Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial
Julie Mankikian, Agnès Caille, Martine Reynaud‐Gaubert, Marie‐Sara Agier, Julien Bermudez, Philippe Bonniaud, Raphaël Borie, Pierre‐Yves Brillet, J. Cadranel, Isabelle Court‐Fortune, Bruno Crestani, Marie‐Pierre Debray, E. Gomez, Anne Gondouin, Sandrine Hirschi-Santelmo, Dominique Israël‐Biet, S. Jouneau, Karine Juvin, Julie Léger, M. Kerjouan, Charles‐Hugo Marquette, Jean‐Marc Naccache, Hilario Nunès, Laurent Plantier, Grégoire Prévôt, Sébastien Quétant, Julie Traclet, V. Valentin, Y. Uzunhan, Lidwine Wémeau-Stervinou, Théodora Bejan‐Angoulvant, Vincent Cottin, S. Marchand‐Adam
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 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.