Cardioprotective mechanisms and efficacy of colchicine, methotrexate, hydroxychloroquine, sulfasalazine and leflunomide in inflammatory rheumatic and musculoskeletal diseases.

Chronic systemic inflammation contributes to the excess risk of atherosclerotic cardiovascular disease (ASCVD) in inflammatory rheumatic and musculoskeletal diseases (RMDs), raising the possibility that anti-inflammatory treatment may modify vascular risk. This review sought to critically review the mechanistic and clinical evidence for atheroprotection with colchicine and the commonly used conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) methotrexate, hydroxychloroquine, sulfasalazine and leflunomide. We performed a targeted narrative review of key experimental studies, randomized cardiovascular outcome trials, observational RMD cohorts and systematic reviews, prioritizing evidence directly relevant to ASCVD outcomes and cardiometabolic mechanisms. Colchicine has the strongest randomized evidence for reducing recurrent ASCVD events in patients with established coronary disease, with supportive observational data in gout. Methotrexate is associated with fewer cardiovascular events in rheumatoid arthritis (RA), whereas the CIRT trial was neutral in patients without inflammatory arthritis. Hydroxychloroquine has favorable lipid, glycaemic and antithrombotic effects and observational associations with lower cardiovascular risk in RA and systemic lupus erythematosus (SLE), but no definitive cardiovascular outcome trial. Evidence for sulfasalazine is limited and observational, and human data for leflunomide are conflicting. Cardiovascular benefit differs substantially between agents and is most convincing for colchicine in secondary prevention and for inflammation control with methotrexate in RA. Dedicated prospective trials in inflammatory RMD populations are needed before any csDMARD can be prescribed primarily for ASCVD prevention.