Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function.
Pescovitz, Mark D. M.D.; Greenbaum, Carla J. M.D.; Krause-Steinrauf, Heidi M.S.; Becker, Dorothy J. M.D.; Gitelman, Stephen E. M.D.; Goland, Robin M.D.; Gottlieb, Peter A. M.D.; Marks, Jennifer B. M.D.; McGee, Paula F. M.S.; Moran, Antoinette M. M.D.; Raskin, Philip M.D.; Rodriguez, Henry M.D.; Schatz, Desmond A. M.D.; Wherrett, Diane M.D.; Wilson, Darrell M. M.D.; Lachin, John M. Sc.D.; Skyler, Jay S. M.D.; the Type 1 Diabetes TrialNet Anti-CD20 Study Group
[Article]
New England Journal of Medicine.
361(22):2143-2152, November 26, 2009.
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Background: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes.
Methods: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose.
Results: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19 B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab.
Conclusions: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)
Copyright (C) 2009 Massachusetts Medical Society. All rights reserved.