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Contents | Zoom In | Zoom Out | Search Issue | Next Page

ISSN: 1545 9616 June 2018 • Volume 17 • Issue 6

JDD
SPECIAL FOCUS:
ACNE AND
ROSACEA
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Image credit page 606

Penalties Apply
Biologically Based Approach to Acne and Rosacea

Frequency of Treatment Switching in Women With Acne

Expert Consensus Suture Technology for Facial Recontouring

Using Thermal Spring Water

National Survey of Medical Coding and Billing Training

Importance of Psychosocial Therapy in Vitiligo

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

ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

ACNE CAN LEAVE HER

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Copy FOR LIFE
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This June, during Acne Awareness Month,
remember Epiduo® Forte (adapalene and benzoyl peroxide) Gel 0.3%/2.5%
reduces acne lesions and the risk of scarring for results your patients can see.1

Important Safety Information

Indication: Epiduo® Forte (adapalene and benzoyl peroxide) Gel, 0.3%/2.5% is indicated for the topical treatment of acne vulgaris.
Adverse Events: In the pivotal study, the most commonly reported adverse reactions (≥1%) in patients treated with Epiduo Forte Gel
were skin irritation, eczema, atopic dermatitis, and skin burning sensation. Warnings/Precautions: Patients using Epiduo Forte Gel
should avoid exposure to sunlight and sunlamps and wear sunscreen when sun exposure cannot be avoided. Erythema, scaling, dryness,
stinging/burning, irritant and allergic contact dermatitis may occur with use of Epiduo Forte Gel and may necessitate discontinuation.
When applying Epiduo Forte Gel, care should be taken to avoid the eyes, lips and mucous membranes.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/Safety/MedWatch or
call 1-800-FDA-1088.

www.epiduoforte.com/hcp

A two-phase, randomized, multicenter, investigator-blinded, vehicle-controlled trial evaluating once-daily

Epiduo Forte Gel compared moderate to severe acne subjects 16 to 35 years old with a clinical diagnosis of
moderate to severe acne vulgaris on the face (deﬁned by IGA score of 3 or 4, with the same score on both
sides); a minimum of 25 inﬂammatory lesions (papules and pustules) in total, with at least 10 on each side
(excluding the nose); and no more than 2 acne nodules (≥1 cm); and ≥10 atrophic acne scars in total (>2 mm),
excluding the nose. Phase 1 was a split-face, 24-week, investigator-blinded, vehicle-controlled evaluation (N=67)
at 8 visits (baseline, weeks 1, 4, 8, 12, 16, 20, and 24). Phase 2 was a whole-face, open-label observation with
2 visits. Primary endpoint was scar count.1
Please see brief summary of full Prescribing Information on next page. A CLEARER TOMORROW STARTS TODAY
8.25”
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

IMPORTANT INFORMATION ABOUT

EPIDUO® FORTE
(adapalene and benzoyl peroxide) GEL, 0.3% / 2.5%

BRIEF SUMMARY WHAT ARE THE MOST COMMON SIDE EFFECTS OF

This summary contains important information about EPIDUO FORTE EPIDUO FORTE GEL?
(Ep-E-Do-Oh For-Tay) Gel. It is not meant to take the place of your doctor’s EPIDUO FORTE Gel may cause serious side effects including:
instructions. Read this information carefully before you start using EPIDUO • Local skin reactions. Local skin reactions are most likely to happen
FORTE Gel. Ask your doctor or pharmacist if you do not understand any during the first 4 weeks of treatment and usually lessen with
of this information or if you want to know more about EPIDUO FORTE Gel. continued use of EPIDUO FORTE Gel. Signs and symptoms of
For full Prescribing Information and Patient Information, please see the local skin reaction include:
package insert.
• Redness
WHAT IS EPIDUO FORTE GEL? • Dryness
EPIDUO FORTE Gel is a prescription medicine used on the skin (topical) • Scaling
to treat acne vulgaris. Acne vulgaris is a condition in which the skin has • Stinging or burning
blackheads, whiteheads and pimples.
Tell your doctor right away if these side effects continue for longer than 4
weeks or get worse; you may have to stop using EPIDUO FORTE Gel.
WHO IS EPIDUO FORTE GEL FOR?
EPIDUO FORTE Gel is for use in people 12 years of age and older. It is not These are not all of the possible side effects of EPIDUO FORTE Gel. For
known if EPIDUO FORTE Gel is safe and effective for children younger than more information, ask your doctor or pharmacist.
12 years old. You are encouraged to report negative side effects of prescription drugs to
Do not use EPIDUO FORTE Gel for a condition for which it was not the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also
prescribed. Do not give EPIDUO FORTE Gel to other people, even if they contact GALDERMA LABORATORIES, L.P. at 1-866-735-4137.
have the same symptoms you have. It may harm them.
HOW SHOULD I USE EPIDUO FORTE GEL?
WHAT SHOULD I TELL MY DOCTOR BEFORE USING • Use EPIDUO FORTE Gel exactly as your doctor tells you to use it.
EPIDUO FORTE GEL? EPIDUO FORTE Gel is for use on the skin only (topical). Do not use
Before you use EPIDUO FORTE Gel, tell your doctor if you: EPIDUO FORTE Gel in or on your mouth, eyes or vagina.
• have other skin problems, including cuts or sunburn. • Apply EPIDUO FORTE Gel 1 time a day.
• have any other medical conditions. • Do not use more EPIDUO FORTE Gel than you need to cover the
• are pregnant or planning to become pregnant. It is not known if treatment area. Using too much EPIDUO FORTE Gel or using it more
EPIDUO FORTE Gel can harm your unborn baby. Talk to your doctor than 1 time a day may increase your chance of skin irritation.
if you are pregnant or planning to become pregnant.
APPLYING EPIDUO FORTE GEL:
• are breastfeeding or plan to breastfeed. It is not known if EPIDUO
FORTE Gel passes into your breast milk and if it can harm your • Wash the area where the Gel will be applied with a mild or soapless
cleanser and pat dry.

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baby. Talk to your doctor about the best way to feed your baby if
you use EPIDUO FORTE Gel. • EPIDUO FORTE Gel comes in a pump. Depress the pump to dispense
a small amount (about the size of a pea) of EPIDUO FORTE Gel and
Tell your doctor about all of the medicines you take, including spread a thin layer over the affected area.
prescription and over-the-counter medicines, vitamins and herbal
• Wash your hands after applying the Gel.

Penalties Apply
supplements. Using other topical acne products may increase the
irritation of your skin when used with EPIDUO FORTE Gel.
WHERE SHOULD I GO FOR MORE INFORMATION ABOUT
EPIDUO FORTE GEL?
WHAT SHOULD I AVOID WHILE USING EPIDUO FORTE GEL?
• Talk to your doctor or pharmacist.
• You should avoid spending time in sunlight or artificial sunlight,
such as tanning beds or sunlamps. EPIDUO FORTE Gel can make • Go to www.EPIDUOFORTE.com or call 1-866-735-4137.
your skin sensitive to sun and the light from tanning beds and
sunlamps. You should use sunscreen and wear a hat and clothes All trademarks are the property of their respective owners.
that cover the areas treated with EPIDUO FORTE Gel if you have to
GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA
be in the sunlight.
Revised: July 2015
• You should avoid weather extremes such as wind and cold as this 20089-0415-BS
may cause irritation to your skin.
• You should avoid applying EPIDUO FORTE Gel to cuts, abrasions
and sunburned skin.
• You should avoid skin products that may dry or irritate your skin
such as medicated or harsh soaps, astringents, cosmetics that have
strong skin drying effects and products containing high levels of
References: 1. Data on file. Galderma Laboratories, L.P.
alcohol, spices or limes.
• You should avoid the use of “waxing” as a hair removal method
on skin treated with EPIDUO FORTE Gel.
All trademarks are the property of their respective owners.
• EPIDUO FORTE Gel may bleach your clothes or hair. ©2018 Galderma Laboratories, L.P.
Allow EPIDUO FORTE Gel to dry completely before dressing to Galderma Laboratories, L.P.
14501 N. Freeway Fort Worth, TX 76177
prevent bleaching of your clothes. USMP/EFO/0038/0218f Printed in USA 06/18 www.epiduoforte.com/hcp
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

June 2018 594 Volume 17 • Issue 6

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: 1.708*
Normalized Eigenfactor® Score: 0.654*
Keyvan Nouri MD (2005-2008)
Article Influence Score: 0.402*
Sherry H. Hsiung MD (2008) *Clarivate Analytics, Formerly the IP & Science Business of
James M. Spencer MD (2009-2013) Thomson Reuters, June 2017
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

June 2018 595 Volume 17 • Issue 6

Special FocuS: acne and RoSacea

GUEST EDITORIAL
599 Who Is Accountable When Patients Do Not Achieve Successful Treatment for Their
Acne?
James Q. Del Rosso DO

ORIGINAL ARTICLES
602 Clinical Experience With Once-Daily Dapsone Gel, 7.5% Monotherapy in Patients
With Acne Vulgaris
Toni C. Stockton MD, Emil A. Tanghetti MD, Edward Lain MD, Joshua A. Zeichner MD,

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and Nancy Alvandi PhD

611 A Biologically Based Approach to Acne and Rosacea

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Penelope J. Kallis BS BA, Alexandra Price MD, Jacquelyn R. Dosal MD, Anna J. Nichols MD PhD,
and Jonette Keri MD PhD

621 Clinically Relevant Reduction in Persistent Facial Erythema of Rosacea on the

First Day of Treatment With Oxymetazoline Cream 1.0%
Emil A. Tanghetti MD, Jeffrey S. Dover MD FRCPC, David J. Goldberg MD, Sunil S. Dhawan MD,
Lei Luo MPH, David R. Berk MD, Gurpreet Ahluwalia PhD, and Nancy Alvandi PhD

632 Frequency of Treatment Switching for Spironolactone Compared to Oral

Tetracycline-Class Antibiotics for Women With Acne: A Retrospective Cohort Study
2010-2016
John S. Barbieri MD MBA, Juliana K. Choi MD PhD, Nandita Mitra PhD, and David J. Margolis MD PhD

June 2018 596 Volume 17 • Issue 6

ORIGINAL ARTICLES (CONTD)

647 Expert Consensus on Achieving Optimal Outcomes With Absorbable Suspension
Suture Technology for Tissue Repositioning and Facial Recontouring
Z. Paul Lorenc MD FACS, Glynis Ablon MD, Julius Few MD, Michael H. Gold MD,
Stephen Mandy MD PhD, Mark S. Nestor MD PhD, and Susan H. Weinkle MD

657 From Probiotic to Prebiotic Using Thermal Spring Water

Joshua Zeichner MD and Sophie Seite PhD

664 Single-Center, Double-Blind, Randomized, Placebo-Controlled, Study of the Efficacy

and Safety of a Cream Formulation for Improving Facial Wrinkles and Skin Quality
Neil Sadick MD, Krista Bohnert BS, Monica Serra, and Neal Kitchen PhD

671 The Effect of an Anti-Inflammatory Botanical Cleanser/Night Mask Combination

on Facial Redness Reduction
Zoe Diana Draelos MD and Angela Donald ND MSc

678 A National Survey of Medical Coding and Billing Training in United States
Dermatology Residency Programs
Karin Blecher Paz MD, Caroline Halverstam MD, Alexandra K. Rzepecki BS, and Beth N. McLellan MD

CASE REPORTS
683
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Naturopathic Self-Treatment of an Atypical Fibroxanthoma: Lessons for
Dermatologic Surgery
Brandon Worley MD MSc, Andrew J. Nemechek MD FACS, Samantha Stoler MD FAAD,

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and Joel L. Cohen MD FAAD FACMS

BRIEF COMMUNICATIONS
686 Currently Constrained, Dermatologists Are Ready for New Acne Therapies
Arielle R. Nagler MD

688 Beyond Traditional Treatment: The Importance of Psychosocial Therapy in Vitiligo

Alexandra K. Rzepecki BS, Beth N. McLellan MD, and Nada Elbuluk MD MSc

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June 2018 598 Volume 17 • Issue 6

LETTERS TO THE EDITOR

694 Erratum
Jennifer C. Tang MD

Publishers Associate Publisher

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

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© 2018 Journal of Drugs in Dermatology

June 2018 599 Volume 17 • Issue 6

Who Is Accountable When

Patients Do Not Achieve
Successful Treatment for Their
Acne?
A
cne vulgaris (AV) is a very common inflammatory facial disorder that is complex
in its pathophysiology, heterogenous in clinical presentation, and affects children
and adults of all ethnicities, races, and skin types.1,2 Although it appears that
dermatologists are seeing more adult and pre-teen patients with AV, the time between follow
up visits for patients with chronic disorders like AV are increasing, likely due to cost factors,
unrealistic expectations regarding response to therapy, and/or searching for alternative
James Q. Del Rosso DO
options, including via the internet.3 Unlike other disease states such as psoriasis and atopic
dermatitis, where new advances have become available or are emerging with biologic
therapies and other systemic agents, AV continues to be managed with combinations of topical agents, oral antibiotics, and oral
isotretinoin. Both topical and oral formulation advances have been very helpful in AV management, especially with topical vehicles
that improve skin tolerability, provide stability with topical combination products, allow for oral formulations that reduce adverse
effects and/or allow for administration without food.

So why do challenges continue to be present with AV management? We have several effective and safe topical and oral therapies
that should be able to control AV in most patients if used consistently, and in most cases, in appropriate combination.4 Unfortunately,
assuming reasonable patient adherence, the most common “modern day” reason I have observed for inadequate treatment of AV
has been that the patient encounters significant barriers when trying to obtain the medications prescribed by their dermatologist.
This is not a problem unique to AV, however, what does occur with AV treatment is that patients only get part of their combination

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regimen. For example, they may be able to get access to one topical medication, but not a second topical agent which targets a
different pathophysiologic component of AV. Another common example is that the patient obtains the topical therapy but the oral
agent is not covered or access is significantly delayed. Except for use of oral isotretinoin for severe AV, or topical monotherapy for
mild AV, successful AV management is highly dependent on the patient utilizing the full combination regimen, with anything less

Penalties Apply
compromising what the dermatologist has designed in their case to achieve therapeutic success.

So, who is accountable when the patient returns and their AV response in not adequate? At face value, it appears that the clinician
is accountable as they were supposed to choose an effective regimen based on their clinical assessment. In fact, successful AV
management is often compromised by incomplete therapy due to coverage issues, barriers encountered at the pharmacy level,
formulary access, and/or cost factors. There is also the “fatigue factor” encountered by patients or their parents in trying to obtain
their prescribed medications as they battle through the maze of pharmacy coverage.

Over the past six months, in anticipation of writing this editorial, I have kept track of patients I have seen in follow-up for AV, looking
at whether or not they were able to get the medications that were prescribed for them at their last visit. In approximately 30% of
cases, the patient was not able to obtain the medications that were prescribed, with this number increasing to around 50% when
brand name medications were prescribed.

It is time that all of the parties who “meddle” into prescribing of therapy for patients with AV, as well as other therapies, take
responsibility for altering the prescribed management plan. Accountability needs to include all who are involved. So far, I have not
seen enough attention placed on parties other than the clinician in taking responsibility for poor treatment outcomes. Hopefully,
action will be taken to improve access to treatment for our patients with AV. I know the American Acne and Rosacea Society has
been carrying out a treatment access initiative. It will take a very large consistent effort from a large number of individuals to make
a difference. May the force be with us.

Enjoy this issue of the Journal of Drugs in Dermatology!

June 2018 600 Volume 17 • Issue 6

James Q. Del Rosso DO

JDR Dermatology Research, Las Vegas, NV
Private Dermatology Practice, Thomas Dermatology, Las Vegas, NV
Touro University Nevada, Henderson, NV

References
1. Bowe WP, Shalita A. Introduction: epidemiology, cost, and psychosocial im-
plications. In: Acne vulgaris, Shalita AR, Del Rosso JQ, Webster GF, eds.
Informa Healthcare, London, United Kingdom, 2011:1-2.
2. Davis SA, Narahari S, Feldman SR, et al. Top dermatologic conditions in pa-
tients of color: an analysis of nationally representative data. J Drugs Derma-
tol. 2012;11(4):466-473.
3. Zeichner JA, Del Rosso JQ. Acne and the internet. Dermatol Clin.
2016;34(2):129-132.
4. Villasenor J, Berson DS, Kroshinsky D. Combination therapy. In: Acne vulgar-
is, Shalita AR, Del Rosso JQ, Webster GF, eds. Informa Healthcare, London,
United Kingdom, 2011:105-112.

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Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

June 2018 602 Volume 17 • Issue 6

Clinical Experience With Once-Daily Dapsone Gel, 7.5%

Monotherapy in Patients With Acne Vulgaris
Toni C. Stockton MD,a Emil A. Tanghetti MD,b Edward Lain MD,c Joshua A. Zeichner MD,d
and Nancy Alvandi PhDe
Stockton Dermatology, Phoenix, AZ
a

Center for Dermatology & Laser Surgery, Sacramento, CA

c
Austin Institute for Clinical Research, Austin, TX
d
The Mount Sinai Hospital, New York, NY
e
Allergan plc, Irvine, CA

ABSTRACT
Background: Dapsone gel, 7.5% is a topical medication approved for acne in patients aged 12 years and older. Clinical trials have dem-
onstrated the safety and efficacy of once-daily dapsone gel, 7.5% in patients with moderate acne.
Objective: The objective of this report is to describe the clinical course of 8 patients who participated in a 12-week program using
once-daily dapsone gel, 7.5% as monotherapy for acne in a real-world clinical setting.
Monotherapy Program: Male and female adults and adolescents with facial acne, representing a broad range of ages, skin photo-
types, and ethnicities, and with no prior use of dapsone gel, 7.5% applied the product once daily for 12 weeks as monotherapy for acne.
Photographs were taken at baseline and at 12 weeks. The treating dermatologists recorded observations of baseline disease, treat-
ment tolerability, and outcomes. An independent rater assessed Global Acne Assessment Score (GAAS) at baseline and at 12 weeks
based on photographs. Patients provided testimonials of their experience with treatment.
Program Outcomes: Acne improvement was evident in the photographs of the 8 patients. Changes in GAAS at week 12 of treatment,
as assessed by an independent rater, ranged from 1- to 3-grade improvement from baseline.
Conclusion: Photographs, dermatologist reports, and patient commentary in an office-based practice demonstrated that 12 weeks
of treatment with only topical dapsone gel, 7.5%, applied once daily, was effective and well tolerated as a stand-alone treatment in 8
patients with facial acne vulgaris, with results that are consistent with the phase 3 pivotal trials.

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J Drugs Dermatol. 2018;17(6):602-608.

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INTRODUCTION

P
atients with facial acne vulgaris may contend with pain- was initiated to evaluate the use of once-daily dapsone gel, 7.5%
ful inflammatory lesions and an appearance altered by as monotherapy for acne in an office-based practice, with der-
erythema, comedones, residual discoloration, and scar- matologists identifying candidates for treatment with dapsone
ring.1-7 They often experience poor self-confidence and quality gel, 7.5% based on indications defined by the drug’s prescribing
of life.1,7,8 It is routine to address the manifold acne lesion types information. Consistently with real-life clinical presentations of
and severity levels through a multimodal approach involving acne,15 the program included male and female adolescents and
oral and topical medications.3,9 adults representing a variety of acne phenotypes, Fitzpatrick
skin phototypes, races, and ethnicities. This paper presents the
Dapsone gel, 7.5% (Aczone Gel, 7.5%; Allergan plc, Dublin, Ire- clinical courses and before- and after-treatment photographs
land) is a once-daily topical medication approved by the US for 8 patients who participated in this program.
Food and Drug Administration (FDA) to treat acne vulgaris in
patients aged 12 years and older.10 Its once-daily application Dapsone Gel, 7.5% Monotherapy Program
may benefit patients by helping to improve their adherence to Dermatologists from 5 locations in New York, California, Texas,
treatment.11 Pivotal clinical trials demonstrated that dapsone and Arizona identified male and female patients aged 12 to 45
gel, 7.5% was safe, well tolerated, and effective as once-daily years with facial acne and no prior use of the product to receive
monotherapy in patients with moderate acne.11-13 dapsone gel, 7.5% once daily as monotherapy for acne vulgaris
according to the FDA-approved indication.
The strictly controlled conditions of a clinical trial may not pre-
dict the experiences and treatment outcomes likely to occur Patients applied dapsone gel, 7.5% once daily for 12 weeks as
with the use of a medication in real life.14 A 12-week program the only prescription acne medication during the treatment
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period. Use of over-the-counter (OTC) non-medicated skin brown-to-black skin discoloration in areas of prior lesions, often
moisturizers and cleansers was permitted. experienced by people with skin of color and negatively impact-
ing their quality of life.2-6,16,17 Both cases of PIH visibly improved
The dermatologists photographed the selected patients at after 12 weeks of dapsone gel, 7.5% monotherapy.
baseline and at 12 weeks of treatment using a Canfield Sci-
entific camera (Canfield Scientific, Inc., Parsippany, NJ) or the Three patients (Cases 4, 5, and 6; Figures 4, 5, and 6, respec-
professional equivalent, with a minimum resolution of 300 dpi tively) exhibited baseline postinflammatory erythema (PIE),
and no additional lighting. Patients were photographed from which is pink-to-red residual discoloration at the site of re-
the collarbone up, without makeup, at 3 different angles—front, solved lesions, primarily experienced in patients with lighter
left oblique, and right oblique—at the same distance from skin (usually Fitzpatrick skin types I−III).6 The 3 patients’ PIE visi-
the camera for each photograph. Consistent lighting, with no bly improved after 12 weeks of dapsone gel, 7.5% monotherapy.
shadowing on the patient or background, was required. Color
balance, brightness, and contrast of some of the images were The patient testimonials were unanimously positive. All pa-
adjusted for visibility of acne signs. tients indicated a desire to continue using the product beyond
12 weeks. The patients in Cases 2 and 3 reported that they
Both patients and dermatologists provided written testimoni- would recommend the treatment to others. The patient in Case
als describing their experience with dapsone gel, 7.5% during 3 also indicated that she felt “a lot better” about her skin after
the program, including any adverse events (AEs). After the treatment and that she had fewer acne lesions and smoother
program concluded, an independent evaluator, blinded to the skin. The patient in Case 5, who had reported experiencing only
treatment approach, graded the acne severity of the patients mild improvement with prior treatment with oral doxycycline,
in baseline and week 12 posttreatment photographs using the stated that dapsone gel, 7.5% was very effective and that she
5-point Global Acne Assessment Score (GAAS) scale (grade was very satisfied. Another patient with prior acne prescription
0=none, 1=minimal, 2=mild, 3=moderate, 4=severe). medication use, Case 6, had described a history of peeling and
minimal acne improvement with the use of topical adapalene/
Program Case Summary benzoyl peroxide gel and tazarotene, as well as nausea and no
Eight patient cases treated with 12 weeks of monotherapy with improvement with oral doxycycline. With dapsone gel, 7.5%,
dapsone gel, 7.5% were selected from the program and are this patient reported that she considered her response to be
detailed in Table 1. A broad range of ages, acne phenotypes, moderate and that she was satisfied.

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Fitzpatrick skin phototypes, and other demographic character-
istics were represented among these patients, all of whom had Clinical Insights from the Dapsone Gel, 7.5% Mono-
acne improvement after 12 weeks of treatment with only topi- therapy Program
cal dapsone gel, 7.5%. More than half of the patients had never The patients in these 8 cases of facial acne all experienced im-

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used prescription acne medications previously (2 had had no provements in their disease, yet they varied in their age, sex, skin
prior acne treatment at all); dapsone gel, 7.5% was effective as phototype, baseline acne characteristics, and racial and ethnic
first-line therapy in these cases. demographics, confirming that once-daily dapsone gel, 7.5% is
effective in a real-world setting. These 8 cases also demonstrat-
Figures 1 to 8 show evident acne improvement in photographs ed the appropriateness of dapsone gel, 7.5% as monotherapy
of the patients at baseline compared to 12 weeks of treatment. for acne vulgaris in adolescents and adults, as the treatment
An independent rater’s GAAS assessments using these pho- was effective without any other prescription acne medications.
tographs indicated that all of the patients at baseline had a Treatment success across the different facial acne phenotypes in
minimum GAAS score of 2 (mild severity), with half of them this program also highlights the potential of dapsone gel, 7.5%
graded as 4 (severe), and all patients experienced at least a to serve as a stand-alone treatment for acne manifestations
1-grade improvement in acne severity after treatment with dap- that may traditionally have required a multimodal approach.
sone gel, 7.5% for 12 weeks. A 3-grade improvement in acne Furthermore, many of these patients had used no previous
severity (from severe to minimal) was noted for Case 1 (Figure prescription acne medications, suggesting that dapsone gel,
1); both Cases 5 and 6 (Figures 5 and 6, respectively) were as- 7.5% may be an effective first-line monotherapy.
sessed as having a 2-grade improvement in acne severity (Case
5 improved from moderate to minimal; Case 6, from severe to An independent evaluator assessed all patients as having at
mild). least a 1-grade improvement from baseline in their acne se-
verity based on photographs taken before and after 12 weeks
Two patients (Cases 2 and 8; Figures 2 and 8, respectively) of treatment. Three of the 8 patients demonstrated at least a
had persistent inflammatory hyperpigmentation (PIH) at 2-grade improvement. Half of the patients achieved a week-12
baseline. PIH is a complication of acne characterized by residual GAAS score of 1 (minimal severity); none of the patients were
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Journal of Drugs in Dermatology T.C. Stockton, E.A. Tanghetti, E. Lain, et al
June 2018 • Volume 17 • Issue 6

TABLE 1.
Case Demographics, Baseline Characteristics, and Treatment Outcomes

Race/ Fitzpatrick Acne Severity

Age Prior Acne Acne Characteristics Continue?
Case Sex Ethnic Skin (GAAS Grade)b AEs
(y) Treatments (Y/N)c
Group Phototypea Baseline Week 12 Baseline Week 12

OTC benzoyl Severe

peroxide and papules and
1 15 F Hispanic IV salicylic acid pustules Almost clear 4 1 None Y
wash/leave-on across all
preparations facial zones

27
5 inflammatory
inflammatory Peeling,
lesions,15
2 28 F Black VI None lesions, 42 2 1 resolved in Y
comedones,
comedones, 1 wk
improved PIH
PIH

39
4 inflammatory
inflammatory
3 27 F White II None lesions, 19 2 1 None Y
lesions, 49
comedones
comedones

Asian,
Overall acne
Indian,
4 15 M III NA PIE, scarring improvement, PIE 4 3 None Y
Middle
improvement
Eastern

Dermatitis
patch on
forehead,
Overall acne
OTC wash, oral resolved
5 19 F White II PIE improvement, PIE 3 1 Y
doxycycline with topical
improvement
triamcinolone
acetonide
cream

Topical

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adapalene
and benzoyl
Overall acne
Hispanic, peroxide
6 23 F V PIE improvement, PIE 4 2 None Y
Mexican combination
improvement
gel and

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tazarotene; oral
doxycycline

72
comedones,
26
inflammatory Overall acne
7 18 M White V OTC bar soap 3 2 None Y
papules, improvement
no cysts,
erythema,
scarring

15 inflamed
Mild perioral
>30 inflamed papules, 25
dermatitis,
American papules, 40 comedones, 1
8 20 F V OTC wash 4 3 resolved with Y
Indian comedones, cyst, overall acne
hydrocortisone
>10 cysts, PIH improvement,
2.5% lotion
PIH improvement

AEs, adverse events; GAAS, Global Acne Assessment Score (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe); NA, not available; OTC, over-the-counter;
PIE, postinflammatory erythema; PIH, persistent inflammatory hyperpigmentation.
a
Skin photosensitivity scale (type I=lightest skin, always burns; VI=darkest skin, never burns).19
b
Assessed by independent rater (blinded to treatment approach) using patients’ pre- and posttreatment photographs after program conclusion.
c
Patients were asked if they wished to continue using dapsone gel, 7.5% after the 12-week program (yes/no).

rated higher than 3 (moderate severity) at week 12. Indeed, observations, which were made in the course of clinical prac-
these improvements are evident in the before-and-after pho- tice under circumstances that reflect practitioners’ experience
tographs presented in Figures 1 to 8. It is notable that these with this drug, are consistent with the data reported in the
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Journal of Drugs in Dermatology T.C. Stockton, E.A. Tanghetti, E. Lain, et al
June 2018 • Volume 17 • Issue 6

FIGURE 1. Case 1 (A) at baseline and (B) after 12 weeks of dapsone FIGURE 3. Case 3 (A) at baseline and (B) after 12 weeks of dapsone
gel, 7.5% monotherapy. gel, 7.5% monotherapy. Brightness and contrast of images were
uniformly adjusted.
(A) (A)

(B) (B)

FIGURE 2. Case 2 (A) at baseline and (B) after 12 weeks of dapsone FIGURE 4. Case 4 (A) at baseline and (B) after 12 weeks of dapsone gel,

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gel, 7.5% monotherapy. Brightness and contrast of images were 7.5% monotherapy. Color balance, brightness, and contrast of baseline
uniformly adjusted. images only were uniformly adjusted. Week 12 images are unadjusted.
(A) (A)

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Journal of Drugs in Dermatology T.C. Stockton, E.A. Tanghetti, E. Lain, et al
June 2018 • Volume 17 • Issue 6

FIGURE 5. Case 5 (A) at baseline and (B) after 12 weeks of dapsone FIGURE 7. Case 7 (A) at baseline and (B) after 12 weeks of dapsone
gel, 7.5% monotherapy. Brightness and contrast of images were gel, 7.5% monotherapy.
uniformly adjusted.
(A) (A)

(B) (B)

FIGURE 6. Case 6 (A) at baseline and (B) after 12 weeks of dapsone FIGURE 8. Case 8 (A) at baseline and (B) after 12 weeks of dapsone

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gel, 7.5% monotherapy. gel, 7.5% monotherapy.

(A) (A)

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607
Journal of Drugs in Dermatology T.C. Stockton, E.A. Tanghetti, E. Lain, et al
June 2018 • Volume 17 • Issue 6

stringently controlled environment of the pivotal clinical trials

of dapsone gel, 7.5%.11 CONCLUSION
The outcomes in these cases provide real-world evidence that
The patients’ own commentaries on their treatment results once-daily dapsone gel, 7.5% monotherapy is effective and well
lend further credence to the photographic evidence and the tolerated for the treatment of patients with acne who are can-
improvements noted by the independent rater. The positive didates for therapy based on product prescribing information.
patient-reported outcomes are important to consider, given The departure from the strictly controlled conditions of a clini-
the low self-esteem and poor quality of life that are pervasive cal trial in this treatment program suggests that these results
among patients with facial acne.1,7,8 These positive outcomes may reflect actual clinical experience with dapsone gel, 7.5%.
are also important because they address the experiences of
patients whose acne has been treated with a combination of DISCLOSURES
regimens without resolution, as in Cases 1, 5, and 6 (see Table This study was sponsored by Allergan plc, Dublin, Ireland.
1). The appeal of applying only one topical medication, once Writing and editorial assistance was provided to the authors
daily, to achieve visible acne improvement may have contrib- by Peloton Advantage, Parsippany, NJ, and was funded by Al-
uted to many of the positive patient testimonials. lergan plc. Neither honoraria nor other forms of payment were
made for authorship. Dr. Stockton, Dr. Tanghetti, Dr. Lain, and
This program also demonstrated that dapsone gel, 7.5% was Dr. Zeichner are investigators for Allergan plc. Dr. Alvandi is an
well tolerated under real-world conditions. Unlike a clinical trial employee of Allergan plc and may own stock/stock options in
in which rigid protocols tightly control any variables that may that company.
affect safety outcomes,14 this program prohibited patients only
from using other prescription acne medications. In this real-life, ACKNOWLEDGMENTS
unregulated setting, 3 AEs were reported in 3 patients (1 case of Writing and editorial assistance was provided to the authors by
peeling and 2 cases of localized dermatitis); all AEs were mild Peloton Advantage, Parsippany, NJ, and was funded by Aller-
and resolved with continued medication use. gan plc, Dublin, Ireland. All authors meet the ICMJE authorship
criteria.
Based on the outcomes of this program, dapsone gel, 7.5%
may also fulfill a need for a single treatment to address both REFERENCES
active acne lesions and the skin discoloration that affects 1. James WD. Acne. N Engl J Med. 2005;352(14):1463-1472.
2. Callender VD, St Surin-Lord S, Davis EC, et al. Postinflammatory hyperpig-

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many patients after these lesions resolve—PIH/PIE, a com- mentation: etiologic and therapeutic considerations. Am J Clin Dermatol.
mon complaint among patients with acne.6,16-18 The patients in 2011;12(2):87-99.
3. Titus S, Hodge J. Diagnosis and treatment of acne. Am Fam Physician.
this program not only experienced improvement in their acne 2012;86(8):734-740.
severity but also visible improvement in PIE and PIH (where 4. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical char-

Penalties Apply
identified among baseline clinical signs). These findings are acteristics, perceptions and behaviors, and psychosocial impact of adult fe-
male acne. J Clin Aesthet Dermatol. 2014;7(7):19-31.
important because some acne treatments can worsen erythe- 5. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the man-
ma and hyperpigmentation.5 Retinoid therapy, for example, agement of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973 e33.
6. Bae-Harboe YS, Graber EM. Easy as PIE (Postinflammatory Erythema). J Clin
a common component of first-line treatment for moderate Aesthet Dermatol. 2013;6(9):46-47.
acne, may cause erythema, irritation, and pigmentary chang- 7. Sanchez Viera M. Management of acne scars: fulfilling our duty of care for
patients. Br J Dermatol. 2015;172 Suppl 1:47-51.
es.5 Benzoyl peroxide and salicylic acid−containing topical 8. Gieler U, Gieler T, Kupfer JP. Acne and quality of life - impact and manage-
medications frequently prescribed for acne may also worsen ment. J Eur Acad Dermatol Venereol. 2015;29 Suppl 4:12-14.
erythema.5 A need exists for PIH/PIE treatments that produce 9. Shamban AT, Narurkar VA. Multimodal treatment of acne, acne scars and
pigmentation. Dermatol Clin. 2009;27(4):459-471, vi.
visible results reasonably soon after initiation and involve un- 10. Aczone Gel, 7.5% [package insert]. Dublin, Ireland: Allergan plc; 2016.
complicated regimens for patients.5,6,9,17 11. Thiboutot DM, Kircik L, McMichael A, et al. Efficacy, safety, and dermal
tolerability of dapsone gel, 7.5% in patients with moderate acne vul-
garis: a pooled analysis of two phase 3 trials. J Clin Aesthet Dermatol.
Limitations of this treatment program include the small num- 2016;9(10):18-27.
12. Eichenfield LF, Lain T, Frankel EH, et al. Efficacy and safety of once-daily dap-
ber of patient cases examined, as well as its real-world design, sone gel, 7.5% for treatment of adolescents and adults with acne vulgaris:
which is less rigorous than a clinical trial and allows the possibil- second of two identically designed, large, multicenter, randomized, vehicle-
ity of a multitude of variables to affect the outcomes. However, controlled trials. J Drugs Dermatol. 2016;15(8):962-969.
13. Stein Gold LF, Jarratt MT, Bucko AD, et al. Efficacy and safety of once-daily
the before-and-after photographs, independent GAAS ratings, dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgar-
and patient testimonials offer multidimensional, realistic clini- is: first of two identically designed, large, multicenter, randomized, vehicle-
controlled trials. J Drugs Dermatol. 2016;15(5):553-561.
cal experience showing that once-daily dapsone gel, 7.5% is 14. Saturni S, Bellini F, Braido F, et al. Randomized controlled trials and real life
an effective and well tolerated monotherapy for patients with studies. Approaches and methodologies: a clinical point of view. Pulm Phar-
macol Ther. 2014;27(2):129-138.
facial acne vulgaris, with results that are consistent with the 15. White GM. Recent findings in the epidemiologic evidence, classification, and
phase 3 pivotal trials. subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39(2 Pt 3):S34-S37.
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16. Perkins AC, Cheng CE, Hillebrand GG, et al. Comparison of the epidemiol-
ogy of acne vulgaris among Caucasian, Asian, Continental Indian and African
American women. J Eur Acad Dermatol Venereol. 2011;25(9):1054-1060.
17. Alexis AF. Acne vulgaris in skin of color: understanding nuances and optimiz-
ing treatment outcomes. J Drugs Dermatol. 2014;13(6):s61-s65.
18. Rendon MI, Rodriguez DA, Kawata AK, et al. Acne treatment patterns, ex-
pectations, and satisfaction among adult females of different races/ethnici-
ties. Clin Cosmet Investig Dermatol. 2015;8:231-238.
19. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through
VI. Arch Dermatol. 1988;124(6):869-871.

AUTHOR CORRESPONDENCE

Toni C. Stockton MD
E-mail:................….............. [email protected]

June 2018 611 Volume 17 • Issue 6

A Biologically Based Approach to Acne and Rosacea

Penelope J. Kallis BS BA,a Alexandra Price MD,a Jacquelyn R. Dosal MD,a Anna J. Nichols MD PhD,a
and Jonette Keri MD PhDa,b
a
University of Miami Miller School of Medicine, Miami, FL
b
Dermatology Service, Miami VA Healthcare System, Miami, FL

ABSTRACT
Complementary and alternative medicine (CAM) therapies are increasing in popularity in the field of dermatology. Natural products and holistic ap-
proaches are in high demand among patients and research has begun to support their roles in acne and rosacea pathophysiology. In this article, com-
monly utilized biologically based complementary and alternative therapies for acne and rosacea are reviewed from an evidence-based perspective.
Therapies discussed include vitamin C, nicotinamide, zinc, tea tree oil, green tea, resveratrol, curcumin, feverfew, licorice, chamomile, polypodium
leucotomos, and nutrition-based approaches.

J Drugs Dermatol. 2018;17(6):611-617.

INTRODUCTION

A
lternative medicine is a term used for treatments Acne
that are used in place of evidence-based, standard Antioxidants
Western medical care. Complementary medicine, 1. Vitamin C
which combines these less-mainstream approaches with Vitamin C (ascorbic acid) is both an antioxidant and an-
conventional medicine is used more often.1,2 In the United ti-inflammatory agent commonly used topically for skin
States, it is estimated that more than 30% of adults and 12% protection in various dermatologic conditions.4,8 Due to its
of children use health care practices outside of traditional chemical instability, vitamin C is available in numerous modi-
Western medicine, 2 translating to $34 billion spent annu- fied formulations that improve stability, with sodium ascorbyl
ally on complementary and alternative medicine (CAM). 3 phosphate (SAP) being commonly studied and commercially

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The most common complementary health approach used available.9 SAP may have utility in the treatment of acne due
by Americans in the 2012 National Health Interview Survey to its strong antimicrobial activity on P. acnes and through re-
was natural products (17.7%), which includes herbs (also duction of lipid oxidation, which may then lead to a decrease
known as botanicals), vitamins, minerals, dietary supple- in inflammation and follicular keratinization.8 Several studies

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ments, and probiotics. 2 Along with foods and special diets, have reported the efficacy of topical SAP for the treatment of
natural products make up biologically based practices of acne both alone and in combination with other medications.
CAM.1 Klock et al reported that 5% SAP cream was more efficacious
than 5% benzoyl peroxide (BP) cream for the treatment of
Patients are often frustrated by the chronicity of dermato- acne vulgaris in a 12-week open-label study of 60 patients.8 A
logic conditions, and this may compel them to experiment randomized control trial (RCT) by Ruamrak et al. found that 5%
with CAM therapies. 4 Results from the 2007 National SAP and 0.2% retinol had synergistic effects in the reduction
Health survey revealed that among those reporting skin of inflammatory acne lesions.10 Another RCT demonstrated
problems in the United States, 84.5% used CAM that year, 5 that monotherapy with 5% SAP lotion led to improvements
an increase from 49.2% in 2002. 6 In a recent study, patients in Investigator’s Global Assessment Scores, Subject’s Global
using CAM treatments for acne thought that CAM therapies Assessment Scores, and lesion counts when compared to
had less potential for adverse effects and were more effi- vehicle.11
cacious than mainstream topical therapies.7 With increased
patient interest in CAM and heightened insight into their 2. Nicotinamide
role on cutaneous disease processes, it is imperative that Nicotinamide, also known as niacinamide, is a form of vitamin
dermatologists be made aware of these advances to make B3 regarded as a potential therapy for acne due to its potent
appropriate recommendations to patients. The goal of this anti-inflammatory and antioxidant effects.12 Nicotinamide may
article is to detail the best evidence for commonly utilized reduce comedogenesis via various mechanisms. Draelos et al.
biologically based CAM practices employed for two com- performed two separate clinical trials in Japan and the USA
mon dermatoses with significant societal impacts: acne to evaluate the effect of 2% topical nicotinamide on sebum
and rosacea. production and sebum levels. In the Japanese group, sebum
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Journal of Drugs in Dermatology P.J. Kallis, A. Price, J.R. Dosal, et al
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excretion rate was significantly reduced after 2 and 4 weeks of used topical acne product, with 2.5% benzoyl peroxide being
use, while in the Caucasian group sebum levels were reduced, the most commonly used product.30 TTO has evidence of broad-
but sebum excretion rate was not significantly reduced after spectrum antimicrobial activity as well as anti-inflammatory
6 weeks of use.13 Nicotinamide also inhibits P. acnes produc- properties which may be useful in the treatment of acne.31 In a
tion of interleukin-8 (IL-8) through the NF-kappaB and MAPK study of 124 patients comparing 5% TTO gel to 5% benzoyl per-
pathways in keratinocytes.14 In a 1995 randomized, double- oxide, both significantly reduced the number of both inflamed
blind, placebo-controlled trial, 4% nicotinamide gel appeared and non-inflamed acne lesions. The TTO treated group had few-
to be more efficacious than 1% clindamycin gel for moderate er side effects, however the onset of action was slower than
inflammatory acne, though this was not statistically significant. the 5% benzoyl peroxide goup.32 Enshaieh et al. performed a
In a multi-center randomized trial, 4% nicotinamide emulsion randomized, double-blind, placebo-controlled clinical trial in 60
was more effective than both 1% clindamycin emulsion and patients to determine the efficacy of 5% TTO for acne vulgaris
the vehicle control.15 Interestingly, combination topical nico- and found a significant improvement in total lesion counts and
tinamide-clindamycin products showed no difference when acne severity index compared to placebo.33 A number of cases,
compared to clindamycin-only products in two studies.16,17 however, have reported allergic contact dermatitis as a result of
These data indicate that topical nicotinamide may be an attrac- TTO use, with positive patch test reactions ranging from 0.1%
tive alternative to topical clindamycin, as it does not carry a to 3.5%.34
risk of antibiotic resistance and has a similar side effect profile
consisting largely of application site reactions.18,19 While a few 2. Green tea
studies have shown some benefit of oral nicotinamide in acne Green tea is produced from fresh leaves of the plant, Camellia si-
vulgaris, they are confounded by the use of other supplements nensis, using a method that prevents oxidation of polyphenolic
used in combination.20,21 compounds called catechins.35 The most abundant, extensively
studied and therapeutically beneficial catechin found in green
3. Zinc tea is (-)-epigallocatechin-3-gallate (EGCG).36 Besides its anti-
Zinc is an essential trace element that decreases oxidative stress microbial activity, in vitro studies suggest that EGCG exerts its
and has demonstrated bacteriostatic effect against P. acnes.22,23 effect in acne by suppressing sebum production though inhi-
Zinc is utilized to improve the efficacy of topical antibiotics in bition of 5-alpha reductase while reducing inflammation and
combination preparations. In multiple studies, the addition of inducing apoptosis of human sebocytes.37-39 In fact, a 3% green
1.2% zinc acetate to 4% topical erythromycin was shown to tea emulsion significantly reduced sebum production in a re-

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form a complex that enhances the penetration of erythromycin cent study in healthy human volunteers.40 EGCG and green tea
into the skin.22,24,25 Daily oral zinc gluconate supplementation polyphenols also work by combatting reactive oxygen species
(30 mg) for 2 months reduced the number of inflammatory and preventing lipid peroxidation, protecting glutathione per-
acne lesions in a small study of 30 patients.26 An oral methi- oxidase and subsequently restoring glutathione levels.41 In an

Penalties Apply
onine-based zinc antioxidant complex containing vitamin C, open-label study of 20 patients with mild-to-moderate acne vul-
mixed carotenoids, d-alpha-tocopherol acetate and chromium garis, twice-daily application of 2% green tea lotion decreased
showed a significant improvement in acne when taken three mean total lesion count by approximately 58% after 6 weeks.42
times daily for 3 months.27 In a multi-center, prospective study
of 235 patients with inflammatory acne, the addition of a novel 3. Resveratrol
prescription dietary supplement containing zinc oxide, nicotin- Resveratrol (3,4,5-trihydroxy-transtilbene) is a phytoalexin
amide, azelaic acid, pyridoxine, copper and folic acid (NicAzel, found in spermatophytes such as grapes, peanuts, mulberries,
Elorac Inc, Vernon Hills, IL) resulted in a statistically significant spruce and eucalyptus.4 Resveratrol has demonstrated an-
improvement of acne severity after 4 and 8 weeks of use.21 Ad- timicrobial effects against P. acnes in vitro as well as potent
ditionally, oral zinc gluconate appears to be a safe option in antioxidant and anti-inflammatory properties.43 Resveratrol
the management of acne in pregnant patients. A retrospective may also play a role in the inhibition of sebocyte growth via
review on zinc gluconate supplementation in doses less than 75 inactivation of the Akt pathway.44 A single-blind study of 20
mg daily found no harmful fetal effects.28 patients with acne vulgaris revealed a reduction in the Global
Acne Grading System scores, a mean reduction in the average
Botanicals areas of microcomedones, and a significant decrease in lesions
1. Tea tree oil in areas treated with a resveratrol-containing hydrogel com-
Tea tree, or malaleuca oil (TTO) is an essential oil derived from pared to vehicle control.45
the leaves of the Australian native plant Malaleuca alternifolia.
TTO is an ingredient included in many over the counter products 4. Curcumin
targeting acne, including face and body washes, toners, masks, Curcumin, a phytochemical derived from the spice turmeric,
gels and lotions.29 In fact, TTO is the second most commonly has demonstrated antimicrobial activity against P. acnes,46,47 as
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well as anti-oxidant and anti-inflammatory effects.48 In a ran- for 4 weeks to the face and one forearm to an untreated con-
domized, double-blind study of 53 patients, the combination of trol. In this study, the nicotinamide-containing moisturizer
oral curcumin and a topical curcumin cream was more effective improved stratum corneum barrier function and hydration
at 4 weeks compared to placebo, oral curcumin alone and oral of the face.63 In an open-label, multicenter, prospective study
curcumin combined with a topical curcumin gel.49 of 198 patients with acne and/or rosacea, an oral formulation
consisting of 750 mg nicotinamide, 25 mg zinc, 1.5 mg copper,
Diet and 500 μg folic acid that was given twice daily for 4 and 8
The association between diet and acne is a controversial. Some weeks showed equivalent clinical response and patient satis-
of the most compelling evidence lies in the link between acne faction when compared with patients taking concomitant oral
and dietary glycemic load, a direct measure of insulin and blood antibiotic therapy. In addition, approximately 55% reported
glucose increasing potential.50 Ingestion of a high-glycemic moderate or substantial improvement in inflammatory lesions,
load triggers a cascade of endocrine responses that promote which was statistically significant.20 There is a slight discrep-
acne formation via androgens and growth hormones.4,50 In a ancy between the formulation studied and the commercially
RCT of 43 men, adherence to a low-glycemic-load (LGL) diet available product, which consists of 750 mg nicotinamide,
resulted in a significant decrease in acne lesion counts and 27 mg zinc, 2 mg copper, 500 μg folic acid, 50 μg selenium and
insulin sensitivity compared to controls.51,52 Another RCT of 100 μg chromium.20,64 Whether these slight differences would
32 patients demonstrated significant clinical improvement of result in a clinically significant change in response than that
inflammatory and non-inflammatory acne lesions in the LGL reported in this study is not known.
diet group with corresponding decreases in inflammation and
sebaceous gland size on histopathology.53 Multiple reports by Botanicals
Adebamowo indicate a relationship between dairy products, 1. Feverfew
particularly skim milk, and acne exacerbations, which may be Feverfew (Tanacetum parthenium, Chrysanthemum partheni-
due to hormonal constituents and increases in plasma IGF-1.54,55 um) is a perennial herb from the daisy family with a long history
The gut-brain-skin hypothesis proposed by Stokes and Pillsbury of medicinal use in treating fever, migraines, and arthritis.4,65
suggests a relationship between emotional stress, alterations One of its active components, parthenolide, limited feverfew’s
in the microbial flora within the gastrointestinal tract, local and use as a topical agent due to reports of skin sensitization. More
systemic inflammation, and the therapeutic utility of probiot- recently, however, a parthenolide-free extract of feverfew (PFE)
ics.56 However, clinical studies supporting the role of probiotics has been developed that maintains feverfew’s anti-inflammato-

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as adjuvant acne therapy are limited. A Russian study reported ry properties without the risk of creating a contact allergy.4 PFE
faster clinical improvement when oral probiotics were com- inhibits the activity of pro-inflammatory enzymes 5-lipoxygen-
bined with standard acne therapy.57 Similarly, a prospective, ase, phosphodiesterase-3, and phoosphodiesterase-4, reducing
open-label study of 45 women showed a significant decrease in the release of pro-inflammatory mediators such as nitric oxide,

Penalties Apply
total acne lesion counts at 8 and 12 weeks in patients receiving prostaglandin-E2, TNF-alpha, IFN-gamma, and interleukins 2
both oral probiotics and minocycline compared to those receiv- and 4.66 In a study by Martin et al, PFE had greater free radi-
ing probiotics or minocycline alone.58 One study found that a cal scavenging activity against a wide range of reactive oxygen
topical probiotic lotion resulted in a 60% reduction in inflam- species compared to vitamin C. Additionally, PFE reduced UV-
matory lesions and 20% reduction in comedones at 8 weeks induced hydrogen peroxide formation and pro-inflammatory
compared to placebo.59 cytokine release and also decreased epidermal hyperplasia,
DNA damage and apoptosis in vitro. The same group also con-
Rosacea ducted a randomized, placebo-controlled, double-blinded study
Nicotinamide of 12 subjects with Fitzpatrick skin types II and III and found that
Nicotinamide, or niacinamide, may be beneficial in the treat- topically applied PFE significantly reduced erythema 24 hours
ment of rosacea due to its ability to mitigate the inflammatory post-UV exposure compared to controls.67
response and stabilize epidermal barrier function.60 In a pilot
study of 34 patients with rosacea treated with a gel containing 2. Licorice
a metabolite of nicotinamide known as 1-methylnicotinamide, The genus Glycyrrhiza is composed of 30 species of lico-
26 patients (76.5%) achieved clinical improvement.61 A study rice plants utilized in Chinese medicine for the treatment of
of two moisturizers containing nicotinamide and glycerin re- a myriad of diseases.68 Glabridin is a main ingredient with
vealed improved skin hydration as measured by corneometry potential photoprotective benefits, showing inhibitory ef-
and improved barrier integrity as measured by transepidermal fects on melanogenesis and inflammation when topically
water loss.62 Draelos et al conducted a randomized, inves- applied in UVB-irradiated murine models.69 In 62 patients with
tigator-blind study in 50 subjects with rosacea comparing mild-to-moderate erythematotelangiectatic rosacea or red fa-
a nicotinamide-containing moisturizer applied twice daily cial skin not attributable to rosacea, a four-product skincare
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614
Journal of Drugs in Dermatology P.J. Kallis, A. Price, J.R. Dosal, et al
June 2018 • Volume 17 • Issue 6

regimen (Eucerin Redness Relief) containing licochalcone A (Lic and anti-inflammatory agent that both promotes collagen syn-
A), an anti-irritant from the licorice plant Glycyrrhiza inflata, was thesis and prevents its degradation when applied topically in its
instituted for 8 weeks. At both 4 and 8 weeks, there were sig- stabilized form.77 Vitamin E, alpha tocopherol, is a lipid-soluble
nificant improvements in average erythema scores as well as vitamin that becomes oxidized while protecting hydropho-
improved quality of life measured by patient questionnaires. In bic cell membranes from free radical lipid peroxidation.78 In a
a subsequent study, patients treated with topical metronidazole study using a porcine model, 15% L-ascorbic acid and 1% alpha
who then used the Lic A-containing products for 2 weeks had tocopherol applied in combination provided significant protec-
continued improvement in erythema with no adverse effects.70 tion against UV-induced erythema and sunburn cell formation.
In a prospective randomized vehicle-controlled trial, topical Though equivalent concentrations of both the L-ascorbic acid
Lic A significantly reduced UV- and shaving-induced erythema and alpha tocopherol alone were protective, the combination
compared to controls, further suggesting therapeutic potential of the two was superior, yielding 4-fold protection.79 The same
for sensitive or irritated skin.71 investigators found that adding 0.5% ferulic acid both improved
stability and doubled the photoprotection from 4- to 8-fold.80
3. Chamomile
Chamomile, Matricaria recutita and Chamaemelum nobile, Polypodium leucotomos (PL) is a fern plant native to Central
has traditionally been used for its soothing effects on both the and South America that has had success as an oral photopro-
gastrointestinal system and cutaneous inflammatory disorders tectant.81 In a study of 10 healthy patients with skin phototypes
including atopic dermatitis.68,72 Chamomile flavonoids and terpi- II to III, psoralen-UVA-induced phototoxicity was lower in those
noids can inhibit cyclooxygenase, lipoxygenase, and histamine using 7.5 mg/kg of oral PL.82 Another study of subjects with
release, exhibiting antioxidant, anti-inflammatory, and antipru- Fitzpatrick skin type I to III exposed to UVB radiation showed
ritic effects.4,72,73 In a randomized, placebo-controlled trial, 246 a decrease in clinical and colorimetric changes in 17 of the 22
patients with moderate rosacea applied either a golden chamo- subjects post-PL administration with reduced UV damage bio-
mile (Chrysanthellum indicum) extract-based cream or placebo markers on histopathology in all subjects.83 Though theoretical
to the face twice daily for 12 weeks. Subjects in the treatment evidence supporting the use of the aforementioned photopro-
group experienced significant reduction in erythema scores and tectants in rosacea is sound, rigorous studies in patients with
overall rosacea severity compared to baseline and placebo with confirmed rosacea are lacking.
mild adverse reactions that were similar to placebo.74
Diet

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4. Green tea Diet-related triggers of rosacea have long been acknowledged.
There is some evidence to suggest that the anti-inflammatory Many foods and drinks exacerbate facial erythema in rosacea,
and anti-angiogenic properties of EGCG present in green tea including alcohol, spicy foods, coffee, hot drinks, and niacin-
may play a role in the prevention of telangiectasias in rosa- containing foods to name a few.84-87 Recently, attention has

Penalties Apply
cea. In a small randomized, double blind trial, 4 volunteers shifted to determining which diet-based factors can alleviate
with significant erythema and telangiectasias applied a cream rosacea symptoms.
containing EGCG to one side of the face and a vehicle control
to the other side twice daily for 6 weeks. Biopsies taken from Omega-3 fatty acids are utilized in meibomian glands on eye-
the EGCG treated sites showed significantly decreased expres- lids for meibum production, and increased dietary intake of
sion of the angiogenic factors hypoxia inducible factor-1-alpha omega-3 fatty acids has been shown to alter the composition
and vascular endothelial growth compared to the control and clearance of meibum secretions, potentially reducing dry
sites.75 EGCG also protects skin against ultraviolet radiation, a eye symptoms in patients with ocular rosacea.88-90 Flaxseed oil
known trigger for rosacea. In a study of healthy volunteers ex- is a rich, natural dietary source of omega-3 essential fatty acids,
posed to solar simulated radiation who were pre-treated with comprised of 57% alpha-linolenic acid.90,91 In a retrospective
topical green tea extract or one of its constituents, the EGCG case series of 27 children with blepharokeratoconjunctivitis, 3
fraction was particularly efficient at inhibiting erythema. Ad- of which had confirmed acne rosacea, oral flaxseed oil helped
ditionally, skin treated with green tea extracts had protected stabilize lid margin disease in all 12 patients who used it used
epidermal Langerhans cells and reduced DNA damage after as an alternative to long-term antibiotics.91 In a multi-center
UV radiation.76 randomized control trial of 130 patients with ocular rosacea,
significant improvement in dry eye symptoms was achieved
Photoprotectants following a 6-month course of an omega-3 fatty acid supple-
The highly sensitive and easily irritated skin in patients with ment compared to the placebo group.92
rosacea often precludes use of commercial sunscreens, caus-
ing patients to seek natural alternatives for protection against A connection between rosacea and small intestinal bacterial
photo-induced rosacea flares.4 Vitamin C is a potent antioxidant overgrowth (SIBO) was demonstrated in a case control study,
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Journal of Drugs in Dermatology P.J. Kallis, A. Price, J.R. Dosal, et al
June 2018 • Volume 17 • Issue 6

11. Woolery-Lloyd H, Baumann L, Ikeno H. Sodium L-ascorbyl-2-phosphate 5%

with rosacea patients experiencing significantly higher levels of lotion for the treatment of acne vulgaris: a randomized, double-blind, con-
SIBO compared to controls. Moreover, eradication of SIBO with trolled trial. J Cosmet Dermatol. 2010;9(1):22-27.
12. Walocko FM, Eber AE, Keri JE, Al-Harbi MA, Nouri K. The role of nicotin-
rifaximin led to a statistically significant improvement in cutane- amide in acne treatment. Dermatol Ther. 2017.
ous lesions including flushing, erythrosis, papules and pustules.93 13. Draelos ZD, Matsubara A, Smiles K. The effect of 2% niacinamide on facial
sebum production. J Cosmet Laser Ther. 2006;8(2):96-101.
Though the mechanism for the development of rosacea is un- 14. Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits Propioni-
known, it is speculated that increased intestinal permeability in bacterium acnes-induced IL-8 production in keratinocytes through the NF-
SIBO may play a role, with resultant translocation of gut bacteria kappaB and MAPK pathways. J Dermatol Sci. 2009;56(2):106-112.
15. Morganti P, Berardesca E, Guarneri B, et al. Topical clindamycin 1% vs. lin-
and pro-inflammatory cytokines into the bloodstream.94,95 A diet oleic acid-rich phosphatidylcholine and nicotinamide 4% in the treatment of
low in fermentable oligosaccharides, disaccharides, monosac- acne: a multicentre-randomized trial. Int J Cosmet Sci. 2011;33(5):467-476.
16. Dos SK, Barbhuiya JN, Jana S, Dey SK. Comparative evaluation of clindamy-
charides and polyols (FODMAP), considered prebiotic substrates, cin phosphate 1% and clindamycin phosphate 1% with nicotinamide gel
has been used to alter the gut microbiota.96 4% in the treatment of acne vulgaris. Indian J Dermatol Venereol Leprol.
2003;69(1):8-9.
17. Sardesai VR, Kambli VM. Comparison of efficacy of topical clindamycin and
CONCLUSION nicotinamide combination with plain clindamycin for the treatment of acne
There is a large and undeniable consumer demand for CAM vulgaris and acne resistant to topical antibiotics. Indian J Dermatol Venereol
Leprol. 2003;69(2):138-139.
in dermatology. Although there is mounting evidence to sup- 18. Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. Topical nicotin-
port the use of some therapies, a significant need to rigorously amide compared with clindamycin gel in the treatment of inflammatory acne
vulgaris. Int J Dermatol. 1995;34(6):434-437.
study these agents remains. Many healthcare providers may 19. Barros BS, Zaenglein AL. The Use of Cosmeceuticals in Acne: Help or Hoax?
still prefer to use traditional medications and procedures as Am J Clin Dermatol. 2017;18(2):159-163.
20. Niren NM, Torok HM. The Nicomide Improvement in Clinical Outcomes
mainstay therapies for acne and rosacea, however the vari- Study (NICOS): results of an 8-week trial. Cutis. 2006;77(1 Suppl):17-28.
ous biologically based therapies discussed herein should be 21. Shalita AR, Falcon R, Olansky A, et al. Inflammatory acne management with a
considered as adjuncts for certain patients as part of a com- novel prescription dietary supplement. J Drugs Dermatol. 2012;11(12):1428-
1433.
prehensive, holistic management plan. In addition, patients 22. Langner A, Sheehan-Dare R, Layton A. A randomized, single-blind compari-
should be counseled about home remedies that do not have son of topical clindamycin + benzoyl peroxide (Duac) and erythromycin +
zinc acetate (Zineryt) in the treatment of mild to moderate facial acne vul-
evidence supporting their use, such as toothpaste, baking soda garis. J Eur Acad Dermatol Venereol. 2007;21(3):311-319.
and diluted apple cider vinegar, which may cause irritation and 23. Dreno B, Amblard P, Agache P, Sirot S, Litoux P. Low doses of zinc gluconate
for inflammatory acne. Acta Derm Venereol. 1989;69(6):541-543.
chemical burns.97 24. Habbema L, Koopmans B, Menke HE, Doornweerd S, De Boulle K. A 4%
erythromycin and zinc combination (Zineryt) versus 2% erythromycin (Ery-
DISCLOSURES derm) in acne vulgaris: a randomized, double-blind comparative study. Br J
Dermatol. 1989;121(4):497-502.

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Jonette Keri MD PhD is a consultant to Hoffman-La Roche 25. Schachner L, Eaglstein W, Kittles C, Mertz P. Topical erythromycin and zinc
and an Advisory Board Member to Pierre Fabre and Ortho therapy for acne. J Am Acad Dermatol. 1990;22(2 Pt 1):253-260.
26. Dreno B, Foulc P, Reynaud A, Moyse D, Habert H, Richet H. Effect of zinc
Dermatologics. gluconate on propionibacterium acnes resistance to erythromycin in pa-
tients with inflammatory acne: in vitro and in vivo study. Eur J Dermatol.

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in acne vulgaris, and its therapeutic effect. J Microbiol. 2009;47(1):101-109. intake and the polar lipid profiles of meibomian gland secretions in women
60. Gehring W. Nicotinic acid/niacinamide and the skin. J Cosmet Dermatol. with Sjogren’s syndrome. Adv Exp Med Biol. 2002;506(Pt A):441-447.
2004;3(2):88-93. 89. Miljanovic B, Trivedi KA, Dana MR, Gilbard JP, Buring JE, Schaumberg DA.
61. Wozniacka A, Wieczorkowska M, Gebicki J, Sysa-Jedrzejowska A. Topical ap- Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry
plication of 1-methylnicotinamide in the treatment of rosacea: a pilot study. eye syndrome in women. Am J Clin Nutr. 2005;82(4):887-893.
Clin Exp Dermatol. 2005;30(6):632-635. 90. Kronemyer B. Dry eye successfully treated with oral flaxseed oil. 2000;
62. Christman JC, Fix DK, Lucus SC, et al. Two randomized, controlled, com- https://www.healio.com/ophthalmology/news/print/ocular-surgery-news-
parative studies of the stratum corneum integrity benefits of two cosmetic europe-asia-edition/%7B4f2c5812-13f1-4b41-abaf-d1d5cf12bed9%7D/dry-
niacinamide/glycerin body moisturizers vs. conventional body moisturizers. J eye-successfully-treated-with-oral-flaxseed-oil, 2017.
Drugs Dermatol. 2012;11(1):22-29. 91. Jones SM, Weinstein JM, Cumberland P, Klein N, Nischal KK. Visual outcome
63. Draelos ZD, Ertel K, Berge C. Niacinamide-containing facial moisturizer improves and corneal changes in children with chronic blepharokeratoconjunctivitis.
skin barrier and benefits subjects with rosacea. Cutis. 2005;76(2):135-141. Ophthalmology. 2007;114(12):2271-2280.
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June 2018 • Volume 17 • Issue 6

92. Bhargava R, Chandra M, Bansal U, Singh D, Ranjan S, Sharma S. A Random-

ized Controlled Trial of Omega 3 Fatty Acids in Rosacea Patients with Dry
Eye Symptoms. Curr Eye Res. 2016;41(10):1274-1280.
93. Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in
rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol.

New Supplement
2008;6(7):759-764.
94. Weinstock LB, Steinhoff M. Rosacea and small intestinal bacterial over-
growth: prevalence and response to rifaximin. J Am Acad Dermatol.
2013;68(5):875-876.
95.

96.
Riordan SM, McIver CJ, Thomas DH, Duncombe VM, Bolin TD, Thomas MC.
Luminal bacteria and small-intestinal permeability. Scand J Gastroenterol.
1997;32(6):556-563.
Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG.
Now Available
Diets that differ in their FODMAP content alter the colonic luminal microen-
vironment. Gut. 2015;64(1):93-100. 17 • Issue 6
• Volume
97. Mill J, Wallis B, Cuttle L, Mott J, Oakley A, Kimble R. Phytophotodermatitis: June 2018

J DD
case reports of children presenting with blistering after preparing lime juice. ISSN: 1545 9616

Burns. 2008;34(5):731-733.

AUTHOR CORRESPONDENCE
A SUPPLEM
ENT TO

J DD
Penelope Kallis BS BA
E-mail:................……................................... [email protected]

E
YING ACN
DEMYSTIF
MS
ALGORITH

Topical Vehi
cle Formulati
the Treatmen ons in
t of Acne

S
PREVIEW
PIPELINE
TRIAL REVIEW
DS CLINICAL
T ROUN
RESIDEN

ISSN: 1545 9616

June 2018 •

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Volume 17 •
Issue 6 ( SUP
PLEMENT)

Topical Vehicle Formulations

Penalties Apply
in the Treatment of Acne
Guest Editor, Leon H. Kircik MD

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Penalties Apply
Not an actual patient.

INDICATIONS AND USAGE eye can cause corneal injury (erosion, ulceration,
ESKATA™ (hydrogen peroxide) topical solution, 40% perforation, and scarring), chemical conjunctivitis,
(w/w) is indicated for the treatment of seborrheic eyelid edema, severe eye pain or permanent eye
keratoses that are raised. injury, including blindness. If accidental exposure
occurs, flush with water for 15 to 30 minutes, initiate
IMPORTANT SAFETY INFORMATION monitoring and further evaluation as appropriate.
WARNINGS AND PRECAUTIONS Skin reactions occurred in the treatment area after
Do not apply ESKATA to the eyes or mucous application of ESKATA. Severe local skin reactions
membranes. Avoid treating seborrheic keratoses included erosion, ulceration, vesiculation and
within the orbital rim. Direct contact with the scarring. Do not retreat until the skin has
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AVAILABLE TO ORDER

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.

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Visit ESKATAHCP.com to learn about
ordering, application, and more.

Penalties Apply

recovered from any reaction caused by the DOSAGE AND ADMINISTRATION

previous treatment. ESKATA is to be administered by a healthcare
provider. For topical use only. Not for oral,
MOST COMMON ADVERSE REACTIONS ophthalmic, or intravaginal use. Not for open or
The most common adverse reactions include
infected seborrheic keratoses.
erythema (99%), stinging (97%), edema (91%),
scaling (90%), crusting (81%), and pruritus (58%). Please see Brief Summary of full Prescribing
Information on the following page.
CONTRAINDICATIONS
None.
© 2018 Aclaris Therapeutics, Inc. All rights reserved. PP-ESK-0298 03/18 ESKATA is a trademark of Aclaris Therapeutics, Inc.
S:6.75”

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
Topical overdosing of ESKATA could result in an increased

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under widely varying conditions, adverse reaction rates observed
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

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in a total of 937 subjects with seborrheic keratoses that are raised. carcinogenic potential of ESKATA or hydrogen peroxide.
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
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June 2018 621 Volume 17 • Issue 6

Clinically Relevant Reduction in Persistent Facial Erythema of

Rosacea on the First Day of Treatment With Oxymetazoline
Cream 1.0%
Emil A. Tanghetti MD,a Jeffrey S. Dover MD FRCPC,b David J. Goldberg MD,c Sunil S. Dhawan MD,d
Lei Luo MPH,e David R. Berk MD,e Gurpreet Ahluwalia PhD,e and Nancy Alvandi PhDe
a
Center for Dermatology & Laser Surgery, Sacramento, CA
b
SkinCare Physicians, Chestnut Hill, MA
c
Skin Laser & Surgery Specialists of NY & NJ, New York, NY
d
Center for Dermatology Clinical Research, Inc, Fremont, CA
e
Allergan plc, Irvine, CA

ABSTRACT
Background: Persistent facial erythema is a clinically challenging feature of rosacea.
Objective: To evaluate persistent erythema reduction on the first day of treatment from pooled data from two pivotal trials of topical
oxymetazoline cream 1.0% (oxymetazoline) in persistent facial erythema of rosacea.
Methods: In two identically designed, phase 3, multicenter trials, adults with moderate to severe persistent facial erythema of rosacea
(Clinician Erythema Assessment [CEA] grade ≥3 and Subject Self-Assessment [SSA] grade ≥3) were randomized 1:1 to once-daily topi-
cal oxymetazoline or vehicle; the primary efficacy endpoint was ≥2-grade composite CEA and SSA improvement from baseline on day
29. This post hoc analysis evaluated the proportion of patients achieving ≥1-grade composite and individual CEA and SSA improvement
at 1, 3, 6, 9, and 12 hours postdose on day 1 (N=885).
Results: Significantly more patients achieved ≥1-grade composite and individual CEA and SSA improvement with the first application of
oxymetazoline than with vehicle (P<0.001) at all postdose time points, beginning with hour 1. Day 1 safety assessments were similar
between treatments.
Limitations: Short-term, post hoc analysis.
Conclusions: A ≥1-grade improvement in persistent erythema achieved after the first dose of once-daily topical oxymetazoline demon-

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strated clinically meaningful improvement from the beginning of therapy.

J Drugs Dermatol. 2018;17(6):621-626.

INTRODUCTION Penalties Apply

R
osacea is a chronic dermatologic disease that affects In 2017, the US Food and Drug Administration (FDA) approved oxy-
approximately 16 million people in the United States.1,2 metazoline hydrochloride cream 1.0% (oxymetazoline; Rhofade™,
Its features include centrofacial persistent erythema, Allergan plc, Dublin, Ireland), the first α1A-adrenoceptor agonist
flushing, telangiectasia, and/or papules and pustules.3-5 that causes vasoconstriction of the cutaneous microvasculature,
for the topical treatment of persistent facial erythema associated
Persistent facial erythema is the most common, bothersome, with rosacea in adults.10,16,17 Data from two identically designed,
and therapeutically challenging feature of rosacea.3,6-9 Most phase 3, pivotal, vehicle-controlled trials (REVEAL) demonstrated
approved topical pharmacologic agents for rosacea reduce that oxymetazoline applied topically once daily for 29 days signifi-
the papules and pustules but are unable to address persistent cantly reduced moderate to severe persistent facial erythema of
erythema. They lack the appropriate mechanism to target the rosacea at 3, 6, 9, and 12 hours postdose on day 29 and was safe
underlying fixed changes in superficial cutaneous vasculature, and well tolerated over 4 weeks.18,19 The primary efficacy endpoint
which are regulated by adrenoceptors at the neuromuscular of these studies was a 2-grade or greater composite improvement
junction that mediate vasoconstriction and vasodilation.7,10-13 from baseline scores on the Clinician Erythema Assessment (CEA)
Most patients prefer rosacea therapies that show a rapid and scale with photonumeric guide and Subject Self-Assessment for
noticeable clinical benefit for persistent erythema from the be- rosacea facial redness (SSA) scale with photo guide. Although
ginning of therapy. An immediate reduction of erythema may the 2-grade or greater composite clinician- and patient-assessed
affect the likelihood that patients will continue with long-term improvement in rosacea facial redness satisfies FDA criteria for
treatment for this chronic disease.7,8,14,15 rosacea indication approval, this outcome is not the only clinically
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622
Journal of Drugs in Dermatology E.A. Tanghetti, J.S. Dover, D.J. Goldberg, et al
June 2018 • Volume 17 • Issue 6

meaningful indicator of erythema improvement; a 1-grade or area; uncontrolled systemic disease or confounding diseases of
greater change is another well-described, reliable measure of no- the vascular system; known hypersensitivity to oxymetazoline;
ticeable improvement in erythema.20-22 characteristics that would interfere with erythema assessments;
or current treatment with related or similarly acting medications.
The objective of the present post hoc analysis was to evaluate
pooled data from the 2 pivotal phase 3 REVEAL trials on persis- Efficacy Assessments
tent erythema reduction, assessing the proportion of patients Proportions of patients with at least 1-grade composite CEA and
achieving at least 1-grade composite and individual CEA and SSA decrease (improvement) from baseline, as well as at least
SSA improvement with oxymetazoline versus placebo on the 1-grade improvement in individual CEA and SSA scores from base-
first day of treatment at 5 postdose time points. line, were evaluated on day 1 at 1, 3, 6, 9, and 12 hours postdose.

METHODS Safety Assessments

Study Design and Treatment Safety assessments included tabulation of overall and treat-
Two previously described, identically designed, phase 3, ment-related TEAEs for oxymetazoline and vehicle on day 1 of
randomized, multicenter, double-blind, parallel-group, vehicle- treatment. Dermal tolerability on day 1, including patient-rated
controlled trials were conducted in the United States: REVEAL pruritus and stinging/burning and clinician-rated dryness and
trial 1 (Clinicaltrials.gov identifier NCT02131636), which was scaling, scored from 0 (none) to 3 (severe), was also assessed.
conducted May to December 2014 across 20 centers, and RE-
VEAL trial 2 (Clinicaltrials.gov identifier NCT02132117), which Patient-Reported Outcome
was conducted June 2014 to May 2015 across 24 centers.18,19 Patient satisfaction was assessed on day 1 predose and at 3, 6,
9, and 12 hours postdose using item 1 of the validated 10-item
Patients in both studies were randomized 1:1 to topical appli- Satisfaction Assessment for Rosacea Facial Redness (SAT-RFR)
cation of oxymetazoline or vehicle cream once each morning. questionnaire, which asked whether patients were satisfied with
They were instructed to apply a pea-sized amount of medica- appearance of facial skin redness. The patients responded using a
tion in a thin layer covering the entire face. 5-point scale from 0 (very dissatisfied) to 4 (very satisfied). Change
from baseline in satisfaction with appearance of facial skin red-
Patients ness was determined for each postdose time point on day 1.
The studies enrolled adults ages 18 years and older who met in-
Statistical Analysis

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clusion and exclusion criteria published previously18,19; briefly, all
patients had moderate to severe persistent facial erythema asso- All efficacy assessments were conducted on the intent-to-treat
ciated with rosacea, defined as CEA and SSA grade 3 or 4 (Table population, which included all randomized patients. Multiple
1), and were excluded if they had more than 3 papules/pustules imputation was used to impute missing values in the pooled

Penalties Apply
on the face; other dermatologic conditions within the treatment dataset. The Markov chain Monte Carlo method was used to
create 20 imputations. The variables included in the multiple
imputation model were age, visit, time point, and CEA score.
TABLE 1.
A Cochran-Mantel-Haenszel model stratified by investigational
CEA and SSA Scale Descriptions site was used to obtain P values for between-treatment com-
Grade CEA Scale Descriptiona SSA Scale Descriptiona parisons for each time point on day 1. The adjusted difference
Clear skin with no signs No signs of unwanted between treatments at each time point and 95% confidence in-
0 tervals (CIs) were calculated using the Mantel-Haenszel method
of erythemab redness
Almost clear; Almost clear of unwanted adjusted for investigational site. Correlations between the SSA
1 and SAT-RFR item 1 and between the CEA and SAT-RFR item
slight redness redness
1 were conducted on the intent-to-treat population based on
Mild erythema;
2 Mild redness the Pearson correlation coefficient. All safety assessments were
definite redness
conducted on the safety population, which included all patients
Moderate erythema;
3 Moderate redness who were treated with at least 1 application of study treatment.
marked redness
Descriptive statistics were used for the safety analysis.
Severe erythema;
4 Severe redness
fiery redness
RESULTS
CEA, Clinician Erythema Assessment; SSA, Subject Self-Assessment for Patients
rosacea facial redness.
a
All assessments were made using photo guides; postbaseline assessments The pooled population comprised 885 patients, 440 in REVEAL
were made by clinicians and patients without access to photos from prior trial 1 and 445 in REVEAL trial 2. Patients were primarily female
assessments.
b
Normal healthy skin color as seen in individuals without rosacea. with Fitzpatrick skin phototypes II or III (Table 2).
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623
Journal of Drugs in Dermatology E.A. Tanghetti, J.S. Dover, D.J. Goldberg, et al
June 2018 • Volume 17 • Issue 6

TABLE 2. FIGURE 1. Persistent facial erythema of rosacea: Significant

Demographics and Baseline Characteristics of Pooled Study improvement of erythema on day 1 with oxymetazoline versus vehicle
Population (N=885)a shown by at least 1-grade composite improvement in CEA and SSA.
CEA, Clinician Erythema Assessment;
Oxymetazoline Vehicle SSA, Subject Self-Assessment for rosacea facial redness.
Characteristic
(n=446) (n=439) ‡
P<0.001 for oxymetazoline versus vehicle at all postdose time points.

Age, y 100 Oxymetazoline (n=446)

Patients Achieving CEA and SSA

Vehicle (n=439)

Composite ≥1-Grade Change, %

Mean (SD) 49.9 (12.8) 49.9 (12.3)
80
Range 18–88 19–87
Sex, n (%) 58.8‡
60 54.4‡ 52.9‡
Female 349 (78.3) 348 (79.3)
40.3‡
Male 97 (21.7) 91 (20.7) 40
Race/ethnicity, n (%) 22.6‡

Caucasian 404 (90.6) 391 (89.1) 20 23.3 23.7

19.7 19.1
Hispanic 36 (8.1) 36 (8.2)
8.0
0
Asian 3 (0.7) 6 (1.4) 1 3 6 9 12
Black 3 (0.7) 1 (0.2) Postdose Hour on Day 1
Other 0 (0) 5 (1.1) 58.8% vs 23.3% at hour 6, 52.9% vs 23.7% at hour 9, and 40.3%
Fitzpatrick skin phototype, n (%)b vs 19.1% at hour 12.
I 44 (9.9) 36 (8.2)
On day 1, significantly more patients treated with oxymetazo-
II 224 (50.2) 217 (49.4)
line also achieved at least 1-grade improvement in individual
III 139 (31.2) 135 (30.8) CEA and SSA scores at hour 1 (CEA: 54.6% vs 30.3%; SSA:
IV 35 (7.8) 43 (9.8) 29.9% vs 17.1%; P<0.001) and maintained this response through
V 2 (0.4) 8 (1.8) hour 12 compared with vehicle recipients (CEA: 81.9% vs 48.9%
at hour 3, 78.9% vs 51.9% at hour 6, 73.0% vs 47.2% at hour
VI 2 (0.4) 0 (0)

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9, 59.8% vs 39.3% at hour 12; SSA: 58.5% vs 28.4% at hour 3,
Baseline CEA, n (%) c
64.2% vs 34.3% at hour 6, 62.6% vs 38.6% at hour 9, 56.3% vs
3 381 (85.4) 378 (86.1) 34.7% at hour 12; P<0.001 for all time points; Figure 2A and 2B).
4 65 (14.6) 61 (13.9)

Penalties Apply
From hour 3 through hour 12 on day 1, a significantly great-
Baseline SSA, n (%) c

er proportion of patients treated with oxymetazoline who

3 413 (92.6) 394 (89.7) achieved at least a 1-grade improvement from baseline in com-
4 32 (7.2) 45 (10.3) posite CEA and SSA scores responded that they were satisfied
CEA, Clinician Erythema Assessment;
or very satisfied with the appearance of their facial redness
SSA, Subject Self-Assessment for rosacea facial redness. compared with patients who did not reach this level of improve-
a
REVEAL trial 1, N=440; REVEAL trial 2, N=445.
b
Fitzpatrick skin phototype scale: I=ivory white (pale white) skin; II=white or
ment (patients with ≥1-grade composite improvement: 37% to
fair skin; III=medium-white skin; IV=beige or lightly tanned or olive skin; 46%; patients without ≥1-grade composite improvement: 8% to
V=moderate-brown or tanned brown skin; VI=dark brown or black skin.
c
Per inclusion criteria, all patients had CEA and SSA grade of 3 or 4 at base-
14%; P<0.001; Figure 3). Patient satisfaction with appearance of
line; 1 patient with an SSA of 2 was mistakenly enrolled and included in facial redness was significantly associated with achievement of
the intent-to-treat population but did not receive study medication.
at least a 1-grade change in CEA score (Pearson correlation co-
efficient [r]: −0.23 [95% CI, −0.32 to −0.14] at hour 3; −0.25 [−0.33
Efficacy to −0.16] at hour 6; −0.26 [−0.35 to −0.17] at hour 9; −0.34 [−0.42
On day 1, a significantly greater proportion of patients achieved to −0.25] at hour 12; P<0.001 for all time points) and SSA score
at least 1-grade composite CEA and SSA improvement with oxy- (r: −0.55 [−0.61 to −0.48] at hour 3; −0.58 [−0.64 to −0.51] at hour
metazoline than with vehicle at hour 1 (22.6% vs 8.0%; P<0.001; 6; −0.56 [−0.62 to −0.49] at hour 9; −0.59 [−0.65 to −0.53] at hour
Figure 1). A statistically significant difference in the proportion 12; P<0.001 for all time points).
of patients achieving at least 1-grade composite CEA and SSA
improvement favoring oxymetazoline (P<0.001, all time points) Figure 4 displays photographs illustrating representative im-
was maintained throughout the 12-hour observation period on provements in facial erythema at each postdose time point on
day 1; composite improvement was 54.4% vs 19.7% at hour 3, day 1 for patients treated with oxymetazoline.
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624
Journal of Drugs in Dermatology E.A. Tanghetti, J.S. Dover, D.J. Goldberg, et al
June 2018 • Volume 17 • Issue 6

FIGURE 2. Persistent facial erythema of rosacea: Significant improvement of erythema on day 1 with oxymetazoline versus vehicle shown by at
least 1-grade improvement in individual CEA scores (A) and individual SSA scores (B).
CEA, Clinician Erythema Assessment; SSA, Subject Self-Assessment for rosacea facial redness.
‡
A vehicle at all postdose time points.
P<0.001 for oxymetazoline versus B
Oxymetazoline (n=446) Vehicle (n=439)
(A) (B)
100 100

81.9‡
78.9‡
Patients Achieving CEA

Patients Achieving SSA

80 73.0‡ 80

≥1-Grade Change, %
≥1-Grade Change, %

64.2‡ 62.6‡
59.8‡ 58.5‡ 56.3‡
60 54.6‡ 60

51.9
40 48.9 47.2 40
39.3 29.9‡
38.6
34.3 34.7
30.3 28.4
20 20
17.1

0 0
1 3 6 9 12 1 3 6 9 12
Postdose Hour on Day 1 Postdose Hour on Day 1

Safety TEAEs were application-site pain (n=1), application-site par-

Similar rates of treatment-emergent adverse events (TEAEs) esthesia (n=1), application-site pruritus (n=4), application-site
occurred with oxymetazoline versus vehicle on day 1 (2.9% warmth (n=1), and angioedema (n=1). In the original analysis
vs 3.6%; Table 3). One TEAE, headache, occurred in 1.1% of pa- of the individual trials, oxymetazoline and vehicle exhibited
tients in the vehicle group. All other TEAEs occurred in less than similar safety profiles over the 29-day treatment period, as has
1% of patients in each treatment group. There were no serious been reported.18,19 The patient-rated assessments of dermal
TEAEs reported in either treatment group. Treatment-related tolerability, which included at least 1 severity grade increase
TEAEs occurred in 1.6% of patients in each treatment group. from baseline in pruritus and stinging/burning, were similar

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In the oxymetazoline group, the treatment-related TEAEs were on day 1 in the oxymetazoline (7.6% and 10.3%, respectively)
application-site paresthesia (n=1), application-site pruritus and vehicle groups (7.8% and 11.9%). The clinician-rated as-
(n=2), application-site warmth (n=1), seborrhea (n=1), and skin sessments, at least 1 severity grade increase from baseline in
tightness (n=2). In the vehicle group, the treatment-related dryness and scaling, also were similar in the treatment groups

Penalties Apply
on day 1 (oxymetazoline: 4.9% and 1.8%, respectively; vehicle:
4.3% and 1.1%). As reported previously, the dermal tolerability
FIGURE 3. Proportion of patients treated with oxymetazoline (n=446) assessments remained similar for oxymetazoline and vehicle
who were satisfied or very satisfied with appearance of facial throughout treatment.18,19
redness, by achievement of at least a 1-grade improvement from
baseline in composite CEA and SSA scores on day 1. Hour 1 data DISCUSSION
are not available because the patient-reported outcome tool that
assessed satisfaction was administered at 3, 6, 9, and 12 hours This analysis of pooled results from the two identically de-
postdose on day 1. signed phase 3, pivotal REVEAL trials shows that once-daily
‡
P<0.001. topical oxymetazoline 1.0% significantly improved moderate
100 Patients who achieved ≥1-grade improvement to severe persistent facial erythema associated with rosacea
Patients who did not achieve ≥1-grade improvement compared with vehicle on the first day of application, reduc-
Patients Satisfied or Very

80 ing erythema by the first hour after application and throughout

the 12-hour observation period, as demonstrated by 1-grade or
Satisfied, %

60 greater composite improvement from baseline in CEA and SSA

46%‡
42%‡ 43%‡ scores, as well as individual CEA and SSA scores.
37%‡
40

Although the previously reported 2-grade or greater improve-

20 ment from baseline in CEA and SSA18,19 is a more stringent
8% 12% 14% criterion for treatment effect than the key outcome measure in
9%
0
3 6 9 12
the present analysis, improvement of erythema from baseline
Postdose Hour on Day 1 by at least 1 grade on the CEA and SSA scales was shown to
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625
Journal of Drugs in Dermatology E.A. Tanghetti, J.S. Dover, D.J. Goldberg, et al
June 2018 • Volume 17 • Issue 6

FIGURE 4. Persistent facial erythema of rosacea: Clinically relevant improvement in persistent facial erythema on day 1 demonstrated by at
least 1-grade composite improvement in CEA and SSA in photographs of representative patients receiving oxymetazoline in the REVEAL trials.
Notable is the natural appearance and lack of blanching of the facial skin throughout the dosing period. Patient 1 had a 1-grade composite CEA
and SSA improvement at hours 3, 6, 9, and 12 (A). Patient 2 had a 1-grade composite CEA and SSA improvement at hours 1, 6, 9, and 12; 2-grade
composite improvement was noted at hour 3 (B).
CEA, Clinician Erythema Assessment; SSA, Subject Self-Assessment for rosacea facial redness.
µ=≥1-grade improvement from baseline in CEA or SSA; µµ=≥1-grade improvement from baseline in both CEA and SSA.
(A) A
Baseline Day 1 1 Hour 3 Hours 6 Hours 9 Hours 12 Hours
Predose Postdose Postdose Postdose Postdose Postdose

CEA: 3

SSA: 3
B
(B) Baseline Day 1 1 Hour 3 Hours 6 Hours 9 Hours 12 Hours
Predose Postdose Postdose Postdose Postdose Postdose

CEA: 3

SSA: 3

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have clinical relevance. The proportion of patients who reported
being satisfied or very satisfied with the appearance of their
indeed a valuable reference point for representing a noticeable
change.22

Penalties Apply
facial redness was significantly associated with the achieve-
ment of at least a 1-grade improvement from baseline in CEA as Rosacea is a common dermatologic disease, the most frequent
well as SSA. Furthermore, the CEA score showed that at least characteristic of which is persistent facial erythema.6,9 Persis-
a 1-grade improvement represented a noticeable difference in tent erythema also is one of the most bothersome signs for
persistent erythema in 81.9% of patients in the oxymetazoline many patients with rosacea.6 These factors underscore the
group at hour 3, compared with 48.9% of patients in the vehicle need for patients with rosacea to successfully initiate and con-
group. The proportion of patients receiving oxymetazoline who tinue a treatment regimen for erythema. With oxymetazoline,
had at least a 1-grade improvement in the SSA score peaked once-daily application resulted in significant proportions of
at 64.2% at hour 6, compared with 34.3% in the vehicle group patients experiencing 1-grade or greater improvement in facial
at hour 6. The higher responder rates observed with the CEA erythema on the first day of treatment.
scale are consistent with those previously reported in the pri-
mary efficacy analysis of the individual trials.18,19 The authors Notably, on the first day of application, oxymetazoline and vehicle
of those reports observed that the greatest erythema improve- exhibited similar rates of TEAEs and had similar dermal tolerability.
ment occurred at hour 3 according to CEA scores as well as Although the phase 3 trials described herein reflect only short-term
digital image analysis. Corroboration of the CEA scores by the treatment, a phase 3, 52-week, open-label trial of patients with
objectivity of digital image analysis suggests that the physi- moderate to severe persistent erythema of rosacea previously
cians’ experience and training may render them more skilled demonstrated the long-term efficacy and safety of oxymetazoline.23
at detecting improvements in facial erythema than patients.
Overall, this analysis indicated that clinicians and patients alike CONCLUSION
recognize effects of treatment with oxymetazoline from the be- The pooled results from two identically designed, phase 3,
ginning of therapy, and that a 1-grade reduction in erythema is randomized, double-blind trials conducted in patients with
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Journal of Drugs in Dermatology E.A. Tanghetti, J.S. Dover, D.J. Goldberg, et al
June 2018 • Volume 17 • Issue 6

TABLE 3.
REFERENCES
Day 1 Safety and Tolerability Profile of Oxymetazoline Favorable
and Similar to Vehicle Profile 1. National Rosacea Society. Rosacea riddle now threatens more than 16 mil-
lion Americans [press release]. 2010. Available at: http://www.rosacea.org/
Oxymetazoline Vehicle press/archive/20100401.php. Accessed: March 9, 2016.
Event, n (%) 2. van der Linden MM, van Rappard DC, Daams JG, Sprangers MA, Spuls PI,
(n=445) (n=439)
de Korte J. Health-related quality of life in patients with cutaneous rosacea:
TEAEs 13 (2.9) 16 (3.6) a systematic review. Acta Derm Venereol. 2015;95(4):395-400.
3. Baldwin HE. Diagnosis and treatment of rosacea: state of the art. J Drugs
Serious TEAEs 0 (0) 0 (0) Dermatol. 2012;11(6):725-730.
4. Jackson JM, Knuckles M, Minni JP, Johnson SM, Belasco KT. The role of
Treatment-related
7 (1.6) 7 (1.6) brimonidine tartrate gel in the treatment of rosacea. Clin Cosmet Investig
TEAEs Dermatol. 2015;8:529-538.
5. Steinhoff M, Schmelz M, Schauber J. Facial erythema of rosacea - aetiol-
Treatment-related
0 (0) 0 (0) ogy, different pathophysiologies and treatment options. Acta Derm Venereol.
serious TEAEs 2016;96(5):579-586.
TEAEs occurring in ≥1% of patients 6. Tan J, Blume-Peytavi U, Ortonne JP, et al. An observational cross-sectional
survey of rosacea: clinical associations and progression between subtypes.
Headache 2 (0.4) 5 (1.1) Br J Dermatol. 2013;169(3):555-562.
7. Del Rosso JQ. Advances in understanding and managing rosacea: part 2: the
Dermal tolerability central role, evaluation, and medical management of diffuse and persistent
(≥1-grade severity Oxymetazoline Vehicle facial erythema of rosacea. J Clin Aesthet Dermatol. 2012;5(3):26-36.
worsening from (n=445) (n=437) 8. Lee WJ, Lee YJ, Lee MH, et al. Prognosis of 234 rosacea patients according
to clinical subtype: the significance of central facial erythema in the progno-
baseline), n (%)
sis of rosacea. J Dermatol. 2016;43(5):526-531.
Patient-rated 9. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clini-
34 (7.6) 34 (7.8) cal presentation, and new therapeutics. Exp Dermatol. 2017;26(8):659-667.
pruritus
10. Gold LM, Draelos ZD. New and emerging treatments for rosacea. Am J Clin
Patient-rated Dermatol. 2015;16(6):457-461.
46 (10.3) 52 (11.9) 11. Del Rosso JQ. Management of facial erythema of rosacea: what is the role
stinging/burning
of topical alpha-adrenergic receptor agonist therapy? J Am Acad Dermatol.
Clinician-rated 2013;69(6 Suppl 1):S44-S56.
22 (4.9) 19 (4.3) 12. Guimaraes S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev.
dryness
2001;53(2):319-356.
Clinician-rated 13. Johnson JM, Kellogg DL Jr. Thermoregulatory and thermal control in the hu-
8 (1.8) 5 (1.1) man cutaneous circulation. Front Biosci (Schol Ed). 2010;2:825-853.
scaling
14. Tanghetti EA, Jackson JM, Belasco KT, et al. Optimizing the use of topical
TEAE, treatment-emergent adverse event. brimonidine in rosacea management: panel recommendations. J Drugs Der-
matol. 2015;14(1):33-40.
15. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a pa-

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tient’s quality of life. Am Health Drug Benefits. 2013;6(6):348-354.
moderate to severe persistent facial erythema of rosacea dem- 16. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing
onstrate that the majority of patients and observers can expect of rosacea using a topically applied selective alpha1-adrenergic receptor ago-
nist, oxymetazoline. Arch Dermatol. 2007;143(11):1369-1371.
to see a 1-grade or greater improvement with oxymetazoline 17. Rhofade [package insert]. Irvine, CA: Allergan; 2017.

Penalties Apply
cream 1.0% from the beginning of therapy. 18. Baumann L, Goldberg DJ, Stein-Gold L, et al. Pivotal trial of the efficacy and
safety of oxymetazoline cream 1.0% for the treatment of persistent facial
erythema associated with rosacea: findings from the second REVEAL trial.
DISCLOSURES J Drugs Dermatol. 2018;17(3):611-619.
This study was sponsored by Allergan plc, Dublin, Ireland. 19. Kircik LH, DuBois J, Draelos ZD, et al. Pivotal trial of the efficacy and safety
of oxymetazoline cream 1.0% for the treatment of persistent facial erythema
Writing and editorial assistance was provided to the authors associated with rosacea: findings from the first REVEAL trial. J Drugs Der-
by Peloton Advantage, Parsippany, NJ, and was funded by Al- matol. 2018;17(1):97-105.
20. Schaller M, Schofer H, Homey B, et al. Rosacea management: update on
lergan plc. Neither honoraria nor other form of payments were general measures and topical treatment options. J Dtsch Dermatol Ges.
made for authorship. 2016;14 Suppl 6:17-27.
21. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L.
Interventions for rosacea. Cochrane Database Syst Rev. 2015(4):CD003262.
EA Tanghetti, JS Dover, DJ Goldberg, and SS Dhawan are in- 22. Fowler J, Tan J, Jackson JM, et al. Treatment of facial erythema in patients
vestigators for Allergan plc. L Luo, DR Berk, and N Alvandi are with rosacea with topical brimonidine tartrate: correlation of patient satisfac-
tion with standard clinical endpoints of improvement of facial erythema. J
employees of Allergan plc, and G Ahluwalia was an employee Eur Acad Dermatol Venereol. 2015;29(3):474-481.
of Allergan plc at the time that the analysis was conducted; all 23. Draelos ZD, Gold MH, Weiss RA, et al. Efficacy and safety of oxymetazo-
line cream 1.0% for treatment of persistent facial erythema associated with
may own stock/stock options in that company. rosacea: findings from the 52-week open label REVEAL trial. J Am Acad
Dermatol. 2018 Jan 31 [Epub ahead of print].
ACKNOWLEDGMENTS
AUTHOR CORRESPONDENCE
Writing and editorial assistance was provided to the au-
thors by Regina Kelly, MA, and Jennifer L. Darby, PharmD
Emil A. Tanghetti MD
of Peloton Advantage, LLC, Parsippany, NJ, and was funded
E-mail:................……............. [email protected]
by Allergan plc, Dublin, Ireland. All authors meet the ICMJE
authorship criteria.
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June 2018 632 Volume 17 • Issue 6

Frequency of Treatment Switching for Spironolactone

Compared to Oral Tetracycline-Class Antibiotics for Women
With Acne: A Retrospective Cohort Study 2010-2016
John S. Barbieri MD MBA,a Juliana K. Choi MD PhD,a,b Nandita Mitra PhD,c David J. Margolis MD PhDa,c
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
a

b
Department of Veteran Affairs, Philadelphia, PA
c
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA

ABSTRACT
Background: Long-term oral antibiotic use in acne may be associated with a variety of adverse effects including antibiotic resistance,
pharyngitis, inflammatory bowel disease, and breast and colon cancer. Spironolactone may represent an effective and safe alternative
to oral antibiotics for women with moderate to severe acne, however comparative studies are lacking.
Methods: Using the OptumInsight™ Clinformatics™ DataMart, we conducted a retrospective analysis of the frequency of switching
to a different systemic agent within the first year of therapy among women with acne who were started on either spironolactone or an
oral tetracycline-class antibiotic between 2010-2016, after controlling for age, topical retinoid, and oral contraceptive use.
Results: Among women with acne who were started on spironolactone, 14.4% were prescribed a different systemic agent within one
year, compared with 13.4% started on an oral tetracycline-class antibiotic. After adjusting for age, topical retinoid, and oral contracep-
tive use, the odds ratio for being prescribed a different systemic agent within one year was 1.07 (95% CI 0.99-1.16) for those prescribed
spironolactone when compared with oral tetracycline-class antibiotics and the risk difference was 0.007 (95% CI -0.002-0.017).
Conclusions: Based on the observation of similar switching between the two groups, spironolactone may have similar clinical effec-
tiveness to that of oral tetracycline-class antibiotics. While ultimately large clinical trials are needed to determine the optimal manage-
ment strategy for women with moderate to severe acne, these results provide additional support that spironolactone represents an
effective treatment for women with acne.

J Drugs Dermatol. 2018;17(6):632-638.

INTRODUCTION
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A Penalties Apply
cne is one of the most common diseases worldwide, antibiotics and its use is becoming more common over time.5,22–27
affecting 85% of adolescents. In addition, acne often However, despite expert opinion supporting the use of spirono-
persists into adulthood, with over 50% of women re- lactone in the treatment of acne, spironolactone is not approved
porting acne between 20-29 years of age and over 35% be- by the Food and Drug Administration for this indication and clini-
tween 30-39 years of age.1,2 While topical agents are typically cal evidence demonstrating the effectiveness of spironolactone
sufficient for mild acne, moderate to severe acne often requires is limited to small studies.24–27 The objective of this study was to
treatment with systemic agents, such as oral antibiotics, spi- compare the outcomes with spironolactone and oral tetracycline-
ronolactone, and isotretinoin.3 class antibiotics among a large, broadly representative population
of women with acne. Specifically, this study sought to characterize
Oral antibiotics are the most common systemic agent used in the the frequency with which women who are started on either spi-
treatment of acne and dermatologists prescribe more antibiot- ronolactone or an oral tetracycline-class antibiotic subsequently
ics per capita than any other specialty.4,5 However, antibiotic use switch to a different systemic agent within the first year of therapy,
may be associated with a variety of adverse outcomes including since this switching may reflect treatment failure, whether due to
antibiotic resistance, pharyngitis, inflammatory bowel disease, lack of efficacy, side-effects, cost, or other reasons.28
and colon and breast cancer.6–15 As a result, there have been
calls to reduce overuse of antibiotics throughout medicine and METHODS
multiple guidelines regarding the treatment of acne recommend Data Source
limiting the duration of therapy with oral antibiotics.16–20,3,21 This study was a retrospective analysis using the OptumInsight™
Clinformatics™ DataMart (OptumInsight, Eden Prairie, MN) be-
For women with moderate to severe acne, spironolactone may tween 2010 and 2016. The OptumInsight Clinformatics DataMart
represent an effective, safe, and well-tolerated alternative to oral includes de-identified commercial claims data for approximately
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633
Journal of Drugs in Dermatology J.S. Barbieri, J.K. Choi, N. Mitra, D.J. Margolis
June 2018 • Volume 17 • Issue 6

12-14 million annual covered lives in the United States. The reflect treatment failure, either due to lack of efficacy, side-ef-
patient population included in the dataset are broadly repre- fects, cost, or other reasons, this outcome was selected as a
sentative of the demographics of the United States population surrogate marker for clinical effectiveness. Given that patients
with respect to gender, age, and geographic distribution. These with acne are often young and without significant comorbidi-
data include both medical and pharmacy claims, as well as pa- ties, and since systemic acne treatments typically have narrow
tient demographic information such as age and gender. indications, any observation of switching is likely to have
clinical relevance. In addition, prior work to evaluate clinical
Study Design and Study Population effectiveness of antibiotics using large administrative datasets
Inclusion criteria were (1) women who were enrolled in the has taken a similar approach.28 Secondary outcomes included
OptumInsight Clinformatics DataMart with at least two claims the timing of the change in therapy and the percentage of pa-
associated with an International Classification of Diseases (ICD) tients on each systemic therapy at time points 90, 180, 270,
Ninth or Tenth Revision code for acne separated by 12 months, and 360 days after starting the index medication. In addition,
(2) at least 6 months of continuous enrollment in the dataset subgroup analyses were conducted among adolescents, who
before the start date of the index course of therapy without any were defined as being age 16 to 20 at the start of treatment, and
prescriptions for spironolactone, an oral antibiotic, or isotreti- adults, who were defined as being age 21 or older as the start of
noin during this period, (3) at least 12 months of continuous treatment.35 Subgroup analyses were also performed compar-
enrollment in the dataset after the start of the index course ing the three most commonly prescribed oral tetracycline-class
of therapy, and (4) who were between 16 and 35 years of age antibiotics to spironolactone.
at the start date of the index course of therapy were included
in the study. Previous studies have validated the accuracy of Statistical Analysis
ICD codes to identify patients with acne.29 A 6-month period Descriptive statistics are presented using means, medians, and
of continuous enrollment before the index course of therapy percentages as appropriate for the outcomes of interest. In ad-
was chosen to increase the probability that the index course dition, the odds ratio and absolute risk difference for switching
of therapy was the initial treatment for these patients. An age to a different systemic agent within the first year of therapy
cutoff of 35 years was chosen since acne is less common after were calculated using logistic regression. Since topical reti-
this age and to reduce the likelihood of including patients with noids and oral contraceptive pills are effective agents in acne
rosacea rather than acne.2 Exclusion criteria included an ICD and are also often prescribed to women on spironolactone
code for rosacea, since systemic antibiotics are also commonly and oral antibiotics, we adjusted for whether the patient had

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used for this condition. received any prescriptions for topical retinoids or oral contra-
ceptives prior to starting the index therapy or concurrently with
Prescriptions for spironolactone, oral antibiotics, and isotreti- the index therapy, in addition to adjusting for age at the start
noin were identified by their National Drug Codes. Prescriptions of treatment, using a multivariable logistic model.38–41 In any

Penalties Apply
were consolidated into courses of therapy with the start date observational study, there is a concern that unmeasured con-
defined as the date of the first prescription of the series and founding could lead to biased estimates. Since claims data do
the end date defined as the date of the last prescription in the not contain information about acne severity, which could be a
series plus the number of days of medication supplied. To ac- potential confounding variable, a formal sensitivity analysis
count for non-adherence that could result in delays between was performed to assess the impact of differing acne severity
prescriptions, prescriptions separated by fewer than 30 days between the spironolactone and oral tetracycline-class anti-
were considered to be part of the same course of therapy.30–36 biotic groups on the primary outcome of interest.42 Statistical
Courses shorter than 30 days were excluded to avoid includ- analyses were performed in Stata 14 (StataCorp, College Sta-
ing prescriptions for acute illnesses (eg, Lyme disease, Rocky tion, Texas) and R version 3.1 (The R Foundation for Statistical
Mountain Spotted Fever). The index therapy was defined as Computing, Vienna, Austria). The Institutional Review Board of
the first course of therapy with either spironolactone or an oral the University of Pennsylvania has granted a blanket exemption
tetracycline-class antibiotic prescribed to patients who had not for all research completed at the University of Pennsylvania us-
received any previous courses of oral antibiotics, spironolac- ing OptumInsight data.
tone, or isotretinoin.
RESULTS
The primary outcome was the frequency with which patients Cohort
were switched to a course of therapy or to combination therapy The characteristics of the study population are summarized
with a different systemic agent used in the treatment of acne in Table 1. There were 6,684 and 31,614 unique women who
(ie, oral antibiotic, spironolactone, or isotretinoin) within the were started on spironolactone and oral tetracycline-class
first year after starting treatment with either spironolactone antibiotics as the index systemic therapy, respectively. The
or an oral tetracycline-class antibiotic.28,37 Since switching may most frequent tetracycline-class antibiotics prescribed were
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634
Journal of Drugs in Dermatology J.S. Barbieri, J.K. Choi, N. Mitra, D.J. Margolis
June 2018 • Volume 17 • Issue 6

TABLE 1.
Characteristics of the Study Population
Spironolactone Tetracycline
Adolescents Adults Overall Adolescents Adults Overall
(N=1,139) (N=5,545) (N=6,684) (N=17,349) (N=14,265) (N=31,614)
Age at time of index
therapy, y, median 18 (17-19) 28 (25-32) 27 (22-31) 17 (16-19) 27 (23-31) 20 (17-26)
(IQR)
Prior treatment with
557 (48.9) 1835 (33.1) 2392 (35.8) 8473 (48.8) 6892 (48.3) 13768 (43.6)
topical retinoid, n (%)
Prior treatment with
oral contraceptive, 519 (45.6) 3227 (58.2) 3746 (56.0) 3658 (21.1) 7369 (51.7) 11027 (34.9)
n (%)
Days in Optum prior to
index therapy, median 2404 (968-3730) 1544 (628-3089) 1657 (661-3268) 2214 (1009-3651) 1452 (640-2898) 1843 (798-3408)
(IQR)
Days in Optum after
index therapy, median 948 (645-1436) 914 (623-1368) 918 (625-1376) 1116 (726-1628) 1048 (697-1530) 1086 (714-1588)
(IQR)

minocycline (34%), doxycycline hyclate (33%), extended-re- Subgroup and Secondary Analyses
lease minocycline (21%), doxycycline monohydrate (8%), and Among adolescent women, the adjusted odds ratio for being
low-dose extended-release doxycycline (3%). prescribed a different systemic agent within one year was 1.58
(95% CI 1.35-1.86) for those prescribed spironolactone when
Frequency of Therapeutic Switching compared with oral tetracycline-class antibiotics and the risk
Among women with acne who were started on spironolac- difference was 0.060 (95% CI 0.039-0.080). The number of ado-
tone, 14.4% were prescribed a different systemic agent within lescent women needed to treat with an oral tetracycline-class
1 year. Among women with acne who were started on oral antibiotic instead of spironolactone to prevent one instance of

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tetracycline-class antibiotics, 13.4% were prescribed a differ- therapeutic switching was 17 women. Among adult women, the
ent systemic agent within 1 year (Table 2). When adjusted for adjusted odds ratio for being prescribed a different systemic
age, topical retinoid, and oral contraceptive use, the odds ratio agent within one year was 0.94 (95% CI 0.86-1.03) for those
for being prescribed a different systemic agent within one year prescribed spironolactone when compared with oral tetracy-

Penalties Apply
was 1.07 (95% CI 0.99-1.16) for those prescribed spironolactone cline-class antibiotics and the risk difference was -0.007 (95%
when compared with oral tetracycline-class antibiotics and the CI -0.018-0.004).
risk difference was 0.007 (95% CI -0.002-0.017). The number of
women needed to treat with an oral tetracycline-class antibiotic Compared to spironolactone, doxycycline was the oral
instead of spironolactone to prevent one instance of switching tetracycline-class antibiotic that was least likely to be
was 143 women. switched. The adjusted odds ratio for being prescribed a

TABLE 2.
Frequency of Switching to Alternative Systemic Agents Within the First Year of Therapy With Either Spironolactone or an Oral
Tetracycline Antibiotic
Spironolactone Tetracycline
Adolescents Adults Overall Adolescents Adults Overall
(N=1,139) (N=5,545) (N=6,684) (N=17,349) (N=14,265) (N=31,614)
Spironolactone - - - 3.10% 7.70% 5.20%
Tetracycline 11.90% 8.70% 9.20% - - -
Other Antibiotic† 3.50% 1.80% 2.10% 4.50% 3.00% 3.80%
Isotretinoin 4.10% 3.80% 3.90% 5.80% 4.40% 5.10%
Any Systemic Agent 18.50% 13.50% 14.40% 12.70% 14.30% 13.40%

Other antibiotic includes trimethoprim-sulfamethoxazole, amoxicillin, cephalexin, and azithromycin.

635
Journal of Drugs in Dermatology J.S. Barbieri, J.K. Choi, N. Mitra, D.J. Margolis
June 2018 • Volume 17 • Issue 6

TABLE 3.
Median Days Before Switching to Alternative Systemic Agents for Women With Acne Who Were Started on Spironolactone or an Oral
Tetracycline Antibiotic
Spironolactone Tetracycline
Adolescents Adults Overall Adolescents Adults Overall
(N=1,139) (N=5,545) (N=6,684) (N=17,349) (N=14,265) (N=31,614)
Spironolactone, days,
- - - 204 (98-294) 154 (74-253) 167 (83-266)
median (IQR)
Tetracycline, days,
131 (61-235) 102 (52-211) 106 (55-220) - - -
median (IQR)
Other Antibiotic†, days,
101 (58-233) 135 (67-224) 131 (61-228) 174 (86-271) 147 (78-246) 166 (84-262)
median (IQR)
Isotretinoin, days,
204 (92-291) 164 (105-257) 167 (102-265) 209 (125-287) 187 (113-280) 200 (21-282)
median (IQR)
†
Other antibiotic includes trimethoprim-sulfamethoxazole, amoxicillin, cephalexin, and azithromycin.

different systemic agent within one year was 1.28 (95% CI A sensitivity analysis to assess the potential impact of dif-
1.16-1.42) for those prescribed spironolactone when com- fering acne severity between the spironolactone and oral
pared with doxycycline hyclate, 0.99 (95% CI 0.90-1.09) for tetracycline-class antibiotic groups on the primary outcome
those prescribed spironolactone when compared with mi- is available in Table 4. In this analysis, the adjusted odds ratio
nocycline, and 1.10 (95% CI 0.99-1.23) for those prescribed did not change substantially from the original estimate across
spironolactone when compared with low-dose extended- a range of values for the prevalence of severe acne between
release minocycline. the two groups. In many plausible scenarios, the odds ratio
for switching becomes smaller and favors spironolactone. In
Switching from spironolactone to isotretinoin occurred af- other scenarios, the odds ratio does become more significant,
ter a median of 167 days (IQR 102-265 days). Switching from but under most plausible scenarios, the odds ratio does not
oral tetracycline-class antibiotics to isotretinoin occurred after become larger than 1.16 (95% CI 1.08-1.26).

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a median of 200 days (IQR 121-282 days) (Table 3). Figure 1
summarizes the systemic agents being prescribed to patients DISCUSSION
at time points 90, 180, 270, and 360 days after starting either In this large, retrospective study, the frequency of switching
spironolactone or an oral tetracycline-class antibiotic. to another systemic agent within the first year of treatment

Penalties Apply
FIGURE 1. Systemic therapies being prescribed following the index therapy. Systemic therapies prescribed at the start date of the index therapy
and at 90, 180, 270, and 360 days after starting spironolactone (A) or an oral tetracycline-class antibiotic overall (B). Other antibiotics includes
trimethoprim-sulfamethoxazole, amoxicillin, cephalexin, and azithromycin.
Spiro-Tetra: Combined therapy with spironolactone and a tetracycline. Spiro-Antibiotics: Combination therapy with spironolactone and another non-tetracycline antibiotic.

636
Journal of Drugs in Dermatology J.S. Barbieri, J.K. Choi, N. Mitra, D.J. Margolis
June 2018 • Volume 17 • Issue 6

was similar among women with acne who were started on on spironolactone. Since switching may reflect treatment fail-
spironolactone compared with those started on oral tetracy- ure, whether due to lack of efficacy, side-effects, cost, or other
cline-class antibiotics. In addition, the frequency of switching factors, these results suggest that spironolactone may have
to isotretinoin was more common among women who were similar clinical effectiveness to oral tetracycline-class antibiot-
started on oral tetracycline-class antibiotics than those started ics, particularly for adult women.

TABLE 4. Compared to oral antibiotics, spironolactone represents an

Sensitivity Analysis enticing therapeutic alternative for women with moderate to
severe acne, with a favorable side-effect profile.43 While spi-
In this sensitivity analysis, we evaluated the potential impact of differing
prevalence of severe acne between the group started on spironolactone ronolactone is pregnancy category C and contraception is
and the group started on oral tetracycline-class antibiotics. This analysis recommended for patients on spironolactone due to concerns
is important because the claims data used in this study do not contain
information about acne severity. As a result, if either the spironolactone about potential feminization of the fetus, oral tetracycline-
or the oral tetracycline-class antibiotic group were to include patients with class antibiotics are also contraindicated in pregnancy and are
more severe acne, this difference could bias our results to favor the group
with less severe acne (of note this is a theoretical risk and there may in category D.44,45 Although there have been concerns about a po-
fact be no significant difference in acne severity between the two groups). tential association between spironolactone and breast cancer
To determine the impact of this potential source of bias, in this analysis
we simulated theoretical scenarios where we assume a difference in acne based on animal studies, large population-based studies have
severity between the two groups. We varied the prevalence of severe acne not confirmed such a risk;43,46,47 in contrast, there is evidence
between 0.15 and 0.35 and we varied the odds of switching therapy for
patients with severe acne compared to those with moderate acne from 1.1 that pronged antibiotic use may be associated with increased
to 2.0. Notably, after accounting for acne severity, the adjusted odds ratio risk of breast and colon cancer.7,14 In addition, recent work has
did not change substantially from the original estimate. Additionally, for
many plausible scenarios, the odds ratio for switching becomes smaller suggested that potassium monitoring is not required in young,
and favors spironolactone. In other scenarios the odds ratio does become healthy women.48 Given that oral antibiotics are included in the
more significant in favor of oral tetracycline-class antibiotics, but under
most plausible scenarios, the odds ratio does not become larger than 1.16 first-line therapeutic regimens for moderate to severe acne,
(95% CI 1.08-1.26). These results highlight that a theoretical difference in spironolactone may represent a favorable alternative therapy,
severity of illness between the two groups is unlikely to have a significant
effect on the primary outcome.
especially for adult women.3

Prevalence of Odds of Adjusted odds

Prevalence of In addition, smaller studies have suggested that spironolactone
severe acne for switching ratio for switching
severe acne for
those started on if severe if started on is effective for women with all types of acne, not only for wom-
those started on
oral tetracycline acne versus spironolactone
spironolactone
antibiotics moderate acne (95% CI) en with acne on the lower face or acne characterized by flares

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associated with the menstrual cycle.22,23,25 It is likely that spi-
0.15 0.25 1.3 1.10 (1.02-1.19)
ronolactone is underutilized in the treatment of acne in women
0.25† 0.25† 1.3† 1.07 (0.99-1.16)†
and increased utilization of spironolactone may decrease reli-
0.35 0.25 1.3 1.04 (0.96-1.13) ance on oral antibiotics and associated complications from

Penalties Apply
0.25 0.15 1.3 1.04 (0.96-1.13) antibiotic use. Since oral antibiotics are currently used much
0.25 0.35 1.3 1.10 (1.02-1.19) more often than spironolactone, the opportunity to increase the
0.15 0.25 1.1 1.08 (1.00-1.17)
use of spironolactone for the treatment of acne in women is
substantial.5
0.25 0.25 1.1 1.07 (0.99-1.16)

0.35 0.25 1.1 1.06 (0.98-1.15)

In subgroup analyses, spironolactone compared favorably to oral
0.25 0.15 1.1 1.06 (0.98-1.15) tetracycline-class antibiotics among adults, while it performed in-
0.25 0.35 1.1 1.08 (1.00-1.17) feriorly to oral tetracycline-class antibiotics among adolescents.
0.15 0.25 1.5 1.12 (1.04-1.21) There are several potential explanations for this finding, includ-
0.25 0.25 1.5 1.07 (0.99-1.16)
ing that spironolactone is less effective for adolescents than
adults, that adolescents who are prescribed spironolactone have
0.35 0.25 1.5 1.02 (0.95-1.11)
more severe acne than adults, or that therapeutic expectations
0.25 0.15 1.5 1.02 (0.95-1.11)
differ among adolescents than adults. This latter explanation is
0.25 0.35 1.5 1.12 (1.03-1.21) important to consider, as adolescents may expect more rapid im-
0.15 0.25 2.0 1.16 (1.08-1.26) provement in their acne or have more significant concerns about
0.25 0.25 2.0 1.07 (0.99-1.16) acne scarring than adults. It is also possible that hormonal factors
may be less influential in adolescent acne and hence spironolac-
0.35 0.25 2.0 0.99 (0.92-1.07)
tone may be less effective in this population.
0.25 0.15 2.0 0.98 (0.91-1.07)

637
Journal of Drugs in Dermatology J.S. Barbieri, J.K. Choi, N. Mitra, D.J. Margolis
June 2018 • Volume 17 • Issue 6

both treatments had similar efficacy at 6 months, oral antibiot- The results of this study should be interpreted in the context
ics were more efficacious at 3 months.38 Given this evidence of the study design. Any retrospective, claims based analysis
that therapies that address the hormonal etiology of acne, such has the potential for treatment selection bias. Since claims data
as oral contraceptive pills and spironolactone, may have slow- lacks information on acne severity, we cannot exclude that pa-
er onset of action when compared with oral antibiotics, oral tients treated with spironolactone may have a different acne
tetracycline-class antibiotics may represent a more effective severity than those treated with oral antibiotics. However, the
strategy for those looking for rapid improvement in their acne. sensitivity analysis demonstrates that plausible differences in
Initial combination therapy with oral tetracycline-class antibi- acne severity between the groups are unlikely to have a sig-
otics and spironolactone, with eventual tapering of the oral nificant effect on the primary outcome. While we are unable
antibiotics and maintenance with spironolactone is another to assess the reasons for switching, and thus cannot measure
potential approach to consider in this population. Finally, it is therapeutic efficacy, since switching reflects some form of treat-
important to consider that over 80% of adolescent women start- ment failure, whether due to lack of efficacy, side-effects, cost,
ed on spironolactone as the index therapy are not prescribed or other reasons, this outcome is likely a reasonable measure
a subsequent systemic agent within the first year of treatment of clinical effectiveness in a real-world setting. Importantly, as
and that the number needed to treat with an oral tetracycline- used in the clinical practice scenarios captured in the dataset,
class antibiotic to prevent one instance of switching was 17, spironolactone appears to be effective when compared with
suggesting that for many adolescent women, spironolactone is oral antibiotics. However, because of these potential source of
an effective therapy for their acne. bias, the results should be interpreted with caution when at-
tempting to generalize to other patient populations. Although
Many patients who were started on either spironolactone or it is possible that we were unable to capture treatment failure
oral tetracycline-class antibiotics were found to be receiving among patients who were never seen in follow-up, given that
no systemic therapy at a later point during the first year of moderate to severe acne is challenging to manage with over the
follow-up. This finding could be a result of periods of remis- counter agents alone, it is likely patients would continue to fol-
sion induced by the systemic agent, successful maintenance low-up for subsequent care if their acne remained uncontrolled.
with topical therapies alone, discontinuation of therapy due Finally, we are not able to capture information about adverse
to guideline recommendations (ie, limiting antibiotics to 3 effects associated with treatment, although prior studies have
months), or patients who stopped seeking care with systemic suggested that spironolactone is generally well tolerated.48,51,52
agents for their acne. While it is difficult to assess which fac-

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tors were the greatest contributors, topical retinoids have been In summary, spironolactone has similar rates of switching when
shown to maintain results following an initial treatment period compared to oral tetracycline-class antibiotics for the treatment
with oral antibiotics, so it is possible that many of these pa- of acne vulgaris, especially among adult women. As a result, spi-
tients started on either spironolactone or oral tetracycline-class ronolactone may represent an effective and safe alternative to oral

Penalties Apply
antibiotics were subsequently able to maintain their improve- antibiotics for women with moderate to severe acne. Increased
ment with topical therapies alone.39–41 utilization of spironolactone is a potential opportunity to improve
antibiotic stewardship and reduce complications associated with
When compared to spironolactone, doxycycline hyclate was antibiotic use. While ultimately large clinical trials are needed to
less likely to be switched than either minocycline or low-dose determine the optimal management strategy for women with
extended-release minocycline. Although these results should moderate to severe acne, these results provide additional support
be interpreted with caution due to potential confounding by in- for the use of spironolactone in this patient population.
dication, these findings are consistent with a recent Cochrane
review which found no evidence to support minocycline as be- DISCLOSURES
ing more effective than other tetracycline-class antibiotics.49 The authors have no conflicts to declare.
Given the potential safety concerns associated with minocy-
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Systematic Review. Am J Clin Dermatol. February 2017. tween tetracycline class antibiotics used for acne vulgaris and lupus erythe-
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28. Berni E, Scott LA, Jenkins-Jones S, et al. Non-Response to Antibiotic Treat- AUTHOR CORRESPONDENCE
ment in Adolescents for Four Common Infections in UK Primary Care 1991-
2012: A Retrospective, Longitudinal Study. Antibiot Basel Switz. 2016;5(3).
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EJD. 2015;25(5):469-471.
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June 2018 641 Volume 17 • Issue 6

The Efficacy and Safety of Azelaic Acid 15% Foam in the

Treatment of Facial Acne Vulgaris
Peter W. Hashim MD MHS,a Tinley Chen BA,a Julie C. Harper MD,b and Leon H. Kircik MDa,c,d
a
The Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY
b
The Dermatology and Skin Care Center of Birmingham, Birmingham, AL
c
Indiana University School of Medicine, Indianapolis, IN
d
Physicians Skin Care PLLC, Louisville, KY

ABSTRACT
Background: Azelaic acid demonstrates anti-inflammatory, anti-oxidative, anti-comedogenic, and anti-microbial effects. Azelaic acid
20% cream is currently approved for the treatment of acne vulgaris, and azelaic acid 15% foam has recently been approved for rosacea.
Given the favorable tolerability profile of foam preparations, it is reasonable to assume that azelaic acid 15% foam could serve as a
viable treatment option for facial acne.
Objective: To examine the efficacy and safety of azelaic acid 15% foam in the treatment of moderate-to-severe facial acne
Methods: Twenty subjects with moderate-to-severe facial acne vulgaris were enrolled in this two-center, open-label pilot study. All
study subjects were treated with azelaic acid 15% foam for 16 weeks. Efficacy analyses were based on the change in facial investigator
global assessment (FIGA) and changes in total, inflammatory, non-inflammatory lesion counts between baseline and week 16.
Results: There was a significant reduction in FIGA scores from baseline to week 16 (p = .0004), with 84% of subjects experiencing at
least a 1 grade improvement, and 63% of subjects achieving a final grade of Clear or Almost Clear. All subjects experienced reductions
in inflammatory and total lesion counts by week 16, and 89% of subjects experienced reductions in non-inflammatory lesions. Azelaic
acid 15% foam was well tolerated, with almost all instances of erythema, dryness, peeling, oiliness, pruritus, and burning being of mild
or trace degree, and most adverse effects resolving by the end of the study.
Conclusion: Azelaic acid 15% foam is effective and safe in the treatment of facial acne vulgaris. Given the convenience of foam
vehicles, azelaic acid 15% foam should be considered as a viable treatment option for this condition.

J Drugs Dermatol. 2018;17(6):641-645.

INTRODUCTION
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A Penalties Apply
cne vulgaris is a common chronic inflammatory skin phase III clinical trials.7-10 It provides an especially useful topical
disorder with a global prevalence reaching as high as treatment for women who are pregnant or breastfeeding (clas-
60-80% in individuals 12-25 years of age.1 Although sified as pregnancy risk category B).
acne is traditionally perceived as a disease affecting adoles-
cents, there is an increasing prevalence of late-onset, recurrent, Although the foam formulation of azelaic acid 15% is currently
or persistent acne in post-adolescent females over the age of only approved for the topical treatment of papulopustular rosa-
25.2,3 The pathogenesis of acne is multifactorial, including ab- cea, it is commonly used off-label in the treatment of acne.11 The
normal follicular hyperkeratinization, androgen-related sebum foam formulation is highly efficacious due to its enhanced drug
overproduction, proliferation of Propionibacterium acnes in release and bioavailability.12,13 Importantly, the favorable cos-
pilosebaceous follicles, and subsequent perifollicular inflam- metic acceptability and tolerability profile of the foam vehicle
mation.3,4 Conventional first-line therapies, such as topical reti- may enhance treatment compliance and outcomes.10,12 This pi-
noids, anti-bacterials, and anti-inflammatory agents, are used lot study aimed to evaluate the efficacy, safety, and tolerability
to address each major factor in acne formation. of azelaic acid 15% foam in the treatment of moderate-to-se-
vere facial acne.
Azelaic acid is a naturally occurring, saturated, dicarboxylic acid
that targets the major factors implicated in the pathogenesis of METHODS
acne through its anti-inflammatory, anti-bacterial, and anti-kera- Study Design and Subjects
tinizing actions.5,6 Azelaic acid 20% cream is currently approved This 16-week, two-center, open-label study was conducted in
for the topical treatment of mild-to-moderate inflammatory patients with moderate-to-severe facial acne. Male and female
acne and has been shown to provide statistically significant re- subjects of any race, 18 years of age or older, were eligible
ductions in both inflammatory and non-inflammatory lesions in for inclusion in the study if they exhibited moderate-to-severe
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642
Journal of Drugs in Dermatology P.W. Hashim, T. Chen, J.C. Harper, L.H. Kircik
June 2018 • Volume 17 • Issue 6

facial acne as defined by a Facial Investigator Global Assess- TABLE 1.

ment (FIGA) score of 3 or 4 (Table 1). Subjects were required Facial Investigator Global Assessment Scale (FIGA)
to be able to understand the requirements of the study and
Score Severity Description
be capable of providing informed consent. Pregnant women,
No inflammatory or non-inflammatory
breastfeeding mothers, and females of childbearing potential 0 Clear
lesions
who were not practicing a reliable method of contraception
were excluded from study participation. Females of childbear- Almost Rare non-inflammatory lesions with no
1
Clear more than one small inflammatory lesion
ing potential were required to have a negative urine pregnancy
test at baseline and at every study visit, in addition to practicing Greater than Grade 1; some
non-inflammatory lesions with no more
a reliable method of contraception for the duration of the study. 2 Mild
than a few inflammatory lesions (papules/
The following exclusionary criteria were also applied: allergy pustules only, no nodular lesions)
or sensitivity to any component of the test medication, medical
Greater than Grade 2; some to many
conditions that contraindicated participation, skin diseases/dis- non-inflammatory lesions and may have
orders that interfered with the diagnosis or evaluation of acne 3 Moderate
some inflammatory lesions, but no more
vulgaris, evidence of recent alcohol or drug abuse, history of than one small nodular lesion
poor cooperation, non-compliance with medical treatment, or Greater than Grade 3; some to many
unreliability. 4 Severe non-inflammatory and inflammatory lesions,
but no more than a few nodular lesions
Subjects were required to complete the following washout peri- Greater than Grade 4; many
Very
ods: 1 week for over-the-counter acne medications or bleaching 5 non-inflammatory and/or inflammatory
Severe
agents; 2 weeks for topical therapy with retinoids, antibiotics, lesions with some or many nodular lesions
benzoyl peroxide, dapsone, bleaching agents, cryotherapy,
chemical peels, or microdermabrasion; 4 weeks for oral antibi- study was the percent of subjects who achieved Clear or Almost
otics or other investigational drugs; 24 weeks for oral retinoids Clear FIGA scores at week 16. Secondary endpoints included
or laser resurfacing and dermabrasion. the percent reduction of total, inflammatory, and non-inflam-
matory lesion counts at week 16 as compared to baseline.
The study was performed in accordance with Good Clinical
Practices, including guidelines outlined by the International Con- At the final visit at week 16, subjects were additionally given

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ference on Harmonisation. Institutional review board approval a “Patient Preference Questionnaire”. This questionnaire asked
was obtained from each participating center. Informed consent subjects to rank different treatment vehicles that they had
was obtained from all study participants prior to enrollment. used in the past (gel, lotion, cream, ointment, and spray) from
“liked the least” to “liked the best”. Subjects were also asked to

Penalties Apply
Treatment compare the study medication against medications that they
All subjects received azelaic acid 15% foam, a white to off-white had used in the past based on ease of use, ability to continue
hydrophilic emulsion supplied in a 50 g aluminum can pressur- daily activities directly after application, feeling of skin after
ized with propellants. Azelaic acid 15% foam contains 15 mg/g application, ability to apply to large body surface areas, and
of azelaic acid in a vehicle consisting of benzoic acid, cetostea- absorption. Finally, subjects were asked to rate the study foam
ryl alcohol, dimethyl isosorbide, medium-chain triglycerides, on the following qualities: moisturizing, lack of residue, grease,
methylcellulose, mono- and di-glycerides, polyoxyl 40 stearate, absorption, ease of application, lack of fragrance, spreadability.
polysorbate 80, propylene glycol, purified water, sodium hy-
droxide, and xanthan gum.11 Safety and Tolerability
Tolerability was evaluated at baseline before drug administra-
Subjects were instructed to apply azelaic acid 15% foam spar- tion and at all visits. Investigator assessments of erythema,
ingly to the entire facial area (cheeks, chin, forehead, and nose) dryness, peeling, and oiliness severity were rated on a 5-point
twice daily (morning and evening) and to massage gently into scale (absent, trace, mild, moderate, severe) (Table 2). Subject
the skin until the foam vanished. assessments of pruritus and burning/stinging severity were
rated on a 6-point scale (absent, trace, mild, moderate, marked,
Efficacy Assessments severe) (Table 3).
All subjects were evaluated at baseline before drug administra-
tion and at follow-up visits at week 4, week 8, week 12, and week Adverse events and concomitant medications or treatments
16. Static assessments of facial acne severity were completed were monitored throughout the study. For each adverse event,
at each visit using the 6-point FIGA, ranging from 0 (clear) to including cutaneous and systemic events and any reported sub-
5 (very severe) (Table 1). The primary efficacy endpoint of this jective skin symptoms, the investigator assessed the duration,
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643
Journal of Drugs in Dermatology P.W. Hashim, T. Chen, J.C. Harper, L.H. Kircik
June 2018 • Volume 17 • Issue 6

TABLE 2.
Investigator Assessments of Erythema, Dryness, Peeling, and Oiliness Severity
Score Severity Erythema Dryness Peeling Oiliness
0 Absent No redness None Smooth Normal
Faint red or pink Barely perceptible dryness by palpation
Fine peeling, barely
1 Trace coloration, barely with no accentuation of skin markings, skin Mild and localized
perceptible
perceptible desquamation (flakes) or fissure formation
Easily perceptible dryness by palpation with
Light red or pink
2 Mild accentuation of skin markings but no skin Slight peeling Mild and diffuse
coloration
desquamation (flakes) or fissure formation
Easily noted dryness with accentuation of
Medium red Definitely noticeable Moderate and
3 Moderate skin markings and skin desquamation (small
coloration peeling diffuse
flakes) but no fissure formation
Easily noted dryness with accentuation of skin
Prominent and
4 Severe Beet red coloration markings, skin desquamation (large flakes) Extensive peeling
dense
and/or fissure formation

severity, seriousness, causal relationship to the study medica- which 75% were white, 20% were black, and 5% were of mixed
tion, and the course of action taken. race. All study subjects were treated with azelaic acid 15% foam
for 16 weeks. All subjects completed the 16-week study peri-
Statistical Analyses od, with the exception of 1 subject who was lost to follow-up
Analyses of efficacy endpoints were based on data from (moved away) after week 8.
subjects who completed the study. All statistical tests were two-
sided and interpreted at a 5% significance level. Changes in Efficacy
FIGA as well as total, inflammatory, and non-inflammatory le- Facial Investigator Global Assessment (FIGA)
sion count were evaluated using the Wilcoxon signed-rank test. There was a significant reduction in FIGA scores from baseline
The incidence and severity of all adverse and/or unexpected to week 16 (p = 0.0004). At baseline, 18 subjects had a FIGA

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events was tabulated and classified by intensity and relation- score of 3 (moderate), and 1 subject had a FIGA score of 4 (se-
ship to the study medication. vere). 12 subjects (63%) were Clear or Almost Clear by week 16.
16 subjects (84%) experienced at least a 1-grade improvement,
RESULTS and 12 subjects (63%) experienced at least a 2-grade improve-

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Subjects ment by week 16.
Twenty subjects with moderate-to-severe facial acne vulgaris
were enrolled (Table 4). The average age was 26 years, with TABLE 4.
ages ranging from 18 to 39 years. All subjects were female, of
Subject Demographic and Baseline Characteristics
Age, years Subject Characteristics (n=20)
TABLE 3.
Mean (SD) 26 (7)
Subject Assessments of Pruritus and Burning/Stinging
Range 18-39
Score Severity Description
Sex, % female 100
0 Absent Normal, no discomfort
Ethnicity
An awareness, but no discomfort and no
1 Trace
intervention required White (%) 15 (75)
Noticeable discomfort causing intermittent Black (%) 4 (20)
2 Mild
awareness
Mixed Race (%) 1 (5)
Noticeable discomfort causing continuous
3 Moderate Mean scores at baseline
awareness
Total lesion count (SD) 38 (17)
Definite discomfort causing continuous
4 Marked awareness interfering occasionally with Inflammatory lesion count
16 (5)
normal daily activities (SD)
Definite, continuous discomfort interfering Non-Inflammatory lesion
5 Severe 23 (18)
with normal daily activities count (SD)
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644
Journal of Drugs in Dermatology P.W. Hashim, T. Chen, J.C. Harper, L.H. Kircik
June 2018 • Volume 17 • Issue 6

TABLE 5.
Summary of FIGA Scores by Study week. Values are count (%)
Facial IGA Clear or
1-Grade 2-Grade
Visit Almost
Clear Almost Clear Mild Moderate Severe Improvement Improvement
Clear
Baseline - - - 18 (95%) 1 (5%) - - -
Week 4 - - 5 (26%) 14 (74%) - - 6 (32%) 0 (0%)
Week 10 - 3 (16%) 7 (37%) 9 (47%) - 3 (16%) 11 (58%) 3 (16%)
Week 12 1 (5%) 5 (26%) 6 (32%) 7 (37%) - 6 (32%) 13 (68%) 6 (32%)
Week 16 2 (10%) 10 (53%) 4 (21%) 3 (16%) - 12 (63%) 16 (84%) 12 (63%)

Lesion Counts was 1 instance of moderate erythema, 2 instances of moderate

Significant reductions in mean and median lesion counts oc- pruritus, and 1 instance of moderate burning. All other instanc-
curred within the first 4 weeks of treatment and were sustained es were mild or trace readings, and most instances involved
or improved throughout the remainder of the study (Figure 1; only trace readings that resolved by the end of study.
Table 6). All subjects experienced reductions in inflammatory
and total lesion counts by week 16, and 17 of 19 experienced Nine subjects experienced a total of 12 adverse events.
reductions in non-inflammatory lesion counts. Non-serious adverse events that were determined by investiga-
tors to be related to the study medication were mild in nature,
Questionnaire cutaneous, and occurred at the application site. These included:
When questioned regarding preferences in treatment itching on an eyebrow after drug application (resolved), itch-
vehicle, subjects indicated that lotions and creams were gen- ing at the application site for 25 minutes (resolved), burning
erally preferred over gels, ointments, and sprays. Subjects at the application site (unresolved), and a tingling sensation at
generally preferred the study medication over previously used the application site (resolved). One subject experienced swell-
medications, and most commonly rated its qualities as “good” ing and peeling in the treatment area of moderate severity that
or “excellent”. was determined to be unlikely to be related to study medica-

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tion. Study drug application was interrupted for 4 days, and
Safety and Tolerability the event resolved with no residual effects. Other non-serious
Azelaic acid 15% foam was well tolerated. There were 14 reports adverse events were mild and determined to be definitely un-
of erythema, 3 reports of dryness, 4 reports of peeling, 4 reports related to study medication included: sunburn, sinus infection,

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of oiliness, 12 reports of pruritus, and 7 reports of burning.There hyperthyroidism, streptococcal pharyngitis, tonsillitis, and

645
Journal of Drugs in Dermatology P.W. Hashim, T. Chen, J.C. Harper, L.H. Kircik
June 2018 • Volume 17 • Issue 6

TABLE 6.
Percent Reduction in Inflammatory, Non-inflammatory, and Total Lesion Count at Each Study Visit
Inflammatory Non-Inflammatory Total
Week % Reduction from % Reduction from % Reduction from
P-Value P-Value P-Value
Baseline (SD) Baseline (SD) Baseline (SD)
4 45 (28) 0.0002 4 (54) 0.39 26 (27) 0.002
8 57 (23) 0.0001 42 (44) 0.004 50 (21) 0.0002
12 64 (24) 0.0002 46 (41) 0.002 55 (27) <0.0001
16 77 (23) 0.0001 64 (33) 0.0003 73 (17) <0.0001

sinus infection. One serious adverse event of bronchitis, mod- 6. Gupta, A. K. and Gover, M. D. (2007), Azelaic acid (15% gel) in the treat-
ment of acne rosacea. Int J Dermatol. 46: 533–538. doi:10.1111/j.1365-
erate severity, was reported and determined to be unrelated to 4632.2005.02769.x
study medication. No therapy was initiated, and the event re- 7. Allergan, Inc. Azelex® Cream, 20% (package insert), 2015.
8. Gollnick HPM, Graupe K, Zaumseil R-P. Azelaic acid 15% gel in the treatment
solved with no residual effects. of acne vulgaris. Combined results of two double-blind clinical comparative
studies. J Dtsch Dermatol Ges J Ger Soc Dermatol. 2004;2(10):841–847.
DISCUSSION 9. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid
(15%) gel as a new treatment for papulopustular rosacea: results from two
Over a 16-week period, treatment with azelaic acid 15% foam vehicle-controlled, randomized phase III studies. J Am Acad Dermatol 2003;
led to decreases in the number of total, inflammatory, and non- 48: 836–845.
10. Draelos ZD, Elewski BE, Harper JC, Sand M, Staedtler G, Nkulikiyinka R, et
inflammatory lesions in subjects with moderate-to-severe facial al. A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid
acne. Subjects showed an average 77% reduction in inflamma- foam 15% in the treatment of papulopustular rosacea. Cutis. 2015;96(1):54–
61.
tory lesion counts, 64% reduction in non-inflammatory lesion 11. Bayer HealthCare Pharmaceuticals Inc. Finacea® Foam, 15% (package in-
counts, and 73% reduction in total lesion counts. Reductions in sert), 2015.
12. Draelos ZD. The rationale for advancing the formulation of azelaic acid ve-
lesion counts were supported by static physician assessments
hicles. Cutis. 2006;77(2 Suppl):7–11.
of facial severity, with a majority of subjects rated as “clear” or 13. Del Rosso, J.Q. Using a foam vehicle for dermatologic applications. The Der-
“almost clear” by the conclusion of the study. Azelaic acid 15% matologist. 2002;10.

foam was well-tolerated on the facial area, and questionnaire

AUTHOR CORRESPONDENCE

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results indicated that subjects viewed the foam vehicle as eas-
ily applicable and cosmetically appealing. Leon H. Kircik MD
E-mail:................…….................................. [email protected]
Future research should expand upon this work in larger sample

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sizes and with vehicle control as well as active comparators.
This study establishes azelaic acid 15% foam as a promising,
safe, and efficacious therapy option for patients with moderate-
to-severe facial acne.

DISCLOSURES
Dr. Hashim and Tinley Chen have no conflicts of interest to dis-
close. Dr. Harper is a consultant, researcher, and speaker for
Bayer HealthCare Pharmaceuticals Inc. Dr. Kircik has served as
an advisor, investigator, consultant, and speaker for Allergan,
Bayer, Galderma, Promius Pharma, Sun Pharma, Stiefel/GSK,
LeoPharma, Taro, Valeant, and Warner-Chilcott. This study was
funded by Bayer as an investigator-initiated study.

REFERENCES
1. Plewig G, Kligman AM: Acne and rosacea, ed 3. Berlin Springer, 2000.
2. Williams C, Layton AM. Persistent acne in women : implications for the pa-
tient and for therapy. Am J Clin Dermatol. 2006;7(5):281-90.
3. Zeichner JA, Baldwin HE, Cook-Bolden FE, et al. Emerging Issues in Adult
Female Acne. J Clin Aesthet Dermatol. 2017 Jan;10(1):37-46. Epub 2017 Jan 1.
4. Toyoda M, Morohashi M. Pathogenesis of acne. Med Electron Microsc.
2001 Mar;34(1):29-40.
5. Sieber MA, Hegel JKE. Azelaic acid: properties and mode of action. Skin
Pharmacol Physiol. 2014;27(Suppl 1):9–17.
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Orlando Dermatology Aesthetic & Clinical Conference

June 2018 647 Volume 17 • Issue 6

Expert Consensus on Achieving Optimal Outcomes With

Absorbable Suspension Suture Technology for Tissue
Repositioning and Facial Recontouring
Z. Paul Lorenc MD FACS,a Glynis Ablon MD,b Julius Few MD,c Michael H. Gold MD,d
Stephen Mandy MD PhD,e Mark S. Nestor MD PhD,f and Susan H. Weinkle MDg
Lorenc Aesthetic Plastic Surgery Center, New York, NY;
a

Lenox Hill Hospital, New York, NY

b
University of California, Los Angeles, CA;
Ablon Skin Institute Research Center, Manhattan Beach, CA
c
Few Institute for Aesthetic Plastic Surgery, Chicago, IL;
University of Chicago Pritzker School of Medicine, Chicago, IL;
Northwestern University, Evanston, IL
d
Gold Skin Care Center, Nashville; Tennessee Clinical Research Center, Nashville, TN;
Vanderbilt University School of Nursing, Nashville, TN;
Meharry Medical College, School of Medicine, Nashville, TN
e
South Beach Dermatology, Miami Beach, FL;
University of Miami Miller School of Medicine, Miami Beach, FL
f
Center for Clinical and Cosmetic Research, Center for Clinical Enhancement, Aventura, FL;
University of Miami Miller School of Medicine, Miami, FL
g
Bay Area Medical Complex, West, Bradenton, FL

ABSTRACT
A complete approach to facial rejuvenation includes restoration of the skin’s surface, relaxation of muscles that contribute to hyperkinet-
ic movement, revolumization, and repositioning/recontouring of descended tissues and fat pads. After receiving 510(k) clearance from
the US Food and Drug Administration (FDA) in 2015, the Silhouette InstaLift™ absorbable suspension suture became the only available

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non-surgical technique for repositioning of facial tissue. In January 2017, a consensus paper presented a review of the literature on the
efficacy and safety of absorbable suspension sutures and provided information on treatment procedures. Since that time, the clinical
experience of the authors has further shaped their treatment practices, highlighting the need for additional guidelines to support an

Penalties Apply
optimal treatment approach. This update will expand upon the 2017 consensus paper on the safety and efficacy of absorbable suspen-
sion sutures and provide guidance for obtaining consistently high patient satisfaction with the procedure. Recommendations are based
on the extensive clinical experience of expert physicians with absorbable suspension sutures over the past 2.5 years. Here, the authors
provide guidance on full face assessment and treatment to support maximum benefit and provide patient selection and procedural
recommendations. In addition, the authors stress the benefits of the dual mechanisms of action within the absorbable suspension
suture: the immediate lift and volumizing over time that together lead to the outcome of recontouring.

J Drugs Dermatol. 2018;17(6):647-655.

INTRODUCTION

T
he hallmarks of facial aging include diminished skin changes result in increased prominence of the nasolabial fold,
tone, increasingly uneven texture, appearance of wrin- redistribution of tissue along the jowl, and descent of facial
kles, volume loss, and the descent of facial features.1 features (inferior displacement).
Age-associated decreases in ligament stability and involution
of bony attachments, coupled with the descent of the fat com- A complete approach to facial rejuvenation and restoration
partments and changes in musculature, cause the inferior dis- generally requires that multiple aspects of facial aging be ad-
placement of tissue characteristic of facial aging.2-4 Compound- dressed. Treatment plans may include resurfacing with lasers,
ing this loss of underlying support is an increase in skin laxity skin tightening with energy-based treatments, relaxation with
caused by a reduction in the supportive capacity of collagen neuromodulators, revolumization with fillers, and reposition-
and dwindling levels of elastin.4 Together, these physiological ing of descended tissue.5 In a global composite approach,
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648
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

correction of inferior displacement through repositioning en- position occurs as a result of the suture passing through an
sures an optimal outcome for each of the other modalities immediately subdermal glide plane, where the cones lift de-
used. Prior to the 2015 FDA 510(k) approval of the Silhouette scended tissue at the retaining ligament level and then adhere
InstaLift™ absorbable suspension suture (Sinclair Pharma, Lon- the tissue in place as a result of neocollagenesis. Recontouring,
don, UK) for use in the midface,6 the primary tool to address rather than mechanical lift alone, is the basis of the ongoing
inferior descent was surgical facelift or placement of a perma- improvement in patient appearance at 12 months and beyond,
nent suture that required open dissection of the temporal fascia and this improvement is reflected by high patient satisfaction
with suture fixation to the fascia. While fillers represent a non- at 12 to 18 months.9,10 For example, patient responses to the
invasive method that can reverse the descent of facial features FACE-Q questionnaire indicated an ongoing improvement at
to some degree through their capacity to restore volume and 12 months in cheek contour and attractiveness, among other
support overlying tissues, they are not designed to reposition measures. For the patient shown in Figure 2, effacement of the
tissue, and their theoretical capacity for lifting is limited by the nasolabial fold and marionette line is apparent at 6 months, and
need for natural looking and aesthetically balanced results. The the jowl visibility is reduced and there has been a significant
Silhouette InstaLift™ absorbable suspension suture is not only enhancement of jawline definition that is maintained until 18
the single available non-surgical tool for repositioning, but also months. Twelve months post procedure, the improvement to
serves to recontour and revolumize through the activities of the the nasolabial fold and marionette line is sustained, and revolu-
PLLA and PLGA within the suture/cones. Furthermore, absorb- mization in the midface has improved the contour of the cheek.
able suspension suture technology is a modality supportive At 24 months, a degree of replenished volume is retained in
of complementary treatments such as energy-based devices, the midface. This timeline is reflected in the overall experi-
fillers, and toxin, and is an important element of the holistic ence of the authors: patients often do not require retreatment
approach to rejuvenation that yields high patient satisfaction. for 18 to 24 months. In addition to the immediate lift provided,
the physiochemical properties of the suture material address
The Silhouette InstaLift™ Suture age-related volume loss, offering another mode by which repo-
The Silhouette InstaLift™ absorbable suspension suture is sitioning with this product can yield optimal results. The impact
unique in that the cones are oriented in a bidirectional fash- of sutures on midface volume are apparent in Figure 3, where
ion along the suture (Figure 1) and that the device is entirely at 15 months, recontouring in the cheeks can be observed in the
absorbable. Both the suture and the cones are composed of frontal and profile views, where both the position and projection
18% poly lactic-co-glycolic acid (PLGA) and 82% poly-L lactic of the cheek is improved, and midface volume is replenished.

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acid (PLLA). Use of absorbable suspension suture technology As the degree of revolumization is linked to the amount of PLLA
affords a non-surgical, segmental approach for the treatment of placed in the cheeks, the use of at least 3 sutures in the midface
facial laxity that can correct inferior displacement by targeted supports desired repositioning and recontouring.
repositioning of descended tissue. Recovery time following su-

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ture placement is minimal, and results are evident immediately. In July 2017, the authors of this manuscript published a consen-
sus paper on the safety and efficacy of absorbable suspension
While the physical lifting capacity of the suture itself is sutures. Since the time when the first consensus manuscript
diminished as the suture is absorbed, the complementary col- was originally submitted (January 2017), the collective clinical
lagen-stimulating properties of PLLA/PLGA7,8 within the suture experience of the authors with this technology has continued
provides revolumization that permits a sustained recontouring to grow, and ongoing communication within the group led to
of the treated area for 18 to 24 months following placement.9,10 recognition of a need for an additional publication detailing
In addition, adhesion or “holding” of tissue in the uplifted the lessons learned over the past 12 to 18 months. With the

649
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

FIGURE 2. Strategically placed sutures in the midface and jawline result in lift and recontouring. A 47-year-old female treated with four 8-cone
sutures, 2 on each side of the face placed strategically along the jawline and in the midface (Panel A). Follow-up profile view at 6 months (B), 18
months (C), and 24 months (D) following treatment. Pre-procedure frontal view (E) and follow-up at 6 months (F), 18 months (G), and 24 months (H)
following treatment. Pre-procedure oblique view (I) with follow-up at 6 months (J), 18 months (K), and 24 months (L) following treatment. The patient
remained on her 4-month cycle of treatment with neuromodulators (standard, FDA-indicated dosing) in the glabella and crows’ feet throughout the
course of treatment.
Provided courtesy of Julius W. Few, MD, FACS.

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

(E) (F) (G) (H)

650
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

FIGURE 3. Impact of sutures in the midface on tissue position and facial contour. 49-year-old female patient treated with three 8-cone sutures.
Baseline profile view (A) and results at 15 months (B) are shown. Baseline frontal view (C) and results at 15 months (D). The patient was
retreated with a single suture at 16 months.
Provided courtesy of Michael H. Gold MD.

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

approval of a new technology comes a need to optimize patient there are many patients outside of this ideal for whom suspen-
selection, clarify the details of an ideal treatment approach, de- sion sutures are an appropriate and beneficial treatment. In
termine how to best use the new technology in combination each of these categories, clear communication between patient
with other modalities, and offer guidance on how to best pre- and physician is key for shaping patient expectations.
vent and manage any adverse events. Within this update, the
authors provide a consensus on each of the above elements The “Ideal Patient”
of patient care, with special consideration for maximizing the The “ideal” patient has strong bony projections, skin of suffi-

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high patient satisfaction achievable with absorbable suspen- cient thickness to prevent palpability of the suture, as well as
sion sutures. pliability and mobility to allow for repositioning. The patient
may have a visible nasolabial fold, visible marionette lines, loss
Patient Selection of definition along the mandibular boarder, and/or jowling, as

Penalties Apply
Absorbable suspension sutures provide a minimally invasive well as some redundancy of the skin. Patients often have an
option for highly specific, segmental treatment of facial lax- additional need for volume restoration due to excess ptosis of
ity. Candidates for absorbable suspension sutures often desire skin that cannot be managed by filler placement only. Patients
facial recontouring but require repositioning of facial tissue with thin skin, excessive fibrosis, sun damage, or excessive lo-
beyond what fillers can provide through volumization alone. cal rhytids are generally not the best candidates for absorbable
These patients may not yet be a candidate for a surgical face- suspension sutures alone.
lift; may wish to delay the procedure for personal or financial
reasons; are unwilling to undergo surgery or require minimal Mature Patients
down time; or have already had a facelift and wish to extend Mature patients also benefit from tissue repositioning and
the results. In each scenario, the patient should be appropri- recontouring. While loss of elastic tissue fibers and a dimin-
ately counseled about the expected results. The lift provided by ished ability to produce collagen may reduce the degree of
absorbable suspension sutures is not a substitute for a surgical volumization achieved by the suture’s PLLA/PGLA, tissue may
facelift. Rather, the sutures provide a combination of reposi- still be effectively repositioned in mature patients and some
tioning and volumization that give rise to a recontouring that is benefit from the biostimulatory activities of PLLA/PGLA likely
unique to this device. Further, absorbable suspension sutures obtained. Absorbable suspension sutures are an important
can be used with a wide range of complementary treatments to treatment modality for patients who are not candidates for a
achieve optimal results. surgical facelift or who wish to maintain the results of a previ-
ous procedure without further surgical intervention. Of note,
Absorbable suspension sutures are a highly adaptable treat- the difficulty in concealing scars from a surgical facelift in men
ment that may benefit a wide array of patients. Below, the makes absorbable suspension sutures a particularly useful
characteristics of the “ideal” patient are presented; however, treatment option for male patients.
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651
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

Sun-damaged skin may be encountered more frequently in this throughout the cheek and midface, and the improved definition
population. In these patients, the increased capillary fragility of the jaw line achievable with absorbable suspension sutures
and comparatively thinner dermis may lead to more bruising; is often a procedure with high patient satisfaction.
however, the patient may be counseled on the relative risk. For
the patient shown in Figure 4, absorbable suspension sutures Additional Patient Populations
were able to address both facial asymmetry and inferior dis- Initial recommendations in the first consensus paper under-
placement. For patients who are not a candidate for surgery, estimated the potential of absorbable suspension sutures in
the effacement of the nasolabial fold, tissue repositioning thicker-skinned patients, as the authors have subsequently
found that positive outcomes are achievable if a sufficient num-
ber of sutures is utilized and the skin is of sufficient mobility
FIGURE 4. Meaningful results from sutures in mature patients and
correction of asymmetry. A 70-year old female treated with four 8-cone and pliability.
sutures on her left side at baseline (A), and 9 weeks after treatment (B)
and two 8-cone sutures on her right side at baseline (C) and 9 weeks Absorbable suspension sutures are a valuable tool for the
after treatment (D). The baseline frontal view (E) and frontal view at treatment of patients with round faces who require volume cor-
9 weeks post treatment (F) are shown. Treatment addressed facial rection or reshaping, but for whom fillers are not ideal, or for
asymmetry, volume loss, and the need for tissue repositioning. Variation the management of facial asymmetry.
in the number of sutures on each side of the face speaks to the flexibility
of the procedure for achieving patient aesthetic goals.
Provided courtesy of Susan H. Weinkle MD. Patients with very early signs of inferior displacement of facial
features are also excellent candidates for absorbable suspen-
(A) (B)
sion sutures. Candidates for prejuvenation may be genetically
predisposed to early development of a more pronounced na-
solabial fold or jowling. In these patients, placement of
comparatively fewer sutures on each side is a procedure as-
sociated with high patient satisfaction. Ideal candidates for
prejuvination wish to prevent or minimize the progression of
tissue inferior displacement, are comfortable with injections
and aesthetic medicine, and have sufficiently mobile skin.

Pre-Treatment Planning

(C) (D) Do Not Copy Placement of absorbable suspension sutures takes approxi-
mately 30 minutes in the hands of a skilled practitioner. The
most time-intensive phase of suture placement is pre-treatment

Penalties Apply
planning; the procedure itself is technically straightforward
and highly adaptable. The number of sutures may be easily in-
creased to suit the needs of the individual patient, as using the
marked entry and exit points of other sutures as a guide elimi-
nates the need to re-measure the patient should the need for
additional sutures emerge after the procedure has begun. The
number of sutures should be adjusted to suit individual patient
treatment goals and may be different on each side of the face
to account for asymmetry. While treatment must be adapted to
suit the needs of individual patients, there are several consid-
(E) (F) erations that have emerged as critically important over the past
year that the authors wish to emphasize.

First, physicians interested in adding absorbable suspension

sutures to their practice should seek out training by contacting
a Silhouette InstaLift™ representative or by submitting a request
through www.instalift.com. In addition, there are CME resourc-
es available that include videos of the procedure performed by
authors of this publication available through X-Medica, LLC.
The procedure is technically straightforward, and the learning
curve is easily managed; however, proper technique is critically
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652
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

important for optimal outcomes. Second, the 8-cone suture is intended to elevate the nasolabial fold should be placed per-
preferred for all applications in the face. Third, for many pa- pendicular to the descended feature (Figure 2). Together, these
tients in need of facial tissue repositioning in multiple distinct principles of SLVP ensure that the lifting capacity of the sutures
anatomical areas, a minimum of 4 sutures per side provides the and clinical result are maximized.
needed mechanical benefit to achieve and maintain a mean-
ingful degree of repositioning. While the technique should be Once the aesthetic needs of the patient have been determined,
tailored to suit the needs of individual patients, the authors the tissue that is to be repositioned, referred to here as the zone
generally recommend 3 to 4 sutures per side in the midface of action, is identified. The entry and exit points of the suture
for moderate to severe mid-facial aging and 2 to 3 sutures in should be determined and marked with the patient in a full up-
the midface for mild to moderate mid-facial aging (Figure 2).11 right position so that the areas to be addressed are evaluated
Common arrangements include 2 to 4 sutures in the midface in their most natural state. During the procedure, the patient is
with additional sutures placed as needed to address other ar- reclined at a 45° angle for suture placement. In general, the exit
eas such as jowling or jawline definition. A sufficient number point should be placed 1.5 cm past the point of action to allow
of sutures ensures that the lifting capacity of the sutures is not for tissue movement (so that the inferior-most cone resides at
surpassed by the amount of advanced tissue and that the me- the point of action). For the nasolabial fold, the inferior-most
chanical burden on each individual suture is minimized, that the exit point is tangent to the lateral side of the of the nasolabial
tissue to be repositioned (the zone of action) is evenly distrib- fold. For each suture, 1 entry site and 2 exit sites are marked,
uted over the sutures, and that the collagen stimulated by the beginning with the points of action and distal exit site, then
PLLA/PLGA that comprises the sutures is sufficient to replenish both the central entry point and proximal exit point are mea-
volume and support both recontouring and ongoing tissue re- sured and marked along the planned straight-line vector.
positioning as the suture is absorbed. Undercorrection, either
through placing a suboptimal number of sutures or failing to Suture Placement
correctly advance the descended tissue, is not only detrimental Once the entry points and exit points have been marked, 1%
to patient satisfaction but is a lost opportunity for use of an lidocaine with epinephrine (1:100,000 dilution) is injected at the
otherwise effective treatment. entry and exit sites. No lidocaine should be injected into the su-
ture paths, as this may cause swelling and interfere with patient
Though sutures should be placed to best support treatment ability to sense pain, an important indicator that the needle is
goals, several canonical pathways of midface sutures are in the incorrect plane. To minimize patient discomfort, use a 32

Do Not Copy
shown in Figures 2, 3, and 4. While early research on absorb- gauge needle to administer 0.5 cc at each entry and exit site.
able suspension sutures focused upon outcomes for on-label To sufficiently dilate the entry point opening (exit points to not
indications such as cheeks and nasolabial folds, the jowls and require an opening to be made in advance), insert an 18 gauge
jawline definition should be considered part of a complete needle into the subcutaneous tissue perpendicular to the skin to

Penalties Apply
treatment plan.12 The contour of the jawline and the position a depth of 5 mm. Prior to inserting the suture, the suture should
and contour of the jowls strongly influence the impact of treat- be grasped near the last cone on each side and pulled taut to
ment in other parts of the midface and neck, and so should be tension, thus tightening the knots. Applying excessive tension
included in patient evaluation. to the suture by grasping the 2 needles can overstress the con-
nection between the suture and needle, leading to breakage.
Straight Line Vector Planning
For all applications, the issue of straight-line vector planning Sutures are then placed using the 23 gauge, 12 cm needle ap-
(SLVP) has evolved as a central principle for ensuring both effi- pended to each suture. First, the needle should be inserted at
cient and enduring tissue repositioning. In order for the suture’s the entry point in a perpendicular fashion, using the 5 mm depth
opposing cones to act in concert to provide support and lift, gauge on the needle as a guide. Once the needle is at a 5 mm
they must be oriented in a straight line (Z.P. Lorenc, MD, per- depth, the needle is turned at a 90° angle into the subcutaneous
sonal communication). Placement of the suture in a “U” or “V” plane. The natural tendency is to withdraw the needle slightly
formation diminishes the additive ability of the cones on each prior to turning it; however, it is important to maintain the 5
side of the suture to reposition tissue and dilutes the oppos- mm depth so that the sutures are not placed too superficially.
ing forces of the bidirectional cones, increasing the likelihood Once the needle is turned, it is carefully advanced toward the
of suture displacement and reducing the overall lifting capac- exit point, maintaining depth in the subcutaneous plane until
ity of the suture. In addition, placement of the suture so that it the exit point is reached. The needle should pass easily through
is perpendicular to the plane it is intended to elevate ensures the subcutaneous layer without resistance: patient discomfort
that all of the supportive force exerted by the suture is directed is an indicator that the needle is either too shallow or too deep
towards repositioning the tissue it is intended to elevate, rath- and no longer in the correct plane. Should the patient show any
er than diluted by an improper angle. For example, a suture signs of discomfort during placement, gently back the needle
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653
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

up until it is in the correct plane. A needle cap may be used to achieve adequate repositioning may seem to be an overcorrec-
catch the needle as it passes through the exit point. Once the tion, this level of tissue elevation is central to obtaining optimal
tract has been created, the suture must be pulled through from results and is a valid aspect of treatment.
the entry point. Slight counter traction on the opposite side of
the entry point from the direction of needle travel permits the If at any time during the procedure a cone becomes exposed
cones to easily pass through the entry point. When pulling the due to disengagement or during tissue advancement, the cone
suture into position, it is important that the tension applied to may be trimmed from the suture so that the suture end remains
the suture be directly in line with the needle tract. Otherwise, beneath the surface of the skin. Suture breakage is uncommon,
the tension can act as a lever and cause the cones to “catch” on but if it does occur, the suture need not be removed, as the ma-
the dermis. Insert the needle appended to the other side of the terial is entirely absorbable. While proper treatment planning
suture through the same entry point, following the direction of and technique obviates the need to manage any asymmetry
the initial needle tract until the 5 mm depth mark is reached. It following the procedure, additional sutures may be added to
is important to place the needle in the same entry point in order ensure an optimal result. The results should be evaluated with
to avoid a dermal bridge at the entry site where the suture is the patient upright prior to trimming the suture ends. If a need
too superficial. Either side of the suture may be placed first, for adjustment to the degree of tissue advancement emerges
depending on the preference of the physician. once a patient is upright, they may be reclined once again to
adjust tissue advancement over the appropriate suture.
Once the suture is in place, tension the suture on both sides to
ensure there is no depression at the entry site. When the suture Post-Procedure Care
is tensioned, the skin will remain evenly taut, and there should Though placement of absorbable suspension sutures is a mini-
not be dimples at any point along the length of the suture, as mally invasive procedure, it does require diligent adherence to
dimples are an indication that the depth of the suture is var- post-care instructions. Post-procedure recommendations pre-
ied, and cones are caught on the dermis. Dimples at the entry sented here are somewhat less restrictive than in the authors’
point indicate a small skin bridge resulting from needle entry 2017 consensus paper but must be followed to ensure optimal
at slightly different points. Any observed dimples at the entry outcomes.
point may be dissipated by gentle massage directly over the
affected area or subcision using the 23 gauge needle if nec- Once the procedure is completed in the office, ice is applied for
essary. After proper placement is confirmed, apply tension to 30 minutes and Aquaphor® is applied to puncture sites. While

Do Not Copy
the inferior potion of the suture, and grasping the suture itself patients may be instructed to continue icing for 24 hours, it
rather than the needle, begin the tissue elevation process by should be noted that patients often apply too much pressure
advancing the tissue in the zone of action over the lower cones, when icing at home and should either be instructed not to do so
engaging the cones. Then, apply sufficient tension to the supe- or instructions to ice at home may be omitted all together. Pa-

Penalties Apply
rior aspect of the suture to further and fully elevate the tissues tients may wash their face or apply makeup after 24 hours, but
in the zone of action to the desired position, and while holding these activities must be gentle, and pushing or pulling of the
tension to maintain this desired level of correction and tissue skin should be avoided. Early animal studies show that tissue
movement, massage the tissue over the superior cones to seat integration of the suture’s knots is complete at one week, and
them into place to anchor the superior aspect of the suture. An- the pull-out force of the suture plateaus at this time (Z.P. Lorenc,
choring the suture will maintain this desired level of elevation. MD, personal communication). Therefore, great care should
Slight and transient pleating or puckering may be observed but be taken not to disturb the suture with physical forces result-
can be expected to resolve within 2 to 3 days. As during place- ing from rigorous application of makeup, cleansing, chewing
ment, the force applied to the suture must be along a single, (a relatively soft diet is recommended), and distorting facial
straight vector in line with the needle track. Incorrectly applied expressions such as grimacing for 1 week. During this week,
tension can disengage the cones. Seat the suture by massag- patients should keep their head elevated on 2 pillows at night.
ing the dermis overlying the superior cones in the direction of Additional common activities that should be avoided include
the exit point. Allow sutures to rest for a few minutes, and then face-down massages, dental procedures or cleanings, and high
adjust further if needed. At this point, if any further adjustment impact exercise. Follow-up should include an office visit 3 to 5
is needed within the zone of action, the tissue may be moved days after treatment and again at 2 weeks if necessary.
over the cones. Any visible gathering or slight pleating of the
skin can be expected to dissipate within 2 to 3 days. Nature and Duration of Outcomes
Though the physical lifting capacity of absorbable suspension su-
The degree of necessary correction varies from patient to pa- tures is responsible for immediate results and initial repositioning,
tient and is largely dictated by pre-treatment plan. While the the initial lift is complemented by a longer-lasting recontouring
amount of tissue advancement or suspension required to effect that is reflected by both patient- and investigator-reported
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654
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

measures of improvement and patient satisfaction. These posi- but are an important aspect of a complete treatment approach.
tive changes have been shown within the context of a clinical Energy-based devices should ideally be used 6 weeks prior to
study to endure for at least 12 months, but in the experience of suture placement so that the treatment does not disrupt the
the authors benefit endures for between 18 and 24 months.9,10 suture once it is placed. Neurotoxin is generally administered
Because collagen stimulation by the PLLA/PLGA within the su- 1 week prior to suture placement and can be used to relax hy-
ture is not complete for between 4 and 6 months,13 it stands to perkinetic muscles, alleviating the degree of force exerted on
reason that the mechanical and biostimulatory qualities of the the cones, thereby maximizing their tissue repositioning poten-
suture act in concert to reposition and recontour facial tissue as tial. Volume replacement with fillers may be completed either
well as improve skin quality. While “lift” in its purely technical 6 weeks prior to suture placement to permit integration and
sense may be considered the primary outcome of absorbable dissipation of swelling or administered on the day of the proce-
suspension suture treatment, the qualitative improvements in dure. Generally, areas in which the suspension suture has been
skin texture and contour are equally as important. This longer- placed should not be treated with additional modalities on the
term improvement is reflected by the authors’ experience with day of the procedure, and only adjacent or distinct anatomical
retreatment. In most cases, patients do not require retreatment areas may be managed with filler or toxin. In some cases, how-
for 24 months: generally, the revolumization that occurs as a re- ever, lifting tissue can unmask volume deficits, and patients
sult of PLLA/PLGA-induced collagenases obviates the need for with moderate to severe volume deficits may be given fillers
additional suture placement before that time. In some cases, re- in those areas as long as fillers are placed outside of the sub-
treatment may include fewer sutures than the initial treatment. cutaneous plane. If administering fillers to an anatomical area
For example, the patient in Figure 3 was retreated at 16 months where sutures have been placed, it is important to account for
with a single suture. the eventual volume that results from the PLLA/PLGA within
the sutures.
Preventing and Treating Adverse Events
As with any medical procedure, a de tailed knowledge of po- Emerging Developments
tential adverse events and how to best treat them is critical. The applications of absorbable suspension sutures continue to
Within the last 12 months, the adverse event rate per 106,810 expand, and research continues to emerge on more systematic
devices sold is 0.006%.14 This remarkably low rate mirrors that inclusion of the jawline and jowls in initial patient assessments,
observed for Silhouette Soft™ (Sinclair Pharma, London, UK), as well as optimal application of absorbable suspension suture
a physiochemically equivalent suture of similar design avail- technology to the neck. Indeed, for some experienced practi-

Do Not Copy
able in Europe.14 Swelling is relatively common, primarily as tioners, a practical approach to treatment may include 2 to 4
a result of the lidocaine injections, and dissipates within 2 to sutures in the midface, 1 to 2 sutures in the jowls or along the
3 days. Bruising is rare and may be managed by icing the area jawline, and 2 in the neck. Overall, the number of sutures need-
or treatment with lasers. While some practitioners may argue ed for a holistic treatment approach that includes the midface,

Penalties Apply
that patients should not take blood thinners for 1 week prior to jowls, jawline, and neck is between 6 and 8 sutures per side.
suture placement, the potential risk of stopping blood-thinning Utilization of this higher number of sutures reflects the inter-
therapy outweighs the increased likelihood of bruising. The play between each of these distinct segmental treatment areas.
patient should be counseled to avoid medically unnecessary For example, the improvements gained by repositioning in the
supplements that may increase bruising, including vitamin E, midface and jowls is further highlighted by improving jawline
garlic, ginger, and ginkgo. While hypersensitivity is rare, it does definition. While there have been some reports of sutures used
occur, and several case studies suggest that it can be success- for brow lifts, the results of the procedure are ambiguous, and
fully managed with steroids (Z.P. Lorenc, MD and M.S. Nestor, patient satisfaction may be limited.
MD, PhD, personal communication). While minor bleeding
consistent with a puncture is part of the treatment process, CONCLUSION
post-procedure bleeding or profuse bleeding during the pro- Absorbable suspension sutures fill an important gap in the
cedure are rare and should be treated immediately. The patient treatment armamentarium: they provide a minimally invasive
should not experience pain during the procedure, and discom- option for tissue repositioning that is expanding to include sev-
fort is a sign that the needle is outside of the correct plane. eral distinct anatomical areas within the face and neck. Utilizing
absorbable suspension sutures as a recontouring treatment in
Recommendations for Combination Treatments these areas, rather than as a basic lifting technique or surrogate
While initial recommendations focused on treatment with for a surgical facelift, is critical for meeting patient expectations
absorbable suspension sutures as a single modality,5 the Sil- and ensuring high patient satisfaction. The recommendations
houette InstaLift™ device is supportive of combination treatment presented here, including proper patient selection, vector de-
with energy-based devices, neurotoxin, or fillers. These addi- termination, and suture placement can serve as a guide for
tional treatments not only enhance the impact of the procedure physicians who hope to further develop their expertise and
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655
Journal of Drugs in Dermatology Z.P. Lorenc, G. Ablon, J. Few, et al
June 2018 • Volume 17 • Issue 6

5. Nestor MS, Ablon G, Andriessen A, et al. Expert consensus on absorbable

utilize absorbable suspension sutures more frequently in their advanced suspension technology for facial tissue repositioning and volume
practice as part of an evolving tool set to maximize clinical re- enhancement. J Drugs Dermatol. 2017;16(7):661-666.
6. Sillhouette InstaLift™ [instructions for use]. Irvine, CA: Sillhouette Lift Inc.;
sults and patient satisfaction. August 3, 2017.
7. Goldberg D, Guana A, Volk A, Daro-Kaftan E. Single-arm study for the charac-
DISCLOSURES terization of human tissue response to injectable poly-L-lactic acid. Dermatol
Surg. 2013;39(6):915-22.
Dr. Lorenc is a consultant for Jonhson & Johnson, Merz, Aller- 8. Stein P, Vitavska O, Kind P, Hoppe W, Wieczorek H, Schurer NY. The bio-
gan, Galderma, Sinclair Pharma, CorMedix, ThermiAesthetics, logical basis for poly-L-lactic acid-induced augmentation. J Dermatol Sci.
2015;78(1):26-33.
and Almirall Pharma. Dr. Ablon is an Associate Clinical Pro- 9. Nestor MS. Facial lift and patient satisfaction following treatment: 12-month
fessor at UCLA, consultant and advisory board member for data - a prospective, masked, controlled clinical study. Poster presented at:
2018 South Beach Symposium (SBS); March 1–4, 2018; Miami Beach, FL.
Galderma, Sinclair, Thermi-Almirall, Erchonia, Sunetics, Nutra- Abstract 66937.
fol, and Lifes2Good. Dr. Few is a consultant and investigator for 10. Nestor MS. Improved patient satisfaction 12 months following treatment
with Silhouette InstaLift™: data from a prospective, masked, controlled clini-
Sinclair Pharma and a consultant and investigator for Allergan, cal study. Poster presented at: IMCAS World Congress 2018; February 1–3,
Galderma, Merz, Venus Concepts, and Zeltiq. Dr. Gold is a con- 2018; Paris, France.
sultant for Sinclair Pharma and Thermi-Almirall. Dr. Goldberg is 11. Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume
deficit: 2-year results from a pivotal single-blind randomized controlled study.
a consultant for Sinclair Pharma. Dr. Mandy is a consultant for Dermatol Surg. 2013;39(11):1602-1612.
and has received salary from Almirall and Sinclair Pharma; is 12. Ogilvie MP, Few JW, Jr., Tomur SS, et al. Rejuvenating the face: an analysis
of 100 absorbable suture suspension patients [published online December
an advisory board member for and has received honoraria from 8, 2017]. Aesthet Surg J.
Galderma USA and Valeant Pharmaceuticals; is an advisory 13. Bauer U, Graivier MH. Optimizing injectable poly-L-lactic acid administration
for soft tissue augmentation: the rationale for three treatment sessions. Can
board member for Merz Aesthetics; and has received hono- J Plast Surg. 2011;19(3):e22-e27.
raria from Procter & Gamble Company and from International 14. Sinclair Pharma plc. Internal safety report. London, UK: December 2017.
Speaker & Faculty Education. Dr. Nestor is a consultant and
advisory board member for and has received research grants
AUTHOR CORRESPONDENCE
from Sinclair Pharma, and is a consultant, advisory board mem-
Z. Paul Lorenc MD FACS
ber, and speaker for Thermi-Almirall; a consultant and advisory
E-mail:................…….......................................... [email protected]
board member for Almirall; a consultant for Bayer Healthcare;
a consultant and speaker for Sensus Healthcare; a speaker and
principal investigator for IFC, S.A; a principal investigator and
consultant for CROMA Pharma, Ferndale, and Johnson & John-

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son; and a principal investigator for Actavis, Allergan, Annacor
Pharmaceuticals, Biofrontera, Brickell Biotech, Cynova Labora-
tories, DUSA Pharmaceuticals, Demira, Evolus, Intraderm, LEO
Pharma, MC2 Therapeutics, and SASIF & Sonoma. Dr. Weinkle

Penalties Apply
is a consultant, principal investigator, advisory board member
and speaker for Allergan; a stock holder and principal investiga-
tor for Derm Advance; an advisory board member, consultant,
and speaker for Ethicon and Merz; a consultant and speaker for
Galderma; a consultant for Proctor & Gamble; and a principal
investigator for Teoxane, Alphaeon, and Sinclair Pharma.

ACKNOWLEDGMENTS
The authors thank Ginny Vachon PhD of Principal Medvantage,
LLC, Atlanta, Georgia, USA for providing medical writing sup-
port, provided by X-Medica, LLC with an educational grant from
Sinclair.

REFERENCES
1. Farkas JP, Pessa JE, Hubbard B, Rohrich RJ. The science and theory behind
facial aging. Plast Reconstr Surg Glob Open. 2013;1(1):e8-e15.
2. 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):253-260.
3. Kretlow JD, Hollier LH, Jr., Hatef DA. The facial aging debate of defla-
tion versus attenuation: attenuation strikes back. Plast Reconstr Surg.
2012;130(1):180e-181e; author reply 182e.
4. Wong CH, Mendelson B. Newer understanding of specific anatomic targets in
the aging face as applied to injectables: aging changes in the craniofacial skel-
eton and facial ligaments. Plast Reconstr Surg. 2015;136(5 Suppl):44S-48S.
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JDDONLINE.COM/PODCAST

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Copy
EPISODE
JDD Podcasts present the latest journal content related
to advances in drugs, devices and treatment methods in
dermatology, in a new convenient audio format. From How Do You Celebrate the Birthday Suit:

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article abstracts to interviews, JDD Podcasts provide a fresh Variations in Skin Cancer Screening Practices
perspective of the peer reviewed content you have come to Among Dermatologist
rely on from JDD (Journal of Drugs in Dermatology).
In this edition of the JDD podcast “Ask the Investigator,”
Hosted by Adam Friedman, MD and released monthly, host Dr. Adam Friedman from the GW School of Medicine
each episode will feature an interview with, and practical and Health Sciences is joined by Dr. Evan Rieder, Assistant
pearls from, the principal investigator of a high-profile JDD Professor of Dermatology at NYU Langone Medical Center
manuscript in a convenient audio format. Each podcast will and one of the few dermatologists double board certified
place the selected article into a clinically useful perspective that in dermatology and psychiatry in the U.S., to discuss his
is easy to listen to in the office or on the go. recent study entitled “Dermatologist Practices During Total
Body Skin Examinations: A Survey Study.” Do we all do
it the same? Are we all checking every nook and cranny?
Do we need better standardization for our greatest weapon
to enable early and life saving skin cancer detection? Call
me crazy, but this is pretty.....preeeetty... pretty important
(as Larry David would say).

Listen Now at JDDonline.com/PODCAST

June 2018 657 Volume 17 • Issue 6

From Probiotic to Prebiotic Using Thermal Spring Water

Joshua Zeichner MDa and Sophie Seite PhDb
Mount Sinai Hospital, New York, NY
a

b
La Roche-Posay Dermatological Laboratories, Levallois-Perret, France

ABSTRACT
Background: La Roche-Posay Thermal Spring Water (LRP-TSW) exhibits both probiotic and prebiotic properties enhancing the diversity
of the skin microbiota.
Methods: A review was undertaken to explore the role of LRP-TSW as a topical probiotic and prebiotic therapy in improving the diver-
sity of the skin microbiota and reducing dryness and pruritus in inflammatory skin diseases.
Results: The concentration of minerals and non-pathogenic microbes in LRP-TSW may explain its therapeutic benefit when used for
inflammatory skin diseases. Clinical studies have shown that topical LRP-TSW treatment results in increases in Gram-negative bacteria
with reduction of Gram-positive bacteria, and improvements in skin microbial diversity. At the same time skin condition in atopic der-
matitis, psoriasis, and general dryness in otherwise healthy skin, has been shown to improve.
Conclusions: Enhancement of skin microbiota diversity using topical LRP-TSW may offer a valuable option for the treatment and main-
tenance of inflammatory skin diseases.

J Drugs Dermatol. 2018;17(6):657-662.

INTRODUCTION

T
hermal water has been used for its medicinal benefits impact the body’s global microbiota.3 Since decades the reac-
since Roman times. It has been reported to benefit a tions catalyzed by formate dehydrogenase of bacteria, or glycine
variety of diseases across dermatology, pulmonology, reductase of clostridia, have been described.3 The common de-
hematology and gastroenterology.1-3 La Roche-Posay Thermal nominator of these selenium-dependent processes is that they
Spring water (LRP-TSW) from France has been useful in treating are all oxidation-reduction reactions.3 The antioxidant properties of

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skin diseases including atopic dermatitis and psoriasis.1,2 The LRP-TSW may help improve skin condition by reducing skin dry-
LRP-TSW Thermal Center serves as a hospital staffed by 8 Der- ness and pruritus of patients affected by chronic dermatoses such
matologists treating over 8,000 patients per year, 25% of whom as atopic dermatitis and psoriasis.2 The effect of selenium on lipid
are children. Patients at the Center are treated with therapeutic peroxidation has been studied in cultured human skin fibroblasts.2

Penalties Apply
baths, known as balneotherapy (BPT). The regimen consists of A reduction of thiobarbituric acid reactive substances (TBARS),
an 18-day treatment with a daily high-pressure filiform shower an index of lipid peroxidation and oxidative stress, was noticed
(15 bars for 3 minutes) using crude thermal spring water. if the cells were cultured in a medium supplemented with Se or
with LRP-TSW compared to the control medium with demineral-
This review discusses the role of TSW as a probiotic and preb- ized water.2 Together, selenium-dependent glutathione peroxidase
iotic therapy in enhancing the diversity of the skin microbiota (Se-GSH.Px) activity and cell viability were significantly increased.2
in inflammatory skin diseases as well as the clinical improve-
ments in signs of these diseases using LRP-TSW balneotherapy. LRP-TSW is rich in non-pathogenic micro-organisms that play a
major role treating various skin diseases. The microbial compo-
Mineral and Microbial Composition of Thermal Spring sition of LRP-TSW has been characterized with a metagenomics
Water and Its Chemical and Physical Properties approach using an Illumina next-generation sequencing (NGS)
LRP-TSW is comprised of specific minerals and non-pathogenic of the V1–V3 hypervariable regions of the 16S rRNA genes. A
microbes.1,2 The low mineral and silicate concentration gives global bacterial picture of LRP-TSW was determined2 and is
LRP-TSW its name in French, “L’eau de velours” or velvet water. shown in Figure 1. The main bacterial characteristics of crude
LRP-TSW is oligotrophic meaning that it contains a low concen- LRP-TSW are:
tration of nutrients (<1 g/L). However, the presence of elements
like selenium (Se) and strontium (Sr) play an important role in • A high bacterial diversity (Da Silva Database)
its biological activities.2 Selenium salts are necessary for cellular
functions including enzyme activity like glutathione peroxidase, • A very low bacterial concentration
thioredoxin (a class of small redox proteins) reductase, and deio-
dinases. Those elements also influence bacterial growth and can • A majority of Gram-negative bacteria
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658
Journal of Drugs in Dermatology J. Zeichner, S. Seite
June 2018 • Volume 17 • Issue 6

FIGURE 1. The bacterial landscape of LRP-TSW crude water at phyla FIGURE 2. Relative abundance of Gram-negative (A) and
level. Gram-positive (B) bacteria at the skin surface of healthy subjects
untreated (Untreated) and treated with LRP-TSW twice a day for
14 days (Treated). For Gram-negative bacteria, Wilcoxon rank sum
test with continuity correction (W =3742, P-value=7.349e-08) and
for Gram-positive bacteria Wilcoxon rank sum test with continuity
correction (W=1158, P-value=7.349e-08).
(A)

As LRP-TSW contains live bacteria that impact the skin’s micro-

biota, the water itself is considered to be a probiotic.2

In discussing the safety of drinking water, the World Health Or-

ganization (WHO-2006) recommends that “Water entering the
distribution system must be microbiologically safe”, meaning
that it should not be contaminated by pathogenic microorgan-
isms. However, the WHO does not contend that drinking water (B)
is microorganism free, and in fact, bacteria are present in rela-
tively high numbers (102 to 104 cells/ml) in drinking water.4-6

Probiotic versus Prebiotic Water

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While a probiotic is a product containing live microorganisms,
a product containing an ingredient or nutrient that selectively
stimulates or inhibits the growth or activity of commensal skin

Penalties Apply
bacteria, is considered a prebiotic.7 Filtered LRP-TSW, that does
not contain living bacteria can be considered a prebiotic. The
product has a low mineral content (<1 g/L) and specific trace el-
ements like Se and Sr, which are necessary for cellular functions
including enzyme activity. Intrinsically its major biological prop-
erties are free radical “scavengers”, anti-inflammatory and toxic
heavy metals protection. Prebiotic TSW has been shown to be
beneficial in subjects with dry but otherwise healthy skin.7 The
effect of LRP-TSW using a commercial spray (2 sprays per appli-
cation) twice a day for 14 days on inner forearms, was evaluated
in 70 healthy subjects with dry skin (corneometry measurement Effect of Balneotherapy on the Skin Microbiome in
≤ 50 au).7 Thirty minutes after the last application of LRP-TSW Some Inflammatory Skin Diseases
microbiome sampling of the treated and nearby untreated skin The microbiota is the collection of microorganisms that live
was performed to determine bacterial community composition. on and in our bodies. The complex diversity and composition
Treatment resulted in a significant increase in Gram-negative of microbial communities on the skin vary by skin region5 and
bacteria and a decrease of Gram-positive bacteria on the skin between individuals.5,6 The skin microbiota is composed of
surface of treated skin areas versus nearby untreated areas was around 80% Gram-positive and 20% Gram-negative bacteria.
noted (Figure 2). Interestingly, topical application of a moistur- Firmicutes and Actinobacteria for Gram-positive bacteria, while
izer containing LRP-TSW in a similar protocol demonstrated a Proteobacteria and Bacteroidetes are the main phyla of skin
significantly increased level of Xanthomonas genus correlated Gram-negative bacteria. The bacterial diversity is mainly driven
with increased skin hydration levels (Figure 3). by Gram-negative bacteria, and abundance by Gram-positive
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Journal of Drugs in Dermatology J. Zeichner, S. Seite
June 2018 • Volume 17 • Issue 6

FIGURE 3. Correlation between Xanthomonas genus relative FIGURE 4. Average taxonomic composition (30 main genera) of the
abundance level at the skin surface and skin hydration level measured skin surface microbiome associated with AD prior (A) and post (B)
by corneometry in healthy subjects after treatment with a moisturizer balneotherapy on unaffected (UAF) and affected (AF) skin areas.
containing 100% of LRP-TSW. Significant positive correlation
(P-value < 0.05) with a correlation coefficient of 0.58 was measured. (A)

(B)

bacteria. Several diseases such as atopic dermatitis and pso-

riasis have been found to be associated with changes in the
composition of the skin microbiota.8-11 Balneotherapy using
probiotic LRP-TSW water has been shown to improve the skin
microbiota in a variety of inflammatory skin conditions.

Effect of LRP-TSW on Atopic Dermatitis

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The effect of LRP-TSW balneotherapy on the microbiome has
been evaluated in patients with atopic dermatitis. Microbial
samples were taken from 31 patients with atopic dermatitis

Penalties Apply
on both affected and adjacent unaffected skin. Repeat samples
were taken after 21 days of balneotherapy to analyze micro-
biota diversity (Shannon index), bacterial phyla, and genus
abundance. At baseline, Shannon diversity was lower in the
lesional AD skin as compared to adjacent clinically normal
skin. After balneotherapy, Shannon diversity index increased
in the lesional areas and became similar to what was observed EASI (Eczema Area and Severity Index) scores also significant-
in the clinically normal appearing skin. In addition, balneother- ly (P<0.0001) improved in 82% of patients from 9.3 (SD±0.8)
apy resulted in a reduction of Firmicutes organisms mainly to 4.6 (SD±0.6). Clinical efficacy correlated with significant
Staphylococci, along with an increase in other bacterial phy- improvements in quality of life measures, as Dermatology
la. Additionally, an increase in the amount of Xanthomonas Life Quality Index (DLQI) and Children’s DLQI (CDLQI) (both
genus was also observed (Figure 4). The increase in bacterial P<0.0001). There was a mean reduction in DLQI scores of 8.1
diversity after balneotherapy was correlated with a significant (SD±1.0) to 4.1 (SD±0.7) and a 28% reduction in CDLQI scores
increase in Gram-negative bacteria and a significant decrease of 7.5 (SD±0.7) to 4.5 (SD±0.5). Balneotherapy was reported to
of Gram-positive bacteria on the skin (Figure 5). provide long-lasting results, with clinical and quality of life im-
provements maintained for an average of 6 months.12
In a 2014 study, 100 patients suffering from chronic AD were treat-
ed with LRP-TSW balneotherapy at the LRP Treatment Center.12 LRP-TSW based skincare products have also been shown to im-
After treatment, SCORing Atopic Dermatitis (SCORAD) scores prove the diversity of the skin microbiome in eczema patients,
significantly (P<0.0001) improved in 90% of subjects, with a after three months of applying an emollient containing at least
mean decrease of 38% from 46.8 (SD±1.9) to 27.8 (SD±1.5). Mean a 50% concentration of LRP-TSW12 and a supplement with a
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Journal of Drugs in Dermatology J. Zeichner, S. Seite
June 2018 • Volume 17 • Issue 6

FIGURE 5. Relative abundance of Gram-negative (A) and Gram-positive Severity Index (PASI) scores, no significant change in the Shannon
(B) bacteria at the surface of affected and unaffected skin of diversity index was observed. The average taxonomic composi-
patients affected by AD prior (D0) and post (D21) balneotherapy. For tion of skin bacterial communities associated with the unaffected
Gram-negative bacteria, a significant Wilcoxon rank sum test with and affected skin of psoriatic patients post-balneotherapy showed
continuity correction (W= 163.5, p-value=0.06711) was measured as a significant increase in the level of Xanthomonas genus and, to a
well as for Gram-positive bacteria (W=320, P-value=0.06887). lesser extent, Corynebacterium genus.14 The Xanthomonas genus
(A) belongs to the main Xanthomonadaceae family found in LRP-
TSW and also, at a low concentration, on the naturally healthy
skin.14 This is associated with a decrease in Staphylococcus genus.
Additionally, in this patient group after balneotherapy, there was
a significant increase of skin surface Gram-negative bacteria and
a significant decrease of Gram-positive bacteria observed (Fig-
ure 6). Two studies have been performed specifically to evaluate
the therapeutic benefits of balneotherapy in treating psoriasis.
In 1995, 92 patients with moderate plaque psoriasis were treated
with balneotherapy. After treatment, there was a mean reduction
in PASI scores of 47% (from 5.5±0.5 to 2.9±0.3, P<0.001), 8% of
patients were completely clear and 48% improved by more than
50%. While the clinical significance is unknown, an increase in the
mean Se plasma level (from 77.1±2.1 to 90.4±2.7 µg/L, P<0.01) was
noted after treatment and correlated with the reduction of PASI
(rs=0.31, P<0.01).3

(B) In 2012, 199 patients with severe plaque psoriasis (74.4%) or

guttate psoriasis (12.1%) were treated with balneotherapy. Af-
ter treatment, mean PASI scores were reduced by 57% (from
17.6±0.9 to 7.8±0.5, P≤0.0001), 96% of patients showed some
degree of improvement in PASI scores, 26% achieved a PASI

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75, and 64% of patients achieved a PASI 50 response, 78% of
patients experienced improvement in DLQI (from 5.9±0.2 to
3.4±0.15, P≤0.0001). Among these patients, 75% had previous-
ly received balneotherapy with an average of 8±9 treatments

Penalties Apply
(max=57 - min=1). Patients reported that balneotherapy contin-
ued to improve their quality of life for 7±3 months and gave a
sustained remission of psoriasis for an average of 6±3 months
following treatment.

DISCUSSION
Healthy human skin normally consists of a mix of Gram-positive
and Gram-negative bacteria of at least 19 phyla. Actinobacteria,
Firmicutes, Proteobacteria, and Bacteroides are the predomi-
biomass of non-pathogenic Gram-negative bacteria such as Vit- nant bacterial phyla in the human skin, regardless of body
reoscilla filiformis (LRP-VFB).13 Improvements were observed in site.9,10 Within these phyla, the 3 most abundant genera are:
the microbiome of the skin of AD patients with an increase in Propionibacterium, Corynebacterium, and Staphylococcus.9,10
microbial diversity.
A variety of inflammatory skin diseases are associated with ab-
Psoriasis Vulgaris normalities in the microbiota with a loss of diversity.7 There is an
The skin microbiome has been evaluated in patients with moderate overrepresentation of Firmicute organisms, like Staphylococci
to severe psoriasis vulgaris at the LRP thermal care center. Similar sp. and an underrepresentation of Actinobacteria, Proteobac-
to studies performed in AD, bacterial swabs were taken from af- teria, and Cyanobacteria.12 Treatment of AD with LRP-TSW has
fected and nearby unaffected skin before and after three weeks of been associated with improvements in diversity of the mi-
TSW balneotherapy.14 While balneotherapy resulted in significant crobiota in patients with AD as well as clinically meaningful
improvements in clinical signs, as measured by Psoriasis Area and improvements in signs of the disease itself.12-14
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661
Journal of Drugs in Dermatology J. Zeichner, S. Seite
June 2018 • Volume 17 • Issue 6

FIGURE 6. Relative abundance of Gram-negative (A) and in microbiota have been correlated to clinical improvement of the
Gram-positive (B) bacteria at the surface of affected and unaffected skin skin in conditions like AD. Although the therapeutic mechanisms
of patients affected by psoriasis prior (D0) and post (D21) balneotherapy. of balneotherapy are not completely understood, in addition to a
A significant Wilcoxon rank sum test with continuity correction was probiotic effect LRP-TSW may have anti-inflammatory effects as
measured for Gram-negative bacteria, (W=1341.5, P-value=0.01622) and well. Finally, it exhibits a prebiotic effect on Gram-negative bacte-
for Gram-positive bacteria (W=2243.5, P-value=0.02006). ria and on the Xanthomonadaceae family, as patients treated with
(A) prebiotic demonstrate improvements in dryness and skin barrier
function.7

LIMITATIONS
Skin microbiome studies are challenging and costly. Currently
results are a discussion of in-vivo data that demonstrated micro-
biome alterations correlated with skin condition improvement
when using balneotherapy at the source with probiotic LRP-
TSW, topical filtered LRP-TSW, and skincare containing more
than 50% LRP-TSW. More comparative studies using TSW with
different mineral compositions are needed to better understand
the mechanism(s) of action.

CONCLUSION
LRP-TSW exhibits both prebiotic for its mineral composition
and probiotic properties for its bacterial diversity. LRP balneo-
therapy has been shown to effectively treat inflammatory skin
(B) conditions including AD and psoriasis. An abnormal microbiota
is associated with skin disease and improvements in microbial
diversity correlated with clinical improvements in the severity
of the skin disease itself. LRP-TSW has been shown in clinical
studies to improve skin microbiome diversity as well as the

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decreased severity of active lesions in skin diseases like AD,
psoriasis, and general dryness in otherwise healthy skin. The
concentration of minerals and non-pathogenic microbes likely
explain its therapeutic benefit and make it an attractive option

Penalties Apply
for treating inflammatory skin diseases.

DISCLOSURES
Joshua Zeichner has served as an advisory board member and
consultant to La Roche Posay. Sophie Seité is an employee of
La Roche-Posay, France.

ACKNOWLEDGMENTS
The author would like to thank Dr. Andriessen of RBC Con-
LRP-TSW may be considered a probiotic, as it naturally contains a sultants for writing assistance. Her support was funded by La
low concentration of bacteria, with a high microbial diversity and Roche-Posay Dermatological Laboratories, France.
more Gram-negative than Gram-positive bacteria. Clinical stud-
ies indicate that balneotherapy with probiotic LRP-TSW stimulates REFERENCES
the growth of Gram-negative bacteria, particularly on Xantho- 1. Gambichler T, Kuster W, Kreuter A et al. Balneotherapy combined treatment
of psoriasis vulgaris and atopic dermatitis with salt water baths and artificial
monadaceae, at the expense of Gram-positive bacteria at the skin ultraviolet radiation. J Eur Acad Dermatol Venereol. 2000;14:425-428.
surface improving microbial diversity associated with decreased 2. Seité S. Thermal waters as cosmeceuticals: La Roche-Posay thermal spring
water example. Clin Cosmet Investig Dermatol. 2013;6:23-28.
severity of inflammatory skin conditions.12-14 Without the use of an 3. Pinton J, Friden H, Kettaneh-Wold N, et al. Clinical and biological effects of
antibiotic, LRP-TSW can modify the microbiota on human skin. balneotherapy with selenium-rich spa water in patients with psoriasis vulgar-
Decreases in Staphylococci sp. have been observed along with is. Br J Dermatol. 1995;133:344-347.
4. Vital M, Dignum M, Magic-Knezev A, et al. Flow cytometry and adenosine tri-phos-
increases in Gram-negative Xanthomonadaceae levels, even after phate analysis: alternative possibilities to evaluate major bacteriological changes in
topical application of LRP-TSW.12-14 Moreover, these improvements drinking water treatment and distribution systems. Water Res. 2012;46:4665-4676.
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June 2018 • Volume 17 • Issue 6

5. Costello EK, Lauber CL, Hamady M, et al. Bacterial community variation in

human body habitats across space and time. Science. 2009;326:1694-1697.
6. Fierer N, Lauber CL, Zhou N, et al. Forensic identification using skin bacterial
communities. Proc Natl Acad Sci U S A. 2010;107:6477-6481.
7. Baldwin HE, Bhatia ND, Friedman A, Eng RM, Seité S. The Role of Cutane-
ous Microbiota Harmony in Maintaining a Functional Skin Barrier. J Drugs
Dermatol. 2017;1;16(1):12-18.
8. Schommer NN, Gallo RL. Structure and function of the human skin microbi-
ome. Trends Microbiol. 2013;21:660-668.
9. Grice EA, Segre JA. The human microbiome: our second genome. Annu Rev
Genomics Hum Genet. 2012;13:151-170.
10. Grice EA. The intersection of microbiome and host at the skin interface:
genomic-and metagenomic-based insights. Genome Res. 2015;25:1514-1520.
11. Rosenthal M, Goldberg D, Aiello A, et al. Skin microbiota: microbial commu-
nity structure and its potential association with health and disease. Infect
Genet Evol. 2011;11:839-848.
12. Seité S, Flores GE, Henley JB, et al. Microbiome of the affected and un-
affected skin of patients with atopic dermatitis before and after emollient
treatment. J Drugs Dermatol. 2014;13:1365-1372.
13. Seité S, Zelenkova H, Martin R. Clinical efficacy of emollients in atopic der-
matitis patients - relationship with the skin microbiota modification. Clin Cos-
met Investig Dermatol. 2017;10:25-33.
14. Martin R, Henley JB, Sarrazin P, et al. Skin Microbiome in Patients With Pso-
riasis Before and After Balneotherapy at the Thermal Care Center of La Ro-
che-Posay. J Drugs Dermatol. 2015;14:1400-1405.

AUTHOR CORRESPONDENCE

Joshua Zeichner MD
E-mail:................……................................. [email protected]

!
E WR As
N O F , and
P

NPs
Ns, For RNs, NPs, PAs
R
www.dermtraining.com

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An online, on-demand comprehensive Provides a Certificate of Completion

dermatology training program for your and Includes 15 CE Credit Hours
Derm Care Team raising the standards of
Brought to you by Perry Robins, MD
patient care and office efficiency
and Deborah S. Sarnoff, MD, FAAD

www.dermtraining.com

CONTINUING EDUCATION JOINTLY PROVIDED BY:

June 2018 664 Volume 17 • Issue 6

Single-Center, Double-Blind, Randomized, Placebo-

Controlled, Study of the Efficacy and Safety of a Cream
Formulation for Improving Facial Wrinkles and Skin Quality
Neil Sadick MD,a,b Krista Bohnert BS,b Monica Serra,b and Neal Kitchen PhDc
a
Weill Cornell Medical College, Cornell University, New York, NY
b
Sadick Dermatology and Research, New York, NY
c
HydroPeptide LLC, Issaquah, WA

ABSTRACT
Introduction: Several therapeutic modalities from topicals to chemical peels and energy-based devices are available to improve skin
quality and reduce the appearance of wrinkles in the face and neck area.
Objective: The objective of this single-center, double blinded, placebo-controlled study was to evaluate the safety and efficacy of Nimni
Cream by Hydropeptide® on skin quality and wrinkles.
Methods: 20 patients were randomized in a 3:1 ratio to use either Nimni Cream by Hydropeptide or placebo starting with twice a week
application and increasing to daily for 8 weeks. Patient and investigator assessments were conducted on week 4 and 8.
Results: At week 8, blinded and treating investigator assessments showed a statistically significant improvement in global aesthetic
improvement scale assessments in the active group for the face, but not the neck area. There was also a trend towards improvement
in Fitzpatrick Wrinkle Scale scores in the active, but not placebo group, at both time-points, for the face and neck, but the results were
not statistically significant. The majority of patients were satisfied with the results and no adverse effects were reported.
Conclusion: Nimni Cream by Hydropeptide is safe and effective for improving skin quality in the face and can be considered a satisfac-
tory therapeutic option adjuvant to aesthetic procedures.

J Drugs Dermatol. 2018;17(6):664-669.

INTRODUCTION
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O
ver time, extrinsic and intrinsic factors indiscrimi- Over the past decade, topical anti-aging compounds have in-
nately contribute to aging of the skin. Excess ex- creased in number, variety, and efficacy in tackling signs of facial

Penalties Apply
posure to UV, lifestyle choices such as smoking and neck aging. Nimni Cream by Hydropeptide® is a patented
and alcohol, genetics, concomitant medical conditions, all formulation created by Dr. Marcel Nimni for topical applica-
together influence and aggravate the rate of degradation of tion designed to enhance collagen and proteoglycan synthesis
skin quality.1-3 Age-dependent collagen/elastin break down, comprising in the skin. The product ingredients include an anti-
loss of hyaluronic acid (HA), epidermal thinning together oxidant compound selected from the group consisting of lipoic
with a decrease in the amount of water held in the epidermis acid, bioflavonoids, constituents of ginkgo, and isoflavones,
leads to fine lines, discoloration, dullness, textural changes soluble in an organic penetrant, and in a quantity sufficient to
and wrinkles.4,5 enhance collagen synthesis in the skin 10,11. Nimni cream also
contains a mixture of essential amino acids comprising: isoleu-
Conversely, several therapeutic modalities have been de- cine, lysine, methionine, phenylalanine, threonine, tryptophan,
veloped over time to prevent and reverse the signs of aging valine, histidine, and arginine in a topical pharmaceutically ac-
primarily in the facial area, but also in the neck, as it has been ceptable carrier. This proprietary combination of ingredients
recognized as an extension of the facial skin that greatly impacts crosses the skin barrier by a patented trans-phase delivery
the overall appearance of an individual. 6. From sunscreens to system. In in vitro studies, the product was shown to increase
sophisticated energy-based devices such as intense-pulsed- deposition of collagen in the dermis and thicken the epidermal
light, fractional lasers, new generation peels, there is a plethora layer of rat skin.12 Moreover, when tested in human volunteers
of cosmetic solutions for improving skin quality and reducing the product was well tolerated and led to results similar to the
wrinkles. Admittedly however, the use of a topical that can have in vitro findings.
these benefits would be preferred and embraced by patients as
the cost-effectiveness compared to other modalities, and ease The objective of this preliminary study was to evaluate the effi-
of use would reign 7-9. cacy of Nimni Cream by Hydropeptide on skin quality of healthy
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665
Journal of Drugs in Dermatology N. Sadick, K. Bohnert, M. Serra, N. Kitchen
June 2018 • Volume 17 • Issue 6

candidates with moderate to severe facial wrinkles and folds. As of the Declaration of Helsinki, current GCP guidelines, and IRB
skin quality is multifactorial assessments included live investigator approval. A total of 20 patients were randomized in a 3:1 ra-
ratings, patient questionnaires and ratings of standardized photo- tio to use either Nimni Cream by Hydropeptide or placebo as
graphs by a qualified evaluator not in involved in patient treatment instructed by protocol. Treatment consisted of topical applica-
and blinded to photographic time points. The tolerability, and safe- tion to facial and neck skin at increasing frequency beginning
ty of Nimni Cream by Hydropeptide was also evaluated. with application two times per week before bed and increas-
ing to once daily application by week 8 based on tolerability.
METHODS All subjects were also provided with an identical regimen of
Patients homecare products (Facial Cleanser (am/pm), Sunscreen (am),
20 subjects were enrolled in the study. All subjects provided and Moisturizer (PRN)). Live efficacy assessments were con-
written informed consent prior to receiving any study-related ducted at weeks 4 and 8 by both subject and investigator, with
procedures. Patients were screened according to the inclusion/ a blinded investigator assessment completed at week 8 using
exclusion criteria of the study and participant eligibility was de- subject photos collected at baseline. Visual assessments of the
termined. Eligible subjects were healthy females (30-70 years of face were conducted on all subjects grading for fine lines, wrin-
age, Fitzpatrick photo skin types I-IV), with moderate to severe kles, mottled pigmentation, pore size, clarity/radiance, laxity,
fine lines, wrinkles, and overall skin quality as determined by and overall global photodamage at each visit by a live quali-
the investigator. Subjects were required to avoid sun-exposure fied investigator. Safety and tolerability assessments included
in the treated areas, and not have any procedures affecting fa- an evaluation of erythema, peeling, dryness, and roughness by
cial wrinkles or skin quality (ex. microdermabrasion, peels, acne both subject and investigator. Subject assessment (patient re-
treatments, filler, botulinum toxin, radiofrequency, laser, IPL, ported outcomes or PROs) of product attributes and impression
ultrasound, etc) for the duration of the study. Patients that had of efficacy were also collected at each visit. Standardized pho-
cosmetic treatments (botulinum toxin, fillers, peels, lasers, derm- tos were taken at in office visits occurring at baseline (D0), week
abrasion) within 3 months of the baseline visit were excluded. 4, and 8. The primary endpoint was defined as the degree of
Subjects with dermatologic conditions including acne, rosacea, improvement in skin quality rated by a blinded, trained evalua-
eczema, psoriasis, actinic keratosis, severe sun damage, scars, tor using standardized photographs, as well as live evaluations
or a history of keloids were also excluded from the study. by the treating investigator and the patient reported outcome
assessments. Secondary endpoints included the positive inves-
Study Design tigator and patient satisfaction assessed with quartile scales,

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This was a single-center, double-blind, randomized, placebo- the efficacy for the correction of moderate to severe facial
controlled, study conducted in accordance with the principles wrinkles and folds with Validated Assessment Scales (VAS), the

666
Journal of Drugs in Dermatology N. Sadick, K. Bohnert, M. Serra, N. Kitchen
June 2018 • Volume 17 • Issue 6

local tolerability of application of the study product, and the

frequency and duration of adverse events. RESULTS
Population
Assessments 20 subjects total (2 male and 18 female) with an average age of
Investigator Assessments 54.9 (±7.5) years were enrolled into this study. Two female sub-
Throughout the study, efficacy assessments were performed jects (1 active and 1 placebo) were lost to follow- up prior to the
on the treatment areas for each subject by the same Live completion of the study and were not included in the statistical
Treating Investigator at baseline, weeks 4 and 8. The efficacy pa- analysis of the results. All female subjects were peri (1) or post-
rameters were Validated Assessment Scales for facial wrinkles menopausal (17). All but one subject were non-smokers, and
(Fitzpatrick Wrinkle Scale), Global Aesthetic Improvement Scale all occasionally use alcohol. Patients had skin type I (n=1), skin
(GAIS) and a customized 10-point scale for the assessment of type II (n=8), skin type III (n=6), and skin type IV (n=5).
skin quality, Visual Assessment of Skin (VAS) Quality and Pho-
todamage (Figure 1). Investigator Assessments
No statistically significant differences were found in baseline
Safety ratings of investigator visual assessments of skin quality for
Local (dermal) tolerability examination (of the face and neck the face between active and placebo groups for all assessment
separately) was performed at all study visits and will include parameters (fine lines, mottled pigmentation, pore size, clar-
assessments of stinging/burning (rated by the patient verbally), ity/radiance, laxity, and overall global photodamage). Between
dryness, scaling, edema, and erythema (rated by the investiga- baseline and week 8, there was an improvement from mild to
tor or appropriately trained designee). Local tolerability on the moderate in Fitzpatrick Wrinkle Scale scores the active group, for
face and neck was rated as none, mild, moderate, or severe. face and neck, but not the placebo group. The results however
did not reach statistical significance. Statistically significant im-
Standardized Photography provements were noted in the investigator visual assessments
Standardized photographs were taken at 0°, 45°, and 315° an- of skin quality for the face in the active group, baseline versus
gles using the Visia® CR system (Canfield Imaging Systems, week 8, in fine lines, mottled pigmentation, pore size, clarity/
Fairfield). For each angle, a set of four different photographs radiance, smoothness, and overall global photodamage (Table
will be taken including non-polarized, cross-polarized and par- 1, Figure 2, 3). In the placebo group a statistically significant
allel-polarized white light as well as UV light images. improvement was noted in mottled pigmentation for facial skin,

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baseline vs. week 8 (P=0.04). No other factors displayed signifi-
Statistical Analysis cant change. When evaluating the neck, statistically significant
Ordinal variables were analyzed using Wilcoxon test for paired improvement was noted in the investigator visual assessments
samples. For ratio scaled variables normal distribution was of skin quality in the active group, baseline versus week 8, in

Penalties Apply
verified by Kolmogorov-Smirnoff test and then analyzed using smoothness (P=0.03). No other factors displayed significant
Student-T test for paired variables or Wilcoxon test. All statisti- change, and no statistically significant results were noted in the
cal tests were two-sided and tested in conjunction with a 0.05 placebo group for neck skin, baseline vs week 8, for investiga-
nominal significance level. Analyses were carried out using tor visual assessments. Assessments of the face, but not the
SAS version 9.4 statistical software (Cary, NC). neck, by both the treating and blinded investigator, demon-

TABLE 1.
Investigator Visual Assessments of Skin Quality for the Face in the Active Group, Baseline versus Week 8
Face Neck
Visual Assessment
Placebo Active Placebo Active
Fine lines NS 0.0001 NS NS
Mottled pigmentation P=0.04 0.01 NS NS
Pore size NS 0.004 NS NS
Clarity/radiance NS 0.02 NS NS
Smoothness NS 0.006 NS P=0.03
Overall global
NS 0.01 NS NS
photodamage
NS= non-significant
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Journal of Drugs in Dermatology N. Sadick, K. Bohnert, M. Serra, N. Kitchen
June 2018 • Volume 17 • Issue 6

FIGURE 2. 54-year-old female before (A) and at week 8 (B) of FIGURE 3. 55-year-old female before (A) and at week 8 (B) of
treatment. There is decreased redness, pore size, fine lines, and treatment. There is decreased redness, pore size, fine lines, and
improved clarity, radiance, pigmentation, and overall photodamage. improved clarity, radiance, pigmentation, and overall photodamage.
(A) (A)

(B) (B)

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strated statistically significant improvements in GAIS (P=0.03 Subject Assessments

and P=0.04, respectively; Figure 4, 5). Collectively, investigator All of the subjects included in the study used the tested ma-
assessments for the face showed moderate improvement in terials as instructed and reported the product to be easy and
64% of subjects, mild improvement in 27% of subjects and no convenient to add a daily skincare routine. There was a 1-point
change in 21% of subjects. increase in subject treatment satisfaction scale rating scores
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668
Journal of Drugs in Dermatology N. Sadick, K. Bohnert, M. Serra, N. Kitchen
June 2018 • Volume 17 • Issue 6

FIGURE 4. Global aesthetic improvement scale assessment by FIGURE 5. Global aesthetic improvement scale assessment by
treating investigator at baseline and 8 week follow up for active and blinded investigator at baseline and 8 week follow up for active and
placebo group. Asterisk indicates statistical significance. placebo group. Asterisk indicates statistical significance.

observed in the neck area. This can be attributed to several fac-

between baseline and week 8 in the active group in both face tors; while the neck shares most of the skin physiology wit the
and neck, whereas there was no change in the placebo group. In face, it has some unique characteristics that can interfere with
terms of skin quality, there was statistically significant improve- the efficacy of topical agents. Neck skin is inherently drier, due
ment in subject rated ‘Rough Texture’ from baseline to week 8 to the sparse sebaceous gland density, and thinner making it
(P=0.01) and ‘Dryness’ (P=0.02) for the face. No statistically sig- more susceptible to aging.13 It is possible that a longer duration
nificant changes were found in subject rated skin quality and of application and potentially an increased amount of product
photodamage assessments of the neck from baseline to week would be required in order to observe clinically significant re-
8. Seventy-one (71%) of subjects were moderately/very satis- sults in this area, compared to the parameters used for the face.

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fied with the product scent, 64% with the product feel, and 71%
with the product texture. Over half the subjects (57%) reported Moreover, Fitzpatrick Wrinkle Scale scores were improved in
that they would consider substituting their current anti-aging the active group compared to placebo, in the face and neck,
skincare with Nimni cream. albeit not significantly. While the product can have a clinical ef-

Penalties Apply
fect on skin quality rather rapidly (4-8 weeks of application),
Adverse Events and Tolerability the study timeframe was too abbreviated to allow a realistic
No adverse events or unexpected side effects were observed evaluation of the treatment effect on the appearance of wrin-
or reported for any of the subjects. No significant tolerability kles. With the exception of dermal fillers that can immediately
events were reported by investigator for face or neck (Table 2). volumize the face, and have a dramatic effect on wrinkles, most
Subjects reported minimal tolerability events for face and neck other anti-wrinkle approaches (energy-based devices, chemical
at all time points post baseline (Table 3). peels), can clinically affect the appearance of lines and wrinkles
after a minimum of twelve weeks. Subject satisfaction was also
DISCUSSION high as the product was easy to use with no adverse effects or
New generation topical agents are continuously developed tolerability issues reported.
to effectively prevent photoaging, collagen degradation and,
stimulate cellular epidermal/dermal remodeling that ultimately
TABLE 2.
improves skin quality. The patented formulation of the study
Investigator Reported Tolerability Events
product contains a mixture of peptides, antioxidants designed
to stimulate the dermal matrix for collagen and proteoglycan Week 4 Week 8
production. In this single-center, double-blind, randomized, Face- Dryness 1-mild 1-mild
placebo-controlled study Hydropeptide Nimni Cream and sup-
Face- Erythema 2-mild 1-mild / 1-moderate
porting regimen was shown to be significantly effective in
Neck- Dryness 1-mild 2-mild
improving signs of aging and skin quality in the face, with no
side effects, after two months of treatment. While shown effec- Neck- Erythema 1-mild 1-moderate
tive in the facial area, there were no significant clinical results Neck- Scaling 1-mild none
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669
Journal of Drugs in Dermatology N. Sadick, K. Bohnert, M. Serra, N. Kitchen
June 2018 • Volume 17 • Issue 6

TABLE 3.
Subject Reported Tolerability Events
Week 2 Week 4 Week 6 Week 8
Face- Stinging/Burning 1-mild None 2-mild 1-mild
Neck- Stinging/Burning 2-mild None 1 – mild / 1-moderate 2-mild

Overall, despite the study limitations that include small number

of subjects and short time of follow-up, the product demon-
strated a good clinical efficacy and safety profile in improving
facial skin quality. To this end, a larger scale study is under-
way, with more subjects and longer follow-up, to assess more
clinical endpoints and evaluate the full effect of the topical on
rhytides and fine lines.

Thus, in the context of a general skincare program that includes

sunscreen, fillers, neurotoxins, and energy-based devices, Hy-
dropeptide® Nimni Cream can be used daily for preventing,
fighting signs of aging and improving skin quality in the face.

DISCLOSURES
Neil Sadick MD, Krista Bohnert BS, and Monica Serra received
a research grant by Hydropeptide. Neal Kitchen PhD is Chief
Operating Officer at HydroPeptide.

REFERENCES
1. Alexis AF, Obioha JO. Ethnicity and Aging Skin. J Drugs Dermatol.
2017;16(6):s77-s80.

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2. Keaney TC. Aging in the Male Face: Intrinsic and Extrinsic Factors. Dermatol
Surg. 2016;42(7):797-803.
3. Tobin DJ. Introduction to skin aging. J Tissue Viability. 2017;26(1):37-46.
4. Oikarinen A. The aging of skin: chronoaging versus photoaging. Photoderma-
tol Photoimmunol Photomed. 1990;7(1):3-4.

Penalties Apply
5. Uitto J, Bernstein EF. Molecular mechanisms of cutaneous aging: connective tis-
sue alterations in the dermis. J Investig Dermatol Symp Proc. 1998;3(1):41-44.
6. Vanaman M, Fabi SG, Cox SE. Neck Rejuvenation Using a Combination
Approach: Our Experience and a Review of the Literature. Dermatol Surg.
2016;42 Suppl 2:S94-S100.
7. Kirkland-Kyhn H, Zaratkiewicz S, Teleten O, Young HM. Caring for Aging Skin.
Am J Nurs. 2018;118(2):60-63.
8. Landau M, Anand CV, Besins T, et al. First Consensus on Primary Prevention and
Early Intervention in Aesthetic Medicine. J Drugs Dermatol. 2017;16(9):846-854.
9. Weinkle S, Saco M. Approach to the Mature Cosmetic Patient: Aging Grace-
fully. J Drugs Dermatol. 2017;16(6):s84-s86.
10. Addor FAS. Antioxidants in dermatology. An Bras Dermatol. 2017;92(3):356-362.
11. Burke KE. Mechanisms of aging and development-A new understanding of
environmental damage to the skin and prevention with topical antioxidants.
Mech Ageing Dev. 2017.
12. Han B, Nimni ME. Transdermal delivery of amino acids and antioxidants en-
hance collagen synthesis: in vivo and in vitro studies. Connect Tissue Res.
2005;46(4-5):251-257.
13. Schlessinger J, Green B, Edison BL, Murphy L, Sabherwal Y. A Firming
Neck Cream Containing N-Acetyl Glucosamine Significantly Improves Signs
of Aging on the Challenging Neck and Decolletage. J Drugs Dermatol.
2016;15(1):47-52.

AUTHOR CORRESPONDENCE

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June 2018 671 Volume 17 • Issue 6

The Effect of an Anti-Inflammatory Botanical Cleanser/Night

Mask Combination on Facial Redness Reduction
Zoe Diana Draelos MDa and Angela Donald ND MScb
a
Dermatology Consulting Services, PLLC, High Point, NC
b
Skinfix, Halifax, Nova Scotia

ABSTRACT
Facial redness is a common difficult to control cosmetic problem representing various phases of rosacea. Using anti-inflammatory/antioxidant
botanicals in moisturizer formulations is a possible approach to minimizing the erythema. This research utilized a common facial cleanser, but
only applied the botanically based moisturizer to one half face to properly assess efficacy. 30 female subjects Fitzpatrick skin types I-IV 30-55
years of age with mild to moderate chronic facial redness, defined as a redness score of 3-6 on a 10-point scale, were enrolled. By the end
of week 4, statistically significant improvement was seen on the cleanser/mask treated side in scaling (P<0.001), flaking (P<0.001), tactile
smoothness (P<0.001), textural smoothness (P<0.001), firmness (P<0.001), radiance (P<0.001), luminosity (P<0.001), and overall appearance
(P<0.001). Thus, cosmetic moisturizers may be useful in reducing facial redness.

J Drugs Dermatol. 2018;17(6):671-676.

INTRODUCTION

F
acial redness is a common manifestation of cosmetically dermatologist investigator visually assessed by the subjects
unattractive inflammation. If the redness becomes per- for the following efficacy criteria on a 10-point scale (0=none to
sistent and more severe, a diagnosis of rosacea is usu- 9=extremely severe): erythema, capillaries, blotchiness, scaling,
ally entertained.1 Most individuals with facial erythema possess flaking, tactile smoothness, textural smoothness, firmness, radi-
sensitive skin manifested by a barrier defect, which can allow ance, luminosity, and overall appearance. Each side of the face
facial cleansers and moisturizers to reach the viable layers of was separately assessed to allow each subject to act as their own

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the epidermis and dermis causing stinging, burning, and/or control. The investigator also assessed the following tolerability
itching accompanied by worsening facial redness. Formulating criteria separately for each side of the face on a 5-point scale
skin care products for this population can be challenging, since (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe): erythema,
minor irritation is perceived as major irritation in rosacea suf- desquamation, stinging, burning, and itching. Noninvasive as-

Penalties Apply
ferers.2 Furthermore, any facial product that induces irritation sessments were performed as follows:
may produce a resultant rosacea flare.
1. Corneometry (Pin probe, Dermalab Combo, Cortex
The goal of this research was to examine the moisturizing and Technologies, Hadsund, Denmark): 2 duplicate touch
redness reducing effect of an anti-inflammatory botanical calm readings were made over the right and left cheeks.
and repair night mask plus cleanser in subjects with mild to
moderate facial redness. 2. D-Squames (CuDerm, Dallas, TX): One tape strip was
obtained from a predefined target spot on the lateral right
METHODS and left cheeks for skin exfoliation analysis.
30 female subjects Fitzpatrick skin types I-IV and 30-55 years of age
with mild to moderate chronic facial redness, defined as a redness Finally, Visia CR-4.3 photographs (Canfield, Parsippany, NJ) of
score of 3-6 on a 10-point scale, were enrolled in this single-site split the center, right, and left face were performed on selected sub-
face study following completion of informed consent and photog- jects to document differences between the two sides of the face
raphy consent (Concordia Clinical Research IRB, Beach Haven, NJ). during the 4-week study.
Subjects used a disposable facial wipe (Simple Wipe, Unilever) to
wash their face followed by 30 minutes of quiet acclimation prior to Following completion of all baseline assessments, subjects were
assessments. Subjects were screened to insure they met all inclu- dispensed a cleanser for full facial washing twice daily for 7 days
sion criteria and none of the exclusion criteria (Table 1). (Foaming Oil Cleanser, SkinFix, Halifax, NS). Subjects were ran-
domized to apply a dime-sized amount of the study mask only to
Evaluations consisted of dermatologist efficacy and toler- one side of the face at bedtime, leaving the untreated side as a con-
ability, subject efficacy, and noninvasive assessments. The trol. Every attempt was made to enroll subjects with symmetrical
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672
Journal of Drugs in Dermatology Z.D. Draelos, A. Donald
June 2018 • Volume 17 • Issue 6

TABLE 1. anti-inflammatory botanical study mask (Calm and Repair Night

Inclusion/Exclusion Criteria Mask, SkinFix, Halifax, NS) following provided instructions to
one randomized side of the face. The subjects were also dis-
Inclusion Criteria
pensed a diary for compliance.
1. Subjects must only use the assigned test product moisturizer
to the randomized side of the face.
Subjects were evaluated post-application with a second corne-
2. Subjects must use the provided facial cleanser for the ometry assessment and a consumer perception questionnaire.
duration of the study. This provide an assessment of the immediate moisturizing ef-
3. Subjects must be females between 30-55 years of age. fect of the study mask on one side of the face as compared to
4. Subjects must possess mild to moderate chronic facial the control facial side. Subjects returned to the research cen-
redness. ter the following morning and again washed their face with
the provided cleanser, waited 30 minutes, and underwent the
5. Subjects may possess Fitzpatrick skin types I-IV.
same evaluations previously discussed for baseline along with
6. Subjects must have no known medical conditions that,
a consumer perception questionnaire to evaluate day 1 effects.
in the investigator’s opinion, may interfere with study
Photography was performed on selected subjects. Subject dia-
participation.
ries and products were checked for compliance and subjects
7. Women of childbearing potential must be willing to use a form were instructed to return to the research center in 1 week and 4
of birth control during the study. For the purpose of this study,
weeks for the same evaluations.
the following are considered acceptable methods of birth
control: oral contraceptives, NorplantÒ, Depo-Provera®, double
There were no concomitant oral medication restrictions. Sub-
barrier methods (e.g., condom and spermicide) and abstinence.
jects did not use any other cosmetic products designed to
8. Subjects must provide written informed consent.
ameliorate facial redness or any other facial moisturizers or
9. Subjects must have no skin disease, other than facial facial cleansers. All oral and topical medications remained un-
redness, in the facial area of evaluation. changed for the duration of the study.
10. Subjects must not use a facial moisturizer for 3 days prior to
study entry. Statistics
Exclusion Criteria A two-tailed Wilcoxon signed rank test was used to analyze the
nonparametric data sets (investigator efficacy and tolerability,
1. Any dermatological disorder, which in the investigator’s

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opinion, may interfere with the accurate evaluation of the subject assessments, D-squames). The noninvasive corneom-
subject's skin. etry parametric numerical data was analyzed by an ANCOVA
model, which included a treatment effect and the baseline as a
2. Subjects who spend excessive time out in the sun.
covariate. Significance was defined at the P=0.05 or less level

Penalties Apply
3. Subjects who have demonstrated a previous hypersensitivity
based on a two-sided test.
reaction to any of the ingredients of the study products.
4. Subjects who are allergic to commonly marketed The safety population included all subjects exposed to study
moisturizers. product who provided any post-treatment safety information.
5. Subjects who are pregnant, breast feeding, or planning a Adverse event analyses were conducted as an overall study
pregnancy. analysis.
6. Subjects with clinically significant unstable medical
disorders. RESULTS
7. Subjects who are unwilling or unable to comply with the 28/30 subjects successfully completed the 4-week study. No
requirements of the protocol. compliance issues were noted during the study based on diary
evaluation and all collected data was utilized in the final analy-
8. Subjects who have history of a psychological illness
or condition that would interfere with their ability to sis. No adverse events or adverse experiences occurred during
understand and follow the requirements of the study. the study. The data was analyzed incrementally as change from
baseline on the side of the face using the cleanser only and as
change from baseline on the opposite side of the face using the
facial redness to insure the validity of the results. Subjects were cleanser and anti-inflammatory botanical night mask.
allowed to continue use of their own self-selected cosmetics, but
no changes in these products were allowed during the study Investigator Efficacy
The investigator assessed each side of the face separately. This
Subjects were then instructed by the research center staff allowed evaluation of the incremental improvement in facial
to wash their face with the provided cleanser and apply the redness induced by the cleanser alone as compared to the
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673
Journal of Drugs in Dermatology Z.D. Draelos, A. Donald
June 2018 • Volume 17 • Issue 6

botanical anti-inflammatory night mask in combination with Investigator Tolerability

the cleanser. The cleanser alone control demonstrated inves- No tolerability issues were identified with the study mask and
tigator assessed improvement after 1 week of use in scaling cleanser in terms of increased erythema, desquamation, sting-
(P=0.027), flaking (P=0.040), tactile smoothness (P=0.012), and ing, burning, or itching at any time during the 4-week study.
textural smoothness (P=0.027). This improvement continued
into week 4 with statistically significant benefits for improved Subject Efficacy
erythema (P=0.012), in addition to the previously observed im- The subject efficacy assessments were completed for the
provement in scaling, flaking, tactile smoothness, and textural cleanser/mask treated side of the face. All assessments were
smoothness. compared longitudinally to baseline. At day one, there was early
single digit improvement in the subject’s skin ratings classified
Skin improvement occurred earlier with the combined anti- as soothed red skin (6%) and diminished appearance of facial
inflammatory night mask and cleanser. At day 1, there was redness (6%). By the end of week 1, there was statistically sig-
statistically significant improvement in tactile smoothness nificant improvement in soothed red skin (P=0.043) translating
(P=0.002) and textural smoothness (P=<0.001) in the botani- to an 8% improvement. At week 4, there was a 10% improve-
cal anti-inflammatory cleanser/mask treated facial side as ment in soothed skin, an 8% improvement in skin health, a 7%
compared to the cleanser only side (Figure 1). By the end of improvement in fine lines, and a 5% improvement in skin reju-
week one, statistically significant improvement was seen on venation over baseline.
the cleanser/mask treated side in scaling (P=0.003), flaking
(P=0.007), tactile smoothness (P=0.002), textural smoothness Photography
(P<0.001), radiance (P=0.003), luminosity (P=0.003), and overall Photography was completed on selected subjects with cross-po-
appearance (<0.001) (Figure 2). By the end of week 4, statisti- larized light. Figure 4 demonstrates the results obtained with the
cally significant improvement was seen on the cleanser/mask cleanser/mask combination as compared to the cleanser alone.
treated side in scaling (P<0.001), flaking (P<0.001), tactile
smoothness (P<0.001), textural smoothness (P<0.001), firmness Corneometry
(P<0.001), radiance (P<0.001), luminosity (P<0.001), and overall The corneometry measured the amount of water present in the
appearance (P<0.001). Thus, the addition of the anti-inflamma- skin as change from baseline. Immediately after application, the
tory botanical night mask to the cleanser resulted in additive skin hydration on the randomized mask applied facial side was
improvement, as demonstrated in Figure 3. statistically significantly superior (P<0.001) to the nontreated

FIGURE 1. Day 1 results.

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Foaming Oil Cleanser + Calm and Repair Sleeping Mask
Penalties Apply
Day 1 Investigator Efficacy Assessment: Mean change from baseline
within and between the regimen and cleanser only groups

Cleanser Cleanser + Mask

#
*
20 * *
15

674
Journal of Drugs in Dermatology Z.D. Draelos, A. Donald
June 2018 • Volume 17 • Issue 6

FIGURE 2. Week 1 results.

Foaming Oil Cleanser + Calm and Repair Sleeping Mask

Week 1 Investigator Efficacy Assessment: Mean change from baseline
within and between the regimen and cleanser only groups

Cleanser Cleanser + Mask

#
#
40
* *
#
*
* *
30

# # *
*
20 #
# # # #
#

0
Erythema Capillaries Blotchiness Scaling Flaking Tactile Textural Firmness Radiance Luminosity Overall
Smoothness Smoothness

FIGURE 3. Week 4 results.

Foaming Oil Cleanser + Calm and Repair Sleeping Mask

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Week 4 Investigator Efficacy Assessment: Mean change from baseline
within and between the regimen and cleanser only groups

Penalties
*
Apply Cleanser Cleanser + Mask

*
60
* * * *
45
* *
* * *
30
# * * *
# #
#
* * # # * #
15
#

0
Erythema Capillaries Blotchiness Scaling Flaking Tactile Textural Radiance Luminosity Overall
Firmness
Smoothness Smoothness

side of the face by 78% at day 1. This superior hydration due to D-Squames
the moisturizer and cleanser continued into week 1 (P=0.002) The D-Squame was a piece of tape placed on the upper cheek
and week 4 (P=0.004) over the cleanser only side of the face. on both sides of the face for exfoliation analysis. The tape
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675
Journal of Drugs in Dermatology Z.D. Draelos, A. Donald
June 2018 • Volume 17 • Issue 6

FIGURE 4. Cross-polarized facial photography. This subject began the TABLE 2.

study with symmetrical facial redness. The cleanser was applied to Moisturizing Mask Ingredients
the entire face with the mask applied to the right face demonstrating Water/Aqua
reduced erythema. Glycerin
Foaming Oil Cleanser + Calm and Repair Sleeping Mask Cetearyl Ethylhexanoate
Tridecyl Neopentanoate
Results
Olus Oil
Propanediol
Ammonium Acryloyldimethyltaurate/VP Copolymer
Representative photograph Glyceryl Stearate Citrate
taken with cross-polarized
light demonstrating the Helianthus Annuus (Sunflower) Seed Oil
redness reduction with the Isosorbide Dicaprylate
cleanser + mask combination Isosorbide Disunflowerseedate
Vitis Vinifera (Grape) Seed Oil
Caprylic/Capric Triglyceride
Butylene Glycol
Cucumis Sativus (Cucumber) Fruit Water
Rosa Damascena Flower Water
Phenoxyethanol
Olea Europaea Husk Oil
Simmondsia Chinensis (Jojoba) Seed Wax
Trisodium Ethylenediamine Disuccinate
removed excess skin scale and was evaluated at baseline, week Camellia Sinensis (Tea) Leaf Extract
1, and week 4. Both sides of the face showed a reduction in Xanthan Gum
Echium Plantagineum Seed Oil
skin scale of 9% at week 1 and the cleanser/mask side showed
Elettaria Cardamomum Seed Extract
11% reduction at week 4 while the cleanser side only showed a
Potassium Sorbate
reduction in skin scale of 12%. Thus, both the cleanser and the
Avena Sativa (Oat) Kernel Flour
mask were effective in reducing retained skin scale. Hydrolyzed Hyaluronic Acid
Tocopherol
DISCUSSION

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Pyrus Malus (Apple) Fruit Extract
The anti-inflammatory botanical cleanser/mask combination Rose Extract
showed incremental improvement over the cleanser alone in Santalum Album (Sandalwood) Extract
subjects with mild to moderate facial redness. The cleanser was Sodium Benzoate

Penalties Apply
important in minimizing barrier damage and redness reduction, Boswellia Serrata Extract
as demonstrated by the corneometry measurements. Cleanser Honey (Mel) Extract
mildness was due to the sulfate-free formulation, excluding so- Aloe Barbadensis Leaf Juice
dium lauryl sulfate and sodium laureth sulfate.3 Sodium Lauroyl Lactylate
Anthemis Nobilis Flower Extract
Cananga Odorata Flower Extract
While the subjects improved on the cleanser alone, the anti-
Citrus Aurantium Dulcis (Orange) Peel Extract
inflammatory botanical mask formulation in addition to the
Cucumis Melo (Melon) Fruit Extract
cleanser was superior. The basis of the mask was glycerin Cucumis Sativus (Cucumber) Fruit Extract
99.7% USP, a known humectant with the ability to modulate Jasminum Officinale (Jasmine) Flower/Leaf Extract
skin aquaporin channels.4 Other minor humectants in the form Lavandula Angustifolia Flower/Leaf/Stem Extract
of oat flour and hydrolyzed hyaluronic acid were also included. Rubus Idaeus (Raspberry) Fruit Extract
The water attracted by the humectants was trapped in the facial Aspalathus Linearis Extract
skin by a film-forming polymer ammonium acryloyldimethyl- Chlorophyllin-Copper Complex
taurate/VP copolymer and botanicals olus, sunflower seed, Ceramide NP
and grape seed oils. Two emollients, cetearyl ethylhexanoate Citric Acid
and tridecyl neopentanoate, were used to smooth skin scale Tetrapeptide-14
Ceramide AP
and improve skin softness, one of the earliest skin benefits
Phytosphingosine
noted by the dermatologist investigator. In addition, com-
Cholesterol
ponents of the intercellular lipids were included in balanced
Carbomer
proportions: ceramides (number 1,3,6), phytosphingosine, Ceramide EOP
and cholesterol.5 Ethylhexylglycerin
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

676
Journal of Drugs in Dermatology Z.D. Draelos, A. Donald
June 2018 • Volume 17 • Issue 6

The most interesting part of the mask formulation was the ex-
tensive combination of botanical extracts with anti-inflammatory
properties listed in Table 2. These extracts included honey, aloe,
orange, melon, cucumber, jasmine, raspberry, apple, sandal-
wood, and stabilized green tea. These ingredients possess
antioxidant/anti-inflammatory properties useful in facial redness
and rosacea.6 The anti-inflammatory botanicals in combination
with humectants, occlusives, emollients, and barrier ingredients
might have provided the observed clinical benefits.

The primary efficacy endpoint was a statistically significant

improvement in facial moisturization after 4 weeks of prod-
uct application as assessed by the investigator comparing the
side of the face with cleanser/mask applied to the side of the
face serving as a nonmoisturized cleanser only control. The
primary efficacy endpoint was met with the glycerin-based
anti-inflammatory formulation.

The secondary efficacy endpoint was the statistically significant dif-

ference in skin moisturization after 4 weeks of product application
as assessed noninvasively through corneometry measurements.
Statistically significant superior hydration due to the cleanser/
mask treatment was seen week 4 (P=0.004) over the cleanser only
side of the face. The secondary efficacy endpoint was met.

SUMMARY
The anti-inflammatory botanically based night time mask
provided excellent moisturization while demonstrating no tol-

Do Not Copy
erability or safety issues in a challenging population of females
with mild to moderate facial erythema resulting in improved
facial appearance.

Penalties Apply
DISCLOSURES
Zoe Diana Draelos MD, received a financial grant from SkinFix
to conduct the research presented in this manuscript. Angela
Donald ND MSc is a full-time employee at Skinfix.

REFERENCES
1. Powell, FC. Rosacea. N Engl J Med. 2005;352:793-803.
2. Draelos, ZD. Sensitive skin: perceptions, evaluation, and treatment. Am J
Contact Dermat. 1997;8(2):67-78.
3. Bruynzeel DP, van Ketel WG, Scheper RJ, von Blomberg-van der Flier BME.
Delayed time course of irritation by sodium lauryl sulfate: observations of
threshold reactions. Contact Derm. 1982;8(4):236-239.
4. Grieve K. Glycerine: the naturally effective humectant. Dermatol Nurs.
2012;11(1):30-34.
5. Joo KM, Hwang JH, Bae SJ, Nahm DH, Park HS, Ye YM, Lim KM. Rela-
tionship of ceramide-, and free fatty acid-cholesterol ratios in the stratum
corneum with skin barrier function of normal, atopic dermatitis lesional and
non-lesional skins. J Dermatol Sci 2015;77(1):71-74.
6. Reuter J, Merfort I, Schempp CM. Botanicals in dermatology. Am J Clin
Dermatol. 2010;11(4):247-267.

AUTHOR CORRESPONDENCE

Zoe Diana Draelos MD

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June 2018 678 Volume 17 • Issue 6

A National Survey of Medical Coding and Billing Training in

United States Dermatology Residency Programs
Karin Blecher Paz MD,a Caroline Halverstam MD,a Alexandra K. Rzepecki BS,b and Beth N. McLellan MDa
a
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY
b
University of Michigan Medical School, Ann Arbor, MI

ABSTRACT
Background: Due to frequent changes in medical coding systems, billing for outpatient visits through Evaluation and Management
(E & M) services has become increasingly complicated. As a result, physicians often bill improperly, costing the United States health
care system billions of dollars annually. Despite the importance of proper documentation, medical coding and billing is largely ignored
during residency training.
Objective: Assess the exposure to and quality of medical coding and billing training in dermatology residency programs.
Methods: A questionnaire was distributed to dermatology programs in the United States consisting of questions pertaining to didactic
education for, experience with, and resident knowledge of medical coding and billing.
Results: 138/443 dermatology residents participated (31.2% response rate). 79% of residents reported receiving some type of formal
training. Nearly 89% reported personally billing patient visits to some degree, with 41.3% billing for 100% of outpatient visits. Over
75% of residents were able to answer basic billing questions and 70% correctly billed a patient visit when given a complex clinical
scenario. Despite these results, only 37% of residents reported feeling confident in their billing abilities. Lastly, 94.9% of respondents
believed medical coding and billing should be integrated into dermatology training curriculums.
Conclusions: The majority of dermatology residents have opportunities to learn medical coding and billing through didactics and clinical
experiences. Many residents were able to answer correctly questions that tested their basic knowledge of E&M coding. These results
are encouraging and reflect the recognition of the importance of medical coding and billing training during residency.

J Drugs Dermatol. 2018;17(6):678-682.

INTRODUCTION
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C
omplex billing practices cost the United States health that there is a lack of medical coding and billing education within
care system billions of dollars annually.1,2 Due to fre- dermatology residency curricula. In this study, we hope to ex-

Penalties Apply
quent changes in coding systems, coding modifiers, and amine the degree of medical coding and billing training during
over 70,000 codes (ICD-103), coding for outpatient office visits dermatology residency by elucidating the didactic and clinical
(Evaluation and Management [E&M] services) has become in- experience, knowledge, and personal reflections of current der-
creasingly complicated.4 As a result, the accuracy of E&M coding matology residents.
is poor, with Medicare audits reporting error rates as high as 91%
for outpatient claims.1,5 In 2012, physicians billed $29.6 billion METHODS
dollars in improper payments.6 Part of this problem may stem To assess the exposure to and knowledge of outpatient cod-
from the lack of medical coding and billing education during ing and billing we developed a 19-item questionnaire that
residency training across all medical and surgical subspecialties. was sent to current dermatology residents affiliated with an
One cross-sectional study of family medicine residencies across ACGME-accredited program in the United States. The 19-item
the Northwest United States reported an annual estimated rev- questionnaire was derived from clinical and academic experi-
enue loss of $481,654 due to improper billing by residents.7 In ences and included definitions and case examples that focused
addition, 62% of orthopedic residents reported no formal medi- on basic concepts of billing. In addition, residents were asked
cal coding and billing training during residency.8 This is despite about their personal exposure to medical coding and billing
the fact that coding and billing is included in the Accreditation with regards to formal education, informal teaching from at-
Council for Graduate Medical Education’s (ACGME) 6 core com- tendings, and hands-on experience during patient encounters.
petencies.9 To our knowledge, very few studies examine medi- These questions were meant to characterize the billing train-
cal coding and billing training during residency, and no previous ing received during dermatology residency. Some questions
studies have examined medical coding in dermatology residen- provided the opportunity for multiple answers. Institutional
cy curricula. Despite the integration of medical documentation Review Board (IRB) permission for this study was granted from
in the 2014 ACGME Dermatology Milestone Project,9 we suspect the Albert Einstein College of Medicine, Bronx, NY.
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679
Journal of Drugs in Dermatology K. Blecher Paz, C. Halverstam, A.K. Rzepecki, B.N. McLellan
June 2018 • Volume 17 • Issue 6

The Web-based program SurveyMonkey.com10 was utilized to TABLE 1.

distribute the questionnaire by e-mail. Program directors and Demographic and Program Characteristics
coordinators affiliated with an ACGME-accredited dermatology
Characteristic n (%)
residency training program were identified and contacted via e-
mail. In the initial e-mail, a brief explanation about the purpose Sex
and confidentiality of the study was included, in addition to a Male 51 (37.0)
link to the survey. Programs were asked to forward this email to Female 87 (63.0)
their current residents for participation. Participation in the sur-
Geographic region
vey was voluntary, and comprehensive safeguards to protect
Northeast 36 (26.1)
confidential information were in place (ie, no identifiers within
the survey). All responses were anonymous, and SurveyMon- Southwest 27 (19.6)
key provided data storage. Participation in this survey was not Midwest 44 (31.9)
incentivized. The survey was open to dermatology residents Southwest 10 (7.3)
from December 1, 2014 to March 31, 2015.
West 21 (15.2)
RESULTS Post-graduate year (PGY)
One hundred eleven ACGME-accredited dermatology programs PGY 2 44 (31.9)
in the United States were contacted via e-mail. Of these programs, PGY3 54 (37.0)
41 agreed to participate in the study. In total, 443 dermatology res-
PGY4 42 (30.4)
idents were sent a link to the online survey and 138 participated,
resulting in a response rate of 31.2%. Sixty-three percent of the Fellow 1 (0.7)
responders were female and 37.0% were male. Thirty-one percent Setting of clinical training
were in their 1st year of dermatology training [Post-Graduate Year Academic 122 (88.4)
(PGY)-2], 37.0% were in their 2nd year (PGY-3), and 30.0% were in
Private 0 (0)
their 3rd year (PGY-4). The resident and program characteristics are
provided in Table 1. A majority of respondents trained in a purely Mix of academic and private 16 (11.6)
academic setting (88.4%) while few trained at institutions with a
mix of academic and private practice (11.6%). difference between a CPT and an ICD-9 code, 75.4% knew the

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correct definition of a new patient, and 83.3% knew which 3
Resident Didactic and Clinical Experience in elements comprise E&M coding for office visits. When given a
Medical Coding and Billing clinical scenario, 60.9% of respondents billed the visit correctly.
Seventy-nine percent of residents reported receiving formal Of those residents who reported feeling confident or very confi-

Penalties Apply
training in medical coding and billing during residency (Table dent in their own billing abilities (Table 2), 88.2% billed the visit
2). This included lectures given by attending dermatologists correctly, compared to 63.9% of residents who reported feeling
(n=77), lectures provided by professional coders (n=59), and neutral or not confident about their billing abilities.
lectures offered at conferences (n=14). 77 residents also report-
ed informal teaching by attendings during clinic. Resident Attitudes Towards Billing and Coding
In total, 94.9% of respondents believed that medical coding and
Of the 138 responders, 10.9% never perform the billing for a billing should be integrated into the dermatology training cur-
patient visit, 22.5% occasionally bill, 25.4% bill for most but riculum, though 97.8% reported that the presence of a billing
not all visits, and 41.2% bill all outpatient visits. Despite the fre- curriculum did not influence their residency selection. 81.2%
quency of resident-performed billing, only 36.9% of responders responded that they would participate in a web-based medical
felt confident in their own billing practices. When considering coding and billing curriculum (Table 4). A similar percentage
the responses based on PGY status, 26.7% of PGY-2 residents reported that they would be more motivated to learn medical
reported feeling confident or very confident about their billing coding and billing if this subject was tested on the Dermatology
abilities. This was compared to 39.2% of PGY-3 residents, and Board Examination.
42.9% of PGY-4 residents. The majority of residents were either
confident or very confident about their attendings’ billing abili- DISCUSSION
ties (76.1%). The importance of medical coding and billing during residency
training has gained recognition, as reflected by its inclusion in
Resident Billing Knowledge the ACGME 6 Core Competencies.9 Though no previous stud-
Several questions tested the residents’ billing knowledge (Ta- ies examined specifically billing in dermatology residency, our
ble 3). Eighty-seven percent of dermatology residents knew the study suggests a promising state of billing exposure through
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680
Journal of Drugs in Dermatology K. Blecher Paz, C. Halverstam, A.K. Rzepecki, B.N. McLellan
June 2018 • Volume 17 • Issue 6

TABLE 2. TABLE 3.
Resident Didactic and Clinical Experience in Medical Coding Resident Billing Knowledge
and Billing
Characteristic n (%)
Characteristic n (%)
What is the difference between a CPT and ICD-9 code?
Overall exposure to formal training in medical coding and
I have no idea 14 (10.1)
billing
Correct Response 120 (87.0)
Yes 109 (79.0)
Incorrect Response 4 (2.9)
No 29 (21.1)
What is the definition of a new patient
Setting(s) in which residents had training in medical coding and
billing (more than one selection possible) I have no idea 3 (2.2)
Lectures by residents 14 (10.1) Correct Response 104 (75.4)
Lectures by attendings 77 (55.8) Incorrect Response 31 (22.4)
Lectures by professional What are the 3 elements which comprise coding for office visits
59 (42.8)
coders
I have no idea 2 (1.5)
Lectures offered at
14 (10.1) Correct Response 115 (83.3)
conferences
Incorrect Response 21 (15.2)
Webinars 2 (1.5)
Correct billing code based on clinical scenario
Informal teaching by
77 (55.8)
attendings during clinic I have no idea 5 (3.6)
Other 8 (5.8) Correct Response 84 (60.9)
Did not receive formal Incorrect Response 50 (35.5)
25 (18.1)
training
How often do you personally code/bill
In addition, 89.1% of residents in our study were required to bill
Never 15 (10.9)
during their resident clinics. Given the exposure and practice
Occasionally (<50% of visits) 31 (22.5) that most residents receive, it is not surprising that the major-

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Most visits (50-99%) 35 (25.4) ity of residents polled correctly answered questions that tested
Every visit (100%) 57 (41.2) their basic medical billing and coding knowledge.

How confident are you in your billing abilities

We suspect that these results reflect the outpatient nature of

Penalties Apply
Very confident 6 (4.3) dermatology residency. In an unpublished pilot study, we sent
Confident 45 (32.6) a similar questionnaire to residents and fellows in other medi-
Neutral 47 (34.0) cal specialties. In this study, 94 residents and fellows comprised
of general medicine residents (n=27), ophthalmology residents
Not Confident 35 (25.4)
(n=18), cardiology fellows (n=9), radiation oncology residents
I have no idea how to bill 5 (3.7)
(n=9), pediatric residents (n=8), radiology residents (n=6), and
How confident are you in your attendings’ billing abilities 17 trainees in other specialties participated for a response rate
Very confident 26 (18.8) of 7.6%. Most of the medical specialties represented practice
Confident 79 (57.3) largely inpatient medicine during residency training, similar to
the orthopedic residency study.8 Only 29.8% of trainees report-
Neutral 22 (15.9)
ed some type of formal training in medical coding and billing
Not Confident 9 (6.5) and almost half (45.7%) reported that they have never person-
They have no idea how to bill 2 (1.5) ally billed a patient visit. This is similar to a previous survey
Total responses 138 study of surgical residents in which 82% reported inadequate
training in documentation and coding.11 In addition, only 8.5%
of non-dermatology residents polled in our study reported feel-
both didactic and clinical experiences. Unlike one previous ing confident in their billing abilities, similar to Fakhry’s study
study, which reported only 38% exposure to medical coding that reported 85% of surgical residents felt they were novices at
and billing during orthopedic residency,8 our study demon- coding and billing.11 Overall, compared with dermatology resi-
strated that 79% of residents receive some formal training dents, there was a trend that non-dermatology residents had
whether it be during dedicated didactic time or at conferences. less teaching, were less comfortable, and performed worse on
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681
Journal of Drugs in Dermatology K. Blecher Paz, C. Halverstam, A.K. Rzepecki, B.N. McLellan
June 2018 • Volume 17 • Issue 6

TABLE 4. individual programs may not have been captured in our study.
Resident Attitudes Towards Billing and Coding However, based on the demographic variability (Table 1), it
seems that our survey represented a wide variety of programs.
Characteristic n (%)
Another limitation may be responder bias. For example, those
Upon completion of dermatology training, do you plan on residents that chose to participate in the survey may have felt
doing your own medical billing?
more confident and knowledgeable about billing and coding
Yes 101 (73.2) compared with those that chose not to participate.
No 37 (26.8)
CONCLUSION
Should medical coding/billing be integrated into the
dermatology curriculum? Overall, this study illustrates that the majority of responding
Yes 131 (94.9) dermatology residents are given opportunities to learn medical
coding and billing through didactics and clinical experiences.
No 7 (5.1)
Many residents were able to answer correctly questions that
Would you participate in a web-based medical coding/billing tested their basic knowledge of E&M coding. These results are
curriculum?
encouraging and reflect the recognition of the importance of
Yes 112 (81.2) medical coding and billing training during residency.
No 26 (18.8)
Would you be more motivated to learn medical coding/billing Nevertheless, there were residents who reported a lack of
if billing questions were asked on the Dermatology Board exposure to billing through both formal lectures and clinical
Examination? practice. Given the rise of inappropriate billing leading to im-
Yes 116 (84.1) proper compensation,2 it is important that all residents leave
their training feeling confident and capable of billing appropri-
No 22 (15.9)
ately. A standardized billing curriculum may help to facilitate
Did the presence of a billing curriculum influence your this goal, and further studies are needed to develop and imple-
residency selection?
ment this. Furthermore, future investigations comparing and
Yes 3 (2.2) contrasting billing exposure in outpatient- vs inpatient-based
No 135 (97.8) specialties are needed to provide further insight on the stark
contrast between these two groups, as elucidated in our pilot

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questions that tested their billing and coding knowledge. We study.
believe that these results reflect the outpatient focus of derma-
tology residency compared with the other medical specialties DISCLOSURES
polled. The authors declare no conflict of interest.

Penalties Apply
In addition to the exposure to medical coding and billing through
didactics and clinical experiences, 94.9% of dermatology resi-
dents believed that medical coding should be integrated into
REFERENCES
1. Tran J, Cennimo D, Chen S, Altschuler EL. Teaching billing and coding to
medical students: a pilot study. Med Educ Online. 2013;18:21455.
2. HHS I. America’s Hidden Healthcare Crisis. National Managed Health Care
the dermatology curriculum (Table 4). Perhaps this is because Congress- Managed Care Leadership Conference Washington, DC: HSS, 7-9
March 2005:1-16.
73.2% of dermatology residents reported that they plan on do- 3. Salz T. How ICD-10 will affect your practice. Med Econ. 2011;88:64,71-2.
ing their own medical coding and billing after they graduate. To 4. Mishuris RG, Linder JA. Electronic Health Records and the Increasing Com-
elucidate whether residents would be interested in furthering plexity of Medical Practice: “It Never Gets Easier, You Just Go Faster.” J Gen
Intern Med. 2013;28(4):490-492.
their medical billing and coding knowledge, respondents were 5. Centers for Medicare & Medicaid Services. Medicare fee for-service 2011
asked whether they would participate in a web-based billing improper payments report. http://www.cms.gov/Research-Statistics-
Data-and-Systems/Monitoring-Programs/CERT/Downloads/MedicareFFS-
course. A majority of residents polled (81.2%) reported that they 2011CERTReport.pdf: Medicare FFS 2011 CERT Report; 2012.
would be interested in such a course, substantiating its future 6. Centers for Medicare & Medicaid Services. Medicare fee for-service 2012
improper payments report. http://www.cms.gov/Research-Statistics-Data-
development. and-Systems/Monitoring-Programs/CERT/Downloads/MedicareFeeforSer-
vice2012ImproperPaymentsReport.pdf Medicare FFS 2012 CERT Report;
The main limitation of this study is that respondents represent 2013.
7. Evans DV, Cawse-Lucas J, Ruiz DR, Allcut EA, Andrilla CH, Norris T. Family
a minority of all dermatology residents in the United States. medicine resident billing and lost revenue: a regional cross-sectional study.
However, despite this limitation our response rate was quite Fam Med. 2015;47:175-81.
8. Wiley KF, Yousuf T, Pasque CB, Yousuf K. Billing and coding knowledge: a
high (31.2%), and it is likely that resident participation was comparative survey of professional coders, practicing orthopedic surgeons,
limited in part by the program directors and coordinators and orthopedic residents. Am J Orthop. (Belle Mead NJ) 2014;43:E107-11.
9. The Dermatology Milestone Project. The Accreditation Councel for Graduate
who declined to provide resident e-mail addresses or did not Medical Education 2014.
forward our survey link to their current residents. As a result, 10. Survey Monkey. surveymonkey.com.
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682
Journal of Drugs in Dermatology K. Blecher Paz, C. Halverstam, A.K. Rzepecki, B.N. McLellan
June 2018 • Volume 17 • Issue 6

11. Fakhry SM, Robinson L, Hendershot K, Reines HD. Surgical residents’

knowledge of documentation and coding for professional services: an op-
portunity for a focused educational offering. Am J Surg. 2007;194:263-7.

AUTHOR CORRESPONDENCE

Alexandra Rzepecki BS
E-mail:................……....................................... [email protected]

Meet the New Derm In-Review Advisory Council

Led by The Derm In-Review Advisory Council is a select

Do Not Copy
Adam Friedman, MD, FAAD
Derm In-Review Advisory Council, Chair panel that offer their expertise to evaluate and
Associate Professor of Dermatology
Residency Program Director
choose practice exam content that will be used
George Washington School of Medicine in the Derm In-Review study tools.

Penalties Apply
and Health Sciences

Michael A. Cardis, MD Christopher English, MD Benjamin Garden, MD Farzam Gorouhi, MD Paul Gruber, MD
Resident Physician, Resident Physician, Resident Physician, Resident Physician, Resident Physician,
Department of Dermatology Dermatology Residency Program Department of Dermatology Department of Dermatology Department of Dermatology
Georgetown University Hospital University of Alabama at Birmingham University of Illinois at Chicago University of California, Davis Saint Louis University

Jordan Heskett, MD Ramya Kollipara, MD Oscar W. Nevarez, MD Nathan W. Rojek, MD Cindy Wassef, MD
Resident Physician, Resident Physician, Resident Physician, Co-Chief Resident, Chief Resident,
Department of Dermatology Department of Dermatology Department of Dermatology Department of Dermatology Department of Dermatology
Indiana University School of Medicine Texas Tech University Health Sciences Center University of Puerto Rico Oregon Health & Science University Stony Brook University Hospital
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June 2018 683 Volume 17 • Issue 6

Naturopathic Self-Treatment of an Atypical Fibroxanthoma:

Lessons for Dermatologic Surgery
Brandon Worley MD MSc,a Andrew J. Nemechek MD FACS,b,c Samantha Stoler MD FAAD,d
and Joel L. Cohen MD FAAD FACMSd,e,f
a
University of Ottawa, Ottawa, ON, Canada
b
Colorado Head and Neck Specialists, Centura Health, Denver, CO
c
University of Colorado School of Medicine, Denver, CO
d
AboutSkin Dermatology, Greenwood Village, Denver, CO
e
University of California Irvine, Irvine, CA
f
University of Colorado School of Medicine, Denver, CO

ABSTRACT
Background: Alternative therapies are favored by some patients. In skin cancer, this may be to try to avoid surgery out of fear for the
procedure and its functional or cosmetic consequences. Frequently, use of these therapies is not curative and can cause harm. Our
objective is to detail a case where black salve was used as a natural remedy for an atypical fibroxanthoma and resulted in a severe
burn. We highlight the challenges of communicating effective treatment options for those who have strong beliefs concerning natural
remedies after a cancer diagnosis.
Case Report: A 78-year-old man was referred for excision of a small atypical fibroxanthoma of the scalp. He had reservations about
conventional treatments, he initially declined surgery. Later, he was found to have a severe burn over the site of the biopsy-proven
AFX, extending to 20% of his scalp. He was found to have been applying black salve. Hospital admission and multiple stages of scalp
reconstruction with Head and Neck Surgery were required.
Conclusion: For patients who desire to use alternative medicine, communication is all important. Integrative approaches to use tra-
ditional therapy while reconciling patient beliefs in natural medicine can improved oncologic, functional, and psychosocial outcomes.

J Drugs Dermatol. 2018;17(6):683-685.

INTRODUCTION Do Not Copy

A
lternative remedies for treating and preventing cancer are to the size and location, wide local excision and a CT scan to

Penalties Apply
not new. Natural remedies appeared in pill form as early rule out bony involvement were discussed. No lymphade-
as the turn of the last century. However, after Max Gerson nopathy was present on examination. Given it was a primary
published his “A Cancer Therapy” in the 1950s a growing inter- tumor without any high-risk features clinically or histological-
est in natural healing emerged. Near identical to Hippocrates’ four ly, adjuvant radiation was not advised. He was referred to a
humors, the theory contends that an imbalance within the body Head and Neck surgeon for management. In the interval time,
exists that alternative medicines correct. Patients have been found he began applying black salve to the tumor and surrounding
to choose complementary and alternative medicine (CAM) after a scalp. In place of the previous site was a well-demarcated ul-
cancer diagnosis because they perceive the unconventional treat- cer with overlying necrotic grey-white slough, ragged borders,
ment to be less harmful or for some reason do not trust their phy- and peripheral erythema. Anterior focal heme-crusted ero-
sician’s recommendation.1 Although they are perceived as natural, sions with a linear extension at the most anterior aspect of
CAM can lead to harm. Serious side effects are possible. the wound was also present. Stippled black chemical staining
was observed. There were no nodular areas within the wound
Here we present a case of a patient who chose to pursue alterna- and no lymphadenopathy was present (Figure 1B). He was ad-
tive self-treatment with black salve for an atypical fibroxanthoma vised to stop using this preparation. At the time of consultation
(AFX) instead of conventional therapy. This led to a poor outcome. with Head and Neck surgery and despite stopping the black
It is reported here to foster discussion on inquiring about conven- salve, the ulcer enlarged to 20 cm in size. His ulcer was full-
tional and alternative medicine during preoperative consultations. thickness to the calvarium. The wound was deeply necrotic and
stained (Figure 1C). The wound appeared infected with associ-
CASE REPORT ated purulence. This prompted a hospital admission for wound
A 78-year old man presented with an 8-week history of a 0.7 x 0.5 care, pain, management, and infection control. He was stabi-
cm atypical fibroxanthoma on the left central scalp (Figure 1A). Due lized and was then referred to the burn wound reconstruction
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684
Journal of Drugs in Dermatology B. Worley, A.J. Nemechek, S. Stoler, J.L. Cohen
June 2018 • Volume 17 • Issue 6

FIGURE 1. Clinical photographs of the initial size of the AFX on presentation (A) and the secondary wound after application of coal tar (B).
Worsening with to 20 cm in diameter with exposed calvarium despite stopping black salve is demonstrated on the far right (C).

team at a neighboring hospital. Over the course of 3 months, In our case, though the resultant burn may have successfully
he underwent three graft reconstructions of his scalp (Figure 2). cleared his AFX, it is not possible to know for certain. Fortu-
nately, AFXs have low metastatic potential (2.5% of cases) with
DISCUSSION a high survival rate overall. Still, recurrences happen in 7.5% of
Black salve has been touted as an alternative treatment for all cases within two years and spontaneous regression of AFXs
skin cancer. It contains inert ingredients along with corrosive is rarely reported.3,4 Our patient will require close follow-up and
bloodroot (S. canadensis) or zinc chloride. Some formulations consideration of surgery to ensure tumor clearance. Yet, his
contain dimethyl sulfoxide (DMSO) for increased epidermal poor outcome may have been avoided through an opportunity
penetration. Bloodroot contains indiscriminate cyotoxic and to discuss his beliefs.

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antiproliferative plant alkaloids. In vitro studies have shown
both equal targeting of cancer cells and keratinocytes as well as From a patient care perspective, the choice of our patient to
excess cytotoxicity against fibroblasts with inferiority in treat- treat himself with black salve occurred without our knowledge.
ing cancer compared to traditional treatment. Zinc chloride and This led to an adverse event. Due to the small tumor size, CAM

Penalties Apply
other plant derivatives within the salve may contribute to cell was not considered in his evaluation. However, strong beliefs
necrosis as they have similar cytotoxicity. Consequently, this in natural treatment or fears regarding treatment may have led
broad-spectrum action of black salve against normal human to its use. As a result of this case, it is clear that communication
cells has led to burns and severe morbidity.2 regarding the use of CAM within the overall treatment plan is
a key consideration. Many perceived natural treatments can be
harmful. In general, use of CAM has been linked to a worse
FIGURE 2. The final result of the graft reconstruction of the scalp. survival rate (HR 2.17-5.68) for lung, breast and colon cancer if
not used in combination with conventional treatment.5 While
AFX is not as life threatening as many internal cancers, poor-
er outcomes (eg, greater surgical morbidity) are more likely
without surgical intervention. Understanding fears regarding
conventional treatment and educating patients on their choices
regarding CAM can help to lessen the risks of this decision.

CONCLUSION
Asking about patient desires to pursue CAM for cancer treatment
is a significant consideration. For skin cancer, it may not be as
commonly discussed or considered since removal of the tumor is
usually easily done with surgery. With the rise in patient interest to
use treatments that are perceived as natural or less harmful than
traditional treatments, deciding how this fits into a patient’s larger
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685
Journal of Drugs in Dermatology B. Worley, A.J. Nemechek, S. Stoler, J.L. Cohen
June 2018 • Volume 17 • Issue 6

treatment plan may become a part of the pre-operative consulta-

tion. Above all, educating patients on the benefits, risks and harms
related to any treatment they decide to pursue is critical.

DISCLOSURES
There are no relevant conflicts of interest.

REFERENCES
1. Shumay DM, Maskarinec G, Kakai H, Gotay CC. Why some cancer patients
choose complementary and alternative medicine instead of conventional
treatment. J Fam Pract. 2001;50(12):1067.
2. Saltzberg F, Barron G, Fenske N. Deforming self-treatment with herbal “black
salve”. Dermatol Surg. 2009;35(7):1152-4.
3. Koch M, Freundl AJ, Agaimy A, Kiesewetter F, Kunzel J, Cicha I, et al. Atypical
Fibroxanthoma - Histological Diagnosis, Immunohistochemical Markers and
Concepts of Therapy. Anticancer Res. 2015;35(11):5717-35.
4. Bagazgoitia L, Morais P, Carrillo R, Jaen P. Complete regression of an atypi-
cal fibroxanthoma. Eur J Dermatol. 2012;22(1):157-8.
5. Johnson SB, Park HS, Gross CP, Yu JB. Use of Alternative Medicine for Can-
cer and Its Impact on Survival. J Natl Cancer Inst. 2018;110(1).

AUTHOR CORRESPONDENCE

Brandon Worley MD MSc

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

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June 2018 686 Volume 17 • Issue 6

Currently Constrained, Dermatologists Are Ready for

New Acne Therapies
Arielle R. Nagler MD
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY

A
cne is the most common skin condition in the United burdensome for patients and providers, and, unsurprisingly,
States, affecting 50 million Americans annually. The isotretinoin use has declined since iPLEDGE’s implementation.
disease’s severity can range from mild to severe, with Although national data is limited, one study at Kaiser Perman-
approximately 20% of people with acne experiencing moderate ente found that prescriptions for isotretinoin decreased by 29%
to severe disease. Acne can be associated with both physical in the first 2 years after iPLEDGE’s implementation.1 Moreover,
and emotional morbidity. Nevertheless, despite the prevalence an FDA special report found that by the fifth year of iPLEDGE,
and impact of moderate to severe acne, therapeutic options for isotretinoin prescriptions dropped by 38% from levels prior
patients are limited, and options have become even more re- to the implementation of pregnancy prevention programs for
stricted with the evolution of medication regulation and acne isotretinoin.2-4
management guidelines. The field needs new tools.
Antibiotic stewardship has also affected acne care as it has
While there has been an explosion in therapeutics for other skin become a national and international priority. The focus on de-
diseases in recent years, advancements for the treatment of creasing antibiotic use has led to calls to decrease the extended
moderate to severe acne have been few and far between. Cur- durations of antibiotics commonly used in treating acne. Ex-
rent treatment for moderate to severe acne primarily relies on tended antibiotic durations in acne have been associated with
systemic medications, including antibiotics (most commonly antimicrobial resistance, decreased responsiveness of acne to
tetracyclines) and isotretinoin. For women, there are also the therapy, and an increased risk for pharyngitis and inflammatory
additional options of combined oral contraceptives (COC) and bowel disease.5-7 Recent American Academy of Dermatology,
the off-label use of spironolactone. While COC have gained spe- Global Alliance to Improve Acne Outcomes, and European Ex-

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cific Food and Drug Administration (FDA) approval for acne in pert Group on Oral Antibiotics and Acne guidelines recommend
the last 20 years, isotretinoin is the only systemic medication limiting antibiotic use to 3-6 months when possible.8-10 It has
specifically and primarily approved by the FDA for the treat- become difficult to justify extended durations of antibiotics in
ment of acne in the last 35 years. patients with moderate to severe acne, even when patients are

Penalties Apply
doing well on antibiotic therapy.
This stands in contrast to, for example, systemic psoriasis
treatments, for which there has been rapid development and So what are we left with? While changes to iPLEDGE may al-
approval of targeted therapies since etanercept was approved leviate some of the challenges we face in treating patients
in 2004. There are now five classes of biologics, including 11 with moderate to severe acne, antibiotic stewardship serves
different drugs, approved for psoriasis. Many of these psoriasis an important public health goal and is here to stay. New drug
drugs have impressive efficacy, creating a world in which we development for patients with moderate to severe acne is the
are talking about psoriasis clearance in the context of Psoriasis true solution. The resources dedicated to research and devel-
Area Severity Index (PASI) 90s and 100s. opment of psoriasis therapies yielded a dramatic expansion
in the available targeted therapies for an important dermato-
Further complicating the treatment of acne, dermatologists logical disease. Acne is the most common condition we treat as
face barriers to prescribing the limited systemic acne therapies dermatologists. New advancements in the treatment of acne,
which are available. Isotretinoin is contraindicated in pregnancy, including the introduction of new medications are needed, as
and since its approval in 1982, the FDA has implemented three our current armamentarium is far too limited.
iterations of pregnancy prevention programs. iPLEDGE, the
current (and most stringent) pregnancy prevention program, DISCLOSURES
is an online system that requires the registration of all parties The authos has no conflicts of interest to declare.
involved in the isotretinoin distribution process (including the
prescribing doctor, the pharmacist, and the patient), monthly REFERENCES
pregnancy testing, and monthly confirmation that two forms 1. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on
isotretinoin fetal exposure in an integrated health care system. J Am Acad
of birth control are being used by female patients. iPLEDGE is Dermatol 2011;65:1117-25.
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Journal of Drugs in Dermatology A.R. Nagler
June 2018 • Volume 17 • Issue 6

2. Isotretinoin Pregnancy Prevention Program Evaluation. 2004. (Ac-

cessed November 29 2017, at https://www.fda.gov/ohrms/dockets/ac/04/
slides/4017S1_06_Pitts.ppt.)
3. Drug Safety and Risk Management Advisory Committee, Dermatologic and
Ophthalmic Drugs Advisory Committee, for iPLEDGE One Year Update.
2007. (Accessed November 29, 2017, at https://www.fda.gov/ohrms/dockets/
ac/07/briefing/2007-4311b1-02-ipledge.pdf.)
4. Drug Safety and Risk Management Advisory Committee, Dermato-
logic and Opthalmic Drugs Advisory Committee, Briefing Document for
iPLEDGE. 2011. (Accessed November 29, 2017, at https://wayback.archive-it.
org/7993/20170114004041/http://www.fda.gov/downloads/AdvisoryCom-
mittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmic-
DrugsAdvisoryCommittee/UCM281376.pdf.)
5. Margolis DJ, Fanelli M, Kupperman E, et al. Association of pharyngitis with
oral antibiotic use for the treatment of acne: a cross-sectional and prospec-
tive cohort study. Arch Dermatol 2012;148:326-32.
6. Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association be-
tween the oral tetracycline class of antimicrobials used to treat acne and
inflammatory bowel disease. The American journal of gastroenterology
2010;105:2610-6.
7. Eady EA, Cove JH, Holland KT, Cunliffe WJ. Erythromycin resistant propi-
onibacteria in antibiotic treated acne patients: association with therapeutic
failure. Br J Dermatol 1989;121:51-7.
8. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management
of acne: an update from the Global Alliance to Improve Outcomes in Acne
group. J Am Acad Dermatol 2009;60:S1-50.
9. Dreno B, Bettoli V, Ochsendorf F, Layton A, Mobacken H, Degreef H. Euro-
pean recommendations on the use of oral antibiotics for acne. Eur J Derma-
tol 2004;14:391-9.
10. Zaenglein AL, Pathy AL, Schlosser BJ et al. Guidelines for the management
of acne vulgaris. J Am Acad Dermatol 2016; 74: 945-73.

AUTHOR CORRESPONDENCE

Arielle R. Nagler MD
E-mail:................……................................ [email protected]

June 2018 688 Volume 17 • Issue 6

Beyond Traditional Treatment:

The Importance of Psychosocial Therapy in Vitiligo
Alexandra K. Rzepecki BS,a Beth N. McLellan MD,b and Nada Elbuluk MD MScc
Department of Dermatology. University of Michigan Medical School, Ann Arbor, MI
a

Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY

c
The Ronald O. Perelman Department of Dermatology. New York University School of Medicine, New York, NY

ABSTRACT
Vitiligo is an acquired depigmentation disorder of the skin. Patients with vitiligo often face a challenging disease course, having to cope
with a condition that is known to be physically disfiguring, psychologically devastating, and socially stigmatizing. Although an exten-
sive amount of research has been directed towards the dermatologic treatment of vitiligo, an overall lack of data exists investigating
treatment of the psychological and emotional burden of patients with vitiligo. This paper reviews the literature for treatment options
in patients with vitiligo that specifically target the psychosocial domain. Despite being limited in quantity, several studies have proven
the benefits of adjuvant care in the form of group therapy, cognitive behavioral therapy, and self-help programs. Although preliminary
evidence is promising, larger prospective studies are needed to further define the role of these psychosocial interventions before inte-
grating them in a more official capacity into the standard of care for patients with vitiligo. Because of the considerable impact of vitiligo
beyond its physical symptoms, dermatologists ought to consider the utility of adjuvant therapies to adequately address impairments in
self-esteem, body image, and quality of life in patients with vitiligo.

J Drugs Dermatol. 2018;17(6):688-691.

INTRODUCTION

V
itiligo is an acquired autoimmune disorder character- and management of the psychologically distressing aspects of
ized by the development of depigmented, non-scaly the disease in addition to its clinically apparent signs.7

Do Not Copy
macules or patches on the skin, hair, or both.1 With
an estimated prevalence of 0.5% to 2%, it is the most frequent Psychosocial Vulnerability in Vitiligo
cause of depigmentation worldwide.2 Because of the sporadic Unlike most internal illnesses, vitiligo is a condition visible to
loss of color, vitiligo can be physically disfiguring, psychologi- others, and those afflicted may suffer social and emotional con-

Penalties Apply
cally devastating, and socially stigmatizing, often profoundly sequences. Patients must not only learn to adapt to the bodily
affecting patients’ quality of life. Despite this, vitiligo is too of- changes they are facing, but they must also be psychologically
ten dismissed as a cosmetic condition with trivialization of the prepared for the possibility that their condition may spread or de-
patients’ distress, which only further exacerbates the intensity teriorate at any time, causing a certain degree of uncertainty and
of negative feelings that can be associated with the disease.3 helplessness.8 Because there is not one distinct etiology for the
condition, patients with vitiligo often live in fear and anxiety of
The psychological status of patients with vitiligo has often what may lead to the appearance of new lesions.9–11 The disease
been investigated, showing that individuals can suffer from a course, which can be progressive and episodic, is unpredictable,
multitude of feelings including anxiety, depression, suicidal at- and to many, a source of psychological stress. Individuals can
tempts, phobias, and limited personal relationships.4 Because ultimately suffer from various psychiatric comorbidities such
of the significant social and emotional burden patients with as depression, which was reported to be five times more likely
vitiligo encounter, a dire need for psychosocial interventions among patients with vitiligo than controls (P<0.001).12 In fact,
exists.5 However, there is a lack of data investigating how in- cyclic antidepressants are widely used to treat the depression
dividuals can emotionally cope with vitiligo as a chronic skin of patients with vitiligo.13 Additionally, studies investigating the
disease.6 psychological status of patients with vitiligo reported that indi-
viduals suffer from feelings of disfigurement and psychological
We conducted a literature review for treatment options in pa- disturbance,14 anxiety,15 depression,12 impaired self-esteem,9
tients with vitiligo that specifically target the psychosocial and sleep disturbances,16 and sexual dysfunction.17
emotional domain of the condition. We provide an overview of
our findings, hoping to raise awareness about the utility of a Various factors may contribute to and potentially worsen the dis-
holistic approach to treatment that includes acknowledgment ease experience, such as extent of skin involvement, distribution
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689
Journal of Drugs in Dermatology A.K. Rzepecki, B.N. McLellan, N. Elbuluk
June 2018 • Volume 17 • Issue 6

of lesions, skin type, and age of onset. For instance, lower qual- also help the body respond to treatment.27 In fact, one study
ity of life (QoL) scores and higher levels of stigmatization were found that patients with worse QoL scores responded less
demonstrated in patients with lesions involving the face, arms, favorably to a given therapeutic modality, suggesting that ad-
legs, and hands,18 than those with concealed lesions.19 Addition- ditional psychological approaches may improve treatment
ally, in some parts of the world, the social stigma associated with outcomes.7,28
vitiligo has significant impairment on social interactions, mari-
tal status, employment prospects, and sexual relationships.20,21 Vitiligo and Psychosocial Therapy
Skin tone or ethnicity can play a remarkable role, with studies Although a plethora of studies exist about QoL in patients with
showing that dark-skinned individuals are more likely to have vitiligo,17,24,29,30 a limited number have investigated coping strat-
traumatizing experiences with vitiligo due to the fact that depig- egies and the efficacy of psychological interventions.22,31 The
mented areas appear more visible and because of the enormous literature search conducted for this paper discovered studies
stigma that the disease carries in certain countries.21–24 utilizing cognitive behavioral therapy (CBT)9,32, group thera-
py,15,33,34 and self-help15 as a means of treatment in patients with
Considering a Holistic Treatment Approach to vitiligo (Table 1).
Vitiligo
Because vitiligo can be both emotionally scarring as it is physi- The first study that explored the effect of CBT on patients with
cally altering, patients require psychosocial support to manage vitiligo required patients to 1) monitor their thoughts for au-
their overall well-being.25 This approach, however, is often lim- tomatic negative cognitions and 2) use newly taught skills
ited during a dermatology appointment by logistic constraints to counter negative social attention such as staring.9 Results
such as lack of time and focus on medical treatment. revealed significant improvements in perceived body im-
age, self-esteem, and QoL for patients in the treatment group.
In order to provide optimal care for patients with vitiligo, cli- Patients were also able to undertake previously avoided behav-
nicians may consider encompassing a holistic approach that iors such as wearing clothing which revealed vitiligo lesions
focuses on all aspects of the disease, such as discussing the and going out in public without camouflage make-up.
emotional impact of vitiligo in patients’ daily routines.26 This
nourishing attitude may not only enhance treatment compli- Next, cognitive behavioral self-help (CBSH), an interven-
ance and resilience in the face of therapeutic failure, but can tion based on CBT techniques delivered in leaflet form, was

TABLE 1.

Year Intervention
Do Not Copy
Studies Examining Psychosocial Interventions in Patients With Vitiligo
Experimental
Group (n)
Control
Group (n)
Concurrent Medical
Treatment
Statistically
Significant Benefit
1999

2004
CBT
CBT
Group person-centered therapy
Penalties Apply 8
15
14
8

15
PUVA therapy in 25%

No
Yes

NB-UVB-activated
2011 Group climatotherapy 71 42 pseudocatalase PC-KUS as Yes
part of climatotherapy
CBSH 25
2014 26 - Yes
CBSH (+) 24
Yes, 31% (experimental)
2017 Support group therapy 29 44 and 27% (control), Yes
but not specified what type

Abbreviations: CBT=cognitive behavioral therapy; CBSH=cognitive behavioral self-help, CBSH(+)=augmented CBSH; PUVA=psoralen and ultraviolet A therapy;
NB-UVB=narrow band ultraviolet B therapy; PC-KUS=pseudocatalase
1. Papadopoulos L, Bor R, Legg C. Coping with the disfiguring effects of vitiligo: A preliminary investigation into the effects of cognitive-behavioural therapy. Br J
Med Psychol. 1999;72:385–96.
2. Papadopoulos L, Walker C, Anthis L. Living with Vitiligo: A Controlled Investigation into the Effects of Group Cognitive-Behavioural and Person-Centred Therapies.
Dermatol Psychosom Dermatol Psychosom. 2004;5:172–7.
3. Krüger C, Smythe J, Spencer J, Hasse S, Panske A, Chiuchiarelli G, et al. Significant Immediate and Long-term Improvement in Quality of Life and Disease Coping
in Patients with Vitiligo after Group Climatotherapy at the Dead Sea. Acta Derm Venereol. 2011;91:152–9.
4. Shah R, Hunt J, Webb T l., Thompson A r. Starting to develop self-help for social anxiety associated with vitiligo: using clinical significance to measure the potential
effectiveness of enhanced psychological self-help. Br J Dermatol. 2014;171:332–7.
5. Zabetian S, Jacobson G, Lim HW, Eide MJ, Huggins RH. Quality of Life in a Vitiligo Support Group. J Drugs Dermatol. 2017;16:344–50.
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690
Journal of Drugs in Dermatology A.K. Rzepecki, B.N. McLellan, N. Elbuluk
June 2018 • Volume 17 • Issue 6

explored in a study in patients with vitiligo, revealing suc- partnership, an initiative where patients and clinicians worked
cessful reductions in social anxiety.15 CBSH had three parts: together to steer future research in the field of vitiligo treatment,
1) psychoeducation, such as how social anxiety is maintained identified that the impact of psychological interventions on the
in vitiligo; 2) symptom monitoring, including recognition of QoL in patients with vitiligo was voted into the top 10 most
anxiety triggers; and 3) guided imagery-based relaxation and important future research areas.39 Recommendations were spe-
techniques for switching attention. The study also had an aug- cifically made regarding the necessity to conduct systematic
mented CBSH+ group, where self-help instructions had specific reviews of the current literature, pursue substantial exploratory
if-then plans to specify exactly when, where, and how to act in and qualitative work, and eventually progress to conducting
future situations. Over 71% of the participants found the leaflet randomized controlled trials. The importance of these research
helpful. Clinically significant changes in social anxiety were ob- efforts is immense as it can help confirm the utility of psycho-
served in 24% of patients in the CBSH+ group, 8% in the CBSH social interventions and make them more accessible to patients
group, and 0% in the control group. The authors speculate that with vitiligo. For instance, if support groups are increasingly
inclusion of a specific plan in the CBSH+ group increased the recognized as an important adjuvant to medical treatment, or-
frequency with which participants used the materials, likely ganizations may be more likely to receive funding. Similarly,
leading to a larger decrease in anxiety. insurance companies may start to recognize the utility of thera-
py in patients with vitiligo, possibly assisting with costs.
The positive effect of group therapy in vitiligo was reported in
two studies.33,34 The first examined the influence of group clima- Although providing a pathway to achieve these ambitious goals
totherapy at the Dead Sea, a successful treatment modality for is an important starting point, pursuing research about psycho-
re-pigmentation in vitiligo that combines bathing in the Dead social therapy in patients with vitiligo is associated with a few
Sea followed by application of pseudocatalase PC-KUS and limitations. These include: 1) limited number of participants; 2)
exposure to UV light.35–37 Climatotherapy entailed a uniquely selection bias; 3) variable compliance among patients—patients
supportive environment where patients with vitiligo shared es- would be required to devote additional time to their disease
sential parts of their day, both with each other and with those outside of the dermatologist’s office whether to complete CBT
who spend significant time with someone who has vitiligo, homework or be motivated to regularly attend group meetings;
such as spouses.33 After a 20-day treatment plan, QoL was sig- and 4) diminishing the purity of group therapy—completing
nificantly improved and remained so after twelve months.33 questionnaires may take away from the experience of providing
peer support since participants may feel that the focus is shifted

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The second study sought to examine QoL impact of a vitiligo towards research rather than solely on their current well-being,
support group on its members,34 defined as those who had at- which is why some groups prefer not to do this.25
tended at least one group meeting, self-identified as members,
and had vitiligo. A questionnaire administered to group and CONCLUSION

Penalties Apply
non-group members revealed similar QoL scores (7.1 and 6.0, Although preliminary studies have exhibited the benefit of ad-
respectively, P=0.2), however, members of the group had a sig- juvant care in the form of group therapy, CBT, and/or self-help
nificantly increased prevalence of poorer QoL indicators, such programs, formal studies on psychosocial interventions for
as higher rates of unemployment (58.6% vs 18.2%, P<0.001), patients with vitiligo—and in fact within dermatology in gen-
lower socioeconomic status, and reports of more severe dis- eral—are still lacking.5 The positive benefit of treating the
ease compared to non-group members. Because the support psychological and emotional burden that patients with vitiligo
group members had factors that would suggest worse QoL, can experience is clear, however, it is only based on a few small
yet the two groups had no significant difference in mean QoL reports. This lack of evidence is a challenge and a real limitation
scores, support group membership seems to have a protective in making psychosocial interventions part of mainstream vitili-
effect and was able to improve overall well-being. In contrast to go therapy. Sufficient data from larger, prospective studies and
these statistically significant findings, we identified one study randomized controlled trials is needed to further define the role
that did not report psychosocial benefit from CBT or group of these psychological interventions before efforts can be made
therapy.32 to integrate them in a more official capacity into the standard
of care for patients with vitiligo. In the meantime, dermatolo-
Future Directions gists ought to consider the impact of vitiligo beyond its physical
Preliminary studies about the utility of psychosocial interven- symptoms, exploring adjuvant therapies that may help to ad-
tions in patients with vitiligo are promising, however, limited equately address the impairments in self-esteem, body image,
empirical data exists to support the creation and implementa- and QoL that their patients may experience.
tion of such programs. Nonetheless, awareness is increasing
about the need to pursue research in this realm of dermatol- DISCLOSURES
ogy.22,38 For instance, the results of a vitiligo priority setting The authors have no conflicts of interest to declare.
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Journal of Drugs in Dermatology A.K. Rzepecki, B.N. McLellan, N. Elbuluk
June 2018 • Volume 17 • Issue 6

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Do Not Copy
cial anxiety associated with vitiligo: using clinical significance to measure the Alexandra Rzepecki BS
potential effectiveness of enhanced psychological self-help. Br J Dermatol.
2014;171(2):332-337. doi:10.1111/bjd.12990 E-mail:................…….............................. [email protected]
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June 2018 692 Volume 17 • Issue 6

Fifteen Minute Test May Save 15% or More on

Rosacea Treatment
Evan Darwin BA, Jessica Cervantes BA, and Hadar Lev-Tov MD
University of Miami Miller School of Medicine, Miami, FL

ABSTRACT
Rosacea is a common inflammatory skin condition that impacts a large portion of fair-skinned populations. The redness associated with
rosacea can be a significant challenge. Brimonidine sulfate and oxymetazoline HCL were both recently approved by the FDA for the
management of facial redness. These agents, however, are costly, and not all patients respond to the medication. Herein, we describe
a clinical pearl that helps to optimize patient selection for the medications. This saves the patient and the health care system both time
and money.

J Drugs Dermatol. 2018;17(5):692-693.

Clinical Challenge

R
osacea is a common chronic inflammatory skin condi- cost patients over $570, and a 30g tube of brimonidine may
tion that impacts 2-22% of fair-skinned populations.1 cost about $494.4 Despite these costs, many patients are nonre-
There are four clinical subtypes of rosacea: erythema- sponders to the medication and do not demonstrate a signifi-
totelangiectatic, papulopustular, phymatous, and ocular.2 How- cant improvement.5-7 These facts may lead to frustration for the
ever, most patients present with the morphologic characteris- physician and the patient who may be paying for an expensive
tics of multiple subtypes, and in clinical practice facial erythema medication only to quickly find out it is unsatisfactory.
is common amongst all subtypes. This facial redness can be a
significant challenge. Survey data indicate that the adverse im- Solution
pact of rosacea on quality of life increases with the severity of In our clinic, we leverage the short acting time of these agents

Do Not Copy
facial erythema.3 Recently, two new medications, brimonidine and the evident clinical outcome for better patient selection.
sulfate 0.33% and oxymetazoline HCL 1%, were approved by Brimonidine acts within 30 minutes of application, and while
the FDA in 2014 and 2017 respectively for management of facial the effect time of oxymetazoline in rosacea is not well de-
redness. Both medications act as vasoconstrictors: brimonidine scribed, our clinical experience indicates a similar time to

Penalties Apply
acts as an alpha-2 agonist, while oxymetazoline is an alpha-1a effect.4,6,8 While the patient is in clinic and after discussion of
agonist.4,5 These agents, while beneficial to many patients, are the medications’ benefits, adverse effects and alternatives, we
limited by a variable patient response rate, cost, and varied in- apply a small amount of brimonidine sulfate to one cheek, and
surance coverage.2 One 30 g tube of oxymetazoline HCL may oxymetazoline HCL to the other (Figure 1; Figure 2). The patient

FIGURE 1. (A) The patient at presentation before application of medications (B) 15 minutes following application of oxymetazoline HCL to right
cheek, a lighter patch is evident (C) 15 minutes following application of brimonidine sulfate to left cheek, no lighter patch was appreciated.
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

693
Journal of Drugs in Dermatology E. Darwin, J. Cervantes, H. Lev-Tov
June 2018 • Volume 17 • Issue 6

FIGURE 2. (A) The patient at application of brimonidine sulfate to the right cheek (B) a lighter patch is present after 15 minutes of treatment in
clinic.

is then allowed to sit with the medication in clinic for 15 to 30

AUTHOR CORRESPONDENCE
minutes. After this short incubation, clinical response is typi-
cally evident as a lighter patch in the area of application. We do Hadar Lev-Tov MD
not need to wait for a full response, as the goal of this test is not E-mail:........................................................ [email protected]
to determine which medication the patient will have the greater
response with, but rather whether or not the patient will have
any response to either medication. The patient can then decide
if they are happy with the response and a relevant prescription
is offered. Treatment of the erythema associated with rosacea
is largely directed at quality of life improvement and this pearl
targets this goal by saving patients time and money as they
can potentially avoid an ineffective medication and get an idea
of what their skin will look like treated. Furthermore, in our an-

Do Not Copy
ecdotal experience this test leads to improved adherence and
patient satisfaction as the patients are aware of their own re-
sponse to the treatments.

Penalties Apply
DISCLOSURES
The authors have no conflicts of interest to report.

REFERENCES
1. Rainer BM, Kang S, Chien AL. Rosacea: Epidemiology, pathogenesis, and
treatment. Dermatoendocrinol. 2017;9(1):e1361574.
2. Del Rosso JQ. Topical a-Agonist Therapy for Persistent Facial Erythema of
Rosacea and the Addition of Oxmetazoline to the Treatment Armamentari-
um: Where Are We Now? J Clin Aesthet Dermatol. 2017;10(7):28-32.
3. Harper J, Del Rosso JQ, Ferrusi IL. Cross-Sectional Survey of the Burden of Ill-
ness of Rosacea by Erythema Severity. J Drugs Dermatol. 2018;17(2):150-158.
4. Hoover RM, Erramouspe J. Role of Topical Oxymetazoline for Management
of Erythematotelangiectatic Rosacea. Ann Pharmacother. 2018;52(3):263-267.
5. Baumann L, Goldberg DJ, Stein Gold L, et al. Pivotal Trial of the Efficacy and
Safety of Oxymetazoline Cream 1.0% for the Treatment of Persistent Facial
Erythema Associated With Rosacea: Findings from the Second REVEAL
Trial. J Drugs Dermatol. 2018;17(3):290-298.
6. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate
gel 0·5% is a novel treatment for moderate to severe facial erythema of
rosacea: results of two multicentre, randomized and vehicle-controlled stud-
ies. Br J Dermatol. 2012;166(3):633-641.
7. Draelos ZD, Gold MH, Weiss RA, et al. Efficacy and safety of oxymetazo-
line cream 1.0% for treatment of persistent facial erythema associated with
rosacea: Findings from the 52-week open label REVEAL trial. J Am Acad
Dermatol. 2018.
8. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing
of rosacea using a topically applied selective alpha1-adrenergic receptor ago-
nist, oxymetazoline. Arch Dermatol. 2007;143(11):1369-1371.
Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

June 2018 694 Volume 17 • Issue 6

Erratum
Jennifer C. Tang MD
Laser and Skin Surgery Center of Indiana, Carmel, IN

Dear Editor,

In the article, Vismodegib and the Hedgehog Pathway Inhibi-

tors: A Historical Perspective to Current Clinical Application, an
inaccurate disclosure statement was published. The disclosure
statement should read:

C. William Hanke MD is a consultant for Genentech.

Ivor Caro MD is a senior medical director at Genentech.

Sincerely,
Jennifer C. Tang MD

References
1. Tang JC, Hanke CW, Caro I. Vismodegib and the hedgehog pathway inhibi-
tors: A historical perspective to current clinical application. J Drugs Derma-
tol. 2018; 17(5):506-508.

JDDONLINE.COM/PODCAST

Penalties Apply
article abstracts to interviews, JDD Podcasts provide a fresh Evidenced Based Overview of the Life and Death
perspective of the peer reviewed content you have come to of the Seborrheic Keratosis
rely on from JDD (Journal of Drugs in Dermatology).
In this bonus edition of the JDD podcast, host Dr.
Hosted by Adam Friedman, MD and released monthly, Adam Friedman, Associate Professor of Dermatology
each episode will feature an interview with, and practical and Residency Program Director at the GW School
pearls from, the principal investigator of a high-profile JDD of Medicine and Health Sciences, discusses in detail the
manuscript in a convenient audio format. Each podcast will ins and outs of the most common benign cutaneous
place the selected article into a clinically useful perspective that neoplasm,the seborrheic keratosis.Clinical presentations,
is easy to listen to in the office or on the go. diagnostic approaches, pearls, and potential pitfalls, and
a tornado of mostly off label treatment approaches - ya
we got you. For the latest and greatest on managing
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This podcast was supported by an educational grant

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Listen Now at JDDonline.com/PODCAST

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.

Do Not Copy
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
can change somebody’s life
Penalties Apply
were giving back to the community and that I could
help people who want to further their education.
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.

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