Quandt Zoe, Kim Stephanie, Villanueva-Meyer Javier, Coupe Catherine, Young Arabella, Kang Jee Hye, Yazdany Jinoos, Schmajuk Gabriela, Rush Stephanie, Ziv Elad, Perdigoto Ana Luisa, Herold Kevan, Lechner Melissa G, Su Maureen A, Tyrrell J Blake, Bluestone Jeffrey, Anderson Mark, Masharani Umesh
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA 94122, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94122, USA.
J Endocr Soc. 2023 Feb 6;7(4):bvad012. doi: 10.1210/jendso/bvad012. eCollection 2023 Feb 9.
Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors.
We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis).
We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis.
Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, = 0.01) and CPI population.
The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.
垂体炎是免疫检查点抑制剂（CPI）已知的免疫相关不良事件（irAE），通常与CTLA-4抑制剂相关，与PD-1/PD-L1抑制剂的相关性较低。
我们旨在确定CPI诱导的垂体炎（CPI-垂体炎）的临床、影像学和HLA特征。
我们检查了CPI-垂体炎患者的临床和生化特征、垂体的磁共振成像（MRI）以及与HLA类型的相关性。
共纳入49例患者。平均年龄为61.3岁，男性占61.2%，白种人占81.6%，38.8%患有黑色素瘤，44.5%接受PD-1/PD-L1抑制剂单药治疗，其余接受CTLA-4抑制剂单药治疗或CTLA-4/PD-1抑制剂联合治疗。比较CTLA-4抑制剂暴露与PD-1/PD-L1抑制剂单药治疗发现，CPI-垂体炎的发病时间更快（中位时间84天对185天，P<0.01），MRI上垂体外观异常（优势比7.00，P=0.03）。我们观察到在CPI类型与CPI-垂体炎发病时间的关联中存在性别效应修饰。特别是，接受抗CTLA-4治疗的男性发病时间比女性短。垂体的MRI变化在垂体炎诊断时最为常见（55.6%增大，37.0%正常，7.4%空蝶鞍或部分空蝶鞍），但在随访中持续存在（23.8%增大，57.1%正常，19.1%空蝶鞍或部分空蝶鞍）。对55名受试者进行了HLA分型；相对于美国白种人群（39.4%对21.5%，P = 0.01）和CPI人群，HLA DQ0602型在CPI-垂体炎中过度表达。
CPI-垂体炎与HLA DQ0602的关联提示其发病存在遗传风险。垂体炎的临床表型似乎具有异质性，在发病时间、甲状腺功能测试变化、MRI变化以及可能与CPI类型相关的性别方面存在差异。这些因素可能在我们对CPI-垂体炎发病机制的理解中发挥重要作用。
