Interstitial lung disease associated with systemic sclerosis: what is the evidence for efficacy of cyclophosphamide?

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) that may be responsible for severe restrictive lung disease and represents one of the two main causes of disease-related death in SSc patients. Since 1993, the beneficial effect of oral or intravenous cyclophosphamide (CYC) in the treatment of SSc-related ILD has been reported in retrospective studies, one study showing improvement of pulmonary function test scores and/or chest computed tomography at 1 year and improvement of survival at 16 months. The results of two controlled trials were recently reported. The Scleroderma Lung Study, a prospective randomized placebo-controlled trial, included 158 patients of whom 145 completed at least 6 months of treatment. The course of forced vital capacity (primary outcome) adjusted at 1 year was significantly better in the group treated with oral CYC (P < 0.03), although the effect of CYC was minor. The Fibrosing Alveolitis in Scleroderma Trial (FAST) included 45 patients with SSc-related ILD who were randomized to receive prednisolone (20 mg per day) and 6 CYC infusions (600 mg/m monthly) or placebo. This trial did not demonstrate significant improvement of the primary or secondary endpoints in the active treatment group versus placebo. Since with the exception of the study of Silver et al. none of the patients included in retrospective or prospective studies were selected on the basis of progression of ILD. Since only a minority of SSc patients develops severe ILD, we propose that further studies evaluating CYC should focus on the subgroup of SSc patients with worsening ILD.