Methotrexate Versus Mycophenolate Mofetil as First-Line Therapy in Systemic Sclerosis: Evidence from Clinical Trials and Real-World Studies—A Narrative Review

Systemic sclerosis (SSc) is a heterogeneous autoimmune connective tissue disease characterized by immune activation, vasculopathy and progressive fibrosis of the skin and internal organs. Immunosuppressive treatment is commonly used in early inflammatory disease and in SSc-associated interstitial lung disease (SSc-ILD), yet the optimal first-line agent depends on the dominant clinical phenotype. Methotrexate (MTX) and mycophenolate mofetil (MMF) are two widely used conventional immunomodulatory options. This review summarizes the clinical trial evidence from the last four decades and places it into the context of contemporary guideline recommendations and real-world comparative effectiveness data. Two randomized placebo-controlled trials support a modest role for MTX in early diffuse cutaneous SSc, particularly for skin and musculoskeletal manifestations, but evidence for lung benefit is limited. MMF has stronger evidence for SSc-ILD, principally from the Scleroderma Lung Study II, a randomized double-blind trial showing comparable efficacy to oral cyclophosphamide with better tolerability, and from subsequent pilot, open-label, and real-world studies. Overall, the current evidence supports a phenotype-driven approach: MTX may be considered when skin or joint disease predominates without clinically relevant ILD, whereas MMF is generally preferred for SSc-ILD and systemic inflammatory disease. Direct head-to-head MTX versus MMF trials are lacking and remain an important research priority.