Methotrexate and rheumatoid arthritis associated interstitial lung disease

doi:10.1183/13993003.00337-2020

Meta-Analysis

. 2021 Feb 11;57(2):2000337.

doi: 10.1183/13993003.00337-2020. Print 2021 Feb.

Methotrexate and rheumatoid arthritis associated interstitial lung disease

Pierre-Antoine Juge^{1

2}, Joyce S Lee^{3

2}, Jessica Lau^{4

2}, Leticia Kawano-Dourado⁵, Jorge Rojas Serrano⁶, Marco Sebastiani⁷, Gouri Koduri⁸, Eric Matteson^{9

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 Gazal^{17

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 Richette^{26

27}, Yannick Allanore^{28

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 Porcher^{37

38}, David A Schwartz³, Robert Vassallo⁴, Bruno Crestani^{20

2}, Philippe Dieudé^{1

2}

Affiliations

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.

PMID: 32646919
PMCID: PMC8212188
DOI: 10.1183/13993003.00337-2020

Meta-Analysis

Methotrexate and rheumatoid arthritis associated interstitial lung disease

Pierre-Antoine Juge et al. Eur Respir J. 2021.

. 2021 Feb 11;57(2):2000337.

doi: 10.1183/13993003.00337-2020. Print 2021 Feb.

Authors

Affiliations

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.

PMID: 32646919
PMCID: PMC8212188
DOI: 10.1183/13993003.00337-2020

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**FIGURE 1**
Methotrexate (MTX) ever-use and risk of rheumatoid arthritis (RA)-associated interstitial lung disease. Forest plot of odds ratios for interstitial lung disease among patients with RA according to MTX ever-use. The square boxes indicate odds ratios, and the horizontal lines indicate 95% confidence intervals for each sample. Diamonds display the pooled estimates. The black vertical line represents a mean odds ratio of 1. Odds ratios were adjusted for age at RA onset, sex, ever-smoking, case series origin, biologic ever-use, MTX exposure duration and periods of MTX use at year of RA onset.

See this image and copyright information in PMC

Comment in

The case of methotrexate and the lung: Dr Jekyll and Mr Hyde.
Cottin V, Bendstrup E, Bonniaud P, Nasser M, Spagnolo P, Valenzuela C, Kolb M. Cottin V, et al. Eur Respir J. 2021 Feb 11;57(2):2100079. doi: 10.1183/13993003.00079-2021. Print 2021 Feb. Eur Respir J. 2021. PMID: 33574052 No abstract available.

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References

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1. Doyle TJ, Lee JS, Dellaripa PF, et al. A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease. Chest 2014; 145: 454–463. - PMC - PubMed
1. Cavagna L, Monti S, Grosso V, et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed Res Int 2013; 2013: 759760. - PMC - PubMed
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[1] Hyldgaard C, Hilberg O, Pedersen AB, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis 2017; 76: 1700–1706. - PubMed

[2] Hyldgaard C, Hilberg O, Pedersen AB, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis 2017; 76: 1700–1706. - PubMed

[3] Doyle TJ, Lee JS, Dellaripa PF, et al. A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease. Chest 2014; 145: 454–463. - PMC - PubMed

[4] Doyle TJ, Lee JS, Dellaripa PF, et al. A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease. Chest 2014; 145: 454–463. - PMC - PubMed

[5] Cavagna L, Monti S, Grosso V, et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed Res Int 2013; 2013: 759760. - PMC - PubMed

[6] Cavagna L, Monti S, Grosso V, et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed Res Int 2013; 2013: 759760. - PMC - PubMed

[7] Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183: 372–378. - PMC - PubMed

[8] Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183: 372–378. - PMC - PubMed

[9] Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76: 960–977. - PubMed

[10] Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76: 960–977. - PubMed

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Methotrexate and rheumatoid arthritis associated interstitial lung disease

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Methotrexate and rheumatoid arthritis associated interstitial lung disease

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