Abstract
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 feature) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinico-biological data and a NSIP-like HRCT 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 six months. The primary endpoint was the change in percent of predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary endpoints 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 to 6.80]; p=0.0273). PFS was better in the rituximab+MMF group (crude HR 0.47 [95%CI 0.23 to 0.96]; p=0.03). Serious adverse events occurred in 26 patients of the rituximab+MMF group (41%) and in 23 of the placebo+MMF group (39%). Nine infections were reported in the rituximab+MMF group (five bacterial infections, 3 viral infections, 1 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 consider the risk of viral infection.
Footnotes
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Conflict of interest: Agnes Caille reports grants from French National Research Agency, outside the submitted work.
Conflict of interest: Philippe Bonniaud reports grants from AstraZeneca, personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Sanofi, GSK and non-financial support (reimbursement for national and international conferences) from Chiesi and Stallergene.
Conflict of interest: Raphael Borie has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, research projects over the past 3 years from Boehringer, Roche, Sanofi- Genzyme, Savara, Chiesi outside the submitted work.
Conflict of interest: Jacques Cadranel reports honoraria for educational events from Boehringer Ingelheim and Roche outside the submitted work.
Conflict of interest: Bruno Crestani has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, research projects over the past 3 years from BMS, Boehringer Ingelheim, Roche, Apellis, Sanofi, Novartis, AstraZeneca, Chiesi outside the submitted work. Bruno Crestani has also received equipment/drugs or other services from Translate Bio.
Conflict of interest: Marie Pierre Debray has received or reimbursement for national and international conferences, educational events over the past 3 years from Boehringer Ingelheim and Roche outside the submitted work.
Conflict of interest: Dominique Israël-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 comittee, supports for attending meetings and/or travel from Boehringer Ingelheim outside the submitted work.
Conflict of interest: Stephane Jouneau has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, 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, Savara.
Conflict of interest: Jean-Marc Naccache has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, research projects over the past 3 years from Astra Zeneca, Boehringer Ingelheim outside the submitted work.
Conflict of interest: Laurent Plantier has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, research projects over the past 3 years from Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Sanofi, Humanair, and Arair outside the submitted work.
Conflict of interest: Victor Valentin, has received fees, funding or reimbursement for national and international conferences, boards from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: Lidwine Wémeau-Stervinou reports personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, Sanofi, BMS outside the submitted work.
Conflict of interest: Vincent 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, and PureTech, Promedior outside the submitted work.
Conflict of interest: Sylvain Marchand-Adam has received fees, funding or reimbursement for national and international conferences, boards from Boehringer Ingelheim, Roche, BMS; Novartis; Astra Zeneca; Pfizer; GSK; Chiesi outside the submitted work.
Conflict of interest: Julie Mankikian, Martine Reynaud-Gaubert, Marie-Sara Agier, Julien Bermudez, Pierre-Yves Brillet, Isabelle Court-Fortune, Emmanuel Gomez, Anne Gondouin, Sandrine Hirschi-Santelmo, Karine Juvin, Julie Leger, Mallorie Kerjouan, Charles-Hugo Marquette, Hilario Nunes, Grégoire Prevot, Sébastien Quetant, Julie Traclet, Yurdagul Uzunhan, Theodora Bejan-Angoulvant, declare no competing interests.
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