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A 47-year-old man presented to an urgent care ambulatory clinic with a 3-day history of swelling around his left eye and a sensation of tightness in his throat. It had become difficult for him to swallow solids, and he felt as though food was sticking in his throat.

BACKGROUND: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for over 40 years, few data on adverse event (AE) rates derive from randomized placebo-controlled trials, where both causality and magnitude of risk can be inferred. OBJECTIVE: To investigate AE rates, risk, and risk differences, comparing LD-MTX to placebo. DESIGN: Pre-specified secondary analyses of a double-blind placebo-controlled randomized trial. SETTING: North America. PARTICIPANTS: Adults with known cardiovascular disease and diabetes or metabolic syndrome. INTERVENTION: Random allocation to LD-MTX (maximum of 20mg/week) or placebo. All subjects received folic acid 1mg per day for six days/week. MEASUREMENTS: The risk of specific AEs of interest as well as all AEs were compared across treatment arms, after blinded adjudication. RESULTS: 6,158 patients were enrolled and 4,786 randomized after an active run-in period; median follow-up was 23 months and median weekly dosage 16mg. Of the randomized subjects, 81.2% were male with a median age of 65.0 years and a median body mass index of 31.5 kg/m2. Of 2,391 subjects randomized to LD-MTX, 2080 (87.0%) experienced an AE of interest compared to 1951 of 2,395 (81.5%) randomized to placebo (HR 1.17, 95% CI 1.10 – 1.25). The relative hazards of gastrointestinal (HR 1.91, 95% CI 1.75 – 2.10), pulmonary (HR 1.52, 95% CI 1.16 – 1.98), infectious (HR 1.15, 95% CI 1.01 – 1.30), and hematologic (HR 1.15, 95% CI 1.07 – 1.23) AEs were elevated, comparing LD-MTX to placebo. With the exception of an increased risk of skin cancers (HR 2.05 (1.28, 3.28)), there was no difference between treatment arms for the risk of other malignancies, mucocutaneous, neuro-psychiatric, or musculoskeletal AEs. Renal AEs were reduced in subjects randomized to LD-MTX (HR 0.86, 95% CI 0.78 – 0.94). LIMITATIONS: The trial was conducted in non-rheumatic disease patients who tolerated LD-MTX during an active run-in. CONCLUSION: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer, gastrointestinal, infectious, pulmonary, and hematologic AEs, while renal AEs were decreased.

Background The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15–20mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.