title: Rituximab selectively suppresses specific islet antibodies.
abstract: 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.
  
  
  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.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA. liping.yu@ucdenver.edu
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Kevan
authors.initials: K
authors.lastname: Herold
authors.forename: Heidi
authors.initials: H
authors.lastname: Krause-Steinrauf
authors.forename: Paula L
authors.initials: PL
authors.lastname: McGee
authors.forename: Brian
authors.initials: B
authors.lastname: Bundy
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
authors.forename: Jeff
authors.initials: J
authors.lastname: Krischer
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D000069283:Rituximab; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D027682:Cation Transport Proteins; D007155:Immunologic Factors; D007328:Insulin; D000069283:Rituximab; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase