Abstract：
There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.
摘要：
有多种改善疾病的免疫疗法显示出预防或延迟1型糖尿病（T1D）进展的潜力。我们设计并进行了这项系统评价和荟萃分析，以概述免疫疗法在T1D治疗中的作用。我们搜索了PubMed,Embase和Cochrane中央控制试验登记册（CENTRAL）从开始到2023年12月。我们纳入了在T1D患者中进行的免疫治疗的临床试验，该临床试验报告了低血糖的发生率或与基线相比的变化，至少在以下结果之一中：2h和4h混合餐刺激的C肽曲线下面积（AUC），空腹C肽，每日胰岛素剂量，糖化血红蛋白（HbA1c）和空腹血糖（FPG）。结果以随机效应模型中的加权平均差（WMD）或比值比（OR）和95％置信区间（CI）计算。总之,包括34项临床试验。与对照组相比，在接受非基于抗原的免疫疗法治疗的患者中，2小时C肽AUC略高（WMD，0.04nmol/L,95%CI，0.00至0.09nmol/L，P=0.05),这主要是由T细胞靶向治疗的影响。在非基于抗原的免疫疗法（WMD，0.10nmol/L，95%CI，0.04至0.16nmol/L，P=0.0007),这主要是由肿瘤坏死因子α（TNF-α）抑制剂和T细胞靶向治疗的作用驱动的。在排除小样本试验后，与对照组相比，接受非基于抗原的免疫疗法治疗的患者每日胰岛素剂量较少(WMD，-0.07单位/千克/天，95%CI，-0.11至-0.03单位/千克/天，P=0.0004)。与对照组相比，使用基于抗原的免疫疗法也与较低的每日胰岛素剂量有关（WMD，-0.11单位/千克/天，95%CI，-0.23至-0.00单位/千克/天，P=0.05)。然而,非基于抗原的免疫疗法或基于抗原的免疫疗法与对照组之间的HbA1c或FBG变化具有可比性.与对照组相比，接受非基于抗原的免疫疗法治疗的患者或接受基于抗原的免疫疗法治疗的患者的低血糖风险没有增加。总之,与对照组相比，非基于抗原的免疫疗法与T1D患者2小时和4小时C肽AUC的保留相关，这主要是由TNF-a抑制剂和T细胞靶向治疗的作用驱动的。与对照组相比，非基于抗原的免疫疗法和基于抗原的免疫疗法都倾向于减少T1D患者的每日胰岛素剂量。然而,它们对HbA1c或FBG的实质性改善没有贡献.T1D患者的非基于抗原的免疫疗法和基于抗原的免疫疗法均具有良好的耐受性，而低血糖的风险并未增加。
