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Methotrexate and rheumatoid arthritis associated interstitial lung disease

Author

Eur Respir J. 2020 Jul 9;2000337. doi: 10.1183/13993003.00337-2020. Online ahead of print.

Pierre-Antoine Juge 1 2, Joyce S Lee 3 2, Jessica Lau 4 2, Leticia Kawano-Dourado 5, Jorge Rojas Serrano 6, Marco Sebastiani 7, Gouri Koduri 8, Eric Matteson 9 10, Karina Bonfiglioli 11, Marcio Sawamura 12, Ronaldo Kairalla 5, Lorenzo Cavagna 13, Emanuele Bozzalla Cassione 13, Andreina Manfredi 7, Mayra Mejia 6, Pedro Rodríguez-Henriquez 14, Montserrat I González-Pérez 6, Ramcés Falfán-Valencia 15, Ivette Buendia-Roldán 16, Gloria Pérez-Rubio 15, Esther Ebstein 1, Steven Gazal 17 18, Raphaël Borie 19, Sébastien Ottaviani 1, Caroline Kannengiesser 20, Benoît Wallaert 21, Yurdagul Uzunhan 22, Hilario Nunes 22, Dominique Valeyre 22, Nathalie Saidenberg-Kermanac'h 23, Marie-Christophe Boissier 23, Lidwine Wemeau-Stervinou 21, René-Marc Flipo 24, Sylvain Marchand-Adam 25, Pascal Richette 26 27, Yannick Allanore 28 29, Claire Dromer 30, Marie-Elise Truchetet 31, Christophe Richez 31, Thierry Schaeverbeke 31, Huguette Lioté 32, Gabriel Thabut 33, Kevin D Deane 3, Joshua Solomon 34, Tracy Doyle 35, Jay H Ryu 4, Ivan Rosas 35, V Michael Holers 3, Catherine Boileau 20, Marie-Pierre Debray 36, Raphaël Porcher 37 38, David A Schwartz 3, Robert Vassallo 4, Bruno Crestani 20 2, Philippe Dieudé 39 2

Author Information

1 Department of Rheumatology, DMU Locomotion, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France.

2 contributed equally.

3 Department 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 Department, Southend University Hospital NHSFT, Southend-on-Sea, United-Kingdom.

9 Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

10 Department 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 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

18 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

19 Department of Pulmonology, Centre de Référence des Maladies Pulmonaires Rares, INSERM UMR1152, DHU APOLLO, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France.

20 Departement of Genetic, 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 Department of Pulmonology, Centre de Référence des Maladies Pulmonaires Rares, Inserm 1272, Hôpital Avicenne, APHP, Université Paris 13, Bobigny, France.

23 Department of Rheumatology, Hôpital Avicenne, APHP, Bobigny, France.

24 CHU de Lille, Service de Rhumatologie, Lille, France.

25 Department 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 Department of Medicine, National Jewish Health, Denver, CO, USA.

35 Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

36 Department 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.

39 Department of Rheumatology, DMU Locomotion, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France philippe.dieude@aphp.fr.

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 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.