NEJM -- Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function

Volume 361:2143-2152 November 26, 2009 Number 22
Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function

Mark D. Pescovitz, M.D., Carla J. Greenbaum, M.D., Heidi Krause-Steinrauf, M.S., Dorothy J. Becker, M.D., Stephen E. Gitelman, M.D., Robin Goland, M.D., Peter A. Gottlieb, M.D., Jennifer B. Marks, M.D., Paula F. McGee, M.S., Antoinette M. Moran, M.D., Philip Raskin, M.D., Henry Rodriguez, M.D., Desmond A. Schatz, M.D., Diane Wherrett, M.D., Darrell M. Wilson, M.D., John M. Lachin, Sc.D., Jay S. Skyler, M.D., for the Type 1 Diabetes TrialNet Anti-CD20 Study Group


ABSTRACT

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 [ClinicalTrials.gov] .)

Source Information

From the Indiana University School of Medicine, Indianapolis (M.D.P., H.R.); the Benaroya Research Institute, Seattle (C.J.G.); the George Washington University Biostatistics Center, Rockville, MD (H.K.-S., P.F.M., J.M.L.); the University of Pittsburgh, Pittsburgh (D.J.B.); the University of California, San Francisco, San Francisco (S.E.G.); Columbia University, New York (R.G.); University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora (P.A.G.); the University of Miami Diabetes Research Institute, Miami (J.B.M., J.S.S.); the University of Minnesota, Minneapolis (A.M.M.); the University of Texas Southwestern Medical School, Dallas (P.R.); the University of Florida, Gainesville (D.A.S.); Hospital for Sick Children, University of Toronto, Toronto (D.W.); and Stanford University, Stanford, CA (D.M.W.).

Address reprint requests to the Type 1 Diabetes TrialNet Chairman's Office, Diabetes Research Institute, University of Miami Miller School of Medicine, P.O. Box 016960 (D-110), Miami, FL 33136, or at diabetestrialnet@med.miami.edu.

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NEJM -- Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function