Endocrine immune-related adverse effects of immune-checkpoint inhibitors

ABSTRACT

Introduction

Immune-checkpoint inhibitor therapy modulates the response of the immune system acting against cancer. Two pathways impacted by this kind of treatment are the CTLA4 and the PD-1/PD-L1 pathways. ICI therapy can trigger autoimmune adverse effects, known as immune-related Adverse Events (irAEs).

Areas covered

This review focuses on irAEs which affect the endocrine system. This review elucidates the pathways used by these drugs with a focus on the hypothetical pathogenesis at their basis. In fact, the pathophysiology of irAEs concerns the possibility of an interaction between cellular autoimmunity, humoral immunity, cytokines, chemokines, and genetics. The endocrine irAEs examined are thyroid dysfunctions, immune related-hypophysitis, diabetes, peripheral adrenal insufficiency, and hypoparathyroidism.

Expert opinion

There is still much to investigate in endocrine irAES of checkpoint inhibitors. In the future, checkpoint inhibitors will be increasingly utilized therapies, and therefore it is crucial to find the proper diagnostic-therapeutic program for irAEs, especially as endocrine irAEs are nonreversible and require lifelong replacement therapies.

KEYWORDS:

• Immune-checkpoint inhibitors
• thyroid
• immune-related hypophysitis
• diabetes
• primary adrenal insufficiency
• hypoparathyroidism

Article highlights

• Immune check-point inhibitors (ICI) are antibodies that target immune-checkpoints, such as PD-1/PD-1 L and CTLA4. They act as a ‘brake’ for immune functions suggesting that immune checkpoints inhibition may reactivate T cells and eliminate cancer cells more effectively.

• ICI therapy could trigger autoimmune adverse effects, known as immune-related Adverse Events (irAEs).

• The time to onset of ICI-related endocrinopathies generally ranges from weeks to months after the initial dose of ICI therapy.

• Endocrinopathies are among the most common irAEs. The pathogenesis of endocrine irAEs is not yet fully understood, but different families of ICI can favorite one or another irAEs.

• Major endocrine irAEs include thyroid dysfunction, hypophysitis, primary adrenal insufficiency, diabetes and hypoparathyroidism.

• Thyroid dysfunction is the most common ICI-related endocrinopathy and is mainly associated with anti-PD-1 and anti PD-L1 therapy or a combination of different therapies; it can present as hypothyroidism or transient thyrotoxicosis followed by hypothyroidism, symptoms are typically nonspecific and mild, and management includes beta blockers as needed for symptomatic thyrotoxicosis and thyroid hormone replacement with levothyroxine for hypothyroidism.

• Hypophysitis, or inflammation of the pituitary gland, is mainly associated with anti-CTLA-4 therapy; it can result in the temporary or permanent deficiencies in one or more pituitary hormones, and can manifest as pituitary enlargement on imaging, and is managed with hormone replacement and supportive care.

• Insulin-deficient diabetes mellitus and primary adrenal insufficiency are infrequent. They can result in life-threatening diabetic ketoacidosis or adrenal crisis, respectively, without prompt diagnosis and proper management.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.