PD-1/PD-L1抑制剂相关垂体炎临床特征分析并文献复习

PD-1/PD-L1 inhibitors induced hypophysitis:A case series and literature review

目的分析恶性肿瘤患者应用程序性死亡受体-1(programmed death-1,PD-1)/程序性死亡配体-1(PD-L1)抑制剂治疗出现垂体炎的临床特征,提高对该类疾病的认识。方法采用回顾性分析的方法,对近3年来收治的18例PD-1/PD-L1抑制剂相关垂体炎的临床表现、实验室检查和影像学特点进行分析。结果PD-1/PD-L1抑制剂相关垂体炎患者共18例(0.49%,18/3689),平均年龄(58.6±10.3)岁,其中男性11例,女性7例;信迪利单抗和帕博利珠单抗各6例、度伐利尤单抗3例,占83.3%(15/18)。垂体炎的中位确诊时间为用药后5.9(3.5,9.6)个月,且发生时间与PD-1/PD-L1抑制剂种类有关。主要的临床表现为乏力、纳差、恶心等(72.2%,13/18),有4例患者发生昏迷,15例发生低钠血症(83.3%)。腺垂体受累激素中,促肾上腺皮质激素(ACTH)缺乏、促甲状腺素(TSH)缺乏、促性腺激素缺乏、生长激素(GH)缺乏和高催乳素血症的发生率分别为100%、27.8%、16.7%、11.1%和44.4%;垂体后叶均未受累。男性和女性垂体炎患者上述特征无统计学差异。有53.3%患者垂体磁共振成像(MRI)未见异常,其余为轻度异常;均无垂体增大;有5例患者合并甲状腺受累,2例合并胰岛损害;免疫相关性不良反应(irAEs)经不良反应通用术语标准(CTCAE)分级3级及以上的有4例(22.2%),其余患者属于CTCAE 1~2级。结论当PD-1/PD-L1抑制剂治疗患者出现乏力、纳差、低血钠等情况,需警惕药物相关垂体炎的可能性。PD-1/PD-L1抑制剂所致垂体炎最易受累的是垂体前叶激素及ACTH减低,后叶不易损害,垂体无明显增大,生理剂量糖皮质激素可有效缓解症状。

Objective To analyze the clinical characteristics of programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitors-induced hypophysitis in patients with malignant tumors,and to improve the understanding of this disease.Methods The clinical manifestations,laboratory tests,and imaging features of 18 cases of PD-1/PD-L1 inhibitors-related hypophysitis cases treated in recent 3 years were analyzed retrospectively.Results Among the 18 patients(0.49%,18/3689)with PD-1/PD-L1 inhibitors-associated hypophysitis,there were 11 males and 7 females,with the average age of(58.6±10.3)years old.There were 6 cases treated with Sindilizumab,6 cases of Pabolizumab,and 3 cases of Duvaliumab,acounting for 83.3%(15/18).The median time to diagnosis of hypophysitis was 5.9(3.5,9.6)months,which was related to the type of PD-1/PD-L1 inhibitors.The main clinical manifestations were fatigue,poor appetite,nausea(72.2%,13/18),with 4 patients experiencing coma and 15 cases of hyponatremia(83.3%).The incidence of adrenocorticotropic hormone(ACTH)deficiency,thyroid stimulating hormone(TSH)deficiency,gonadotropins deficiency,growth hormone(GH)deficiency and hyperprolactinemia were 100%,27.8%,16.7%,11.1%and 44.4%,respectively.No posterior pituitary was involved.There was no statistical difference between male and female patients with pituitary inflammation.53.3%of the patients had no abnormal pituitary magnetic resonance imaging(MRI),and the rest were mildly abnormal,without pituitary enlargement.There were 5 patients with primary thyroid involvement and 2 patients with damaged pancreas.Four cases(22.2%)of immune-related reactions(irAEs)were grade 3 and above according to the Common Terminology Criteria for adverse Events(cTCAE),and the rest of the patients were CTCAE grade 1-2.Conclusion When patients receiving PD-1/PD-L1 inhibitors present with symptoms such as fatigue,poor appetite,and hyponatremia,caution should be exercised for the possibility of drug-related hypophysitis.Hypophysitis induced by PD-1/PD-L1 inhibitors primarily affects the anterior pituitary lobe with a decrease in ACTH hormone levels,while the posterior lobe is less affected,and there is no significant enlargement of the pituitary gland.Physiological doses of glucocorticoids can effectively alleviate symptoms.