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[专业资源] 免疫检查点抑制剂诱导癌症患者内分泌疾病的频谱:病例报告的范围审查

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发表于 2019-3-13 00:00:34 | 显示全部楼层 |阅读模式
概要
背景
自2011年以来,六种免疫检查点抑制剂(ICI)已被批准用于治疗患有许多晚期实体瘤和血液恶性肿瘤的患者,以改善其预后。他们的内分泌免疫相关不良事件[irAEs]的病例报告越来越多地发表,因为这些恶性肿瘤的更多现实世界的患者用这些药物治疗。他们提醒医生注意药物的AEs(可能在药物的生命周期中发生变化),并为上市后的安全监督做出贡献。使用Arksey和O'Malley的修改框架,我们对ICI上市前后ICI诱发的内分泌病例报告的频谱和特征进行了范围审查。

方法
2017年7月,我们在没有日期和语言限制的情况下搜索了4个ICI引起的内分泌病的引用数据库。我们还手工搜索文章的参考文献,相关期刊的内容,并进行补充搜索以捕获截至2018年1月的最新报告。对于这项研究,一个案例应该有关于癌症类型,ICI类型,临床表现,生化测试,治疗加上ICI起始与内分泌病的时间关联。两名内分泌学家独立提取数据,然后对数据进行汇总和分类。

结果
共有79篇文章报道了451例ICI诱发的内分泌病 -  222例垂体功能减退症,152例甲状腺疾病,66例糖尿病,6例原发性肾上腺皮质功能不全,1例ACTH依赖性库欣综合征,1例甲状旁腺功能减退症和3例尿崩症病例。他们的临床表现反映了激素过量或缺乏。有些是无症状的,有些是危及生命的。一个或多个内分泌腺可能会受到影响。多腺内分泌病可以同时或依次存在。许多发生在治疗开始的5个月内; ICI停止后发生了一些事情。大多数是不可逆转的,他们需要长期激素替代。当非内分泌AE共存或作为肾上腺功能不全的治疗时,使用高剂量类固醇。病例报告中的信息存在差异,但均符合研究标准以进行诊断。


ICI诱导的内分泌病的范围很广(受影响的5个腺体)并且它们的表现各不相同(12个内分泌病)。需要整合临床,生化和治疗信息的临床推理才能正确诊断和管理它们。医生应该对其发生保持警惕,并能够在发病和随访时对其进行适当的诊断,调查和管理。

关键词:癌症免疫治疗,免疫检查点抑制剂(ICI),ICI诱导内分泌病,内分泌免疫相关AE

介绍
我们对癌症免疫应答和免疫调节机制的理解进展已被转化为免疫疗法,用于治疗许多晚期实体瘤和血液系统恶性肿瘤。癌症免疫疗法中最有希望的两项进展是基于细胞的过继治疗方式和免疫调节方式。目前,免疫调节方式比基于细胞的疗法具有更广泛的治疗效用。它们由称为免疫检查点调节剂的蛋白质单克隆抗体(mAb)组成 - 细胞毒性T淋巴细胞相关抗原-4(CTLA-4),程序性细胞死亡蛋白-1(PD-1)和程序性死亡配体1和2( PD-L1和PD-L2)[1-6]。

在淋巴细胞上发现PD-1和CTLA-4。 PD-L1 / L2存在于许多细胞上,包括肿瘤细胞。这些检查点调节蛋白的典型功能是减少对抗原的免疫反应,起到免疫系统的制动作用[1-6]。这些检查点调节蛋白的单克隆抗体,称为免疫检查点抑制剂(ICIs),释放已置于免疫系统上的制动器,使患者的免疫系统能够攻击癌细胞和某些健康组织。目前有6个ICI被批准用于治疗许多晚期癌症(表11)。

表格1
免疫检查点抑制剂由美国食品和药物管理局批准

* FDA首次表明批准日期

ICI的使用带来了一种称为免疫相关不良事件(irAE)的新毒性,其机制和表现与细胞毒性化疗,放射或分子靶向药物的机制和表现完全不同。这些irAE本质上是炎性的,可能影响多器官系统。虽然并非在所有患者中发生,但它们被认为是由正常免疫调节途径阻断引起的自身免疫反应。常见的ICI irAE包括结肠炎,肝炎,肺炎,皮炎和内分泌病。

虽然非内分泌IRAE需要停止免疫治疗,并且通常采用免疫抑制治疗[1-6],但如果管理得当,内分泌irAE不需要停止ICI,并且在很大程度上是不可逆转的,需要长期管理[7]。 ,8]。通常会咨询内分泌学家以共同管理这些患者,并且应该熟悉这些内分泌irAE(在本文中称为ICI诱导的内分泌病)。

药物的AE曲线可能在其生命周期中发生变化。在现实世界的患者中,市售药物可能先前未报告过AE,因为这些患者不必满足临床试验的研究入选标准。此外,市售药物可能有罕见的AE,当更多患者接受治疗时,这些AE会浮出水面。在美国(US),医疗保健提供者,患者和其他人直接或间接向食品和药物管理局(FDA)报告市售药物的AE。医疗保健提供者也可以将其患者的AE作为病例报告发布在医学期刊中。这些出版物有助于药物的上市后安全监督,并提醒临床医生注意这些可能的药物AE。

对CTLA-4和PD-1阻断治疗相关的irAE病例报告的2016年系统评价[9]是基于2015年8月进行的文献检索,即抗CTLA-4 mAB(ipilimumab)批准后4年。 2011年和2014年批准抗PD-1单克隆抗体(nivolumab和pembrolizumab)后几个月。其中包括84例ICI诱导的内分泌病 - 其中79例使用ipilimumab,2例使用pembrolizumab,3例使用nivolumab。

自那次综述[9]以来,ICI诱发的内分泌病的概况由于各种原因而发生了变化:(a)许多更晚期的癌症患者已接受过ICI治疗; (b)ICI的销售时间更长; (c)已批准更多癌症接受ICI治疗; (d)2016/2017年批准了新的ICI药物亚类(抗PDL-1单克隆抗体); (e)由于更多患者接受这些药物治疗,因此报告了罕见的ICI诱发的内分泌病例。

在本文中,我们基于2017年7月,ipilimumab批准后6年,nivolumab和pembrolizumab批准后3年进行的文献检索,报告了ICI引起的内分泌病例报告的范围审查结果,以及在atezolimumab,avelumab和durvalumab批准后的一年。我们的目标是在市场营销之前和之后发现ICI诱导的内分泌病变的新知识,因为更多真实世界的患有不同晚期癌症的患者接受这些药物治疗。

方法
我们使用了Arksey和O'Malley提出的框架[10]并由Levac等人修改。 [11]进行这一范围界定审查,以确定ICI诱导的内分泌病。

第1阶段:确定研究问题 - 目的
ICI诱导的内分泌病的频谱(范围,范围和性质)是多少?他们如何以及何时临床表现?进行了哪些调查来支持他们的诊断?他们如何在发病时进行管理,结果如何?

第2阶段:确定相关研究 - 数据来源和搜索
2017年7月,我们在4个引文数据库中搜索了与ICI癌症治疗相关的内分泌病例的已发表文章和摘要。该搜索最初是在3个Ovid MEDLINE数据库(MEDLINE,In-Process和其他非索引引文,Epub Ahead of Print)中开发的,然后通过Wiley Online Library和Clarivate Analytics针对Embase.com,Cochrane对照试验中心注册进行了优化Web of Science。搜索是使用受控术语(医学主题标题和EMTREE,如果可用)和标题或摘要关键词的组合构建的。搜索中未包含日期或语言限制,但动物研究,社论和评论被排除在审核之外。

在整个审查过程中,直到2018年1月31日,作者对文章中的参考文献列表进行了手工搜索,审查了相关期刊的内容,并在Ovid MEDLINE,Embase和Cochrane中心注册中进行了补充搜索,以捕获最近发表的报告。 EndNote X6(Clarivate Analytics)中排除了重复引用。 (所有可重现的搜索策略可在附加文件1:附录1中找到)。

第3阶段:研究选择
对于资格筛选,引用按内分泌病的类型分类。对于本综述,病例应该有关于癌症类型,使用的ICI类型,临床表现,生化测试结果,成像结果(如果完成)以及初始和后续治疗的信息。

第4阶段:绘制数据图表 - 数据提取
引用被分发给至少2名内分泌学家的小组进行复查(垂体,肾上腺和甲状旁腺,尿崩症:MHT和LYS;甲状腺:RI和MHT;糖尿病:KMS,RG和MHT)。使用两步法,每个团队成员审查标题和摘要,以确定可能符合条件的相关引用。然后,检索全文,如果可用,则检查并提取数据。

评审员使用标准化数据提取表格(附加文件2:附录2)独立筛选所有指定的引文,根据国际药物流行病学会和国际药物警戒学会推荐的AEs出版物指南收集每个病例的数据评估病例报告的质量[12]。然后,他们比较了他们的决定,并通过共识解决了。

第5阶段:整理,总结和报告结果
对于本综述,病例应该有关于癌症类型,使用的ICI类型,临床表现,生化测试结果,成像结果(如果完成)以及初始和后续治疗的信息。如果未报告上述所有情况,则该病例应包含以下2项信息:临床,生化和治疗信息。为了暗示关联,ICI治疗开始与内分泌病的后续发展之间应该存在密切的时间关系。我们根据受影响的内分泌腺对所鉴定的ICI诱导的内分泌病进行了总结和分类,无论其是否与腺体的功能亢进或功能减退有关,以及它是否涉及一种或多种内分泌病(多腺内分泌病)。

结果
图图11显示了文献检索的结果。在所鉴定的1041个引文中,218个具有ICI诱导的内分泌病引用,并且具有足够信息用于该评价。这些文章中的一些有关于两种或更多种内分泌病的信息。消除这些重复文章留下了179篇独特的文章(116篇论文,43篇摘要和20篇致编辑的信件),报告了451例ICI诱发的内分泌病,符合诊断病例的研究标准。


图1
PRISMA流程图

五种内分泌腺受到12种内分泌疾病的影响:

垂体(垂体功能减退症(多发性或孤立性激素缺乏症),尿崩症和ACTH依赖性库欣综合征);
甲状腺炎(甲状腺毒症[格雷夫斯病和甲状腺炎]和甲状腺功能减退症[原发性甲状腺功能减退症和甲状腺功能亢进症进展为甲状腺功能减退症]),
肾上腺(原发性肾上腺皮质功能不全),
胰腺(1型糖尿病(T1DM)和2型糖尿病(T2DM)),和
甲状旁腺(原发性甲状旁腺功能减退症)
垂体前列腺炎/前垂体功能减退症
表表22总结了来自222例垂体炎/前垂体功能减退症[13-96]的数据。 (每个案例的细节见附加文件3:附录3)。 222例中,220例符合纳入标准; 没有生化检测的2结果有临床和治疗信息。

表2
免疫检查点抑制剂诱发的垂体炎和垂体前叶功能不全的病例

该队列的中位年龄为61岁。大多数(65%)是男性(与非ICI诱导的自身免疫性垂体炎中的大多数女性相反)。大多数(87%)患有黑色素瘤。 CTLA-4和PD-1 / PD-L1单克隆抗体分别用于200例和15例患者的单药治疗,两者均为7例。在开始ICI后,临床表现的中位数开始是12周(范围3-76周)。症状反映了相关的激素缺乏症,有或没有垂体增大的质量效应(例如头痛)。在具有详细激素信息的176名患者中,36名患有一种激素缺乏症,47名患有两种激素,72名患有3名,14名患有4名,7名患有5名。继发性肾上腺缺乏占83%,继发性甲状腺功能减退占77%,继发性性腺功能减退占53%。在167例垂体磁共振成像(MRI)/计算机断层扫描(CT)扫描的患者中,108例显示扩大/增强的垂体。并非所有垂体增大的患者都出现头痛,而且并非所有患有头痛的患者(n = 126)都有垂体增大。高剂量类固醇用作初始治疗69%,生理剂量类固醇29%,2%患者无类固醇。当病例发表时,有220例存活,2例患病(未说明死亡原因)。在220名中,184名接受了替代治疗,32名没有关于出院药物的信息,4名没有替代药物。在预审批和上市后期间,分别有18和204(营销的前4年166)。有9例多发性内分泌病,包括前垂体功能减退症和甲状腺炎[31,45,89],加上原发性甲状腺功能减退[60,82,90,93],加上格雷夫斯病和T​​1DM [76],再加上T1DM [95] 。

甲状腺疾病
表表33总结了来自152例ICI诱导的甲状腺疾病的数据(每个病例的细节[31,60,76,80,82,90,97-138]在附加文件4中:附录4)。

表3
免疫检查点抑制剂诱发甲状腺毒症和甲状腺功能减退症的病例

甲状腺毒症
在73例甲状腺毒症中,6例患有格雷夫斯病,67例患有甲状腺炎。除临床和治疗信息外,所有患者均有降低的甲状腺刺激素(TSH)和升高的游离甲状腺素(FT4)/游离三碘甲状腺原氨酸(FT3)。患有格雷夫斯病的人也有阳性促甲状腺激素受体抗体(TRAb)或甲状腺刺激免疫球蛋白(TSI)。两组均可具有或不具有阳性甲状腺过氧化物酶(TPO)和/或甲状腺球蛋白(TG)Ab。对于那些接受放射性同位素甲状腺扫描的患者,格雷夫斯病患者的摄取增加,甲状腺炎患者的摄取减少。

格雷夫斯病
该队列的中位年龄为54∙5年。 6名患者中有4名是男性。全部都有转移性黑色素瘤。 Ipilimumab用于5/6患者,4例用于单一疗法,1例用于Nivolumab。临床表现的中位数开始于ICI开始后7周(范围= 6-416)。症状范围从格雷夫斯的眼病[97,98]到甲状腺功能亢进。高剂量类固醇用作初始治疗3例,抗甲状腺药物4例。所有患者均有改善,2例患者接受甲状腺切除术(1例甲状腺切除术,另一例甲状腺功能减退症)。在ipilimumab批准和3个上市后报告了两例。一例使用了尚未批准的tremelimumab。一例多腺内分泌疾病患有格雷夫斯病,其次是T1DM和前垂体功能低下[76]。

甲状腺炎
该队列的中位年龄为61岁。在那些确定性别的人中,53%是女性。大多数(61%)患有转移性黑色素瘤。抗PD-1 mAb用于60/67患者,单药治疗44例,Ipilimumab治疗后8例和8例。症状的中位数发作在ICI开始后6周(范围= 3-28)。临床表现从无症状到甲状腺风暴[105,106,110]。高剂量类固醇用作初始治疗6例(其中2例伴有肾上腺皮质功能不全),6例抗甲状腺药物,15例β-受体阻滞剂和3例碘化物溶液。在随访资料的67例患者中, 46需要甲状腺素替代。在预批准和上市后期间,分别有2和65个报告。有7例多腺内分泌病累及甲状腺炎 - 加前侧垂体功能低下[31,123,126];加上原发性肾上腺皮质功能不全[126];加垂体促肾上腺皮质激素(ACTH)依赖性库欣综合征和前垂体功能低下[127];加上甲状旁腺功能减退症[122];加上1型糖尿病[128,130]。

甲状腺功能减退症
在79例甲状腺功能减退症中,29例患有原发性甲状腺功能减退症,50例甲状腺功能减退症伴有短暂性甲亢。原发性甲状腺功能减退症患者TSH升高,FT4 / FT3降低。在甲状腺功能亢进症发展为甲状腺功能减退症的患者中,TSH(当报道时)高达19例。其余31人据称患有甲状腺功能减退症,并附有临床和/或治疗信息。

原发性甲状腺功能减退症
该队列的中位年龄为64岁。在那些确定性别的人中,52%是男性。百分之六十二有转移性黑色素瘤。单药治疗16例使用抗PD-1 / PDL-1单克隆抗体;用ipilimumab 11(按顺序在9和2组合)和ipilimumab单一疗法2.症状的中位数发作在ICI开始后12周(范围= 7-36)。症状范围从轻度至重度粘液性水肿昏迷[133]。左旋甲状腺素(LT4)于26日开始,未报告1和2中没有LT4。由于伴随肾上腺皮质功能不全,3例使用类固醇作为初始治疗,2例用胰岛素治疗糖尿病。在随访中,23例需要替换LT4,5例未报告,我死亡(原因未知)。在预审批和上市后期间,分别报告了1例和28例。有6例多发性内分泌病,包括原发性甲状腺功能减退症 - 加前侧垂体功能低下[60,82,90,93]和糖尿病[132,134]。

甲状腺毒症进展为甲状腺功能减退症
该队列的中位年龄为63岁。在那些确定性别的人中,56%是男性。大多数(59%)患有黑色素瘤。抗PD-1 / PDL-1单克隆抗体用于48例患者 - 单药治疗36例,ipilimumab治疗5例,联合ipilimumab治疗7例。甲状腺功能亢进症发病后中位数为6周(范围3-15)。许多患者被称为甲状腺功能减退症,没有关于症状的临床信息。在症状出现时,39名患者被处方LT4。在随访中,44例需要更换LT4,6例患者未报告LT4替代。所有50例病例均在上市后报告。有7例多腺内分泌病,甲亢进展为甲状腺功能减退症加前侧垂体功能低下[76,123];加上原发性肾上腺皮质功能不全(PAI)[126];加垂体ACTH依赖性库欣综合征[127];加上甲状旁腺功能减退症[122];加上T1DM [76,128]。

糖尿病
表表44总结了来自66例ICI诱导的糖尿病的数据。 (每个案例[76,127,128,130,139-185]的细节见附加文件5:附录5)。所有人都符合纳入标准。

表4
免疫检查点抑制剂诱发糖尿病的病例

*治疗剂量类固醇作为化疗方案的一部分(n = 2),治疗其他自身免疫表现(n = 3),逆转自身免疫性糖尿病(n = 2),降低胰岛素抵抗(n = 1);肾上腺功能不全(n = 2)

T1DM的诊断基于临床(发作,临床症状,立即和随后的胰岛素治疗)和生化(葡萄糖,酮体,胰岛抗体,酸性状态)数据。具有阳性胰岛抗体的任何病例基于假定的潜在自身免疫性质被诊断为T1DM。在胰岛抗体阴性或未报告的情况下,我们诊断他们患有T1DM,基于他们在先前血糖正常的患者中的糖尿病酮症酸中毒(DKA)的呈现,新发病的严重高血糖症,患有未知糖尿病的患者的低C肽,已知T2DM患者的新胰岛素需求量;任何有“爆发性”T1DM的人。

该队列的中位年龄为63岁。大多数(64%)是男性,大多数(45%)患有转移性黑色素瘤。使用的ICI是抗PD-1 mAb(n = 45);抗PD-L1单克隆抗体(n = 5);抗PD-1 mAb +抗-CTLA-4 mAb(n = 7);抗-CTLA-4 mAb然后抗-PD-1 mAb(n = 8);抗CTLA-4 mAb(n = 1)。临床表现的中位数开始于ICI开始后7.5周(范围= 1-52周)。根据我们的诊断标准(参见上文),65名患有T1DM,其中一名可能患有T2DM(进行十二指肠切除术并且不需要胰岛素治疗轻度高血糖)[178]。在ICI治疗前有4例患有T2DM,并且在ICI时根据新的胰岛素需求开发了T1DM [132,149,171]。

在T1DM队列中,43个呈现在DKA中,20个呈现出显着的高血糖症。在DKA组12中,大部分来自日本,被描述为具有暴发性T1DM [130,139,147,148,152-157,165,168-170]。胰岛相关的抗体(谷氨酸脱羧酶65(GAD 65),胰岛抗原2(IA2),胰岛素自身抗体(IAA)或锌转运蛋白8(ZnT8)Ab阳性率为51.5%(n = 34),阴性为41 %(n = 27)且未报告为7.5%(n = 5)。临床表现开始时,10例使用高剂量类固醇,60例使用胰岛素,口服降糖药物最初持续4例, 2没有治疗信息。所有66例患者从治疗后的高血糖中恢复 -  53例仍然是胰岛素依赖性的,未报告13例结果。一例患者,最初需要胰岛素,在停用pembrolizumab后第81天停用胰岛素[142]。上市后报告使​​用抗PD-1单克隆抗体的病例,在2014年批准后大多数2  -  3年。有6例多发性内分泌病,包括T1DM  - 加前垂体功能减退[75,95],加前侧垂体功能低下+ Graves '疾病[76],加上,甲状腺炎[129,130​​],plu原发性甲状腺功能减退症[132],甲状腺功能亢进加上甲状腺功能减退[76,130]。

原发性肾上腺皮质功能不全,ACTH依赖性库欣综合征,甲状旁腺功能减退症和尿崩症
表表55总结了来自ICI治疗的6例PAI,1例垂体ACTH依赖性库兴氏综合征,1例原发性甲状旁腺功能减退症和3例尿崩症的数据。 (案例详情[16,19,34,41,122,126,127,186-189]见附加文件6:附录6)。 所有人都符合纳入本次审查的标准。

表5
免疫检查点抑制剂引起原发性肾上腺功能不全,库欣病,甲状旁腺功能减退症和尿崩症的病例

原发性肾上腺皮质功能不全[16,34,126,186-188]
该队列的中位年龄为52岁。在确定性别的人中,60%是男性。在6名患者中,3名患有转移性黑素瘤。抗PD-1 mAb在4/6患者中用作单一疗法。 Ipilimumab用于2名患者。症状发作的中位数是ICI开始后10周(范围= 1.5-36)。高剂量类固醇用作4种初始治疗,2种用于生理类固醇。所有患者均在临床上接受治疗,并接受替代口服氢化可的松,其中两种[126,186]也使用氟氢可的松。 [188]报告的患者接受静脉注射泼尼松龙,其中含有一些盐皮质激素作用,但在出院时未提及氟氢可的松。一例[34]最初患有继发性肾上腺皮质功能不全(SAI),但在ipilimumab启动后第16周发现肾上腺增大。当进行cosyntropin刺激测试然后显示没有皮质醇反应时,作者得出结论,患者也有PAI。 PAI中出现负CST,但也可能出现持续时间很长的SAI。

垂体ACTH依赖性库欣综合征[127]
在ipilimumab加nivolumab开始治疗黑色素瘤后12周,出现了皮质醇增多症状。四周后,继发性肾上腺皮质功能不全发展。这些都在第6周之前出现短暂甲状腺功能亢进,在第一剂ICI后第9周发展为继发性甲状腺功能减退症。

原发性甲状旁腺功能减退症[122]
用ipilimumab加nivolumab治疗的这名黑色素瘤患者在第一剂ICI后6周出现急性低钙血症的症状。在住院的第3天,他患上了短暂性甲状腺炎,进展为甲状腺功能减退症。

尿崩症(DI)[19,41,189]
两名患者接受ipilimumab治疗,1名患者接受avelumab治疗(抗PD-L1治疗后第一例DI)。在ICI开始后12周,症状的中位数发作(烦渴和多尿伴有血糖正常)。两个[41,189]报告了与DI保持一致的生化数据,这两个在去氨加压素上排出。

报告的内分泌病不受数据支持
两例低钠血症归因于不适当的ADH分泌综合征[22,186]。然而,两者都有继发性肾上腺皮质功能不全,可能导致低钠血症。

唯一的高钙血症病例与PTH相关肽增加有关,而非PTH;因此,它不是原发性甲状旁腺功能亢进[189]。

讨论
临床表现
与ICI治疗的癌症患者中包括84例内分泌irAE的IRAE病例报告的2016年系统评价相比[9],我们的综述显示内分泌irAE病例报告增加了5倍(从84到451)。这种增加很可能反映了ICI治疗在更多癌症患者中的广泛应用 - (a)更多的黑色素瘤患者(原始适应症)现在用2类ICI治疗; (b)由于新的适应症被批准用于其他癌症,现在更多的患者接受ICI治疗(表1); 1); (c)2014年批准后,过去3年内报告了更多抗PD-1诱导的内分泌病例(图2)。在每一类ICI(2011年ipilimumab和2014年nivolumab和pembrolizumab)批准后的3  -  4年期间,ICI诱发内分泌病例的显着增加发表在其后2  -  3年内使用营销期(图(图2).2)。随着2016年和2017年针对癌症患者引入抗PD-L1药物,将在未来3  -  4年内报告更多ICI诱发的内分泌病[190]。


图2
报告的免疫检查点抑制剂诱导的内分泌病例正在增加

在2016年的综述[9]中,ipilimumab与68例垂体炎,4例甲状腺功能亢进,4例甲状腺功能减退,1例抗利尿激素分泌不当,1例中枢性肾上腺皮质功能不全,1例原发性肾上腺皮质功能不全有关。; pembrolizumab与1例甲状腺功能减退症和1例糖尿病有关; 和nivolumab与2例甲状腺功能减退症有关。 我们的范围研究揭示了更广泛的ICI诱导的内分泌疾病 -  222个垂体功能减退症,152个甲状腺功能紊乱,66个糖尿病,6个原发性肾上腺皮质功能不全,1个垂体ACTH依赖性库欣综合征,1个甲状旁腺功能减退症和3个尿崩症病例(图(图)0.33)。


图3
免疫检查点抑制剂诱导内分泌病的谱

临床上,内分泌病可以表现出激素缺乏,激素过量或两者(在相同或不同的腺体中)的症状。临床表现范围从无症状[93,111,112,116,118,135](生化检查诊断)到严重的危及生命的症状 - 甲状腺风暴[105],粘液性水肿昏迷[133]和糖尿病酮症酸中毒[144]。当有症状时,这些ICI诱导的内分泌病的表现反映了受影响的腺体产生的激素的扰动。

单一激素缺乏症 - 孤立性ACTH缺乏症中的ACTH [34,45,70,86]或T1DM中的胰岛素[132,139,140,​​142])比单一激素过量更常见 - 格雷夫斯病中的甲状腺素[102]和库欣综合征的ACTH [127]。偶尔,内分泌病可能出现一种激素过量的症状,其次是反映相同激素缺乏的症状 - 甲亢进展为甲状腺机能减退[116]。

多腺可能会受到影响,表现为多腺内分泌病。患者可以依次呈现两种内分泌腺体的症状和生化变化 - 甲状腺炎和1型糖尿病[130],甲状旁腺功能减退和甲状腺炎[122],甲状腺炎和ACTH依赖性库欣综合征[127],原发性甲状腺功能减退症和孤立性ACTH缺乏[93]。

当分泌7种激素的脑垂体受到影响时,可同时发生多种激素缺乏症;然后,患者出现多种垂体激素缺乏的症状[14]。在我们的综述中,发生了垂体激素缺乏的各种组合,其中3种激素缺乏是最常见的。最后,患有垂体炎的患者生病,并且在疾病的急性期可以抑制其甲状腺/性腺轴。

症状的发作可以早在1周[140]或最晚416周[102],最初的20周内发生。

垂体ACTH依赖性库欣综合征[127]是第一例报道,需要确诊。 ACTH分泌增加的病因可能是由于异位促肾上腺皮质激素释放激素(CRH)的产生,因为晚期黑色素瘤细胞已报道CRH的表达[191],并且已报道由于异位CRH分泌引起的库欣综合征[192]。由于该病例报告的作者没有对此进行调查,我们无法进一步评论,但提出这可能是病因,并指出该患者的库欣综合征和垂体炎不太可能相关。 ICI是否以及如何刺激CRH的分泌仍有待报道。

给予高剂量全身性糖皮质激素作为免疫抑制剂以治疗伴随的非内分泌IRAB(结肠炎,肝炎等)。对于内分泌IRABs,给予高剂量全身性糖皮质激素治疗肾上腺危象,垂体炎和选定的甲状腺炎病例。这种治疗并未改善黑色素瘤患者中ipilimumab相关性垂体炎的结果[8]。最近,大剂量糖皮质激素治疗黑色素瘤患者的ipilimumab相关性垂体炎与生存率降低有关[193]。当给予糖尿病患者时,高剂量全身性糖皮质激素(见表4)4)可使其高血糖症恶化。

ICI和ICI诱导的内分泌病的亚类
我们发现抗-CTLA-4 mAb是与抗PD-1单克隆抗体(n = 13)相比最常与垂体前叶炎和垂体前叶激素缺乏相关的ICI(单药治疗n = 188)。上述观察到的差异可能反映了更长的使用时间,因为ipilimumab在2011年被批准,在nivolumab和pembrolizumab之前3年。其他原因,包括内分泌腺的生物学,可以解释这种差异(见下文)。

我们发现抗-PD-1单克隆抗体更常与ICI相关(与CTLA-4 Ab相比)与自身免疫性甲状腺炎(37对6作为单药治疗),原发性甲状腺功能减退症(15对2作为单药治疗),甲状腺功能亢进进展为甲状腺功能减退(30 vs 2作为单一疗法)和1型糖尿病(45 vs 1作为单一疗法)。值得注意的是,在我们的综述中,所有6名Graves病患者均接受了抗-CTLA-4 mAb治疗(5例为单药治疗)。一项荟萃分析报道CTLA-4的多态性可增加格雷夫斯病的风险[194],但这与ICI的相互作用尚不清楚。

在本评价中计算每种ICI诱发的内分泌病的频率是不合适的,因为我们没有报告的病例总数,而不是已发表的病例。 Cukier等人。报告了用免疫疗法观察到的内分泌irAE的频率[195]。与本综述相关,ipilimumab,nivolumab和pembrolizumab的内分泌irAEs频率分别为:hypophysitis 1.5-17,0.6-1.5和0.6-1%;甲状腺功能减退症1.5-6.8,9-10.8和7-9.1%;甲状腺功能亢进4,2.7和3.4-7.8%;原发性肾上腺皮质功能不全0.8-1.6,1%未报告;没有报告1型糖尿病,0.9和0.2%。与Cukier等报道的不同ICI相关的内分泌病的频率有相似之处。 [195]以及本次审查报告的内容。

发病
ICI如何损害内分泌腺体尚不清楚;然而,有几种假设可以解释这一点[196]。所有与ICI治疗相关的内分泌病症都被假设为病因学中的自身免疫。检查点调节蛋白减少对抗原的免疫反应,因此对免疫系统起到制动作用[1-6]。阻断这些检查点调节蛋白会释放这种制动作用,使患者的免疫系统能够攻击癌细胞,并通过自身免疫机制损伤某些健康组织(图44)。


图4
抗PD(L)1和CTLA-4药物的作用机制。 1a与抗原呈递细胞(APC)相互作用后T细胞的正常活化状态。 TCR = T细胞受体。 1b由于CTLA-4竞争CD28与CD80 / 86相互作用而抑制T细胞活化。 1c抗-CTLA-4药物抑制CTLA-4,因此CD28能够与CD80 / 86相互作用并激活T细胞。 2a肿瘤细胞上的PD-L1阻止T细胞活化。 2b PD-L1被抗PD(L)1药物阻断,T细胞对肿瘤的活化是可能的

对于垂体炎,抗CLTA-4诱导的垂体炎的小鼠模型证明CTLA-4在垂体内分泌细胞中表达,并且当通过施用抗-CTLA-4mAb阻断时,导致补体成分的位点特异性沉积,垂体浸润和垂体Ab形成。该研究还评估了用ipilimumab治疗的前列腺癌和黑色素瘤患者,并显示发生垂体炎的患者发生垂体抗体,而未发生垂体炎的患者未见[47]。 Caturegli等人还报道了用CTLA-4阻断治疗的癌症患者的垂体内分泌腺表达的CTLA-4抗原。 [63]。

在用抗PD-1 / PD-L1药物治疗的患者中,较少见的是垂体炎。一些人假设这是因为对于nivolumab和pembrolizumab的mAb属于免疫球蛋白(IgG)4类[197],而ipilimumab是IgG1类的CTLA-4抗体,可以激活经典补体途径[47]。

抗PD-1诱导甲状腺功能障碍的机制尚不清楚。然而,抗PD-1治疗开始后抗甲状腺抗体的发展表明这些药物可能正在调节自身免疫平衡并揭示潜伏的自身免疫[119]。由于许多ICI引起的甲状腺功能减退症病例发生一段时间的短暂甲状腺功能亢进,其机制可能是破坏性甲状腺炎伴甲状腺抗原的释放和随后的二级抗体产生[111]。在我们研究的甲状腺炎队列中,49名接受TPO / TG Ab检测的患者中,只有18名患者具有阳性滴度。此外,在一名患者中,甲状腺功能减退症发生在格雷夫斯病之前[76]。

在我们的研究中,在那些接受胰岛相关抗体(GAD65,IA2,ZnT8,IAA)检测的自身免疫性糖尿病患者中,51.5%具有阳性滴度,41%具有阴性滴度,7.5%未报告。超过70%的患者注意到低C肽的胰岛素缺乏。 ICI治疗后自身免疫性糖尿病的几例病例报告[130,147,148,152,176,177]报道​​其患者的HLA类型增加了患1型糖尿病的风险。

在2014年批准抗PD-1药物后,2016年和2017年报告了ICI治疗后的许多糖尿病病例。在此之前,据报道ICI治疗后T1DM很少见 - (a)糖尿病未报告2016年荟萃分析[198](b)报道抗PD-1后为0.2-0.9%,2017年抗PD-L1治疗后为0.1-0.3%[195],(c)仅13例(0.2%) )在2018年系统评价和荟萃分析[199]。我们的研究确定了65例T1DM病例报告,其中许多报告超过了临床试验的荟萃分析[199]。在我们的研究中,12例T1DM病例暴发性T1DM-急性,最近发生严重高血糖,酮症酸中毒,胰岛相关的阴性一般[200]。最近Stamatouli等人。据报道,与经典T1DM相比,用检查点抑制剂诱导的胰岛素依赖性糖尿病具有相似性和差异[201]。

案例文档
我们的评价中很少有病例报告指出在报告不良事件时被认为是“必需”的内分泌IRAB的严重程度[12]。但是,根据病例报告中的信息,大多数是2级或3级,少数4级病例。对内分泌疾病的严重程度进行分级可能会有所帮助,因为一些内分泌IRAB是紧急情况 -  DKA,肾上腺危象,甲状腺风暴和粘液性水肿昏迷 - 并且可能危及生命,需要紧急护理。同样,除DM病例外,有关特定内分泌紊乱或自身免疫性疾病的个人和家族史的信息很少。最后,只有91/445例病例报告在发生irAE时停止了ICI药物,但没有足够的信息表明它们是短暂的还是永久性的。令人感兴趣的是1例T1DM患者在停用pembrolizumab后81天不需要胰岛素[144]。

局限和优势
该范围审查具有局限性。首先是已发表的病例报告中信息的可变性。有些人没有将所有数据确定为“必需”或“非常可取”[12],但已足以满足研究标准。所做的诊断测试存在差异,包括其时间。在垂体炎症病例中,垂体成像可能会延迟,并且并非所有患者都进行了治疗前成像以进行比较。其次,虽然几乎所有人都有紧密的时间关系,但是后来发生了一些irAEs [45,56,94,102,144,147]。第三,尽管报告的许多案例都是完整的论文,但43篇是摘要,因为在撰写本文时无法找到完整的报告。第四,我们的范围研究仅涵盖主要在上市后的已发表的案例报告。第五,我们的范围界定审查包括截至2018年1月31日的病例报告。此后,其他病例报告已经发表[193]。最后,正如系统评价[202]所指出的,在我们的综述中,一些关于临床试验中的irAE的报告并没有提供所有必需的信息。

我们的评论具有以下优势:(a)从销售已发布的病例报告之前和之后以标准化方式收集的数据是全面的,并且可以发现以前未解决过的重要的irAE。 2018年的一项荟萃​​分析[199]仅针对甲状腺功能减退症,甲亢,垂体炎,原发性肾上腺皮质功能不全和糖尿病。 (b)使用临床推理,诊断基于综合临床,生物化学和管理文献,并辅之以ICI开始与内分泌病发展之间的时间关系[203]; (c)我们的研究揭示了更多ICI诱导的T1DM病例,而不是2016年irAE病例报告的系统评价[9]和2018年临床试验数据的荟萃分析[199]; (d)我们报告了先前系统评价和荟萃分析[199]中未提及的独特或首发的内分泌疾病[122,127]。

结论
最后,该范围审查绘制了1种抗CTL4-1单克隆抗体(2011年批准),2种抗PD-1单克隆抗体(2014年批准)和3种抗PDL-1销售前后ICI引起的内分泌病变的不断变化的情况。单克隆抗体(2016/2017批准)。在大多数现实世界的患者中,我们发现了一系列内分泌疾病 - 在5个腺体中,12个内分泌病症表现出激素过剩或缺乏的症状。

病例报告可以提醒医生注意药物的AE [12]。 随着ICI使用的增加,许多医学专科(肿瘤学,内分泌学,急诊医学和初级保健)的医生应警惕这些ICI引起的内分泌病的发生,并能够诊断和治疗它们。 已经提出了用于肿瘤学家和内分泌学家之间的协作护理的“串话”[204]。 超出本文的范围涵盖癌症患者中ICI诱导的内分泌病的诊断和管理的算法和指南。 一些肿瘤学中心[205,206],国家肿瘤学会[207,208]和内分泌学会紧急指导文件[209]已经公布了算法和临床实践指南。 内分泌irAE的报告可以改善[12,202]。 我们的研究结果可以帮助医生管理他们的患者和专业协会制定他们的临床实践指南。

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