Methotrexate does not increase risk for rheumatoid arthritis-associated ILD

Methotrexate use by patients with rheumatoid arthritis was not associated with an increased risk for developing interstitial lung disease, according to a study published in European Respiratory Journal.

“Methotrexate is recommended as the first-line treatment of rheumatoid arthritis as it effectively reduces disease activity, morbidity and mortality,” Pierre-Antoine Juge, MD, rheumatologist in the department of rheumatology at Bichat-Claude Bernard Hospital, Paris, and colleagues wrote. “Methotrexate has long been suspected as a causative agent in lung disease, including fibrotic ILD and many rheumatologists and pneumologists are reluctant at introducing or maintaining methotrexate in patients with rheumatoid arthritis-ILD.”

Researchers conducted a case-control study of 410 patients with chronic fibrotic ILD associated with rheumatoid arthritis (RA) and 673 patients with RA who did not have ILD. The researchers assessed methotrexate exposure via a systematic chart review of all patients. Patients were assigned to different samples and estimates were pooled over the samples using meta-analysis.

In the discovery sample, which included 100 patients with RA-ILD and 165 patients with RA without ILD, 60% of those with RA-ILD and 83% with RA and no ILD had used methotrexate. The researchers reported a negative association between methotrexate use and RA-ILD after controlling for age, sex, smoking status, methotrexate exposure duration, length of methotrexate use at RA onset and biologic use (adjusted OR = 0.46; 95% CI, 0.24-0.9; P = .022). In the pooled replication sample, which included 310 patients with RA-ILD and 508 patients with RA without ILD, the researchers found a similar association, with fewer methotrexate users among those with RA-ILD compared with those with RA and no ILD (79.7% vs. 95.5%; aOR = 0.39; 95% CI, 0.19-0.79; P = .009).

In the combined population of both samples, the researchers reported an inverse relationship between methotrexate ever use and ILD occurrence among patients with RA (aOR = 0.43; 95% CI, 0.26-0.69; P = .0006). Methotrexate ever users were less frequent among the population of patients with RA-ILD compared with those without ILD.

ILD detection was delayed among ever users in patients with RA-ILD compared with never users (P < .001).

“These results suggest that methotrexate could be considered as having a disease-modifying effect on RA-ILD that could result from distinct anti-inflammatory mechanisms. ... We acknowledge that a prospective study would be required to further establish that methotrexate ever use is delaying the onset of RA-ILD, such a trial is unlikely to be performed due to the central role of methotrexate in the management of RA,” the researchers wrote.