Treatment with methotrexate and risk of lung disease in patients with rheumatoid arthritis: a nationwide population-based cohort study from Denmark

Objectives. Methotrexate (MTX) is the most commonly recommended disease-modifying anti-rheumatic drug (DMARD) for first-line treatment of rheumatoid arthritis (RA), however it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications.
Methods. From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30,512 persons with RA registered year 1997-2015. Information on ILD and respiratory failure was obtained from NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analyzed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized Incidence Ratios (SIRs) of lung disease were calculated to compare the RA population to the general population.
Results. There was no increased risk of lung disease with MTX treatment (1+ 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 persons but at the same level for the whole RA population compared to the background population.
Conclusion. Persons with RA had an increased risk of ILD compared to the general population but there was no further increased risk associated with MTX treatment.