Randomised controlled trials in systemic sclerosis: patient selection and endpoints for next generation trials

Abstract

The heterogeneity in the natural history of systemic sclerosis is a major issue in both clinical management and trial design and is dictated by the complex and multifactorial pathogenesis of the disease. Systemic sclerosis is an autoimmune disease and therefore many trials for the disease have targeted immune activation pathways; however, the phase 3 trials that have been positive have targeted pathways directly linked to tissue damage rather than systemic immune activation. On one hand, these results represent enormous progress that has led to the first approved drugs for this extremely challenging condition. On the other hand, they have revealed a possible selection bias in our current approach to trial design. In this Series paper, we describe randomised controlled trials from the past 4 years we believe to be most relevant to future strategies in systemic sclerosis. Based on advances in our understanding of the pathogenesis and natural history of disease, we will also identify important points to consider in the design of the next generation of systemic sclerosis trials.