Disease-Modifying Antirheumatic Drugs, Rheumatoid Arthritis-Associated Lung Disease, and Serious Infection: Risks and Associations

Abstract

Abstract for paper 1: Objective: To investigate the association of disease-modifying antirheumatic drugs (DMARDs) and risk of incident interstitial lung disease (ILD) among patients with rheumatoid arthritis (RA) using a systematic literature review and meta-analysis. Methods: We performed a systematic literature review and meta-analysis of studies examining the association of DMARDs with incident RA-ILD. PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to November 2023 for randomized controlled trials (RCTs), observational studies, and post-marketing surveillance studies that investigated adults with RA and compared DMARDs of interest with placebo, no DMARDs, or other DMARDs. The outcome was incident ILD. We summarized the literature on DMARDs and incident RA-ILD risk. Among studies with sufficient quality, we performed meta-analyses to obtain odds ratios (OR) and 95% confidence intervals (95%CI) using the Mantel-Haenszel method. Results: Among 3,612 studies, we identified a total of 40 papers that encompassed 486,465 patients with RA and 3,928 incident ILD outcomes that were included in the final systematic review and meta-analysis. Among the studies, 24 were RCTs, 4 were prospective cohort studies, 9 were retrospective cohort studies, 2 were case-control studies, and 1 was a post-marketing surveillance study. The pooled analysis from RCTs revealed no statistically significant difference in the odds of ILD development for any specific DMARD across all comparisons examined. The largest identified RCT (Oral Surveillance trial) of tofacitinib (n=2,911) vs. tumor necrosis factor inhibitor (TNFi, n=1,451) found no relationship with incident ILD (OR 0.94, 95%CI 0.52 to 1.69, p=0.828). In 7 observational studies, the use of methotrexate (MTX) yielded a pooled OR for ILD of 0.49 (95%CI 0.32 to 0.76, p.001) compared to those not using MTX. In a single observational study, tofacitinib users had an OR for ILD of 0.36 (95%CI 0.15 to 0.87, p=0.024) compared to TNFi users. Conclusion: Observational data suggest no increased risk of MTX and tofacitinib for incident RA-ILD. However, these studies may be susceptible to bias, and no specific DMARD showed associations with incident RA-ILD in RCTs. Further well-designed prospective studies are warranted for definitive conclusions on the potential relationship between DMARDs and RA-ILD risk. Abstract for paper 2: Objective: To investigate the association between rheumatoid arthritis-associated lung disease (RA-LD) and serious infection risk. Methods: We conducted a retrospective cohort study using the MGB Biobank (Boston, Massachusetts), comparing RA-LD to RA patients without lung disease (RA-no LD), matched by age, sex, and RA duration. RA-LD cases were verified by medical record review and chest imaging for clinically apparent RA-associated interstitial lung disease (RA-ILD) and/or RA-associated bronchiectasis (RA-BR). The primary outcome was serious infection. Incidence rates and propensity score-adjusted subdistribution hazard ratios (sdHR) were calculated using Fine and Gray models to account for competing risk of death. Results: Among 221 RA-LD cases (151 RA-ILD and 70 RA-BR) and 980 RA-no LD comparators, RA-LD had a significantly higher serious infection risk compared to RA-no LD comparators (55.8 vs. 25.8 per 1,000 person-years, sdHR 1.60, 95%CI 1.20-2.12). The increased risk remained significant for RA-ILD cases (sdHR 1.79, 95%CI 1.33-2.41), but not for RA-BR (sdHR 1.19, 95%CI 0.72-1.97). Anatomic sites of infection that were more common in RA-LD included pulmonary, skin and soft tissue, and ear, nose and throat; RA-LD was associated with various pathogen types: virus, bacteria, fungus, and mycobacteria. Specific pathogens with higher frequency in RA-LD cases, particularly among RA-BR, included influenza virus, respiratory syncytial virus, Staphylococcus, Pseudomonas, and nontuberculous mycobacteria. Conclusion: RA-LD, particularly RA-ILD, is associated with a significant increased risk of serious infection across anatomic sites and diverse pathogen types. RA-BR is associated with increased pulmonary infections. Tailored infection prevention strategies, including vaccination, are essential for this vulnerable population.