Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment

Abstract

Introduction: Hypophysitis caused by immune checkpoint inhibitors (ICIs) has risen to the medical attention during the past decade. ICIs are monoclonal antibodies that block the interaction between molecules that normally inhibit the function of effector T cells, ultimately increasing their ability to destroy cancer cells but also causing immune-related adverse events, such as hypophysitis. Ipilimumab, a CTLA-4 blocker, was the first ICI approved from the Food and Drug Administration for advanced melanoma patients in 2011. Several additional ICIs targeting CTLA-4, PD-1, or PD-L1 are now used in many clinical trials, making it important for physicians to recognize and treat hypophysitis adequately.Areas covered: This review will provide insights into the mechanisms of pituitary toxicity, highlight the complexity of clinical phenotypes of ICI hypophysitis, and offer practical recommendations.Expert opinion: ICI hypophysitis differs in many respects from primary hypophysitis, and also according to the type of ICI that caused it. Its pathogenesis remains unknown, although the expression of CTLA-4 and PD-1 on pituitary cells could play a role. The diagnosis is mainly clinical since there are no specific serological markers and MRI findings are subtle. The treatment is based on long-term hormone replacement and does not typically require discontinuation of immunotherapy.

Keywords: CTLA-4; Hypophysitis; PD-1; PD-L1; immune checkpoint inhibitors.

Figure 1.

Epidemiology of ICI hypophysitis. A) Distribution of 203 ICI hypophysitis papers according to the type of article. B) Yearly counts of ICI hypophysitis papers (circles for all article types, and diamonds for reviews), from July 2003 to August 2019. C) Geographical location and count of ICI hypophysitis patients published in USA from 2003 to 2019. D) Geographical location and count of ICI hypophysitis patients published in Japan from 2016 to 2019.

Figure 2.

Expression of CTLA-4 and PD-1. A) mRNA expression of CTLA-4 and PD-1 in human tissues collected by the Genotype-Tissue Expression RNA-seq project. B) Protein expression of CTLA-4 in pituitary endocrine cells (40x).

Figure 3.

Comparison of ICI hypophysitis to primary hypophysitis. A) Distribution of primary and ICI hypophysitis patients by sex, and age at diagnosis. B) Distribution of primary and ICI hypophysitis patients by hormonal deficiencies at diagnosis. * < 0.005, *** < 0.0001 by Pearson chi2. C) Follow-up time in primary hypophysitis and ICI hypophysitis patients. **< 0.001 by Wilcoxon rank sum test. D) Distribution of primary and ICI hypophysitis patients by outcome.

Figure 4.

Comparison of ICI hypophysitis caused by CTLA-4 blockade to that caused by PD1/PD-L1 blockade. A) Number of published patients with hypophysitis secondary to CTLA-4 or PD-1/PDL-1 blockade from 2003 to 2019. B) Time of hypophysitis onset according to the type of ICI and the treatment regimen (mono- or combination therapy). C) Distribution of patients with hypophysitis secondary to CTLA-4 or PD-1/PDL-1 blockade by hormonal deficiencies at diagnosis D) Distinctive features of hypophysitis secondary to CTLA-4 or PD-1/PDL-1 blockade.

Figure 5.

Mechanisms of hyponatremia in ICI hypophysitis. Low cortisol induces hyponatremia by increasing the levels of ADH through several mechanisms (direct stimulation of ADH, stimulation of CRH release, reduction of blood pressure and cardiac output, and up-regulation of aquaporin-2 expression in the kidney tubuli). Increased serum ADH levels lead to free water retention and hypotonic hyponatremia.