Around the world, low-dose methotrexate (LD-MTX) is the medication most commonly for systemic rheumatic diseases and is the recommended first-line agent for rheumatoid arthritis. Little information is available to inform clinicians about the nature and prevalence of adverse events. North American research has now addressed AE rates, risk, and risk differences comparing LD-MTX versus placebo in clinical trials. The people studied were unrolled in clinical trials that involved random allocation to LD-MTX (≤20 mg/wk) or placebo, and all received folic acid, 1 mg/d, for sis days of each week. After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. There were 2391 people who were assigned to receive LD-MTX, and of these 2080 (87.0%) developed an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were higher with LD-MTX versus placebo. Apart from an increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were actually less frequent in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). The results were not startling – essentially they confirmed what clinicians have long held as conventional wisdom, but nevertheless the information should be regarded as a guide to the processes that should be in place for patient monitoring and counselling. Details of the study, published recently in The Annals of Internal Medicine, can be viewed here.