Rationally-based therapeutic disease modification in systemic sclerosis: Novel strategies.

Systemic sclerosis (SSc) is a highly challenging chronic condition that is dominated by the pathogenetic triad of vascular damage, immune dysregulation/autoimmunity and fibrosis in multiple organs. A hallmark of SSc is the remarkable degree of molecular and phenotypic disease heterogeneity, which surpasses that of other complex rheumatic diseases. Disease trajectories in SSc are unpredictable and variable from patient to patient. Disease-modifying therapies for SSc are lacking, long-term morbidity is considerable and mortality remains unacceptably high. Currently-used empirical approaches to disease modification have modest and variable clinical efficacy and impact on survival, are expensive and frequently associated with unfavorable side effects, and none can be considered curative. However, research during the past several years is yielding significant advances with therapeutic potential. In particular, the application of unbiased omics-based discovery technologies to large and well-characterized SSc patient cohorts, coupled with hypothesis-testing experimental research using a variety of model systems is revealing new insights into SSc that allow formulation of a more nuanced appreciation of disease heterogeneity, and a deepening understanding of pathogenesis. Indeed, we are now presented with numerous novel and rationally-based strategies for targeted SSc therapy, several of which are currently, or expected to be shortly, undergoing clinical evaluation. In this review, we discuss promising novel therapeutic targets and rationally-based approaches to disease modification that have the potential to improve long-term outcomes in SSc.