Background/Purpose: Prior observational studies have estimated the risk of adverse events with low dose methotrexate (MTX). However, prior randomized controlled trials (RCT) were too small to precisely estimate the risk of MTX-related adverse events (AEs). We investigated the risk of AEs in patients without rheumatic disease using MTX compared with placebo.

Methods: We conducted pre-specified secondary analyses of the CIRT randomized controlled trial (Ridker et al, NEJM, 2019). The trial was conducted in N. America among adults with known cardiovascular disease and diabetes or metabolic syndrome. Subjects were randomly allocated to low dose MTX (maximum 20mg/week) or placebo. All subjects received folic acid 1mg for six days/week. The “AEs of interest” were adjudicated blinded to study drug assignment; they included gastrointestinal (hepatic or other), pulmonary (COPD, bronchitis, or pneumonitis), infectious, hematologic (bleeding or cytopenias), malignant, mucocutaneous (skin, alopecia or oral lesions), renal (acute kidney insufficiency or nephrolithiasis), neuropsychiatric, and musculoskeletal. The frequency and relative rates of the specific AEs of interest, laboratory AEs (AST, ALT, and CBC) as well as all reported AEs were compared across treatment arms in intention to treat analyses.  We estimated the hazard ratios (HR) using Cox proportional hazards regression. Skin cancers were further examined by sub-type using the same methods.

Results: 6,158 patients were enrolled and 4,786 randomized after a 5-8 week active run-in period and followed for a mean of 27 months on a median dosage of 16mg. Of the 2,391 subjects randomized to MTX, 2,104 (84.5%) experienced any AE and 1,968 (82.3%) experienced an AE of interest. This compared to 1,998 (78.0%) of the 2,395 randomized to placebo who experienced any AE and 1,796 (75.0%) who experienced an AE of interest.  The relative rate of an AE of interest (Table 1) was 27% higher for those randomized to MTX (HR 1.27, 95% CI 1.19– 1.35) compared to placebo.  The relative rates of gastrointestinal (HR 1.88, 95% CI 1.71-2.07), infectious (HR 1.16, 95% CI 1.03-1.31), pulmonary (HR 1.41, 95% CI 1.14-1.75), and hematologic (HR 1.17, 95% CI 1.09-1.26) events were elevated for those randomized to MTX.  There was no difference between treatment arms for the risk of malignant, mucocutaneous, neuropsychiatric, musculoskeletal, or renal AEs. While there were no overall differences in malignancies, skin cancers were more common in patients randomized to MTX than placebo, with a composite skin cancer HR 2.20 (95% CI 1.39-3.50) and squamous cell cancer HR 3.55 (95% CI 1.78-7.05) (Table 2).

Conclusion: In this large RCT among patients with known cardiovascular disease, MTX was associated with a significantly increased risk of AEs compared with placebo. While the trial was conducted in non-rheumatic disease patients and only select adverse events were adjudicated, the elevated risks observed for infectious, pulmonary, gastrointestinal, hematologic and skin cancer events represent a broad range of clinical issues, requiring further examination. These results quantify risk of MTX for the many clinicians and patients considering treatment across the spectrum of systemic rheumatic diseases.

Table 1.ACRabstract.solomon

Table 2.ACRabstract.solomon

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-adverse-events-in-a-randomized-double-blind-placebo-controlled-trialresults-from-the-cardiovascular-inflammation-reduction-trial-cirt/