MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis

Abstract

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

MECHANISMS IN ENDOCRINOLOGY: Autoimmune hypopituitarism: novel mechanistic insights

“…Mid-tomoderate diffuse enlargement of the pituitary gland, with either homogenous or heterogenous enhancement after contrast administration is typically observed in patients with CTLA-4 inhibitor-induced hypophysitis. In contrast, permanent and exclusive ACTH deficiency is observed and obvious enlargement of the pituitary is rare with the use of PD-1/PDL-1 inhibitors (40). These data strongly suggest the difference in the underlying mechanisms of CTLA-4 and PD-1/PDL-1 inhibitors.…”

“…Importantly, the profile of endocrine irAE is different depending on each ICI that was used (as in isolation or with combination therapy). Because of the emerging topics, the underlying mechanisms and management for ICI-induced hypophysitis have recently been reviewed (2,3,40). With the use of CTLA-4 inhibitors, hypophysitis is predominantly observed in 8-13% of the patients (2,39).…”

“…With the use of CTLA-4 inhibitors, hypophysitis is predominantly observed in 8-13% of the patients (2,39). In contrast, with PD-1/PDL-1 inhibitors, thyroiditis is predominant and hypophysitis is relatively rare (0.1-0.4%) (40). The incidence of hypophysitis was 8.5-9.0% when a combination of CTLA4 and PD1 inhibitors was used (41).…”

“…The other important issue is the difference in the onset of hypophysitis and profile of the impaired hormone. The median time to occurrence is 2-4 months with CTLA-4 inhibitors, 3-6 months with PD-1 inhibitors, up to 1 year with PDL-1 inhibitors (44), and earlier for those on combination treatment (30 days on average) (40). ACTH and/or TSH deficiency are the most common pituitary hormone abnormalities followed by LH and FSH deficiency with the use of CTLA-4 inhibitors.…”

“…CTLA-4 is also expressed in normal human pituitary and pituitary adenomas, with different expression levels, which may explain the risk of hypophysitis (46). Importantly, with the use of CTLA-4 inhibitors, the subclass of ipilimumab is IgG1 and that of tremelimumab is IgG2, which can activate the classical complement pathway and lead to antibody-dependent cell-mediated cytotoxicity (40). An autopsy study of a patient with CTLA-4 inhibitor-induced hypophysitis revealed a strong expression of CTLA-4 in the anterior pituitary cells and similar features as type II hypersensitivity reactions (47).…”