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

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.

Clonally expanded, thyrotoxic effector CD8 + T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

“…We recognize that preclinical models have inherent limitations in their ability to simulate human disease. ICI treatment of NOD mice recapitulates important aspects of the ICI autoimmune toxicity seen in humans, including multiorgan immune infiltrates (49,(57)(58)(59)(60), increasing toxicity with combination versus monotherapy (3,5), and a similar genetic basis for IRAE susceptibility (61)(62)(63)(64)(65)(66). However, the pattern of IRAEs in our mouse model does not align completely with that seen in patients.…”

Stocking the toolbox—Using preclinical models to understand the development and treatment of immune checkpoint inhibitor‐induced immune‐related adverse events

“…Tissue‐specific irAE profiles have emerged, relating to both the ICI target and type of cancer for which a patient is receiving treatment (Figure 2). For example, anti‐CTLA‐4 preferentially induces hypophysitis and gastrointestinal irAEs such as colitis and diarrhea, while autoimmune diabetes predominantly occurs following exposure to anti‐PD‐1/PD‐L1 treatment 10–13 . Different mechanisms have been suggested for the development of these and other irAEs, including the disruption of unique immunomodulatory receptor–ligand interactions that lead to a breakdown in tolerance, or the potential for complement‐initiated cell killing both of which may be caused by exposure to specific ICIs 14 .…”

“…For instance, an enrichment in HLA‐DR4 was observed in ICI‐induced autoimmune diabetes, which is also associated with conventional type 1 diabetes (T1D) 13 . Alternatively, in ICI‐induced hypophysitis, HLA‐DQ0602 appears to be enriched, whereas HLA‐DQ8 and DR53 are seen to be the dominant HLA type in the sporadic form of the disease, illustrating potentially divergent genetic susceptibility and mechanisms of antigen presentation for pathologies directed to the same organ 12 . Determining additional genetic variants associated with irAEs by genome‐wide association study (GWAS) may assist in uncovering other genomic alterations that impact immune function.…”

“…For example, anti-CTLA-4 preferentially induces hypophysitis and gastrointestinal irAEs such as colitis and diarrhea, while autoimmune diabetes predominantly occurs following exposure to anti-PD-1/PD-L1 treatment. [10][11][12][13] Different mechanisms have been suggested for the development of these and other irAEs, including the disruption of unique immunomodulatory receptorligand interactions that lead to a breakdown in tolerance, or the potential for complement-initiated cell killing both of which may be caused by exposure to specific ICIs. 14 In contrast, vitiligo, which is an autoimmune attack toward melanocytes leading to depigmentation, occurs predominantly in melanoma patients due to cross-reactivity between the cancer and site of irAE.…”

“…13 Alternatively, in ICI-induced hypophysitis, HLA-DQ0602 appears to be enriched, whereas HLA-DQ8 and DR53 are seen to be the dominant HLA type in the sporadic form of the disease, illustrating potentially divergent genetic susceptibility and mechanisms of antigen presentation for pathologies directed to the same organ. 12 Determining additional genetic variants associated with irAEs by genome-wide association study (GWAS) may assist in uncovering other genomic alterations that impact immune function. In ICI-treated patients with a diverse range of cancer types, development of severe irAEs independent of tissue-type was related to modifications to the IL7 gene, leading to alterations in lymphocyte stability and activity.…”