Barbara Seitz-Polski1,2,3, Karine Dahan4, Hanna Debiec5,6, Alexandra Rousseau7, Marine Andreani2, Christelle Zaghrini3, Michel Ticchioni8, Alessandra Rosenthal8, Sylvia Benzaken8, Ghislaine Bernard8, Gérard Lambeau3, Pierre Ronco4,5,6, Vincent L M Esnault2. 1. Department of Immunology, Hôpital l'Archet, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; seitz-polski.b@chu-nice.fr. 2. Department of Nephrology-Dialysis-Transplantation, Hôpital Pasteur, CHU de Nice, Université Côte d'Azur, Nice, France. 3. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, Nice, France. 4. Department of Nephrology and Dialysis, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France. 5. Unité Mixte de Recherche_S 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France. 6. Sorbonne Université, Université Pierre et Marie Curie University Paris 06, Paris, France; and. 7. Department of Clinical Pharmacology and Clinical Research, Hôpital Saint Antoine, AP-HP, Paris, France. 8. Department of Immunology, Hôpital l'Archet, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France.
Abstract
BACKGROUND AND OBJECTIVES: Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. RESULTS:Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0-10.8] versus 0.0 [IQR, 0.0-0.0] P<0.001 and 0.0 [IQR, 0.0-2.0] versus 16.5 [IQR, 2.5-31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0-8.0] versus 8.3 [IQR, 0.0-73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0-10.9] versus 0.0 µg/ml [IQR, 0.0-0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses. CONCLUSIONS: Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.
RCT Entities:
BACKGROUND AND OBJECTIVES: Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. RESULTS: Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0-10.8] versus 0.0 [IQR, 0.0-0.0] P<0.001 and 0.0 [IQR, 0.0-2.0] versus 16.5 [IQR, 2.5-31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0-8.0] versus 8.3 [IQR, 0.0-73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0-10.9] versus 0.0 µg/ml [IQR, 0.0-0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses. CONCLUSIONS: Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.
Authors: Hanna Debiec; Vincent Guigonis; Béatrice Mougenot; Fabrice Decobert; Jean-Philippe Haymann; Albert Bensman; Georges Deschênes; Pierre M Ronco Journal: N Engl J Med Date: 2002-06-27 Impact factor: 91.245
Authors: L D Piro; C A White; A J Grillo-López; N Janakiraman; A Saven; T M Beck; C Varns; S Shuey; M Czuczman; J W Lynch; J E Kolitz; V Jain Journal: Ann Oncol Date: 1999-06 Impact factor: 32.976
Authors: Isabelle Semac; Carmen Palomba; Karina Kulangara; Natacha Klages; Gerhild van Echten-Deckert; Bettina Borisch; Daniel C Hoessli Journal: Cancer Res Date: 2003-01-15 Impact factor: 12.701
Authors: Maxime Teisseyre; Marion Cremoni; Sonia Boyer-Suavet; Caroline Ruetsch; Daisy Graça; Vincent L M Esnault; Vesna Brglez; Barbara Seitz-Polski Journal: Front Immunol Date: 2022-05-04 Impact factor: 8.786