Systemic sclerosis (SSc) is a complex autoimmune disease that affects multiple organs. SSc is associated with the highest mortality rate among rheumatic diseases and significantly diminishes quality of life. Consequently, research efforts have focused on understanding its etiopathogenesis and on developing related targeted therapies. Over the past decade, organ-specific therapies (such as tocilizumab and nintedanib for lung fibrosis) have been introduced to manage various manifestations of SSc. However, there is a lack of approved therapies for the overall disease. Currently, many novel compounds are being further evaluated in ongoing clinical trials. This article reviews drugs currently in phase 2 and phase 3 trials and highlights the key disease mechanisms they target in SSc. Recent advances in understanding the pathogenesis of SSc have facilitated the identification of actionable molecular and cellular pathways, leading to the testing of targeted therapeutic strategies. Concurrently, increasing emphasis is being placed on patient stratification and personalised treatment approaches to optimise clinical trial design, improve treatment responsiveness, and enhance the generalisability of trial outcomes. Among emerging treatments, cellular therapies, including chimeric antigen receptor T-cell therapy, represent a significant innovation. This paradigm shift offers substantial potential for improving outcomes in systemic sclerosis.
