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

, Stephanie Kim, Javier Villanueva-Meyer, Catherine Coupe, Arabella Young, Jee Hye Kang, , Gabriela Schmajuk, Stephanie Rush,
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Published: 6 February 2023

Abstract: Introduction: 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. Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary and association with HLA type in patients with CPI-induced hypophysitis (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 versus PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 days vs 185 days, p<0.01) and abnormal pituitary appearance on MRI [odds ratio (OR) 7.00, p=0.03]. 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 overrepresented 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, imaging changes on MRI and possibly sex related to CPI-type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.
Keywords: hypophysitis / HLA type / monotherapy / empty / inhibitor / MRI changes / CPI type / sex

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