The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Abstract

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

Rare Immune-Related Adverse Events (irAEs): Approach to Diagnosis and Management

“…Immune checkpoint inhibitor-induced endocrinopathies are common, affecting 10% of patients managed with ICIs, with thyroiditis and hypophysitis being amongst the most commonly reported syndromes [ 85 , 86 ]. Immune checkpoint inhibitor-related hypoparathyroidism, is a rare entity with a reported incidence of 0.18–0.28% of all endocrinopathies, with most data available from case reports [ 86 ]. Time to onset is variable, with cases being reported from 6 weeks post-ICI initiation to 18 months following cessation [ 82 , 86 , 87 ].…”

“…Immune checkpoint inhibitor-related hypoparathyroidism, is a rare entity with a reported incidence of 0.18–0.28% of all endocrinopathies, with most data available from case reports [ 86 ]. Time to onset is variable, with cases being reported from 6 weeks post-ICI initiation to 18 months following cessation [ 82 , 86 , 87 ]. Clinical features range from asymptomatic biochemical abnormalities to severe symptomatic hypocalcaemia requiring hospitalisation.…”

“…Normal magnesium levels are required to exclude a diagnosis of pseudohypoparathyroidism. Furthermore, it is important to explore a past history of neck surgery or irradiation and familial cases of hypocalcaemia to exclude more commonly recognised aetiologies of hypoparathyroidism [ 86 ]. In addition, investigation of other glandular involvement is important to rule out autoimmune polyglandular syndrome 1, of which hypoparathyroidism is the most common manifestation [ 82 , 86 ].…”

“…Furthermore, it is important to explore a past history of neck surgery or irradiation and familial cases of hypocalcaemia to exclude more commonly recognised aetiologies of hypoparathyroidism [ 86 ]. In addition, investigation of other glandular involvement is important to rule out autoimmune polyglandular syndrome 1, of which hypoparathyroidism is the most common manifestation [ 82 , 86 ]. While the pathophysiology is incompletely understood, potential mechanisms include antibody-mediated activation of the calcium-sensing receptor (CaSR) resulting in reduced PTH secretion or T cell-mediated damage directly to the parathyroid gland [ 86 ].…”

“…In addition, investigation of other glandular involvement is important to rule out autoimmune polyglandular syndrome 1, of which hypoparathyroidism is the most common manifestation [ 82 , 86 ]. While the pathophysiology is incompletely understood, potential mechanisms include antibody-mediated activation of the calcium-sensing receptor (CaSR) resulting in reduced PTH secretion or T cell-mediated damage directly to the parathyroid gland [ 86 ]. Due to its rare occurrence, predictive biomarkers have not been established for this syndrome [ 85 ].…”