Background/Purpose: Methotrexate (MTX) is the most commonly used medication for patients with rheumatoid arthritis (RA), however, the frequency of MTX adverse events (AE) has not been fully described. We surveyed patients exposed to multiple MTX courses to characterize MTX-associated AEs.

Methods: A random sample of patients enrolled in the prospective Veterans Affairs RA (VARA) registry was selected. Medical records were reviewed for MTX-associated AEs from the time of MTX initiation until 120 days following MTX cessation. Separate MTX courses were defined by a gap > 90 days in the pharmacy data. The AEs abstracted included: dermatologic (alopecia, rash, photosensitivity, or nodulosis); gastrointestinal (oral ulcers/ stomatitis, nausea/vomiting/anorexia/dyspepsia, or diarrhea); hematologic (leukopenia <3,500, thrombocytopenia <100,000, or new-onset anemia [hemoglobin <13.5 g/dL in men and <12.0g/dL in women]); hepatic (transaminitis >upper limit of normal, fibrosis, or cirrhosis); infectious (clinical diagnosis defined by the treating physician); central nervous system (headache, dizziness/vertigo, fatigue within 48 hours of MTX, mood alteration, or memory impairment as defined by the patient or physician); respiratory (dry cough, dyspnea, or interstitial lung disease [ILD]); and other (AE defined by physician or patient as associated with MTX). Significant AEs (SigAE) were defined as an AE leading to drug discontinuation (operationalized as any AE preceding MTX cessation by ≤ 120 days).

Results: Of the 319 patients for whom records were abstracted (1196 total patient-years [PY] of observation), 642 AEs were recorded in 270 patients during 614 total courses of MTX. The first AEs (n=268) occurred over a course of 496.5 PY of observation, yielding an incidence rate of first AE of 0.54 per PY (95% CI 0.48-0.61). SigAE (n=93) had an incidence rate of 0.08 per PY. The most common AEs were hematologic (30.4% of all AE), with anemia the leading subcategory (27.9%) (see Table). The most common SigAE was respiratory (22.6% of all SigE) but the incidence of ILD was low at 4.1%.

Conclusion: Among US veterans with RA,MTX has a high AE rate, with approximately one AE noted per patient over a two-year period of treatment. In contrast, the rate of SigAE mandating drug discontinuation is much lower. The most common SigAE was respiratory, which may reflect physicians’ high level of concern for MTX- associated ILD. However, the incidence of ILD in the cohort was low.

Table: Adverse and Significant Methotrexate Adverse Events in VARA cohort

*SigAE=significant AE; N=nausea; V=vomiting; N=total number of reported AE; n=total number of reported significant Aes

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-adverse-events-in-a-cohort-of-us-veterans-with-rheumatoid-arthritis/