Based On A Real-world Study Of Endocrine Adverse Reactions Associated With Immune Checkpoint Inhibitors

Background:The clinical application of immune checkpoint inhibitors(ICIs)is developing rapidly.By blocking the inhibitory signaling pathways needed to maintain immune tolerance,ICIs reactivate the immune system to recognize and destroy cancer cells,bringing unprecedented therapeutic effects to cancer patients.However,due to its complex mechanism of action,ICIs can also cause highly variable non-specific autoinflammation and other tissue-directed autoimmune manifestations,leading to immune-related adverse events(ir AEs).Endocrine dysfunction is one of the most common ir AEs reported in ICIs clinical trials and mainly includes pituitaritis,thyroid injury,primary adrenocortical hypofunction and diabetes.At present,studies on ICIsrelated endocrine adverse reactions are mostly based on single-disease studies,and systematic and comprehensive exploration of endocrine-related adverse reactions in the real world is lacking.Objective:Based on retrospective analysis of clinical data of patients with solid tumor treated with ICIs for the first time,this study comprehensively evaluated the clinical characteristics of ICIs-related endocrine adverse events in clinical practice,explored risk and predictive factors to provide clinical basis for the diagnosis,treatment and management of ICIS-related endocrine adverse reactions.Methods:This study retrospectively analyzed the clinical data of 269 patients with malignant tumors who met the inclusion and exclusion criteria after initial ICIs treatment in the First Bethune Hospital of Jilin University from May 2021 to October 2022.Clinical characteristics,incidence,time characteristics and severity grades of ICIs-related endocrine adverse reactions were analyzed.Adverse events mainly included ICIsrelated thyroid injury,ICIs-related pituitaritis,ICIs-related diabetes and ICIs-related adrenocortical hypofunction.The patients were divided into two groups according to whether thyroid injury occurred.The baseline differences of gender,age,body mass index,past history and thyroid hormone level between the two groups were described.The risk factors of thyroid injury were further studied by Logistic regression.The predictive factors of thyroid injury were analyzed by receiver operating characteristic curves(ROC).Since ICIs-related adverse events such as diabetes,hypophysitis and adrenocortical hypofunction were rare,only descriptive analysis was conducted and discussed in combination with previous literatures.Results:1.In this study,the incidence of ICIs-related endocrine adverse reactions was 31.6%(85/269),including the autoimmune polyendocrinopathy syndrome(APS)incidence of1.1%(3/269).The incidence of grade 2 and above adverse events was 12.3%(33/269)and grade 3 and above was 1.1%(3/269).The median time for the first adverse reaction was 46 days.2.The incidence of ICIs-related thyroid injury was 27.5%(74/269),and the incidence of grade 2 and above adverse reactions was 9.3%(25/269).The median time for thyroid dysfunction was 46.5 days.The median time for hyperthyroidism was earlier than hypothyroidism(P<0.05)and grade 1 damage occurred earlier than grade 2damage(P<0.05).42.9%(9/21)of patients with thyroid injury had thyroiditis evolution.Female(OR=2.723,95%CI:1.447-5.125)and chemotherapy history(OR=2.716,95%CI:1.079-6.836)were independent risk factors for ICIs-related thyroid injury(P<0.05).Thyroglobulin antibodies(TGAb)(AUC=0.717)and thyroid peroxidase antibodies(TPOAb)(AUC=0.690)were predictors of ICIs-associated thyroid injury(P<0.05),TGAb was more sensitive than TPOAb.3.The incidence of ICIs-related hypophysitis was 1.5%(4/269),and the incidence of grade 3 and above adverse reactions was 0.7%(2/269).The median time of occurrence was 146.5 days,with more males than females.Pituitary hormones were mainly deficient in adrenocorticotropic hormone(ACTH)and thyroid stimulating hormone(TSH).Some patients had no abnormal pituitary in MRI findings.After suspension of ICIs,some hormone levels returned to normal.4.The incidence of ICIs-related diabetes was 3.7%(10/269),and the incidence of grade 3 and above adverse reactions was 0.4%(1/269).The median time of occurrence was 45 days,and some patients combined ICIs-related thyroid injury.5.No case of ICIs-related adrenocortical hypofunction was found in this study.Conclusions:1.This study retrospectively reported the clinical data of ICIs-related endocrine adverse reactions in malignant tumor patients who received ICIs for the first time in clinical practice,with unique patients’ characteristics.The incidence of ICIs-related endocrine adverse reactions was high,and the incidence of grade 3 and above adverse reactions was low.2.The incidence of ICIs-related thyroid injury was high,and the incidence of grade2 and above adverse reactions was low.Women and chemotherapy history were independent risk factors for ICIs-related thyroid injury.TGAb and TPOAb had predictive value for ICIs-related thyroid injury,and TGAb was more sensitive.3.The incidence of ICIs-related diabetes might be underestimated in clinical practice,with more males than females and a lower incidence of grade 3 and above adverse events.4.The incidence of ICIs-related pituitaritis was low,the pituitary hormones were mainly deficient in TSH and ACTH,and the pituitary MRI could show no abnormal changes.5.ICIs-related adrenocortical dysfunction rarely occurred.