Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.
Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.
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DOI：
10.1056/nejmoa0904452
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发表时间：
2009-11-26
期刊：
影响因子：
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通讯作者：
Type 1 Diabetes TrialNet Anti-CD20 Study Group
中科院分区：
文献类型：
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作者：
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;Type 1 Diabetes TrialNet Anti-CD20 Study Group
1型糖尿病的免疫发病机制与t淋巴细胞自身免疫有关。然而，越来越多的证据表明B淋巴细胞在许多t淋巴细胞介导的疾病中发挥作用。使用抗cd20单克隆抗体利妥昔单抗可以实现B淋巴细胞的选择性消耗。这项2期研究评估了b淋巴细胞耗竭在1型糖尿病患者中的作用。我们进行了一项随机双盲研究，其中87名年龄在8至40岁之间的新诊断为1型糖尿病的患者被分配在研究的第1,8,15和22天接受利妥昔单抗或安慰剂的输注。第一次输注1年后评估的主要结果是混合膳食耐受性试验前2小时血清c肽水平的几何平均曲线下面积（AUC）。次要结局包括安全性、糖化血红蛋白水平和胰岛素剂量的变化。1年时，利妥昔单抗组C肽水平的平均AUC显著高于安慰剂组。利妥昔单抗组糖化血红蛋白水平也显著降低，需要的胰岛素也更少。在3个月到12个月之间，利妥昔单抗组c肽水平下降的速度明显低于安慰剂组。利妥昔单抗组患者的CD19+ B淋巴细胞减少，但在12个月时水平增加到基线值的69%。与安慰剂组相比，利妥昔单抗组有更多的患者在第一次输注后出现不良事件，主要是1级或2级。在随后的输液中，这些反应似乎微乎其微。利妥昔单抗没有增加感染或中性粒细胞减少。在1型糖尿病患者中，四个剂量的利妥昔单抗在1年内部分保存了β细胞功能。B淋巴细胞参与1型糖尿病发病机制的发现可能为探索1型糖尿病患者的治疗开辟新的途径。（ClinicalTrials.gov号码：NCT00279305）
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. 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. 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. 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.)