绘制免疫检查点抑制剂的内分泌毒性谱：使用世界卫生组织药物不良反应数据库VigiBase进行的不成比例分析。
Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.
作者信息
Bai Xuefeng, Lin Xiahong, Zheng Kainan, Chen Xiaoyu, Wu Xiaohong, Huang Yinqiong, Zhuang Yong
机构信息
Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, No. 950 Donghai Street, Fengze District, Quanzhou, Fujian Province, China.
Department of Medical Administration, The Second Affiliated Hospital of Fujian Medical University, No. 950 Donghai Street, Fengze District, Quanzhou, Fujian Province, China.
出版信息
Endocrine. 2020 Sep;69(3):670-681. doi: 10.1007/s12020-020-02355-9. Epub 2020 Jun 7.
PURPOSE
Our study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs).
METHODS
We obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associated with ICIs and ROR to compare differences between ICI subgroups of ADRs. IC (lower end of the 95% confidence interval of IC) is considered significant if larger than 0.
RESULTS
In all, 6089 reports for endocrinopathies associated with ICIs were involved, with a male to female ratio of 1.5:1. The disproportionality analysis indicated significance of not only common endocrinopathies: thyroid dysfunction, hypophysitis/hypopituitarism, adrenal insufficiency, T1DM, fulminant T1DM (IC: 4.12-6.62), but also rare endocrinopathies: hypoparathyroidism, diabetes insipidus, hypogonadism (IC: 1.56-2.04). Increased risk of ADR reporting emerged in anti-CTLA-4 (e.g., hypophysitis/hypopituitarism, adrenal insufficiency) or in anti-PD-1/PD-L1 (e.g., thyroid dysfunction, T1DM, fulminant T1DM). In general, combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) had a stronger association with endocrinopathies than monotherapy (ROR: 2.8, 95% CI: 2.5-3.1). Onset time of common endocrinopathies differed between different ICI therapies, typically within 12 weeks in anti-CTLA-4 monotherapy but diffusely ranging from 0 to 48 weeks in anti-PD-1 monotherapy.
CONCLUSIONS
Our study shows rising reporting frequencies of endocrinopathies caused by ICIs, especially aggravated in combination therapy. Clinicians should be early aware of latent endocrine toxicity and different onset time of endocrinopathies when implementing ICI therapies.
目的
我们的研究旨在描绘免疫检查点抑制剂（ICI）的内分泌毒性谱。
方法
我们获取了2011年1月1日至2019年3月6日期间来自VigiBase的数据。所有内分泌药物不良反应（ADR）根据《药物监管活动医学词典》通过分组查询进行分类。使用信息成分（IC）和报告比值比（ROR）进行不成比例分析。我们用IC识别与ICI相关的有意义的内分泌疾病，并用ROR比较ADR的ICI亚组之间的差异。如果IC（IC的95%置信区间下限）大于0，则认为具有显著性。
结果
总共涉及6089份与ICI相关的内分泌疾病报告，男女比例为1.5:1。不成比例分析表明，不仅常见的内分泌疾病具有显著性：甲状腺功能障碍、垂体炎/垂体功能减退、肾上腺功能不全、1型糖尿病、暴发性1型糖尿病（IC：4.12 - 6.62），而且罕见的内分泌疾病也具有显著性：甲状旁腺功能减退、尿崩症、性腺功能减退（IC：1.56 - 2.04）。抗CTLA - 4（如垂体炎/垂体功能减退、肾上腺功能不全）或抗PD - 1/PD - L1（如甲状腺功能障碍、1型糖尿病、暴发性1型糖尿病）中ADR报告风险增加。一般来说，联合治疗（抗CTLA - 4加抗PD - 1/PD - L1）与内分泌疾病的关联比单一治疗更强（ROR：2.8，95%CI：2.5 - 3.1）。不同ICI治疗中常见内分泌疾病的发病时间不同，抗CTLA - 4单一治疗通常在12周内，但抗PD - 1单一治疗的发病时间广泛分布于0至48周。
结论
我们的研究表明，ICI引起的内分泌疾病报告频率不断上升，联合治疗时尤其加重。临床医生在实施ICI治疗时应尽早意识到潜在的内分泌毒性以及内分泌疾病的不同发病时间。
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