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.
ABSTRACT
Background: The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is of particular concern for people with rheumatoid arthritis (RA), with concerns that these people may be at higher risk and have poorer outcomes. However, at present the implications of COVID-19 for people with RA remain poorly understood. Objectives: To investigate the associations between rheumatoid arthritis and the risk of COVID-19 diagnosis, hospitalisation with COVID-19 and COVID-19-related death. Methods: A population-based cohort study including all individuals registered in the Information System for Research in Primary Care (SIDIAP). SIDIAP includes primary care records covering over 80% of the population of Catalonia, Spain, and was linked to region-wide SARS-CoV-2 PCR testing, hospital and mortality records. Outpatient diagnoses of COVID-19, hospitalisations with COVID-19 and deaths with COVID-19 were identified as study outcomes between 1st March and 6th May 2020. A multi-state model was used, with cause-specific Cox survival models estimated for each transition, adjusted for age and sex. Results: A total of 5,586,565 individuals were identified in SIDIAP as of the 1st March 2020, of which 16,344 had RA. RA patients were median (IQR) 63 years (52.0, 74.0) and the majority (n=11,727, 71.8%) were female. Having RA was positively associated with being diagnosed with COVID-19 (adjusted HR 1.14 (1.03 to 1.28)), with hospitalisation with COVID-19 (HR 1.66 (1.35 to 2.04)). However, we did not find an association between RA status and the risk of worsening from outpatient diagnosis to hospitalization or death, or from hospitalization to death (see Table 1). Conclusion: To our knowledge, this is the largest study performed to date looking at COVID-19 outcomes in RA patients. Individuals with RA were found to have an increased risk of COVID-19 diagnosis and hospitalisation with COVID-19, compared to the general population. Further research is needed to address factors associated with this including the presence of other co-morbidities, underlying RA disease activity and the use of immunosuppressive medications.