Below is the abstract of the manuscript that summarizes the findings:
Objective: Recent systematic reviews and guidelines acknowledge a lack of data on the comparative safety of disease modifying antirheumatic drugs (DMARDs). We assessed the comparative risk/s associated with first-line disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA).
Design: Multinational network cohort and meta-analysis.
Settings: Routine health data from 8 databases (5 US, 1 UK, 1 Germany, and 1 Spain) mapped to a common data model.
Participants: New users of monotherapy DMARD after RA diagnosis at age 18+.
Interventions: The four most commonly used first-line DMARDs: Methotrexate (MTX), Hydroxychloroquine (HCQ), Sulfasalazine (SSZ), and Leflunomide (LEF).
Main outcome measures: Adverse events of interest included leuko/pancytopenia, infection, myocardial infarction, stroke, and cancer. Cox regression after propensity score stratification was used to estimate hazard ratios (HRs) for the risk of each event according to drug use, with MTX as reference. Negative control outcomes were used to estimate confounding-free calibrated HR (cHR). Findings were meta-analysed where I2<40%.
Results: In total, 247,511 participants were included: 141,647 (57%) MTX, 73,286 (30%) HCQ, 16,521 (7%) SSZ, and 16,057 (6%) LEF. LEF appeared associated with reduced risk of leukopenia (cHR 0.68 95% CI 0.41-1.13) and pancytopenia (0.51, 0.24-1.06), and with reduced risk of cancer (0.77, 0.53-1.12) compared to MTX. SSZ may be associated with increased risk of leukopenia (1.43, 0.96-2.15), but with a lower infection risk (cHR 0.76, 0.58-0.97 for serious, cHR 0.73, 0.62-0.86 for any). HCQ was associated with a reduced risk of stroke (0.88, 0.79-0.98).
Conclusions: Compared to MTX, leukopenia is 40% more common with SSZ, and 30% less with LEF. Infections (both serious and overall) appear to be about 25% less frequent in users of SSZ. HCQ in turn is associated with a 12% reduction in risk of stroke. These findings will inform personalized first-line treatment for newly diagnosed RA patients worldwide.
Below are links for study-related artifacts that have been made available as part of this study: