Evaluating the Differential Risk of Rheumatoid Arthritis-Associated Interstitial Lung Disease with Biological and Targeted Synthetic DMARDs: A Nationwide Cohort Study in Taiwan

Background: Rheumatoid Arthritis-associated Interstitial Lung Disease (ILD) contributes substantially to morbidity and represents a major cause of mortality in patients with rheumatoid arthritis (RA). Recent studies have identified a decreased risk of ILD in Western patients treated with tofacitinib, a distinction not observed with other biological disease-modifying antirheumatic drugs (bDMARDs). Nonetheless, the disparity in various factors between Western and Asian populations potentially affects the applicability and generalizability of these findings.

Objectives: To assess the differential risk of RA-ILD associated with various biological and targeted synthetic DMARDs (tsDMARDs).

Methods: Employing a new-user design, this nationwide cohort study includes adult RA patients from the Taiwan National Health Insurance Research Database (NHIRD), who initiated b/tsDMARDs treatment from 2010 to 2021. The bDMARDs evaluated include adalimumab (ADA), golimumab (GOL), abatacept (ABA), etanercept (ETN), certolizumab pegol (CET), and tocilizumab (TOC), alongside tofacitinib (TOF) as the tsDMARD. Patients with a history of other autoimmune diseases or ILD were excluded. Participants were categorized into distinct exposure groups based on their initial b/tsDMARDs usage. The primary endpoint was the incidence of ILD events. An intention-to-treat approach was adopted with 3 years follow-up period. The main analysis involved calculating hazard ratios (HR) using a Cox proportional hazard model, with ADA users as the reference group and applying inverse probability treatment weighting (IPTW) by propensity scores.

Results: A total of 16,456 patients were included with distribution of patients across ADA, ETN, GOL, CET, TOC, ABA, and TOF groups was 4108, 3394, 2652, 999, 1610, 1517, and 2176, respectively. They are predominantly female (71.6 - 82.2%), and the mean age ranged from 52.2 to 56.8 years. The ADA group exhibited an incidence rate of 4.7 per 1,000 person-years (PY), with the lowest and highest rates observed in TOF (4.1 per 1,000 PY) and ABA (8.1 per 1,000 PY) respectively. Post-IPTW adjustment indicated no significant difference in ILD risk among the b/tsDMARDs compared to the ADA group. However, tofacitinib users exhibited a tendency towards a reduced ILD risk [HR = 0.71 (0.48-1.04)], contrasting with other bDMARDs [1.04 (0.66-1.64) – 1.38 (0.98-1.95)].

Conclusions: In this nationwide Taiwanese study, despite the results indicating no significant difference between adalimumab and other b/tsDMARDs, there would be a potential protective effect of tofacitinib in mitigating RA progression to significant morbidity. However, more extensive follow-ups and larger sample sizes are requisite in Asian populations.