Methotrexate and rheumatoid arthritis associated interstitial lung disease

Pierre Antoine Juge; Joyce S. Lee; Jessica Lau; Leticia Kawano-Dourado; Jorge Rojas Serrano; Marco Sebastiani; Gouri Koduri; Eric Matteson; Karina Bonfiglioli; Marcio Sawamura; Ronaldo Kairalla; Lorenzo Cavagna; Emanuele Bozzalla Cassione; Andreina Manfredi; Mayra Mejia; Pedro Rodríguez-Henriquez; Montserrat I. González-Pérez; Ramcés Falfán-Valencia; Ivette Buendia-Roldán; Gloria Pérez-Rubio; Esther Ebstein; Steven Gazal; Raphaël Borie; Sébastien Ottaviani; Caroline Kannengiesser; Beno t. Wallaert; Yurdagul Uzunhan; Hilario Nunes; Dominique Valeyre; Nathalie Saidenberg-Kermanac h; Marie Christophe Boissier; Lidwine Wemeau-Stervinou; René Marc Flipo; Sylvain Marchand-Adam; Pascal Richette; Yannick Allanore; Claire Dromer; Marie Elise Truchetet; Christophe Richez; Thierry Schaeverbeke; Huguette Lioté; Gabriel Thabut; Kevin D. Deane; Joshua J. Solomon; Tracy Doyle; Jay H. Ryu; Ivan Rosas; V. Michael Holers; Catherine Boileau; Marie Pierre Debray; Raphaël Porcher; David A. Schwartz; Robert Vassallo; Bruno Crestani; Philippe Dieudé

doi:10.1183/13993003.00337-2020

Methotrexate and rheumatoid arthritis associated interstitial lung disease

Pierre Antoine Juge, Joyce S. Lee, Jessica Lau, Leticia Kawano-Dourado, Jorge Rojas Serrano, Marco Sebastiani, Gouri Koduri, Eric Matteson, Karina Bonfiglioli, Marcio Sawamura, Ronaldo Kairalla, Lorenzo Cavagna, Emanuele Bozzalla Cassione, Andreina Manfredi, Mayra Mejia, Pedro Rodríguez-Henriquez, Montserrat I. González-Pérez, Ramcés Falfán-Valencia, Ivette Buendia-Roldán, Gloria Pérez-RubioEsther Ebstein, Steven Gazal, Raphaël Borie, Sébastien Ottaviani, Caroline Kannengiesser, Beno t. Wallaert, Yurdagul Uzunhan, Hilario Nunes, Dominique Valeyre, Nathalie Saidenberg-Kermanac h, Marie Christophe Boissier, Lidwine Wemeau-Stervinou, René Marc Flipo, Sylvain Marchand-Adam, Pascal Richette, Yannick Allanore, Claire Dromer, Marie Elise Truchetet, Christophe Richez, Thierry Schaeverbeke, Huguette Lioté, Gabriel Thabut, Kevin D. Deane, Joshua J. Solomon, Tracy Doyle, Jay H. Ryu, Ivan Rosas, V. Michael Holers, Catherine Boileau, Marie Pierre Debray, Raphaël Porcher, David A. Schwartz, Robert Vassallo, Bruno Crestani, Philippe Dieudé

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 highresolution 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.

Original language	English (US)
Article number	2000337
Journal	European Respiratory Journal
Volume	57
Issue number	2
DOIs	https://doi.org/10.1183/13993003.00337-2020
State	Published - Feb 1 2021

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

Access to Document

10.1183/13993003.00337-2020

Cite this

Juge, P. A., Lee, J. S., Lau, J., Kawano-Dourado, L., Serrano, J. R., Sebastiani, M., Koduri, G., Matteson, E., Bonfiglioli, K., Sawamura, M., Kairalla, R., Cavagna, L., Cassione, E. B., Manfredi, A., Mejia, M., Rodríguez-Henriquez, P., González-Pérez, M. I., Falfán-Valencia, R., Buendia-Roldán, I., ... Dieudé, P. (2021). Methotrexate and rheumatoid arthritis associated interstitial lung disease. European Respiratory Journal, 57(2), [2000337]. https://doi.org/10.1183/13993003.00337-2020

Methotrexate and rheumatoid arthritis associated interstitial lung disease. / Juge, Pierre Antoine; Lee, Joyce S.; Lau, Jessica; Kawano-Dourado, Leticia; Serrano, Jorge Rojas; Sebastiani, Marco; Koduri, Gouri; Matteson, Eric; Bonfiglioli, Karina; Sawamura, Marcio; Kairalla, Ronaldo; Cavagna, Lorenzo; Cassione, Emanuele Bozzalla; Manfredi, Andreina; Mejia, Mayra; Rodríguez-Henriquez, Pedro; González-Pérez, Montserrat I.; Falfán-Valencia, Ramcés; Buendia-Roldán, Ivette; Pérez-Rubio, Gloria; Ebstein, Esther; Gazal, Steven; Borie, Raphaël; Ottaviani, Sébastien; Kannengiesser, Caroline; Wallaert, Beno t.; Uzunhan, Yurdagul; Nunes, Hilario; Valeyre, Dominique; Saidenberg-Kermanac h, Nathalie; Boissier, Marie Christophe; Wemeau-Stervinou, Lidwine; Flipo, René Marc; Marchand-Adam, Sylvain; Richette, Pascal; Allanore, Yannick; Dromer, Claire; Truchetet, Marie Elise; Richez, Christophe; Schaeverbeke, Thierry; Lioté, Huguette; Thabut, Gabriel; Deane, Kevin D.; Solomon, Joshua J.; Doyle, Tracy; Ryu, Jay H.; Rosas, Ivan; Michael Holers, V.; Boileau, Catherine; Debray, Marie Pierre; Porcher, Raphaël; Schwartz, David A.; Vassallo, Robert; Crestani, Bruno; Dieudé, Philippe.

In: European Respiratory Journal, Vol. 57, No. 2, 2000337, 01.02.2021.

Research output: Contribution to journal › Article › peer-review

Juge, PA, Lee, JS, Lau, J, Kawano-Dourado, L, Serrano, JR, Sebastiani, M, Koduri, G, Matteson, E, Bonfiglioli, K, Sawamura, M, Kairalla, R, Cavagna, L, Cassione, EB, Manfredi, A, Mejia, M, Rodríguez-Henriquez, P, González-Pérez, MI, Falfán-Valencia, R, Buendia-Roldán, I, Pérez-Rubio, G, Ebstein, E, Gazal, S, Borie, R, Ottaviani, S, Kannengiesser, C, Wallaert, BT, Uzunhan, Y, Nunes, H, Valeyre, D, Saidenberg-Kermanac h, N, Boissier, MC, Wemeau-Stervinou, L, Flipo, RM, Marchand-Adam, S, Richette, P, Allanore, Y, Dromer, C, Truchetet, ME, Richez, C, Schaeverbeke, T, Lioté, H, Thabut, G, Deane, KD, Solomon, JJ, Doyle, T, Ryu, JH, Rosas, I, Michael Holers, V, Boileau, C, Debray, MP, Porcher, R, Schwartz, DA, Vassallo, R, Crestani, B & Dieudé, P 2021, 'Methotrexate and rheumatoid arthritis associated interstitial lung disease', European Respiratory Journal, vol. 57, no. 2, 2000337. https://doi.org/10.1183/13993003.00337-2020

Juge, Pierre Antoine ; Lee, Joyce S. ; Lau, Jessica ; Kawano-Dourado, Leticia ; Serrano, Jorge Rojas ; Sebastiani, Marco ; Koduri, Gouri ; Matteson, Eric ; Bonfiglioli, Karina ; Sawamura, Marcio ; Kairalla, Ronaldo ; Cavagna, Lorenzo ; Cassione, Emanuele Bozzalla ; Manfredi, Andreina ; Mejia, Mayra ; Rodríguez-Henriquez, Pedro ; González-Pérez, Montserrat I. ; Falfán-Valencia, Ramcés ; Buendia-Roldán, Ivette ; Pérez-Rubio, Gloria ; Ebstein, Esther ; Gazal, Steven ; Borie, Raphaël ; Ottaviani, Sébastien ; Kannengiesser, Caroline ; Wallaert, Beno t. ; Uzunhan, Yurdagul ; Nunes, Hilario ; Valeyre, Dominique ; Saidenberg-Kermanac h, Nathalie ; Boissier, Marie Christophe ; Wemeau-Stervinou, Lidwine ; Flipo, René Marc ; Marchand-Adam, Sylvain ; Richette, Pascal ; Allanore, Yannick ; Dromer, Claire ; Truchetet, Marie Elise ; Richez, Christophe ; Schaeverbeke, Thierry ; Lioté, Huguette ; Thabut, Gabriel ; Deane, Kevin D. ; Solomon, Joshua J. ; Doyle, Tracy ; Ryu, Jay H. ; Rosas, Ivan ; Michael Holers, V. ; Boileau, Catherine ; Debray, Marie Pierre ; Porcher, Raphaël ; Schwartz, David A. ; Vassallo, Robert ; Crestani, Bruno ; Dieudé, Philippe. / Methotrexate and rheumatoid arthritis associated interstitial lung disease. In: European Respiratory Journal. 2021 ; Vol. 57, No. 2.

@article{e214a61a547a451c8541e8e806cbb8b3,

title = "Methotrexate and rheumatoid arthritis associated interstitial lung disease",

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 highresolution 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.",

author = "Juge, {Pierre Antoine} and Lee, {Joyce S.} and Jessica Lau and Leticia Kawano-Dourado and Serrano, {Jorge Rojas} and Marco Sebastiani and Gouri Koduri and Eric Matteson and Karina Bonfiglioli and Marcio Sawamura and Ronaldo Kairalla and Lorenzo Cavagna and Cassione, {Emanuele Bozzalla} and Andreina Manfredi and Mayra Mejia and Pedro Rodr{\'i}guez-Henriquez and Gonz{\'a}lez-P{\'e}rez, {Montserrat I.} and Ramc{\'e}s Falf{\'a}n-Valencia and Ivette Buendia-Rold{\'a}n and Gloria P{\'e}rez-Rubio and Esther Ebstein and Steven Gazal and Rapha{\"e}l Borie and S{\'e}bastien Ottaviani and Caroline Kannengiesser and Wallaert, {Beno t.} and Yurdagul Uzunhan and Hilario Nunes and Dominique Valeyre and {Saidenberg-Kermanac h}, Nathalie and Boissier, {Marie Christophe} and Lidwine Wemeau-Stervinou and Flipo, {Ren{\'e} Marc} and Sylvain Marchand-Adam and Pascal Richette and Yannick Allanore and Claire Dromer and Truchetet, {Marie Elise} and Christophe Richez and Thierry Schaeverbeke and Huguette Liot{\'e} and Gabriel Thabut and Deane, {Kevin D.} and Solomon, {Joshua J.} and Tracy Doyle and Ryu, {Jay H.} and Ivan Rosas and {Michael Holers}, V. and Catherine Boileau and Debray, {Marie Pierre} and Rapha{\"e}l Porcher and Schwartz, {David A.} and Robert Vassallo and Bruno Crestani and Philippe Dieud{\'e}",

note = "Funding Information: Support statement: Supported by grants from Soci{\'e}t{\'e} Fran{\c c}aise de Rhumatologie, National Heart, Lung, and Blood Institute (K23-HL138131 and K23-HL119558). Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Conflict of interest: P-A. Juge has nothing to disclose. J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech and Celgene, outside the submitted work. J. Lau has nothing to disclose. L. Kawano-Dourado has nothing to disclose. J. Rojas-Serrano has nothing to disclose. M. Sebastiani has nothing to disclose. G. Koduri has nothing to disclose. E. Matteson has nothing to disclose. K. Bonfiglioli has nothing to disclose. M. Sawamura has nothing to disclose. R. Kairalla has nothing to disclose. L. Cavagna has nothing to disclose. E. Bozzalla Cassione has nothing to disclose. A. Manfredi has nothing to disclose. M. Mejia has nothing to disclose. P. Rodr{\'i}guez-Henriquez has nothing to disclose. M.I. Gonz{\'a}lez P{\'e}rez has nothing to disclose. R. Falf{\'a}n-Valencia has nothing to disclose. I. Buendia-Rold{\'a}n has nothing to disclose. G. P{\'e}rez-Rubio has nothing to disclose. E. Ebstein reports personal fees from Sanofi, outside the submitted work. S. Gazal has nothing to disclose. R. Borie reports grants and personal fees for lectures from Roche and Boehringer Ingelheim, outside the submitted work. S. Ottaviani has nothing to disclose. C. Kannengiesser has nothing to disclose. B. Wallaert reports grants and personal fees for advisory board work and meeting attendance from Boehringer Ingelheim and Roche, outside the submitted work. Y. Uzunhan reports personal fees from Roche and Boehringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. H. Nunes has nothing to disclose. D. Valeyre reports personal fees for advisory board work from Roche and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, outside the submitted work. N. Saidenberg-Kermanac{\textquoteright}h has nothing to disclose. M-C. Boissier has nothing to disclose. 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. R.M. Flipo reports grants and personal fees from Roche Chugai, Abbvie and Pfizer, personal fees from Bristol-Meyers Squibb, outside the submitted work. 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. P. Richette reports personal fees from Ipsen/Menarini, AstraZeneca, Savient and Gr{\"u}nenthal, outside the submitted work. Y. Allanore reports personal fees from Actelion, Bayer, Bristol-Myers Squibb, Boehringer and Inventiva, grants from Sanofi and Roche, outside the submitted work. C. Dromer has nothing to disclose. M-E. Truchetet has nothing to disclose. C. Richez has nothing to disclose. T. Schaeverbeke has nothing to disclose. H. Liot{\'e} has nothing to disclose. G. Thabut reports personal fees from AstraZeneca, outside the submitted work. K.D. Deane has nothing to disclose. J. Solomon has nothing to disclose. T. Doyle has nothing to disclose. J.H. Ryu has nothing to disclose. I. Rosas reports personal fees for advisory board work from Genentech, Boehringer and Three Lakes Partners, outside the submitted work. V.M. Holers reports grants from NIH/NIAID (U01 Grant), during the conduct of the study. C. Boileau has nothing to disclose. M-P. Debray reports personal fees and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, outside the submitted work. R. Porcher has nothing to disclose. 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. R. Vassallo reports grants from Pfizer, Bristol-Myers-Squibb and SunPharma, outside the submitted work. 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. P. Dieud{\'e} 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. Publisher Copyright: {\textcopyright} 2021 European Respiratory Society. All rights reserved.",

year = "2021",

month = feb,

day = "1",

doi = "10.1183/13993003.00337-2020",

language = "English (US)",

volume = "57",

journal = "European Respiratory Journal",

issn = "0903-1936",

number = "2",

}

TY - JOUR

T1 - Methotrexate and rheumatoid arthritis associated interstitial lung disease

AU - Juge, Pierre Antoine

AU - Lee, Joyce S.

AU - Lau, Jessica

AU - Kawano-Dourado, Leticia

AU - Serrano, Jorge Rojas

AU - Sebastiani, Marco

AU - Koduri, Gouri

AU - Matteson, Eric

AU - Bonfiglioli, Karina

AU - Sawamura, Marcio

AU - Kairalla, Ronaldo

AU - Cavagna, Lorenzo

AU - Cassione, Emanuele Bozzalla

AU - Manfredi, Andreina

AU - Mejia, Mayra

AU - Rodríguez-Henriquez, Pedro

AU - González-Pérez, Montserrat I.

AU - Falfán-Valencia, Ramcés

AU - Buendia-Roldán, Ivette

AU - Pérez-Rubio, Gloria

AU - Ebstein, Esther

AU - Gazal, Steven

AU - Borie, Raphaël

AU - Ottaviani, Sébastien

AU - Kannengiesser, Caroline

AU - Wallaert, Beno t.

AU - Uzunhan, Yurdagul

AU - Nunes, Hilario

AU - Valeyre, Dominique

AU - Saidenberg-Kermanac h, Nathalie

AU - Boissier, Marie Christophe

AU - Wemeau-Stervinou, Lidwine

AU - Flipo, René Marc

AU - Marchand-Adam, Sylvain

AU - Richette, Pascal

AU - Allanore, Yannick

AU - Dromer, Claire

AU - Truchetet, Marie Elise

AU - Richez, Christophe

AU - Schaeverbeke, Thierry

AU - Lioté, Huguette

AU - Thabut, Gabriel

AU - Deane, Kevin D.

AU - Solomon, Joshua J.

AU - Doyle, Tracy

AU - Ryu, Jay H.

AU - Rosas, Ivan

AU - Michael Holers, V.

AU - Boileau, Catherine

AU - Debray, Marie Pierre

AU - Porcher, Raphaël

AU - Schwartz, David A.

AU - Vassallo, Robert

AU - Crestani, Bruno

AU - Dieudé, Philippe

N1 - Funding Information: Support statement: Supported by grants from Société Française de Rhumatologie, National Heart, Lung, and Blood Institute (K23-HL138131 and K23-HL119558). Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Conflict of interest: P-A. Juge has nothing to disclose. J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech and Celgene, outside the submitted work. J. Lau has nothing to disclose. L. Kawano-Dourado has nothing to disclose. J. Rojas-Serrano has nothing to disclose. M. Sebastiani has nothing to disclose. G. Koduri has nothing to disclose. E. Matteson has nothing to disclose. K. Bonfiglioli has nothing to disclose. M. Sawamura has nothing to disclose. R. Kairalla has nothing to disclose. L. Cavagna has nothing to disclose. E. Bozzalla Cassione has nothing to disclose. A. Manfredi has nothing to disclose. M. Mejia has nothing to disclose. P. Rodríguez-Henriquez has nothing to disclose. M.I. González Pérez has nothing to disclose. R. Falfán-Valencia has nothing to disclose. I. Buendia-Roldán has nothing to disclose. G. Pérez-Rubio has nothing to disclose. E. Ebstein reports personal fees from Sanofi, outside the submitted work. S. Gazal has nothing to disclose. R. Borie reports grants and personal fees for lectures from Roche and Boehringer Ingelheim, outside the submitted work. S. Ottaviani has nothing to disclose. C. Kannengiesser has nothing to disclose. B. Wallaert reports grants and personal fees for advisory board work and meeting attendance from Boehringer Ingelheim and Roche, outside the submitted work. Y. Uzunhan reports personal fees from Roche and Boehringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. H. Nunes has nothing to disclose. D. Valeyre reports personal fees for advisory board work from Roche and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, outside the submitted work. N. Saidenberg-Kermanac’h has nothing to disclose. M-C. Boissier has nothing to disclose. 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. R.M. Flipo reports grants and personal fees from Roche Chugai, Abbvie and Pfizer, personal fees from Bristol-Meyers Squibb, outside the submitted work. 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. P. Richette reports personal fees from Ipsen/Menarini, AstraZeneca, Savient and Grünenthal, outside the submitted work. Y. Allanore reports personal fees from Actelion, Bayer, Bristol-Myers Squibb, Boehringer and Inventiva, grants from Sanofi and Roche, outside the submitted work. C. Dromer has nothing to disclose. M-E. Truchetet has nothing to disclose. C. Richez has nothing to disclose. T. Schaeverbeke has nothing to disclose. H. Lioté has nothing to disclose. G. Thabut reports personal fees from AstraZeneca, outside the submitted work. K.D. Deane has nothing to disclose. J. Solomon has nothing to disclose. T. Doyle has nothing to disclose. J.H. Ryu has nothing to disclose. I. Rosas reports personal fees for advisory board work from Genentech, Boehringer and Three Lakes Partners, outside the submitted work. V.M. Holers reports grants from NIH/NIAID (U01 Grant), during the conduct of the study. C. Boileau has nothing to disclose. M-P. Debray reports personal fees and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, outside the submitted work. R. Porcher has nothing to disclose. 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. R. Vassallo reports grants from Pfizer, Bristol-Myers-Squibb and SunPharma, outside the submitted work. 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. 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. Publisher Copyright: © 2021 European Respiratory Society. All rights reserved.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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 highresolution 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.

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 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 highresolution 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.

UR - http://www.scopus.com/inward/record.url?scp=85091117988&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85091117988&partnerID=8YFLogxK

U2 - 10.1183/13993003.00337-2020

DO - 10.1183/13993003.00337-2020

M3 - Article

C2 - 32646919

AN - SCOPUS:85091117988

VL - 57

JO - European Respiratory Journal

JF - European Respiratory Journal

SN - 0903-1936

IS - 2

M1 - 2000337

ER -

Methotrexate and rheumatoid arthritis associated interstitial lung disease

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