Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

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

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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.)

Original languageEnglish
Pages (from-to)2143-2152
Number of pages10
JournalNew England Journal of Medicine
Volume361
Issue number22
DOIs
StatePublished - Nov 26 2009

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pescovitz, M. D., Greenbaum, C. J., Krause-Steinrauf, H., Becker, D. J., Gitelman, S. E., Goland, R., Gottlieb, P. A., Marks, J. B., McGee, P. F., Moran, A. M., Raskin, P., Rodriguez, H., Schatz, D. A., Wherrett, D., Wilson, D. M., Lachin, J. M., & Skyler, J. S. (2009). Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New England Journal of Medicine, 361(22), 2143-2152. https://doi.org/10.1056/NEJMoa0904452