Recent insights into the pathogenesis of autoimmune hypophysitis

Frasca, Francesco; Piticchio, Tommaso; Moli, Rosario Le; Malaguarnera, Roberta; Campennì, Alfredo; Cannavò, Salvatore; Ruggeri, Rosaria Maddalena

doi:10.1080/1744666x.2021.1974297

Cited by 9 publications

(6 citation statements)

References 103 publications

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“… 11 There is currently no consensus on the pathogenesis of ICI-associated hypophysitis, and studies have found that the presence of antipituitary gland autoantibodies and human leukocyte antigens (HLAs) in the serum of patients may increase the susceptibility of ICIs-induced hypophysitis. 12 The occurrence time of hypophysitis was related to ICI type, 10 among which the incidence of PD-L1/PD-1 plus CTLA-4 inhibitor was the highest (6.4%), followed by CTLA-4 inhibitor (3.2%), PD-1 inhibitor (0.4%) and PD-L1 inhibitor (less than 0.1%). 7 , 13 Some studies have shown that the incidence of hypophysitis induced by CTLA-4 inhibitor therapy is much higher in men than in women.…”

Section: Discussionmentioning

confidence: 95%

“… 6 , 9 The higher incidence in males may be explained by the positive effect of androgens on the expression of CTLA-4. 12 Therefore, it is suggested that male patients treated with ICIs need to pay attention to the occurrence of hypophysitis, especially in those treated with CTLA-4 inhibitor or combination therapy, and the onset time is mostly within the first half-year after treatment. 3 In this case, the patient was male, and hypopituitarism was found due to fatigue after KN046 immunotherapy, which was consistent with the sex characteristics of hypophysitis-related cases reported in the past, but the onset time was later than in most related cases.…”

Section: Discussionmentioning

confidence: 99%

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Autoimmune Polyendocrinopathy Induced by an Antibody (KN046) That Simultaneously Inhibits PD-L1 and CTLA-4: A Case Report and Literature Review

Li¹,

Wu²,

Liu³

et al. 2022

DMSO

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Endocrine adverse reactions are one of the most common adverse reactions in the treatment of immune checkpoint inhibitors (ICIs), mainly involving the pituitary gland, pancreas, thyroid gland, adrenal gland and other glands, resulting in corresponding endocrine dysfunction. We report a 45-year-old man with non-small-cell lung cancer who developed hypophysitis 11 months after initiation of treatment with an anti-PD-L1/CTLA-4 bispecific antibody (KN046) that blocks both programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), followed by regular oral replacement doses of prednisone and levothyroxine tablets. The patient was diagnosed with type 1 diabetes mellitus (T1DM) with diabetic ketoacidosis (DKA) 25 months after the start of immunotherapy, presenting with acute hyperglycemic symptoms, ketoacidosis, and negative diabetic autoantibodies. By describing a case of KN046 immunotherapy involving multiple endocrine glands and reviewing relevant literature, we were able to summarize the clinical characteristics of KN046 immunotherapy-induced endocrine system-related immune-related adverse events (irAEs) for use in early detection, diagnosis and treatment.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Autoimmune Polyendocrinopathy Induced by an Antibody (KN046) That Simultaneously Inhibits PD-L1 and CTLA-4: A Case Report and Literature Review

Li¹,

Wu²,

Liu³

et al. 2022

DMSO

View full text Add to dashboard Cite

show abstract

“…The difference between the frequency of pituitary involvement by anti-CTLA-4 and anti-PD-1 can be explained by the broader action of anti-CTLA-4, which affects the immune cycle in the initial stages of its activation. This action differs from that of anti-PD1 and anti-PD-L1, which act in tumor microenvironment and in circulation ( 35 ). Other explanations may be the presence of pituitary CTLA-4 receptors, complement deposition in the pituitary with local cell infiltration, and the formation of antibodies against pituitary cells ( 1 , 27 , 36 ).…”

Section: Discussionmentioning

confidence: 96%

Frequency and clinical characteristics of hypophysitis and hypopituitarism in patients undergoing immunotherapy – A systematic review

et al. 2023

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ObjectiveTo describe the frequency of hypophysitis and hypopituitarism in cancer patients who are undergoing antineoplastic treatment with immunotherapy, as well as to describe the clinical, epidemiological, and demographic characteristics of these patients.MethodsA systematic search of the literature in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Controlled Register of Trials took place on May 8 and 9, 2020. Randomized and nonrandomized clinical trials, cohort studies, case-control studies, case series and case reports were included.ResultsA total of 239 articles were obtained, in which 963 cases of hypophysitis and 128 cases of hypopituitarism were found in a treated population of 30,014 individuals (3.20% and 0.42% of the evaluated population, respectively). In the cohort studies, the incidence of hypophysitis and hypopituitarism ranged from 0% to 27.59% and from 0% to 17.86%, respectively. In the non-randomized clinical trials, the incidence of hypophysitis and hypopituitarism ranged from 0% to 25% and from 0% to 14.67%, and in randomized clinical trials from 0% to 16.2% and from 0% to 33.33%. The most common hormonal changes were in the corticotrophic, thyrotrophic and gonadotrophic axes. The main magnetic resonance imaging (MRI) findings were enlargement of the pituitary gland and enhanced contrast uptake. The main symptoms presented by patients with hypophysitis were fatigue and headache.ConclusionThe present review reported a frequency of hypophysitis and hypopituitarism of 3.20% and 0.42%, respectively, in the evaluated population. The clinical-epidemiological characteristics of patients affected by hypophysitis were also described.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42020175864.

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“…It has been proposed that ICI-induced pituitary destruction results from the activation of the classic complement cascade, which is triggered by the combined action of these endogenous autoAbs and the exogenous anti-CTLA4 IgG1 Abs [78]. Pituitary toxicity perfectly reflects the complexity and multifactorial nature of irAEs [80].…”

Section: Direct Effect Of Monoclonal Absmentioning

confidence: 99%

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Casagrande,

Sopetto,

Bertalot

et al. 2024

Cancers

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The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

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Recent insights into the pathogenesis of autoimmune hypophysitis

Cited by 9 publications

References 103 publications

Autoimmune Polyendocrinopathy Induced by an Antibody (KN046) That Simultaneously Inhibits PD-L1 and CTLA-4: A Case Report and Literature Review

Autoimmune Polyendocrinopathy Induced by an Antibody (KN046) That Simultaneously Inhibits PD-L1 and CTLA-4: A Case Report and Literature Review

Frequency and clinical characteristics of hypophysitis and hypopituitarism in patients undergoing immunotherapy – A systematic review

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

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