Methotrexate Treatment and Risk for Interstitial Lung Disease or Respiratory Failure in Rheumatoid Arthritis

Individuals with rheumatoid arthritis had an increased risk of interstitial lung disease compared with the general population, however, there was no greater risk associated with MTX treatment.

Methotrexate treatment for rheumatoid arthritis (RA) is not associated with an increased risk for interstitial lung disease (ILD) or respiratory failure, according to study results published in Rheumatology.

While methotrexate is the most common disease modifying anti-rheumatic drug for RA, limited data exist on the long-term lung toxicity secondary to the treatment. The goal of the current study was to explore the risk for ILD and respiratory failure associated with methotrexate in patients with RA.

Using the Danish National Patient Register and the DANBIO register for rheumatic diseases, 30,512 (68.7% women) patients with RA were identified and researchers collected data from additional Danish registers on ILD and respiratory failure, as well as demographic data and medical treatment.

Standardized incidence ratios (SIRs) were calculated to assess the level of lung disease among patients with RA, compared with that in the background population.

During 5-year follow-up, 18,045 (60.3%) patients purchased methotrexate and 10,789 (35.4%) subjects purchased sulfasalazine.

At 1 year, respiratory failure was documented in 109 patients with RA  and after 5 years, 359 patients were diagnosed with respiratory failure. ILD was evident in 127 patients after 1 year and in 285 patients after 5 years. Of these, 29 patients were diagnosed with drug-induced ILD after 5 years.

There was no association between methotrexate treatment and ILD after 1 year (hazard ratio [HR], 1.03; 95% CI, 0.71-1.47) or 5 years (HR, 1.00; 95% CI, 0.78-1.27) of follow-up. Risk for respiratory failure was lower among patients who purchased methotrexate after both 1 year (HR, 0.48; 95% CI, 0.32-0.73) and 5 years (HR, 0.54; 95% CI, 0.43-0.67).

For ILD, SIRs were 3.63 (95% CI 2.9-4.3) for methotrexate, 4.12 (95% CI, 2.7-5.5) for sulfasalazine and 3.38 (95% CI, 2.6-4.1) for those who purchased neither methotrexate nor sulfasalazine.

For respiratory failure, the SIR was not increased for patients who purchased methotrexate, while SIRs were mildly elevated for those who purchased sulfasalazine but not methotrexate (SIR, 1.72; 95% CI, 1.2-2.2) and for those who purchased none of these medications (SIR, 1.65; 95% CI, 1.4-1.9).

The study had several limitations, including the potential of misclassification of the RA diagnosis as RA registration in the registry does not confirm the diagnosis, no data on the actual use of the purchased medication, and potential underestimation of the incidence of lung disease as the RA population was not systematically screened for ILD.

“[O]ur study adds to the accumulating evidence that treatment with MTX [methotrexate] does not increase the risk of ILD or respiratory failure in persons with RA, who have an increased risk of ILD as a manifestation of their underlying RA,” concluded the researchers.


Ibfelt EH, Jacobsen RK, Kopp TI, et al. Methotrexate and risk of interstitial lung disease and respiratory failure in rheumatoid arthritis: a nationwide population-based study. Rheumatology (Oxford). Published online Aug 11, 2020. doi:10.1093/rheumatology/keaa327