Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Front Immunol. 2023 Jun 9;14:1164120. doi: 10.3389/fimmu.2023.1164120. eCollection 2023.
To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China.
We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing.
The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB10901-DQA103-DQB10303 (DR9) and DRB10405-DQA103-DQB10401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA10501-DQB10201 (DR3) and DR9 haplotypes were less frequent (17.7% 2.3%; =0.011 and 34.4% 15.9%; =0.025), whereas the protective haplotypes (DRB11101-DQA105-DQB10301 and DRB11202-DQA10601-DQB10301) were more frequent in ICI-DM patients (2.1% 13.6%; =0.006 and 4.2% 15.9%; =0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB10405-DQB10401 or DRB10901-DQB10303).
ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.
研究中国免疫检查点抑制剂相关糖尿病（ICI-DM）患者的临床特征和 HLA 基因型。
我们纳入了 23 例 ICI-DM 患者和 51 例 1 型糖尿病（T1D）患者。收集患者的临床特征。通过下一代测序进行 HLA-DRB1、HLA-DQA1 和 HLA-DQB1 基因分型。
ICI-DM 患者以男性为主（70.6%），平均体重指数（BMI）为 21.2±3.5kg/m²，ICI 治疗后 5（IQR，3-9）个周期出现 ICI-DM。大多数（78.3%）ICI-DM 患者接受抗 PD-1 治疗，78.3%表现为糖尿病酮症酸中毒，且所有患者 C 肽水平较低，均接受多次胰岛素注射。与 T1D 患者相比，ICI-DM 患者年龄明显较大（57.2±12.4 vs. 34.1±15.7 岁），血糖较高，但 HbA1c 水平较低（<0.05）。仅有 2（8.7%）例 ICI-DM 患者胰岛自身抗体阳性，低于 T1D 患者（66.7%，P<0.001）。22 例 ICI-DM 患者中 59.1%（13/22）为 HLA T1D 风险单倍型杂合子，主要易感单倍型为 DRB10901-DQA103-DQB10303（DR9）和 DRB10405-DQA103-DQB10401。与 T1D 相比，易感 DR3-DQA10501-DQB10201（DR3）和 DR9 单倍型频率较低（17.7% vs. 34.4%，=0.011 和 34.4% vs. 15.9%，=0.025），而保护性单倍型（DRB11101-DQA105-DQB10301 和 DRB11202-DQA10601-DQB10301）在 ICI-DM 患者中更为常见（2.1% vs. 13.6%，=0.006 和 4.2% vs. 15.9%，=0.017）。ICI-DM 患者均无 T1D 相关高危基因型 DR3/DR3、DR3/DR9 和 DR9/DR9。在 23 例 ICI-DM 患者中，7 例（30.4%）为 ICI 相关暴发性 1 型糖尿病（IFD），16 例（69.6%）为 ICI 相关 1 型糖尿病（IT1D）。与 IT1D 患者相比，IFD 患者表现为明显的高血糖和低 C 肽及 HbA1c 水平（<0.05）。高达 66.7%（4/6）的 IFD 患者为报道的暴发性 1 型糖尿病易感 HLA 单倍型（DRB10405-DQB10401 或 DRB10901-DQB10303）杂合子。
ICI-DM 与 T1D 具有相似的临床特征，如急性起病、胰岛功能差和胰岛素依赖。然而，缺乏胰岛自身抗体、T1D 易感单倍型频率较低和保护性 HLA 单倍型频率较高提示 ICI-DM 代表一种与经典 T1D 不同的新模式。
