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Frontiers in Endocrinology 2023Immune checkpoint inhibitors (ICIs) have increasingly been the mainstay of treatment for numerous malignancies. However, due to their association with autoimmunity, ICIs... (Review)
Review
Immune checkpoint inhibitors (ICIs) have increasingly been the mainstay of treatment for numerous malignancies. However, due to their association with autoimmunity, ICIs have resulted in a variety of side effects that involve multiple organs including the endocrine system. In this review article, we describe our current understanding of the autoimmune endocrinopathies as a result of the use of ICIs. We will review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of the most commonly encountered endocrinopathies, including thyroiditis, hypophysitis, Type 1 diabetes, adrenalitis, and central diabetes insipidus.
Topics: Humans; Immune Checkpoint Inhibitors; Endocrine System; Endocrine System Diseases; Adrenal Gland Diseases; Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 37251665
DOI: 10.3389/fendo.2023.1157805 -
Endocrine Journal Jun 2023Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its...
Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.
Topics: Humans; Autoimmune Hypophysitis; Paraneoplastic Endocrine Syndromes; Autoantibodies; Hypophysitis; Paraneoplastic Syndromes; Neoplasms; Adrenocorticotropic Hormone
PubMed: 37045779
DOI: 10.1507/endocrj.EJ23-0050 -
Medicina 2021Since their approval in 2011, immune checkpoint inhibitors (ICPis) are increasingly used to treat several advanced cancers. ICPis target certain cellular molecules that... (Review)
Review
Since their approval in 2011, immune checkpoint inhibitors (ICPis) are increasingly used to treat several advanced cancers. ICPis target certain cellular molecules that regulate immune response resulting in antitumor activity. The use of these new agents needs careful monitoring since they brought a whole new spectrum of adverse events. In this review, we aim to describe different endocrine dysfunctions induced by ICPis and to underline the importance of diagnosing and managing these adverse effects. Immune-related endocrine toxicities include thyroid dysfunction, hypophysitis and, less frequently, type 1 diabetes, primary adrenal insufficiency and hypoparathyroidism. Diagnosis of endocrine adverse events related to ICPis therapy can be challenging due to nonspecific manifestations in an oncological scenario and difficulties in the biochemical evaluation. Despite the fact that these endocrine adverse events could lead to life-threatening consequences, the availability of effective replacement treatment enables continuing therapy and together with an interdisciplinary approach will impact positively on survival.
Topics: Endocrine System Diseases; Humans; Hypophysitis; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms
PubMed: 33906146
DOI: No ID Found -
QJM : Monthly Journal of the... Jan 2022
Topics: Autoimmune Diseases; Autoimmune Hypophysitis; Humans; Pituitary Diseases; Pituitary Gland
PubMed: 34373912
DOI: 10.1093/qjmed/hcab218 -
Cureus Jul 2021Immunotherapy-based regimens are currently the standard treatment for many different types of cancers. Monoclonal antibodies against cytotoxic T lymphocytes antigen...
Immunotherapy-based regimens are currently the standard treatment for many different types of cancers. Monoclonal antibodies against cytotoxic T lymphocytes antigen (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1) are the major subgroups of immune checkpoint inhibitors, which are being used widely in the treatment of various malignancies. They function by reactivating the immune system against the tumor cells but can also trigger autoimmune side effects, which are termed immune-related adverse effects (irAEs). In this report, we present a case of irAEs in a patient treated for colorectal cancer with combination therapy with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody).
PubMed: 34430146
DOI: 10.7759/cureus.16538 -
European Endocrinology Apr 2020Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors... (Review)
Review
Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors render the cancer cells susceptible to immune destruction, but also predispose to autoimmune disorders like primary hypothyroidism as well as central hypothyroidism secondary to hypophysitis. Tyrosine kinase inhibitors act by blocking vascular endothelial growth factor receptors and their downstream targets. Disruption of the vascular supply from the inhibition of endothelial proliferation damages not only cancer cells but also organs with high vascularity like the thyroid. Interferon-α, interleukin-2 and thalidomide analogues can cause thyroid dysfunction by immune modulation. Alemtuzumab, a monoclonal antibody directed against the cell surface glycoprotein CD52 causes Graves' disease during immune reconstitution. Metaiodobenzylguanidine, combined with 131-iodine, administered as a radiotherapeutic agent for tumours derived from neural crest cells, can cause primary hypothyroidism. Bexarotene can produce transient central hypothyroidism by altering the feedback effect of thyroid hormone on the pituitary gland. Thyroid dysfunction can be managed in the usual manner without a requirement for dose reduction or discontinuation of the implicated agent. This review aims to highlight the effect of various anticancer agents on thyroid function. Early recognition and appropriate management of thyroid disorders during cancer therapy will help to improve treatment outcomes.
PubMed: 32595767
DOI: 10.17925/EE.2020.16.1.32 -
Endocrine Reviews Apr 2020Some endocrine disorders, including hypophysitis and isolated adrenocorticotropic hormone (ACTH) deficiency, are caused by an autoimmune response to endocrine organs.... (Review)
Review
Some endocrine disorders, including hypophysitis and isolated adrenocorticotropic hormone (ACTH) deficiency, are caused by an autoimmune response to endocrine organs. Although the pathogenesis of some autoimmune endocrine diseases has been elucidated, it remains obscure for most. Anti-PIT-1 hypophysitis (anti-PIT-1 antibody syndrome) is a newly described pituitary autoimmune disease characterized by acquired and specific growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies. This disorder is associated with a thymoma or neoplasm that ectopically expresses pituitary-specific transcription factor 1 (PIT-1) protein. Circulating anti-PIT-1 antibody is a disease marker, and PIT-1-reactive cytotoxic T cells (CTLs) play a pivotal role in disease development. In addition, isolated ACTH deficiency appears to be caused by autoimmunity to corticotrophs; however, the pathogenesis remains unclear. A recently described case of isolated ACTH deficiency with large cell neuroendocrine carcinoma (LCNEC) showed ectopically expressed proopiomelanocortin (POMC), and circulating anti-POMC antibody and POMC-reactive CTLs were also detected. As CTL infiltrations around corticotrophs were also observed, isolated ACTH deficiency may be associated at least in part with a paraneoplastic syndrome. Although several underlying mechanisms for pituitary autoimmunity have been proposed, these observations highlight the importance of paraneoplastic syndrome as a cause of pituitary autoimmune disease. In this review, we focus on the pathophysiology and connection of anti-PIT-1 hypophysitis and isolated ACTH deficiency and discuss the state-of-art knowledge for understanding pituitary autoimmunity.
Topics: Adrenocorticotropic Hormone; Autoimmune Diseases of the Nervous System; Autoimmune Hypophysitis; Endocrine System Diseases; Genetic Diseases, Inborn; Humans; Hypoglycemia; Paraneoplastic Syndromes; Pituitary Diseases
PubMed: 31513261
DOI: 10.1210/endrev/bnz003 -
Presse Medicale (Paris, France : 1983) Apr 2020IgG4-related hypophysitis is a rare disease, due to a lymphoplasmocytic IgG4 positive infiltration of the pituitary. Literature data are scarce, even though the... (Review)
Review
IgG4-related hypophysitis is a rare disease, due to a lymphoplasmocytic IgG4 positive infiltration of the pituitary. Literature data are scarce, even though the description of cases has drastically increased over the last years. The aim of this review is to better characterize the natural history, the diagnosis and the management of IgG4-related hypophysitis, based on a clinical case, an exhaustive Pubmed research, and a reappraisal of the criteria for diagnosis. We will specifically focus on the differences with other etiologies of hypophysitis, in the aim of improving the diagnostic procedures for all the physicians who could have to take care of such patients.
Topics: Adult; Autoimmune Hypophysitis; Female; Humans; Immunoglobulin G4-Related Disease; Magnetic Resonance Imaging; Male; Middle Aged; Symptom Assessment
PubMed: 32234384
DOI: 10.1016/j.lpm.2020.104016 -
Journal of Personalized Medicine Jul 2023Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent... (Review)
Review
Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis. Primary autoimmune hypophysitis (PAH): During the acute phase of the disease, the pituitary gland in enlarged due to the infiltration of T and B lymphocytes. The chronic phase is characterized by progressive and irreversible pituitary atrophy. APA may play a role in the management, diagnosis, and prognosis of PAH. Specific autoantibodies such as anti-GH, anti-PIT-1, and anti-T-PIT have been found in patients with hypophysitis and hypopituitarism. A recent study suggested that a mechanism of escaping clonal deletion and mounting an immune response against self antigens can explain the unusual nature of the immune response observed in PAH patients. A cytokine array shows the presence of gamma-interferon and interleukin-17. Patients carrying mutations in the PIT1 or PROP1 genes may present PAH. Individuals carrying the HLA DQ8 haplotype are four times more likely to develop PAH. Immune checkpoint inhibitors induce hypophysitis (IIHs): IIHs is an increasingly frequent toxicity of in patients on treatment with inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). ICIs inhibit the CTLA-4 pathway, leading to overactivation of T lymphocytes. The binding of PD-1/PD-L1 suppresses the activity of T cells, promotes the conversion of T-helpers into T-regulatory cells, and activates pro-survival signaling pathways in cancer cells. Cytokines play a crucial role in IIHs. B-cell infiltration has been observed in IIHs, suggesting that antibody-mediated pituitary injury may contribute. Genetic polymorphisms of CTLA-4 and PD-1 genes can increase the risk of IIHs. HLA alleles may also be involved in the onset of IIHs; this HLA association presents a possible alternative mechanistic hypothesis. IIHs may also be linked to a paraneoplastic syndrome triggered by ectopic expression of pituitary specific antigens. SARS-CoV-2-related hypophysitis: Recently, the literature has reported occurrences of hypophysitis associated with the SARS-CoV-2 virus; long COVID-19 may also present as infundibulo-neuro-hypophysitis. The virus enters the central nervous system because of its distinct interaction with angiotensin-converting enzyme receptors via spike proteins binding the capillary endothelium, and it directly damages the pituitary cells. The effect of SARS-CoV-2 can occur indirectly through inflammation and the release of cytokines. The exact mechanism remains ambiguous. The available data on endocrine complications associated with the SARS-CoV-2 vaccine are scant. Nonetheless, isolated cases of hypophysitis have been documented. Treatment of hypophysitis: Glucocorticoids are the cornerstone in managing primary hypophysitis, given their targeted action on inflammation. A better understanding of the etiopathogenesis and molecular mechanism of hypophysitis can lead to more effective and personalized treatment strategies.
PubMed: 37623461
DOI: 10.3390/jpm13081210