The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

SIMPLE SUMMARY: Immune checkpoint inhibitors (ICIs) are considered to be the standard of care in multiple types of cancers. However, ICIs are implicated in a wide range of side effects, referred to as immune-related adverse events (irAEs). Endocrine irAEs, especially thyroid dysfunction and hypophysitis, are some of the most frequently reported side effects. However, several other endocrine irAEs have been described less frequently and can be encountered more recurrently as the use of ICIs expands. This systematic review includes all published cases with rare and very rare endocrine irAEs, emphasizing mostly their diagnostic and therapeutic approach as well as their underlying pathogenesis. The aim of our study is to raise clinical awareness related to early diagnosis and proper treatment of these rare but, in some cases, potentially fatal endrocine irAEs. 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.