Rituximab Selectively Suppresses Specific Islet Antibodies
- Liping Yu1⇓,
- Kevan Herold2,
- Heidi Krause-Steinrauf3,
- Paula L. McGee3,
- Brian Bundy4,
- Alberto Pugliese5,
- Jeff Krischer6,
- George S. Eisenbarth1 and
- for the Type 1 Diabetes TrialNet Anti-CD20 Study Group
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
- 2Yale University School of Medicine, New Haven, Connecticut
- 3Biostatistics Center, George Washington University, Rockville, Massachusetts
- 4Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, New York
- 5Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida
- 6Division of Informatics and Biostatistics, University of South Florida, Tampa, Florida
- Corresponding author: Liping Yu, .
OBJECTIVE 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.
RESEARCH DESIGN AND METHODS 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.
RESULTS 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.
CONCLUSIONS 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.
- Received May 18, 2011.
- Accepted July 7, 2011.
- © 2011 by the American Diabetes Association.
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