Abstract
About 20% of patients with a history of atherosclerotic cardiovascular disease will experience further cardiovascular events despite maximal pharmacological treatment with cardioprotective drugs. This highlights the presence of residual cardiovascular risk in a significant proportion of patients and the need for novel, more effective therapies. These therapies should ideally target different pathophysiological pathways involved in the onset and the progression of atherosclerosis, particularly the inflammatory and immune pathways. Methotrexate is a first-line disease-modifying antirheumatic drug that is widely used for the management of autoimmune and chronic inflammatory disorders. There is some in vitro and in vivo evidence that methotrexate might exert a unique combination of anti-inflammatory, blood pressure lowering, and vasculoprotective effects. Pending the results of large prospective studies investigating surrogate end-points as well as morbidity and mortality, repurposing methotrexate for cardiovascular risk management might represent a cost-effective strategy with immediate public health benefits. This review discusses the current challenges in the management of cardiovascular disease; the available evidence on the effects of methotrexate on inflammation, blood pressure, and surrogate markers of arterial function; suggestions for future research directions; and practical considerations with the use of methotrexate in this context.