• arthritis, rheumatoid
• epidemiology
• therapeutics

For more than three decades, low-dose methotrexate (MTX) has been the first-line treatment for patients with rheumatoid arthritis (RA). Even after the introduction of biologics/biosimilars and janus kinase (JAK)-inhibitors, MTX has maintained its importance and is used as a combination partner in the most cases.1 Clinicians are well aware of several toxicities of MTX, including constitutional symptoms (such as nausea and malaise) as well as haematological, gastrointestinal and hepatic adverse events (AEs). In the vast majority of cases, these are clinically manageable.

Despite the extensive use of MTX, we have little information about the magnitude of the adverse effects of MTX compared with placebo because, for ethical reasons, we cannot withhold effective therapy in patients with inflammatory rheumatic diseases for longer periods of time to avoid disease progression and occurrence of further comorbidities. It is therefore of utmost interest that a study has now been published in the Annals of Internal Medicine that has examined the safety profile of MTX compared with placebo in a large group of patients without inflammatory rheumatic disease.2

The Cardiovascular Inflammation Reduction Trial3 (CIRT) was a randomised, double-blind, placebo-controlled trial designed to evaluate the efficacy of MTX (target dose of 15–20 mg weekly) versus placebo in lowering the number of cardiovascular (CV) events. Both arms were carried out in combination with folic acid. Patients enrolled in the trial were required to have severe cardiovascular risks: a known history of myocardial infarction or multivessel obstructive coronary artery disease, in combination with type 2 diabetes or metabolic syndrome. The aim was to evaluate the efficacy of MTX to prevent myocardial infarction, stroke or death due to cardiovascular events. The rationale was based on previous findings in RA that had suggested a lower CV complication rate on MTX therapy.4 5 The CIRT study was terminated …