Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

Mark D. Pescovitz, Carla J. Greenbaum, Heidi Krause-Steinrauf, Dorothy J. Becker, Stephen E. Gitelman, Robin Goland, Peter A. Gottlieb, Jennifer B. Marks, Paula F. McGee, Antoinette M. Moran, Philip Raskin, Henry Rodriguez, Desmond A. Schatz, Diane Wherrett, Darrell M. Wilson, John M. Lachin, Jay S. Skyler

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Abstract

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

Original languageEnglish (US)
Pages (from-to)2143-2152
Number of pages10
JournalNew England Journal of Medicine
Volume361
Issue number22
DOIs
StatePublished - Nov 26 2009

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Lymphocyte Depletion
B-Lymphocytes
Type 1 Diabetes Mellitus
C-Peptide
Placebos
Glycosylated Hemoglobin A
Area Under Curve
T-Lymphocytes
Rituximab
Neutropenia
Autoimmunity
Double-Blind Method
Meals
Monoclonal Antibodies
Insulin
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pescovitz, M. D., Greenbaum, C. J., Krause-Steinrauf, H., Becker, D. J., Gitelman, S. E., Goland, R., ... Skyler, J. S. (2009). Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New England Journal of Medicine, 361(22), 2143-2152. https://doi.org/10.1056/NEJMoa0904452

Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. / Pescovitz, Mark D.; Greenbaum, Carla J.; Krause-Steinrauf, Heidi; Becker, Dorothy J.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Marks, Jennifer B.; McGee, Paula F.; Moran, Antoinette M.; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond A.; Wherrett, Diane; Wilson, Darrell M.; Lachin, John M.; Skyler, Jay S.

In: New England Journal of Medicine, Vol. 361, No. 22, 26.11.2009, p. 2143-2152.

Research output: Contribution to journalArticle

Pescovitz, MD, Greenbaum, CJ, Krause-Steinrauf, H, Becker, DJ, Gitelman, SE, Goland, R, Gottlieb, PA, Marks, JB, McGee, PF, Moran, AM, Raskin, P, Rodriguez, H, Schatz, DA, Wherrett, D, Wilson, DM, Lachin, JM & Skyler, JS 2009, 'Rituximab, B-lymphocyte depletion, and preservation of beta-cell function', New England Journal of Medicine, vol. 361, no. 22, pp. 2143-2152. https://doi.org/10.1056/NEJMoa0904452
Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New England Journal of Medicine. 2009 Nov 26;361(22):2143-2152. https://doi.org/10.1056/NEJMoa0904452
Pescovitz, Mark D. ; Greenbaum, Carla J. ; Krause-Steinrauf, Heidi ; Becker, Dorothy J. ; Gitelman, Stephen E. ; Goland, Robin ; Gottlieb, Peter A. ; Marks, Jennifer B. ; McGee, Paula F. ; Moran, Antoinette M. ; Raskin, Philip ; Rodriguez, Henry ; Schatz, Desmond A. ; Wherrett, Diane ; Wilson, Darrell M. ; Lachin, John M. ; Skyler, Jay S. / Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. In: New England Journal of Medicine. 2009 ; Vol. 361, No. 22. pp. 2143-2152.
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AU - Pescovitz, Mark D.

AU - Greenbaum, Carla J.

AU - Krause-Steinrauf, Heidi

AU - Becker, Dorothy J.

AU - Gitelman, Stephen E.

AU - Goland, Robin

AU - Gottlieb, Peter A.

AU - Marks, Jennifer B.

AU - McGee, Paula F.

AU - Moran, Antoinette M.

AU - Raskin, Philip

AU - Rodriguez, Henry

AU - Schatz, Desmond A.

AU - Wherrett, Diane

AU - Wilson, Darrell M.

AU - Lachin, John M.

AU - Skyler, Jay S.

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N2 - BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

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