Methotrexate and risk of Lung disease in Rheumatoid Arthritis: A nationwide population-based cohort study from Denmark

Background: Methotrexate (MTX) is the most commonly recommended disease-modifying anti-rheumatic drug (DMARD) for first-line treatment of rheumatoid arthritis (RA); however, MTX has been suspected to cause lung disease as an adverse effect. Objectives: To investigate the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in RA patients treated with MTX and other medications. Methods: From the Danish National Patient Register (NPR) and the clinical DANBIO register for rheumatic diseases, we retrieved data on 30,512 RA patients registered between 1997 and 2015. Information on ILD and respiratory failure was obtained from NPR. Information on age and gender for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Register. Associations between MTX and lung disease outcomes were analyzed in Cox regression models with adjustment for age, calendar time, gender and other medications. Standardized Incidence Ratios (SIRs) of lung disease were calculated to compare RA patients to the general population. Results: There was no increased risk of lung disease with MTX treatment (one or more purchases compared to no purchases), HR (95% CI) 1.00 (0.78-1.27) for ILD and 0.54 (0.43-0.67) for respiratory failure at 5-year follow-up. SIR was 3-4 times increased for ILD in MTX treated RA patients but at the same level for the whole RA population compared to the background population. Conclusion: RA patients had an increased risk of ILD compared to the general population, but there was no further increased risk associated with MTX treatment.