COMPARATIVE RISK OF INFECTION FOR FIRST-LINE CSDMARD THERAPY IN RHEUMATOID ARTHRITIS: A MULTINATIONAL COHORT ANALYSIS OF REAL WORLD DATA

ABSTRACT

Background/Aims Infections on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are an important concern for rheumatoid arthritis (RA) patients, especially during the COVID-19 pandemic. However comparative safety data between csDMARDs have been conflicting and limited in power. The objective was to assess the comparative safety of serious, opportunistic and all infections (including nonserious) of first-line csDMARDs in RA through a large multinational observational study. Methods We evaluated first-line new users of methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SZ) and leflunomide (LEF) monotherapy. Data was obtained from four US databases (IQVIA US Ambulatory EMR (AMBER), Optum® De-identified Clinformatics® Datamart (Optum), IBM MarketScan® Medicare Supplemental Database (MDCR), and IBM MarketScan Commercial Database (CCAE)), one from Germany (IQVIA Disease Analyser Germany EMR (Germany)), and another from the UK (IQVIA UK The Health Improvement Network). Patients included were ≥18 years with a RA diagnosis between 2005-2019, without prior inflammatory arthritis, cancer or infection (in the preceding 30 days). Serious infections were defined as those requiring hospitalisation or resulting in death within 30 days;opportunistic infections were defined as per published EULAR consensus. Patients were followed from 1-day following treatment initiation to the earliest of treatment discontinuation, switching, or addon plus 14 days, or loss to follow-up. Cox proportional-hazards models for MTX against each csDMARD with large-scale propensity score stratification were performed. A large set of negative control outcomes were used to calibrate hazard ratios (cHR) to account for potential residual confounding. Estimates were pooled where homogeneity across sources was adequate (I2<0.4). Results A total of 247,511 patients were included (MTX 141,647;HCQ 73,286, SSZ 16,521, LEF 16,057), with pooled incidence rates of serious, opportunistic and all infections across sources for MTX users of 33.7, 20.1 and 311.8 per 1,000 pyrs, respectively. With MTX as the referent, for all infections, the pooled cHR (with 95% Confidence Intervals) for SSZ was 0.73 (0.62, 0.86);HCQ, 0.96 (0.89, 1.04);and LEF, 0.74 (0.50, 1.08). The serious infection pooled cHR for SSZ was 0.75 (0.58, 0.97) and for LEF, 0.93 (0.61, 1.40). For opportunistic infections, pooled cHR for HCQ was 1.04 (0.92, 1.19). Conclusion SSZ, LEF and less consistently HCQ had a lower risk of all (including non-serious) infections, compared to MTX. SSZ and LEF were associated with a 25% reduction in the expected risk of all infections. SSZ was associated with a 25% lower risk of serious infections relative to MTX. In the first large scale observational network study assessing comparative risk of infection with csDMARDs there were differences between drugs in risk for all infections, with potential implications for clinical care.