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Clinical Characteristics of 5 Cases of Immune Checkpoint Inhibitor Induced Diabetes Mellitus
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摘要:
目的 总结分析5例免疫检查点抑制剂相关糖尿病(ICI-DM)患者临床特点及治疗随访结局，并复习相关文献，以期为临床医生诊治该病提供参考。 方法 回顾性分析2018年12月至2023年2月于北京协和医院就诊的5例ICI-DM患者的临床资料。 结果 5例患者平均年龄(65±7)岁，均使用程序性细胞死亡受体1(PD-1)或其配体抑制剂(PD-L1)治疗。5例患者从第1次免疫治疗到发现血糖升高的中位时间为100(43，210)d，接受免疫治疗的中位周期为7(2.5，10.5)周期。5例患者均以糖尿病酮症或酮症酸中毒起病。起病时尿酮体阳性，随机血糖为(36.36±15.89)mmol/L，糖化血红蛋白(8.6%±0.66%)，动脉血pH值(7.28±0.16)，中位空腹C肽水平为0.09(0.05，0.32)μg/L。5例患者起病血糖水平3或4级，均暂停ICI治疗，启动胰岛素治疗，胰岛素日治疗用量(56±20)IU，并辅以降糖药物治疗。治疗后尿酮体转阴，pH值升至正常范围，随机血糖明显下降(治疗前后随机血糖差值中位数为21.30 mmol/L，P=0.043)，治疗有效。随访患者均继续使用胰岛素，血糖稳定后重启PD-1或PD-L1抑制剂治疗，肿瘤病情控制稳定。 结论 ICI-DM主要发生于PD-1或PD-L1抑制剂治疗后，多以急性高血糖起病，实验室检查提示胰岛素分泌缺陷，部分患者伴胰岛细胞抗体、谷氨酸脱羧酶抗体、自身抗体阳性，需要早期诊断并持续接受胰岛素治疗，内分泌科予以控制血糖后可重启ICI治疗。 Abstract:Objective By summarizing the clinical characteristics and follow-up outcomes of 5 patients with immune checkpoint inhibitor induced diabetes mellitus (ICI-DM) and reviewing the relevant literatures, the article aims at providing reference to clinicians in the diagnosis and treatment of the ICI-DM. Methods Clinical data of 5 patients with ICI-DM who were admitted to Peking Union Medical College Hospital from December 2018 to February 2023 and did retrospectively analyzed. Results Five patients with a mean age of (65±7)years received treatment by the programmed cell death 1 (PD-1) or its ligand inhibitor (PD-L1). The median time from the first immunotherapy to the discovery of elevated plasma glucose was 100 (43, 210)days, and the median cycle of immunotherapy was 7 (2.5, 10.5). The onset of the illness of all the 5 patients started with diabetic ketosis or ketoacidosis. At the onset, urine ketone bodies were positive, random plasma glucose was (36.36±15.89)mmol/L, glycosylated hemoglobin A1c (HbA1c)was (8.6%±0.66%), arterial blood pH was (7.28±0.16), and the median fasting C-peptide level was 0.09 (0.05, 0.32)μg/L. Five patients had an onset plasma glucose level of grade 3 or 4.Then, ICI treatment was discontinued in all patients and insulin therapy started. The daily dosage of insulin was (56±20)IU, supplemented with hypoglycemic drugs. After treatment, urine ketone body turned negative, pH value increased to normal range, and random plasma glucose decreased significantly (the median difference of random blood glucose before and after treatment was 21.30 mmol/L, P=0.043) showing that the treatment was effective. During the follow-up, all patients continued to use insulin. The PD-1 or PD-L1 inhibitors were restarted after hyperglycemia remission. The tumor condition was under control. Conclusions ICI-DM mainly occurs in patients who receive treatment with PD-1 or PD-L1 inhibitors usually with acute hyperglycemia whose laboratory tests indicate insulin secretion defects. Some patients had positive islet cell antibodies, glutamic acid decarboxylase antibodies and autoantibodies.Patients with positive autoantibodies needed early diagnosis and continuous insulin treatment. ICI treatment can be restarted after endocrinologists brought the blood glucose under control. -
Key words:
- immune checkpoint inhibitors /
- diabetes mellitus /
- immunoadverse reaction
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表 1 5例免疫检查点抑制剂相关糖尿病(ICI-DM)患者的一般情况
Table 1. General information of the 5 patients with immune checkpoint inhibitors diabetes mellitus (ICI-DM)
例序 性别 年龄
(岁)BMI
(kg/m2)“三多一少”或酮症症状持续时间 家族史 原发肿瘤 药品名称 治疗周期
(程)发病时间
(d)1 女 73 26.19 (-) 肝癌 左肾透明细胞癌 信迪利单抗 14 300 2 男 53 21.20 4个月 乳腺癌 右肺小细胞肺癌 德瓦鲁单抗 4 120 3 男 65 18.69 1周 贲门癌、胃癌 右输尿管鳞状细胞癌 替雷丽珠单抗 7 28 4 女 67 25.77 2周 (-) 卵巢癌 帕博力珠单抗 1 100 5 女 67 22.38 3 d (-) 乳腺癌 帕博力珠单抗 7 58 (-)为阴性；BMI：体重指数；ICI：免疫检查点抑制剂 
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表 2 5例ICI-DM患者的实验室指标
Table 2. Clinical indicators of 5 patients with ICI-DM
例序 血
pH值治疗前血糖
(mmol/L)起病血糖
(mmol/L)血钠
(mmol/L)血钾
(mmol/L)淀粉酶
(U/L)HbA1c
(%)胰岛自身抗体 空腹C肽
(μg/L)甲状腺功能 甲状腺相关抗体 日胰岛素用量(IU) 1 7.42 (-) 28 134 4.5 (-) 8.9 均(-) 0.09 正常 (-) 48 2 7.48 FBG 7~8
PBG 11~1324.1 136 4.6 59 9.5 ICA (+)26.07
GADA(+)2330.54 (-) NA 64 3 7.14 正常，具体数值病历中未记载 64 (-) (-) 99 7.7 均(-) 0.047 正常 (-) 38 4 7.13 FBG 5.6~7.3 32.2 125 5.0 (-) 8.7 均(-) 0.09 原发甲减 TPOAb(+) 90 5 7.22 FBG 4~5 33.48 (-) (-) (-) 8.4 均(-) ＜0.05 正常 (-) 56 (-)为阴性；(+)为阳性；FBG：空腹血糖；PBG：餐后2 h血糖；HbA1c：糖化血红蛋白；ICA：胰岛细胞抗体；GADA：谷氨酸脱羧酶抗体；TPOAb：甲状腺过氧化物酶抗体; NA为无相关数据
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表 3 5例ICI-DM患者治疗前后临床指标
Table 3. Clinical data of 5 patients with ICI-DM before and after treatment
例序 治疗前 治疗后 尿酮体 动脉血
pH随机血糖
(mmol/L)尿酮体 动脉血
pH随机血糖
(mmol/L)1 + 7.42 28 - 7.42 11 2 + 7.48 24.1 - 7.50 9.9 3 + 7.14 64 - 7.43 9.6 4 +++ 7.13 32.2 - 7.45 10.9 5 +++ 7.22 33.48 - 7.42 12
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表 4 ICI-DM血糖水平分级与ICI治疗
Table 4. ICI-DM blood glucose level classification and ICI treatment
等级 空腹血糖(mmol/L) 糖尿病治疗 是否停用ICI治疗 1 大于正常上限但小于8.9 部分可启用口服药治疗，若有血糖急性升高或考虑酮症应及时启用胰岛素治疗 否 2 8.9~13.9 内分泌门诊评估可调整口服药物剂量或添加胰岛素治疗无法进行早期门诊评估或存在酮症酸中毒迹象，请优先使用胰岛素 暂停ICI治疗直至血糖得到控制 3 13.9~27.8 及时启用胰岛素，需住院治疗，进行内分泌科会诊 暂停ICI治疗直至血糖得到控制 4 ＞27.8 及时启用胰岛素，住院治疗，紧急进行内分泌科会诊 暂停ICI治疗直至血糖得到控制
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[1] 中华医学会内分泌学分会免疫内分泌学组. 免疫检查点抑制剂引起的内分泌系统免疫相关不良反应专家共识(2020)[J]. 中华内分泌代谢杂志, 2021, 37(1): 1-16. [2] Wu L, Tsang VHM, Sasson SC, et al. Unravelling checkpoint inhibitor associated autoimmune diabetes: from bench to bedside[J]. Front Endocrinol (Lausanne), 2021, 12: 764138. doi: 10.3389/fendo.2021.764138 [3] Zhang W, Chen J, Bi J, et al. Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM[J]. Front Endocrinol (Lausanne), 2022, 13: 1084441. [4] Grimmelmann I, Momma M, Zimmer L, et al. Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy-a multicentre study of 90 patients from the German Dermatooncology Group[J]. Eur J Cancer, 2021, 149: 1-10. doi: 10.1016/j.ejca.2021.02.017 [5] Zhang R, Cai XL, Liu L, et al. Type 1 diabetes induced by immune checkpoint inhibitors[J]. Chin Med J(Engl), 2020, 133(21): 2595-2598. [6] Perdigoto AL, Deng S, Du KC, et al. Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes[J]. JCI Insight, 2022, 7(17): e156330. doi: 10.1172/jci.insight.156330 [7] 邱俊霖, 罗说明, 殷文凤, 等. 免疫检查点抑制剂相关1型糖尿病的临床特征分析[J]. 中华医学杂志, 2023, 103(1): 38-41. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGTL202207008.htm [8] Akturk HK, Kahramangil D, Sarwal A, et al. Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis[J]. Diabet Med, 2019, 36(9): 1075-1081. doi: 10.1111/dme.14050 [9] 张瑞, 刘柳, 蔡晓凌, 等. 免疫检查点抑制剂治疗后发生1型糖尿病二例报道并文献综述[J]. 中国糖尿病杂志, 2020, 28(1): 62-70. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGTL202001013.htm [10] Chen X, Affinati AH, Lee Y, et al. Immune checkpoint inhibitors and risk of type 1 diabetes[J]. Diabetes Care, 2022, 45(5): 1170-1176. doi: 10.2337/dc21-2213 [11] Ding JT, Yang KP, Lin KL, et al. Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes[J]. Front Endocrinol(Lausanne), 2023, 13: 1090842. doi: 10.3389/fendo.2022.1090842 [12] Youssef N, Noureldein M, Daoud G, et al. Immune checkpoint inhibitors and diabetes: mechanisms and predictors[J]. Diabetes Metab, 2021, 47(3): 101193. doi: 10.1016/j.diabet.2020.09.003 [13] Qiu J, Luo S, Yin W, et al. Characterization of immune checkpoint inhibitor-associated fulminant type 1 diabetes associated with autoantibody status and ethnic origin[J]. Front Immunol, 2022, 13: 968798. doi: 10.3389/fimmu.2022.968798 [14] Peyrony O, Ellouze S, Fontaine JP, et al. Fulminant diabetes due to immune checkpoint inhibitors in the emergency department[J]. Am J Emerg Med, 2020, 38(2): 408.e3-408.e4. doi: 10.1016/j.ajem.2019.158495 [15] Liu J, Shi Y, Liu X, et al. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus[J]. Transl Oncol, 2022, 24: 101473. doi: 10.1016/j.tranon.2022.101473 [16] Byun DJ, Braunstein R, Flynn J, et al. Immune checkpoint inhibitor-associated diabetes: a single-institution experience[J]. Diabetes Care, 2020, 43(12): 3106-3109. doi: 10.2337/dc20-0609 [17] Lo Preiato V, Salvagni S, Ricci C, et al. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature[J]. Rev Endocr Metab Disord, 2021, 22(2): 337-349. doi: 10.1007/s11154-020-09618-w [18] Clotman K, Janssens K, Specenier P, et al. Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus[J]. J Clin Endocrinol Metab, 2018, 103(9): 3144-3154. doi: 10.1210/jc.2018-00728 [19] Quandt Z, Young A, Anderson M. Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes[J]. Clin Exp Immunol, 2020, 200(2): 131-140. [20] 罗说明, 邓敏, 杨涛, 等. 免疫检查点抑制剂诱导的1型糖尿病[J]. 中华医学杂志, 2020, 100(26): 2067-2070. https://www.cnki.com.cn/Article/CJFDTOTAL-HLZH202303012.htm [21] Zhang AL, Wang F, Chang LS, et al. Coexistence of immune checkpoint inhibitor-induced autoimmune diabetes and pancreatitis[J]. Front Endocrinol (Lausanne), 2021, 12: 620522. -
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