Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis

Abstract

Background: Sarcoidosis is an idiopathic, granulomatous disease for which molecular and immunologic studies have shown an association between it and mycobacterial antigens. Microbial antigens can reduce expression of the tyrosine kinase Lck, which has been associated with sarcoidosis severity. Here we investigate the efficacy of Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (the CLEAR regimen) for treatment of chronic, pulmonary sarcoidosis.

Methods: Fifteen chronic, pulmonary sarcoidosis patients with forced vital capacities (FVC) between 45-80% of predicted were enrolled in this open-label trial. The primary efficacy endpoint was change in absolute FVC from baseline to completion of therapy. Secondary endpoints were change in functional capacity measured by Six Minute Walk Distance (6MWD) and quality of life assessment measured by St. George's Respiratory Questionnaire (SGRQ).

Results: Of 15 patients enrolled, 11 completed 4 weeks of therapy, and 8 completed 8 weeks of therapy. The CLEAR regimen was associated with an increase in FVC of 0.23 liters at 4 weeks and 0.42 liters at 8 weeks (P=0.0098 and 0.016, respectively). The 6MWD increased by 87 meters from baseline to 8 weeks (p=0.0078). The mean score of the validated SGRQ was improved at 8 weeks over baseline (p=0.023). Normalized expression of Lck and NF-κB was observed in those with clinical improvement.

Conclusions: The CLEAR regimen is associated with improved absolute FVC, as well as increased functional capacity and quality-of-life in selected chronic pulmonary sarcoidosis patients. Larger, randomized, controlled trials are needed to confirm these findings and to identify patients most likely to benefit from therapy. ClinicalTrials.gov number NCT01169038.

Figures

Fig. 1

Enrollment and Outcomes for Pulmonary Sarcoidosis subjects

Fig. 2

Percent change in forced vital capacity following completion of 8 weeks of CLEAR regimen. FVC was measured at baseline and following completion of 8 weeks of CLEAR regimen. Four of the eight subjects demonstrated improvement in FVC of >10%.

Fig. 3

Anti-mycobacterial therapy increases activated Lck and NF-κB expression. Y394-Lck and NF-κB levels were measured from whole-cell lysates generated from 1 × 106 CD4+ T cells unstimulated or stimulated for 5 minutes with plate-bound anti-CD3 and soluble anti-CD28 antibodies before and after completion of anti-mycobacterial therapy. Protein expression was normalized to β-actin levels. (*=p

Fig. 4

Reductions in immune responses against ESAT-6. Analogous to reports of declining immunoreactivity against microbial antigens following antifungal and antituberculous treatment, reductions in adaptive immune responses against ESAT-6 was noted post completion of the CLEAR regimen. Data was collected on the six subjects for whom PBMC were available.