PT - JOURNAL ARTICLE AU - Pierre-Antoine Juge AU - Joyce S. Lee AU - Jessica Lau AU - Leticia Kawano-Dourado AU - Jorge Rojas Serrano AU - Marco Sebastiani AU - Gouri Koduri AU - Eric Matteson AU - Karina Bonfiglioli AU - Marcio Sawamura AU - Ronaldo Kairalla AU - Lorenzo Cavagna AU - Emanuele Bozzalla Cassione AU - Andreina Manfredi AU - Mayra Mejia AU - Pedro Rodríguez-Henriquez AU - Montserrat I. González-Pérez AU - Ramcés Falfán-Valencia AU - Ivette Buendia-Roldán AU - Gloria Pérez-Rubio AU - Esther Ebstein AU - Steven Gazal AU - Raphaël Borie AU - Sébastien Ottaviani AU - Caroline Kannengiesser AU - Benoît Wallaert AU - Yurdagul Uzunhan AU - Hilario Nunes AU - Dominique Valeyre AU - Nathalie Saidenberg-Kermanac'h AU - Marie-Christophe Boissier AU - Lidwine Wemeau-Stervinou AU - René-Marc Flipo AU - Sylvain Marchand-Adam AU - Pascal Richette AU - Yannick Allanore AU - Claire Dromer AU - Marie-Elise Truchetet AU - Christophe Richez AU - Thierry Schaeverbeke AU - Huguette Lioté AU - Gabriel Thabut AU - Kevin D. Deane AU - Joshua Solomon AU - Tracy Doyle AU - Jay H. Ryu AU - Ivan Rosas AU - V. Michael Holers AU - Catherine Boileau AU - Marie-Pierre Debray AU - Raphaël Porcher AU - David A. Schwartz AU - Robert Vassallo AU - Bruno Crestani AU - Philippe Dieudé TI - Methotrexate and rheumatoid arthritis associated interstitial lung disease AID - 10.1183/13993003.00337-2020 DP - 2020 Jan 01 TA - European Respiratory Journal PG - 2000337 4099 - http://erj.ersjournals.com/content/early/2020/06/18/13993003.00337-2020.short 4100 - http://erj.ersjournals.com/content/early/2020/06/18/13993003.00337-2020.full AB - Question addressed by the study 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.Methods 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.Results Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.46; 95% confidence interval [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).Answer to the Question 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. JUGE has nothing to disclose.Conflict of interest: Dr. Lee reports grants from NIH, personal fees from Genentech, personal fees from Celgene, outside the submitted work.Conflict of interest: Dr. Lau has nothing to disclose.Conflict of interest: Dr. Kawano-Dourado has nothing to disclose.Conflict of interest: Dr. Rojas-Serrano has nothing to disclose.Conflict of interest: Dr. Sebastiani has nothing to disclose.Conflict of interest: Dr. Koduri has nothing to disclose.Conflict of interest: Dr. MATTESON has nothing to disclose.Conflict of interest: Dr. Bonfiglioli has nothing to disclose.Conflict of interest: Dr. Sawamura has nothing to disclose.Conflict of interest: Dr. Kairalla has nothing to disclose.Conflict of interest: Dr. Cavagna has nothing to disclose.Conflict of interest: Dr. Bozzalla Cassione has nothing to disclose.Conflict of interest: Dr. Manfredi has nothing to disclose.Conflict of interest: Dr. Mejia has nothing to disclose.Conflict of interest: Dr. Rodríguez-Henriquez has nothing to disclose.Conflict of interest: Dr. González Pérez has nothing to disclose.Conflict of interest: Dr. Falfán-Valencia has nothing to disclose.Conflict of interest: Dr. Buendia-Roldan has nothing to disclose.Conflict of interest: Dr. Pérez-Rubio has nothing to disclose.Conflict of interest: Dr. Ebstein reports personal fees from Sanofi, outside the submitted work.Conflict of interest: Dr. Gazal has nothing to disclose.Conflict of interest: Dr. Borie reports grants and personal fees from Roche, grants and personal fees from Boerhinger Ingelheim, outside the submitted work.Conflict of interest: Dr. Ottaviani has nothing to disclose.Conflict of interest: Dr. KANNENGIESSER has nothing to disclose.Conflict of interest: Dr. Wallaert reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Roche, outside the submitted work.Conflict of interest: Dr. Uzunhan reports personal fees from Roche, personal fees from Bohringer Ingelheim, non-financial support from Oxyvie, outside the submitted work.Conflict of interest: Dr. NUNES has nothing to disclose.Conflict of interest: Dr. VALEYRE reports personal fees from Roche, personal fees from Bohringer Ingelheim, personal fees from Astra Zenecca, outside the submitted work.Conflict of interest: Dr. SAIDENBERG has nothing to disclose.Conflict of interest: Dr. BOISSIER has nothing to disclose.Conflict of interest: Dr. Wemeau-Stervinou reports personal fees and non-financial support from Roche, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Janssen-Cilag, personal fees from Bristol-Myers-Squibb, outside the submitted work.Conflict of interest: Dr. FLIPO reports grants and personal fees from Roche Chugai, grants and personal fees from Abbvie, personal fees from Bristol-Meyers Squibb, grants and personal fees from Pfizer, outside the submitted work.Conflict of interest: Dr. marchand-adam reports non-financial support from Roche, non-financial support from Boehringer-Ingelheim, non-financial support from novartis, outside the submitted work.Conflict of interest: Dr. Richette reports personal fees from Ipsen/Menarini, personal fees from Astra Zeneca, personal fees from Savient, personal fees from Grünenthal, outside the submitted work.Conflict of interest: Dr. ALLANORE reports personal fees from Actelion, personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Boehringer, personal fees from Inventiva, grants from Sanofi, grants from Roche, outside the submitted work.Conflict of interest: Dr. DROMER has nothing to disclose.Conflict of interest: Dr. Truchetet has nothing to disclose.Conflict of interest: Dr. RICHEZ has nothing to disclose.Conflict of interest: Dr. SCHAEVERBEKE has nothing to disclose.Conflict of interest: Dr. Lioté has nothing to disclose.Conflict of interest: Dr. THABUT reports personal fees from Astra-Zeneca, outside the submitted work.Conflict of interest: Dr. Deane has nothing to disclose.Conflict of interest: Dr. Solomon has nothing to disclose.Conflict of interest: Dr. Doyle has nothing to disclose.Conflict of interest: Dr. Ryu has nothing to disclose.Conflict of interest: Dr. Rosas reports personal fees from Genentech, personal fees from Boehringer, personal fees from Three Lakes Partners, outside the submitted work.Conflict of interest: Dr. Holers reports grants from NIH/NIAID, during the conduct of the study.Conflict of interest: Dr. BOILEAU has nothing to disclose.Conflict of interest: Dr. DEBRAY reports personal fees and non-financial support from Boehringer-Ingelheim, Roche, personal fees and non-financial support from Roche, outside the submitted work.Conflict of interest: Dr. Porcher has nothing to disclose.Conflict of interest: Dr. Schwartz reports grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from DOD Focused Program Grant, during the conduct of the study; other from Eleven P15, Inc., personal fees from NuMedii, Inc., outside the submitted work; In addition, Dr. Schwartz 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: Dr. Vassallo reports grants from Pfizer, grants from Bristol-Myers-Squibb, grants from SunPharma, outside the submitted work.Conflict of interest: Dr. crestani reports grants from Apellis, grants and personal fees from Boehringer Ingelheim, personal fees from Astra Zeneca, grants from MedImmune, grants and personal fees from Roche, personal fees from Sanofi, from null, outside the submitted work.Conflict of interest: Dr. DIEUDE reports grants from PFIZER, grants and personal fees from ROCHE, grants and personal fees from CHUGAI, grants and personal fees from BMS, personal fees from ABBVIE, personal fees from MSD, outside the submitted work.