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

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.

Informations de copyright

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Déclaration de conflit d'intérêts

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.