1252 Letters
JUNE 2016
IGA score of ‘‘clear’’ or ‘‘almost clear’’ (success
criterion: IGA score \2) from week 9 until the study
end (week 12: 53.2% vs 19.6%; P ¼.001) (Fig 2). More
subjects treated with FMX-101 4% versus vehicle also
had an IGA improvement of $2 grades at week 12
(36.2% vs 15.2%; P ¼ .021). There was no significant
difference in IGA improvement for FMX-101 1%
versus vehicle.
Treatment with FMX-101 was well tolerated and safe,
with no drug-related systemic side effects or serious
adverse events. Five reported adverse events were
transient, mild in severity, and considered unrelated to
the study medication. All adverse events resolved
spontaneously by study end, except for a case of
laryngitis, which was treated with medication. There
were no significant differences in tolerability parameters
between the FMX-101 and vehicle groups.
Overall, these data suggest that FMX-101 may be
an effective and well-tolerated treatment for
moderate-to-severe AV. FMX-101 4% is the appro-
priate dose for further evaluation in phase 3 trials.
Avner Shemer, MD,a Joseph Shiri, MD,b Jacob
Mashiah, MD, MHA,c Renata Farhi, MD,d and
Aditya K. Gupta, MD, PhD, FRCP(C)e
The Chaim Sheba Medical Center, Affiliated with
Tel-Aviv University, Sackler School of Medicine,a
Clalit Health Services Clinic,b and Department of
Dermatology, Pediatric Dermatology Unit, Tel
Aviv Sourasky Medical Center,c Tel Aviv, Israel;
Dermatology Department, Hospital Nossa
Senhora da Sa ude (Gamboa),d Rio de Janeiro,
Brazil; Department of Medicine, University of
Toronto, and Mediprobe Research Inc, London,
Ontario, Canadae
Funding sources: Foamix Pharmaceuticals Ltd.
Disclosures: Dr Shemer is a consultant for Foamix
Ltd. Drs Shiri, Mashiah, Farhi, and Gupta have
no conflicts of interest to declare.
Correspondence to: Aditya K. Gupta, MD, PhD,
FRCP(C), 645 Windermere Rd, London, Ontario,
Canada N5X 2P1
E-mail: agupta@execulink.com
REFERENCES
1. Well D. Acne vulgaris: a review of causes and treatment options.
Nurse Pract. 2013;38:22-31.
2. Kircik LH. Doxycycline and minocycline for the management of
acne: a review of efficacy and safety with emphasis on clinical
implications. J Drugs Dermatol. 2010;9:1407-1411.
3. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a
systematic review. Clin Ther. 2005;27:1329-1342.
http://dx.doi.org/10.1016/j.jaad.2015.09.065
J AM ACAD DERMATOL
Use of topical retinoids by dermatologists
and non-dermatologists in the
management of acne vulgaris
To the Editor: Acne vulgaris, a chronic inflammatory
disease of the pilosebaceous unit, is the most com-
mon dermatologic disorder in the United States.1
Recently, both the American Acne and Rosacea
Society, endorsed by the American Academy of
Pediatrics, and the Global Alliance to Improve
Outcomes in Acne published their evidence-based
acne management guidelines recommending that
topical retinoids be used as first-line and mainte-
nance therapy for all types of acne.2,3 The purpose of
this study is to determine how frequently acne
patients are prescribed a retinoid medication by
dermatologists and nondermatologist physicians.
Data were obtained from the Humana database, a
large dataset for claims and reimbursed costs, en-
compassing 18,162,539 patients covered between
2007 and the present. We searched by International
Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9-CM) code 706.1 for patients in
the United States with a primary diagnosis code of
acne vulgaris between 2012 and 2014. Within this
group, we identified patients that were prescribed a
retinoid and further separated the data by patients
who were seen by dermatologists or nondermatol-
ogists for the primary diagnosis visit. Further break-
down by gender and age was done. The percentages
of retinoid prescriptions between the 2 groups were
determined and compared. Since registration in the
iPLEDGE Program is not limited to dermatologists,
oral isotretinoin was also included in the study.
Topical retinoids included in the study were
tretinoin, adapalene, and tazarotene, as well as the
brand names associated with them. This study was
declared exempt by the Wake Forest School of
Medicine Institutional Review Board.
From 2012 to 2014, 54.7% of acne patients seen by
all physicians in the database were prescribed a
retinoid. Dermatologists saw 84.5% of all acne
patients, for which 58.8% were prescribed a retinoid.
Nondermatologists saw 15.5% of acne patients, for
which 32.4% were prescribed a retinoid (Table I).
Table I. Retinoid prescription percentages by
specialty, 2012-2014
Total Retinoids Percentage
Patients with acne, total 87,970 48,139 54.7%
Patients with acne seen by 74,371 43,729 58.8%
dermatologist
Patients with acne seen by 13,599 4410 32.4%
nondermatologist
J AM ACAD DERMATOL Letters 1253
VOLUME 74, NUMBER 6

Fig 1. Using data from the Humana database, the age and gender distribution of acne patients
who were prescribed a retinoid was determined. Dermatologists treated a substantially higher
percentage of acne patients with retinoids than other physicians did regardless of age or gender
of the patient. These findings suggest that more has to be done to encourage non-
dermatologists to adhere to acne treatment guidelines.

The age and gender distribution of all acne patients Sandra Pena, BA,a Dane Hill, MD,a and Steven R.
on retinoids for acne management was determined Feldman, MD, PhDa,b,c
(Fig 1). Dermatologists treated a substantially higher
Center for Dermatology Research, Department
percentage of patients with retinoids than other
of Dermatology,a Department of Pathology,b
physicians did across all age groups.
Department of Public Health Sciences,c Wake
Acne constitutes a substantial burden on the
Forest School of Medicine, Winston-Salem, NC
healthcare system, equaling about $3 billion per
year in the cost of treatment and loss of productivity, Funding source: None.
and $12 billion in intangible costs due to quality of
Conflict of interest: The Center for Dermatology
life impact.4 Retinoids are considered the corner-
Research is supported by an unrestricted educa-
stone of acne management. Physicians, however, still
tional grant from Galderma Laboratories, L.P. Dr
significantly underprescribe retinoids, particularly
Feldman is a speaker for Janssen and Taro. He is
nondermatologists.5
a consultant and speaker for Galderma, Stiefel/
There are several limitations to our study,
GlaxoSmithKline, Abbott Labs, and Leo Pharma
typical of a claims-based study. We used ICD-9
Inc. Dr Feldman has received grants from
claims in the patients’ history to diagnose acne.
Galderma, Janssen, Abbott Labs, Amgen, Stiefel/
Our study and data are subject to coding errors. We
GlaxoSmithKline, Celgene, and Anacor. He is a
were unable to determine the reasons for the
consultant for Amgen, Baxter, Caremark, Gerson
differences in the prescribing patterns, including
Lehrman Group, Guidepoint Global, Hanall
severity of acne, failed treatments, insurance
Pharmaceutical Co Ltd, Kikaku, Lilly, Merck &
coverage, or cost.
Co Inc, Merz Pharmaceuticals, Mylan, Novartis
The prevalence of retinoids in the management of
Pharmaceuticals, Pfizer Inc, Qurient, Suncare
acne has been increasing, but continues to fall short
Research, and Xenoport. He is on an advisory
of the mark.3 Increased education about treatment
board for Pfizer Inc. Dr Feldman is the founder
guidelines and medication side effects may help
and holds stock in Causa Research and holds
physicians, particularly nondermatologists, feel
stock and is majority owner in Medical Quality
more comfortable using retinoids in the manage-
Enhancement Corporation. He receives royalties
ment of acne.
1254 Letters J AM ACAD DERMATOL
JUNE 2016

from UpToDate and Xlibris. Dr Hill’s transla-
tional research is funded by Janssen Pharma-
ceuticals. Sandra Pena has no conflict of interest
to declare.
This study was declared exempt by the Wake Forest
School of Medicine Institutional Review Board.
Correspondence to: Steven R. Feldman, MD, PhD,
Department of Dermatology, Wake Forest School
of Medicine, Medical Center Blvd, Winston-
Salem, NC 27157-1071
E-mail: sfeldman@wakehealth.edu
REFERENCES
1. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J
Dermatol. 2013;168(3):474-485.
2. Eichenfield LF, Krakowski AC, Piggott C, et al. American Acne
and Rosacea Society. Evidence-based recommendations for
the diagnosis and treatment of pediatric acne. Pediatrics. 2013;
131(Suppl 3):S163-S186.
3. 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(5Suppl):S1-S50.
4. Bickers DR, Lim HW, Margolis D, et al. American Academy
of Dermatology Association; Society for Investigative
Dermatology. The burden of skin diseases: 2004 a joint project
of the American Academy of Dermatology Association and the
Society for Investigative Dermatology. J Am Acad Dermatol.
2006;55(3):490-500.
5. Balkrishnan R, Fleischer AB Jr, Paruthi S, Feldman SR. Physi-
cians underutilize topical retinoids in the management of acne
vulgaris: analysis of U.S. National Practice Data. J Dermatolog
Treat. 2003;14(3):172-176.
http://dx.doi.org/10.1016/j.jaad.2016.01.011
Thrombophilic status may predict
prognosis in patients with metastatic
BRAFV600-mutated melanoma who are
receiving BRAF inhibitors
To the Editor: Coagulation and cancer are strictly
linked. There is increasing evidence that the
activation of the coagulation cascade correlates
with prognosis in preclinical models.1 Melanoma
cells are able to change the thrombophilic status (TS)
of endothelial cells and microenvironment,2,3
and contribute to angiogenesis and metastatic
progression through their proteolytic properties.4
We investigated the TS and hemostatic variables in
patients with BRAFV600-mutated melanoma (MPs)
with the hypothesis that circulating TS could
correlate with the extension of disease and predict
clinical response and outcome in metastatic MPs
who were receiving BRAF inhibitors (BRAFis). Two
cohorts of MPs consecutively observed from
November 2011 to August 2014 at the Division of
Oncology, Hospital Papa Giovanni XXIII, in
Bergamo, Italy were enrolled in the study. The
main cohort included 43 MPs who were prospec-
tively diagnosed with locally advanced or metastatic
melanoma and who were treated with BRAFis. The
second cohort included 37 MPs with stage I to III
melanoma. Forty healthy subjects (20 men and
20 women) were included as reference group for
coagulation biomarker studies. All investigations
were approved by the local ethical committee
(Comitato di Bioetica, Hospital Papa Giovanni
XXIII, Bergamo), and all study subjects gave
informed written consent to the study. The routine
hematologic assays, coagulation biomarker studies,
and immunohistochemical analyses used for
assessment of these melanoma tissues can be viewed
in Supplemental Table IS and Fig 1S (available online
at http://www.jaad.org).
Levels of D-dimer in the group of MPs were
significantly (P \ .01) higher compared to healthy
subjects. By using a logistic model, patients with
higher D-dimer levels at enrollment into the study
had a significantly lower probability to achieve an
objective response (Table I).
Using multivariate analysis and after adjusting
for age, sex, and tumor stage, high baseline levels of

Table I. Logistic model: objective response according to the circulating thrombophilic status in patients with
BRAV600 melanoma receiving BRAF inhibitors
Variables OR 95% CI P value
ETP HEPES ( for 500 increase) 1.547 0.791-3.025 .2025
Peak HEPES ( for 50 increase) 1.991 0.982-4.037 .0562
ETP 1 pmol/L TF ( for 500 increase) 0.891 0.373-2.127 .7954
Peak 1 pmol/L TF ( for 50 increase) 0.860 0.610-1.211 .3868
ETP 5 pmol/L TF ( for 500 increase) 0.821 0.356-1.894 .6437
Peak 5 pmol/L TF ( for 50 increase) 0.738 0.471-1.155 .1838
Platelets ( for 10 increase) 1.045 0.935-1.167 .4378
D-dimer ( for 10 increase) 0.946 0.911-0.982 .0037
PPL ( for 10 increase) 0.500 0.259-0.966 .0390

CI, Confidence interval; ETP, endogenous thrombin potential; OR, odds ratio; PPL, endogenous plasma phospholipids; TF, tissue factor.