A Comparative Study Of Immune Checkpoint Inhibitor-associated Thyroiditis And Hashimoto Thyroiditis

Objective: Immune checkpoint inhibitors include antibodies against cytotoxic T lymphocyte associated antigen-4,programmed cell death protein 1 and programmed cell death ligand-1.Despite the effectiveness of ICIs for tumor therapy,with the increasing use of ICIs,the number of reports of various autoimmune disease complications has gradually increased.These autoimmune complications,known as immune-related adverse events can affect multiple systems in the body.Endocrine disease include pituitary adenitis,thyroiditis,adrenal glands and autoimmune diabetes.Thyroid-related adverse reactions are the most common endocrine ir AEs.In this study,we compared the dosing of patients with ICIsassociated thyroiditis to that of patients with Hashimoto thyroiditis.We obtained the optimal L-Thyroxine Sodium dose for patients with ICIs-associated hypothyroidism to guide clinical management and improve patient outcomes.Methods: Patients with thyroid ir AEs who were treated with ICIs in Affiliated Hospital of Qing Dao University from July 2018 to January 2023 were collected.At the same time,patients with primary hypothyroidism due to Hashimoto’s thyroiditis who were admitted to our hospital were collected and matched for age and sex.The clinical characteristics of TSH,FT4,thyroid autoantibody level and LT4 dosage were compared between the two groups.At the same time,the patients with hypothyroidism after ICIs were grouped according to whether they had positive thyroid-associated antibody,whether they had transient thyrotoxicosis and the types of ICIs used,the time of occurrence of thyroid ir AEs and the optimal LT4 dosage were compared under the three different situations.Results: There were 162 cases in ICIs-associated thyroid adverse reaction group,149 cases were treated with LT4 because of hypothyroidism,Matched 149 patients with primary hypothyroidism due to Hashimoto’s thyroiditis.(1)There was a difference in initial TSH between the ICIs-associated hypothyroidism group(n=149)and the Hashimoto thyroiditis group(n=149).The initial TSH was 44.70(14.73,82.03)u IU/ml in the ICIs-associated hypothyroidism group and 15.87(8.69,33.92)u IU/ml in the Hashimoto thyroiditis group,with a significant difference(z=5.442,P<0.01);(2)There was a difference in FT4 at the initial onset between the ICIs-associated hypothyroidism group and the Hashimoto thyroiditis group.FT4 was 8.00(4.23,11.35)pmol/L in the ICIs-associated hypothyroidism group and11.62(7.93,14.20)pmol/L in the Hashimoto thyroiditis group.There was a significant difference between the two groups(z=-5.599,P<0.01);(3)There was a difference in LT4 supplementation between the ICIs-associated hypothyroidism group and the Hashimoto thyroiditis group.The median dose of LT4 was 0.96(0.62,1.49)ug/kg in the ICIs-related hypothyroidism group and 0.83(0.63,1.18)ug/kg in the Hashimoto thyroiditis group,with a significant difference(z=-2.026,P<0.05);(4)In the ICIs-associated hypothyroidism group,there was a difference in LT4 supplementation dose between the group with positive thyroid autoantibody(n=67)and the group with negative thyroid autoantibody(n=82).The median LT4 dose was 1.36(0.84,1.69)ug/kg in the antibody positive group and 0.78(0.54,1.16)ug/kg in the antibody negative group.There was a significant difference between the two groups(z=-4.335,P<0.01);(5)In the ICIs-associated hypothyroidism group,there was a difference in LT4 supplementation dose between the group with a history of transient thyrotoxicosis followed by hypothyroidism(n=45)and the group with a direct progression to hypothyroidism(n=104).The median LT4 dose was 1.11(0.80,1.66)ug/kg in patients with transient thyrotoxicosis and 0.83(0.59,1.41)ug/kg in patients with direct hypothyroidism,there was significant difference between the two groups(z=-2.109,P <0.05);(6)In the ICIs-associated hypothyroidism group,there was a difference in LT4 supplementation dose between PD-1 inhibitor-induced hypothyroidism group(n=129)and PD-L1 inhibitor-induced hypothyroidism group(n=20).The median LT4 dose was1.07(0.63,1.53)ug/kg in the PD-1 group and 0.67(0.47,1.05)ug/kg in the PD-L1 group,with a significant difference(z=-2.473,P<0.05).Conclusion: There were significant differences in LT4 supplementation doses between hypothyroidism induced by ICIs-associated thyroiditis and hypothyroidism induced by Hashimoto thyroiditis.The amount of LT4 required for ICIs-associated hypothyroidism was related to the presence or absence of thyroid autoantibodies,the presence or absence of transient thyrotoxicosis,and the type of ICIs.Based on this study,we recommend screening for thyroid antibodies in patients before starting immunotherapy and more frequent thyroid function testing in patients with concurrent antibody positivity.If the patients with positive thyroid autoantibodies or with transient thyrotoxicosis or treated with PD-1 inhibitor,we should choose a higher initial dose of LT4 as an alternative therapy to make the thyroid function return to normal as soon as possible to reach the goal of relieving patients’ pain and prolonging patients’ life.