Methotrexate Not Associated with Lung Disease in RA


The prior use of methotrexate for rheumatoid arthritis patients doesn't seem to be associated with an increased risk of developing fibrotic interstitial lung disease, a common and potentially deadly complication of RA.


Methotrexate does not increase the risk of interstitial lung disease (ILD) in patients with rheumatoid arthritis, a study published in the European Respiratory Journal has confirmed.

Fibrotic interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis but whether use of methotrexate increases the risk of ILD further in patients with rheumatoid arthritis has been unclear. As a consequence, many rheumatologists and respiratory physicians have been reluctant to initiate or continue methotrexate in rheumatoid arthritis patients with ILD.

“Methotrexate has long been suspected to cause RA-ILD. Our international study, which included a large population of patients with RA-ILD and RA-no ILD, confirmed that methotrexate was not associated with an increased risk of chronic fibrotic ILD in rheumatoid arthritis,” said Professor Philippe Dieudé, head of the department of rheumatology, Bichat Claude-Bernard Hospital, University of Paris, France.

“Our findings suggest that methotrexate should not be systematically discontinued in patients with RA-ILD,” he added. “However, these results should be taken cautiously as we did not study the impact of methotrexate treatment on RA-ILD progression.”

The researchers examined the association of exposure to methotrexate to ILD in a retrospective case-control study involving 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD were included in the study. All the patients included in the study received a chest high-resolution CT scan; date of inclusion in the study was the date of the chest high-resolution CT scan excluding ILD diagnosis or date of ILD diagnosis.

Initially the researchers looked at the impact of methotrexate in a small group of French patients, and then the results were confirmed in a larger international sample including patients from five countries (Italy, United Kingdom, Mexico, Brazil and the United States).

Overall, the results showed there was an inverse relationship between methotrexate exposure and ILD in rheumatoid arthritis patients 0.43 (95% CI, 0.26-0.69; P=0.0006). Rheumatoid arthritis patients with ILD were also less likely to have ever used methotrexate than those without ILD.

Outside methotrexate-related hypersensitivity pneumonitis, which is a rare event, methotrexate should not be considered at risk for ILD in patients with rheumatoid arthritis, Professor Dieudé said. “The occurrence of ILD in a patient with RA should not lead to a systematic discontinuation of methotrexate and require a multidisciplinary discussion with at least rheumatologists and pulmonologists.”

The results also showed that ILD went undetected for significantly longer in rheumatoid arthritis patients with ILD who had used methotrexate compared with patients who had never used it---by approximately 3.6 years (95% confidence interval 2.6–4.7)---supporting the hypothesis of a possible inverse relationship between methotrexate ever use and ILD development in patients with rheumatoid arthritis.

A number of potential mechanisms could be responsible for the inverse relationship observed between methotrexate exposure and the occurrence of ILD in patients with rheumatoid, Professor Dieudé suggested. “First, a direct immunomodulating effect of methotrexate on ILD similar to that observed in other inflammatory diseases such as sarcoidosis. Second, an indirect effect related to methotrexate-driven decrease of RA-related systemic inflammation. Indeed, previous studies have reported that higher RA disease activity is associated with an increased risk of ILD.”

He emphasised: “Our study only describes a statistical relationship and did not provide evidence for causality.”

The researchers did not find any similar inverse relationship with the ever use of biological agents suggesting that the inverse relationship detected is likely be specific to methotrexate and not apply to other DMARDs.



Juge P-A, Lee JS, Lau J, et al. "Methotrexate and rheumatoid arthritis associated interstitial lung disease." European Respiratory Journal 2020; DOI: 10.1183/13993003.00337-2020

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