MTX Not Associated With Increased Interstitial Lung Disease Risk in RA

Researchers sought to determine whether exposure to methotrexate for rheumatoid arthritis may lead to interstitial lung disease.

Results from a multivariate analysis published in BMJ Open suggest that methotrexate (MTX) exposure may delay onset of rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

Investigators abstracted data from 2 multicenter cohorts of patients with a new RA diagnosis: the Early RA Study (ERAS) group and the Early RA Network (ERAN). Conducted from 1986 to 2001 across 9 district general hospitals in England, ERAS recruited 1465 patients with <2 years’ disease duration and no prior conventional exposure to synthetic disease-modifying antirheumatic drugs (sDMARDs). ERAN, conducted from 2002 to 2012, recruited 1236 patients with <3 years’ disease duration from 23 centers in England, Wales, and Ireland. For both cohorts, researchers captured demographic and clinical data at baseline, between 3 and 6 months, at 12 months, and then once yearly until conclusion of follow-up. They extracted methotrexate use and diagnosis of RA-ILD as primary exposure and outcome measures, respectively. Secondary outcomes were the association of demographic, comorbid, and RA-specific factors on RA-ILD diagnosis. The investigators also calculated association of MTX exposure on time to RA-ILD diagnosis.

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Demographic features were similar across the ERAS and ERAN cohorts, as was the incidence of ILD diagnosis (4.2% in ERAS; 3.2% in ERAN; P =.206). Of 1578 patients exposed to MTX, 39 (2.5%) were diagnosed with ILD; among the 1114 patients not exposed to MTX, 53 (4.8%) were diagnosed with ILD.

Among patients who developed RA-ILD after sDMARD exposure (n=67), MTX was not associated with incident RA-ILD (odds ratio [OR], 0.85; 95% CI, 0.49-1.49; P =.578). In fact, among these patients, MTX exposure was associated with delayed ILD diagnosis (hazard ratio, 0.54; 95% CI, 0.28-1.06; P =.072), although the trend was not statistically significant.

In an extended analysis including patients with ILD already present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk for incident RA-ILD (OR, 0.48; 95% CI, 0.3-0.79) and longer time to ILD diagnosis (OR, 0.41; 95% CI, 0.23-0.75; both P =.004).

Other independent baseline characteristics linked to incident RA-ILD were older age at onset of RA (P <.001), history of ever smoking (P =.016), male sex (P =.03), rheumatoid nodules (P =.029), and longer time from first RA symptom to first outpatient visit (P =.04).

These data suggest that exposure to MTX does not increase risk for RA-ILD and, in fact, may delay its onset. However, further research is necessary to investigate the latter claim.


Kiely P, Busby AD, Nikiphorou E. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open. 2019;9(5):e028466.