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BMJ Open. 2019 May 5;9(5):e028466. doi: 10.1136/bmjopen-2018-028466.

Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts.

Author information

Department of Rheumatology, St Georges University Hospitals NHS Foundation Trust, London, UK.
Institute of Medical and Biomedical Education, St George's , University of London, London, UK.
Center for Health Services and Clinical Research and Post Graduate Medicine, University of Hertfordshire, Hatfield, UK.
Department of Academic Rheumatology, King's College, London, UK.
Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
Department of Rheumatology, North Bristol NHS Trust, Bristol, UK.
Department of Rheumatology, The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Shrewsbury, UK.



To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early rheumatoid arthritis (RA) inception cohorts with a focus on methotrexate (MTX) exposure.


Multicentre prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN).


Secondary care, ERAS nine centres, ERAN 23 centres in England, Wales and Ireland.


Patients with new diagnosis of RA, n=2701. Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3-6 months, at 12 months and annually thereafter.


Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA-specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis.


Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any conventional synthetic disease-modifying antirheumatic drug treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (OR 0.85, 95% CI 0.49 to 1.49, p=0.578) and a non-significant trend for delayed ILD diagnosis (OR 0.54, 95% CI 0.28 to 1.06, p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (OR 0.48, 95% CI 0.3 to 0.79, p=0.004) and longer time to ILD diagnosis (OR 0.41, 95% CI 0.23 to 0.75, p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first outpatient visit.


MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may delay the onset of ILD.


interstitial lung disease; methotrexate; rheumatoid arthritis

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