Abstract：
OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs).
METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI.
RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature.
CONCLUSIONS: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.
METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI.
RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature.
CONCLUSIONS: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.
摘要：
目的：本研究的目的是报告与免疫检查点抑制剂（ICIs）相关的自主神经失调的临床特征。
方法：我们报告了2例自身免疫性自主神经节病变（AAG）患者的免疫相关不良事件（irAEs）。我们还对ICI治疗期间出现自主神经障碍的先前病例报告进行了回顾。此外，我们使用美国食品和药物管理局不良事件报告系统(FAERS)进行药物警戒分析,以调查与ICI相关的自主神经失调.
结果：我们护理的两名患者在ICI治疗肺癌后同时发展为AAG和自身免疫性脑炎。我们全面审查了13例已发表的ICI相关自主神经失调的病例（M：F=11：2，平均发病年龄为53岁），包括AAG（n=3）和自主神经病变（n=10）。其中,ICI单药治疗7例，联合ICI使用6例。13名患者中有6名，在ICIs开始后1个月内出现自主神经失调.7例观察到体位性低血压，5例观察到尿失禁或尿潴留。除3例患者均有胃肠道症状。检测不到抗神经节乙酰胆碱受体抗体。除两名患者外，所有患者均接受了免疫调节治疗。免疫调节治疗对3例AAG患者和2例自主神经病变患者有效，但在其他人中无效。五名病人死亡,神经系统IRAE(n=3)或癌症(n=2)。使用FAERS的药物警戒分析表明，ipilimumab单一疗法以及nivolumab和ipilimumab的组合构成了发生自主神经失调的重大风险。与文献综述一致。
结论：ICIs可引起包括AAG在内的自主神经失调，自主神经病变是一种神经系统疾病。
方法：我们报告了2例自身免疫性自主神经节病变（AAG）患者的免疫相关不良事件（irAEs）。我们还对ICI治疗期间出现自主神经障碍的先前病例报告进行了回顾。此外，我们使用美国食品和药物管理局不良事件报告系统(FAERS)进行药物警戒分析,以调查与ICI相关的自主神经失调.
结果：我们护理的两名患者在ICI治疗肺癌后同时发展为AAG和自身免疫性脑炎。我们全面审查了13例已发表的ICI相关自主神经失调的病例（M：F=11：2，平均发病年龄为53岁），包括AAG（n=3）和自主神经病变（n=10）。其中,ICI单药治疗7例，联合ICI使用6例。13名患者中有6名，在ICIs开始后1个月内出现自主神经失调.7例观察到体位性低血压，5例观察到尿失禁或尿潴留。除3例患者均有胃肠道症状。检测不到抗神经节乙酰胆碱受体抗体。除两名患者外，所有患者均接受了免疫调节治疗。免疫调节治疗对3例AAG患者和2例自主神经病变患者有效，但在其他人中无效。五名病人死亡,神经系统IRAE(n=3)或癌症(n=2)。使用FAERS的药物警戒分析表明，ipilimumab单一疗法以及nivolumab和ipilimumab的组合构成了发生自主神经失调的重大风险。与文献综述一致。
结论：ICIs可引起包括AAG在内的自主神经失调，自主神经病变是一种神经系统疾病。
