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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
[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{at}med.miami.edu.
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