SAT0137 METHOTREXATE ASSOCIATED ADVERSE EVENTS AND THEIR PREDICTORS IN METHOTREXATE-NAÏVE PATIENTS WITH RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW
Authors: A. Sherbini, S. Sharma, J. Gwinnutt, K. Hyrich, S. Verstappen
Journal: Annals of the Rheumatic Diseases (2020)

Background: The adverse events (AEs) associated with methotrexate (MTX) treatment for rheumatoid arthritis (RA) have been studied extensively, but precise estimates of the incidence and prevalence of AEs are lacking. There is also limited published data on the predictors of AEs. Objectives: To summarise and pool incidence and prevalence rates of AEs in patients treated with MTX for RA, and to identify treatment, clinical and disease related predictors of AEs. Methods: A systematic literature search was carried out using Embase, Medline, and CENTRAL databases to identify relevant studies published between 1/1/2005 and 12/2/2019. The eligibility criteria included RCTs, non-randomized trials, and observational studies of first-time users of MTX in adults (≥ 18 years old) with RA and reported incidence, prevalence or predictors of the most common MTX related AEs, including: any AE, serious AEs, discontinuation due to AEs, elevated liver enzymes, gastrointestinal (GI), mucocutaneous (MC), central nervous system (CNS), and pulmonary AEs. Pooled proportions of GI AEs and elevated liver enzymes of patients treated with MTX monotherapy were estimated using random effects meta-analysis. Results: Of 3142 records screened, we included 46 articles (35 clinical trials and 11 cohort studies) with a total of 9646 patients, and a mean follow-up duration of 70±35 weeks (range: 13 - 104 weeks for RCTs, 40 - 156 weeks for observational cohorts). Six studies reported incidence rate (IR) of any AE (range: 196 - 595 per 100 person-years), and eight studies reported IR of serious AEs (range: 3.7 - 15.9 per 100 person-years). The percentage of patients with any AE, reported in 32 studies, varied between 37% and 100% in RCTs, and between 13% and 34% in observational studies. Discontinuation of MTX due to AEs ranged between 1% and 29% in RCTs, and between 8% and 38% in observational studies. The reported prevalence of MC events (4% - 54%), CNS events (12% - 59%) and pulmonary events (10% - 67%) varied between studies. The estimated pooled prevalence from studies with a MTX monotherapy arm was 14% (95% CI: 9%, 19%; N=7 studies) for liver enzymes elevation (Figure 1), and 29% (95% CI: 13%, 44%; N=7 studies) for GI AEs (Figure 2). Figure 1. Forest plot of pooled prevalence of elevated liver enzymes Figure 2. Forest plot of pooled prevalence of gastrointestinal adverse events No statistically significant predictors of “any AE” were identified. For discontinuation of MTX due to AEs, RF positivity was associated with lower risk of MTX discontinuation due to MTX (HR 0.37, 95%CI: 0.21, 0.64), while other studies found that baseline HAQ score (OR 1.87, 95%CI: 1.11, 3.15) and BMI (OR 1.21, 95%CI: 1.02, 1.44) were associated with increased risk of MTX discontinuation due to AEs. ACPA positivity (OR 1.8, 95%CI: 1.1, 3.1), and high baseline alanine aminotransferase (ALT) (OR 3.1, 95%CI: 1.6, 6.2) were both independent predictors of two-fold elevation of ALT in one paper, and baseline creatinine (OR 1.03, 95%CI: 1.00, 1.07) and high baseline ALT (OR 1.03, 95%CI: 1.00, 1.06) were associated with increased risk of elevated ALT above the upper limit of normal in a different study. Conclusion: These findings affirm the high prevalence of GI AEs and elevated liver enzymes among patients treated with MTX for RA. The identified predictors of MTX withdrawal and elevated ALTs may be useful for identifying future patients likely to experience these AEs early in the course of treatment. However, the results of the predictors should be interpreted with caution, and further work is needed to replicate the results in studies with larger sample sizes and to assess the prognostic value of established predictors. Disclosure of Interests: Ahmad Sherbini: None declared, Seema Sharma: None declared, James Gwinnutt Grant/research support from: BMS, Kimme Hyrich Grant/research support from: Pfizer, UCB, BMS, Speakers bureau: Abbvie, Suzanne Verstappen Grant/research support from: BMS, Consultant of: Celltrion, Speakers bureau: Pfizer