Methotrexate Appears Safe in Rheumatoid Arthritis–Associated Interstitial Lung Disease
Methotrexate use does not appear to increase the risk or accelerate the progression of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA), according to findings from a large systematic review.
Study Overview
Researchers analyzed sixteen studies encompassing 36,444 patients with RA, half of whom were receiving methotrexate. The review assessed whether methotrexate exposure contributed to either the development or worsening of RA-ILD. Control groups included patients with rheumatoid arthritis not treated with methotrexate.
Across the studies, lung function and disease progression were evaluated using high-resolution computed tomography, pulmonary function testing, arterial blood gas analysis, and survival data. Nine studies reported no link between methotrexate and the development of interstitial lung disease. Similarly, five studies found no evidence that methotrexate use led to worsening of established RA-ILD.
Methotrexate Exposure and Pulmonary Outcomes
One study observed a faster decline in lung function among patients receiving low-dose methotrexate, but this finding was not consistent across other analyses. Another study showed that patients treated with methotrexate had better overall survival compared with those who did not receive the drug. However, isolated data linked methotrexate to a higher incidence of acute exacerbations in some cases, highlighting the need for clinical vigilance.
Clinical Implications
These findings suggest that methotrexate remains a viable treatment option for rheumatoid arthritis without an increased risk of interstitial lung disease onset or progression. While monitoring remains essential, the overall evidence indicates methotrexate can be used safely in patients with coexisting or potential pulmonary involvement.
These results provide reassurance for clinicians concerned about pulmonary toxicity, supporting methotrexate’s continued role as a cornerstone therapy for rheumatoid arthritis and underscoring the importance of individualized risk assessment and ongoing patient monitoring.
Reference: Mahmou I et al. Methotrexate use in the treatment of rheumatoid arthritis associated-interstitial lung disease: a systematic review. Rheumatology (Oxford). 2025;keaf538.
