Challenges in systemic sclerosis trial design.

Systemic sclerosis (scleroderma; SSc) is an autoimmune rheumatic disease with high clinical burden and unmet need due to connective tissue fibrosis and vascular damage. It has the highest case specific mortality of any rheumatic disease, with approximately half of patients diagnosed eventually dying as a direct result of SSc. There are no approved diseases modifying treatments. This is partly related to the difficulty of conducting clinical trials for regulatory approval. Traditionally skin thickness has been assessed using the modified Rodnan skin score (MRSS) that has been shown to correlate with survival and risk of complications in SSc. However recent trials have highlighted the limitations of MRSS which often improves over time, even on placebo. A new composite measure integrating changes in multiple domains of lung function, skin, patients and physician global and HAQ disability index has been developed, the CRISS (Composite Response Index for Systemic Sclerosis). This measure looks promising and has provisional acceptance by American College of Rheumatology (designated ACR CRISS) but is unlikely to be strongly persuasive to Health Authorities in isolation unless there are also clinically meaningful changes in relevant domains that reflect how patients feel, function or survive.