title: 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.
  
  
  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.
authors.affiliation: Corresponding author: Jay S. Skyler, jskyler@miami.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: Brian
authors.initials: B
authors.lastname: Bundy
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Becker
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Robin
authors.initials: R
authors.lastname: Goland
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Marks
authors.forename: Antoinette
authors.initials: A
authors.lastname: Moran
authors.forename: Philip
authors.initials: P
authors.lastname: Raskin
authors.forename: Henry
authors.initials: H
authors.lastname: Rodriguez
authors.forename: Desmond A
authors.initials: DA
authors.lastname: Schatz
authors.forename: Diane K
authors.initials: DK
authors.lastname: Wherrett
authors.forename: Darrell M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Jay S
authors.initials: JS
authors.lastname: Skyler
mesh_terms: D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D019540:Area Under Curve; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology*; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D010919:Placebos; D000069283:Rituximab; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D010919:Placebos; D000069283:Rituximab
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