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Original Investigation |

Oral Antimycobacterial Therapy in Chronic Cutaneous Sarcoidosis:  A Randomized, Single-Masked, Placebo-Controlled Study

Wonder P. Drake, MD1,2; Kyra Oswald-Richter, PhD2; Bradley W. Richmond, MD3; Joan Isom, LPN1; Victoria E. Burke, MD4; Holly Algood, PhD1; Nicole Braun, PhD1; Thyneice Taylor, PhD1; Kusum V. Pandit, PhD5; Caroline Aboud, BS5; Chang Yu, PhD6; Naftali Kaminski, MD5; Alan S. Boyd, MD7; Lloyd E. King, MD, PhD7
[+] Author Affiliations
1Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
2Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
3Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
5Division 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
6Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
7Division of Dermatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
JAMA Dermatol. 2013;149(9):1040-1049. doi:10.1001/jamadermatol.2013.4646.
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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

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Figure 1.
Cutaneous Sarcoidosis Trial Flow Diagram

Recruitment and enrollment of patients with chronic cutaneous sarcoidosis.

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Figure 2.
Change in Lesion Diameter and Sarcoidosis Activity Severity Index (SASI) From Baseline to 8 Weeks

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.

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Figure 3.
Photographs of Observed Clinical Improvement of Ulcerative Sarcoidosis

Photographic depictions of ulcerative sarcoidosis at baseline (A) and following completion of the concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen (B).

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Figure 4.
Gene Expression Profile Changes Following Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (CLEAR) Treatment

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.

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

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 γ (IFN-γ) 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.

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