Cardiovascular effects of methotrexate in immune-mediated inflammatory diseases

Abstract

The cardiovascular effects of disease-modifying antirheumatic drugs and particularly of methotrexate (MTX) are complex and frequently incorrectly understood, which might lead to the unjustified discontinuation of this treatment. MTX, 'the gold standard' and first line treatment in rheumatoid arthritis, psoriatic arthritis, and other immune-mediated inflammatory diseases, has been proven to decrease inflammation, improve cardiovascular risk factors, and reduce mortality. This is supported by both the mechanism of action, as well as a body of clinical data evidence. MTX's cardiovascular effects, although incompletely understood, are explained by its antiproliferative, immunosuppressive, anti-inflammatory, and antiatherogenic effects. Several clinical trials have shown that MTX is associated with improved endothelial function, slower atherosclerosis progression, decreased risk of major cardiovascular adverse events, and benefits on survival. Given its systemic cardiovascular effects, MTX could be regarded as an important therapeutic agent not only to control disease activity in rheumatic diseases, but also to reduce cardiovascular risk and mortality.

Keywords: atherosclerosis; cardiovascular risk; inflammation; methotrexate; psoriatic arthritis; rheumatoid arthritis.

Figure 1.

Folate pathway and methotrexate. 5-CH₃-THF, 5-methyl-tetrahydrofolate; 5,10-CH₂-THF, 5,10-methylene-tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; MTHFR, methylene tetrahydrofolate reductase; MTX, methotrexate; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate.