Azithromycin a Treatment for Pulmonary Sarcoidosis

Disease behavior in sarcoidosis is variable and difficult to predict. Spontaneous improvement may occur, but even then evidence of persistent low grade granulomatous inflammation is common and disabling symptoms such as fatigue may persist. Patients with milder chronic sarcoidosis may suffer significant symptoms and disability, but active monitoring and supportive care are the only currently suitable management options. Recurrence after remission is a problem, with some patients suffering from chronic ill health, progressive disease and fibrosis, potentially leading to organ failure and death or transplantation. Management is further complicated because some patients with symptomatic, progressive sarcoidosis have a high burden of granulomatous disease, often affecting the lungs, whereas other patients have limited disease in a dangerous location such as the heart or nervous system.

Cure is not a realistic option whilst the cause(s) of sarcoidosis remain unknown. Ideally, treatment should be aimed at preventing or slowing progression to irreversible fibrosis and organ failure, reducing symptoms, and improving quality of life. The evidence that currently used treatments achieve these aims is weak, and the risk of adverse effects is concerning for patients and may outweigh perceived benefits. Treatment with corticosteroids is suppressive rather than curative, and guidelines recommend at least 1 years' therapy for patients with progressive disease. In the BTS sarcoidosis study, long term corticosteroids given to patients with non-resolving pulmonary disease after six months' initial observation improved lung function and chest x-ray appearances by a small amount. Importantly, of patients who were given early steroids for troublesome symptoms, almost half were still taking steroids 5 years later. Yet whether steroids prevent fibrosis or improve clinically meaningful outcomes that are important to patients in the longer term is unknown. Worryingly, there is evidence that early steroid therapy may promote more aggressive disease later on. Side effects of steroid therapy are often distressing and disfiguring, and sometimes serious or fatal. When sarcoidosis is refractory to steroid treatment, second line immunomodulators such as methotrexate, azathioprine, or mycophenolate are commonly prescribed based on their efficacy in treating rheumatic diseases, and are recommended in guidelines. In sarcoidosis, the best evidence is that they are steroid sparing (i.e. permit a lower dose of corticosteroid to be used). As with steroids, long term benefits have not been demonstrated and liver and bone marrow toxicity is a concern, requiring regular blood testing.

Whilst a unifying cause of sarcoidosis remains elusive, it has been established that inflammatory cells including T lymphocytes, monocytes, and macrophages become hyper-activated in the lungs and peripheral blood. Recently, using mouse models it has been shown that chronic signalling through the mTOR complex 1 (mTORC1) in macrophages pathway drives the formation of sarcoid-like granulomas that closely mimic non-resolving sarcoidosis in humans. mTOR (mammalian/mechanistic target of rapamycin) links growth factors and availability of amino acids to protein synthesis and cell growth, proliferation, and differentiation. mTOR activity and gene targets correlating to sarcoidosis progression in lung biopsies have implicated a potential role for targeting mTOR in human disease. These datasets indicate a key role for mTOR pathways and the metabolic status of tissue macrophages in triggering and driving disease pathology.

The macrolide antibiotic azithromycin is immunomodulatory and anti-bacterial, both of which are plausible beneficial properties in sarcoidosis. Many studies have implicated bacteria as triggers for sarcoidosis, and although convincing evidence implicating a specific organism is lacking, improvements in sarcoidosis have been described in antibiotic combination studies that included azithromycin. Beneficial immunomodulatory properties of macrolides became apparent in the treatment of Asian diffuse panbronchiolitis, where reduced inflammatory cytokine production in several cell types was demonstrated. Recently, it has been determined that azithromycin directly suppresses mTOR activity in a subset of T lymphocytes (CD4+ T-cells).

Patients with pulmonary sarcoidosis need treatment options that effectively modulate disease activity, reduce risk of disease progression, and improve symptoms and quality of life, with an acceptable side effect profile. Azithromycin is a cheap, readily available generic drug. Long term treatment with azithromycin has been shown to be safe in other chronic lung diseases. Azithromycin is preferable to other macrolide antibiotics because of its safety data for long term use, once daily administration, and lack of inhibition of liver CYP3A isoenzymes. The safety profile of azithromycin makes it preferable to non-antibiotic macrolide mTOR inhibitors such as rapamycin (sirolimus, used to treat transplant rejection)) and everolimus (an anti-cancer drug). Whether azithromycin will benefit patients with sarcoidosis can only be answered definitively by a large multicenter clinical trial. The Investigators proposed exploratory study aims to facilitate this aim by exploring mechanisms and evaluating potential blood biomarkers, and assessing feasibility of a subsequent large clinical trial.