Journal Article

Rituximab Selectively Suppresses Specific Islet Antibodies

Herold, Kevan, Pugliese, Alberto, Eisenbarth, George S., McGee, Paula L., Krause-Steinrauf, Heidi, Yu, Liping, Krischer, Jeff, Bundy, Brian

2011

Overview

The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients (P < 0.0001). In the subgroup (n = 6) treated within 50 days of diabetes, IAAs were markedly suppressed by rituximab in all patients for 1 year and for four patients as long as 3 years despite continuing insulin therapy. Independent of rituximab treatment, the mean level of IAAs at study entry was markedly lower (P = 0.035) for patients who maintained C-peptide levels during the first year of follow-up in both rituximab-treated and placebo groups. A single course of rituximab differentially suppresses IAAs, clearly blocking IAAs for >1 year in insulin-treated patients. For the patients receiving insulin for >2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific effects of rituximab on levels of IAAs.

• Publisher: American Diabetes Association
• Subject: Adolescent / Adult / Antibodies, Monoclonal, Murine-Derived - pharmacology / Antibodies, Monoclonal, Murine-Derived - therapeutic use / Autoantibodies - immunology / Autoantibodies - metabolism / Autoimmune diseases / Biological and medical sciences / Cation Transport Proteins - immunology / Child / Diabetes / Diabetes Mellitus, Type 1 - drug therapy / Diabetes Mellitus, Type 1 - immunology / Diabetes. Impaired glucose tolerance / Double-Blind Method / Drug Administration Schedule / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Glutamate Decarboxylase - immunology / Humans / Immunologic Factors - pharmacology / Immunologic Factors - therapeutic use / Immunology and Transplantation / Insulin / Insulin - immunology / Islets of Langerhans - drug effects / Islets of Langerhans - immunology / Medical sciences / Monoclonal antibodies / Patients / Peptides / Proteins / Receptor-Like Protein Tyrosine Phosphatases, Class 8 - immunology / Rituximab / Young Adult