▴ Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med2006;354:2655–66OpenUrlCrossRefPubMedWeb of Science

Around 40% of patients with systemic sclerosis will develop significant interstitial lung disease. No agent has been proved in a randomised controlled trial to be effective in this condition. This multicentre, double blind, randomised, placebo controlled trial evaluated the effectiveness of oral cyclophosphamide in patients with scleroderma who had restrictive lung function, exertional dyspnoea, and evidence of active alveolitis.

One hundred and fifty eight patients were randomised to receive cyclophosphamide (up to 2 mg/kg/day) or placebo for 1 year. There was a small but significant difference in the primary outcome measure—change in forced vital capacity (FVC)—at 12 months, favouring cyclophosphamide (−1.0 (0.92)% predicted v −2.6 (0.9)% predicted, p<0.03). This benefit was maintained after a further 12 months off study medication. There was no improvement in gas transfer but small improvements were seen in the transitional dyspnoea index and some quality of life measures. Those with more severe fibrosis at baseline had the greatest benefit in FVC.

Adverse events were more common in the cyclophosphamide group, including a significantly greater incidence of leucopenia and neutropenia. The potential longer term associations with malignancy were not evaluated within this 2 year period.

This is the first placebo controlled study to demonstrate a benefit of treatment for scleroderma related interstitial lung disease. However, these benefits were small and need to be weighed against the risk of adverse side effects.