Research

Original Investigation

Oral Antimycobacterial Therapy in Chronic

Cutaneous Sarcoidosis
A Randomized, Single-Masked, Placebo-Controlled Study
Wonder P. Drake, MD; Kyra Oswald-Richter, PhD; Bradley W. Richmond, MD; Joan Isom, LPN;
Victoria E. Burke, MD; Holly Algood, PhD; Nicole Braun, PhD; Thyneice Taylor, PhD; Kusum V. Pandit, PhD;
Caroline Aboud, BS; Chang Yu, PhD; Naftali Kaminski, MD; Alan S. Boyd, MD; Lloyd E. King, MD, PhD

IMPORTANCE Sarcoidosis is a chronic granulomatous disease for which there are limited
therapeutic options. This is the first randomized, placebo-controlled study to demonstrate
that antimycobacterial therapy reduces lesion diameter and disease severity among patients
with chronic cutaneous sarcoidosis.
OBJECTIVE To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the
resolution of chronic cutaneous sarcoidosis lesions.
DESIGN AND PARTICIPANTS A randomized, placebo-controlled, single-masked trial on 30
patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require
therapeutic intervention.
SETTING A tertiary referral dermatology center in Nashville, Tennessee.
INTERVENTIONS Participants were randomized to receive either the oral concomitant

levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative

placebo regimen for 8 weeks with a 180-day follow-up.
MAIN OUTCOMES AND MEASURES Participants were monitored for absolute change in lesion
diameter and decrease in granuloma burden, if present, on completion of therapy.
OBSERVATIONS In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD)
decrease in lesion diameter of 8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in
the placebo-treated group (P = .05). The CLEAR group had a significant reduction in
granuloma burden and experienced a mean (SD) decline of 2.9 (2.5) mm in lesion severity
compared with a decline of 0.6 (2.1) mm in the placebo group (P = .02).
CONCLUSIONS AND RELEVANCE Antimycobacterial therapy may result in significant
reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These
observed reductions, associated with a clinically significant improvement in symptoms, were
present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells
revealed reversal of pathways associated with disease severity and enhanced T-cell function
following T-cell receptor stimulation.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01074554

Author Affiliations: Author

affiliations are listed at the end of this
article.

JAMA Dermatol. 2013;149(9):1040-1049. doi:10.1001/jamadermatol.2013.4646

Published online July 17, 2013.
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Corresponding Author: Wonder P.

Drake, MD, Division of Infectious
Diseases, Department of Medicine,
Vanderbilt University School of
Medicine, 21st Ave S, Medical Center
North, Room A-3314, Nashville, TN
37232 (wonder.drake@vanderbilt
.edu).
jamadermatology.com

Antimycobacterial Therapy in Sarcoidosis

utaneous sarcoidosis is one of the most common extrapulmonary manifestations of pulmonary sarcoidosis in the United States. It is difficult to treat.1 Current
treatment algorithms for cutaneous sarcoidosis support the
use of corticosteroids, tumor necrosis factor inhibitors, antimalarials, and antimetabolites.2-4 Despite universal acceptance as standard care, the aforementioned treatments often
result in an incomplete clinical response or unacceptable adverse events. In such situations, more innovative treatment
options may be investigated.5 A growing body of literature supports the immunomodulatory effects of antimicrobial therapy,
such as quinolones increasing interleukin 2 (IL-2) production
in monocytes and macrolides decreasing neutrophil
chemotaxis.6 Case reports show improvement of cutaneous sarcoidosis lesions with antibiotic therapy, such as tetracyclines.7,8
Numerous agents have been attributed to sarcoidosis
pathogenesis, such as serum amyloid A, proprionibacteria, and
mycobacteria.9-13 Because of the possible association between sarcoidosis and mycobacterial antigens, we postulated
that broad-spectrum antimycobacterial therapy could lead to
clinical improvement of chronic cutaneous sarcoidosis lesions through immunomodulation of T-cell function. Independent molecular and immunologic investigations strengthen
the association between mycobacterial antigens and sarcoidosis pathogenesis. Molecular analysis of sarcoidosis granulomas reveals the presence of mycobacterial DNA and proteins
that are significantly absent from granulomatous controls.14-16
Mycobacterial DNA has been detected in cutaneous sarcoidosis lesions,17 in addition to systemic immune responses against
mycobacterial antigens.18-20 We investigated the safety and efficacy of concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) therapy among patients with chronic
cutaneous sarcoidosis, with a change in lesion diameter from
baseline to completion of 8 weeks of therapy as the primary
end point; we assessed for decreases in granuloma burden, if
granulomas were evident on histologic examination. Change
in the modified Sarcoidosis Activity Severity Index (SASI) was
the secondary end point.

Methods
Protocol
This study was a randomized, single-masked, placebocontrolled trial of the effectiveness of adding antimycobacterial therapy or placebo to a standard regimen among patients
with chronic cutaneous sarcoidosis. Patients with cutaneous
sarcoidosis were enrolled, regardless of whether they had received therapy, if they were 18 years or older and had clinically active chronic lesions. Patients with clinically active sarcoidosis had active disease, as evidenced by expansion of the
existing lesion, progressive induration, erythema, or desquamation of the existing lesion or the development of new lesions in previously uninvolved areas. Sarcoidosis was defined according to the statement by the American Thoracic
Society, European Respiratory Society, and World Association for Sarcoidosis and Other Granulomatous Disorders.21 Volunteers were ineligible if they were allergic to or had potenjamadermatology.com

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Original Investigation Research

tial interactions with one of the antibiotics in the CLEAR

regimen or had had a change in their immunosuppressive regimen within the past 3 months. The inclusion and exclusion criteria are provided in the clinicaltrials.gov registration of the
study (http://clinicaltrials.gov/ct2/show/NCT01074554). The
study protocol was approved by the institutional review board
at the Vanderbilt University Human Research Protection Program. Declaration of Helsinki protocols were followed, and all
patients provided written informed consent before enrolling
in the study. Participants completed 3 study visits. At baseline, the index lesion was originally selected by the lead dermatologist (L.E.K.) and confirmed by the patient that this lesion had been identified by his or her private dermatologist as
cutaneous sarcoidosis. The index lesion was biopsied immediately at study enrollment and again following completion of
the 8-week regimen. Direct measurement in a region unaffected by biopsy and photography of the lesion were obtained at baseline and at 4 and 8 weeks, before each biopsy.
Characterization of lesion severity was conducted independently by 2 authors (L.E.K. and W.P.D.) using the modified SASI,
measuring erythema, induration, and desquamation at baseline and at 4 and 8 weeks.22 The modification was that the same
scale was applied to any part of the body, instead of the face
alone, as originally described.22 At weeks 4 and 8, participants had complete blood count and complete metabolic profile tests to assess for toxicity and were interviewed regarding adverse events, medication diary review, and pill count to
determine compliance with the regimen. The participants were
followed up for 180 days from baseline. Histologic analysis of
the biopsy specimens for granulomas was conducted by the
lead pathologist (A.S.B.). All investigators (A.S.B., L.E.K., and
W.P.D.) were masked to the treatment arm. All data were collected at Vanderbilt University Medical Center.
Enrolled participants were randomized in a 1:1 ratio by the
biostatistician (C.Y.) to receive either placebo or 8 weeks of oral
antimycobacterial therapy, in addition to their standard
therapy. The treatment assignment and individual subject identification number were assigned at the time of enrollment via
a computer-generated randomization process. Medications
were dispensed by the Vanderbilt Investigation Drug Pharmacy. Antibiotic dosages were based on guidelines from the
American Thoracic Society and Infectious Diseases Society of
America23 for the treatment of atypical mycobacterial infection. The 8-week regimen consisted of levofloxacin,750 mg on
day 1, followed by 500 mg/d; ethambutol, 25 mg/kg/d up to a
maximum dosage of 1200 mg/d; azithromycin, 500 mg on day
1, followed by 250 mg/d; and rifampin, 10 mg/kg/d up to a maximum dosage of 300 mg/d. The placebo regimen consisted of
riboflavin (in place of rifampin) and lactose (in place of the other
3 drugs). Treatment with study drugs was stopped upon reaching one of the following conditions: drug toxicity, pill burden, failure to maintain study visits, or completion of the
8-week regimen.

Outcomes
The primary outcome was change in lesion diameter after the
completion of therapy as a continuous end point. If there was
evidence of granuloma formation on histologic examination,
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Antimycobacterial Therapy in Sarcoidosis

Table 1. Baseline Characteristics of the Cutaneous Sarcoidosis Study Population

Characteristic

Total
(N = 29)

CLEAR
(n = 14)

Placebo
(n = 15)

Age, y
Mean

51

50

52

Median (IQR)

53 (42-58)

55 (41-60)

53 (42-57)

Range

23-72

23-63

35-72

Sex, No. (%)

Male

10 (34)

5(36)

5 (33)

Female

19 (66)

9 (64)

10 (67)

Race, No. (%)

White

18 (62)

9 (64)

9 (60)

African American

11 (38)

5 (36)

6 (40)

Years since histologic diagnosis

(N = 22)

(n = 12)

(n = 10)

Mean

8.3

9.2

7.2

Median (IQR)

5 (3-9)

4 (3-10)

6 (3-9)

Range

1-40

1-40

1-18

Concomitant therapy, No. (%)

Corticosteroids only

1 (3)

1 (7)

Immunomodulators only

8 (28)

2 (14)

6 (40)

Corticosteroids + immunomodulators

3 (11)

1 (7)

2 (13)

Corticosteroid dose (daily prednisone dose), mg

Mean (range)

11 (1.5-40)

12.5 (5-20)

15 (1.5-40)

Lesion diameter, mm
Mean
Median (IQR)

22.4

17.1

12.5 (7-34)

10 (7-23)

2-97

4-60

Mean

4.9

4.6

Median (IQR)

5 (3-7)

4 (3-6)

Range

1-8

1-10

Range
SASI

reduction in granuloma burden was also assessed. A secondary end point was change in modified SASI. A 3-point or greater
decline in SASI at the completion of therapy was considered
clinically significant, due to the observation of reduced symptoms. With a sample size of 32 patients and a 5% significance
level, the study was expected to have a 92% probability of detecting a therapeutic benefit if the true difference in benefit
was 60% (from 10% to 70%) with antimycobacterial therapy.

Molecular Microarray Analysis

RNA Isolation
Samples were obtained from patients at baseline and after receiving 8 weeks of antibiotics. Total RNA was extracted from
CD4+ and CD8+ sorted T cells using the miRNeasy Mini Kit
(QIAGEN). The quantity and quality were checked on the Nanodrop and Bioanalyzer (both from Agilent Technologies), respectively.

Abbreviations: CLEAR, concomitant

levofloxacin, ethambutol,
azithromycin, and rifampin; IQR,
interquartile range; SASI, Sarcoidosis
Activity Severity Index.

anti-CD28 antibodies. Extracellular cytokine expression and Tcell proliferation were determined as previously described.13

Statistical Analysis
We performed intention-to-treat analyses. An analysis of differences in lesion size at baseline and 8 weeks in individual subjects between treatment groups, as well as between-group comparisons on a continuous end point, was conducted using the
Wilcoxon rank sum test. Continuous variables were also compared between baseline and week 8 within treatment arm using
the Wilcoxon signed rank test. Laboratory data are presented
as means and standard deviations, unless otherwise stated. All
tests are 2-tailed. Statistical analyses were performed using the
statistical package SAS for Windows (version 9; SAS Institute)
and the statistical software R (www.r-project.org).

Results
Gene Expression Microarrays
RNA was labeled and hybridized to Agilent 8X60K whole human genome microarrays and analyzed as previously
described.24,25 The complete microarray data have been deposited in the Gene Expression Omnibus (GSE39606).
T-Cell Function Assay
For T-cell receptor stimulation, 2 105 CD4+ T cells were stimulated through their receptor by plate-bound anti-CD3 and soluble
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Characteristics and Randomization of the Study Population

The 30 patients enrolled in the cutaneous sarcoidosis study had
clinical or histologic evidence of chronic sarcoidosis previously documented. Twenty-two patients had biopsy-proven
cutaneous disease and 8 had biopsy-proven pulmonary disease with dermatologic lesions consistent with cutaneous sarcoidosis. The histologic diagnosis of cutaneous sarcoidosis was
confirmed in 7 of 8 patients; 1 patient did not have lesions consistent with cutaneous sarcoidosis at study enrollment. Enjamadermatology.com

Antimycobacterial Therapy in Sarcoidosis

Original Investigation Research

Figure 1. Cutaneous Sarcoidosis Trial Flow Diagram

Enrollment

68 Assessed for eligibility

38 Excluded
29 Did not meet inclusion criteria
9 Declined to participate
0 Other
30 Randomized

15 Allocated to treatment intervention

15 Received allocated intervention
Histologic diagnosis:
3 Had annular sarcoidosis
6 Had erythematous papular
sarcoidosis
1 Had subcutaneous
granulomatous sarcoidosis
1 Had plaque stage sarcoidosis
1 Had ulcerative sarcoidosis
2 Had macular sarcoidosis
1 Had incorrect diagnosis

4 Discontinued intervention (diarrhea,

joint pain, insomnia, and incorrect
diagnosis)

11 Completed per-protocol analysis

Allocation

15 Allocated to placebo intervention

15 Received allocated intervention
Histologic diagnosis:
3 Had annular sarcoidosis
3 Had erythematous papular
sarcoidosis
5 Had subcutaneous
granulomatous sarcoidosis
1 Had plaque stage sarcoidosis
1 Had ulcerative sarcoidosis
2 Had lupus pernio

Follow-up

3 Discontinued intervention
(diarrhea, joint pain, pill burden)
1 Failed to maintain study visits

Analysis

11 Completed per-protocol analysis

rollment occurred from February 10, 2010, through October 20,

2010, in Nashville. Of the 30 patients, the mean age was 51 years,
19 of 30 were women, and 19 of 30 were white; 10 of 30 were
using immunosuppressants. With regard to immunosuppression, 8 of 15 patients randomized to placebo were using immunosuppressants compared with 4 of 15 randomized to the
CLEAR regimen (Table 1). The immunosuppressants used
among the 8 patients randomized to placebo were methotrexate (n = 1), pentoxifylline (n = 1), hydroxychloroquine (n = 3),
remicade (n = 1), or prednisone and methotrexate (n = 2). The
immunosuppressant regimen of the 4 patients randomized to
the CLEAR regimen was prednisone (n = 1), methotrexate
(n = 1), hydroxychloroquine (n = 1), and prednisone and hydroxychloroquine (n = 1). The mean time in years since their
histologic diagnosis was 7 years. There were no significant differences between the placebo and treatment groups with respect to age, sex, ethnicity, immunosuppression use, or years
since histologic diagnosis (Table 1).
The clinical diagnosis of the 15 patients randomized to
the CLEAR regimen was as follows: macular sarcoidosis
(n = 2), annular sarcoidosis (n = 3), erythematous papular
sarcoidosis (n = 6), plaque stage sarcoidosis (n = 1), subcutaneous granulomatous sarcoidosis (n = 1), and ulcerative sarcoidosis (n = 1). One patient who was randomized to the
CLEAR regimen did not have lesions compatible with sarcoidosis at baseline. The lesions were believed to be more
consistent with chronic inflammatory changes from
repeated cutaneous injections. Because sarcoidosis is a diagnosis of exclusion, we did not proceed with study participajamadermatology.com

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Recruitment and enrollment of

patients with chronic cutaneous
sarcoidosis.

tion in this patient. The clinical diagnoses of 15 participants

randomized to placebo were as follows: annular sarcoidosis
(n = 3), erythematous papular sarcoidosis (n = 3), subcutaneous granulomatous sarcoidosis (n = 5), plaque stage sarcoidosis (n = 1), ulcerative sarcoidosis (n = 1), and lupus pernio
(n = 2). There was no significant difference in any form of
cutaneous sarcoidosis between the CLEAR regimen and placebo cohort. Assessment for latent tuberculosis by skin testing was performed at the discretion of the primary care physician. Fourteen patients in the placebo-treated group and 14
patients in the CLEAR-treated group had been tested previously. All were negative for the purified protein derivative of
tuberculin. All 30 patients denied a history of tuberculosis or
a known tuberculosis exposure.
Thirty patients were randomized to either the CLEAR regimen (n = 15) or placebo (n = 15), with 11 of 15 patients (73%) in
each group completing 8 weeks of therapy. Reasons for study
discontinuation are outlined in Figure 1.

Effects of Treatment on Lesion Diameter and SASI

Of the patients randomized to the CLEAR regimen, 10 had evidence of granulomas on biopsy of the index lesion, with 7 of
10 having a reduction in lesion diameter and granulomas. The
remaining 3 patients did not complete the 8-week regimen.
Seven of the 15 patients in the placebo cohort had granulomas on biopsy; none had a reduction in lesion diameter and
granuloma burden. For the primary end point of change in lesion size, as evidenced by a reduction in lesion diameter and
number of granulomas, 7 of 10 patients randomized to the
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Table 2. Intention-to-Treat Analysis of the Effects of the CLEAR Regimen on Index Lesion Diameter, SASI, and ALT
CLEAR
(n = 14)

Placebo
(n = 15)

Baseline

8 Weeks

Absolute
Difference

P Valuea

P Valueb

Baseline

8 Weeks

Absolute
Difference

22.4 (24.9)

14.0 (25.8)

8.4 (14.0)

.05

.008

17.1 (16.0)

17.9 (16.0)

0.07 (3.2)

.87

SASI

4.9 (2.1)

2.0 (2.2)

2.9 (2.5)

.02

.002

4.6 (2.3)

4.0 (2.2)

0.6 (2.1)

.34

ALT

24.6 (17.4)

21.3 (8.9)

10.6

.71

.17

27.1 (14.8)

27.1 (14.8)

8.4

.37

Characteristic
Lesion diameter, mm

Abbreviations: ALT, alanine aminotransferase; CLEAR, concomitant

levofloxacin, ethambutol, azithromycin, and rifampin; SASI, Sarcoidosis Activity
Severity Index.
a

P Valuea

Statistical difference in lesion diameter and severity within treatment group

after completion of therapy.

Statistical difference between 8 weeks of CLEAR therapy or placebo.

Table 3. Per-Protocol Analysis of the Effects of the CLEAR Regimen on Index Lesion Diameter, SASI, and ALT
CLEAR
(n = 11)

Placebo
(n = 11)

Baseline

8 Weeks

Absolute
Difference

P Valuea

P Valueb

Baseline

8 Weeks

Absolute
Difference

P Valuea

25.8 (27.1)

15.2 (29.1)

10.6 (15.1)

.04

.008

15.5 (11.9)

15.6 (12.9)

0.1 (3.7)

.87

SASI

5.7 (1.5)

2.0 (2.4)

3.7 (2.2)

.02

.002

4.5 (2.5)

3.7 (2.3)

0.8 (2.3)

.34

ALT

24.6 (17.4)

21.3 (8.9)

10.6

.90

.17

27.6 (15.4)

22.5 (6.1)

8.1

.27

Abbreviations: See Table 2.

a

Statistical difference between 8 weeks of CLEAR therapy or placebo.

CLEAR regimen met this benchmark compared with 0 of 7 randomized to placebo (P = .01, Fisher exact test).
In the intention-to-treat analysis, the 14 patients randomized to the CLEAR regimen demonstrated a mean (SD) decrease in index lesion size from 22.4 (24.9) mm to 14.0 (25.8)
mm, reflecting a decrease of 8.4 (14.0) mm (P = .008). Of the
15 patients randomized to placebo, the index lesion diameter
changed from a mean (SD) of 17.1 (16.0) mm to 17.9 (16.0) mm,
reflecting an increase of 0.07 (3.2) mm (P = .87). While there
was no significant difference in lesion diameter between the
2 groups at baseline (P = .62), there was a significant difference in the absolute change in lesion diameter after 8 weeks
of therapy. The CLEAR-treated group had a mean (SD) decrease of 8.4 (14.0) mm compared with an increase of 0.07 (3.2)
mm in the placebo-treated group (P = .05). In the perprotocol analysis, there were 11 patients in each group. Nine
of 11 patients in the CLEAR-treated group had reductions in lesion diameter compared with 2 of 11 patients in the placebo
group (P = .009, Fisher exact test). After 8 weeks of the CLEAR
regimen or placebo, the index lesion diameter decreased from
a mean (SD) of 25.8 (27.1) mm to 15.2 (29.1) mm (P = .008) in 11
patients receiving the CLEAR regimen and from 15.5 (11.9) mm
to 15.6 ( 12.9) mm (P = .87) among the 11 patients in the placebotreated group (Table 2 and Table 3). While there was no significant difference in lesion diameter between the 2 groups at
baseline (P = .40), there was a significant difference in the absolute difference in lesion diameter after 8 weeks of therapy.
The CLEAR-treated cohort had a mean (SD) absolute difference of 10.6 (15.1) mm compared with 0.1 (3.7) mm in the placebo-treated group (P = .04). Five patients randomized to the
CLEAR regimen had complete resolution of their lesions compared with 1 in the placebo-treated group (Figure 2A); there
was no recurrence of lesions at the 180-day follow-up.
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Statistical difference in lesion diameter and severity within treatment group

after completion of therapy.

Figure 2. Change in Lesion Diameter and Sarcoidosis Activity Severity

Index (SASI) From Baseline to 8 Weeks
A

Lesion Diameter, mm

Lesion diameter, mm

P =.87

P =.008

50
45
40
35
30
25
20
15
10
5
0
Baseline

8 Weeks

Baseline

8 Weeks

Placebo

CLEAR

P =.34

P =.002

12
10
8

SASI

Characteristic

6
4
2
0
Baseline

8 Weeks

Placebo

Baseline

8 Weeks

CLEAR

A, Change in lesion diameter was apparent in those randomized to the

concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR)
regimen compared with the cohort taking placebo, with complete resolution of the
cutaneous lesions among 5 patients in the CLEAR group. B, A significant decline in
the SASI was observed in the CLEAR group; minimal change was observed in the
placebo group. Each colored bar represents an individual study participant.

jamadermatology.com

Antimycobacterial Therapy in Sarcoidosis

This reduction in lesion diameter was associated with a

decrease in symptoms. A secondary end point was change in
lesion severity, as determined by the SASI, which measures
erythema, induration, and desquamation. In the intentionto-treat analysis, 9 of 14 patients in the CLEAR-treated group
had more than a 3-point drop in SASI compared with 3 of 15
placebo-treated patients (P = .03, 2-tailed Fisher exact test).
The index lesion severity decreased from a mean (SD) of 4.9
(2.1) mm to 2.0 (2.2) mm (P = .002) in the CLEAR-treated
group and from 4.6 (2.3) mm to 4.0 (2.2) mm (P = .34) in the
placebo-treated group (Table 2 and Figure 2B). While there
was no significant difference in lesion severity between the
placebo-treated and CLEAR-treated patients at baseline
(P = .53), there was a significant difference in the lesion
severity between the 2 cohorts at 8 weeks (P = .03). The
CLEAR-treated group experienced a mean (SD) decline of
2.9 (2.5) mm in lesion severity compared with a decline of
0.6 (2.1) mm among patients randomized to placebo
(P = .02). In the per-protocol analysis, 9 of 11 CLEAR-treated
patients experienced more than a 3-point decline in SASI
compared with 3 of 11 patients in the placebo group (P = .03,
2-tailed Fisher exact test). The reduction in lesion diameter
and SASI seen with the CLEAR regimen was associated with
reductions in granulomatous inflammation per the lead
pathologist (A.S.B.), who reviewed all slides of each participant while masked to the treatment arm. A photograph demonstrating the observed clinical improvement is provided
(Figure 3).

Transcriptional Signatures Associated

With Cutaneous Resolution
To determine the mechanisms associated with clinical improvement following the CLEAR regimen, we conducted transcriptome analysis of CD4+ and CD8+ T cells of patients randomized to the CLEAR or placebo regimen at baseline
compared with completion at 8 weeks.
No changes in gene expression were detected in the
patients who were administered the placebo regimen. Significant distinctions in expression were noted in those randomized to the CLEAR regimen. On comparing baseline transcriptome expression with transcriptome expression after
completion of the CLEAR regimen, 443 and 352 genes were differentially expressed (Figure 4A and B). Relevant functional
categories in both data sets were statistically significant, including antigen presentation and immune cell responses
(Figure 4C and D). Enriched pathways included normalization of those previously reported to contribute to sarcoidosis
pathogenesis, such as Wingless and integrase-1 (wnt/catenin) signaling and the Jak-Stat pathway (Figure 4 and
Table 4).
In many chronic cutaneous diseases, a fundamental contributor to disease progression is reduced IL-2 production and
T-cell proliferation. We postulated that alterations in gene expression seen with the CLEAR regimen would be associated
with improvement in CD4+ T-cell biological function, exhibited by increased interferon (IFN-) expression and cellular
proliferation. Measurement of IL-2 and IFN- production following T-cell receptor stimulation revealed an increase in exjamadermatology.com

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Original Investigation Research

Figure 3. Photographs of Observed Clinical Improvement

of Ulcerative Sarcoidosis
B

Photographic depictions of ulcerative sarcoidosis at baseline (A) and following

completion of the concomitant levofloxacin, ethambutol, azithromycin, and
rifampin (CLEAR) regimen (B).

pression after completion of the CLEAR regimen. The increase in IL-2 expression was not significant (P= .07); however,
the increase in IFN- production was significant (P = .04)
(Figure 5A). There was not a significant increase in IL-2 or IFN-
expression among the patients with sarcoidosis who were randomized to the placebo regimen. In addition, we measured
CD4+ T-cell proliferation following T-cell receptor stimulation. We noted a significant increase in proliferative capacity
among those randomized to the CLEAR regimen (P= 2 107)
but not among those randomized to placebo (P = .95) (Figure 5B
and C).

Adverse Events
Six of the 30 patients with chronic cutaneous sarcoidosis (3 in
the CLEAR-treated group and 3 in the placebo-treated group)
experienced an adverse event that resulted in study withdrawal. Among those randomized to the CLEAR regimen, 1 developed diarrhea, 1 had joint pain, and 1 had insomnia. A fourth
patient was asked to withdraw because, upon examination, cutaneous lesions were not consistent with sarcoidosis. Among
those randomized to placebo, 1 developed diarrhea, 1 had joint
pain, and 1 withdrew because of pill burden. One patient denied any adverse events but did not maintain any study visits
after enrollment. Review of baseline and week 8 alanine aminotransferase of the patients as a cohort did not reveal any significant differences (Table 2).

Discussion
Cutaneous sarcoidosis is a chronic granulomatous disease characterized by genetic susceptibility and CD4+ T-cell predominance. To our knowledge, this phase I study is the first ranJAMA Dermatology September 2013 Volume 149, Number 9

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Figure 4. Gene Expression Profile Changes Following Concomitant

Levofloxacin, Ethambutol, Azithromycin, and Rifampin (CLEAR)
Treatment
A

pre

post

pre

Table 4. List of Enriched Pathways in CD4+ and CD8+ Sorted Cells

Pathway

post
1
0

P Value

Differentially Expressed Genes

Interferon signaling

<.01

BAX, IFNA21, and PIAS1

NOD-like receptor
signaling

<.01

NLRC4, CCL13, MAPK12, MAPK9,

RIPK2, and NAIP

Arginine and proline

metabolism

.06

NOS1, GATM, PRODH, and CKB

Endocytosis

.10

RET, RAB5C, ACAP1, HLA-A, RAB5A,

IQSEC3, and SH3GL2

Jak-Stat signaling

<.01

PIAS1 and PIAS4

MAPK

<.01

UBB, CCKBR, MAPK9, RPS6KA3,

ITPKB, RIPK2, TAOK3, RET, and
MAPK12

MIF regulation of innate immunity

<.01

MAPK9 and MAPK12

Abbreviations: MAPK, mitogen-activated protein kinase; MIF, macrophage

migration inhibitory factor; NOD, nitric oxide synthase.

CD4+

CD8+

C CD4+

Threshold

Cell-to-cell signaling and interaction

Antigen presentation
Inflammatory disease
Immunologic disease
Cellular compromise
Infectious disease
Immune cell trafficking
Lymphoid tissue structure and development
Inflammatory response
Cell-mediated immune response
Cell signaling
0

log (P Value)
D CD8+

Threshold

Antigen presentation
Inflammatory disease
Immunologic disease
Infectious disease
Immune cell trafficking
Cellular growth and proliferation
Inflammatory response
Cell-mediated immune response
0

log (P Value)

The heat maps represent statistically significant (P < .05), differentially

expressed genes in CD4+ (A) and CD8+ (B) sorted cells, respectively.
Upregulated genes are shown in progressively brighter shades of yellow,
depending on the fold difference, and downregulated genes are shown in
progressively brighter shades of purple. Gray, expression of genes that show no
difference between the 2 groups being compared. The functional enrichment of
these differentially expressed genes in CD4+ (C) and CD8+ (D) sorted cells is
shown. Post indicates postintervention; pre, preintervention.

domized, placebo-controlled, masked study to demonstrate

that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoid1046

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osis. Decreased severity was defined as reductions in erythema, induration, or desquamation after completion of
therapy. Clinical resolution was associated with alterations of
the sarcoidosis CD4+ immunologic transcriptome. The major
benefit was reduction in lesion diameter, as well as severity.
All enrolled patients had recalcitrant disease that was clinically active, whether receiving therapy or not. Notably, clinical improvement was observed despite the variant of chronic
cutaneous sarcoidosis. The observed improvement with the
8-week CLEAR regimen was still present 180 days after baseline among all but 1 patient, despite no changes in their immunosuppressant regimen.
In defining the molecular mechanisms associated with
clinical improvement, we conducted a gene expression microarray of participants at baseline and following completion
of their regimen. No significant alterations in gene expression were observed among those randomized to placebo, even
if they were using immunosuppressant therapy. Among patients randomized to the CLEAR regimen, analysis of the immunologic transcriptome identified enrichment in terms of
pathways associated with immune regulation and cytokine expression, whether or not they were using immunosuppressant therapy. A significant portion of the genes identified were
involved in the innate and adaptive immune response, such
as the interferon signaling pathway (P < .01), with genes such
as BAX (OMIM 600040), IFNA21 (OMIM 147584), and PIAS1
(OMIM 603566); Jak-Stat signaling (P < .01); and mitogenactivated protein kinase (P < .01) (Table 3). All of these categories contain genes involved in the immune response, which are
important in diseases such as psoriasis.26 Additional investigations support the role of the Jak-Stat pathway in sarcoidosis specimens.27,28 Microarray analysis has confirmed reductions in wnt/-catenin expression among patients improving
with CLEAR therapy (Figure 4). Increases in Wnt expression
also have been seen with sarcoidosis progression.29 Antibiotics are known to exert effects on the immune transcriptome.
Levofloxacin affects intracellular cyclic adenosine monophosphate, phosphodiesterases, nuclear factorB, and activator
protein 1,6 as well as IL-2 production by monocytes. Azithromycin decreases neutrophil chemotaxis and reduces tumor necrosis factor production in lipopolysaccharide-stimulated
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Antimycobacterial Therapy in Sarcoidosis

Original Investigation Research

Figure 5. T-Cell Function Improvement With Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (CLEAR) Therapy
A

.07

P = .04

Baseline

8 Weeks

Change in TH1 Cytokine (8 wk/Baseline)

2.0
1.8
1.6

400
400

Placebo
CLEAR

64%

36%

300

300

1.2
1.0

Placebo

200

200

0.8
0.6

100

100

0.4
0.2
0

IL-2

70

IFN-

P = 2 107

80
Placebo
CLEAR

60

% Proliferation

66%

34%

1.4

50

P = .95

0
100

101

102

0
100

104

100

100

80

80

60
23%

40
30

103

101

102

103

104

60

76%

32%

68%

40

40

20

20

CLEAR

20
10
0

Baseline 8 Weeks

Baseline 8 Weeks

0
100

101

102

103

0
100

104

101

102

103

104

CFSE

CD4+ T cells were stimulated with anti-CD3/anti-CD28 antibodies. A,

Supernatants were collected at 24 hours and measured for fold change in
interleukin 2 (IL-2) and interferon (IFN-) production by a cytokine bead array
in patients receiving CLEAR therapy. B, Representative change in percentage of
CD4+ T-cell proliferation from baseline to 8 weeks among patients randomized
to the CLEAR- and placebo-treated groups. CD4+ T cells were labeled with
carboxyfluorescein succinimidyl ester and stimulated with anti-CD3/anti-CD28

antibodies. Cells were collected after 5 days, and proliferation was measured by
flow cytometry. C, Cumulative proliferation data. Specimens were chosen solely
based on availability of peripheral blood mononuclear cells. Data represent the
mean (horizontal bars) percentage from 9 patients in the CLEAR-treated group
and 4 placebo-treated patients. CFSE indicates carboxyfluorescein succinimidyl
ester.

monocytes by modifying p38 signaling pathways. 30 Rifampin inhibits monocyte secretion of IL-1 and tumor necrosis factor and increases secretion of IL-6 and IL-10.31 The presence of amelioration of the transcriptome supports that
immunoregulation is a mechanism by which the CLEAR regimen has efficacy. Because no viable infectious agent has been
associated with sarcoidosis pathogenesis, it is unclear whether
the regimen works through antimicrobial effects; however, further investigation into this possibility is warranted.
We also investigated whether the observed alterations in
the T-cell transcriptome carried functional significance. Consistent with observations of enhanced CD4+ T-cell function and
clinical resolution following antimicrobial therapy,32,33 we
noted enhanced TH1 cytokine expression and proliferative capacity in the CD4+ T cells of patients with sarcoidosis experiencing clinical improvement.
Despite the observed clinical benefit, there are some limitations to this trial. First, there were only 30 participants. We
chose this number because it was statistically predicted to show
a benefit. We were reluctant to needlessly expose a larger number of patients to a regimen with known toxic effects. Sec-

ond, the dropout rate was 4 of 15 in both treatment arms. This

adherence rate is consistent with prior reports of nonadherence ranges of 17.5% to 50% among patients using a 4-drug antimycobacterial regimen.34 The same factors associated with
nonadherence in those trials, including number of pills and toxicity profile, contributed to our dropout rate.35-37 In future trials,
we will consider continued participation with 3 of the 4 drugs
if an enrollee has a toxic reaction to a single agent. We noted
no evidence of rifamycin-induced hepatotoxicity.
A third study limitation is that 8 of 15 patients in the placebo-treated group were using immunosuppressant therapy
compared with 4 of 15 on the CLEAR regimen (Table 1). Although each patient was randomized at the time of presentation, this could imply that the control group had more difficultto-treat disease. We did not observe distinctions in the lesion
severity as measured by the SASI; in fact, the SASI was higher
in the CLEAR-treated group, suggesting that they had more severe manifestations of disease, possibly because fewer patients were using immunosuppressant therapy. Future studies will involve a crossover arm to assess the effects of the
regimen regardless of the form of cutaneous sarcoidosis.

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JAMA Dermatology September 2013 Volume 149, Number 9

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Research Original Investigation

Antimycobacterial Therapy in Sarcoidosis

Great efforts are needed to identify therapeutics that

will effectively alleviate chronic cutaneous sarcoidosis. The
CLEAR regimen leads to lesion regression and severity of
symptoms in a cohort of patients with chronic cutaneous

ARTICLE INFORMATION

REFERENCES

Accepted for Publication: March 23, 2013.

1. Baughman RP. Sarcoidosis. Clin Dermatol.

2007;25(3):231. doi:10.1016/
j.clindermatol.2007.03.014.

Published Online: July 17, 2013.

doi:10.1001/jamadermatol.2013.4646.
Author Affiliations: Division of Infectious Diseases,
Department of Medicine, Vanderbilt University
School of Medicine, Nashville, Tennessee (Drake,
Isom, Algood, Braun, Taylor); Department of
Pathology, Microbiology, and Immunology,
Vanderbilt University School of Medicine, Nashville,
Tennessee (Drake, Oswald-Richter); Division of
Allergy, Pulmonary, and Critical Care Medicine,
Department of Medicine, Vanderbilt University
School of Medicine, Nashville, Tennessee
(Richmond); Department of Medicine, Vanderbilt
University School of Medicine, Nashville, Tennessee
(Burke); Division of Pulmonary, Allergy, and Critical
Care Medicine, Dorothy P. and Richard P. Simmons
Center for Interstitial Lung Disease, University of
Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania (Pandit, Aboud, Kaminski);
Department of Biostatistics, Vanderbilt University
School of Medicine, Nashville, Tennessee (Yu);
Division of Dermatology, Department of Medicine,
Vanderbilt University School of Medicine, Nashville,
Tennessee (Boyd, King).
Author Contributions: Drs Drake and King had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Drake, Oswald-Richter,
Yu, King.
Acquisition of data: Drake, Oswald-Richter,
Richmond, Isom, Burke, Algood, Taylor, Pandit,
Aboud, Kaminski, King.
Analysis and interpretation of data: Drake,
Oswald-Richter, Richmond, Burke, Algood, Braun,
Pandit, Aboud, Yu, Kaminski, Boyd, King.
Drafting of manuscript: Drake, Oswald-Richter,
Richmond, Burke, Pandit, King.
Critical revision of the manuscript for important
intellectual content: Drake, Burke, Algood, Braun,
Taylor, Aboud, Yu, Kaminski, Boyd, King.
Statistical Analysis: Pandit, Yu, Kaminski.
Administrative, technical, or material support:
Oswald-Richter, Isom, Burke, Algood, Braun, Taylor,
Pandit, Aboud, Boyd, King.
Study supervision: Drake, Oswald-Richter, Kaminski,
King.
Conflict of Interest Disclosures: None reported.
Funding/Support: The study was supported in part
by grants 1K01HL103179-01, T32HL069765-08,
5T32HL094296-04, U01 HL112694-01, and UL1
RR-024975 from the National Institutes of Health;
the Foundation for Sarcoidosis Research; the
Dorothy P. and Richard P. Simmons Endowed Chair
for Pulmonary Research; The Mona Eliassen
Foundation; and the Pierce Family Foundation.
Additional Contributions: We thank the patients
with sarcoidosis who participated in the trial, and
the Vanderbilt Investigation Drug Pharmacy. Jo D.
Fine, MD, provided a critical review of the
manuscript.

1048

sarcoidosis. A multicenter trial of a larger cohort should be

conducted to confirm these findings, further delineate the
adverse effect profile, and determine optimal dosing and
patient selection.

2. Rosen T, Doherty C. Successful long-term

management of refractory cutaneous and upper
airway sarcoidosis with periodic infliximab infusion.
Dermatol Online J. 2007;13(3):14.
3. Badgwell C, Rosen T. Cutaneous sarcoidosis
therapy updated. J Am Acad Dermatol.
2007;56(1):69-83.
4. Marchell RM, Judson MA. Cutaneous
sarcoidosis. Semin Respir Crit Care Med.
2010;31(4):442-451.
5. Doherty CB, Rosen T. Evidence-based therapy
for cutaneous sarcoidosis. Drugs.
2008;68(10):1361-1383.
6. Dalhoff A, Shalit I. Immunomodulatory effects of
quinolones. Lancet Infect Dis. 2003;3(6):359-371.
7. Schmitt CE, Fabi SG, Kukreja T, Feinberg JS.
Hypopigmented cutaneous sarcoidosis responsive
to minocycline. J Drugs Dermatol.
2012;11(3):385-389.

16. Song Z, Marzilli L, Greenlee BM, et al.

Mycobacterial catalase-peroxidase is a tissue
antigen and target of the adaptive immune
response in systemic sarcoidosis. J Exp Med.
2005;201(5):755-767.
17. Li N, Bajoghli A, Kubba A, Bhawan J.
Identification of mycobacterial DNA in cutaneous
lesions of sarcoidosis. J Cutan Pathol.
1999;26(6):271-278.
18. Allen SS, Evans W, Carlisle J, et al. Superoxide
dismutase A antigens derived from molecular
analysis of sarcoidosis granulomas elicit systemic
Th-1 immune responses. Respir Res. 2008;9:36.
doi:10.1186/1465-9921-9-36.
19. Drake WP, Dhason MS, Nadaf M, et al. Cellular
recognition of Mycobacterium tuberculosis ESAT-6
and KatG peptides in systemic sarcoidosis. Infect
Immun. 2007;75(1):527-530.
20. Hajizadeh R, Sato H, Carlisle J, et al.
Mycobacterium tuberculosis antigen 85A induces
Th-1 immune responses in systemic sarcoidosis.
J Clin Immunol. 2007;27(4):445-454.

8. Bachelez H, Senet P, Cadranel J, Kaoukhov A,

Dubertret L. The use of tetracyclines for the
treatment of sarcoidosis. Arch Dermatol.
2001;137(1):69-73.

21. Costabel U, Hunninghake GW; Sarcoidosis

Statement Committee; American Thoracic Society;
European Respiratory Society; World Association
for Sarcoidosis and Other Granulomatous
Disorders. ATS/ERS/WASOG statement on
sarcoidosis. Eur Respir J. 1999;14(4):735-737.

9. Chen ES, Song Z, Willett MH, et al. Serum

amyloid A regulates granulomatous inflammation in
sarcoidosis through Toll-like receptor-2. Am J Respir
Crit Care Med. 2010;181(4):360-373.

22. Baughman RP, Judson MA, Teirstein A, et al.

Chronic facial sarcoidosis including lupus pernio:
clinical description and proposed scoring systems.
Am J Clin Dermatol. 2008;9(3):155-161.

10. Furusawa H, Suzuki Y, Miyazaki Y, Inase N, Eishi

Y. Th1 and Th17 immune responses to viable
Propionibacterium acnes in patients with
sarcoidosis. Respir Investig. 2012;50(3):104-109.

23. Griffith DE, Aksamit T, Brown-Elliott BA, et al;

ATS Mycobacterial Diseases Subcommittee;
American Thoracic Society; Infectious Disease
Society of America. An official ATS/IDSA statement:
diagnosis, treatment, and prevention of
nontuberculous mycobacterial diseases [published
correction appears in Am J Respir Crit Care Med.
2007;175(7):744-745]. Am J Respir Crit Care Med.
2007;175(4):367-416.

11. Negi M, Takemura T, Guzman J, et al.

Localization of Propionibacterium acnes in
granulomas supports a possible etiologic link
between sarcoidosis and the bacterium. Mod
Pathol. 2012;25(9):1284-1297.
12. Agarwal R, Gupta D, Srinivas R, Verma I,
Aggarwal AN, Laal S. Analysis of humoral responses
to proteins encoded by region of difference 1 of
Mycobacterium tuberculosis in sarcoidosis in a high
tuberculosis prevalence country. Indian J Med Res.
2012;135(6):920-923.
13. Oswald-Richter KA, Beachboard DC, Seeley EH,
et al. Dual analysis for mycobacteria and
propionibacteria in sarcoidosis BAL. J Clin Immunol.
2012;32(5):1129-1140.
14. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL,
Blaser MJ. Molecular analysis of sarcoidosis tissues
for Mycobacterium species DNA. Emerg Infect Dis.
2002;8(11):1334-1341.
15. Dubaniewicz A, Dubaniewicz-Wybieralska M,
Sternau A, et al. Mycobacterium tuberculosis
complex and mycobacterial heat shock proteins in
lymph node tissue from patients with pulmonary
sarcoidosis. J Clin Microbiol. 2006;44(9):34483451.

JAMA Dermatology September 2013 Volume 149, Number 9

Downloaded From: http://archderm.jamanetwork.com/ on 10/08/2014

24. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini

Z. GOrilla: a tool for discovery and visualization of
enriched GO terms in ranked gene lists. BMC
Bioinformatics. 2009;10:48. doi:10.1186/1471-2105
-10-48.
25. Huang DW, Sherman BT, Lempicki RA.
Systematic and integrative analysis of large gene
lists using DAVID bioinformatics resources. Nat
Protoc. 2009;4(1):44-57.
26. Gervin K, Vigeland MD, Mattingsdal M, et al.
DNA methylation and gene expression changes in
monozygotic twins discordant for psoriasis:
identification of epigenetically dysregulated genes.
PLoS Genet. 2012;8(1):e1002454.
doi:10.1371/journal.pgen.1002454.
27. Rosenbaum JT, Pasadhika S, Crouser ED, et al.
Hypothesis: sarcoidosis is a STAT1-mediated
disease. Clin Immunol. 2009;132(2):174-183.
28. Crouser ED, Culver DA, Knox KS, et al. Gene
expression profiling identifies MMP-12 and
ADAMDEC1 as potential pathogenic mediators of
jamadermatology.com

Antimycobacterial Therapy in Sarcoidosis

pulmonary sarcoidosis. Am J Respir Crit Care Med.

2009;179(10):929-938.
29. Levnen B, Wheelock AM, Eklund A,
Grunewald J, Nord M. Increased pulmonary Wnt
(wingless/integrated)signaling in patients with
sarcoidosis. Respir Med. 2011;105(2):282-291.
30. Ikegaya S, Inai K, Iwasaki H, Naiki H, Ueda T.
Azithromycin reduces tumor necrosis factoralpha
production in lipopolysaccharide-stimulated THP-1
monocytic cells by modification of stress response
and p38 MAPK pathway. J Chemother.
2009;21(4):396-402.

Original Investigation Research

31. Ziglam HM, Daniels I, Finch RG.

Immunomodulating activity of rifampicin.
J Chemother. 2004;16(4):357-361.

tuberculosis treatment: a systematic review of

qualitative research. PLoS Med. 2007;4(7):e238.
doi:10.1371/journal.pmed.0040238.

32. Wood KL, Hage CA, Knox KS, et al.

Histoplasmosis after treatment with antitumor
necrosis factor therapy. Am J Respir Crit Care
Med. 2003;167(9):1279-1282.

35. Okayasu S, Matsuura K, Kondoh Y, et al. A

survey on diarrhea and convenience of intake
associated with a single-dose extended release
formulation of azithromycin. Pharmazie.
2011;66(3):226-229.

33. Mansour MK, Yauch LE, Rottman JB, Levitz SM.

Protective efficacy of antigenic fractions in mouse
models of cryptococcosis. Infect Immun.
2004;72(3):1746-1754.
34. Munro SA, Lewin SA, Smith HJ, Engel ME,
Fretheim A, Volmink J. Patient adherence to

36. Hopkins S. Clinical toleration and safety of

azithromycin. Am J Med. 1991;91(3A):40S-45S.
37. Liu HH. Safety profile of the fluoroquinolones:
focus on levofloxacin. Drug Saf.
2010;33(5):353-369.

NOTABLE NOTES

Hippocrates on Ulcers
Faisal R. Ali, MA, MRCP; James Fox, MA, PhD; Alexander E. T. Finlayson, BMedSci, MRCP

The father of medicine, Hippocrates, is arguably the most renowned and

enduring of all physicians. He constructed the eponymous oath on which
all physicians swear allegiance. Residing in the Greek island of Kos from
460 BC to 370 BC, Hippocrates was a gifted orator and philosopher. In
the later years of his career, he devoted time to establishing a practice
of medicine that sought to describe diseases in a natural, scientific way,
in contrast to the sorcery and superstition that dominated Greek medicine at that time. In the fourth century BC, the Corpus Hippocraticum1 was
compiled by his followers and comprises a heterogeneous collection of
essays relating to various bodily systems.
One chapter is devoted to the care of ulcers and contains a plethora
of suggested remedies and medicaments to be deployed in various circumstances (we cannot to do justice to all of them herein). For ulcers,
he claimed that the principal aim was to simulate normality, with dry ulcers being nearer to the sound and wet to the unsound.2
For inflamed swellings and ulcers requiring cleansing, Hippocrates recommended boiled mullein plant, raw leaves of the trefoil, and boiled leaves
of the epipetrum and poley, or, alternatively, boiled leaves of the fig tree,
olive, and horehound. In cases in which there was a risk of infection overriding the ulcer, he proposed that linseed with leaves of a woad or the juice
of strychnos be applied as a cataplasm. For clean ulcers with inflamed surrounding skin, he recommended finely ground lentils boiled in wine.
Certain body parts were afforded dedicated treatments. Wounds of
the head, ears, and penis could be treated with a combination of dried

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ox bile, honey, white wine, lotus shavings, frankincense, and myrrh. As

an emollient in winter, Hippocrates recommended goose and pig fat
blended with squill and oil.
Lessons from this work remain pertinent to todays physician, including the elevation of bleeding limbs to assuage exsanguination. While
visual descriptions of ulcers are scant, the advice to rest and avoid standing remains relevant advice for current patients with varicose ulcers. Contemporary dermatologists may be accused of overlooking the Hellenistic advice that ulcers benefit from a spare diet, the summer season, and
purging of the bowels.
Above all, Hippocrates work underlines the perpetual need for physicians to use evidence-based treatments, their responsibility to contribute to that evidence base, and, where necessary, to challenge the prevailing dogma in pursuit of clinical excellence.
Author Affiliations: Dermatology Centre, Salford Royal NHS Foundation Trust,
Manchester, England (Ali); Department of History of Art, University of
Cambridge, Cambridge, England (Fox); Centre for Global Health, Kings Health
Partners, Denmark Hill, London, England (Finlayson).
Corresponding Author: Faisal R. Ali, MA, MRCP, Dermatology Centre, Salford
Royal NHS Foundation Trust, Manchester, Greater Manchester M6 8HD,
England (f.r.ali.01@cantab.net).
1. Iniesta I. Hippocratic Corpus. BMJ. 2011;342:d688.
2. Ulcers by Hippocrates. Adams F, trans. Internet Classics Archive.
http://classics.mit.edu/Hippocrates/ulcers.mb.txt. Accessed March 4, 2013.

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