Clinical features and thyroid dysfunction in adverse events involving the pituitary gland during PD‐1 blockade therapy

Abstract

ObjectiveProgrammed cell death‐1 (PD‐1) blockade therapy, an immune checkpoint treatment, can induce hypophysitis or hypopituitarism as an immune‐related adverse event (pituitary irAE). We aimed to clarify the clinical features of pituitary irAEs during PD‐1 blockade therapy.Design, Patients and MeasurementsThis retrospective study investigated consecutive patients treated with nivolumab, an anti‐PD‐1 antibody, at Kyoto University Hospital between 1 September 2014 and 31 August 2019. We examined patients’ baseline characteristics and analysed the clinical data of those who developed pituitary irAEs.ResultsOf the 374 recruited patients, 7 (1.9%) developed pituitary irAEs, and each presented with isolated secondary adrenal insufficiency. In 4 patients, changes in ACTH were delayed relative to those in cortisol: when serum cortisol levels fell below the reference range, plasma ACTH levels were still normal. Pituitary irAEs were accompanied by elevated serum‐free T3 (fT3) levels, which resolved with glucocorticoid replacement. Serum TSH levels were not suppressed despite elevated serum fT3 levels and 1 patient even presented with high fT3 level above the reference range (fT3, 7.1 pmol/L; free T4 (fT4), 13.9 pmol/L; and TSH, 5.1 mIU/L).ConclusionsIsolated secondary adrenal insufficiency was a common pituitary irAE during PD‐1 blockade therapy. This condition was accompanied by thyroid dysfunction, including elevation of fT3 without TSH suppression.

Eosinophil counts can be a predictive marker of immune checkpoint inhibitor-induced secondary adrenal insufficiency: a retrospective cohort study

“…The signs of ICI-induced AI are based on glucocorticoid deficiency and the resultant hyponatremia, changes in blood count (anemia, eosinophilia, lymphocytosis), and hypoglycemia 5 , 6 , which can be assessed by routine biochemical practice. Measurement of plasma ACTH and serum cortisol are recommended for AI-suspected patients 5 , 6 because transient ACTH elevation occurring prior to the onset of a pituitary irAE has been reported 10 , 11 . However, rapid assays for cortisol and ACTH are not available at most medical institutes.…”

“…It has been recognized for more than 70 years that patients with Addison disease have eosinophilia 26 . Beishuizen et al reported that 80% of suspected clinical cases of relative adrenal insufficiency had relative eosinophil counts of at least 3% 27 , and some reports have shown that eosinophilia is relevant to adrenal crisis 11 , 16 , 28 . Two reports found that eosinophil counts tended to increase before the diagnosis of ICI-induced AI 11 , 16 .…”

“…Beishuizen et al reported that 80% of suspected clinical cases of relative adrenal insufficiency had relative eosinophil counts of at least 3% 27 , and some reports have shown that eosinophilia is relevant to adrenal crisis 11 , 16 , 28 . Two reports found that eosinophil counts tended to increase before the diagnosis of ICI-induced AI 11 , 16 . Therefore, we statistically analyzed whether eosinophil counts can predict AI.…”

Delayed-onset immune-related adverse events involving the thyroid gland by immune checkpoint inhibitors in combination with chemotherapy: a case report and retrospective cohort study

“…PD-1 blockade with anti-PD-1 antibodies or anti-PD-L1 antibodies is frequently associated with irAEs involving the thyroid gland (thyroid irAEs). The incidence of overt thyroid irAEs with anti-PD-1 antibodies has been reported as 11.9-13.5% in clinical settings [2][3][4][5]. The typical clinical course of thyroid irAEs during PD-1 blockade is transient thyrotoxicosis within 2 to 6 weeks after the first dose of nivolumab with subsequent hypothyroidism requiring persistent levothyroxine replacement from 12 weeks [2,6].…”

“…In the present study, we exclusively focused on overt thyroid irAEs, namely, situations where neither serum fT4 nor TSH levels were normal. Pituitary irAE was diagnosed by physicians according to clinical symptoms and low levels of ACTH and cortisol, as in our previous study [5]. Insulin-dependent diabetes as an irAE was defined as hyperglycemia with low serum C-peptide levels, exclusion of other causes, and requirement of continuous insulin treatment.…”