Background:Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed.Objectives:We aimed to evaluate the association of antecedent MTX use with development of RA-ILD.Methods:Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques.Results:Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; P<0.001). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI, 0.28 to 0.65; P<0.0001). 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 onset was significantly delayed in MTX ever users compared to never users (11.5 ± 10.6 years and 3.7 ± 7.1 years, respectively; P<0.001).Conclusion:Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD.Disclosure of Interests:Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodríguez Henríquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramcés Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoît Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Lioté: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphaël Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieudé: None declared
Background:Interstitial lung disease (ILD) is a common extra-articular manifestation of RA and is associated with increased morbidity and mortality.1-3 Studies have shown variability in the prevalence and mortality rate of patients with RA-associated ILD (RA-ILD).4 Further studies are needed to better characterise the epidemiology of RA-ILD.Objectives:To estimate the prevalence and incidence of clinical RA-ILD in France and to compare mortality rates between patients with RA-ILD and patients with RA without clinical ILD (RA-noILD).Methods:A historical cohort study was conducted using data from the French national claims database (SNDS) between 1 January 2013 and 31 December 2018. Adults with an RA diagnosis (International Classification of Diseases, Tenth revision [ICD-10] codes M05, M06.0, M06.8 and M06.9) and ≥2 distinct dates of DMARD delivery were included. Onset of RA was defined as the first date of occurrence between RA codes and the first known DMARD reimbursement. ILD diagnosis was defined as having ICD-10 code J84 and ≥1 computed tomography scan after, but within 1 year of, the first date of ILD occurrence. All patients had ≥6 months’ reimbursement after RA-ILD onset. The prevalence and incidence (2014–2018) of RA-ILD were estimated. The mortality rate was calculated, comparing patients with RA-ILD and patients with RA-noILD, matched 1:1 for age, sex, age at RA-ILD onset, duration of RA and presence of diabetes, arterial disease, dyslipidaemia and cardiac disease. Mortality was compared between patients with RA with and without clinical ILD in the matched population using Cox proportional hazards regression.Results:The prevalence of RA-ILD was 6.52 per 100,000 inhabitants (incidence=1.04 per 100,000 person-years). Of the 173,138 patients with RA included in the overall population, 4330 (2.5%) had clinical ILD. Patients with RA-ILD were older at RA diagnosis (mean [SD] age: 63.3 [13.7] vs 56.9 [15.2] years) and were more likely to be male (39.8% vs 27.0%) compared with patients with RA-noILD. Patients with RA-ILD were more likely to have cardiac disease (84.9% vs 63.1%), arterial disease (38.0% vs 19.3%), diabetes (21.4% vs 12.5%) and dyslipidaemia (44.7% vs 32.9%) compared with those with RA-noILD. The mortality rate in patients with clinical RA-ILD was 1.71 per 100,000 inhabitants. The mortality rate increased according to age (0.28 per 100,000 inhabitants for patients aged <65 years, 4.60 per 100,000 inhabitants for patients aged 65–74 years and 11.4 per 100,000 inhabitants for patients aged ≥75 years). After matching, the adjusted mortality risk was three times higher (HR [95% CI]: 3.1 [3.1, 3.9]) in patients with RA-ILD than in those with RA-noILD (Figure 1).Conclusion:This is the largest epidemiological study of RA-ILD in France. The prevalence of clinical RA-ILD in this population was towards the lower end of previous estimates (1–58%),3 possibly due to under-reporting of claims data. However, the occurrence of clinical ILD was associated with a strong increase in mortality compared with patients with RA-noILD.References:[1]Bodolay E, et al. Rheumatology (Oxford) 2005;44:656–661.[2]Duarte AC, et al. Rheumatology (Oxford) 2019;58:2031–2038.[3]Hyldgaard C, et al. Ann Rheum Dis 2017;76:1700–1706.[4]Spagnolo P, et al. Arthritis Rheumatol 2018;70:1544–1554.Acknowledgements:This study was funded by Bristol Myers Squibb. Claire Line, PhD of Caudex provided medical writing support, funded by Bristol Myers Squibb.Disclosure of Interests:Pierre-Antoine Juge Consultant of: Bristol Myers Squibb, Lidwine Wemeau Stervinou Consultant of: Boehringer Ingelheim, Bristol Myers Squibb, Roche, Sanofi, Sebastien Ottaviani Consultant of: AbbVie, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Roche-Chugai, SOBI, UCB, Guillaume Desjeux: None declared, Joe Zhuo Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Bruno Bregman Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Virginie Vannier-Moreau Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Rene-Marc Flipo Speakers bureau: AbbVie, Bristol Myers Squibb, Janssen, Lilly, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche-Chugai, Grant/research support from: Amgen, Janssen, Novartis, Pfizer, Bruno Crestani: None declared, Philippe Dieudé Consultant of: Boehringer Ingelheim, Bristol Myers Squibb, Chugaï, Lilly, Medac, Novartis, Pfizer, Sanofi, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Pfizer
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