −35.4% for placebo (P<0.0001).
SC1401, 21.9% of the sarecycline group versus 10.5% of the pla-
cebo group achieved IGA success at week 12 (P<0.0001; Figure Mean absolute change from baseline in noninflammatory le-
3). In study SC1402, the IGA success rate at week 12 was 22.6% sion count was significantly greater in the sarecycline group
Penalties Apply
for sarecycline versus 15.3% for placebo (P=0.0038). than the placebo group beginning at week 6 in study SC1401
and at week 9 in study SC1402 and continuing through week 12
Mean percentage change from baseline in inflammatory le- in both studies (Figure 5). In study SC1401, sarecycline-treated
sion count was significantly greater in the sarecycline group patients had a mean absolute change from baseline in nonin-
FIGURE 4. Mean percentage change from baseline through week 12 in inflammatory lesion counts for patients taking sarecycline compared with
placebo (ITT population). ITT, intent-to-treat; LS, least squares.*P=0.0003 vs placebo; †P<0.0001 vs placebo.
0 SC1401 0 SC1402
Inflammatory Lesion Count, %
Sarecycline Sarecycline
-10 -10
LS Mean (SE) Change in
Placebo Placebo
−18.6
−22.4 -20
-20
−27.3
−28.9
−31.9
-30 −34.9 −35.1 -30 −28.0† −35.4
−29.6*
-40 -40 −39.1†
−42.2
†
−44.5†
-50 -50
−47.4†
−49.9†
−51.8†
-60 -60
0 3 6 9 12 0 3 6 9 12
Time (Weeks) Time (Weeks)
992
FIGURE 5. Mean absolute change from baseline through week 12 in noninflammatory lesion counts for patients taking sarecycline compared with
placebo (ITT population). ITT, intent-to-treat; LS, least squares. *P<0.05 vs placebo; †P<0.01 vs placebo.
0 SC1401 0 SC1402
in Noninflammatory Lesion Count
LS Mean (SE) Absolute Change
-2 -2
-4 Placebo -4 Placebo
−7.1 −7.4
-6 -6
−8.6
-8 −9.6 -8 −10.0
-10 −7.9 −11.2 -10 −7.7 −12.1
-12 −13.4
-12 −10.6* −11.6
-14 -14
−13.0†
-16 -16
−15.1† −15.2†
-18 -18 −16.2†
-20 -20
0 3 6 9 12 0 3 6 9 12
flammatory lesion count at week 12 of −15.1 versus −11.2 in Among patients who had baseline IGA scores of ≥2 for back
the placebo group (P<0.01). In study SC1402, the mean abso- or chest acne, the proportions achieving IGA success at these
lute change was −16.2 for sarecycline versus −13.4 for placebo locations (≥2-point improvement in IGA score) at week 12 were
(P<0.01) at week 12. significantly higher in the sarecycline than the placebo group
in both studies (Figure 8). For back acne, this comparison was
Among patients who had ≥10 baseline noninflammatory le- significant beginning at week 3 in study SC1401 and at week 9
sions in study SC1401, the mean percentage change from in study SC1402. For chest acne, significance was noted at week
baseline in noninflammatory lesion count was significantly 6 and week 12 in study SC1401, and at week 12 in study SC1402.
greater for sarecycline than placebo starting at week 6 and con-
tinuing through week 12 (−34.5% vs −26.0%; P<0.05; Figure 6). In study SC1401, significant mean differences for sarecycline
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In study SC1402, the mean percentage change from baseline over placebo (95% CI) were achieved in Skindex-16 scores for
in noninflammatory lesion count for patients with ≥10 baseline symptoms (−4.7 [−7.0, −2.4]), and emotion (−4.7 [−8.1, −1.4])
noninflammatory lesions was significantly greater for sarecy- scales, and total score (−3.5 [−6.0, −1.1]). The mean difference
cline than for placebo starting at week 9 and continuing through for functioning (95% CI) was −1.5 (−4.3, 1.3). In study SC1402,
Penalties Apply
week 12 (−35.6% vs −28.2%; P<0.01). Figure 7 shows photo- the mean differences for sarecycline over placebo (95% CI)
graphs depicting response to sarecycline treatment at week 12 were significant for symptoms (−5.1 [−7.2, −2.9]), emotion (−7.7
in representative patients in studies SC1401 and SC1402. [−11.0, −4.4]), functioning (−4.8 [−7.3, −2.2]), and total score (−5.9
[−8.1, −3.6]).
FIGURE 6. Mean percentage change from baseline through week 12 in noninflammatory lesion counts for patients with ≥10 noninflammatory
lesions at baseline (ITT population); sarecycline group compared with placebo group. In SC1401, 97.7% of the ITT population had ≥10 baseline
noninflammatory lesions; in SC1402, it was 95.8%. ITT, intent-to-treat; LS, least squares. *P<0.05 vs placebo; †P<0.01 vs placebo.
0 0 SC1402
LS Mean (SE) Change From Baseline
SC1401
in Noninflammatory Lesions, %
Placebo Placebo
-10 -10 −13.9
−15.5
−19.7 −20.9
-20 −16.2 -22 .8 -20 −16.8
−26.0 −25.2
−28.2
−24.9* −25.3
-30 -30
−29.7†
−32.8†
−34.5† −35.6†
-40 -40
0 3 6 9 12 0 3 6 9 12
993
FIGURE 7. Response to sarecycline in (A) a 23-year-old female patient in SC1401a; (B) a 14-year-old male patient in SC1402b; (C) a19-year-old
female patient in SC1401.c IGA, Investigator’s Global Assessment. aIGA score: 4 at baseline, 1 at week 12. Inflammatory lesions: 50 at baseline, 4 at
week 12. Noninflammatory lesions: 22 at baseline, 17 at week 12. bIGA score: 4 at baseline, 1 at week 12. Inflammatory lesions: 42 at baseline, 8 at
week 12. Noninflammatory lesions: 74 at baseline, 31 at week 12. cIGA score: 4 at baseline, 1 at week 12. Inflammatory lesions: 33 at baseline, 8 at
week 12. Noninflammatory lesions: 33 at baseline, 5 at week 12.
(A) (B) (C)
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Penalties Apply
Safety
Overview
In study SC1401, TEAEs occurred in 29.3% (141/481) of pa- 0.3% and 1.0% of female patients in SC1402, all of whom com-
tients in the sarecycline group and 29.8% (144/483) of patients pleted the study. They did not occur in the placebo group in
in the placebo group. In study SC1402, TEAEs occurred in either study.
25.0% (128/513) of patients in the sarecycline group and 26.7%
(137/513) of patients in the placebo group (Table 2). TEAEs considered by the investigator to be related or possibly
related to study treatment occurred in 1.9% (9/481) and 8.7%
The most common TEAEs (in ≥2% of patients in either group) (42/481), respectively, of patients in the sarecycline group, and
were nausea (4.6% sarecycline, 2.5% placebo), nasopharyngitis 0.4% (2/483) and 8.3% (40/483), respectively, of patients in the
(3.1% and 1.7%), headache (2.7% in both groups), and vomiting placebo group in study SC1401. TEAEs considered by the in-
(2.1% and 1.4%) in study SC1401, and nasopharyngitis (2.5% vestigator to be related or possibly related to study treatment
sarecycline and 2.9% placebo) and headache (2.9% and 4.9%) in occurred in 1.6% (8/513) and 6.4% (33/513), respectively, of
study SC1402. Vulvovaginal candidiasis and vulvovaginal my- patients in the sarecycline group, and 0.6% (3/513) and 5.1%
cotic infection were rare in the sarecycline group, occurring in (26/513), respectively, of patients in the placebo group in study
1.1% and 0.7%, respectively, of female patients in SC1401 and SC1402.
994
TABLE 2. TABLE 3.
Overall Summary of Adverse Events (Safety Population) Treatment-Emergent Adverse Events Common
to Tetracycline-Class Antibiotics (Safety Population)
SC1401 SC1402
SC1401 SC1402
Event Sarecycline Placebo Sarecycline Placebo
Event, n (%) Sarecycline Placebo Sarecycline Placebo
(n=481) (n=483) (n=513) (n=513)
(n=481) (n=483) (n=513) (n=513)
Overview of TEAEs
Gastrointestinal effects in ≥1% of patients in any group
Death 0 0 0 0
Nausea 22 (4.6) 12 (2.5) 10 (1.9) 5 (1.0)
SAE 3 (0.6)a 5 (1.0)b 4 (0.8)c 1 (0.2)d
Vomiting 10 (2.1) 7 (1.4) 3 (0.6) 2 (0.4)
TEAEs leading
to study 3 (0.6) e
7 (1.4)f
11 (2.1) g
6 (1.2) h Abdominal
6 (1.2) 6 (1.2) 3 (0.6) 1 (0.2)
discontinuation pain
Any TEAE 141 (29.3) 144 (29.8) 128 (25.0) 137 (26.7) Abdominal
5 (1.0) 1 (0.2) 2 (0.4) 2 (0.4)
discomfort
Any treatment-
51 (10.6) 42 (8.7) 41 (8.0) 29 (5.7) Diarrhea 5 (1.0) 8 (1.7) 6 (1.2) 6 (1.2)
related TEAEi
TEAEs reported by ≥2% of patients in any group Vestibular effects
Headache 13 (2.7) 13 (2.7) 15 (2.9) 25 (4.9) Dizziness 3 (0.6) 7 (1.4) 2 (0.4) 4 (0.8)
Nausea 22 (4.6) 12 (2.5) 10 (1.9) 5 (1.0) Motion

0 0 1 (0.2) 1 (0.2)
sickness
Nasopharyngitis 15 (3.1) 8 (1.7) 13 (2.5) 15 (2.9)
Tinnitus 0 0 0 0
Vomiting 10 (2.1) 7 (1.4) 3 (0.6) 2 (0.4)
Vertigo 0 0 0 0
Phototoxic effects
Data are (n) % of patients.
AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent Photosensitivity 0 0 1 (0.2) 0
adverse event.
a
Five SAEs occurred in 3 patients (increased alanine aminotransferase, Sunburn 3 (0.6) 2 (0.4) 4 (0.8) 1 (0.2)
aspartate aminotransferase, and gamma-glutamyl transferase [all considered
Vaginal yeast infections in females
possibly related to treatment], n=1; diabetic ketoacidosis, n=1; and nephroli-
thiasis, n=1 [both considered not related to treatment]). Vulvovaginal
b
Six SAEs occurred in 5 patients (spontaneous abortion, n=2; appendicitis, 3 (1.1) 0 1 (0.3) 0
candidiasisa
n=1; cellulitis and suicide attempt, n=1 [all considered not related to treat-
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ment]; and miscarriage of partner [considered possibly related to treatment], Vulvovaginal
n=1).
c
Four SAEs occurred in 4 patients (Crohn’s disease, tonsillitis, depression, and
mycotic 2 (0.7) 0 3 (1.0) 0
abortion [all considered not related to treatment], n=1). infectiona
d
Oppositional defiant disorder was reported in 1 patient (considered not
Penalties Apply
related to treatment).
e
One case each of increased gamma-glutamyl transferase, thyroid-stimulating Percentages were calculated based on the number of female patients.
a
hormone, and nausea.

f
One case each of maculopapular rash, abdominal pain, diarrhea, nausea,
acne, latent tuberculosis, headache, urticaria, and panic attack.
g
Diarrhea, headache, and nausea (all in 1 patient), muscle spasms and pho-
tosensitivity reaction (both in 1 patient), 2 cases of acne, and 1 case each of
dizziness, abdominal discomfort, upper abdominal pain, peripheral edema,
urticaria, and increased hepatic enzyme, alanine aminotransferase, and aspar-
tate aminotransferase (the latter two occurring in 1 patient).
h
Peripheral edema and urticaria (both in 1 patient), 2 cases of headache, and 1
case each of abdominal pain, urticaria, and increased alanine aminotransfer- There were no clinically meaningful differences between the
ase and aspartate aminotransferase (the latter two occurring in 1 patient).
i
Includes TEAEs considered “possibly related” or “related” by the investigator.
sarecycline and placebo groups in clinical laboratory, vital sign,
and ECG measurements in either study.
TEAE severity was mild or moderate in most patients in both Adverse Events Leading to Discontinuations
studies; 95.9% (233/243) of TEAEs in the sarecycline group and In study SC1401, TEAEs leading to study discontinuations
96.0% (238/248) in the placebo group in study SC1401 were occurred in 0.6% (3/481) and 1.4% (7/483) of patients in the sare-
mild or moderate, as were 97.8% (224/229) of TEAEs in the sarecycline and placebo groups, respectively, but none were judged
cycline group and 97.0% (226/233) in the placebo group in study by the investigator as being related to study treatment; most
SC1402. were judged as possibly related (Table 2). In study SC1402,
2.1% (11/513) and 1.2% (6/513) of patients in the sarecycline
Serious adverse events were rare in both studies, and all were and placebo groups, respectively, discontinued due to AEs, the
considered not related or possibly related to study treatment. majority of which were judged by the investigator as possibly
There were no deaths during either study. related or related to study treatment.
995
FIGURE 8. Percentage of patients with nonfacial IGA success at week 12 (ITT population). Nonfacial IGA success was defined as a ≥2-point
decrease (improvement) in nonfacial IGA score from baseline and a score of clear/almost clear. In SC1401, 39.0% and 55.0% of the ITT population
had baseline IGA scores ≥2 for chest and back acne, respectively. In SC1402, 47.7% and 62.1% of the ITT population had baseline IGA scores ≥2
for chest and back acne, respectively. IGA, Investigator’s Global Assessment; ITT, intent-to-treat. *P<0.001 vs placebo; †P<0.05 vs placebo.
Back Chest
SC1401 SC1402 SC1401 SC1402

40
36.6*
Decrease From Baseline to Week 12
and With Baseline IGA Score ≥2, %
32.9 * 33.2†
Patients With ≥2−Point IGA
29.6†
30
25.7
21.6
19.6
20 17.1
10
0
Sarecycline Placebo Sarecycline Placebo Sarecycline Placebo Sarecycline Placebo
Adverse Events Reported with Other explanation may be that sarecycline exerts anti-inflammatory
Tetracycline-Class Antibiotics effects on an early inflammatory process that is postulated to
Among AEs reported with other tetracycline-class antibiotics, occur during the development of comedones.11,12
vestibular TEAEs (specifically dizziness, vertigo, tinnitus) and
phototoxic TEAEs (photosensitivity, sunburn) were rare in sare- Antibiotic resistance is a concern with oral antibiotic treat-
cycline-treated patients, occurring in ≤1% of patients, and rates ments for acne.3-7 Agents that unnecessarily target a broad
of GI TEAEs for sarecycline were low (Table 3). In each study, spectrum of bacteria are associated with greater potential for
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there were no cases of vertigo or tinnitus, and fewer cases of antibiotic resistance,13 and the American Academy of Derma-
dizziness in sarecycline-treated patients than in placebo-treated tology recommends responsible usage of systemic antibiotics
patients. The most common GI TEAEs were nausea, vomiting, for acne.1 The current first-line antibiotics for moderate to se-
diarrhea, abdominal pain, abdominal discomfort, and constipa- vere acne are broad-spectrum tetracycline-class antibiotics,
Penalties Apply
tion. such as minocycline and doxycycline,1 highlighting the need
for a narrow-spectrum antibiotic that can be used as first-line
DISCUSSION treatment for moderate to severe acne. In vitro studies have
Sarecycline is the first narrow-spectrum tetracycline-class an- demonstrated the narrow antibacterial spectrum of sarecycline
tibiotic for the treatment of moderate to severe acne. These and its limited activity against enteric gram-negative bacteria
pivotal phase 3 studies demonstrated that oral sarecycline 1.5 (Data on file; Allergan plc, Dublin, Ireland).
mg/kg per day for 12 weeks was effective in the treatment of
moderate to severe acne vulgaris, with an onset of efficacy for The antibacterial profile of sarecycline, particularly its targeted
inflammatory lesions observed as early as the first follow-up activity against P. acnes, may reduce its potential for disrupt-
visit at week 3, and an overall safety profile generally similar ing the human gut microbiome. In contrast, administration
to that of placebo. In addition, sarecycline showed a significant of the tetracycline-class antibiotics doxycycline, minocycline,
effect on acne severity in nonfacial sites. and tetracycline has been associated with disruption of the gut
microbiome.14-16 The favorable safety profile of sarecycline in
Interestingly, sarecycline showed a statistically significantly these studies represents an important finding for a tetracycline-
greater improvement than placebo in noninflammatory le- class antibiotic. Tetracycline-class antibiotics may be associated
sion counts beginning at week 6 in study SC1401 and week 9 with GI side effects and phototoxicity (typically seen with doxy-
in study SC1402, with continued improvement through week cycline) or vestibular side effects (observed with minocycline),3
12. The analyses in patients with at least 10 noninflammatory yet low rates of such side effects were reported in these studies
lesions at baseline provided further evidence of the therapeutic with sarecycline. In the current phase 3 studies, the incidence
effect on noninflammatory lesions. Although the exact effect of of AEs related to the GI tract, including nausea, vomiting, diar-
sarecycline on noninflammatory lesions is unknown, a possible rhea, and abdominal pain, was low.
996
The patient-reported outcomes for Skindex-16 symptoms, Funding Disclosures

emotion, and functioning indicate that patient quality of life im- This study was sponsored by Allergan plc, Dublin, Ireland.
proved with the use of sarecycline over 12 weeks. They are also Writing and editorial assistance was provided to the authors
similar to Skindex-16 outcomes in patients with moderate to by Peloton Advantage, Parsippany, NJ, and was funded by Al-
severe acne who were treated with minocycline.17 lergan plc. Neither honoraria nor other form of payments were
made for authorship.
Limitations
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monly used by dermatologists. J Clin Aesthet Dermatol. 2016;9(5):11-17.
for noninflammatory lesions and nonfacial acne. 8. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications,
molecular biology, and epidemiology of bacterial resistance. Microbiol Mol
CONCLUSIONS Biol Rev. 2001;65(2):232-260.
9. Leyden JJ, Sniukiene V, Berk DR, et al. Efficacy and safety of sarecycline, a
Sarecycline is a novel, tetracycline-class antibiotic represent- novel, once-daily, narrow spectrum antibiotic for the treatment of moderate
to severe facial acne vulgaris: results of a phase 2, dose-ranging study. J
ing the first narrow-spectrum, targeted therapy for acne. Oral Drugs Dermatol. 2018;17(3):611-616.
sarecycline 1.5 mg/kg per day was effective for improving acne 10. Chren MM, Lasek RJ, Sahay AP, et al. Measurement properties of Skin-
severity and inflammatory and noninflammatory lesion counts, dex-16: a brief quality-of-life measure for patients with skin diseases. J Cu-
tan Med Surg. 2001;5(2):105-110.
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with onset of efficacy for inflammatory lesions observed as 11. Norris JF, Cunliffe WJ. A histological and immunocytochemical study of early
early as week 3, and onset of efficacy for absolute reduction acne lesions. Br J Dermatol. 1988;118(5):651-659.
12. Jeremy AH, Holland DB, Roberts SG, et al. Inflammatory events are involved
in noninflammatory lesion count observed at week 6 for study in acne lesion initiation. J Invest Dermatol. 2003;121(1):20-27.
SC1401 and at week 9 for study SC1402. A benefit was also 13. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management
Penalties Apply
of acne: an update from the Global Alliance to Improve Outcomes in Acne
seen for nonfacial acne at week 12. Sarecycline was well toler- Group. J Am Acad Dermatol. 2009;60(5):S1-S50.
ated and associated with low rates of vestibular side effects, 14. Becker E, Schmidt TSB, Bengs S, et al. Effects of oral antibiotics and isotreti-
phototoxicity, and GI side effects, all of which are commonly noin on the murine gut microbiota. Int J Antimicrob Agents. 2017;50(3):342-
351.
observed with use of currently available first-line oral tetracy- 15. Ferrer M, Mendez-Garcia C, Rojo D, et al. Antibiotic use and microbiome
cline-class antibiotics for moderate to severe acne. function. Biochem Pharmacol. 2017;134:114-126.
16. Zaura E, Brandt BW, Teixeira de Mattos MJ, et al. Same exposure but two
radically different responses to antibiotics: resilience of the salivary micro-
DISCLOSURES biome versus long-term microbial shifts in feces. mBio. 2015;6(6):e01693-
01615.
S. Bruce, F. E. Cook-Bolden, S. S. Dhawan, D. Forsha, M. H. Gold, 17. Hayashi N, Kawashima M. Efficacy of oral antibiotics on acne vulgaris and
L. J. Green, S. Guenthner, S. E. Kempers, L. H. Kircik, A. Moore, their effects on quality of life: a multicenter randomized controlled trial using
A. Nasir, J. L. Parish, M. I. Rendon, P. Rich, N. Sadick, L. Stein- minocycline, roxithromycin and faropenem. J Dermatol. 2011;38(2):111-119.
Gold, E. Tschen, S. K. Tyring, R. A. Weiss, and W. P. Werschler

are investigators for Allergan plc. T. I. Boodhoo and D. R. Berk
are employees of Allergan plc, and C. Schmitz and A. Kaoukhov AUTHOR CORRESPONDENCE
were employees of Allergan plc at the time the studies were
Angela Moore MD
conducted; all may own stock/stock options in that company.
E-mail:................….............. acdermacderm@gmail.com
ACKNOWLEDGMENTS
Writing and editorial assistance was provided to the authors by
Peloton Advantage, Parsippany, NJ, and was funded by Aller-
gan plc, Dublin, Ireland. All authors meet the ICMJE authorship
criteria.
FOR YOUR PATIENTS WITH RAISED SEBORRHEIC KERATOSES (SK)
Make your mark by the

way you remove theirs
ESKATA™ is the first and only FDA-approved

topical treatment for raised SKs.
Visit ESKATAHCP.com to learn about

ordering, application, and more.
Not an actual patient.
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INDICATIONS AND USAGE MOST COMMON ADVERSE REACTIONS
Penalties Apply
ESKATA™ (hydrogen peroxide) topical solution,
40% (w/w) is indicated for the treatment of seborrheic
keratoses that are raised.
The most common adverse reactions include erythema
(99%), stinging (97%), edema (91%), scaling (90%),
crusting (81%), and pruritus (58%).
IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
None.
Do not apply ESKATA to the eyes or mucous membranes.
Avoid treating seborrheic keratoses within the orbital DOSAGE AND ADMINISTRATION
rim. Direct contact with the eye can cause corneal
ESKATA is to be administered by a healthcare
injury (erosion, ulceration, perforation, and scarring),
provider. For topical use only. Not for oral, ophthalmic,
chemical conjunctivitis, eyelid edema, severe eye pain or
or intravaginal use. Not for open or infected
permanent eye injury, including blindness. If accidental
seborrheic keratoses.
exposure occurs, flush with water for 15 to 30 minutes,
initiate monitoring and further evaluation as appropriate. Please see Brief Summary of full Prescribing
Information on the following page.
Skin reactions occurred in the treatment area after
application of ESKATA. Severe local skin reactions
included erosion, ulceration, vesiculation and scarring. © 2018 Aclaris Therapeutics, Inc. All rights reserved.
Do not retreat until the skin has recovered from any PP-ESK-0296 05/18
ESKATA is a trademark of Aclaris Therapeutics, Inc.
reaction caused by the previous treatment.
| | | | | |
S:6.75”
Previous Page Contents Zoom In Zoom Out Search Issue Cover Next Page
ESKATATM Table 1. Percentage of Subjects with Local Skin Reactions by

(hydrogen peroxide) topical solution, 40% (w/w) Severity (Cont’d)
BRIEF SUMMARY OF PRESCRIBING INFORMATION ESKATA Vehicle
N=467 N=470
INDICATION AND USAGE
ESKATA is indicated for the treatment of seborrheic keratoses that Mild Moderate Severe Total Mild Moderate Severe Total
are raised. Hypopig-
16 3 <1 19 1 <1 0 1
DOSAGE AND ADMINISTRATION mentation
Important Administration Information Erosion 12 2 1 15 <1 0 0 1
ESKATA is to be administered by a healthcare provider.
Ulceration 6 2 <1 9 1 1 0 2
For topical use only. Not for oral, ophthalmic, or intravaginal use.
Do not apply ESKATA topical solution to open or infected Atrophy 4 0 0 4 0 0 0 0
seborrheic keratoses. Scarring 3 <1 <1 3 0 0 0 0
During a single in-office treatment session, apply ESKATA to
seborrheic keratoses 4 times, approximately 1 minute apart. After Common local skin reactions observed 10 minutes after treatment
one use, discard the unit dose applicator. include: erythema (98%), stinging (93%), edema (85%),
pruritus (32%), and vesiculation (18%).
If the treated lesions have not completely cleared approximately
3 weeks after treatment, another treatment may be administered Common local skin reactions observed 1 week after treatment are
following the same procedure. scaling (72%), erythema (66%), crusting (67%), pruritus (18%),
erosion (9%), and ulceration (4%).
DOSAGE FORMS AND STRENGTHS
ESKATA topical solution is a clear, colorless solution containing Common local skin reactions observed 15 weeks after the initial
40% (w/w) hydrogen peroxide. treatment are erythema (21%), hyperpigmentation (18%),
scaling (16%), crusting (12%), and hypopigmentation (7%).
CONTRAINDICATIONS
None. Less common adverse reactions occurring in ≥0.5% of subjects
treated with ESKATA include eyelid edema (0.6%) and
WARNINGS AND PRECAUTIONS herpes zoster (0.6%).
Eye Disorders
Do not apply to the eyes or mucous membranes. Avoid treating USE IN SPECIFIC POPULATIONS
seborrheic keratoses within the orbital rim. Direct contact with the Pregnancy Risk Summary Hydrogen peroxide is not absorbed
eye can cause corneal injury (erosion, ulceration, perforation, and systemically following topical administration, and maternal use is
scarring), chemical conjunctivitis, eyelid edema, severe eye pain, not expected to result in fetal exposure to the drug.
or permanent eye injury, including blindness. Lactation Risk Summary Hydrogen peroxide is not absorbed
systemically by the mother following topical administration, and
If accidental exposure occurs, flush with water for 15 to 30 minutes
breastfeeding is not expected to result in exposure of the child to
and initiate monitoring, and further evaluation as appropriate.
hydrogen peroxide.
Local Skin Reactions
Pediatric Use Seborrheic keratosis is not seen in the pediatric
Skin reactions occurred in the treatment area after application of
population.
ESKATA. Severe local skin reactions included erosion, ulceration,
vesiculation and scarring. Do not initiate a second treatment course Geriatric Use Of the 841 subjects treated with ESKATA in the clinical
with ESKATA until the skin has recovered from any reaction caused trials, 70% were 65 years of age and older and 26% were 75 years
by the previous treatment. of age and older. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects.
ADVERSE REACTIONS
Clinical Trials Experience Because clinical trials are conducted OVERDOSE
under widely varying conditions, adverse reaction rates observed Topical overdosing of ESKATA could result in an increased
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in the clinical trials of a drug cannot be directly compared to rates incidence and severity of local skin reactions.
in the clinical trials of another drug and may not reflect the rates NONCLINICAL TOXICOLOGY
observed in practice. Carcinogenesis, Mutagenesis, Impairment of Fertility
The data described below reflect exposure to ESKATA or vehicle Long-term animal studies have not been performed to evaluate the
carcinogenic potential of ESKATA or hydrogen peroxide.
Penalties Apply
in a total of 937 subjects with seborrheic keratoses that are raised.
Overall, 42% of the subjects were male and 58% were female. Hydrogen peroxide has been found to exhibit positive results
Ninety-eight (98) percent of the subjects were Caucasian and the in in vitro tests for genotoxicity, but has not exhibited positive
mean age was 68.7 years. results in in vivo tests for genotoxicity, presumably due to the
rapid metabolism of hydrogen peroxide.
At each visit, local skin reactions were graded for severity to
determine the maximum severity after treatment. Table 1 presents The effects of hydrogen peroxide on fertility have not been
the percentage of subjects with the local adverse reactions by the evaluated. Hydrogen peroxide has been associated with effects
most severe grade reported during the course of the trials. on sperm function and elevated testicular hydrogen peroxide
concentration has been implicated in male infertility, although in
Table 1. Percentage of Subjects with Local Skin Reactions by vivo, no effect of hydrogen peroxide on sperm function has been
Severity demonstrated.
ESKATA Vehicle PATIENT COUNSELING INFORMATION
N=467 N=470 Advise the patient to read the FDA-approved patient labeling
Mild Moderate Severe Total Mild Moderate Severe Total (Patient Information).
Erythema 13 67 19 99 29 5 <1 34 Ophthalmic Adverse Reactions
Inform patients that severe eye injury can occur with ESKATA
Stinging 34 49 15 97 9 1 <1 10 application. Advise patients to inform the healthcare provider
Edema 28 48 15 91 6 1 0 6 immediately if ESKATA runs into eyes, mouth, or nose during
administration
Scaling 49 36 5 90 28 5 1 33
Local Skin Reactions
Crusting 34 38 8 81 13 5 1 19 Inform patients that treatment with ESKATA may lead to local
Pruritus 34 18 5 58 7 1 <1 8
skin reactions
Rx only This Brief Summary is based on ESKATA Prescribing
Hyperpig-
32 7 <1 39 1 <1 0 1 Information, issued December 2017.
mentation
Manufactured by: James Alexander Corp.,
Vesicles 21 3 1 24 <1 0 0 <1 Blairstown, NJ 07825
Marketed by: Aclaris Therapeutics, Inc.,
Malvern, PA 19355

SPECIAL TOPIC
A Single Site, Open Label Clinical Trial, Evaluating the

Duration, Efficacy, and Safety of a Novel Lip Plumper
Monica Boen MD, Marwan Alhaddad MD, Isabella Guiha BSc,
Douglas P. Wu MD PhD, Mitchel P. Goldman MD
Cosmetic Laser Dermatology, San Diego, CA
ABSTRACT
Introduction: Lip plumpers are topical agents that offer immediate, but temporary, volumization of the lips. While these products are
becoming increasingly popular and are available at multiple retailers, there is a lack of clinical studies to evaluate the efficacy, longevity,
and safety of the lip plumping products.
Methods: This is a prospective, single center, clinical trial to evaluate the duration, efficacy, and safety of a lip plumping agent in two
clinical visits. Lip volume and adverse event were assessed by two clinicians at various time points: 15 minutes, 1 hour, 2 hours, 3
hours, and 4 hours.
Results: Twenty-two subjects were enrolled in the study, and eighteen completed the study. Investigator assessments of global im-
provement 15 minutes after application of the lip plumping product demonstrated improvement in lip fullness in 100% of the subjects
(18/18), and 1 hour post-application 67% (12/18) showed an improvement in lip fullness that was statistically significant compared to
the 2-hour assessment (P<0.05). Subject evaluations noted improvement in lip fullness 15 minutes post-application in 94.4% (17/18) of
subjects, and 1 hour post-application, 89% (16/18) of the subjects who completed the trial noted some improvement in the volume of
their lips that was statistically significant compared to the 2-hour post-application time point (P<0.0001). Subjects noted that they did
experience a tingling and heat sensation, but a majority noted that that this sensation lasted less than 15 minutes.
Discussion: Our study demonstrated that the lip plumping product increased lip volume in almost all patients 15 minutes post-appli-
cation and showed a continued improvement in lip fullness per investigator assessments 1 hour after application. Adverse events of a
tingling or heat sensation were expected and observed as the topical product contained capsaicin, cinnamon, and menthol, all of which
can induce this sensation by the release of substance P.
J Drugs Dermatol. 2018;17(9):999-1004.
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Penalties Apply
INTRODUCTION
F
ull and well-defined lips impart a sense of youth, attrac- ers have been available over the counter for over a decade,
tiveness, and health.1 While the ideal lip varies across however, there are few studies in the literature to evaluate
cultures, the appropriate upper to lower lip balance and their effectiveness and tolerability.5,6 This prospective study will
a defined vermillion border has been associated a pleasing ap- evaluate the efficacy and safety of novel lip plumper using 3D
pearance of the lips.2 Lip augmentation has been on the rise in photography, and will relay subjects’ assessment and opinions
recent years, with a 53% increase in the number of lip augmen- of this product.
tations between 2000 and 2016 according the American Society
of Plastic Surgeons Statistics report.3 These increases maybe MATERIALS AND METHODS
caused by the already present trend of fuller lips in Western The study was approved by a centralized Institutional Review
culture, the advent of cosmetic fillers, and social media influ- Board (Schulman Associates IRB, Inc.) and conducted in accor-
ences. In particular, the use of “selfies” in social media may dance with Good Clinical Practices conforming to the ethical
have spurred patients to seek cosmetic augmentation of their guidelines of the 1975 Declaration of Helsinki.
lips to portray their desired lip volume in their digital images.
Participants
Minimally invasive treatment options with dermal fillers can Eligible subjects were men or women 18 years of age or older
give immediate and significant benefit to the lips.4 However, enrolled from October to November 2017. Written informed
due to cost, pain, and potential risk for complications, some in- consent was obtained from all participants before study entry.
dividuals elect to opt-out of having these procedures. For these Exclusion criteria included subjects with a history of sensitiv-
reasons, a topical lip-care treatment to temporarily plump the ity or allergy to any component of the topical lip care product;
lips may be an attractive option to many women. Lip plump- history or current evidence of a medical or current evidence of
1000
Journal of Drugs in Dermatology M. Boen, M. Alhaddad, I. Guiha, et al
FIGURE 1. Mean investigator-assessed global improvement score FIGURE 3. Mean subject-assessed global improvement score (GAIS)
(GAIS) in lip volume from baseline. in lip volume from baseline.
FIGURE 2. Mean of investigator assessed Medicis Lip Fullness FIGURE 4. A) Baseline B) 15 minutes post-application of the lip
Scale of the upper and lower lip at varying time points after product plumper C) 1 hour post-application of the lip plumper. Increased lip
application. fullness maintained at both time points.
for the designated time (one hour before and two hours after
the application of the lip-care product); inability to comply with
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the entire course of the study; and participation within 30 days
prior to the start of the study in a drug or other investigational
research study.
Penalties Apply
Intervention
Twenty-two (22) subjects were enrolled in this prospective,
single center, clinical trial consisting of two visits. Of note, dur-
ing the treatment, subjects abstained from food and drink for
one hour prior and two hours after the application of the prod-
uct and they did not apply any product over their lips the day
before the treatment. Subjects were required to have two ap-
plications of the study product with ensuing assessments on
two consecutive days.
Prior to application of the lip care product (Lucy & Co, Del Mar,
CA), the lips of the subjects were graded on fullness by the
investigators using the validated Medicis Lip Fullness Scale
(MLFS), and VECTRA 3D photography (Canfield Scientific Inc.,
a medical, psychological or other disorder that, in the inves- NJ) was performed. For each subject, a sufficient amount of
tigator’s opinion, would preclude enrollment into the study; the lip care product was applied over the mucosal upper and
and a history of or the presence of any skin condition/disease lower lip using a one-time disposable plastic applicator. Pho-
in the treatment area that might interfere with the diagnosis tography and subject and investigator assessments, adverse
or evaluation of study parameters (ie, infection, active herpes event assessments were performed at intervals of 15 minutes,
labialis, actinic keratosis or skin cancer). Other exclusion cri- 1 hour, 2 hours, 3 hours, and 4 hours. The patients were given
teria included the inability to refrain from food and beverage a self-assessment questionnaire prior to the lip care product
1001
TABLE 1. TABLE 2.
Global Aesthetic Improvement Score Patient Questionnaire 1 – Pre-Treatment
Score Rating Definition Statement Response N (%)
Optimal aesthetic result Very Thin 0
3 Very Much Improved
for the subject Thin 4 (18.2%)
1 My Lips Are: Medium 12 (54.5%)
Marked improvement in
Full 5 (22.7%)
appearance from the initial
2 Much Improved Very Full 1 (4.5%)
condition, but not completely
optimal for this subject. Have you had soft
tissue filler injected Yes 6 (27.3%)
Obvious improvement 2
into your lips in the No 16 (72.7%)
1 Improved in appearance from the
past 6 months?
initial condition.
How often do you 3 times or more/day 11 (50.0%)
The appearance is essentially
0 No Change apply chapstick/ 2-3 times/day 7 (31.8%)
the same as baseline. 3
lip moisturizer? 2-3 times/week 2 (9.1%)
The appearance is worse Hardly ever 2 (9.1%)
-1 Worse
than the original condition.
Have you ever
Yes 12 (54.5%)
Marked worsening in appearance 4 tried a lip plumper
-2 Much Worse No 10 (45.5%)
from the initial condition. in the past?
Obvious worsening in appearance
-3 Very Much Worse from the initial
condition.
application, and another questionnaire at the 15 minute and application assessment, 67% (12/18) showed an improvement
1-hour interval. This entire protocol was repeated on the next in lip fullness that was statistically significant compared to the
day. 2-hour assessment (P<0.05). There was no statistically signifi-
cant difference between the GAIS scores between 15 minutes
Study Endpoints and 1 hour showing that lip volume was maintained in a ma-
The primary endpoint of the study the seven-point investiga- jority of patients during this time period. Four of the eighteen
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tor-assessed global aesthetic improvement score during the patients had continued improvement for 2 hours post-applica-
various time intervals after application of the lip care prod- tion and two patients showed improvement for 4 hours. There
uct: 15 minutes, 1 hour, 2 hours, 3 hours, and 4 hours (Table was some improvement in the Medicis lip fullness scale on in-
1). Secondary endpoints included a change from baseline in vestigator and subject assessments, but these values were not
Penalties Apply
investigator assessed MLFS, investigator assessment of the statistically significant (Figure 2).
tolerability of the product, subject-assessed global aesthetic
improvement score (GAIS), and the patient questionnaire. The investigator tolerability assessments showed that the pa-
tients tolerated the lip plumper product well, with only two
Statistical Analyses patients who had a mild irritant contact dermatitis that resolved
Statistical analyses were conducted on an intent-to-treat basis within 2 hours after removal of the product. Two patients had
(ie, all randomized subjects with at least 1 follow-up visit were mild erythema 1-hour post-application of the product that re-
included). All statistical tests utilized ANOVA or Student's t test solved within 4 hours and one patient experienced a significant
interpreted at a 5% significance level. Continuous variables are burning or stinging sensation that resolved within 4 hours
reported as mean ± SD (range). as well. On subject GAIS, 94.4% (17/18) of patients who com-
pleted the study noted improvement in lip fullness 15 minutes
RESULTS post-application that was statistically significant compared to
Twenty-two patients were enrolled with a mean age of 31.4 subject evaluations one-hour post-application (P<0.5; Figure 3).
(21-57) years, with 19 women and 3 men. Two subjects did not In addition, and 6 of the 18 patients assessed their lips as much
complete the entire study because of an irritant dermatitis to improved to very much improved 15 minutes post-application
the study product, one patient withdrew consent, and one pa- (Figure 3). One hour post-application, 89% (16/18) of patients
tient only completed one of the two visits in the trial. who completed the trial noted some improvement in the vol-
ume of their lips that was statistically significant compared to
Investigator GAIS showed an improvement in lip volume at 15 the 2-hour post-application time point (P<0.0001). Three hours
minutes in 100% of the subjects (18/18) who completed the trial post-application, 2 patients noted continued improvement in
with a mean score of 1 (improved; Figure 2). At the 1-hour post- their lip fullness (P<0.05).
1002
TABLE 3.
Patient Questionnaire 15 Minutes and 1 Hour Post-Application of the Lip Care Product
Response N (%) Response N (%)

Statement
15 minutes post-application 1 hour post-application
Much Improved 5 (23.8%) Much Improved 1 (5%)
Do you feel the overall volume of your Somewhat Improved 14 (66.7%) Somewhat Improved 9 (45%)
1
lips has: No Change 2 (9.5%) No Change 9 (45%)
Got Worse 0 Got Worse 1 (5%)
Strongly Agree 4 (4.8%) Strongly Agree 2 (10%)
Do you feel the overall natural color of your
Agree 15 (71.4%) Agree 11 (55%)
2 lips has been enhanced:
Disagree 2 (9.5%) Disagree 7 (35%)
Strongly Disagree 0 Strongly Disagree 0
Do you feel the overall outline contour of Somewhat Improved 14 (66.7%) Somewhat Improved 8 (40%)
3
your lips has: No Change 4 (19.0%) No Change 11 (55%)
Got Worse 1 (4.8%) Got Worse 0
Do you feel the overall smoothness/ Somewhat Improved 11(52.4%) Somewhat Improved 9 (45%)
4
softness of your lips has: No Change 7 (33.3%) No Change 9 (45%)
Got Worse 0 Got Worse 0
Do you feel the overall appearance of Somewhat Improved 14 (66.7%) Somewhat Improved 10 (50%)
5
your lips has: No Change 1 (4.8%) No Change 9 (45%)
Got Worse 1 (4.8%) Got Worse 0
Strongly Agree 0 Strongly Agree 1 (5%)
I feel that this lip plumper made my lips Agree 14 (66.7%) Agree 9 (45%)
6
look younger : Disagree 7 (33.3%) Disagree 10 (50%)
Strongly Disagree 0 Strongly Disagree 0
Yes 20 (95.2%) Yes 10 (50%)
7 Did you notice an increase in your lip volume:
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No 1 (4.8%) No 10 (50%)
Every Day 10 (47.6%) Every Day 11 (55%)
I am interested in having full/plump lips:
8 A few times a week 5 (23.8%) A few times a week 2 (10%)
Only on special occasions 6 (28.6%) Only on special occasions 7 (35%)
10
were available?
Penalties Apply
Would you purchase this product if it
I would recommend this product to a friend:

Yes 12 (57.1%)
No 9 (42.9%)
Yes 11 (52.4%)
Yes 9 (45%)
No 11 (55%)
Yes 9 (45%)
No 10 (47.6%) No 11 (55%)
< 5 Minutes 1 (4.8%) < 5 Minutes 2 (10%)
How long would you estimate the 6-10 Minutes 5 (23.8%) 6-10 Minutes 4 (20%)
11
length of the tingling sensation? 11-15 Minutes 9 (42.9%) 11-15 Minutes 6 (30%)
>15 Minutes 6 (28.6%) >15 Minutes 8 (40%)
< 5 Minutes 2 (9.5%) < 5 Minutes 2 (10%)
How long would you estimate the length of 6-10 Minutes 4 (19.0%) 6-10 Minutes 3 (15%)
12
the warming/heat sensation? 11-15 Minutes 8 (38.1%) 11-15 Minutes 8 (40%)
>15 Minutes 7 (33.3%) >15 Minutes 7 (35%)
Very Well 1 (4.8%)
Very Well 2 (10%)
Well 3 (14.3%)
How well did you tolerate the Lip Plumper Well 4 (20%)
W/ Noticeable Discomfort 9 (42.9%)
13 after application? W/ Noticeable Discomfort 11 (55%)
W/ Very Noticeable
W/ Very Noticeable Discomfort 2 (10%)
Discomfort 6 (28.6%)
W/ Significant Discomfort 1 (5%)
W/ Significant Discomfort 2 (9.5%)
1003
TABLE 3. (CONTINUED)
Patient Questionnaire 15 Minutes and 1 Hour Post-Application of the Lip Care Product
Very Well 1 (4.8%)
Very Well 2 (10%)
Well 3 (14.3%)
How well did you tolerate the Lip Plumper Well 4 (20%)
W/ Noticeable Discomfort 9 (42.9%)
13 after application? W/ Noticeable Discomfort 11 (55%)
W/ Very Noticeable
W/ Very Noticeable Discomfort 2 (10%)
Discomfort 6 (28.6%)
W/ Significant Discomfort 1 (5%)
W/ Significant Discomfort 2 (9.5%)
Very Happy 2 (10%)
Happy 6 (30%)
14 How happy were you with this product? n/a
Slightly Happy 4 (20%)
Unhappy 8 (40%)
Strongly Agree 3 (15%)
I felt the Lip Plumper was quick and easy Agree 13 (65%)
15 to use: n/a Disagree 3 (15%)
Strongly Disagree 1 (5%)
On the pre-treatment questionnaire, most of the patients had pathway.7 Some of the ingredients in the lip plumpers that can
tried a lip plumper in the past (54.5%), used a lip moisturizer create this vasodilatory effect include capsaicin, cinnamon,
more than 2 times a day (81.8%), and a majority rated their lips menthol, peppermint, and niacinamide. Another common
as medium or full (77.2%) and had previous lip filler injections ingredient, marine-derived collagen, creates fuller lips in a dif-
(72.7%; Table 2). ferent manner—increasing skin hydration by binding water in
the strateum corneum.8
A separate patient questionnaire was administered 15 minutes
post-treatment and 1-hour post-treatment evaluation and re- There have been only two small clinical trials evaluating lip
sults were tabulated from the first visit. There was somewhat plumpers in the literature. Lee and colleagues performed a pro-
to much improvement in lip volume in 90.4% of patients after spective study of seven patients to quantify the effects of an
15 minutes and this dropped to 50% of patients after 1 hour of over the counter lip plumper using measurements on digital
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application of the product (Table 3). Patients noted an enhance- photography.6 The patients were instructed to apply the prod-
ment of the natural color of their lips both 15 minutes (90.4%) uct 3 times a day for an average of 1.7 months, after which the
and 1 hour (65%) post-application of the product. The outline of authors found no statistically significant change in lip volume.
the lips was mainly improved in the 15 minutes post-application Mazzarello and colleagues performed a randomized and con-
Penalties Apply
of the product (76%) and there was no change in 55% of patients trolled double blind study of 60 patients and found statistically
after 1 hour. Similarly, they noted an improved smoothness and significant increases in lip volume and lip erythema maximally
softness of the lips after 15 minutes (67%), while after 1 hour 15 minutes after application and gradually decreases over time,
there was no change in 45% of patients. Overall appearance of similar to our study5. They used colorimetry to show that vaso-
lips had somewhat to much improved in 90.4% of patients after dilation lasted 1 hour after product application and was most
15 minutes and decreased to 55% of patients after 1 hour. Addi- likely responsible for increased lip volume. Adverse events in-
tionally, 66.7% of patients agreed that the lip plumping product cluded stinging in 57% of patients and a stretching sensation
made them feel younger 15 minutes post-application, while in 77%.
this decreased to 50% 1 hour post-application, which correlates
to the peak efficacy of the product (Figure 5). Most patients did Our study demonstrated that the lip plumping product increased
acknowledge that they had some discomfort after application lip volume in almost all patients 15 minutes post-application
of this product and experienced a tingling and heat sensation, and showed a continued improvement in lip fullness per in-
but the majority of patients noted that that this sensation lasted
less than 15 minutes. FIGURE 5. A) Baseline B) 15 minutes post-application of the lip
plumper C) 1 hour post-application of the lip plumper. Increased lip
DISCUSSION fullness at the 15-minute time point, and decreases to baseline at 1
Lip plumpers are topical agents designed to transiently in- hour post-application.
crease lip volume and definition. These products produce lip
augmentation by vasodilation secondary to irritant contact
dermatitis, due to the release of substance P, or nonimmuno-
logic contact urticaria, most likely through the prostaglandin
1004
vestigator assessments 1 hour after application. There were no

statistically significant changes in the Medicis lip fullness scale,
which maybe in part because many of the patients already had
full lips and changes are better seen in patients with thin lips.
Adverse events of a tingling or heat sensation were expected New Supplement
and observed as the topical product contained capsaicin, cin-
namon, and menthol, all of which can induce this sensation by
the release of substance P from the nociceptors. Still Available
From the subject questionnaire, it appears that most of the
17 • Issue 6
• Volume
patients had the most benefit from the product 15 minutes June 2018
J DD
9616
ISSN: 1545
post-application as patients noted the most volume, natural
lip color enhancement, lip outline and smoothness and overall
appearance during this time period compared to 1 hour post-
treatment. One of the limitations of this study was that it was A SUPPLEM
ENT TO
J DD
performed on a predominantly cosmetic clientele, who had ex-
perience with more lasting lip augmentations, such as dermal
fillers. This may explain why only half of patients would recom-
E
mend this product to a friend or purchase this product. YING ACN
DEMYSTIF
MS
ALGORITH
Lip plumpers are becoming more and more popular, as evi-
denced by our study where more than half of the subjects used Topical Vehi
cle Formulati
a lip plumper in the past. There are several lip plumpers on the the Treatmen ons in
t of Acne
market that can be found in various drug stores to high end cos-
metic retailers. It is important for dermatologists to be familiar TRIAL RE
VIEW
PIPELINE
PREVIEW
S
CLINICAL
with the risks and benefits associated with these cosmeceutical

DS
T ROUN
RESIDEN
products, and their role in the spectrum of lip augmentation

techniques. ISSN: 1545 9616
Do Not Copy
June 2018 •
Volume 17 •
Issue 6 ( SUP
PLEMENT)
DISCLOSURE
Dr. Goldman is a minor investor in Lucy & Co.
Topical Vehicle Formulations
Penalties Apply
REFERENCES
1.
in the Treatment of Acne
Klein AW. In search of the perfect lip: 2005. Dermatol Surg 2005;31:
1599-603.
2. Kane MA, Lorenc ZP, Lin X , Smith SR. Validation of a lip fullness scale for Guest Editor, Leon H. Kircik MD
assessment of lip augmentation. Plast Reconstr Surg 2012;129:822e-8e.
3. Surgeons ASoP. 2016 Cosmetic plastic surgery statistics; Cosmetic Proce-
dural Trends 2016.
4. Chiu A, Fabi S, Dayan S , Nogueira A. Lip Injection Techniques Using Small-
Particle Hyaluronic Acid Dermal Filler. J Drugs Dermatol 2016;15:1076-82.
5. Mazzarello V, Solinas G, Bandiera P, Pomponi V, Piu G, Ferrari M et al. How
long does the volumizing effect of a Zingiber officinale-based lip plumper
last? Int J Cosmet Sci 2017;39:373-8.
6. Lee S , Most SP. Efficacy of an over-the-counter lip enhancer in lip augmenta-
tion. Arch Facial Plast Surg 2005;7:203-5.
7. Firoz EF, Levin JM, Hartman RD , James WD. Lip plumper contact urticaria.
J Am Acad Dermatol 2009;60:861-3.
8. Swatschek D, Schatton W, Kellermann J, Muller WE , Kreuter J. Marine
sponge collagen: isolation, characterization and effects on the skin param-
eters surface-pH, moisture and sebum. Eur J Pharm Biopharm 2002;53:
JDDonline.com
107-13.
This research was supported by a grant from
Aqua Pharmaceuticals LLC, Exton, PA 19341
Monica Boen MD
E-mail:................……............................. mboen@clderm.com
Derm In-Review welcomes our

advertising supporters and thanks them for their
commitment to resident education.
Do Not Copy
Penalties Apply
Thank you also to our educational
partner Aurora Diagnostics for their
continued support of the Dermpath
components of Derm In-Review.
DermInReview.com

SPECIAL TOPIC
Artificial Intelligence for the Objective Evaluation

of Acne Investigator Global Assessment
Antonella Melina MSc,a Nhan Ngo Dinh MSc,b Benedetta Tafuri MSc,c Giusy Schipani MD,d
Steven Nisticò MD,d Carlo Cosentino PhD,a Francesco Amato PhD,a Diane Thiboutot MD,e
Andrea Cherubini PhDb
Faculty of Biomedical Engineering, University “Magna Graecia”,Viale Europa, Catanzaro, Italy
a
b
Linkverse, Rome, Italy
c
Institute of Molecular Bioimaging and Physiology (CNR-IBFM), Catanzaro, Italy
d
Department of Dermatology, University “Magna Graecia”,Viale Europa, Catanzaro, Italy
e
Penn State University College of Medicine, Hershey, PA
ABSTRACT
Introduction: The evaluation of Acne using ordinal scales reflects the clinical perception of severity but has shown low reproducibility
both intra- and inter-rater. In this study, we investigated if Artificial Intelligence trained on images of Acne patients could perform acne
grading with high accuracy and reliabilities superior to those of expert physicians.
Methods: 479 patients with acne grading ranging from clear to severe and sampled from three ethnic groups participated in this study.
Multi-polarization images of facial skin of each patient were acquired from five different angles using the visible spectrum. An Artificial
Intelligence was trained using the acquired images to output automatically a measure of Acne severity in the 0-4 numerical range of
the Investigator Global Assessment (IGA).
Results: The Artificial Intelligence recognized the IGA of a patient with an accuracy of 0.854 and a correlation between manual and
automatized evaluation of r=0.958 (P<.001).
Discussion: This is the first work where an Artificial Intelligence was able to directly classify acne patients according to an IGA ordinal
scale with high accuracy, no human intervention and no need to count lesions.
J Drugs Dermatol. 2018;17(9):1006-1009.
INTRODUCTION
Do Not Copy METHODS
T Penalties Apply
he measurement and grading of acne severity is a rec- An imaging device (FaceAtlas, www.linkverse.com) was used
ognized challenge1-3, since it is known to depend on the to acquire high-resolution multi-polarization images of facial
number and type of lesions and the extent of involve- skin using the visible spectrum (Figure 1). During the devel-
ment. The method of reference for acne grading is lesion count- opment of the device, a database of 479 subjects (age range,
ing4-6; however, it is time-consuming and not well-suited to 11-46 years, median 17.4 years; female 58%) with acne grading
clinical practice. For this reason, health agencies4,6 recommend ranging from clear to severe, sampled from three ethnic groups
the use of an Investigator Global Assessment (IGA) with up to (Caucasian-white 79%, African-black 13%, Asian 8%), was ac-
six ordinal grades (clear, almost clear, mild, moderate, severe quired at the Department of Dermatology of University “Magna
and very severe). In order to improve reliability, the FDA rec- Graecia” after informed consent and approval from the local
ommends co-primary endpoints that evaluate both IGA scale Institutional Review Board. Three experienced dermatologists
and acne lesion count assessments.6 Computational methods assessed acne severity according to the FDA ordinal scale (pro-
based on imaging techniques7-9 have been proposed in scientif- portion in the dataset; 0-clear: 18.1%; 1-almost clear: 18.4%;
ic literature to reduce the problems associated to low inter- and 2-mild: 20.4%; 3-moderate: 23.3%; 4-severe: 19.8%). The clinical
intra-rater reliability of acne grading.10-12 To date, however, all evaluation resulting from majority voting among the three rat-
attempts have focused on the automatization of lesion count- ers represented the ground truth for supervised learning.
ing. In the present work, we intend to investigate if an Artificial
Intelligence (AI) could perform IGA grading of digital images of The image acquisition and postprocessing workflow is de-
acne patients with reliabilities comparable or superior to those picted in Figure 1. As result of this workflow, multiple images
of expert physicians. collected from a patient were first converted to a standardized
planar representation. Subsequently, the planar image was
1007
Journal of Drugs in Dermatology A. Melina, N.N. Dinh, B. Tafuri, et al
FIGURE 1. Workflow for the image acquisition and processing. The subject, seated in front of the device (A), was asked to rotate its head in five
different poses (B) with a 30° tilt respect to the lens axis. For each pose, lateral flash bulbs were lighted to collect a first reference image and a
second image with cross-polarized filters to reduce reflections in the images. Artificial Intelligence (C) identified human anatomical landmarks on
each view and it used these landmarks to reconstruct the three-dimensional shape (D) of the individual face. Subsequently, the device projected
the reconstructed skin of the patient into a “flattened” image (F) showing the entire facial skin in a single bi-dimensional facial template. In this
planar reconstruction, the same spatial region (green squared patch) on different faces corresponded to the same anatomical region on all sub-
jects. At the end of this process, each patient image was converted into a series of about ten thousand ordered parameters that conveyed all in-
formation regarding anatomical skin pattern and texture useful for IGA classification. These numbers were then used to train the AI for automatic
acne grading (F). The author A.M. is depicted in the figure for the purpose of method illustration and she consents to publication of her images.
(A) (B) (C)
(D) (E)
(F)
Do Not Copy
Penalties Apply
converted into a long feature vector carrying an over-complete
representation with redundant information. In particular, the
planar images were converted into a hemoglobin/melanin color
tilayer perceptron network. The network contained two fully
connected hidden layers, one with 500 neurons and one with
100 neurons. The output layer contained a single neuron with
space,13,14 and from each patch and each color channel, several an identity activation function. The squared-loss was optimized
statistical measures were calculated: mean, standard deviation, using stochastic gradient descent, running 200000 iterations
skewness, kurtosis, and local binary pattern.15-16 A principal using batches of 50 instances. Thanks to this training, the AI
component analysis was performed on the entire dataset in “learned” to build up its own rules to determine which com-
order to reduce the dimension of the vector to ten thousand bination of these numbers was relevant for evaluating the IGA
values that represented the most discriminating features char- grade for the patient image. The validation dataset was then fed
acterizing the IGA class of each subject analyzed. The value of to the AI and its output was compared to the dermatologists
ten thousand was chosen to retain an average of 8 values (4 for ground truth.
first order momentum and 4 for local binary pattern) for each
patch and each channel. RESULTS
Since the AI outputs the IGA prediction as a continuous num-
The whole patient population was split into a 60% that was used ber, it can output also values outside the 0-4 numerical range.
as training dataset, 20% used as testing, and a remaining 20% Thresholds used for separating the five ordinal categories
of the patients used as validation data. The n-dimensional vec- were: clear: AI<0.5; almost clear: 0.5<AI<1.5; mild: 1.5<AI<2.5;
tor containing the numbers corresponding to patient of training moderate: 2.5<AI<3.5; severe: AI>3.5. The AI showed a global
dataset together with the IGA classification of the same patient accuracy of 0.854 in predicting the IGA based only on patient
performed by dermatologists (ground truth) were fed to a mul- images (Figure 2). The correlation between manual evaluation
1008
FIGURE 2. Distribution (violin plots) of patients according the IGA representation). In fact, while AI algorithms are superior to hu-
expressed by the dermatologists (horizontal axis) versus the IGA man in finding complex relations between the high number of
evaluated by AI (vertical axis). The AI showed an accuracy of 0.854 input parameters that can be extracted from digital images, it
in predicting the IGA based only on images of the patient (Spearman is however necessary for the classification that these numbers
r=0.958, P<0.001). are fed to the AI in a reproducible anatomical order that is the
same for each subject. The standardized planar flattening of
three-dimensional skin surface used in this work, allowed us
to translate the image parameters in an input that can be easily
interpreted by an AI algorithm.
A limitation of the present work is represented by the image

spectrum used for acquiring the images, that is restricted to the
visible light. In fact, it is known from the literature9,17 that more
information on acne lesions could be gathered using ultraviolet
(fluorescent) or infrared light. Indeed, it is probable that using a
wider spectral window both for illumination and for acquisition
will increase the observed accuracies, that are nevertheless
very high using visible light only. A similar argument holds for
the statistical parameters that we chose to employ to character-
ize each patch (ie, to convert each image patch in a series of
numbers).
Another limitation of this work consists in the uncertainty of the

and automatized IGA was r=0.958 (Spearman rank correlation, ground truth used. In fact, the IGA evaluation expressed by the
P<0.001). The accuracies for the different grades of IGA were dermatologist contains a percentage of error that is variable,
as follows: 0.977 for 0-clear; 0.852 for 1-almost clear; 0.806 for but that can be estimated from the literature10-12 at around 20%.
2-mild; 0.793 for 3-moderate; 0.863 for 4-severe. Indeed, within the 15% patients that our AI misclassified when
compared to the manual evaluation, there exists a large pro-
DISCUSSION
Do Not Copy
portion of subjects that after visual inspection seemed closer to
In this work we obtained a remarkable result for three reasons. the AI evaluation if compared to the physicians estimate.
In fact, this is the first time that an AI was able to directly clas-
sify acne patients according to an IGA ordinal scale with no Finally, we chose a deep neural network as AI, however other
Penalties Apply
human intervention and no need to count lesions. Second, the AIs or machine learning methods could be probably used with
accuracy observed is comparable to those reported for skilled similar success. Our choice was motivated by the ability of deep
physicians.10-12 Third, the algorithm was tested on a large da- neural network to build its own rules for classifying input data
taset comprising subjects belonging to three different ethnic into categories from the training dataset, without the need to
groups, suggesting that the observed results have a high gen- explicitly program these rules into the algorithm. In this frame-
eralizability. work, it could be certainly varied the AI neural network used
to interpret the input data, as well as the kind of image that is
Previous works7-9 using computerized processing of digital im- collected by the camera. In fact, future work will focus on fur-
ages in acne patients focused on the automatization of lesion ther increasing the accuracy obtained so far by expanding the
counting on small datasets. Although some of these works dataset and introducing images acquired with multiple devices.
reported good correlations between automated and manual
lesion counting, none of these methods can be used directly DISCLOSURE
to generate an estimate of IGA for a patient. In fact, a human Dr. Cherubini and Mr. Ngo Dinh are employees of Linkverse;
performing an IGA evaluation considers several other factors Dr. Thiboutot has served as a paid consultant to Linkverse.
not related to the lesion number,1-3,5 including if a lesion is in-
flammatory or non-inflammatory, the type of lesion (papules, REFERENCES
pustules, nodular lesions, etc.), the size and the lesion distri- 1. Agnew T., Furber G., Leach M. e al. A Comprehensive Critique and Review
of Published Measures of Acne Severity. J Clin Aesthet Dermatol, 2016;
bution within the areas considered. The key factor used in the 9(7):40-52.
present work that allowed an AI to mimic the human ability to 2. Layton, A.M., Eady, E.A., Thiboutot, D.M. et al., Acne Core Outcomes Re-
search Network (ACORN) Outcomes Identification Group. Identifying What
evaluate a qualitative ordinal scale such as the IGA is repre- to Measure in Acne Clinical Trials: First Steps towards Development of a
sented by the standardization of images used as input (planar Core Outcome Set. J Invest Dermatol. 2017 Aug;137(8):1784-1786. doi:
1009
10.1016/j.jid.2017.04.017.
3. Ramli, R., Malik, A. S., Hani, A. F. M. et al. Acne analysis, grading and com-
putational assessment methods: an overview. Skin Res Technol, 2012; 18:
1–14. doi:10.1111/j.1600-0846.2011.00542.x.
Now Available
4. Dréno B., Poli F., Pawin H. et al. Development and evaluation of a Global
Acne Severity Scale (GEA Scale) suitable for France and Europe. J Eur Acad
Dermatol Venereol, 2011; 25: 43–48. doi:10.1111/j.1468-3083.2010.03685.x.
5. Tan J1, Wolfe B, Weiss J et al. Acne severity grading: determining essential
clinical components and features using a Delphi consensus. J Am Acad Der-
matol. Aug 2012; 67(2):187-93. doi: 10.1016/j.jaad.2011.09.005. Epub 2011
Oct 27.
6. U.S. Department of Health and Human Services Food and Drug Administra-
tion. Guidance for Industry Acne Vulgaris: Developing Drugs for Treatment.
Center for Drug Evaluation and Research (CDER); 2005.
7. Malik, A. S., Humayun, J., Kamel, N. et al. Novel techniques for enhance-
ment and segmentation of acne vulgaris lesions. Skin Res Technol, 2014; 20:
322–331. doi:10.1111/srt.12122.
8. Min, S., Kong, H.-j., Yoon, C. et al. Development and evaluation of an auto-
matic acne lesion detection program using digital image processing. Skin
Res Technol, 2013; 19: e423–e432. doi:10.1111/j.1600-0846.2012.00660.x.
9. Patwardhan SV, Kaczvinsky JR, Joa JF et al. Auto-Classification of acne le-
sions using multimodal imaging. J Drugs Dermatol. 2013 Jul 1;12(7):746-56.
10. Beylot, C., Chivot, M., Faure, M. et al. Inter-observer agreement on acne
severity based on facial photographs. J Eur Acad Dermatol Venereol, 2010;
24: 196–198. doi:10.1111/j.1468-3083.2009.03278.x.
11. Foolad, N., Ornelas, J. N., Clark, A. K. et al. International inter-rater agree-
ment in scoring acne severity utilizing cloud-based image sharing of mobile
phone photographs. Int J Dermatol, 2017; 56: 920–925. doi:10.1111/ijd.13621.
12. Lucky AW, Barber BL, Girman CJ et al. A multirater validation study to assess
the reliability of acne lesion counting. J Am Acad Dermatol, 1996; Volume
35, Issue 4, 559 – 565
13. Liu Yang, Suk-Hwan Lee, Seong-Geun Kwon, Ha-Joo Song and Ki-Ryong
Kwon. Skin Pigment Recognition using Projective Hemoglobin- Melanin Co-
ordinate Measurements. J Electr Eng Technol.2016;11(6):1825-1838, http://
dx.doi.org/10.5370/JEET.2016.11.6.1825
14. Zhao Liu, Josiane Zerubia. Melanin and Hemoglobin Identification for Skin Managing Seborrheic Keratosis:
Disease Analysis. Asian Conference on Pattern Recognition (ACPR), Nov
2013, Okinawa, Japan. IEEE, 2013. Evolving Strategies and Optimal
15. S. Liao, Max W. K. Law, and Albert C. S. Chung. Dominant Local Binary Pat-
terns for Texture Classification. IEEE Trans Image Process, VOL. 18, NO. 5, Therapeutic Outcomes
May 2009.
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16. Di Huang, Caifeng Shan, Mohsen Ardebilian, Yunhong Wang, and Liming
Chen. Local Binary Patterns and Its Application to Facial Image Analysis: A
Survey. IEEE Trans. Syst., Man, Cybern. C; Volume: 41, Issue: 6, Nov. 2011.
17. Lucchina LC, Kollias N, Gillies R, et al. Fluorescence photography in the
evaluation of acne. J Am Acad Dermatol, 1996; Volume 35, Issue 1, 58 – 63.
Andrea Cherubini PhD

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E-mail:................….............. andrea.cherubini@linkverse.com
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for the healthcare team.

Copyright © 2018 BRIEF COMMUNICATION Journal of Drugs in Dermatology
SPECIAL TOPIC
A Comparative Analysis of Electric and Radiofrequency

Microneedling Devices on the Market
Tudor Puiu BS,a Tasneem F. Mohammad MD,b David M. Ozog MD,b Pranita V. Rambhatla MDb
University of Michigan Medical School, Ann Arbor, MI
Henry Ford Hospital Department of Dermatology, Detroit, MI
INTRODUCTION
M
icroneedling was first described in 1995 by Orent- such as the nose and skin adjacent to the lips and eyes.2 The
reich and Orentreich for the treatment of atrophic addition of radiofrequency technology to automated pens has
scars and wrinkles.1 The local injury induced by der- the advantage of utilizing insulated needles to deliver thermal
mal penetration of microneedling causes release of growth energy localized to a targeted depth. These devices are believed
factors such as transforming growth factor (TGF)-α, TGF-β, and to be safer in darker skin types as there is minimal to no dam-
platelet-derived growth factor (PDGF). This stimulates collagen age to the epidermis.2
and elastin fiber production as well as capillary formation, ul-
timately leading to tissue remodeling.2 Since its initial descrip- Commercially available automated microneedling device
tion in the literature, microneedling has been expanded to effec- brands include Réjuvapen™ (Refine USA, LLC), InnoPen™
tively treat a variety of cosmetic and dermatological conditions, (Clinical Resolution Laboratory, Inc.), Collagen P.I.N.™ (Induc-
including rhytides, scars, dyspigmentation, and hair patholo- tion Therapies™), and Eclipse MicroPen® (Salient Medical
gy.2 It should be noted that several of these studies were split Solutions). Considerations when choosing a brand include cost
face in nature. However, none directly compared microneedling of the pen and needle replacements, number of needles per de-
devices to each other. A benefit of microneedling is that an vice tip, and range of depths and speeds available (Table 1). The
intact epidermis is maintained, leading to minimal side effects, Réjuvapen, retailing at $2,495, is a corded device containing a
most commonly erythema and pinpoint bleeding. Tram-track tip with 3, 5, or 9 needles, varying in depth from 0.2-2.5 mm
scarring3 and granuloma formation when used in conjunction and functioning at four different speeds of up to 11,000 RPM.
Do Not Copy
with topical applications4 have been observed rarely. Since its The InnoPen is also a corded device, similarly priced at $2,499,
inception, microneedling technology has evolved from manual and contains a 13-needled tip with depth variation between
roller devices to automated devices, some of which have radio- 0-2 mm and five speed settings. The Collagen P.I.N., priced at
frequency technology. Here, we aim to provide a brief review $2,995, can function as a cordless device with a single speed
Penalties Apply
of the cost and technology, particularly of the newer micronee- setting or while corded with seven speeds up to 23,750 RPM,
dling electric and RF pen devices. No comparisons of efficacy and is available with either 12 or 36 needles in depths varying
are possible with current published research. between 0-3 mm. The Eclipse MicroPen, retailing at $3,500, is
a cordless device that utilizes 12 needles functioning at a set
DISCUSSION speed of 6,900 RPM with fixed depth of 2 mm. It is worthwhile
There are currently multiple microneedling devices being noting that while needle penetration up to 1mm is accurate, ac-
utilized in clinical practice. Three broad categories include tual achieved depths past this threshold can be more variable.5
the traditional manual rollers (eg, Dermaroller®, Cynergy®),
automated pens, and automated pens with combined RF tech- Radiofrequency microneedling devices are more costly than
nology. The Dermaroller is a hand-held device with 192 needles traditional electric microneedling pens. Currently available
of fixed length, varying in depth from 0.5-3 mm with a diam- devices include the Infini™ (Lutronic), which has 49 bipolar
eter of 0.1-0.25 mm, loaded on a cylindrical roller. The ultimate needles functioning at depths of 1-3.5 mm and three separate
penetration depth achieved with a Dermaroller is variable and intensities. The Infini retails for $60,000, a cost that includes 10
dependent on pressure application by the user. In contrast, au- needles, with a price of $95 per needle tip replacement. The
tomated pens utilize a disposable tip with varying numbers of Profound® (Syneron Medical Ltd.) is the most expensive de-
needles hidden inside a guide, which can be set to cycle at dif- vice at $114,900 and is the only one to combine fractionated
ferent frequencies. The guide allows for safer application and radiofrequency with traditional microneedling. It includes two
disposable needles allow for pen reusability. An advantage of separate sets of bipolar needles for both dermal and sub-cuta-
automated pens is that needle lengths are adjustable and the neous penetration. To target the dermis, the device uses 5 pairs
depth of penetration is not user-dependent. The relatively small of needles at a depth range of 1-2 mm, with a cost $2,100 for a
tip size allows for treatment of anatomically challenging areas, set of 6. For sub-cutaneous penetration, the device utilizes a set
1011
Journal of Drugs in Dermatology T. Puiu, T. Mohammad, D. Ozog, and P. Rambhatla
TABLE 1.
Specifications of Traditional Electric and RF Pen Microneedling Devices
Speeds/
Needle Needle Range of Anti- Return
Brand Price Warranty Fre- Other
Cost Number Depths suctin Policy
quency
Traditional Electric MN Pens
Réjuvapen™ $2,495 1 year $250 for a Available 0.2-2.5 mm Four total Represen- No infor- Sales
with no box of 10 with 3, speeds tative will mation are final
need to needles 5, or 9 (11,000 demonstrate available
fill out needles RPM the device
any forms max)
InnoPen™ $2,499 Lifetime $480 for a 13 0-2 mm Five Made in USA Yes 30-day
(must box of 24 needles by 0.1 mm speeds with ease return
pay for open tips increments with half- of supply policy
shipping (faster) or notch delivery
and closed tips intervals
handling), (decreased in
must risk of PIH, between
fill out safer)
warranty
form
Collagen $2,995 Lifetime $672 for a Available 0-3 mm, by Single Available as Yes Can return
P.I.N.™ with no box of 24 with 12 0.25 mm speed cordless or product
need to needles or 36 increments with corded. in original
fill out for the 12 needles battery; packaging
any forms pin tip; Seven Training with 10 day
$768 for a speeds available and notification
box of 24 corded represen- within 21
needles (10,250 tative can days of
for the 36 – 23,750 demonstrate. purchase
Eclipse
MicroPen®
$3,500
(includes
Lifetime
with
Do Not Copy
pin tip
$876.60
for 24
12
needles
2.0 mm
RPM)
One
speed
Representative
will
Yes Can return
product
Penalties Apply
24 tips) purchase treatment (6900 demonstrate though re-
of two kits or RPM); stocking
boxes of $487 for available fee of 15-
tips per 12 kits as 20% may
quarter, (one cordless apply and
otherwise treatment only (two requires
1 year; kit batteries approval
must includes provided)
fill out needle
warranty cartridges,
form numbing
product,
Hyaluronic
Acid
serum,
and
needle
protective
sheath)
1012
Needle Needle Range of Speeds/ Anti- Return

Brand Price Warranty Other
Cost Number Depths Frequency suctin Policy
Radiofrequency MN Devices
Infini™ $60,000 One year $95 per 49 bipolar 1-3.5 mm 3 different A day of No infor- Sales
warranty tip (10 tips needles in intensities training for mation are final
included included a 7x7 array (low, providers is available
with with initial medium, included in
purchase purchase) high) the device
with price
option of
purchasing
extended
warranty
Vivace™ $95,500 One year $75 per 36 needles 0.5-3.5 Variable In-service No infor- Sales
warranty needle available mm pulse training mation are final
included (ten micro- as durations included available
with needling insulated (100 ms- with device
purchase; kits and non- 800 ms) purchase
additional included insulated
years with Blue and red
can be purchase) LED lights
purchased included with
at $5,000 purchase
per year
Profound® $114,900 Three year $2,100 for 5 pairs of 1-2 mm 460 KHz +/- Device No infor- Sales
warranty pack of bipolar for dermal 5 KHz specialist mation are final
included 6 dermal needles needles available available
Do Not Copy
with single for dermal
purchase cartridges depth; 2.9-5.8 Evidence
7 pairs mm for of elastin
$2,700 for sub- sub- production
for pack cutaneous cutaneous with device
Penalties Apply
of 6 sub- depth needles use
cutaneous
cartridges Only device
on market
to currently
combine
fractionated
RF with
micro-
needling
1013
Needle Needle Range of Speeds/ Anti- Return
Brand Price Warranty Other
Cost Number Depths Frequency suctin Policy
Radiofrequency MN Devices
Fractora™ No infor- No infor- No infor- 24 or 60 0.6-3 mm 1MHz No infor- No infor- No infor-
mation mation mation needles mation mation mation
available available available if tips are available available available
uncoated;
24 needles
if tips are
coated
INTRAcel™ $75,000 1 year or Needle 49 insulated 0-4 mm 1MHz Both No infor- Return
multi-year cost is needles bipolar and mation possible
depending dependent monopolar available if device
on on the modes does not
contract contract available; meet
unique active specifi-
impedance cations
monitoring
system to
optimize
energy
delivered
*All device pricing is up to date at time of writing of this article in December 2017.
Do Not Copy
of 7 needles at a target depth range of 2.9-5.8 mm, with needle
replacement cost at $2,700 for a set of 6. The device delivers en-
ergy at a frequency of 460 KHz +/- 5 KHz. The INTRAcel™ device
and combined RF pens have allowed for devices that are safer
and more effective.
Penalties Apply
(Perigree™), retailing for $75,000, utilizes 49 insulated needles DISCLOSURES
that can function as either a unipolar or bipolar device. Cost of None of the authors have any financial disclosures.
needle replacement is variable based on the contract. The IN-
TRAcel functions at a frequency of 1 MHz and utilizes a unique REFERENCES
impedance monitoring system to optimize energy delivery. The 1. Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) sur-
gery for the correction of depressed scars and wrinkles. Dermatol Surg.
Vivace™ (Aesthetics Biomedical, Inc.), retailing for $95,500, a 1995;21(6):543-549.
cost that includes 10 needle kits, utilizes a 36 needle at a depth 2. Singh A, Yadav S. Microneedling: Advances and widening horizons. Indian
Dermatol Online J. 2016;7(4):244-254.
range of 0.5-3.5 mm. The needles can be purchased as insulated 3. Pahwa M, Pahwa P, Zaheer A. "Tram track effect" after treatment of acne
or non-insulated and replacement cost is $75 per needle. Other scars using a microneedling device. Dermatol Surg. 2012;38(7 Pt 1):1107-
1108.
devices, such as the Fractora™ (InMode Aesthetic Solutions), 4. Soltani-Arabshahi R, Wong JW, Duffy KL, Powell DL. Facial allergic granu-
are also currently available on the market, though limited in- lomatous reaction and systemic hypersensitivity associated with micronee-
dle therapy for skin rejuvenation. JAMA Dermatology. 2014;150(1):68-72.
formation is available with regards to device specification and 5. Sasaki GH. Micro-Needling Depth Penetration, Presence of Pigment Par-
cost without scheduling an in-person representative visit. Infor- ticles, and Fluorescein-Stained Platelets: Clinical Usage for Aesthetic Con-
cerns. Aesthet Surg J. 2017;37(1):71-83.
mation regarding warranty, return policy, and demonstration
are also important when making a decision on which device to AUTHOR CORRESPONDENCE
purchase (Table 1).
Tudor Puiu BS
CONCLUSION E-mail:................……......................................tudorp10@gmail.com
Evidence for the effectiveness of microneedling in treating vari-
ous dermatologic conditions is rapidly expanding and its use
is increasing. Technological advances in the form of automated
We’ve
Moved!
ODAC
SAVE the DATE
ODAC is the premier annual CME conference
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expertly curated to provide comprehensive, annual
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updates and Apply
fresh pearls in medical, aesthetic and
surgical dermatology.
Orlando Dermatology Aesthetic & Clinical Conference

JANUARY 18-21, 2019
JW MARRIOTT | ORLANDO, FL
ORLANDODERM.ORG

Copyright © 2018 BRIEF COMMUNICATION Journal of Drugs in Dermatology
SPECIAL TOPIC
Facial Volumetric Structural Rejuvenation: A Natural Approach

to Restoring Youthfulness and Preventing Aging
Neil Sadick MD
Weill Cornell Medical College, Cornell University, New York, NY
Sadick Dermatology and Research, New York, NY
W
hen rejuvenating the face with soft tissue fillers, Following these injections, three supportive ligament sites
one must consider its structural framework, and are marked and filler is placed in the deep dermis to provide
patient specific goals/needs holistically to achieve fibrous fixation points and restrain the facial skin against gravi-
natural results.1-3 I have developed a distinct methodology tational changes: the pyriform (superior part nasolabial fold),
called volumetric structural rejuvenation (VSRTM), that can be the modiolus (lateral to the inferior part of nasolabial fold), and
applied to both genders and all ages.4-5 My ultimate goal is to McGregor’s patch (posterior to the zygomaticus minor muscle).
deliver true to life and form results amalgamated in my pa-
tient’s look. The benefits of VSR are a) minimal patient discom- The final step of VSR involves dermal/subcutaneous injections
fort, b) no incisions, c) no downtime. I have treated hundreds to customize facial contouring and focal points depending on
of patients with VSR and results are durable, require minimal the physician’s assessment of patient’s anatomy and individual-
touchups, and reflect on an overall glow/radiance due to the ized goals. These include focal injections in sites of superficial
biological properties of the fillers. lipoatrophy, injections to contour the face and soften any sharp
angles (particularly the jawline area), and injections towards
The first step to volumetric structural rejuvenation is to place the hairline for lateral vectoring. This last step of customiza-
the fillers supra-periosteally to lay the foundation of the up- tion requires an intimate communication, prior to treatment,
per, mid, and lower face. The goal is to replete volume loss between the patient and physician. As a provider, I make sure to
due to deflation of the temporal, preauricular lateral cheek, describe all available options, for example tapered vs rounded
mid-cheek, and mandibular fat pads and to address mus- cheek, for optimal results.8
culoskeletal atrophy.4,6,7 The three key access points of
Do Not Copy
injections are the temporal fossa, the midface, and the jawline. Finally, as different patients, regardless of their age, present
varying levels of lipoatrophy, the VSR technique can be readily
modified to adapt to the needs of the patient for panfacial struc-
tural rejuvenation. Beginning the VSR program early is central
Penalties Apply
FIGURE Bimodal trivector approach for volumetric structural to age prophylaxis and ensuring skin health.
rejuvenation (VSRTM). The three trivector sites for supraperiosteal
injections are depicted (arrows) in the temporal fossa (to address REFERENCES
forehead atrophy, brow ptosis), the midface (to address tear trough, 1. Fitzgerald, R. and A.G. Rubin, Filler placement and the fat compartments.
infranasal, mid/lateral cheek fat), and the jawline (mandibular angle, Dermatol Clin, 2014. 32(1):37-50.
maxilla, marionette lines). The injection sites for ligament support (red 2. Greco, T.M., M.B. Antunes, and S.A. Yellin, Injectable fillers for volume re-
dots) are the (1) McGregor’s patch (posterior to the zygomaticus minor placement in the aging face. Facial Plast Surg, 2012. 28(1):8-20.
3. Solish, N., The aging face: global approach with fillers and neuromodulators.
muscle), (2) pyriform aperture (superior part nasolabial fold), and (3) Semin Cutan Med Surg, 2016. 35(6 Suppl):S120-1.
modiolus (lateral to the inferia part of nasolabial fold). Customized 4. Sadick, N.S., et al., The Facial Adipose System: Its Role in Facial Aging and
dermal/subcutaneous injections according to individual anatomy, Approaches to Volume Restoration. Dermatol Surg, 2015. 41 Suppl 1:S333-9.
patient goals, and needs follow the trivector/ligament site injections. 5. Sadick, N.S., S. Manhas-Bhutani, and N. Krueger, A novel approach to struc-
tural facial volume replacement. Aesthetic Plast Surg, 2013. 37(2):266-76.
6. Kruglikov, I., et al., The Facial Adipose Tissue: A Revision. Facial Plast Surg,
2016. 32(6):671-682.
7. Sandoval, S.E., et al., Facial fat compartments: a guide to filler placement.
Semin Plast Surg, 2009. 23(4):283-7.
8. Shamban, A., Customized Approach to Facial Enhancement. Facial Plast
Surg Clin North Am, 2015. 23(4):471-7.
Neil Sadick MD
E-mail:................…….............. nssderm@sadickdermatology.com
I have created a comprehensive online

education and training course that will
improve the efficiency
and competency
of your nurses and physician assistants.
This program will save you the time and
burden of initial training and increase
the skills to assist you in common
office surgical and cosmetic procedures.
Perry Robins, MD
Advanced Training
in Dermatology
www.dermtraining.com
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Optimize your practice efficiency & increase patient
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satisfaction through staff training & development
• 40 hours of self-paced online training for RNs, NPs, PAs, & MAs
• Certificate of Completion & 15 Continuing Education*
credits available
CONTACT INFORMATION
Email: admin@dermtraining.com • Call: 904-494-8389
www.dermtraining.com
Continuing education credits jointly provided with Creighton University Health Sciences

Copyright © 2018 LETTERS TO THE EDITOR Journal of Drugs in Dermatology
Erratum
Dear Editor,
I
n the article that appeared in the March 2018 issue, Intra-
muscular Steroids in the Treatment of Dermatologic Dis-
ease: A Systematic Review, there was an error in the author-
ship line. The authorship line should read:
Logan W. Thomas MS4,a Ashley Elsensohn MD MPH,a

Aaron Secrest MD PhD,b Terese Bergheim MD,a
Jessica Shiu MD PhD,a Anand Ganesan MD PhDa
a
Department of Dermatology, University of California Irvine, Irvine, CA
b
Dermatology and Population Health Sciences, University of Utah,
Salt Lake City, UT
Sincerely,
Ashley Elsensohn MD MPH
References
1. Thomas LW, Elsensohn A, Bergheim T, et al. Intramuscular Steroids
in the Treatment of Dermatologic Disease: A Systematic Review.
4 REASONS TO Find us on Facebook, Instagram

J Drugs Dermatol. 2018;17(3):323-329.
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Copyright © 2018 LETTERS TO THE EDITOR Journal of Drugs in Dermatology
Approach to Skin Lightening

in Patients With Melasma
Philip R. Cohen MD
Department of Dermatology, University of California San Diego, La Jolla, CA
I
read with interest the informative article by Spencer et al1 that TABLE 1.
describes the efficacious use as a novel skin lightening agent
Novel Topical Approach for Melasma Managementa
(LumaPro-C) for the treatment of patients with melasma. The
topical preparation contains not only a resurfacing peptide with 2-Drug 3-Drug 4-Drug
Drug
therapy therapy therapy
stabilized vitamin C and botanicals (including resveratrol, daisy
and pine extracts, and ginger extract), but also an encapsulated Anti-estrogenb x x x
plankton extract and a probiotic regulator. The components of VEGF inhibitor c
x x x
the researchers’ preparation promoted skin lightening by exfo- Hydroquinoned x x
liation, impeding melanogenesis, and reducing inflammation.
Sunscreen e
x
Seventeen women with facial melasma used the LumaPro-

C cream and sunscreen on one side of their face and a a
Abbreviations: VEGF, vascular endothelial growth factor.
placebo preparation and sunscreen on the other side of
b
The anti-estrogen therapy may include either a selective
estrogen receptor modulator (such as tamoxifen or raloxifen)
their face for eight weeks. The investigators observed an
or an aromatase inhibitor (such as anastrozole or letrozole or
objective decrease in hyperpigmentation on the treat- exemestane) or a selective estrogen receptor degrader (such as
ed side versus the control side: 14.60 percent as com- fulvestrant).
pared to 9.82 percent. There was no significant irritation.1 c
The VEGF inhibitor would be bevacizumab.
d
The hydroquinone could be a 4 percent preparation.
e
The sunscreen would be a physical sunscreen containing either
The topical management of melasma usually incorporates the
zinc oxide or titanium dioxide or both.
use of sunscreen. Spencer et al1 also included sunscreen as
a topical adjuvant agent for the women they treated. How-
Disclosure
Do Not Copy
ever, since 1975 when Drs. Kligman and Willis described
their topical formula (which included 5% hydroquinone, 0.1% The author has no financial relationship with industry or poten-
tretinoin, and 0.1% dexamethasone) for depigmenting hu- tial perceived conflicts of interest as relevant to the manuscript.
man skin, other topical agents have been concurrently or
Penalties Apply
separately used to treat melasma with variable success.2 References
1. Spencer JM, Accioly J, Kitchen N. Double blind, placebo controlled evalu-
ation of a novel skin lightening agent. J Drug Dermatol 2018;17:113-115.
Similar to Spencer et al, I recently proposed a novel topical
1
2. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch
Dermatol 1975;111:40-48.
approach for the management of melasma for which the active 3. Cohen PR. Melasma treatment: A novel approach using a topical agent that
agents target etiologic factors in the pathogenesis of the condi- contains an anti-estrogen and a vascular endothelial growth factor inhibitor.
Med Hypotheses 2017;101-1-5.
tion: estrogen and angiogenesis.3 Specifically, the topical agent
contains an anti-estrogen and a vascular endothelial growth AUTHOR CORRESPONDENCE
factor inhibitor. In addition to this double-drug topical therapy,
triple-drug (by adding hydroquinone) and quadruple-drug (by Philip R. Cohen MD
also adding a sunscreen) therapy may be provided (Table 1). E-mail:................……......................................mitehead@gmail.com
In conclusion, new topical agents and physical modalities

continue to expand the therapeutic armentarium for manag-
ing patients with melasma. Individual and combination topi-
cal treatments directed at various etiologic factors of melasma
may provide greater success in achieving depigmentation. The
concurrent use of my novel topical agent and that of Spencer et
al1 may warrant further investigation to improve the observed
skin depigmentation in melasma patients.
B:8.625”
Previous Page | Contents | Zoom In | Zoom
T:7.875” Out | Search Issue | Cover | Next Page
S:7”
IMPORTANT INFORMATION ABOUT • Intestine infection (pseudomembranous colitis). Pseudomembranous colitis can
Oracea® happen with most antibiotics, including ORACEA Capsules. Call your doctor right
(doxycycline, USP) 40 mg* Capsules away if you get diarrhea or bloody stools.
*30 mg Immediate Release & 10 mg Delayed Release Beads • Immune system reactions including a lupus-like syndrome, hepatitis, and
inflammation of blood or lymph vessels (vasculitis). Stop taking ORACEA Capsules
BRIEF SUMMARY and tell your doctor right away if you get joint pain, fever, rash or body weakness.
This summary contains important information about ORACEA (Or-RAY-sha) Capsules. • Discoloration (hyperpigmentation). ORACEA Capsules can cause darkening of
It is not meant to take the place of your doctor’s instructions. Read this information your skin, scars, teeth, gums, nails, and whites of your eyes.
carefully before you start taking ORACEA Capsules. Ask your doctor or pharmacist • Benign intracranial hypertension, also called pseudotumor cerebri. This is a
if you do not understand any of this information or if you want to know more about condition where there is high pressure in the fluid around the brain. The swelling
ORACEA Capsules. For full Prescribing Information and Patient Information please see may lead to vision changes and permanent vision loss. Stop taking ORACEA
the package insert. Capsules and tell your doctor right away if you have blurred vision, vision loss, or
WHAT IS ORACEA CAPSULES? unusual headaches.
ORACEA Capsules are a tetracycline class medicine. ORACEA Capsules are a prescription The most common side effects of ORACEA Capsules include: soreness in the nose
medicine to treat only the pimples or bumps (papules and pustules) caused by a and throat, diarrhea, sinus infection, stomach (abdominal) bloating or pain, fungus
condition called rosacea. ORACEA Capsules do not lessen redness caused by rosacea. infection, high blood pressure (hypertension), flu-like symptoms, and change in
ORACEA Capsules should not be used for the treatment or prevention of infections. certain blood tests.
It is not known if ORACEA Capsules are effective for use for longer than 16 weeks, Tell your doctor if you have any side effect that bothers you or does not go away.
safe for use longer than 9 months, or safe and effective in children. ORACEA Capsules These are not all the possible side effects of ORACEA Capsules. For more information,
should not be used in infants and children less than 8 years of age because it may ask your doctor or pharmacist.
cause stained teeth in infants and children.
Call your doctor for medical advice about side effects. You may report
WHO SHOULD NOT TAKE ORACEA CAPSULES? side effects to FDA at 1-800-FDA-1088. You may also report side effects to
Do not take ORACEA Capsules if you are allergic to doxycycline or other medicines in GALDERMA LABORATORIES, L.P. at 1-866-735-4137.
the tetracycline class. Ask your doctor or pharmacist for a list of these medicines if HOW SHOULD I TAKE ORACEA CAPSULES?
you are not sure.
• Take ORACEA Capsules exactly as prescribed by your doctor. Taking more than your
WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING ORACEA CAPSULES? prescribed dose may increase your chance of side effects, including the chance that
Before you take ORACEA Capsules tell your doctor if you: bacteria will become resistant to ORACEA Capsules.
• have kidney problems. • Take ORACEA Capsules 1 time a day in the morning on an empty stomach.
• have liver problems. • You should take ORACEA Capsules at least one hour before or two hours after a meal.
• have diarrhea or watery stools. • Take ORACEA Capsules with enough fluid to completely swallow the capsule and to
• have vision problems. lower your risk of getting irritation or ulcer in your esophagus. Your esophagus is
• have had surgery on your stomach (gastric surgery). the tube that connects your mouth to your stomach.
• have or had a yeast or fungal infection in your mouth or vagina. • If you took too much ORACEA Capsules, call your doctor right away.
• have any other medical condition. • Your doctor may do blood tests during treatment with ORACEA Capsules to check
• are pregnant or planning to become pregnant. ORACEA Capsules may harm your for side effects.
unborn baby. Taking ORACEA Capsules while you are pregnant may cause serious WHAT SHOULD I AVOID WHILE TAKING ORACEA CAPSULES?
side effects on the growth of bone and teeth of your baby. Stop taking ORACEA • Avoid sunlight or artificial sunlight, such as a tanning booth or sunlamp. You could
Capsules and call your doctor right away if you become pregnant while taking get severe sunburn. Use sunscreen and wear clothes that cover your skin while out
ORACEA Capsules. in sunlight.
• are breastfeeding or plan to breastfeed. ORACEA Capsules can pass into your breast
milk and may harm your baby. Talk to your doctor about the best way to feed your HOW SHOULD I STORE ORACEA CAPSULES?
baby if you take ORACEA Capsules. You and your doctor should decide if you will • Store ORACEA Capsules at room temperature between 59ºF to 86ºF (15ºC to 30ºC).
take ORACEA Capsules or breastfeed. You should not do both. • Keep ORACEA Capsules in a tightly closed container.
You should not take ORACEA Capsules if you are male with a female sexual partner • Keep ORACEA Capsules inside container and out of light.
who plans to become pregnant at any time while you are being treated with ORACEA Keep ORACEA Capsules and all medicine out of the reach of children.
Capsules.
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GENERAL INFORMATION ABOUT ORACEA CAPSULES
Tell your doctor about all of the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. ORACEA Capsules and Medicines are sometimes prescribed for purposes other than those listed in a Patient
other medicines can affect each other causing serious side effects. Information leaflet. Do not take ORACEA Capsules for a condition for which it was not
prescribed. Do not give ORACEA Capsules to other people, even if they have the same
Especially tell your doctor if you take: symptoms you have. It may harm them.
Penalties Apply
• birth control pills. ORACEA Capsules may reduce the effectiveness of birth control This Brief Summary summarizes the most important information about ORACEA
pills. Talk to your doctor about what types of birth control you can use to prevent Capsules. If you would like more information, talk with your doctor. You can also ask
pregnancy while taking ORACEA Capsules. your doctor or pharmacist for information that is written for health professionals.
• a blood thinner medicine
• a penicillin (antibacterial medicine). WHAT ARE THE INGREDIENTS IN ORACEA CAPSULES?
• proton pump inhibitors or antacids that contain aluminum, calcium, or magnesium. Active ingredient: doxycycline. Inactive ingredients: hypromellose, iron oxide red, iron
• products containing iron or bismuth subsalicylate. oxide yellow, methacrylic acid copolymer, polyethylene glycol, Polysorbate 80, sugar
• a medicine taken by mouth that contains isotretinoin or acitretin. spheres, talc, titanium dioxide, and triethyl citrate.
• a medicine to treat seizures, such as carbamazepine or phenytoin. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT ORACEA CAPSULES?
Ask your doctor or pharmacist for a full list of your medicines, if you are not sure. • Talk to your doctor or pharmacist
Know the medicines you take. Keep a list of your medicines and show it to your doctor • Go to www.oracea.com or call 1-866-735-4137
and pharmacist when you get a new medicine. GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA
WHAT ARE THE POSSIBLE SIDE EFFECTS OF ORACEA CAPSULES? Revised: August 2013
ORACEA Capsules may cause serious side effects, including:
• Harm to an unborn baby. See “What should I tell my doctor before taking
ORACEA Capsules?”
• Permanent teeth discoloration. ORACEA Capsules may permanently turn a baby Reference: 1. Data on file. Galderma Laboratories, L.P.
or child’s teeth yellow-grey-brown during tooth development. ORACEA Capsules
should not be used during tooth development. Tooth development happens in the
last half of pregnancy, and from birth to 8 years of age. See “What should I tell my
doctor before taking ORACEA Capsules?”
All trademarks are the property of their respective owners.

TRICARE is a registered trademark of the Department of Defense (DoD), DHA.
All rights reserved.
©2017 Galderma Laboratories, L.P.
Galderma Laboratories, L.P. ®
14501 N. Freeway
Fort Worth, TX 76177
ORA-00073 Printed in USA 01/17 hcp.oracea.com
T:7.875”
Previous Page | Contents | Zoom In | Zoom
S:7” Out | Search Issue | Cover | Next Page
The only FDA-approved oral formulation for the inflammatory lesions of rosacea.
Prescribe Oracea® (doxycycline, USP) 40 mg Capsules for a
Dose of Precision
The specifically engineered, time-released

microbead formulation delivers immediate and sustained
anti-inflammatory efficacy in a non-antibiotic dose.1*
Do Not Copy
In 2 pivotal clinical studies, the most common treatment-related adverse events (>2%)
were nasopharyngitis (4.8%), diarrhea (4.5%), hypertension (3.0%),
sinusitis (2.6%), and aspartate aminotransferase increase (2.2%).
Penalties Apply
Oracea Capsules are precisely formulated for powerful control.
Learn more at www.oracea.com/hcp.
The Galderma CareConnect Patient Savings Card Helps Make Treatment More Affordable†
*A multicenter, outpatient, double-blind, placebo-controlled, parallel-group trial was Warnings/Precautions: ORACEA Capsules should not be used to
conducted over 16 weeks to evaluate the safety and efficacy of Oracea Capsules. A treat or prevent infections. ORACEA Capsules should not be taken
total of 251 rosacea patients (≥18 years of age with 10 to 40 papules and pustules
and ≤2 nodules, plus an Investigator’s Global Assessment [IGA] score of 2 to 4) by patients who have a known hypersensitivity to doxycycline or
participated. other tetracyclines. ORACEA Capsules should not be taken during
†
Restrictions apply. Patients are not eligible if enrolled in Medicare Part D, Medicaid, pregnancy, by nursing mothers, or during tooth development (up to
Medigap, VA, DoD, TRICARE® or any other government-run or government-sponsored
health care program with a pharmacy benefit, or where prohibited by law. Please see the age of 8 years). Although photosensitivity was not observed in
Galderma CareConnect savings card for details. clinical trials, ORACEA Capsules patients should minimize or avoid
Important Safety Information exposure to natural or artificial sunlight. The efficacy of ORACEA
Indication: ORACEA® (doxycycline, USP) 40 mg‡ Capsules are indicated Capsules treatment beyond 16 weeks and safety beyond 9 months
for the treatment of only inflammatory lesions (papules and pustules) have not been established.
of rosacea in adult patients. ORACEA Capsules do not lessen the facial You are encouraged to report negative side effects of prescription
redness caused by rosacea.
drugs to the FDA. Visit www.fda.gov/Safety/MedWatch or call
Adverse Events: In controlled clinical studies, the most commonly 1-800-FDA-1088.
reported adverse events (>2%) in patients treated with ORACEA
30 mg immediate release & 10 mg delayed release beads.
‡
Capsules were nasopharyngitis, sinusitis, diarrhea, hypertension and
aspartate aminotransferase increase. Please see brief summary of Prescribing Information on adjacent page.

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ISSN: 1545 9616 September 2018 • Volume 17 • Issue 9

Men’s Trends in Aesthetic Treatment

Scar Treatment With Botulinum Toxin

Vacuum-Assisted Subcision of Cellulite

A I for Evaluation of Acne

ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

ALL ABOARD ONEXTON GEL

INSTANT SAVINGS FOR ELIGIBLE PATIENTS AT ORTHORXACCESS.COM

INDICATION Do Not Copy

LEARN MORE AT ONEXTON.COM

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION Neuromuscular Blocking Agents

September 2018 924 Volume 17 • Issue 9

SENIOR ASSOCIATE ASSOCIATE EDITORS Neil Alan Fenske MD Ariel Ostad MD

Dr. Linda Stein Gold began serving as one of

Hear from 2017 winner Robby Ruffolo at aspirehigherscholarships.com

Ortho Dermatologics is a trademark of Ortho Dermatologics’ affiliated entities.

September 2018 926 Volume 17 • Issue 9

Special FocuS: aeStheticS

956 Penalties Apply

960 Three-Dimensional Analysis of Minimally Invasive Vacuum-Assisted Subcision

970 A Randomized, Double-Blind, Placebo-Controlled, Split-Face Study of the Efficacy

POWERFUL, UNIQUE AND CLINICALLY

Help your skin protect itself from the harmful

Free radicals can accelerate skin aging.

Free radicals are everywhere. Sun exposure,

help Providing free radicals with

Use Heliocare daily to promote more

September 2018 928 Volume 17 • Issue 9

ORIGINAL ARTICLES (CONTD)

982 Using a New Photo Scale to Compare Product Integration of Different

1015 Facial Volumetric Structural Rejuvenation: A Natural Approach to Restoring

September 2018 930 Volume 17 • Issue 9

LETTER TO THE EDITOR

1018 Approach to Skin Lightening in Patients With Melasma

Publishers Associate Publisher

Associate Editor Design

REPRINTS & PERMISSIONS: Contact Luz Figueroa at 646-736-4338

SUBSCRIPTIONS: Email info@jddonline.com or call 212-213-5434 ext. 4

POSTMASTER: Send address changes to the Journal of Drugs in Dermatology,

Journal of Drugs in Dermatology (JDD)

© 2018 Journal of Drugs in Dermatology

September 2018 931 Volume 17 • Issue 9

MANAGING SEBORRHEIC KERATOSIS: EVOLVING STRATEGIES AND OPTIMAL THERAPEUTIC OUTCOMES

• Discuss developments in topical treatment options for SK

• Develop a new clinical approach to SK management

• Formulate effective and cost-efficient SK treatment plans

September 2018 932 Volume 17 • Issue 9

The faculty/authors have disclosed the following relationships

The planning committee of this activity have disclosed the

Disclosure of Unlabeled Use: This educational activity may

September 2018 933 Volume 17 • Issue 9

Managing Seborrheic Keratosis: Evolving Strategies and

J Drugs Dermatol. 2018;17(9):933-940.

(A) (B) (C) (D) (E)

(A) (B) (C) (D) (E)

(F) (G) Do Not Copy (H) (I) (J)

9. Vachiramon V, Thadanipon K. Postinflammatory hypopigmentation. Clin Exp

September 2018 939 Volume 17 • Issue 9

5. What are the most sensitive epidermal cells to severe

a. Trichloroacetic acid a. Keratinocytes

3. What is a well-documented adverse event associated

September 2018 940 Volume 17 • Issue 9