Below is the abstract of the manuscript that summarizes the findings:
Objective: There is a lack of evidence on the comparative safety of conventional synthetic disease modifying antirheumatic drugs (csDMARDs). We assessed the comparative risks associated with first line csDMARDs in rheumatoid arthritis (RA).
Design: Multinational network cohort study with meta-analysis.
Setting: 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 csDMARD after RA diagnosis at age 18+ from 2005-2019.
Interventions: The four most commonly used first line csDMARDs for RA: methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), and leflunomide (LEF). MTX was the reference drug for comparisons.
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 calibrated HRs (cHRs). 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. Compared to MTX, SSZ was associated with a lower risk of infection: pooled cHRs 0.74 (95% confidence interval: 0.55-1.00) for serious infections, and 0.72 (0.57-0.90) for any infection. SSZ may also confer a reduced risk of myocardial infarction (0.86, 0.62-1.18) and stroke (0.82, 0.61-1.12), but also an increased risk of leukopenia (1.41, 0.91-2.18). While not significant in meta-analyses, risk estimates implied LEF may be associated with reduced risk of leukopenia (0.68, 0.42-1.11), pancytopenia (0.51, 0.24-1.07), any infection (0.74, 0.51-1.06), and cancer (0.77, 0.53-1.11) compared to MTX. Meanwhile, HCQ appeared associated with a reduced risk of myocardial infarction (0.93, 0.83-1.04) and stroke (0.88, 0.78-0.98).
Conclusions: There are differential risks associated with each of the studied csDMARDs. These findings will inform personalized treatment for newly diagnosed RA patients.
Below are links for study-related artifacts that have been made available as part of this study: