Department of Endocrinology and Metabolism, National Hospital Organization Sendai Medical Center.
Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine.
Tohoku J Exp Med. 2021 Aug;254(4):253-256. doi: 10.1620/tjem.254.253.
The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.
细胞毒性 T 淋巴细胞相关抗原 4 和程序性死亡受体 1 通路是癌症免疫检查点抑制剂 (ICI) 治疗的新的治疗靶点。然而，它们可能引起内分泌相关的不良反应，包括垂体炎、自身免疫性甲状腺炎和 1 型糖尿病 (DM)。此外，ICI 治疗停药后还会出现延迟性免疫相关不良反应 (irAE)。本文报道了 1 例 60 岁女性晚期肾细胞癌伴脑转移患者，接受纳武利尤单抗、伊匹单抗和泼尼松龙治疗。在联合治疗第 3 疗程时，因结肠炎发作和泼尼松龙剂量增加而停止治疗。停药约半年后，患者因全身不适、高血糖（330 mg/dL）和糖尿病酮症酸中毒入院。糖化血红蛋白水平为 6.5%。胰岛相关自身抗体阴性。胰高血糖素耐量试验显示胰岛素完全耗竭。因此，我们诊断为暴发性 1 型 DM，并给予多次胰岛素注射治疗。接受 ICI 联合治疗的患者中，1 型 DM 的发病通常迅速。本例是纳武利尤单抗和伊匹单抗停药后半年发生暴发性 1 型 DM 的罕见病例。文献报道了 2 例使用纳武利尤单抗或阿替利珠单抗停药 4 个月后发生 1 型 DM 的病例。本例表明，即使在低剂量泼尼松龙治疗下，ICI 治疗停药后也必须定期监测暴发性 1 型 DM 和其他迟发性 irAE。
