Review Assesses Impact of Methotrexate in Patients With RA

Larry Hanover

Methotrexate reduces cardiovascular risk in patients with inflammatory disease but not in the general population.

Methotrexate (MTX) reduces cardiovascular risk in patients with rheumatoid arthritis (RA) because of its effects in reducing systemic inflammation, not from direct effects on the cardiovascular system, according to a new review of the drug.

Cardiovascular risk is one of the most prevalent comorbidities in patients with RA, axial spondyloarthritis, or psoriatic arthritis (PsA). Various factors elevate the risk, including high doses and/or prolonged use of glucocorticoids and nonsteroidal anti-inflammatory drugs.

RA was previously considered an independent cardiovascular risk factor, on par with diabetes, but mortality rates have been declining with better management of comorbidities, according to authors of a report in Expert Review of Clinical Pharmacology.

Although MTX—an older drug initially used for leukemia—can reduce cardiovascular events in patients with inflammatory disease, it cannot do so in the general population and should not be used to prevent cardiovascular events, the authors said.

The effectiveness of MTX in reducing cardiovascular risk in patients with RA occurs via reduced production of pro-inflammatory cytokines, the authors said. The drug decreases interleukin-6 (IL-6) and tumor necrosis factor (TNF) expression and increases gene expression of the soluble TNF receptor.

MTX is also associated with decreased expression of vascular adhesion molecules and has an impact on oxidative stress and the formation of free radicals, researchers said.

A 2015 meta-analysis found treatment with MTX was associated with a significant decrease in the risk of cardiovascular events (relative risk [RR] 0.72; 95% CI, 0.57-0.91). There was also a decrease in the risk of myocardial infarction after MTX (RR 0.81; 95% CI, 0.68-0.96). MTX was not found to have a significant effect on the risk of stroke, possibly due to a lack of power in the analysis (RR 0.78; 95% CI, 0.40-1.50).

In addition, a study of the risk of major cardiovascular events in 10,254 patients who had experienced a first event found that compared with TNF inhibitors, the rate ratio for subsequent cardiovascular events was 1.11 (95% CI, 0.70-1.75) for conventional standard disease-modifying antirheumatic drugs (including MTX), authors said.

MTX treatment has been found to decrease triglyceride levels and increase high-density lipoprotein (HDL) cholesterol in patients with early RA, they explained. Furthermore, in psoriasis, MTX treatment was associated with a significant decrease in proprotein convertase subtilisin/kexin type 9 levels, which is associated with an improvement in the lipid profile.

A decrease in the incidence of type 2 diabetes (T2D) has been associated with MTX treatment as well, the authors said, due to reduction in insulin resistance. A review of 16 studies found a promising, yet nonsignificant protective effect of MTX on the risk of diabetes (RR 0.48; 95% CI, 0.16-1.43). Another meta-analysis of 7 studies totaling almost 30,000 patients with RA found a significant 19% reduction in the risk of incident T2D (hazard ratio [HR] 0.81; 95% CI, 0.75-0.87).

Few studies have investigated how MTX impacts blood pressure, the authors said. A recent one found those who received MTX had lower blood pressure compared with those not receiving it, but the association with disease-modifying antirheumatic drugs in the study may have been a confounding factor. Also, surprisingly—considering cardiovascular events in RA are mainly the consequence of atherosclerosis—there is little data regarding the effect of MTX on endothelial dysfunction.

It is difficult to evaluate the impact of MTX on cardiovascular risk for patients with PsA because most available studies include both PsA and RA patients, the authors said. One meta-analysis does point to a reduction in cardiovascular events with treatment by MTX and TNF inhibitors. For plaque psoriasis, data is sparse as well. A first prospective study found no significant differences between adalimumab (Humira) and MTX.


Verhoeven F, Prati C, Chouk M, Demougeot C, and Wendling D. Methotrexate and cardiovascular risk in rheumatic diseases: a comprehensive review. Expert Rev Clin Pharmacol. Published online May 19, 2021. doi:10.1080/17512433.2021.1932461