Oral Antimycobacterial Therapy in Chronic Cutaneous Sarcoidosis

Abstract

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.

Etiologies of Sarcoidosis

“…Working under the hypothesis that sarcoidosis is caused by an active replicating mycobacterial infection, Drake and colleagues studied a series of patients with severe cutaneous and pulmonary sarcoidosis who were treated with a four-drug regimen of concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) [135]. Drug dosages were based on guidelines for the treatment of atypical mycobacterial infection.…”

Sarcoidosis: treatments beyond prednisone and methotrexate

“…A recent randomized single-blind controlled trial in 29 subjects evaluated the use of antimycobacterial therapy (concomitant levofloxacin, ethambutol, azithromycin, and rifampin-clear) versus placebo in patients with cutaneous sarcoidosis [34]. Intention-to-treat analysis showed a significant reduction in lesion size in the treatment group compared to placebo.…”

“…Intention-to-treat analysis showed a significant reduction in lesion size in the treatment group compared to placebo. An open-label trial in pulmonary sarcoidosis likewise suggested that CLEAR therapy over eight weeks may lead to improved quality of life, vital capacity, and 6-min walk distance [35]. Currently, a phase II clinical trial is evaluating the efficacy of CLEAR in patients with progressive pulmonary sarcoidosis (NCT02024555).…”

Sarcoidosis: Unknown Etiology and Genetic Predisposition Provides Therapeutic Challenges

“…Concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) is a synergistic antibiotic regimen recently utilized as a clinical trial therapy for chronic pulmonary sarcoidosis exhibiting decreased levels of LCK and NF-κB [134,135]. Clonal exhaustion, or anergy, of T-cells is characterized by a decrease in NF-κB, CD3 delta and LCK [136].…”

“…In the event of LCK inactivation, no phosphorylation of CD3 tyrosine residues on activation motifs occurs which blocks CD4 T-cell response [136]. Restoration of LCK and NF-κB expression by antimycobacterial therapy in chronic sarcoidosis patients improves forced vital capacity while also further indicting Mycobacterium as a putative contributor and CLEAR as a therapeutic alternative [134].…”