Leflunomide for Connective Tissue Diseases: A Narrative Review of Efficacy and Safety.

Connective tissue diseases (CTDs) are a heterogeneous group of systemic autoimmune disorders characterized by immune-mediated inflammation and multisystem involvement, frequently requiring long-term immunomodulatory therapy. Leflunomide, a conventional synthetic disease-modifying antirheumatic drug (csDMARD) with established efficacy in rheumatoid arthritis (RA), has increasingly been used off-label in various CTDs, although its clinical role remains incompletely defined. This narrative review synthesizes evidence published between 2015 and 2025 on the efficacy and safety of leflunomide in CTDs, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome, idiopathic inflammatory myopathies (IIMs), mixed connective tissue disease (MCTD), and overlap syndromes. Available data, largely derived from small clinical trials, observational studies, and case series, indicate that leflunomide may offer clinically meaningful benefit in patients with predominant inflammatory musculoskeletal manifestations, particularly inflammatory arthritis, and may function as a steroid-sparing alternative in individuals who are intolerant of or inadequately responsive to methotrexate. The safety profile of leflunomide in CTD populations appears broadly comparable to that observed in RA when appropriate patient selection, counselling, and laboratory monitoring are employed. However, interpretation of current evidence is limited by heterogeneity in study designs, variable outcome measures, and a lack of disease-specific randomized controlled trials. Leflunomide occupies a defined but limited role as a second-line csDMARD in non-organ-threatening CTDs, highlighting the need for further high-quality studies to clarify its optimal positioning within CTD treatment algorithms.