Pierre-Antoine Juge1,2, Joyce S Lee3,2, Jessica Lau4,2, Leticia Kawano-Dourado5, Jorge Rojas Serrano6, Marco Sebastiani7, Gouri Koduri8, Eric Matteson9,10, Karina Bonfiglioli11, Marcio Sawamura12, Ronaldo Kairalla5, Lorenzo Cavagna13, Emanuele Bozzalla Cassione13, Andreina Manfredi7, Mayra Mejia6, Pedro Rodríguez-Henriquez14, Montserrat I González-Pérez6, Ramcés Falfán-Valencia15, Ivette Buendia-Roldán16, Gloria Pérez-Rubio15, Esther Ebstein1, Steven Gazal17,18, Raphaël Borie19, Sébastien Ottaviani1, Caroline Kannengiesser20, Benoît Wallaert21, Yurdagul Uzunhan22, Hilario Nunes22, Dominique Valeyre22, Nathalie Saidenberg-Kermanac'h23, Marie-Christophe Boissier23, Lidwine Wemeau-Stervinou21, René-Marc Flipo24, Sylvain Marchand-Adam25, Pascal Richette26,27, Yannick Allanore28,29, Claire Dromer30, Marie-Elise Truchetet31, Christophe Richez31, Thierry Schaeverbeke31, Huguette Lioté32, Gabriel Thabut33, Kevin D Deane3, Joshua J Solomon34, Tracy Doyle35, Jay H Ryu4, Ivan Rosas35, V Michael Holers3, Catherine Boileau20, Marie-Pierre Debray36, Raphaël Porcher37,38, David A Schwartz3, Robert Vassallo4, Bruno Crestani20,2, Philippe Dieudé1,2. 1. Dept of Rheumatology, DMU Locomotion, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France. 2. These authors contributed equally. 3. Dept of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. 4. Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. 5. Pulmonary Division, Heart Institute (InCor) Medical School of the University of São Paulo, São Paulo, Brazil. 6. Unidad de Enfermedades del Intersticio Pulmonar y Reumatología, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosió Villegas, Ciudad de México, México. 7. Rheumatology Unit, Azienda Ospedaliera Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy. 8. Rheumatology Dept, Southend University Hospital NHSFT, Southend-on-Sea, UK. 9. Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. 10. Dept of Health Sciences Research, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. 11. Division of Rheumatology, Medical School of the University of São Paulo, São Paulo, Brazil. 12. Division of Radiology, Medical School of the University of São Paulo, São Paulo, Brazil. 13. University and IRCCS Policlinico S. Matteo Foundation of Pavia, Pavia, Italy. 14. Departamento de Reumatologia, Hospital General Dr. Manuel Gea González, Ciudad de México, México. 15. HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México. 16. Research Direction, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad de México, México. 17. Dept of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 18. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 19. Dept of Pulmonology, Centre de Référence des Maladies Pulmonaires Rares, INSERM UMR1152, DHU APOLLO, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France. 20. Dept of Genetics, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France. 21. CHRU de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de compétence des maladies pulmonaires rares, FHU IMMINENT, Lille, France. 22. Dept of Pulmonology, Centre de Référence des Maladies Pulmonaires Rares, Inserm 1272, Hôpital Avicenne, APHP, Université Paris 13, Bobigny, France. 23. Dept of Rheumatology, Hôpital Avicenne, APHP, Bobigny, France. 24. CHU de Lille, Service de Rhumatologie, Lille, France. 25. Dept of Pulmonology, CHRU Tours, Tours, France. 26. AP-HP, Hôpital Lariboisière, Service de Rhumatologie, DMU Locomotion, Université de Paris, Paris, France. 27. INSERM, UMR_1132, Paris, France. 28. APHP, Hôpital Cochin, Service de Rhumatologie A, Université de Paris, Paris, France. 29. INSERM, U1016, UMR_8104, Paris, France. 30. Service de Pneumologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 31. CHU de Bordeaux, Service de Rhumatologie, Bordeaux, France. 32. APHP, Hôpital Tenon, Service de Pneumologie, Paris, France. 33. APHP, Hôpital Bichat, INSERM 1152, Service de Pneumologie B, DHU FIRE, Université de Paris, Paris, France. 34. Dept of Medicine, National Jewish Health, Denver, CO, USA. 35. Dept of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 36. Dept of Radiology, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France. 37. Université de Paris, CRESS, INSERM, INRA, Paris, France. 38. Centre d'Epidémiologie Clinique, AP-HP, Hôpital Hôtel-Dieu, Paris, France.
Abstract
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 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). 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.
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 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). 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.
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