Rituximab preserved beta-cell function in type 1 diabetes

Patients with type 1 diabetes treated with a four-dose course of rituximab experienced partially preserved beta-cell function during one year, showing that a therapy that targets beta cells may have a positive effect on beta-cell function in early type 1 diabetes.

New data “support the hypothesis that B lymphocytes play a role in the pathogenesis of type 1 diabetes,” researchers for the Type 1 Diabetes TrialNet Anti-CD20 Study Group wrote in The New England Journal of Medicine. This finding “may open a new pathway for exploration in the treatment of patients with this condition.”

One dose of rituximab (Rituxan, Genentech and Biogen Idec) administered soon after the diagnosis of type 1 diabetes appeared to preserve insulin secretion for at least one year, improved C-peptide levels and lowered HbA1c levels and insulin dose compared with placebo.

Rituximab is an anti-CD20 monoclonal antibody that is used to treat many lymphomas, leukemias and some autoimmune disorders.

The phase-2 study evaluated the role of B lymphocyte depletion in 87 patients aged 8 to 40 years with newly diagnosed type 1 diabetes. Researchers randomly assigned patients to receive intravenous infusions of rituximab 375 mg/m² or placebo on days one, eight, 15 and 22. Four doses constituted one course of treatment.

The primary outcome was geometric mean area under the curve (AUC) for serum C-peptide level during the first two hours of a mixed-meal tolerance test.

At one year, the mean AUC for C-peptide level at two hours was 20% higher among patients assigned rituximab compared with placebo (P=.03) — 0.56 pmol/L vs. 0.47 pmol/L.

“We observed an initial improvement shortly after the administration of rituximab but with a subsequent resumption in the decline of the AUC for C-peptide,” the researchers wrote.

Between three months and one year, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. AUC for C-peptide declined steadily in the placebo group at a rate of 55% per year, according to the researchers.

Rituximab was also associated with lower levels of HbA1c (6.76% vs. 7%) and insulin requirements (0.39 U/kg vs. 0.48 U/kg) at one year (P<.001 for both).

“Analyses suggest that the effects of treatment on the glycated hemoglobin level and insulin dose were related to the preservation of C-peptide levels,” the researchers wrote.

The rituximab group had depleted CD19+ B lymphocytes, which indicated B-cell depletion, but levels recovered to 69% of baseline values at one year. In the placebo group, CD19+ cells remained relatively stable.

Immunoglobulin M levels were markedly declined with rituximab and did not fully recover to baseline levels at one year. At three months, immunoglobulin G levels were 5% higher in the rituximab group vs. placebo group (P=.048).

Adverse events were more common in the rituximab group (93%) during the first infusion compared with the placebo group (23%). The opposite was true for patients receiving more than one dose (89% vs. 97%). Most events were grade 1 or grade 2, and reactions appeared to be minimal with subsequent infusions. They reported no increase in infections or neutropenia with rituximab.

Subgroup analyses hint at a greater response with rituximab in children and adolescents than in adults, which may be related to a more rapid reduction in the AUC for C-peptide in younger patients, according to the researchers.

“An intervention that maintains endogenous insulin production might improve the management of type 1 diabetes and reduce long-term complications,” the researchers said.

However, the course of rituximab administered in this study would unlikely be optimal, they said. The trial did not assess repeat or long-term administration of rituximab because of a lack of information on the safety or efficacy of such an approach.

“Given our results, we believe that other anti-B lymphocyte agents should be tested — for example, humanized anti-CD20 antibodies,” they wrote. “Whether anti-B lymphocyte therapy would prevent or delay diabetes in patients with autoantibodies, dysglycemia or both is currently unknown.”

Pescovitz MD. N Engl J Med. 2009;361:2143-2152.