B-lymphocyte depletion with rituximab and β-cell function: two-year results

Abstract

Objective: We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.

Research design and methods: Eighty-seven subjects (aged 8-40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome-baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year-showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.

Results: The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (P = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.

Conclusions: Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.

Trial registration: ClinicalTrials.gov NCT00279305.

Figures

Figure 1

A: Linear modeling of mean AUC of C-peptide over 2 h, over time by treatment group. Number of subjects available for analysis is displayed along the x axis. B: Rate of fall (slope) in C-peptide AUC. The placebo-predicted line leads the rituximab line by 8.2 months. The model assumed that each subject’s C-peptide values on the scale tended to follow a straight line (i.e., two random effects: the intercept and constant decay rate over time). C: Time to C-peptide failure by treatment group. C-peptide failure was defined as the first time at which the maximum C-peptide during a 2-h MMTT was <0.2 nmol/L.

Figure 2

A: HbA1c and 95% confidence limits over time by treatment group. B: Insulin dose (units per kilogram) over time by treatment group. Number of subjects available for analysis is displayed along the x axis.

Figure 3

A: Absolute CD19 counts over time by treatment group. Multiparameter flow cytometry was performed by the Immune Tolerance Network (at Roswell Park Cancer Institute, Buffalo, NY) from fresh blood. B: IgM (milligrams/deciliter and 95% CI) concentrations over time by treatment group. C: IgG (milligrams/deciliter and 95% CI) concentrations over time by treatment group. Number of subjects available for analysis is displayed along the x-axis.