Methotrexate and rheumatoid arthritis associated interstitial lung disease.

Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

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Conflict of interest: P-A. Juge has nothing to disclose. Conflict of interest: J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech and Celgene, outside the submitted work. Conflict of interest: J. Lau has nothing to disclose. Conflict of interest: L. Kawano-Dourado has nothing to disclose. Conflict of interest: J. Rojas-Serrano has nothing to disclose. Conflict of interest: M. Sebastiani has nothing to disclose. Conflict of interest: G. Koduri has nothing to disclose. Conflict of interest: E. Matteson has nothing to disclose. Conflict of interest: K. Bonfiglioli has nothing to disclose. Conflict of interest: M. Sawamura has nothing to disclose. Conflict of interest: R. Kairalla has nothing to disclose. Conflict of interest: L. Cavagna has nothing to disclose. Conflict of interest: E. Bozzalla Cassione has nothing to disclose. Conflict of interest: A. Manfredi has nothing to disclose. Conflict of interest: M. Mejia has nothing to disclose. Conflict of interest: P. Rodríguez-Henriquez has nothing to disclose. Conflict of interest: M.I. González Pérez has nothing to disclose. Conflict of interest: R. Falfán-Valencia has nothing to disclose. Conflict of interest: I. Buendia-Roldán has nothing to disclose. Conflict of interest: G. Pérez-Rubio has nothing to disclose. Conflict of interest: E. Ebstein reports personal fees from Sanofi, outside the submitted work. Conflict of interest: S. Gazal has nothing to disclose. Conflict of interest: R. Borie reports grants and personal fees for lectures from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S. Ottaviani has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: B. Wallaert reports grants and personal fees for advisory board work and meeting attendance from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: Y. Uzunhan reports personal fees from Roche and Boehringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Roche and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, outside the submitted work. Conflict of interest: N. Saidenberg-Kermanac'h has nothing to disclose. Conflict of interest: M-C. Boissier has nothing to disclose. Conflict of interest: L. Wemeau-Stervinou reports personal fees for lectures and travel support from Roche, personal fees for lectures and advisory board work, and travel support from Boehringer-Ingelheim, personal fees for lectures from Janssen-Cilag and Bristol-Myers-Squibb, outside the submitted work. Conflict of interest: R.M. Flipo reports grants and personal fees from Roche Chugai, Abbvie and Pfizer, personal fees from Bristol-Meyers Squibb, outside the submitted work. Conflict of interest: S. Marchand-Adam reports fees for research, lectures, meeting attendance, consultancy and advisory board work from Roche, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: P. Richette reports personal fees from Ipsen/Menarini, AstraZeneca, Savient and Grünenthal, outside the submitted work. Conflict of interest: Y. Allanore reports personal fees from Actelion, Bayer, Bristol-Myers Squibb, Boehringer and Inventiva, grants from Sanofi and Roche, outside the submitted work. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: M-E. Truchetet has nothing to disclose. Conflict of interest: C. Richez has nothing to disclose. Conflict of interest: T. Schaeverbeke has nothing to disclose. Conflict of interest: H. Lioté has nothing to disclose. Conflict of interest: G. Thabut reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: K.D. Deane has nothing to disclose. Conflict of interest: J. Solomon has nothing to disclose. Conflict of interest: T. Doyle has nothing to disclose. Conflict of interest: J.H. Ryu has nothing to disclose. Conflict of interest: I. Rosas reports personal fees for advisory board work from Genentech, Boehringer and Three Lakes Partners, outside the submitted work. Conflict of interest: V.M. Holers reports grants from NIH/NIAID (U01 Grant), during the conduct of the study. Conflict of interest: C. Boileau has nothing to disclose. Conflict of interest: M-P. Debray reports personal fees and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: R. Porcher has nothing to disclose. Conflict of interest: D.A. Schwartz reports grants from NIH-NHLBI (P01 HL092870, R01 HL097163, R33 HL120770 and UH2 HL123442) and DOD Focused Program (W81XWH-17-1-0597), during the conduct of the study; personal fees for consultancy and advisory board work from NuMedii, Inc., and is an employee of Eleven P15, Inc., outside the submitted work; and has a patent Compositions and Methods of Treating or Preventing Fibrotic Diseases pending, a patent Biomarkers for the Diagnosis and Treatment of Fibrotic Lung Disease pending, and a patent Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders issued. Conflict of interest: R. Vassallo reports grants from Pfizer, Bristol-Myers-Squibb and SunPharma, outside the submitted work. Conflict of interest: B. Crestani reports grants from Apellis and MedImmune, grants and personal fees for lectures from Boehringer Ingelheim and Roche, personal fees for lectures from AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: P. Dieudé reports fees for consultancy from Pfizer, Abbvie and MSD, grants and personal fees for consultancy and lectures from Roche, Chugai and BMS, outside the submitted work.