Treatment of systemic sclerosis: is there any hope for the future?

Correspondence to Professor Yannick Allanore; [email protected] Systemic sclerosis (SSc) is an orphan connective tissue disease characterised by skin and multiorgan involvement. The following original pathological processes distinguish SSc from other connective tissue diseases: (1) microvascular modifications, initially functional and partly reversible, (2) perivascular inflammation which appears to be moderate and perhaps transitory, (3) autoimmune activation, leading to the production of specific and persistent autoantibodies and (4) fibroblast activation, producing an excess of extracellular matrix leading to fibrosis. Therefore, SSc is a complex disease with the implication of multiple players in its pathogenesis. SSc is a major medical challenge with high mortality and morbidity. In a meta-analysis, the pooled standardised mortality ratio (SMR) was measured as 3.53 (95% CI 3.03 to 4.11) and adjusted metaregression did not show significant changes in SMR over time. Nevertheless, some reports did suggest an improved survival in recent years. In an Italian study, the 10-year survival showed a clear-cut increase (81%) compared with older series (69%) from the same centre. However, the discrepancy may not only come from improved therapeutic management, but might be due to some changes in the natural history, to an earlier referral of the patients and, even more likely, to the better recognition of patients with milder disease. Accordingly, in the recent Italian series, there were more patients with the limited cutaneous SSc (LcSSc) than in the older study (87.5% vs 72%). In terms of organ involvement and progression of the disease, the outcomes in LcSSc and diffuse cutaneous SSc (DcSSc) are different. The new classification criteria will more easily identify patients with LcSSc. Therefore, it will become core to require the cutaneous subsetting for any scientific work on SSc and, beyond skin, subclassification or clustering is awaited to improve SSc patient risk stratification. Regarding morbidity, accumulating evidence has shown the huge impact of SSc on quality of life (QOL). With the support of patients associations and international medical societies, we have performed a large survey (1902 patients with SSc from 60 countries). The results confirmed the impaired QOL in SSc as measured by the short-form 36 (SF-36) questionnaire; it was particularly marked for physical health (mean±SD 43.4 ±23.4; 100=best health), but mental health was also impaired (mean±SD 52.3±23.1). Patients with DcSSc had poorer QOL scores than patients with LcSSc, for the physical (mean±SD 39.8±22.3 vs 46.6±23.7; p<0.0001) and mental (mean±SD 50.3±23.2 vs 53.8 ±23.0; p=0.003) components. The dimension of QOL and patient-reported outcomes is moving in SSc, and it should provide meaningful information on future drugs. The majority of ongoing or upcoming trials target skin fibrosis and the early DcSSc subset. Indeed, no drug has been so far labelled according to the properties to reduce skin fibrosis or organ involvements. Many trials failed in the past and one might question whether the failure is mostly driven by the wrong choice of the drug, the use of imprecise outcome measures or imperfect selection of the included patients. Regarding the drug to be investigated, we will comment later on the new trials, but it is obvious that SSc is far more than a ‘simple’ inflammatory or autoimmune disease. The relationships between vasculopathy, immune disturbances and fibroblast activation are complex and may challenge the identification of the efficacy of a single therapeutic agent. Regarding outcome measures, although not perfect, several lines of evidence have shown that skin sclerosis measured by the modified Rodnan skin score (mRSS) is a robust surrogate marker for SSc. The last point about the targeted population has been addressed by several recent studies. One of the methodological issues in past trials has been the observation that the control arm experienced a decrease in mRSS. Therefore, the drug under investigation had to show further acceleration of the decrease in skin fibrosis