More on Methotrexate and ILD Risk

Jack Cush, MD

Nov 12, 2025 6:19 pm

To assess the progression of the interstitial lung disease related to Methotrexate (MTX) exposure, and to evaluate the lung involvement in RA non-ILD patients with MTX exposure, a systematic review was performed to assess whether RA patients receiving methotrexate (MTX) are at greater risk for rheumatoid arthritis (RA-ILD).

It appears that MTX does not have association with an increased risk of ILD and/or its progression in RA patients.

A systematic review of 16 studies and 36 444 RA patients, including 18 548 (50.8%) were treated with MTX. The Non exposed MTX subjects (N-MTX) were considered as the control group in 14 studies. Studies included High-Resolution Computed Tomography (10 studies), pulmonary function tests (8 studies), arterial blood gas analysis (one study) and survival (5 studies).

MTX was not associated with a risk of developing ILD (9 studies).
5 studies suggested that MTX was not associated with the progression of RA-ILD.
1 study showed an accelerated decline in lung function with low-dose MTX
Overall, better survival was shown in MTX patients compared with the N-MTX group (one study).
1 study, MTX use was significantly associated with the development of acute exacerbations

Another recent review and metanalysis of 19 studies and 47,271 RA patients receiving MTX found14 studies with no evidence of an association between MTX and ILD, with some even suggested that MTX has protective properties reducing inflammation and limiting lung damage. There were five studies suggesting a link between MTX use and increased risk or worsening of RA-associated ILD (RA-ILD).