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

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.)

Figure 1.. Enrollment, Randomization, and Follow-up of Study Participants.

Between May 2006 and August 2007, a total of 126 patients were screened and 87 underwent randomization. Of the 87 patients who underwent randomization, 81 composed the intention-to-treat cohort, of whom 78 contributed to the primary effectiveness analyses at 12 months. In 5 of the 6 patients who were excluded, infusions were stopped after an FDA safety alert concerning the development of progressive multifocal leukoencephalopathy in other study populations receiving rituximab; in the other patient, parental consent was withdrawn before administration of the initial infusion.

Figure 2.. Effects of Rituximab on C-Peptide Level, Glycated Hemoglobin Level, Insulin Dose Required, CD19+ Cell Counts, and IgM Level.

For each panel, 95% confidence limits are shown at each time point within each group.