Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis

Zoe Quandt; Stephanie Kim; Javier Villanueva-Meyer; Catherine Coupe; Arabella Young; Jee Hye Kang; Jinoos Yazdany; Gabriela Schmajuk; Stephanie Rush; Elad Ziv; Ana Luisa Perdigoto; Kevan Herold; Melissa G Lechner; Maureen A Su; J Blake Tyrrell; Jeffrey Bluestone; Mark Anderson; Umesh Masharani

doi:10.1210/jendso/bvad012

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis

J Endocr Soc. 2023 Feb 6;7(4):bvad012. doi: 10.1210/jendso/bvad012. eCollection 2023 Feb 9.

Authors

Zoe Quandt^{1

2}, Stephanie Kim¹, Javier Villanueva-Meyer³, Catherine Coupe², Arabella Young^{2

4

5}, Jee Hye Kang², Jinoos Yazdany^{6

7}, Gabriela Schmajuk^{6

7

8

9}, Stephanie Rush⁶, Elad Ziv¹⁰, Ana Luisa Perdigoto^{11

12

13}, Kevan Herold^{11

12

13}, Melissa G Lechner¹⁴, Maureen A Su^{15

16}, J Blake Tyrrell¹, Jeffrey Bluestone², Mark Anderson^{1

2}, Umesh Masharani^{1

2}

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA 94122, USA.
² Diabetes Center, University of California, San Francisco, San Francisco, CA 94122, USA.
³ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94122, USA.
⁴ Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
⁵ Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁶ Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94122, USA.
⁷ Division of Rheumatology, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA 94110, USA.
⁸ Division of Rheumatology, Department of Medicine, San Francisco VA Medical Center, San Francisco, CA 94121, USA.
⁹ Philip R. Lee Institute for Health Policy Studies, San Francisco, CA 94158, USA.
¹⁰ Department of Medicine, University of California, San Francisco, San Francisco, CA 94122, USA.
¹¹ Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
¹² Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
¹³ Division of Endocrinology and Metabolism, Department of Medicine, Yale University, New Haven, CT 06520, USA.
¹⁴ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UCLA David Geffen School of Medicine, CA 90095, USA.
¹⁵ Department of Microbiology, Immunology, and Medical Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
¹⁶ Department of Pediatrics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.

Abstract

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors.

Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis).

Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis.

Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, P < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, P = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, P = 0.01) and CPI population.

Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.

Keywords: adrenal insufficiency; hypophysitis; immune checkpoint inhibitors; immune-related adverse events; immunotherapy; pan-hypopituitarism.

Abstract

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