Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

Autor:	Mankikian J; CHRU Tours, Service de Pneumologie et d'Explorations Fonctionnelles Respiratoires, Tours, France., Caille A; CIC, INSERM 1415, CHRU Tours, Tours, France.; Methods in Patients-Centered Outcomes and Health Research, INSERM UMR 1246, Nantes, France., Reynaud-Gaubert M; Service de Pneumologie, Centre de Compétences des Maladies Pulmonaires Rares, APHM, CHU Nord, 13015 Marseille, France.; Aix Marseille Université, Marseille, France., Agier MS; CHRU Tours, Service de Pharmacosurveillance, Centre Régional de Pharmacovigilance, Tours, France., Bermudez J; Service de Pneumologie, Centre de Compétences des Maladies Pulmonaires Rares, APHM, CHU Nord, 13015 Marseille, France.; Aix Marseille Université, Marseille, France., Bonniaud P; Centre de Référence Constitutif des Maladies Pulmonaires Rares de l'Adulte, Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalo-Universitaire de Dijon-Bourgogne, Dijon, France.; UFR des Sciences de Santé, Université de Bourgogne-Franche Comté et INSERM UMR 1231, Dijon, France., Borie R; Université de Paris, Inserm, U1152, laboratoire d'excellence INFLAMEX, F-75018 Paris, France.; Hôpital Bichat, APHP, Service de Pneumologie A, Centre Constitutif du Centre de Référence des Maladies Pulmonaires Rares, FHU APOLLO, F-75018 Paris, France., Brillet PY; APHP, Service de Radiologie, Hôpital Avicenne, Université Paris Sorbonne Nord, Bobigny, France., Cadranel J; APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'adulte et Sorbonne Université, Hôpital Tenon, Paris, France., Court-Fortune I; Sainbiose DVH U1059 Inserm, Faculté de Médecine J Lisfranc, Université Jean Monnet, Saint Etienne, France., Crestani B; Université de Paris, Inserm, U1152, laboratoire d'excellence INFLAMEX, F-75018 Paris, France.; Hôpital Bichat, APHP, Service de Pneumologie A, Centre Constitutif du Centre de Référence des Maladies Pulmonaires Rares, FHU APOLLO, F-75018 Paris, France., Debray MP; Université de Paris, Inserm, U1152, laboratoire d'excellence INFLAMEX, F-75018 Paris, France.; APHP, Service de Radiologie, Hôpital Bichat, Paris, France., Gomez E; Service de Pneumologie et Transplantation, Hopitaux Universitaires de Strasbourg - Nouvel Hôpital Civil, Strasbourg, France., Gondouin A; Université de Paris, APHP, Service de Pneumologie, Centre de Compétences Maladies Pulmonaires Rares, Hôpital Européen Georges Pompidou, Paris, France., Hirschi-Santelmo S; Hôpital de Pontchaillou, Service de Pneumologie, Centre de Compétences pour les Maladies Pulmonaires Rares, Rennes, France., Israel-Biet D; Université Rennes, INSERM, EHESP, IRSET UMR S1085, Rennes, France., Jouneau S; Université Côte d'Azur, Département de Pneumologie, CHU de Nice, Nice, France.; Groupe Hospitalier Paris Saint Joseph, Service de Pneumologie-Allergologie-Oncologie Thoracique, Paris, France., Juvin K; Université de Paris, APHP, Service de Pneumologie, Centre de Compétences Maladies Pulmonaires Rares, Hôpital Européen Georges Pompidou, Paris, France., Leger J; CIC, INSERM 1415, CHRU Tours, Tours, France., Kerjouan M; Hôpital de Pontchaillou, Service de Pneumologie, Centre de Compétences pour les Maladies Pulmonaires Rares, Rennes, France., Marquette CH; APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Hôpital Avicenne, Bobigny, France., Naccache JM; APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'adulte et Sorbonne Université, Hôpital Tenon, Paris, France.; Université de Tours, Centre d'Etude des Pathologies Respiratoires (CEPR) INSERM U1100 Faculté de Médecine, Tours, France., Nunes H; Service de Pneumologie, Hôpital Larrey, Toulouse, France., Plantier L; CHRU Tours, Service de Pneumologie et d'Explorations Fonctionnelles Respiratoires, Tours, France.; CHU de Grenoble-Alpes Service de Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, La Tronche, France., Prevot G; Centre National de Référence des Maladies Pulmonaires Rares, Hôpital Louis-Pradel, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Service de Pneumologie, Lyon, France., Quetant S; CHU Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Référence des Maladies Pulmonaires Rares (site constitutif), Lille, France., Traclet J; Université de Tours, EA 4245, Tours, France., Valentin V; CHRU de Tours, Service de Pharmacologie Clinique, Tours, France., Uzunhan Y; APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Hôpital Avicenne, Bobigny, France., Wémeau-Stervinou L; CHU Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Référence des Maladies Pulmonaires Rares (site constitutif), Lille, France., Bejan-Angoulvant T; Université de Tours, EA 4245, Tours, France.; CHRU de Tours, Service de Pharmacologie Clinique, Tours, France., Cottin V; Centre National de Référence des Maladies Pulmonaires Rares, Hôpital Louis-Pradel, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Service de Pneumologie, Lyon, France., Marchand-Adam S; CHRU Tours, Service de Pneumologie et d'Explorations Fonctionnelles Respiratoires, Tours, France s.marchandadam@univ-tours.fr.; Université de Tours, Centre d'Etude des Pathologies Respiratoires (CEPR) INSERM U1100 Faculté de Médecine, Tours, France.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2023 Jun 08; Vol. 61 (6). Date of Electronic Publication: 2023 Jun 08 (Print Publication: 2023).
DOI:	10.1183/13993003.02071-2022
Abstrakt:	Background: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. Methods: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. Findings: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. Interpretation: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection. Competing Interests: Conflict of interest: A. Caille reports grants from French National Research Agency, outside the submitted work. P. Bonniaud reports grants from AstraZeneca, personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Sanofi and GSK, and non-financial support (reimbursement for national and international conferences) from Chiesi and Stallergene. R. Borie has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from Boehringer, Roche, Sanofi-Genzyme, Savara and Chiesi, outside the submitted work. J. Cadranel reports honoraria for educational events from Boehringer Ingelheim and Roche, outside the submitted work. B. Crestani has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from BMS, Boehringer Ingelheim, Roche, Apellis, Sanofi, Novartis, AstraZeneca and Chiesi, outside the submitted work; and has also received equipment/drugs or other services from Translate Bio. M-P. Debray has received or reimbursement for national and international conferences and educational events over the past 3 years from Boehringer Ingelheim and Roche, outside the submitted work. D. Israel-Biet reports consulting fees from Boehringer Ingelheim, honoraria for educational events from Boehringer Ingelheim and Roche, payments from Galapagos as a member of an adjudication committee, and support for attending meetings and/or travel from Boehringer Ingelheim, outside the submitted work. S. Jouneau has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AIRB, Bellorophon Therapeutics, Biogen, Boehringer, Chiesi, Fibrogen, Galecto Biotech, Gilead, LVL, Novartis, Olam Pharm, Pfizer, Pliant Therapeutics, Roche, Sanofi-Genzyme and Savara. J-M. Naccache has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca and Boehringer Ingelheim, outside the submitted work. L. Plantier has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Sanofi, Humanair and Arair, outside the submitted work. V. Valentin has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, outside the submitted work. L. Wémeau-Stervinou reports personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, Sanofi and BMS, outside the submitted work. V. Cottin reports grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Roche, personal fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, MSD, CSL Behring, Galapagos, Galecto, Shionogi, Fibrogen, RedX, PureTech and Promedior, outside the submitted work. S. Marchand-Adam has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, Roche, BMS, Novartis, AstraZeneca, Pfizer, GSK and Chiesi, outside the submitted work. The remaining authors declare no competing interests. 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