2019, Vol. 26
肿瘤免疫检查点抑制剂(immune checkpoint inhibitors, ICPis)通过阻断免疫抑制分子，恢复或增强T细胞对肿瘤细胞的杀伤力，开启了治疗进展性恶性肿瘤的新篇章。目前应用较多的ICPis包括细胞毒性T淋巴细胞相关抗原4 (cytotoxic T lymphocyte associated antigen-4, CTLA-4)抑制剂伊匹单抗(ipilimumab)和曲美母单抗(tremelimumab)，程序性死亡受体-1 (programmed death-1, PD-1)抑制剂纳武单抗(nivolumab)和派姆单抗(pembrolizumab)以及程序性死亡受体配体1 (programmed death ligand 1, PD-L1)抑制剂阿特珠单抗(atezolizumab)、阿维单抗(avelumab)和德瓦鲁单抗(durvalumab)。
ICPis在多种进展期恶性实体瘤及血液肿瘤中表现出良好的疗效，但缺乏肿瘤组织特异性，也可能破坏T细胞对自身抗原的免疫耐受，导致免疫相关不良反应(immune-related adverse events, irAEs)的发生，按发生时间先后主要累及皮肤、胃肠道、肝脏、肺部、内分泌腺、肾脏等[1]。其中，ICPis相关内分泌疾病往往不能被及时正确诊断并处理。因此，本文主要就ICPis相关内分泌疾病的研究进展和临床管理建议进行总结。
1 垂体炎和垂体功能不全 1.1 发生率ICPis导致的垂体炎发生率约为0.5%~5.6%[2]，主要发生在CTLA-4抑制剂治疗后(发生率为10%~13%)，远高于PD-1/PD-L1抑制剂治疗后(约1%)[3]，联合治疗发生率高于单药治疗[2]。其发生率和严重程度可能具有剂量依赖性，应用伊匹单抗10 mg/kg的患者较应用3 mg/kg者总体生存期延长，但irAEs增加，垂体炎发生率也增加了1倍[4]。队列研究[5]则发现，高剂量伊匹单抗不是发生垂体炎的危险因素。ICPis垂体炎中位发病年龄约为60岁，男女比例约为2:1[3]，绝大多数为黑素瘤[6]，但此结果可能受药物应用时长、肿瘤发生年龄、性别以及ICPis适应证的影响。
1.2 临床表现ICPis相关垂体炎的发生距初始用药的中位时间为12周(3~76周)，多以头痛、疲乏为首发症状，可有单种或多种垂体前叶激素不足相关疾病或症状。其中，最为多见的是中枢性甲减(93%)，而后是低促性腺激素性功能减退(86%)和中枢性肾上腺功能不全(75%)[7]，少数发生尿崩症[8-9]、低泌乳素血症和生长激素水平异常[6, 10-11]。垂体影像学检查显示，约60%患者有垂体增大或信号增强(可能伴有视力障碍)，与是否头痛或临床诊断先后没有必然关系[6]；增大的垂体可在7~40 d内减小[5, 12]。因此垂体影像正常也不能排除垂体炎，同时需要鉴别肿瘤的垂体转移。
1.3 预后半数以上的病例未报道是否停药，约70%用了高剂量皮质激素，30%用了替代剂量的皮质激素[6]。替代剂量的皮质激素往往能有效改善头痛和疲乏等症状，但是并不能促进垂体功能恢复(即使应用高剂量激素)[3]。停药可能使促甲状腺激素和促性腺激素不足得以恢复[13-14]，但促肾上腺皮质激素(ACTH)不足通常是永久性的，即绝大多数患者出院后都需要继续应用皮质激素替代治疗[5, 15]。应用大剂量激素对ICPis相关垂体炎患者的总体生存率没有明显影响[3, 16]，但也有研究[17]认为其可能会降低患者生存率。
1.4 相关机制小鼠实验发现，CTLA-4表达于垂体内分泌细胞中，应用CTLA-4抗体可致细胞中补体聚集、炎性细胞浸润和循环抗体阳性[18]。经CTLA-4抑制剂治疗的肿瘤患者的垂体病理检查也检测到CTLA-4，且表达水平高的患者临床症状更明显[10]；发生垂体炎者抗垂体抗体阳性，而没有发生垂体炎者则不然[18]。因此可以推测，CTLA-4抗体通过结合垂体前叶细胞中表达的CTLA-4蛋白介导了Ⅱ型超敏反应，且垂体细胞中浸润的CD4+ T细胞和CD20+B细胞说明存在Ⅳ型超敏反应[10]。此外，CTLA-4抑制剂相关垂体炎发生率明显高于PD-1/PD-L1抑制剂相关垂体炎，可能是因为PD-1抑制剂(纳武单抗和派姆单抗)为人IgG4，而伊匹单抗为人IgG1，后者可以激活经典补体通路和抗体依赖的细胞介导的细胞毒性作用(antibody-dependent cell-mediated cytotoxicity, ADCC)[18-19]。
1.5 临床管理建议2017年欧洲临床肿瘤协会(ESMO)临床实践指南[20]提示，ICPis相关垂体炎应该根据症状作相应的处理。若患者有严重占位效应(头痛、视力障碍)或严重肾上腺功能不全(低血压、严重电解质紊乱)，应暂停ICPis治疗，进行垂体各轴功能评估并行起始静脉(甲基)泼尼松龙1 mg/kg治疗，根据症状控制情况在4周内逐步减量至5 mg并长期维持；若患者症状中度(头痛不伴视力障碍)或仅乏力且无电解质紊乱，应暂停ICPis并进行垂体功能评估，口服泼尼松龙0.5~1 mg/kg，若48 h内没有改善，应静脉应用(甲基)泼尼松龙1 mg/kg，根据症状在2~4周内减量至5 mg并长期维持；若患者仅有轻微乏力或没有症状，应先评估垂体各轴功能，告知患者若有相应症状及时就诊，在适当激素替代治疗的情况下可以继续ICPis治疗。另外，应进一步进行垂体MRI检查、排除脑转移、监测甲状腺功能。而美国临床肿瘤学会联合美国国家综合癌症网络(ASCO/NCCN)指南则建议一旦确诊为垂体炎，需暂停免疫治疗，予甲基泼尼松龙/泼尼松1~2 mg·kg-1·d-1，并根据指征给予甲状腺激素、性激素替代治疗[21]，根据患者症状决定是否继续ICPis治疗。
2 甲状腺功能障碍 2.1 发生率ICPis相关的甲状腺功能异常包括甲状腺功能减退(甲减)、甲状腺功能亢进(甲亢)和甲状腺炎[6]。与垂体炎相反，原发性甲减主要发生在PD-1/PD-L1抑制剂治疗后。伊匹单抗、PD-1抑制剂、PD-L1抑制剂治疗后，甲减的发生率分别约为3.8%、8.0%~8.5%、4.7%~6.0%，甲亢的发生率分别约为1.4%、2.8%~3.7%、2.3%，联合用药后甲减发生率约为PD-1抑制剂单药治疗的2倍，甲亢发生率约为10%[2]。目前仅有一项研究表明曲美母单抗相关甲状腺功能异常的发生率为5.2%[22]。ICPis相关甲状腺炎发生率约为2%[2]。
2.2 临床表现甲状腺功能异常中位发生时间为治疗开始后6~12周，发生率无性别差异[6, 23]。甲亢症状可以是疲乏、消瘦、心悸、手抖等，也可能是高热、室上性心动过速、高血压、恶心、呕吐等[24-25]，也有7例Grave病的报道[26-31]。随访到的甲亢患者中，80%进展为甲减，进展时间为4~7周[23, 32-33]。甲减表现为乏力、怕冷、皮肤干燥、面部浮肿、体质量增加等。联合用药和PD-1抑制剂单药治疗后甲亢的中位发生时间分别为21 d和47 d，甲减的中位发生时间分别为63 d和70 d[33]。
2.3 抗体及相关机制甲状腺相关自身抗体(TPOAb、TGAb、TRAb)的有无和出现时间与用药开始时间、甲状腺功能异常没有必然关系。因此有人认为ICPis导致的甲状腺功能异常与甲状腺相关抗体不相关，也可能还有其他的甲状腺抗体未被检测[11]。但是，有研究[34-35]发现，基线或ICPis治疗过程中TPOAb和TGAb水平升高可能是ICPis相关性甲状腺功能异常的危险因素。用药后抗甲状腺抗体的产生说明免疫平衡被打破或潜伏的自身免疫被激活，甲减前的一过性甲状腺毒症说明可能是破坏性甲状腺炎释放了抗原，并激发了抗体产生[34]。流式细胞分析发现，在PD-1抑制剂治疗后发生甲状腺炎的患者中，不成熟自然杀伤细胞(NK)和人类白细胞抗原DR(HLA-DR)低表达的CD14+免疫抑制单核细胞减少，而HLA-DR高表达的CD14+CD16+单核细胞增加，说明PD-1抑制剂相关甲状腺炎可能与单核细胞激活、自身免疫增强有关[23]。
2.4 临床管理建议ESMO指南[20]建议，采用ICPis治疗的患者在每周期用药之前或用药过程中至少每个月(对用药周期为2周的患者而言)检查1次甲状腺功能。即使是亚临床甲减，若患者有乏力或其他甲减主诉，也应该考虑进行甲状腺激素替代治疗(0.5~1.5 μg/kg)，老年、有心脏病史的患者中起始剂量应低一些，同时可以继续应用ICPis治疗。在症状性甲亢患者中，应进行β受体阻滞剂对症处理，监测促甲状腺激素(TSH)受体抗体(若阳性，可以应用卡比马唑)、TPO抗体，并进行甲状腺核素扫描以鉴别Grave病。疼痛性甲状腺炎患者可应用泼尼松0.5 mg/kg，并逐渐减量，若症状不缓解，需要中断ICPis治疗，至症状控制之后考虑重新用ICPis。ASCO/NCCN指南则根据患者症状和甲状腺功能对甲亢和甲减分别进行分级，并给出了不同的处理建议[21, 36]。
3 糖尿病 3.1 发生率和临床表现目前报道的ICPis相关糖尿病主要发生在PD-1/PD-L1抑制剂治疗后。纳武单抗、派姆单抗、PD-L1抑制剂治疗后糖尿病发生率分别为2.0%、0.4%、1.1%~1.4%[2]。CTLA-4抑制剂导致的糖尿病罕见[37-38]。ICPis相关糖尿病患者发病时间差异较大，中位时间7.5周(1~52周)[6]，表现为多尿、多饮、体质量下降等显著高血糖症状，其中约60%发生了糖尿病酮症酸中毒(DKA)。该类患者HbA1c常不高(< 8.0%)[6, 11, 39]，说明其血糖在短期内急剧升高。70%~80%的ICPis相关糖尿病患者β细胞功能迅速衰竭，C肽很低，胰岛素缺乏[6, 39]。ICPis相关糖尿病起病特点类似于暴发性糖尿病[40]，但是往往前期没有流感样症状和胰酶升高，而糖尿病相关抗体可能为阳性[41-47]。
3.2 相关抗体1型糖尿病自身抗体是否阳性与发生ICPis相关糖尿病没有必然关系，但可能与ICPis相关糖尿病发生时间有关。至少1种1型糖尿病相关抗体阳性的患者和1型糖尿病相关抗体全阴性的患者发生ICPis相关糖尿病时的平均用药时间分别为2.5周期和13周期[39]。PD-1抑制剂治疗后发生糖尿病的患者中，谷氨酸脱羧酶抗体(GADA)阳性者和阴性者在ICPis治疗至发生糖尿病的中位时间分别为3周和12.5周[48-49]。
3.3 致病机制某些HLA基因型如HLA-DQ2和HLA-DQ8与1型糖尿病易感性增加有关[50]，而HLA-DR4在ICPis治疗后发生糖尿病的患者中最多见(76%)[39]。发生自身免疫性糖尿病的非肥胖小鼠中，存活的β细胞表面PD-L1表达增加，而CTLA-4的配体CD80和CD86表达不变[51]，说明PD-1通路在胰岛β细胞避免自身免疫杀伤中具有重要作用。此外，PD-1转基因小鼠不易发生自身免疫性糖尿病，而阻断PD-1/PD-L1通路则会导致其发生糖尿病，伴有胰岛中T辅助细胞1(Th1)极化[52]，且不一定产生自身抗体[53-54]，说明细胞免疫激活可能为其主要机制。
3.4 临床预后目前没有明确的方法阻止或逆转ICPis相关糖尿病。研究[55-58]中4例泼尼松龙或甲基泼尼松龙治疗的患者未见胰岛β细胞恢复，并需要继续使用胰岛素治疗。仅1例男性派姆单抗相关1型糖尿病患者停止治疗后，胰岛β细胞功能逐渐自然恢复，并在54 d后停用胰岛素[59]。然而，该患者病程中C肽水平正常，说明有功能正常的β细胞残留。因此，大多数ICPis相关糖尿病患者需要长期依赖胰岛素治疗。
3.5 临床管理建议ESMO指南[20]指出，ICPis相关糖尿病可以是1型或2型，可以通过测定C肽、谷氨酸脱羟酶抗体(GADA)和胰岛细胞抗体进行鉴别，且即使是2型糖尿病也可能发生糖尿病酮症酸中毒(DKA)，需要及时处理。ASCO/NCCN指南[21]建议，在基线和接受治疗后12周内每1个治疗周期、12周后每3~6周监测患者有无高血糖或糖尿病恶化症状，并根据空腹血糖和临床表现对此类高血糖不良反应进行分级；一旦发生DKA，应立即暂停ICPis治疗，并根据DKA诊疗指南紧急处理。空腹血糖在正常参考值上限至8.9 mmol/L，可以在密切临床随访和监测下继续ICPis治疗，同时进行1型糖尿病筛查及降糖治疗；空腹血糖在8.9~13.9 mmol/L，需暂停ICPis治疗至血糖控制良好；空腹血糖在13.9 mmol/L以上者，需暂停ICPis治疗，至空腹血糖控制为8.9 mmol/L以下，并请内分泌科急会诊，启动胰岛素强化治疗。对于有DKA风险、严重高血糖症状或1型糖尿病患者，建议住院治疗。值得注意的是，这类新发的ICPis相关糖尿病患者胰岛素敏感性好，所需胰岛素剂量一般低于普通1型糖尿病患者。对于2型糖尿病患者，可连续数天监测血糖，以动态调整胰岛素应用剂量并拟定血糖控制方案。目前没有足够证据表明糖皮质激素可逆转免疫治疗诱发的糖尿病，反而可能进一步影响血糖水平变化并对肿瘤治疗不利。因此，ICPis相关糖尿病不适宜应用皮质醇或其他免疫抑制剂[36]。
4 原发性肾上腺功能不全 4.1 发病率和临床表现在接受ICPis治疗的进展性恶性肿瘤患者中，肾上腺功能不全可能由垂体炎、肿瘤垂体转移、ICPis相关的原发性肾上腺功能不全、肿瘤肾上腺转移、肾上腺出血等原因引起[11]。原发性肾上腺功能不全的病例报道相对少见[60-64]，其发病率约为0.7%，ICPis联合用药后发病率高于单药治疗[7, 65]。ICPis相关原发性肾上腺功能不全中位发生时间为用药后10周(1.5~36周)[6]，临床表现无特异性，可以表现为乏力、恶心、疲乏、厌食、低血压等；血皮质醇水平降低而ACTH水平升高，ACTH兴奋试验阴性，可伴有醛固酮水平降低和肾素水平升高；影像学检查可见双侧肾上腺增大[63]或缩小[60]，PET/CT检查可见18-氟代脱氧葡萄糖摄取增加[62-63]，提示肾上腺炎。1例派姆单抗导致的原发性肾上腺功能不全患者21-羟化酶抗体与肾上腺皮质抗体均阳性，但这些抗体与肾上腺功能不全发生的关系仍不清楚[60]。此类患者在应用皮质激素后临床症状改善，但多需依赖糖皮质激素替代治疗。
4.2 临床管理建议对怀疑有肾上腺功能不全的患者，应评估清晨ACTH和皮质醇水平、基础代谢检查(钠、钾、CO2、血糖)，并评估是否存在肾上腺危象诱因。一旦确诊，应优先用皮质类固醇避免肾上腺危象发生，并暂停ICPis治疗至病情稳定[21]。
5 多内分泌腺疾病等ICPis治疗后的患者可能发生多内分泌腺疾病，如：阿特珠单抗治疗2周期后出现高血糖，4周期后出现DKA、原发性肾上腺皮质功能减退症、垂体炎伴垂体功能不全[66]；派姆单抗治疗5个月后出现甲状腺毒症，6个多月后出现急性肾上腺功能不全[60]；也可发生垂体前叶功能不全、原发性甲状腺功能异常、糖尿病等的组合。也有伊匹单抗、阿维单抗治疗后发生尿崩症的报道[9, 67-68]。
6 小结ICPis相关内分泌疾病与普通内分泌疾病患病特点有所不同，目前发病机制未明确，应该提高肿瘤科、内分泌科、急诊科、社区医院医师等对该病的认识。对接受ICPis治疗的患者，在用药前后和用药过程中监测相关内分泌指标，告知患者可能出现的不良反应及表现，并根据症状作进一步评估及相应处理，以改善患者预后。
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