Endocrine Abstracts

Background: Immune checkpoint inhibitors (ICIs) are a novel group of drugs, used for treatment of various types of malignancies. The receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) or its ligand (PDL-1) are targeted by those inhibitors. They are associated with immune-related adverse events (irAEs). Endocrinopathies are the most frequent irAEs with a prevalence of approximately 10%.

Case study: We retrospectively described a series of patients with endocrine complications caused by ICIs. Out of 24 patients treated with single or combination therapies, 18 patients developed endocrinopathies. The median age at diagnosis was 59 years and onset of endocrine dysfunction occurred within a median of 12 weeks of first ICIs exposure. Our case reports uncover a broad spectrum of ICI-induced endocrinopathies: 13 patients with thyroid dysfunction, 6 patients with hypopituitarism and one with primary adrenal deficiency. Polyglandular endocrine complications were described in two patients. Clinical presentation varied from asymptomatic patients to life-threatening symptoms. Thyroid disease ranged from subacute thyroiditis to subclinical hypothyroidism or hyperthyroidism, overt thyrotoxicosis and even myxedema. The most frequent ICIs used were PD-1 and PDL-1 inhibitors. Three patients had previous tyrosine-kinase inhibitor (Sunitib)-induced hypothyroidism and four patients had already autoimmune thyroiditis. We encountered six patients with hypophysitis, from which four presented isolated deficiencies (2 with secondary adrenal deficiency and 2 with secondary hypogonadism) and two had multiple deficiencies (one with panhypopituitarism and one with secondary hypothyroidism and adrenal deficiency). Five patients were treated with anti PD-1 or PDL-1 monoclonal antibodies (mAb) and only one with anti CTLA-4 mAb (Ipilimumab).

Conclusions: The most frequent ICIs induced endocrinopathy is thyroid dysfunction, followed by hypophysitis. Primary adrenal insufficiency, although a rare complication, was also reported. In most of our cases, they were irreversible and required hormone replacement. Anti-PD-1 and anti-PDL-1 mAb were frequently associated with thyroid disease. Several studies indicate that CTLA-4 inhibitor is most related to hypophysitis (1), but in our series, we had a single patient in treatment with Ipilimumab, being the one with panhypopituitarism. Therefore, physicians should be aware of ICIs induced-endocrine irAEs in order to properly address, diagnose and treat them at onset and follow-up.

References: 1. Tan MH et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin Diabetes Endocrinol. 2019 Jan 22;5(1):1.