This systematic review aims to summarise rates of adverse events (AEs) in patients with rheumatoid arthritis (RA) or inflammatory arthritis starting methotrexate (MTX) as monotherapy or in combination with other csDMARDs, and to identify reported predictors of AEs.Three databases were searched for studies reporting AEs in MTX-naïve patients with RA. Randomised controlled trials (RCTs) and observational cohort studies were included. Prevalence rates of AEs were pooled using random effects meta-analysis, stratified by study design.46 articles (34 RCTs and 12 observational studies) were identified. The pooled prevalence of total AEs was 80.1% in RCTs [95% CI 73.5, 85.9], compared with 23.1% in observational studies [95% CI 12.3, 36.0]. The pooled prevalence of serious AEs was 9.5% in RCTs [95% CI 7.4, 11.7], and 2.1% in observational studies [95% CI 1.0, 3.4]. MTX discontinuation due to AEs was higher in observational studies (15.5% [95% CI 9.6, 22.3]) compared with RCTs (6.7% [95% CI 4.7, 8.9]). Gastrointestinal events were the most commonly reported AEs (pooled prevalence: 32.7% [95% CI 18.5, 48.7]).Five studies examined predictors of AEs. Rheumatoid factor status, body mass index and HAQ score were associated with MTX discontinuation due to AEs; anti-citrullinated protein antibody negativity, smoking and elevated creatinine were associated with increased risk of elevated liver enzymes.The review provides an up-to-date overview of the prevalence of AEs associated with MTX in patients with RA. The findings should be communicated to patients to help them make informed choices prior to commencing MTX.
Ahmad A Sherbini, Seema D Sharma, James M Gwinnutt, Kimme L Hyrich, Suzanne M M Verstappen