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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 -
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 -
International Journal of Molecular... May 2019Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal... (Review)
Review
Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin-dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Autoimmune Diseases; Endocrine System Diseases; Humans; Immunotherapy; Neoplasms
PubMed: 31137683
DOI: 10.3390/ijms20102560 -
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 -
Clinical Medicine Insights.... 2015Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may... (Review)
Review
Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may include hypophysitis-related hypopituitarism. The clinical features of six patients with ipilimumab-induced hypophysitis (IH) are described. The clinical features of IH reported in clinical trials, including the incidence of IH by gender and the likelihood of adrenal axis recovery, are summarized. Following the development of IH, most patients remain on glucocorticoid replacement despite efforts to withdraw therapy. Analysis of gender information in published clinical trials suggests that men are more prone to developing IH than women, and few patients fully recover the pituitary-adrenal axis function. Ipilimumab and other drugs within its class are likely to be used to treat many forms of cancer. Endocrinologists should anticipate a significant increase in the incidence of autoimmune hypophysitis. Strategies for early detection of IH and long-term management should be considered.
PubMed: 25861234
DOI: 10.4137/CMED.S22469 -
International Journal of Molecular... Mar 2023Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis... (Review)
Review
Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, medications, and more. Although hypophysitis was previously accepted as an exceedingly rare diagnosis, a greater understanding of the disease process and new insights into possible etiologic sources have contributed to an increased frequency of recognition. This review provides an overview of hypophysitis, its causes, and detection strategies and management.
Topics: Humans; Hypophysitis; Pituitary Gland; Lymphocytes
PubMed: 36982990
DOI: 10.3390/ijms24065917