Conceptual framework for the definition of disease modification in systemic sclerosis and potential implications for drug development and clinical study design.

Abstract

Systemic sclerosis (SSc) is a multifaceted systemic autoimmune disease, characterised by the interplay of vascular alterations, immune dysregulation, and fibrosis. The molecular changes and the clinical presentation of SSc are highly heterogeneous and vary considerably between individual patients. This heterogeneity has hampered efforts to reach a unified and pragmatic definition of disease modification in SSc. Using a consensus approach among SSc experts, the authors seek to identify current challenges in defining SSc disease modification. The definition of disease modification in SSc requires a nuanced approach that considers molecular, mechanistic, and clinical aspects. Disease-modifying treatments in SSc should target core pathways or cells rather than regulatory mechanisms. Disease-modifying treatments should show sustained effects on disease activity and prevent progression of damage across organs, manifestations, disease stages, and disease endotypes. The complex and variable nature of SSc needs to be reflected in preclinical drug development efforts and clinical trial designs to demonstrate disease-modifying effects of drug candidates for SSc. We herein provide a first framework for the definition of disease modification of vascular, inflammatory, and fibrotic domains in SSc. Advances in our understanding of the cellular and molecular mechanisms driving the progression of SSc will enable further refinement of the definition of disease modification and guide optimal preclinical modelling and innovative clinical trial design in future efforts.