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
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
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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