Research

JAMA Dermatology | Brief Report

Efficacy and Tolerance of AntiTumor Necrosis Factor

Agents in Cutaneous Sarcoidosis
A French Study of 46 Cases
Valentine Heidelberger, MD; Saskia Ingen-Housz-Oro, MD; Alicia Marquet, MD; Matthieu Mahevas, MD, PhD; Didier Bessis, MD, PhD;
Laurence Bouillet, MD, PhD; Frdric Caux, MD, PhD; Catherine Chapelon-Abric, MD; Sbastien Debarbieux, MD; Emmanuel Delaporte, MD;
Anne-Bndicte Duval-Modeste, MD; Olivier Fain, MD, PhD; Pascal Joly, MD, PhD; Sylvain Marchand-Adam, MD, PhD; Jean-Benot Monfort, MD;
Nicolas Nol, MD, PhD; Thierry Passeron, MD, PhD; Marc Ruivard, MD, PhD; Franoise Sarrot-Reynauld, MD; Denis Verrot, MD; Diane Bouvry, MD;
Laurence Fardet, MD, PhD; Olivier Chosidow, MD, PhD; Pascal Sve, MD, PhD; Dominique Valeyre, MD, PhD

IMPORTANCE Evidence for the long-term efficacy and safety of antitumor necrosis factor
agents (anti-TNF) in treating cutaneous sarcoidosis is lacking.

OBJECTIVE To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis
in a large observational study.

DESIGN, SETTING, AND PARTICIPANTS STAT (Sarcoidosis Treated with Anti-TNF) is a French
retrospective and prospective multicenter observational database that receives data from
teaching hospitals and referral centers, as well as several pneumology, dermatology, and
internal medicine departments. Included patients had histologically proven sarcoidosis and
received anti-TNF between January 2004 and January 2016. We extracted data for patients
with skin involvement at anti-TNF initiation.

MAIN OUTCOMES AND MEASURES Response to treatment was evaluated for skin and visceral
involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score
(from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous
features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall
cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0
or 1) or partial response (ePOST drop 2 points from baseline but >1 at last follow-up).

RESULTS Among 140 patients in the STAT database, 46 had skin involvement. The most
frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median
cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for
skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF
were failure or adverse effects of previous therapy in 42 patients (93%). Most patients
received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and
immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103)
months. Of the 46 patients with sarcoidosis and skin involvement who were treated with
anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were
women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months.
Steroid sparing was significant. Treatment was discontinued because of adverse events in 11
patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more
frequent in patients treated for visceral involvement than in those treated for skin
involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate
was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred
in 35% of cases, mostly during anti-TNF or concomitant treatment tapering.
Author Affiliations: Author
CONCLUSIONS AND RELEVANCE Anti-TNF agents are effective but suspensive in cutaneous affiliations are listed at the end of this
sarcoidosis. The risk of infectious events must be considered. article.
Corresponding Author: Saskia
Ingen-Housz-Oro, MD, Dermatology,
AP-HP Hpital Henri Mondor, 51
avenue du Marchal de Lattre
JAMA Dermatol. doi:10.1001/jamadermatol.2017.1162 de Tassigny, 94010 Crteil, France
Published online May 31, 2017. (saskia.oro@aphp.fr).

(Reprinted) E1
2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 05/31/2017

 Research Brief Report
T
he management of skin sarcoidosis is still based on small
trials and case series, mainly because therapeutic strat-
egy depends on visceral prognosis. Limited skin le-
sions are generally treated with topical steroids, tetracycline
antibiotics, or hydroxychloroquine,1 despite a low level of evi-
dence for efficacy. In case of failure or extensive and/or stig-
matizing lesions, such as lupus pernio, systemic steroids (SS)
and/or immunosuppressive agents (IS) have been shown to
be useful.2 Thalidomide is also considered in some patients,
despite a negative trial and potential adverse effects.3
High-quality trials demonstrating efficacy of antitumor
necrosis factor agents (anti-TNF) for the treatment of
severe skin sarcoidosis are few. We investigated the efficacy
and tolerance of anti-TNF in 46 patients.
Methods
STAT (Sarcoidosis Treated with Anti-TNF) is a French na-
tional voluntary retrospective and prospective database
investigating the efficacy and safety of anti-TNF in sarcoid-
osis. Inclusion criteria in STAT were as follows: diagnosis of
histologically proven sarcoidosis made in accordance with the
guidelines of the World Association of Sarcoidosis and Other
Granulomatous diseases,4 age older than 18 years, and cur-
rent or previous treatment with anti-TNF. The initiation of anti-
TNF therapy in each participating center was decided by the
referral physician, according to real-life standard practice.
Patients provided written consent for inclusion, and physi-
cians collected the following data: demographics, character-
istics of the disease at baseline (ie, initiation of anti-TNF), pre-
vious treatments, concomitant SS or IS, and adverse events
(AEs). The severity scoring for each organ (including skin) used
the ePOST (extra-pulmonary Physician Organ Severity Tool)
ranging from 0 (not affected) to 6 (very severe involvement).5
All patients with skin involvement at baseline were in-
cluded in the present study. The primary end point was the
overall cutaneous response rate (OCRR) to anti-TNF at 3, 6, and
12 months; complete response was defined as a cutaneous
ePOST score 0 or 1 and partial response was defined as a
decrease or 2 or more points from baseline. Secondary objec-
tives included AEs, steroid sparing, and relapses.
Categorical variables were compared using the 2 test and
continuousvariableswerecomparedusingtheWilcoxonranksum
test. We first assessed efficacy and safety in the whole cohort and
then compared patients with a skin-only indication for anti-TNF
(Group 1) and patients treated for visceral involvement (Group 2).
The response rates and infections, according to the duration of
exposure, were described by Kaplan-Meier analysis. Univariate
analyses of the predictor of response and infection were con-
ducted using the log-rank test. All tests were 2-sided, and a P value
less than .05 was considered significant. Analyses were performed
using R statistical software, version 3.2.2 (R Foundation) for 2
analyses and Stata 14.0 (StataCorp LLC) for log-rank analyses.
In France, observational studies that do not change rou-
tine patient management do not require ethics committee or
institutional review board approval; all patients included in the
STAT database provided informed consent.
E2 JAMA Dermatology Published online May 31, 2017 (Reprinted)
2017 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 05/31/2017
Efficacy and Tolerance of Anti-TNF Agents in Cutaneous Sarcoidosis
Key Points
Question What is the long-term efficacy and safety of
antitumor necrosis factor agents (anti-TNF) in treating
cutaneous sarcoidosis?
Findings In this multicenter observational study of 46 patients
with sarcoidosis and skin involvement who were treated with
anti-TNF, the overall cutaneous response rate was 24% after
3 months, 46% after 6 months, and 79% after 12 months. Eleven
(24%) patients stopped anti-TNF because of adverse events, and
patients treated for visceral involvement had significantly more
infections (48% vs 9.5%), and relapses occurred in half of the
patients after discontinuation of anti-TNF.
Meaning Anti-TNF agents are effective against cutaneous
sarcoidosis with a low infectious rate in patients treated for
skin involvement.
Results
Forty-six patients of 140 included in the STAT database had
skin lesions (Table). A total of 66 individual courses of anti-
TNF were administrated (14 patients received more than 1
course). Anti-TNF were administered with SS (mean dose of
prednisone of 17.5 mg/d) in 28 cases (61%) and IS (methotrex-
ate n = 26) in 32 cases (69.5%). Group 1 consisted of 21
patients; Group 2, 25 patients. The median (range) follow-up
was 45 (3-109) months.
Overall cutaneous response rate is presented in Figure 1,
and Figure 2 shows an example of a complete cutaneous
response. The mean dose of SS decreased from 17.5 mg/d at
baseline to 8.4 mg/d at the last follow-up (P < .001).
In univariate analysis, OCRR was associated with nod-
ules but not with other lesions (lupus pernio, plaques), age,
sex, or duration of the disease.
Fourteen patients (30%) experienced 21 infectious AEs:
urinary tract infections (n = 6), bronchopneumonitis (n = 7),
sinusitis (n = 2), dental abscess, cellulitis, angiocholitis,
herpes zoster, flu, and gastroenteritis (n = 1 for each). Seven
patients (50%) were hospitalized for infection (grade 3/4):
pneumonitis (n = 3), urinary tract infection, herpes zoster,
facial cellulitis, and angiocholitis (n = 1 for each). Treatment
was discontinued in 4 patients (3 for pneumonitis and 1 for
facial cellulitis) and a patient in his 80s treated with concomi-
tant prednisone of 40 mg/d and azathioprine died of pneu-
monitis. Thirteen of 14 patients who experienced infections
were patient receiving SS and/or IS.
Sixteen patients with response stopped treatment (10
for AE; 6 for remission); 8 of these patients relapsed with a
relapse rate of 20% at 1 year and 44% at 18 months. Treat-
ment was resumed for 5 patients who had achieved previous
remission with a response rate of 100%. Ten patients stopped
first-line anti-TNF because of failure. Five patients received a
second anti-TNF with efficacy in 3 cases.
Among 31 patients who responded to anti-TNF, 11 pa-
tients (35%) relapsed during treatment. Relapse occurred for
8 patients during dose spacing or reduction of anti-TNF (n = 3)
jamadermatology.com
 Efficacy and Tolerance of Anti-TNF Agents in Cutaneous Sarcoidosis Brief Report Research

Table. Characteristics of the 46 Patients at Baseline Figure 1. Cutaneous Response to AntiTumor Necrosis Factor Agents

Characteristic No. (%)

1.00
Age, median (range), y 50 (14-78)
Women, No. (%) 33 (72)
Disease duration, median (range), y 10 (1.3-33) 0.75

Geographical origin, No. (%)

Response Rate
Caucasian 14 (30) 0.50
Northern African 14 (30)
Caribbean 9 (20)
0.25
African 6 (13)
Organs involved, No. (%)
Skin 46 (100) 0
Lungs 0 3 6 9 12 15 18 21 24
Asymptomatic 28 (61) Time of Exposure, mo
No. at risk 46 45 32 20 17 5 3
Symptomatic 8 (20)
Joints 14 (30)
The overall cutaneous response rate was 24% (95% CI, 14%-40%) after 3 months,
Ear, nose, and throat 13 (28) 46% (95% CI, 32%-62%) after 6 months, and 79% (95% CI, 64%-98%) after
Heart 8 (20) 12 months. Median ePOST severity score decreased from 5 at baseline to 3 at the
Central nervous system 7 (17) last follow-up. Among a total of 31 responders, 13 achieved complete response and
18 achieved partial response as best response during follow-up.
Liver 7 (17)
Eye 5 (11)
By comparing groups, cutaneous ePOST scores at base-
Organs involved, median (range) 3 (1-8)
line were higher in Group 1 (5 vs 3; P < .001). Patients were
Type of cutaneous lesions
treated with more concomitant SS (18 [76%] vs 7 [33%];
Lupus pernio 21 (46)
P = .003) and IS (21 [84%] vs 11 [53%]; P = .02) in Group 2, but
Nodules (small and large) 20 (43)
OCRR was not different (13 [62%] in Group 1 and 19 [72%] in
Plaques 11 (24)
Group 2; P = .67). Infections were more frequent in Group 2:
Subcutaneous lesions 3 (6)
12 of 25 patients (48%) vs 2 of 21 patients (9.5%) (P = .02). In
Alopecia 3 (6)
univariate analysis, age, sex, SS before baseline, associated IS,
Localization, No. (%)
or associated SS were not associated with infections.
Face and neck 33 (69)
Trunk and limbs 22 (48)
Cutaneous ePOST, median (range) 5 (1-6)
Previous treatment, No.(%) Discussion
Methotrexate 39 (85)
This large multicenter observational study showed that:
Prednisone 35 (76)
(1) anti-TNF agents were effective in treating cutaneous sar-
Hydroxychloroquine 27 (59)
Azathioprine 14 (30)
coidosis with an OCRR of 46% at 6 months and 79% at 12
Thalidomide 10 (22)
months after the initiation of treatment; (2) anti-TNF had a
Tetracycline 7 (15)
significant steroid-sparing effect; (3) in total, 11 patients (24%),
Other 18 (39)
among whom one died, had to stop anti-TNF due to AEs (5
Prior immunosuppressive agents, median (range) 1.7 (0-4)
being infectious); (4) 14 of 46 patients (30%) experienced
Main indication for anti-TNF, No. (%) infections of varying severity, especially patients from Group
Severe disease 38 (83) 2 compared with Group 1 (n = 12 of 25 [48%] vs n = 2 of 21
Previous treatment failure 42 (93) [9.5%], respectively); (5) relapses occurred in almost half of
Previous adverse effects 23 (50) the patients after discontinuation, but all patients in whom anti-
Steroid-dependent disease 11 (24) TNF was discontinued because of remission achieved remis-
Type of anti-TNF used as first line, No. (%) sion again upon resuming anti-TNF.
Infliximab (various regimen) 40 (87) In our study, we showed similar OCRR as previous
Adalimumab 5 (11) studies. 6-10 Response was rather slow. In the literature,
Etanercept 1 (2) infliximab and adalimumab are the most effective anti-TNF
in sarcoidosis, but questions remain regarding dose and du-
Abbreviation: anti-TNF, antitumor necrosis factor agents.
ration of therapy. In our series, anti-TNF had a suspensive
effect. Expert consensus on the use of anti-TNF for the treat-
or tapering of the concomitant SS (n = 3) or IS (n = 2). The out- ment of sarcoidosis has recommended gradually prolonging
come was favorable for 8 patients upon resumption of the prior the interval between injections before discontinuing anti-
treatment, shortening of the dosing interval, and/or increas- TNF to limit the risk of relapses.11
ing the dose of steroids. Anti-TNF was definitively discontin- We found more infections in patients of Group 2, who
ued in the other 3 patients. received more SS and IS.

jamadermatology.com (Reprinted) JAMA Dermatology Published online May 31, 2017 E3

2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 05/31/2017

 Research Brief Report Efficacy and Tolerance of Anti-TNF Agents in Cutaneous Sarcoidosis

Figure 2. Response to Infliximab

A Pretreatment B Posttreatment

Clinical photographs of a patient with

large subcutaneous nodules of the
fingers show complete response to
infliximab.

There is little consensus in the literature on the
increased risk of infection with anti-TNF treatment when
used in combination with SS and/or IS vs monotherapy.
Similar rates of infection were observed in the treatment of
inflammatory bowel diseases in randomized clinical trials12
and reports to the US Food and Drug Administration,13 but a
clear increased risk of infection with combination therapy
has been described in observational studies.14,15
Limitations
Limitations were the volunteer inclusion in STAT, heteroge-
neous severity of cases, and unknown reproducibility
of ePOST for skin lesions. However, the ePOST score
was the simplest tool to evaluate severity and response
in all organs. Adverse effects could have been
underreported.
Conclusions
Anti-TNF agents are effective in cutaneous sarcoidosis, but
relapses are frequent after discontinuation. Clinicians must
be aware of infections, especially if patients are being treated
with concomitant SS or IS.

ARTICLE INFORMATION
Accepted for Publication: March 18, 2017.
Published Online: May 31, 2017.
doi:10.1001/jamadermatol.2017.1162
Author Affiliations: Department of Dermatology,
AP-HP Hpital Henri Mondor, Crteil, France
(Heidelberger, Ingen-Housz-Oro, Fardet,
Chosidow); Department of Dermatology,
EA 7379 EpiDermE, Universit Paris Est, Crteil,
France (Ingen-Housz-Oro, Fardet, Chosidow);
Department of Internal Medicine, Hpital
de la Croix-Rousse, Lyon, France (Marquet, Sve);
Department of Internal Medicine, APHP Hpital
Henri Mondor, Crteil, France (Mahevas);
Department of Dermatology, Hpital Saint-Eloi,
Montpellier, France (Bessis); Department of Internal
Medicine, Centre hospitalier universitaire
de Grenoble-Alpes, Grenoble, France (Bouillet,
Sarrot-Reynauld); Department of Dermatology,
APHP Hpital Avicenne, Bobigny, France (Caux);
Department of Internal Medicine, APHP Hpital
de la Piti-Salptrire, Paris, France
(Chapelon-Abric); Department of Dermatology,
Centre hospitalier Lyon-Sud, Lyon, France
(Debarbieux); Department of Dermatology, Hpital
Claude Huriez, Lille, France (Delaporte);
Department of Dermatology, Hpital Charles
Nicolle, Rouen, France (Duval-Modeste, Joly);
Department of Internal Medicine, APHP Hpital
Saint-Antoine, Paris, France (Fain); Department of
Pneumology, Hpital Bretonneau, Tours, France
(Marchand-Adam); Department of Dermatology,
APHP Hpital Tenon, Paris, France (Monfort);
Department of Internal Medicine, APHP Hpital
Bictre Le Kremlin-Bictre, France (Nol);
Department of Dermatology, Hpital de lArchet,
Nice, France (Passeron); Department of Internal
Medicine, Hpital Estaing, Clermont-Ferrand,
France (Ruivard); Department of Internal Medicine,
Hpital Saint-Joseph, Marseille, France (Verrot);
Department of Pneumology, APHP Hpital
Avicenne, Bobigny, France (Bouvry, Valeyre);
Department of Dermatology, Universit Paris Est
UPEC, Crteil, France (Fardet, Chosidow).
Author Contributions: Drs Heidelberger and
Ingen-Housz-Oro had full access to all data in the
study and take responsibility for its integrity and
the accuracy of the data analysis. Drs Chosidow,
Sve, and Valeyre contributed equally.
Study concept and design: Heidelberger,
Ingen-Housz-Oro, Mahevas, Fain, Monfort,
Fardet, Sve, Valeyre.
Acquisition, analysis, or interpretation of data:
Heidelberger, Ingen-Housz-Oro, Marquet, Bessis,
Bouillet, Caux, Chapelon-Abric, Debarbieux,
Delaporte, Duval-Modeste, Joly, Marchand-Adam,
Nol, Passeron, Ruivard, Sarrot-Reynauld, Verrot,
Bouvry, Fardet, Chosidow, Sve, Valeyre. A randomized, investigator-masked, double-blind,
Drafting of the manuscript: Heidelberger,
Ingen-Housz-Oro, Marquet, Duval-Modeste,
Monfort, Verrot, Bouvry.
Critical revision of the manuscript for important
intellectual content: Mahevas, Bessis, Bouillet, Caux,
Chapelon-Abric, Debarbieux, Delaporte, Fain, Joly,
Marchand-Adam, Nol, Passeron, Ruivard,
Sarrot-Reynauld, Fardet, Chosidow, Sve, Valeyre.
Statistical analysis: Heidelberger, Fardet.
Obtained funding: Monfort.
Administrative, technical, or material support: Verrot.
Study supervision: Bessis, Bouillet, Chapelon-Abric,
Fain, Chosidow, Sve, Valeyre.
Conflict of Interest Disclosures: Dr Chosidow is
the primary investigator of the prospective French
cohort Psobioteq evaluating efficacy and tolerance
of systemic agents in real-life psoriasis patients. The
study is supported by both public and private
research grants; the private grants are from Abbvie,
Pfizer, Janssen, and MSD and are managed by the
French Society of Dermatology, which is one of the
sponsors. No other conflicts are reported.
Additional Information: Denis Verrot, MD, died
before the publication of this article.
REFERENCES
1. Jones E, Callen JP. Hydroxychloroquine is
effective therapy for control of cutaneous sarcoidal
granulomas. J Am Acad Dermatol. 1990;23(3 Pt 1):
487-489.
2. Baughman RP, Lower EE. Evidence-based
therapy for cutaneous sarcoidosis. Clin Dermatol.
2007;25(3):334-340.
3. Droitcourt C, Rybojad M, Porcher R, et al.
placebo-controlled trial on thalidomide in severe
cutaneous sarcoidosis. Chest. 2014;146(4):1046-
1054.
4. Hunninghake GW, Costabel U, Ando M, et al.
ATS/ERS/WASOG statement on sarcoidosis.
American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and other
Granulomatous Disorders. Sarcoidosis Vasc Diffuse
Lung Dis. 1999;16(2):149-173.
5. Judson MA, Baughman RP, Costabel U, et al;
Centocor T48 Sarcoidosis Investigators. Efficacy of

E4 JAMA Dermatology Published online May 31, 2017 (Reprinted) jamadermatology.com

2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 05/31/2017

 Efficacy and Tolerance of Anti-TNF Agents in Cutaneous Sarcoidosis Brief Report Research

infliximab in extrapulmonary sarcoidosis: results
from a randomised trial. Eur Respir J. 2008;31(6):
1189-1196.
6. Pariser RJ, Paul J, Hirano S, Torosky C, Smith M.
A double-blind, randomized, placebo-controlled
trial of adalimumab in the treatment of cutaneous
sarcoidosis. J Am Acad Dermatol. 2013;68(5):765-
773.
7. Baughman RP, Judson MA, Lower EE, et al;
Sarcoidosis Investigators. Infliximab for chronic
cutaneous sarcoidosis: a subset analysis from a
double-blind randomized clinical trial. Sarcoidosis
Vasc Diffuse Lung Dis. 2016;32(4):289-295.
8. Stagaki E, Mountford WK, Lackland DT, Judson
MA. The treatment of lupus pernio: results of 116
treatment courses in 54 patients. Chest. 2009;135
(2):468-476.
9. Sen T, Juillard C, Rybojad M, et al. Infliximab as
a steroid-sparing agent in refractory cutaneous
sarcoidosis: single-center retrospective study of 9
patients. J Am Acad Dermatol. 2012;66(2):328-332.
10. Russell E, Luk F, Manocha S, Ho T, OConnor C,
Hussain H. Long term follow-up of infliximab
efficacy in pulmonary and extra-pulmonary
sarcoidosis refractory to conventional therapy.
Semin Arthritis Rheum. 2013;43(1):119-124.
11. Drent M, Cremers JP, Jansen TL, Baughman RP.
Practical eminence and experience-based
recommendations for use of TNF- inhibitors in
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;
31(2):91-107.
12. Jones JL, Kaplan GG, Peyrin-Biroulet L, et al.
Effects of concomitant immunomodulator therapy
on efficacy and safety of anti-tumor necrosis factor
therapy for Crohns disease: a meta-analysis of
placebo-controlled trials. Clin Gastroenterol Hepatol.
2015;13(13):2233-2240.e1-2;quiz e177-178.
13. Deepak P, Stobaugh DJ, Ehrenpreis ED.
Infectious complications of TNF- inhibitor
monotherapy versus combination therapy with
immunomodulators in inflammatory bowel disease:
analysis of the Food and Drug Administration
Adverse Event Reporting System. J Gastrointestin
Liver Dis. 2013;22(3):269-276.
14. Toruner M, Loftus EV Jr, Harmsen WS, et al.
Risk factors for opportunistic infections in patients
with inflammatory bowel disease. Gastroenterology.
2008;134(4):929-936.
15. Fidder H, Schnitzler F, Ferrante M, et al.
Long-term safety of infliximab for the treatment of
inflammatory bowel disease: a single-centre cohort
study. Gut. 2009;58(4):501-508.

jamadermatology.com (Reprinted) JAMA Dermatology Published online May 31, 2017 E5

2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 05/31/2017