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van Dijk B, Janssen JC, van Daele PLA, de Jonge MJA, Joosse A, Verheul HMW, Epker JL, van der Veldt AAM. From ICI to ICU: A systematic review of patients with solid tumors who are treated with immune checkpoint inhibitors (ICI) and admitted to the intensive care unit (ICU). Cancer Treat Rev 2025; 136:102936. [PMID: 40222269 DOI: 10.1016/j.ctrv.2025.102936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/04/2025] [Accepted: 04/06/2025] [Indexed: 04/15/2025]
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) have improved the survival of patients with different solid tumors and even resulted in cure of metastatic disease. Since the introduction of ICIs, an increasing number of patients is admitted to the ICU for severe and potentially life-threatening immune related adverse events (irAEs). The outcome of patients who are admitted to the ICU because of severe irAEs is still unknown. The aim of this systematic review is to collect evidence on the outcomes of patients with solid tumors who are admitted to the ICU because of irAEs. METHODS Medline, Embase, Cochrane central register of controlled trials and Google Scholar were searched systematically from 1975 to 24 September 2024. Articles were only included when describing patients with solid tumors who were admitted to the ICU because of irAEs after treatment with ICIs. Two independent reviewers extracted the data and assessed the risk of bias. RESULTS A total of 183 articles were included: two prospective ICU population-based studies, four retrospective ICU population-based studies, 25 retrospective studies describing irAEs with incidental ICU admissions, one review of case reports, and 153 articles with a total of 177 case reports. The six ICU population-based studies contained a total of 169 patients who were admitted to the ICU due to irAEs. In these six studies, the most frequently reported irAEs were pneumonitis and neurological irAEs. Of these 169 patients, 26% of the patients died on the ICU and an additional 8% of patients in the three to six months thereafter due to irAEs or disease progression. In all 183 included articles, various irAEs were described and the reported mortality rate varied from 0 to 53%. CONCLUSION The potential favorable outcomes of both the solid tumors and irAEs will probably result in more need for ICU admissions. Prospective clinical trials are needed to optimize the treatment strategy of severe irAEs at the ICU. Based on the favourable outcomes after life-threatening irAEs, ICU admission should definitely be considered for patients with solid tumors who have life-threatening irAEs.
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Affiliation(s)
- Brigit van Dijk
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands
| | - Joséphine C Janssen
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands; Department of Oncological Surgery, Erasmus MC, Rotterdam, the Netherlands
| | - Paul L A van Daele
- Department of Clinical Immunology, Erasmus MC, Rotterdam, the Netherlands
| | - Maja J A de Jonge
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands
| | - Arjen Joosse
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands
| | - Jelle L Epker
- Department of Intensive Care, Erasmus MC, Rotterdam, the Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands; Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.
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Colombo C, De Leo S, Campisi I, Palesandro E, Turco F, Buttigliero C, Fugazzola L, Tucci M. Endocrinological toxicities related to immunotherapy combinations for advanced renal cell carcinoma: Practical expert-based management recommendations. Crit Rev Oncol Hematol 2025; 209:104627. [PMID: 39922397 DOI: 10.1016/j.critrevonc.2025.104627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/19/2025] [Accepted: 01/21/2025] [Indexed: 02/10/2025] Open
Abstract
Nowadays immune-based combinations are the standard first-line treatment for metastatic renal cell carcinoma and involve the use of either two immunotherapy agents or an immunotherapeutic drug associated with a tyrosine kinase inhibitor. Treatment-related toxicity is the primary cause of drug discontinuation or dose reduction. A thorough understanding of the prevention and management of adverse events of the immune-based combinations is critical to ensure the success of treatment. Endocrinological toxicities during treatment with immune-based combinations are frequent and often manageable. However, in some cases, diagnosis can be complex, and the treatment requires multidisciplinary discussion. In addition, it is often challenging to determine which agent in the combination is responsible for a specific toxicity. In this review, we analyze the evidence regarding treatment-related endocrinopathies in renal cell carcinoma first-line therapy. We also discuss monitoring strategies to diagnose endocrinological adverse events and provide some practical tools for their daily management.
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Affiliation(s)
- Carla Colombo
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Simone De Leo
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Ilaria Campisi
- Department of Oncology, University of Turin, Turin, Italy
| | | | - Fabio Turco
- Department of Oncology, Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Consuelo Buttigliero
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
| | - Laura Fugazzola
- Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Marcello Tucci
- Department of Oncology, Cardinal Massaia Hospital, Asti, Italy.
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Iwama S, Kobayashi T, Arima H. Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors. Nat Rev Endocrinol 2025; 21:289-300. [PMID: 39779950 DOI: 10.1038/s41574-024-01077-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2024] [Indexed: 01/11/2025]
Abstract
Immune-related adverse events (irAEs), including endocrine irAEs, can occur in response to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Of the endocrine irAEs, pituitary and thyroid irAEs are most frequently observed, followed by primary adrenal insufficiency, type 1 diabetes mellitus and hypoparathyroidism. Notably, pituitary irAEs and type 1 diabetes mellitus can be lethal if overlooked, potentially leading to adrenal crisis and diabetic ketoacidosis, respectively. On the other hand, pituitary and thyroid irAEs are reported to be associated with more favourable prognoses in some cancers if treated appropriately with hormone-replacement therapies. It would be useful to identify those people who are likely to develop endocrine irAEs before initiating therapy with ICIs. Anti-pituitary antibodies and thyroid autoantibodies have been identified as potential biomarkers for the development of pituitary and thyroid irAEs, respectively. This Review elaborates on the clinical characteristics and management strategies of several endocrine irAEs, using the latest research findings and guidelines published by several academic societies.
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Affiliation(s)
- Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan.
| | - Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Spagnolo CC, Campo I, Campennì A, Cardile D, Cannavò S, Silvestris N, Santarpia M, Ruggeri RM. Challenges and pitfalls in the management of endocrine toxicities from immune checkpoint inhibitors: a case presentation of synchronous thyrotoxicosis and primary adrenal insufficiency in a melanoma patient. Hormones (Athens) 2024; 23:759-764. [PMID: 38421588 DOI: 10.1007/s42000-024-00535-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/09/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.
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Affiliation(s)
- Calogera Claudia Spagnolo
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, AOU G. Martino, V. Consolare Valeria 1, 98125, Messina, Italy
| | - Irene Campo
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, AOU G. Martino, V. Consolare Valeria 1, 98125, Messina, Italy
| | - Alfredo Campennì
- Unit of Nuclear Medicine, Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125, Messina, Italy
| | - Davide Cardile
- Unit of Nuclear Medicine, Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125, Messina, Italy
| | - Salvatore Cannavò
- Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125, Messina, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, AOU G. Martino, V. Consolare Valeria 1, 98125, Messina, Italy
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, AOU G. Martino, V. Consolare Valeria 1, 98125, Messina, Italy.
| | - Rosaria Maddalena Ruggeri
- Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125, Messina, Italy
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Escaño L, Desai P. Secondary Adrenal Insufficiency as an Immune-Related Adverse Event of Pembrolizumab Therapy. Cureus 2024; 16:e65163. [PMID: 39176308 PMCID: PMC11339576 DOI: 10.7759/cureus.65163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 08/24/2024] Open
Abstract
Pembrolizumab is an immune checkpoint inhibitor that blocks the PD1 receptor and is currently used in the treatment of a vast variety of malignancies. Despite adrenal insufficiency already being documented as a rare but potential side effect, its diagnosis is usually delayed due to its vague presentation, increasing the risk of deleterious outcomes. We present a case of secondary adrenal insufficiency while on pembrolizumab, in which the diagnosis was delayed due to a nonspecific clinical picture. This case highlights the importance of maintaining a high index of suspicion for endocrine dysfunction in patients treated with immune checkpoint inhibitors, as early recognition and appropriate intervention are paramount to preventing serious complications in these patients.
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Pan Q, Li P. Challenges in autoimmune polyendocrine syndrome type 2 with the full triad induced by anti-programmed cell death 1: a case report and review of the literature. Front Immunol 2024; 15:1366335. [PMID: 38707904 PMCID: PMC11067522 DOI: 10.3389/fimmu.2024.1366335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 04/02/2024] [Indexed: 05/07/2024] Open
Abstract
Background Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at least two of the following endocrinopathies: autoimmune thyroid disease, type 1 diabetes, and Addison's disease. Cases with the full triad are rare. We present a case of an elderly woman who developed APS-2 with the complete triad shortly after starting anti-programmed cell death 1 (anti-PD1) treatment and review the related literature. Case A 60-year-old woman, without any personal or family history of autoimmune and endocrine diseases, started the immunotherapy of anti-PD1 (camrelizumab) for squamous cell carcinoma of the urethral meatus. She developed primary hypothyroidism with elevated antibodies to thyroid peroxidase and thyroglobulin after 25 weeks of treatment, and developed primary adrenal insufficiency with adrenal crisis and fulminant type 1 diabetes with ketoacidosis after 45 weeks. Therefore, this patient met the diagnosis of APS-2 and was given multiple hormone replacement including glucocorticoid, levothyroxine and insulin therapy. Continuous improvement was achieved through regular monitoring and titration of the dosage. Conclusions Different components of APS-2 may appear at different time points after anti-PD1 administration, and can be acute and life-threatening. A good prognosis can be obtained by appropriate replacement with multiple hormones. Insights With the clinical application of ICPis to APS-2, the complexity of its treatment should be paid enough attention.
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Affiliation(s)
- Qin Pan
- Department of Endocrinology, Chengdu Eighth People’s Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, Sichuan, China
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ping Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Martin-Grace J, Tomkins M, O'Reilly MW, Sherlock M. Iatrogenic adrenal insufficiency in adults. Nat Rev Endocrinol 2024; 20:209-227. [PMID: 38272995 DOI: 10.1038/s41574-023-00929-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/23/2023] [Indexed: 01/27/2024]
Abstract
Iatrogenic adrenal insufficiency (IAI) is the most common form of adrenal insufficiency in adult patients, although its overall exact prevalence remains unclear. IAI is associated with adverse clinical outcomes, including adrenal crisis, impaired quality of life and increased mortality; therefore, it is imperative that clinicians maintain a high index of suspicion in patients at risk of IAI to facilitate timely diagnosis and appropriate management. Herein, we review the major causes, clinical consequences, diagnosis and care of patients with IAI. The management of IAI, particularly glucocorticoid-induced (or tertiary) adrenal insufficiency, can be particularly challenging, and the provision of adequate glucocorticoid replacement must be balanced against minimizing the cardiometabolic effects of excess glucocorticoid exposure and optimizing recovery of the hypothalamic-pituitary-adrenal axis. We review current treatment strategies and their limitations and discuss developments in optimizing treatment of IAI. This comprehensive Review aims to aid clinicians in identifying who is at risk of IAI, how to approach screening of at-risk populations and how to treat patients with IAI, with a focus on emergency management and prevention of an adrenal crisis.
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Affiliation(s)
- Julie Martin-Grace
- Department of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Maria Tomkins
- Department of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Michael W O'Reilly
- Department of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Mark Sherlock
- Department of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland.
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland.
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Deng Y, Huang M, Deng R, Wang J. Immune checkpoint inhibitor-related adrenal hypofunction and Psoriasisby induced by tislelizumab: A case report and review of literature. Medicine (Baltimore) 2024; 103:e37562. [PMID: 38518047 PMCID: PMC10956970 DOI: 10.1097/md.0000000000037562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/20/2024] [Indexed: 03/24/2024] Open
Abstract
RATIONALE Immune-related adverse events following treatment with immune checkpoint inhibitors can affect almost every organ. Tislelizumab, a novel humanized Ig G4 programmed death receptor 1 inhibitor, was started for bladder cancer in 2019, but the adverse effects of this drug may not yet be known due to its short time on the market, and there are still some clinical safety concerns. There are few reports of adrenal insufficiency after tislelizumab treatment, which is easily missed, misdiagnosed and life-threatening. PATIENT CONCERNS A 67-year-old male with bladder cancer who developed rash, water-sodium retention, electrolyte disturbances, hypoalbuminemia, low-grade fever, nausea and vomiting, and fatigue after 2 cycles of tislelizumab. DIAGNOSIS Immune checkpoint inhibitor-related adrenal hypofunction and Psoriasisby. INTERVENTIONS Suspended tislelizumab treatment and continued glucocorticoid therapy. OUTCOMES The patient showed significant improvement in the above symptoms. But bladder cancer reemerged at the same site. CONCLUSIONS The advent of immune-related adverse events has increased the complexity of the application of tislelizumab in the treatment of bladder cancer and further research is needed to develop the best treatment guidelines. Early diagnosis and treatment are crucial since the adverse events could endanger lives.
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Affiliation(s)
- Yisi Deng
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
- Department of Urology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
| | - Manling Huang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
- Department of Urology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
| | - Runpei Deng
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China
| | - Jun Wang
- Department of Urology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
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Zhang S, Wu J, Zhao Y, Zhang J, Zhang X, Wu C, Zhang Z, Guo Z. Immune-Related Adverse Event-Related Adrenal Insufficiency Mediates Immune Checkpoint Inhibitors Efficacy in Cancer Treatment. Cancer Manag Res 2024; 16:151-161. [PMID: 38501053 PMCID: PMC10946443 DOI: 10.2147/cmar.s444916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 03/05/2024] [Indexed: 03/20/2024] Open
Abstract
Purpose Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer; however, these agents may initiate immune-related adverse events (irAEs). Previous studies have demonstrated a robust correlation between disease prognosis and the occurrence of irAEs, specifically skin or endocrine irAEs. Herein, we aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy. Patients and methods Patients diagnosed with gastrointestinal, respiratory, head and neck, urological, skin and gynecologic cancers treated with anti-programmed cell death 1 (PD-1)/anti-programmed cell death ligand 1 (PD-L1) antibody as monotherapy or combined therapy (combined with chemotherapy or targeted therapy) were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method with the log-rank test. Results Of the 192 patients enrolled in our study, 17 developed irAE-related AI and 83 developed other irAEs. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group (P<0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs non-irAE, P=0.008; irAE-B vs non-irAE, P=0.020), Eastern Cooperative Oncology Group (ECOG) status (P=0.045), tumor-node-metastasis (TNM) stage (P=0.000), and treatment line (P=0.002) were independent predictors of PFS. Contrarily, irAE status (irAE-A vs non-irAE, P=0.009; irAE-B vs non-irAE, P=0.013), ECOG status (P=0.007), TNM stage (P=0.035), treatment line (P=0.001) and treatment modality (P=0.008) were independent predictors for OS. Conclusion IrAE-related AI was significantly associated with ICI treatment efficacy in patients with cancer, which could be a potentially predictable marker. Due to the destruction of adrenal tissue by T cells with enhanced activity, AI reflects enhanced T cell activity to some extent.
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Affiliation(s)
- Shasha Zhang
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Jianhua Wu
- Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Yue Zhao
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Jingjing Zhang
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Xiaoyun Zhang
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Chensi Wu
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Zhidong Zhang
- Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
| | - Zhanjun Guo
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China
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Øksnes M, Husebye ES. Approach to the Patient: Diagnosis of Primary Adrenal Insufficiency in Adults. J Clin Endocrinol Metab 2023; 109:269-278. [PMID: 37450570 PMCID: PMC10735307 DOI: 10.1210/clinem/dgad402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/28/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Affiliation(s)
- Marianne Øksnes
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway
- Department of Medicine Haukeland, University Hospital, N-5021 Bergen, Norway
| | - Eystein S Husebye
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway
- Department of Medicine Haukeland, University Hospital, N-5021 Bergen, Norway
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11
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Basek A, Jakubiak GK, Cieślar G, Stanek A. Life-Threatening Endocrinological Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2023; 15:5786. [PMID: 38136332 PMCID: PMC10742092 DOI: 10.3390/cancers15245786] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/29/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Malignant neoplasms are currently one of the leading causes of morbidity and mortality worldwide, posing a major public health challenge. However, recent advances in research in cancer biology and immunity have led to the development of immunotherapy, which is now used on an everyday basis in cancer treatment in addition to surgical treatment, classical cytostatics, and radiotherapy. The efficacy of immunotherapy has promoted the great popularity of this treatment among patients, as well as significant research interest. The increasing number of patients being treated with immunotherapy not only reassures physicians of the efficacy of this technique but also shows the wide spectrum of side effects of this therapy, which has not been considered before. Immune-related adverse events may affect many systems and organs, such as digestive, cardiovascular, respiratory, skin, or endocrine organs. Most complications have a mild or moderate course, but there are life-threatening manifestations that are essential to be aware of because if they are not properly diagnosed and treated on time, they can have fatal consequences. The purpose of this paper was to present the results of a literature review on the current state of knowledge on life-threatening endocrine side effects (such as adrenal crisis, thyroid storm, myxoedema crisis, diabetic ketoacidosis, and severe hypocalcaemia) of immune checkpoint inhibitors to provide information on symptoms, diagnostics, and management strategies.
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Affiliation(s)
- Aleksandra Basek
- Student Research Group, Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland;
| | - Grzegorz K. Jakubiak
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
| | - Grzegorz Cieślar
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
| | - Agata Stanek
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
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12
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Martella S, Lucas M, Porcu M, Perra L, Denaro N, Pretta A, Deias G, Willard-Gallo K, Parra HS, Saba L, Scartozzi M, Wekking D, Kok M, Aiello MM, Solinas C. Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects. Semin Oncol 2023; 50:144-148. [PMID: 38151399 DOI: 10.1053/j.seminoncol.2023.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 12/29/2023]
Abstract
Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.
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Affiliation(s)
- Serafina Martella
- Medical Oncology, University Hospital Policlinico G.Rodolico-San Marco, 95123, Catania, Italy
| | - Minke Lucas
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Michele Porcu
- Department of Radiology, AOU Cagliari, University of Cagliari, Cagliari, Italy
| | - Laura Perra
- Azienda Tutela Salute Sardegna, via Enrico Costa n. 57, Sassari, Italy
| | - Nerina Denaro
- Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Italy
| | - Giulia Deias
- Medical Oncology Unit, University Hospital and University of Cagliari, Italy
| | - Karen Willard-Gallo
- Molecular Immunology Unit, Institut Jules Bordet, Boulevard de Waterloo, 121, Brussels, Belgium
| | - Hector Soto Parra
- Medical Oncology, Azienda Ospedaliero Universitaria Policlinico "G. Rodolico-S. Marco", 95123, Catania, Italy
| | - Luca Saba
- Department of Radiology, AOU Cagliari, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Italy
| | - Demi Wekking
- Location Academic Medical Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| | - Marleen Kok
- Department of Medical Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, North Holland, the Netherlands.; Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marco Maria Aiello
- Azienda Ospedaliero Universitaria Policlinico San Marco, Via Santa Sofia, 78, Catania, Italy
| | - Cinzia Solinas
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato, Cagliari, Italy
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13
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Bhanderi H, Khalid F, Bodla ZH, Muhammad T, Du D, Meghal T. Autoimmune diabetes from pembrolizumab: A case report and review of literature. World J Clin Oncol 2023; 14:535-543. [PMID: 38059185 PMCID: PMC10696214 DOI: 10.5306/wjco.v14.i11.535] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/13/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Immunotherapy, specifically the use of checkpoint inhibitors such as pembrolizumab, has become an important tool in personalized cancer therapy. These inhibitors target proteins on T-cells that regulate the immune response against tumor cells. Pembrolizumab, which targets the programmed cell death 1 receptor on T-cells, has been approved for the treatment of metastatic melanoma and non-small cell lung cancer. However, it can also lead to immune-related side effects, including pneumonitis, colitis, thyroid abnormalities, and rare cases of type 1 diabetes. CASE SUMMARY The case presented involves an adult patient in 30s with breast cancer who developed hyperglycemia after receiving pembrolizumab treatment. The patient was diagnosed with diabetic ketoacidosis and further investigations were performed to evaluate for new-onset type 1 diabetes. The patient had a history of hypothyroidism and a family history of breast cancer. Treatment for diabetic ketoacidosis was initiated, and the patient was discharged for close follow-up with an endocrinologist. CONCLUSION This literature review highlights the occurrence of diabetic ketoacidosis and new-onset type 1 diabetes in patients receiving pembrolizumab treatment for different types of cancer. Overall, the article emphasizes the therapeutic benefits of immunotherapy in cancer treatment, particularly pembrolizumab, while also highlighting the potential side effect of immune-related diabetes that can occur in a small percentage of patients. Here we present a case where pembrolizumab lead to development of diabetes after a few cycles highlighting one of the rare yet a serious toxicity of the drug.
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Affiliation(s)
- Hardikkumar Bhanderi
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Farhan Khalid
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Zubair Hassan Bodla
- Department of Internal Medicine, University of Central Florida College of Medicine, Gainesville, FL 32303, United States
| | - Tayyeb Muhammad
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Doantrang Du
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Trishala Meghal
- Department of Hematology-Oncology, Monmouth Medical Center, Long Branch, NJ 07740, United States
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14
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Tayyeb M, Tariq M, Khan AM, Khalid F, Meghal T, Du D. When Hormones are Being Difficult: A Rare Case and the Literature Review of Pembrolizumab-Induced Polyendocrinopathy. J Community Hosp Intern Med Perspect 2023; 13:90-94. [PMID: 38596553 PMCID: PMC11000850 DOI: 10.55729/2000-9666.1270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 04/11/2024] Open
Abstract
Immune Checkpoint inhibitors (ICIs) such as nivolumab, pembrolizumab, and ipilimumab are monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA4) or program death (PD)1 and its ligand PDL1. Agents targeting PD1, such as pembrolizumab, have shown widespread efficacy in the past and are also associated with a wide range of immune-related adverse events (irAEs), including endocrine toxicities. A 31-year-old female with a medical history significant for Stage IIb Breast cancer on chemo and immunotherapy (pembrolizumab) presented with nausea, vomiting, and generalized abdominal pain. Laboratory studies showed a blood glucose level of 356 mg/dl, elevated Anion gap 18 meq/L, beta-hydroxybutyrate 46 mg/d, and low C-peptide levels <0.10 ng/ml. The patient was treated for Diabetic Ketoacidosis (DKA). Further testing revealed high Thyroid Stimulating Hormone (TSH) levels along with elevated thyroid peroxidase levels of 38 IU/L. After discharge from the hospital on insulin and levothyroxine therapy, the patient reported increasing fatigue and further testing revealed low cortisol levels <0.5 mcg/dl with elevated ACTH consistent with primary adrenal insufficiency. The patient was started on hydrocortisone therapy with improvement in symptoms. Endocrine toxicities are not uncommon in patients receiving pembrolizumab, but polyendocrinopathy in a relatively rare side effect of pembrolizumab. Only a few cases of pembrolizumab-induced polyendocrinopathy have been reported so far which we have mentioned in this article. While patients are on immunotherapy, close monitoring for clinical signs & symptoms can lead to an early diagnosis, substantially improving morbidity and mortality.
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Affiliation(s)
- Muhammad Tayyeb
- Department of Medicine, Monmouth Medical Center, Long Branch, NJ,
USA
| | - Maham Tariq
- Department of Medicine, Services Institute of Medical Sciences, Lahore,
Pakistan
| | - Ahsan M. Khan
- Emergency Critical Care Center, Michigan Medicine, Ann Arbor, MI,
USA
| | - Farhan Khalid
- Department of Medicine, Monmouth Medical Center, Long Branch, NJ,
USA
| | - Trishala Meghal
- Department of Hematology-Oncology, Monmouth Medical Center, Long Branch, NJ,
USA
| | - Doantrang Du
- Department of Medicine, Monmouth Medical Center, Long Branch, NJ,
USA
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15
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Trevisani V, Iughetti L, Lucaccioni L, Predieri B. Endocrine immune-related adverse effects of immune-checkpoint inhibitors. Expert Rev Endocrinol Metab 2023; 18:441-451. [PMID: 37682107 DOI: 10.1080/17446651.2023.2256841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 07/31/2023] [Accepted: 09/05/2023] [Indexed: 09/09/2023]
Abstract
INTRODUCTION Immune-checkpoint inhibitor therapy modulates the response of the immune system acting against cancer. Two pathways impacted by this kind of treatment are the CTLA4 and the PD-1/PD-L1 pathways. ICI therapy can trigger autoimmune adverse effects, known as immune-related Adverse Events (irAEs). AREAS COVERED This review focuses on irAEs which affect the endocrine system. This review elucidates the pathways used by these drugs with a focus on the hypothetical pathogenesis at their basis. In fact, the pathophysiology of irAEs concerns the possibility of an interaction between cellular autoimmunity, humoral immunity, cytokines, chemokines, and genetics. The endocrine irAEs examined are thyroid dysfunctions, immune related-hypophysitis, diabetes, peripheral adrenal insufficiency, and hypoparathyroidism. EXPERT OPINION There is still much to investigate in endocrine irAES of checkpoint inhibitors. In the future, checkpoint inhibitors will be increasingly utilized therapies, and therefore it is crucial to find the proper diagnostic-therapeutic program for irAEs, especially as endocrine irAEs are nonreversible and require lifelong replacement therapies.
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Affiliation(s)
- Viola Trevisani
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Lorenzo Iughetti
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Lucaccioni
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Barbara Predieri
- Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
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16
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Profili NI, Castelli R, Gidaro A, Merella A, Manetti R, Palmieri G, Maioli M, Delitala AP. Endocrine Side Effects in Patients Treated with Immune Checkpoint Inhibitors: A Narrative Review. J Clin Med 2023; 12:5161. [PMID: 37568563 PMCID: PMC10419837 DOI: 10.3390/jcm12155161] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/19/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Checkpoint inhibitors are monoclonal antibodies that elicit an anti-tumor response by stimulating immune system. Their use has improved the treatment of different types of cancer such as melanoma, breast carcinoma, lung, stomach, colon, liver, renal cell carcinoma, and Hodgkin's lymphoma, but several adverse events have been reported. Although the etiology of these effects is not completely understood, an uncontrolled activation of the immune system has been postulated. Indeed, some studies showed a cross reactivity of T cells, which acted against tumor antigens as well as antigens in the tissues of patients who developed immune-related adverse events. Despite the known possibility of developing immune-related adverse events, early diagnosis, monitoring during therapy, and treatment are fundamental for the best supportive care and administration of immune checkpoint inhibitors. The aim of this review is to guide the clinician in early diagnosis, management, and treatment of the endocrinological adverse effects in the major endocrine glands (thyroid, pituitary, adrenal, endocrine pancreas, and parathyroid).
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Affiliation(s)
- Nicia I. Profili
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Roberto Castelli
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Antonio Gidaro
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Luigi Sacco Hospital, 20157 Milan, Italy
| | - Alessandro Merella
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Roberto Manetti
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Giuseppe Palmieri
- Department of Biochemical Science, University of Sassari, 07100 Sassari, Italy
| | - Margherita Maioli
- Department of Biochemical Science, University of Sassari, 07100 Sassari, Italy
| | - Alessandro P. Delitala
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
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17
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Zilberman S, Rafii DC, Giunta J. Pembrolizumab-Induced Adrenal Insufficiency Presenting Eight Months After Cessation of Treatment. Cureus 2023; 15:e41049. [PMID: 37519548 PMCID: PMC10374333 DOI: 10.7759/cureus.41049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
Pembrolizumab is a monoclonal antibody that functions as an immune checkpoint inhibitor. It is an FDA-approved immunotherapy used to treat various malignancies. With its wide use in cancer therapy, there are many known side effects. It is a common cause of endocrinopathies such as thyroid disease and adrenal insufficiency (AI). AI has been most commonly reported during active treatment cycles with pembrolizumab, as well as quickly after the termination of treatment. However, we describe a case of pembrolizumab-induced AI with an onset at eight months following the discontinuation of treatment and discuss prompt treatment when AI is diagnosed.
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Affiliation(s)
- Stephanie Zilberman
- Internal Medicine, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, USA
| | - Daniel C Rafii
- Endocrinology, Diabetes, and Metabolism, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, USA
| | - Judith Giunta
- Endocrinology, Diabetes, and Metabolism, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, USA
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18
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Cardona Z, Sosman JA, Chandra S, Huang W. Endocrine side effects of immune checkpoint inhibitors. Front Endocrinol (Lausanne) 2023; 14:1157805. [PMID: 37251665 PMCID: PMC10210589 DOI: 10.3389/fendo.2023.1157805] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/05/2023] [Indexed: 05/31/2023] Open
Abstract
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.
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Affiliation(s)
- Zulma Cardona
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Jeffrey A. Sosman
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Sunandana Chandra
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Wenyu Huang
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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19
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Helderman N, Lucas M, Blank C. Autoantibodies involved in primary and secondary adrenal insufficiency following treatment with immune checkpoint inhibitors. IMMUNO-ONCOLOGY TECHNOLOGY 2023; 17:100374. [PMID: 36937704 PMCID: PMC10014276 DOI: 10.1016/j.iotech.2023.100374] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Primary and secondary adrenal insufficiency (AI) are commonly known immune-related adverse events following treatment with immune checkpoint inhibitors (ICIs), and are clinically relevant due to their morbidity and potential mortality. For this reason, upfront identification of patients susceptible for ICI-induced AI could be a step in improving patient's safety. Multiple studies have focused on the identification of novel biomarkers for ICI-induced AI, including autoantibodies, which may be involved in ICI-induced AI as a result of the T-cell-mediated activation of autoreactive B cells. This review highlights the currently described autoantibodies that may be involved in either primary [e.g. anti-21-hydroxylase, anti-17α-hydroxylase, anti-P450scc, anti-aromatic L-amino acid decarboxylase (AADC), anti-interferon (IFN)α and anti-IFNΩ] or secondary AI [e.g. anti-guanine nucleotide-binding protein G(olf) subunit alpha (GNAL), anti-integral membrane protein 2B (ITM2B), anti-zinc finger CCHC-type containing 8 (ZCCHC8), anti-pro-opiomelanocortin (POMC), anti-TPIT (corticotroph-specific transcription factor), anti-pituitary-specific transcriptional factor-1 (PIT-1) and others], and discusses the current evidence concerning their role as biomarker for ICI-induced AI. Standardized autoantibody measurements in patients (to be) treated with ICIs would be a clinically accessible and patient-friendly screening method to identify the patients at risk, and could change the management of ICI-induced AI.
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Affiliation(s)
- N.C. Helderman
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - M.W. Lucas
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam
| | - C.U. Blank
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam
- Correspondence to: Prof. Dr Christian U. Blank, Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121 A, 1066 CX, Amsterdam, The Netherlands. Tel: +31-(0)20-512-9111
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20
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Fujita Y, Kamitani F, Yamamoto M, Fukuoka H, Hirota Y, Nishiyama N, Goda N, Okada Y, Inaba Y, Nakajima H, Kurematsu Y, Kanie K, Shichi H, Urai S, Suzuki M, Yamamoto N, Bando H, Iguchi G, Suto H, Funakoshi Y, Kiyota N, Takahashi Y, Ogawa W. Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors. J Endocr Soc 2023; 7:bvad002. [PMID: 36694808 PMCID: PMC9856268 DOI: 10.1210/jendso/bvad002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Indexed: 01/09/2023] Open
Abstract
Context The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.
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Affiliation(s)
| | | | - Masaaki Yamamoto
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hidenori Fukuoka
- Correspondence: Hidenori Fukuoka MD, PhD, Division of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017 Japan.
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nobuharu Nishiyama
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
| | - Naho Goda
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
| | - Yuko Okada
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
| | - Yuiko Inaba
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
| | - Hiroki Nakajima
- Department of Diabetes and Endocrinology, Nara Medical University, Nara, Japan
| | - Yukako Kurematsu
- Department of Diabetes and Endocrinology, Nara Medical University, Nara, Japan
| | - Keitaro Kanie
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroki Shichi
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shin Urai
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masaki Suzuki
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Naoki Yamamoto
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hironori Bando
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan,Division of Development of Advanced Therapy for Metabolic Diseases, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Genzo Iguchi
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan,Medical Center for Student Health, Kobe University, Kobe, Japan,Division of Biosignal Pathophysiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hirotaka Suto
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan,Department of Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Yohei Funakoshi
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan,Department of Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Naomi Kiyota
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan,Department of Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Yutaka Takahashi
- Department of Diabetes and Endocrinology, Nara Medical University, Nara, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
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21
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Khatri S, Alom M, Kashfi S, Atallah J, Goswami G. Simultaneous Presentation of Secondary Adrenal Insufficiency and Primary Hypothyroidism due to Pembrolizumab: A Case Report. J Investig Med High Impact Case Rep 2023; 11:23247096231194401. [PMID: 37642143 PMCID: PMC10467221 DOI: 10.1177/23247096231194401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/23/2023] [Accepted: 07/26/2023] [Indexed: 08/31/2023] Open
Abstract
Checkpoint inhibitors have gained increased traction in recent years as they have improved prognosis in various malignancies. Pembrolizumab, an anti-programmed cell death protein (PD-1) monoclonal antibody, has become a first-line chemotherapeutic agent for stage II non-small cell lung cancer since 2019. Although much more common with nivolumab, several immune-related adverse effects, particularly endocrinopathies, have been linked with pembrolizumab. We describe a case of a 59-year-old man with a history of unspecified lung cancer who presented with severe hyponatremia later attributed to secondary adrenal insufficiency and accompanying primary hypothyroidism secondary to pembrolizumab. Diagnosing adrenal insufficiency in patients on immune checkpoint inhibitors like pembrolizumab can be challenging due to nonspecific symptoms, making it crucial to rule out other causes of hyponatremia. Immunotherapy is known to cause thyroid immune-related adverse events, and anti-thyroid antibodies may not always be present in the diagnosis of hypothyroidism. Although there are some reported cases of pembrolizumab-induced adrenal insufficiency, the link between immunotherapy and endocrine disorders remains unclear. To our knowledge, no case reports exist that describe both primary hypothyroidism and secondary adrenal insufficiency after taking pembrolizumab, although such cases have been documented with axitinib. Timely diagnosis and treatment of adrenal insufficiency is crucial to prevent adverse effects, especially in patients with cancer receiving immunotherapy, as highlighted in this case.
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Affiliation(s)
- Shivam Khatri
- City University of New York School of Medicine, New York City, USA
| | | | - Simon Kashfi
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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22
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Husebye ES, Castinetti F, Criseno S, Curigliano G, Decallonne B, Fleseriu M, Higham CE, Lupi I, Paschou SA, Toth M, van der Kooij M, Dekkers OM. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. Eur J Endocrinol 2022; 187:G1-G21. [PMID: 36149449 PMCID: PMC9641795 DOI: 10.1530/eje-22-0689] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022]
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.
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Affiliation(s)
- Eystein S Husebye
- Department of Clinical Science and K.G. Jebsen Center of Autoimmune Diseases, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Correspondence should be addressed to E S Husebye;
| | - Frederik Castinetti
- Aix Marseille Univ, INSERM U1251, Marseille Medical genetics, Department of Endocrinology, Assistance Publique-Hopitaux de Marseille, 13005 Marseille, France
| | - Sherwin Criseno
- Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Giuseppe Curigliano
- Department of Oncology and Hematology, University of Milan, European Institute of Oncology, IRCCS, Milan, Italy
| | | | - Maria Fleseriu
- Pituitary Center, Department of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA
| | - Claire E Higham
- Department of Endocrinology, Christie Hospital NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Isabella Lupi
- Endocrine Unit, Pisa University Hospital, Pisa, Italy
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Miklos Toth
- Department of Internal Medicine and Oncology, ENETS Center of Excellence, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | | | - Olaf M Dekkers
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Kwon H, Roh E, Ahn CH, Kim HK, Ku CR, Jung KY, Lee JH, Kim EH, Suh S, Hong S, Ha J, Moon JS, Kim JH, Kim MK, The Committee of Clinical Practice Guideline of the Korean Endocrine Society. Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society. Endocrinol Metab (Seoul) 2022; 37:839-850. [PMID: 36604955 PMCID: PMC9816514 DOI: 10.3803/enm.2022.1627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/05/2022] [Indexed: 12/28/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.
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Affiliation(s)
- Hyemi Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Roh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
| | - Chang Ho Ahn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hee Kyung Kim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Cheol Ryong Ku
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyong Yeun Jung
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Ju Hee Lee
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
| | - Eun Heui Kim
- Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea
| | - Sunghwan Suh
- Department of Internal Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Sangmo Hong
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Jeonghoon Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jun Sung Moon
- Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Jin Hwa Kim
- Department of Internal Medicine, Chosun University Hospital, Chosun University College of Medicine, Gwangju, Korea
| | - Mi-kyung Kim
- Department of Internal Medicine, Inje University Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Korea
- Corresponding author: Mi-kyung Kim. Department of Internal Medicine, Inje University Haeundae Paik Hospital, College of Medicine, Inje University, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea Tel: +82-51-797-2060, Fax: +82-51-797-2070, E-mail:
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Raschi E, Fusaroli M, Massari F, Mollica V, Repaci A, Ardizzoni A, Poluzzi E, Pagotto U, Di Dalmazi G. The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System. J Clin Endocrinol Metab 2022; 107:e3107-e3114. [PMID: 35704533 PMCID: PMC9282361 DOI: 10.1210/clinem/dgac359] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Indexed: 12/18/2022]
Abstract
CONTEXT Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. OBJECTIVE This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). METHODS A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. RESULTS We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors-ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. CONCLUSION We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers.
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Affiliation(s)
- Emanuel Raschi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum–University of Bologna, Bologna 40138, Italy
| | - Michele Fusaroli
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum–University of Bologna, Bologna 40138, Italy
| | - Francesco Massari
- Medical Oncology Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna 40138, Italy
| | - Veronica Mollica
- Medical Oncology Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna 40138, Italy
| | - Andrea Repaci
- Division of Endocrinology and Diabetes Prevention and Care Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna 40138, Italy
| | - Andrea Ardizzoni
- Medical Oncology Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna 40138, Italy
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum–University of Bologna, Bologna 40138, Italy
| | - Elisabetta Poluzzi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum–University of Bologna, Bologna 40138, Italy
| | - Uberto Pagotto
- Division of Endocrinology and Diabetes Prevention and Care Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna 40138, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum–University of Bologna, Bologna 40138, Italy
| | - Guido Di Dalmazi
- Correspondence: Guido Di Dalmazi, MD, Division of Endocrinology and Diabetes Prevention and Care Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Department of Medical and Surgical Sciences, Alma Mater Studiorum–University of Bologna, via Massarenti, 9, 40138 Bologna, Italy.
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Chye A, Allen I, Barnet M, Burnett DL. Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy. Front Oncol 2022; 12:894015. [PMID: 35912205 PMCID: PMC9329613 DOI: 10.3389/fonc.2022.894015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.
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Affiliation(s)
- Adrian Chye
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
| | - India Allen
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
| | - Megan Barnet
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
| | - Deborah L. Burnett
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
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Atkinson M, Lansdown AJ. Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy. Best Pract Res Clin Endocrinol Metab 2022; 36:101635. [PMID: 35382989 DOI: 10.1016/j.beem.2022.101635] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.
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27
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Dasgupta A, Tsay E, Federman N, Lechner MG, Su MA. Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α. Pediatrics 2022; 149:e2021053363. [PMID: 35274131 PMCID: PMC9804498 DOI: 10.1542/peds.2021-053363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/14/2021] [Indexed: 01/03/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known β cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.
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Affiliation(s)
- Aditi Dasgupta
- Dept. of Pediatrics, UCLA Geffen School of Medicine, Los Angeles, CA
| | - Eric Tsay
- Div. of Pediatric Endocrinology, UCLA Geffen School of Medicine, Los Angeles, CA
| | - Noah Federman
- Div. of Pediatric Hematology and Oncology, UCLA Geffen School of Medicine, Los Angeles, CA
| | - Melissa G. Lechner
- Div. of Endocrinology, Diabetes, and Metabolism, UCLA Geffen School of Medicine, Los Angeles, CA
| | - Maureen A. Su
- Div. of Pediatric Endocrinology, UCLA Geffen School of Medicine, Los Angeles, CA
- Dept. of Microbiology, Immunology, and Molecular Genetics, UCLA Geffen School of Medicine, Los Angeles, CA
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Bischoff J, Fries C, Heer A, Hoffmann F, Meyer C, Landsberg J, Fenske WK. It’s not always SIAD – Immunotherapy-triggered Endocrinopathies enter the Field of Cancer-related Hyponatremia. J Endocr Soc 2022; 6:bvac036. [PMID: 35356006 PMCID: PMC8962447 DOI: 10.1210/jendso/bvac036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Indexed: 11/19/2022] Open
Abstract
Abstract
While the syndrome of inadequate antidiuresis (SIAD) is still the most common cause of hyponatremia in cancer patients, the rise in endocrine immune-related adverse events (irAEs) owing to immune checkpoint inhibitors (ICI) considerably shaped the differential diagnosis of electrolyte disorders in cancer patients. We here report three cases of different endocrine irAEs, first manifesting with new-onset hyponatremia under ICI therapy for malignant melanoma: one with primary adrenal insufficiency, one with hypophysitis and one with autoimmune type 1 diabetes. Early diagnosis of endocrine toxicities can save lives, but may be challenged and essentially delayed by subtle or nonspecific clinical presentation and lacking availability of readily available endocrinological laboratory evaluation in primary care setting.
This exemplary case series demonstrates the broad spectrum of endocrinopathies that physicians should be aware of under ICI therapy and emphasizes new-onset hyponatremia as a possibly early, simple and low-cost biomarker of irAEs, which may be considered as a red flag in patients receiving checkpoint blockade. As ICI-induced endocrinopathies are still under-represented in clinical practice guidelines, we here propose an updated algorithm for diagnosis of cancer-related hyponatremia, highlighting the important diagnostic steps to be considered before making the diagnosis of SIAD.
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Affiliation(s)
- Jenny Bischoff
- University Hospital Bonn, Internal Medicine I, Department of Endocrinology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Charlotte Fries
- University Hospital Bonn, Internal Medicine I, Department of Endocrinology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Alexander Heer
- University Hospital Bonn, Internal Medicine I, Department of Endocrinology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Friederike Hoffmann
- University Hospital Bonn, Department of Dermatology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Carsten Meyer
- University Hospital Bonn, Department for Diagnostic and Interventional Radiology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Jennifer Landsberg
- University Hospital Bonn, Department of Dermatology, Venusberg Campus 1, 53127 Bonn, Germany
| | - Wiebke K Fenske
- University Hospital Bonn, Internal Medicine I, Department of Endocrinology, Venusberg Campus 1, 53127 Bonn, Germany
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29
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Lu D, Gao Y. Immune Checkpoint Inhibitor-related Endocrinopathies. J Transl Int Med 2022; 10:9-14. [PMID: 35702188 PMCID: PMC8997801 DOI: 10.2478/jtim-2022-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Difei Lu
- Department of Endocrinology, Peking University First Hospital, Beijing100034, China
| | - Ying Gao
- Department of Endocrinology, Peking University First Hospital, Beijing100034, China
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Chiloiro S, Bianchi A, Giampietro A, Milardi D, De Marinis L, Pontecorvi A. The changing clinical spectrum of endocrine adverse events in cancer immunotherapy. Trends Endocrinol Metab 2022; 33:87-104. [PMID: 34895977 DOI: 10.1016/j.tem.2021.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several malignancies, improving patient survival and quality of life. Endocrinopathies have emerged as a clinically significant group of immune-related adverse events (IRAEs). Although the mechanism of ICI toxicities has not been clarified, inhibition of immune checkpoints reduces immune tolerance to autoantigens, resulting in the development of autoimmunity disorders. We report current evidence regarding endocrine IRAEs that may have diagnostic and therapeutic implications. Management should be focused on a multidisciplinary approach to reach a prompt diagnosis and an appropriate and safe treatment.
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Affiliation(s)
- Sabrina Chiloiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy.
| | - Antonio Bianchi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Antonella Giampietro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Domenico Milardi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Laura De Marinis
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Alfredo Pontecorvi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
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31
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Stress Axis in the Cancer Patient: Clinical Aspects and Management. ENDOCRINES 2021. [DOI: 10.3390/endocrines2040044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hypothalamus–pituitary–adrenal (HPA) axis alterations are common in cancer patients, mainly due to the different antitumoral therapies, which lead to several acute and late endocrine side effects. This review summarizes the most recent evidence regarding HPA derangement, both in patients with active neoplasms and in cancer survivors, with particular attention to the impact of the different antitumoral treatments, focusing on the major clinical aspects. While acute hormone failure usually results from injury caused directly by tumor burden or surgical interventions, short- and long-term effects are generally due to chemotherapy, radiotherapy and, as more recently shown, to different types of targeted- and immuno-therapy. Adrenal insufficiency (AI) is mostly caused by pituitary or hypothalamic injury rather than a direct damage of the adrenal gland. Moreover, other treatments commonly employed as supportive therapy or in the context of palliative care (i.e., glucocorticoids, opioids) can lead to HPA dysfunction. Epidemiology and pathophysiology of stress axis alterations in cancer patients still require clarification. Since AI may represent a life-threatening condition, monitoring adrenal function in cancer patients is mandatory, especially in subjects who experience fatigue or during stress conditions, in order to promptly start replacement treatment when needed.
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Lopez AG, Duparc C, Wils J, Naccache A, Castanet M, Lefebvre H, Louiset E. Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions. Mol Cell Endocrinol 2021; 535:111377. [PMID: 34216641 DOI: 10.1016/j.mce.2021.111377] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022]
Abstract
The human adrenal cortex is a complex organ which is composed of various cell types including not only steroidogenic cells but also mesenchymal cells, immunocompetent cells and neurons. Intermingling of these diverse cell populations favors cell-to-cell communication processes involving local release of numerous bioactive signals such as biogenic amines, cytokines and neuropeptides. The resulting paracrine interactions play an important role in the regulation of adrenocortical cell functions both in physiological and pathophysiological conditions. Especially, recent evidence indicates that adrenocortical cell microenvironment is involved in the pathogenesis of adrenal disorders associated with corticosteroid excess. The paracrine factors involved in these intraadrenal regulatory mechanisms may thus represent valuable targets for future pharmacological treatments of adrenal diseases.
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Affiliation(s)
- Antoine-Guy Lopez
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France; Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen, France
| | - Céline Duparc
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France
| | - Julien Wils
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France; Rouen University Hospital, Department of Pharmacology, Rouen, France
| | - Alexandre Naccache
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France; Rouen University Hospital, Department of Pediatrics, Rouen, France
| | - Mireille Castanet
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France; Rouen University Hospital, Department of Pediatrics, Rouen, France
| | - Hervé Lefebvre
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France; Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen, France.
| | - Estelle Louiset
- Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen, France
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Figueroa-Perez N, Kashyap R, Bal D, Anjum Khan S, Pattan V. Autoimmune Myasthenia, Primary Adrenal Insufficiency, and Progressive Hypothyroidism Due to Pembrolizumab and Axitinib Combination Regimen. Cureus 2021; 13:e16933. [PMID: 34513503 PMCID: PMC8412885 DOI: 10.7759/cureus.16933] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2021] [Indexed: 11/29/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have been among the increasingly used antineoplastic agents for advanced cancers including renal cell carcinoma (RCC). Although these antineoplastic agents have broad range of efficacy, rare adverse events - mild and fatal, acute and chronic, immune and non-immune mediated - have been reported. We report a case of a 73-year-old Caucasian male patient with stage IV right-sided clear cell RCC who was treated with a pembrolizumab-axitinib combination regimen and suffered life-threatening, acute onset immune-related myasthenia gravis (MG), subsequently progressive hypothyroidism, and primary adrenal insufficiency.
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Affiliation(s)
| | - Rahul Kashyap
- Internal Medicine/Critical Care, Centennial Medical Center, Hospital Corporation of America (HCA) Healthcare, Nashville, USA
| | - Deepinder Bal
- Internal Medicine, Centennial Medical Center, Hospital Corporation of America (HCA) Healthcare, Nashville, USA
| | - Syed Anjum Khan
- Critical Care Medicine, Mayo Clinic Health System, Mankato, USA
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Mai K, Fassnacht M, Führer-Sakel D, B. Honegger J, M. Weber M, Kroiss M. The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors. DEUTSCHES ARZTEBLATT INTERNATIONAL 2021; 118:arztebl.m2021.0143. [PMID: 33724917 PMCID: PMC8378258 DOI: 10.3238/arztebl.m2021.0143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/01/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The immunologically mediated side effects of immune checkpoint inhibitors (CPI) often involve the endocrine system as well, and they can even be fatal, as in the case of unrecognized hypophysitis. Distinguishing such side effects from tumor-related changes is often difficult, because their clinical features can be nonspecific. METHODS This review is based on publications retrieved by a selective search in PubMed, with special attention to international recommendations. RESULTS Depending on their target molecules, the CPI now in use differ from one another in the incidence of side effects such as autoimmune thyroid disease (4-16%), hypophysitis (0.1- 18%), adrenalitis (0.7-8%), and autoimmune diabetes mellitus (0.5-2%). The typical clinical warning signs and laboratory constellations of hypophysitis include exhaustion, hyponatremia, and headache. Hypo- and hyperthyroidism and primary adrenocortical insufficiency likewise have nonspecific manifestations. Autoimmune diabetes mellitus often takes a fulminant course. Patients being treated with CPI should be monitored at close intervals, at least as frequently as the administration of the drug, so that endocrine side effects can be recognized in time. In case of doubt, glucocorticoid supplementation should be given whenever hypocortisolism is suspected, even before endocrine evaluation is completed and the results are available. Interrupting or discontinuing CPI treatment is rarely indicated. CONCLUSION With the increasing number of patients being treated with CPI, more and more physicians from a wide variety of specialties, not necessarily working in specialized centers, now have to consider immunologically mediated endocrine side effects in the differential diagnosis, and treat them properly when they arise. These things should be done in collaboration with endocrinologists. The ongoing study of such side effects of the CPI now in use, and of those that will be introduced in the future, is important and will lead to improved understanding.
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Affiliation(s)
- Knut Mai
- Department of Endocrinology, Diabetes and Nutrition, Charité–Universitätsmedizin Berlin: Prof. Dr. med. Knut Mai
| | - Martin Fassnacht
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University of Würzburg, University Hospital Würzburg, Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
| | - Dagmar Führer-Sakel
- Department of Endocrinology, Diabetology and Metabolism, Essen University Hospital, University of Duisburg-Essen: Prof. Dr. med. Dr. rer. nat. Dagmar Führer-Sakel
| | - Jürgen B. Honegger
- Department of Neurosurgery, Tübingen University Hospital: Prof. Dr. med. Jürgen B. Honegger
| | - Matthias M. Weber
- Department of Internal Medicine I, Endocrinology, Johannes Gutenberg University Hospital Mainz: Prof. Dr. med. Matthias M. Weber
| | - Matthias Kroiss
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University of Würzburg, University Hospital Würzburg, Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
- Department of Internal Medicine IV, Ludwig-Maximilians-University Munich: Prof. Dr. med.Dr. rer. nat. Matthias Kroiss
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Zhao Z, Wang X, Bao XQ, Ning J, Shang M, Zhang D. Autoimmune polyendocrine syndrome induced by immune checkpoint inhibitors: a systematic review. Cancer Immunol Immunother 2021; 70:1527-1540. [PMID: 33200250 DOI: 10.1007/s00262-020-02699-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To summarize the clinical characteristics and immunological and genetic features of patients who developed autoimmune polyendocrine syndrome type II (APS-2) after treatment with immune checkpoint inhibitors (ICIs). DESIGN AND METHODS Several databases (MEDLINE/EMBASE/Cochrane) were searched for studies published between January 2000 and February 2020 involving patients with two or more endocrine disorders after ICI therapy. RESULTS Our final review included 22 articles comprising 23 patients (median age 56 years; 65.2% male patients). Of these patients, 60.9% received anti-programmed cell death 1 (PD-1) therapy, 17.4% received anti-programmed cell death ligand 1 (PD-L1) therapy, and 4.3% received anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monotherapy. Patients underwent a median of four treatment cycles before the onset of the primary adverse event; the median time of onset was 8.5 weeks. Endocrine organs affected by ICI administration included the thyroid gland (18/23, 78.3%), pancreatic islets (17/23, 73.9%), pituitary gland (11/23, 47.8%), and adrenal gland (2/23, 8.7%). Related autoantibodies were detected in 65.2% of patients. In patients with diabetes, glutamic acid decarboxylase antibody was closely related to the development of diabetes ketoacidosis. The human leukocyte antigen genotype was reported in 34.8% (8/23) of patients, 5 (62.5%) of which had risk genotypes. CONCLUSIONS As a serious adverse event of ICI treatment, APS-2 is presented with abrupt initiation time and rapid development. Physicians should be aware of potential endocrine disorders and continue monitoring hormone status when treating cancer patients with ICIs.
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Affiliation(s)
- Zhe Zhao
- State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China
| | - Xinfeng Wang
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiu-Qi Bao
- State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China
| | - Jingwen Ning
- State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China
| | - Meiyu Shang
- State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China
| | - Dan Zhang
- State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
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George AS, Fernandez CJ, Eapen D, Pappachan JM. Organ-specific Adverse Events of Immune Checkpoint Inhibitor Therapy, with Special Reference to Endocrinopathies. TOUCHREVIEWS IN ENDOCRINOLOGY 2021; 17:21-32. [PMID: 35118443 PMCID: PMC8320015 DOI: 10.17925/ee.2021.17.1.21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/09/2021] [Indexed: 02/05/2023]
Abstract
Immune checkpoint inhibitors are potent and promising immunotherapeutic agents that are increasingly used for the management of various types of advanced cancers. The widespread approval of this group of drugs simultaneously revealed immune-related adverse events as unique side-effects. Endocrinopathies are one of the most common immune-related adverse events. The precise pathogenic mechanisms for these endocrinopathies are still unclear. Though few of the endocrinopathies are reversible, calling for only symptom control, most are irreversible, requiring multiple long-term hormone replacement therapies. However, in contrast to other organ-specific immune-related adverse events, patients with endocrinopathies can continue their immune checkpoint therapy, provided the hormone replacement therapy is adequate and the symptoms are controlled. Though patients who have developed immune-related adverse events demonstrate superior antitumor activity and overall survival, due to the high morbidity associated with the immune-related adverse events, researchers are trying to uncouple the antitumour activity associated with immune checkpoint inhibitor therapy from the immune-related adverse events, to preserve antitumour activity without adverse events.
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Affiliation(s)
- Annu Susan George
- Department of Medical Oncology, Lakeshore Hospital, Cochin, Kerala, India
| | - Cornelius J Fernandez
- Department of Endocrinology, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston, UK
| | - Dilip Eapen
- Department of Endocrinology, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston, UK
| | - Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK
- Manchester Metropolitan University, Manchester, UK
- The University of Manchester, Manchester, UK
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Hattersley R, Nana M, Lansdown AJ. Endocrine complications of immunotherapies: a review. Clin Med (Lond) 2021; 21:e212-e222. [PMID: 33762389 DOI: 10.7861/clinmed.2020-0827] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Use of immune checkpoint inhibitors in cancer treatment has increased vastly over the past decade, as both single and combination agent therapies. While having a positive impact on survival rates, adverse effects have been noted, with endocrine effects in around 10% of patients. Thyroid disease and hypophysitis are the most commonly encountered, with diabetes mellitus and primary adrenal insufficiency also reported, as well as more rare endocrinopathies. Patient and clinician education to raise awareness of these effects, as well as regular monitoring to enable early recognition, diagnosis and prompt treatment of the immune side effects, are key. In this review, we discuss the aetiology, presentation and management of the endocrine complications of immunotherapies that are relevant to the general physician, as well as highlighting important areas where further research is still needed.
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Newman C, Kgosidalwa O, Hakami OA, Kennedy C, Grogan L, Agha A. Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature. BMC Endocr Disord 2021; 21:33. [PMID: 33639911 PMCID: PMC7912868 DOI: 10.1186/s12902-021-00693-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 02/09/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy. CASE PRESENTATION A 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38-5.33) mIU/L, free T4 of 66.9 (7-16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2-2.5) mmol/l and parathyroid hormone (PTH) of 9 (10-65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis - both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient's thyrotoxicosis had resolved without anti-thyroid mediations - consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone. CONCLUSION This is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.
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Affiliation(s)
- Christine Newman
- Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin 9, Republic of Ireland.
| | - Oratile Kgosidalwa
- Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin 9, Republic of Ireland
| | - Osamah A Hakami
- Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin 9, Republic of Ireland
| | - Carmel Kennedy
- Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin 9, Republic of Ireland
| | - Liam Grogan
- Department of Medical Oncology, Beaumont Hospital, Dublin 9, Republic of Ireland
| | - Amar Agha
- Department of Diabetes and Endocrinology, Beaumont Hospital, Dublin 9, Republic of Ireland
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Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet 2021; 397:613-629. [PMID: 33484633 DOI: 10.1016/s0140-6736(21)00136-7] [Citation(s) in RCA: 180] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/12/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.
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Affiliation(s)
- Eystein S Husebye
- Department of Clinical Science and KG Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Simon H Pearce
- Department of Endocrinology, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Nils P Krone
- Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK; Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Olle Kämpe
- Department of Clinical Science and KG Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway; Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Molecular Medicine, and Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
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Shi Y, Shen M, Zheng X, Yang T. Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management. Endocr Pract 2021; 27:165-169. [PMID: 33554872 DOI: 10.1016/j.eprac.2020.09.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/21/2020] [Accepted: 09/27/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)-rare but lethal endocrine immune-related adverse events-in patients who underwent ICI therapy. METHODS We searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs. RESULTS We identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs. CONCLUSION Given the morbidity and mortality associated with acute adrenal crisis, physicians-especially endocrinologists and oncologists-should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.
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Affiliation(s)
- Yun Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Shen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xuqin Zheng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Paschou SA, Stefanaki K, Psaltopoulou T, Liontos M, Koutsoukos K, Zagouri F, Lambrinoudaki I, Dimopoulos MA. How we treat endocrine complications of immune checkpoint inhibitors. ESMO Open 2021; 6:100011. [PMID: 33399077 PMCID: PMC7807832 DOI: 10.1016/j.esmoop.2020.100011] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
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Affiliation(s)
- S A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Stefanaki
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - T Psaltopoulou
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M Liontos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Koutsoukos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - F Zagouri
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - I Lambrinoudaki
- Second Department of Obstetrics and Gynecology, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M-A Dimopoulos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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George AS, Department of Medical Oncology, Lakeshore Hospital, Cochin, Kerala, India, Fernandez CJ, Department of Endocrinology, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston, UK, Eapen D, Department of Endocrinology, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston, UK, Pappachan JM, Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK, Manchester Metropolitan University, Manchester, UK, The University of Manchester, Manchester, UK. Organ-specific Adverse Events of Immune Checkpoint Inhibitor Therapy, with Special Reference to Endocrinopathies. EUROPEAN ENDOCRINOLOGY 2021; 1:21. [DOI: 10.17925/ee.2021.1.1.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Shi Y, Shen M, Zheng X, Chen Y, Zhao R, Gu Y, Yang T. ICPis-Induced Autoimmune Polyendocrine Syndrome Type 2: A Review of the Literature and a Protocol for Optimal Management. J Clin Endocrinol Metab 2020; 105:5903403. [PMID: 32905579 DOI: 10.1210/clinem/dgaa553] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 09/01/2020] [Indexed: 01/15/2023]
Abstract
CONTEXT Immune checkpoint inhibitors (ICPis) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) are now approved to treat a variety of cancers. However, ICPis therapy is associated with a risk of immune-related adverse events (irAEs). Autoimmune polyendocrine syndrome type 2 (APS-2) is a rare endocrine irAE. EVIDENCE ACQUISITION Several databases (PubMed, Web of Science, Cochrane Central Registry of Controlled Trials, ClinicalTrials.gov, and Scopus) were searched up to February 18, 2020, for case reports on endocrine irAEs and ICPis. The reported side effects and adverse events of the ICPis therapy in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) adverse events pharmacovigilance registries are also included. EVIDENCE SYNTHESIS Here, we provide an overview of all published and reported cases (n = 30) of ICPis-induced APS-2. We summarize the clinical characteristics, autoantibodies, human leukocyte antigen (HLA) genotypes, and therapies and propose an APS-2 screening strategy. CONCLUSIONS Given the life-threatening risks of endocrine dysfunction if it is not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis), physicians (especially endocrinologists and oncologists) should be familiar with APS-2. After diagnosis of an autoimmune disease induced by ICPis (especially PD-1 inhibitors), patients with a high-risk HLA allele (HLA-DR4) require close monitoring for the development of APS-2.
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Affiliation(s)
- Yun Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Shen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xuqin Zheng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - RuiLing Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Gu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Abstract
Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.
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Affiliation(s)
- Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya 466-8550, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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Deligiorgi MV, Trafalis DT. Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event. Int Immunopharmacol 2020; 89:107050. [PMID: 33069924 DOI: 10.1016/j.intimp.2020.107050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/01/2020] [Accepted: 09/24/2020] [Indexed: 11/28/2022]
Abstract
The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 μg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology, Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, 75 Mikras Asias, Str., 115 27 Athens, Greece.
| | - Dimitrios T Trafalis
- Department of Pharmacology, Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, 75 Mikras Asias, Str., 115 27 Athens, Greece.
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Muir CA, Menzies AM, Clifton-Bligh R, Tsang VHM. Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer. Thyroid 2020; 30:1458-1469. [PMID: 32264785 DOI: 10.1089/thy.2020.0032] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.
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Affiliation(s)
- Christopher A Muir
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
| | - Alexander M Menzies
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Melanoma Medical Oncology, Melanoma Institute Australia, Wollstonecraft, Australia
- Department of Medical Oncology and Royal North Shore Hospital, St. Leonards, Australia
| | - Roderick Clifton-Bligh
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
- Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Australia
| | - Venessa H M Tsang
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
- Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Australia
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Stelmachowska-Banaś M, Czajka-Oraniec I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr Connect 2020; 9:R207-R228. [PMID: 33064663 PMCID: PMC7576644 DOI: 10.1530/ec-20-0342] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/16/2020] [Indexed: 12/18/2022]
Abstract
Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Affiliation(s)
- Maria Stelmachowska-Banaś
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
- Correspondence should be addressed to M Stelmachowska-Banaś:
| | - Izabella Czajka-Oraniec
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
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Quandt Z, Young A, Perdigoto AL, Herold KC, Anderson MS. Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors. Annu Rev Med 2020; 72:313-330. [PMID: 32886542 DOI: 10.1146/annurev-med-050219-034237] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.
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Affiliation(s)
- Zoe Quandt
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California 94143, USA; , , .,Diabetes Center, University of California, San Francisco, California 94143, USA
| | - Arabella Young
- Diabetes Center, University of California, San Francisco, California 94143, USA.,QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - Ana Luisa Perdigoto
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
| | - Kevan C Herold
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; .,Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
| | - Mark S Anderson
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California 94143, USA; , , .,Diabetes Center, University of California, San Francisco, California 94143, USA
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Grouthier V, Lebrun‐Vignes B, Moey M, Johnson DB, Moslehi JJ, Salem J, Bachelot A. Immune Checkpoint Inhibitor-Associated Primary Adrenal Insufficiency: WHO VigiBase Report Analysis. Oncologist 2020; 25:696-701. [PMID: 32390168 PMCID: PMC7418341 DOI: 10.1634/theoncologist.2019-0555] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 04/03/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE. MATERIALS AND METHODS Suspected PAI-irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports. RESULTS From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were "definite PAI" and 406 "possible PAI." Patients were mainly male (58.1%) with a median age of 66 years (range, 30-95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6-576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between "definite" versus "possible" PAI group. CONCLUSION Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.
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Affiliation(s)
- Virginie Grouthier
- Department of Endocrinology, Diabetes and Nutrition, University of Bordeaux, USN Haut LevequeBordeauxFrance
| | - Bénédicte Lebrun‐Vignes
- Pharmacovigilance Unit, Department of Pharmacology, Unité de Cardio‐Oncologie Sorbonne Université–Groupe de Recherche Clinique en Cardio‐Oncologie (UNICO‐GRECO), INSERM Centre d'Investigation Clinique (CIC)‐1901, Pitié‐Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris (AP‐HP)ParisFrance
- Equipe d'Accueil 7379 EpiDermE, Université Paris‐Est Créteil (UPEC)ParisFrance
| | - Melissa Moey
- Cardio‐Oncology Program, Departments of Medicine and Pharmacology, Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Douglas B. Johnson
- Cardio‐Oncology Program, Departments of Medicine and Pharmacology, Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Javid J. Moslehi
- Cardio‐Oncology Program, Departments of Medicine and Pharmacology, Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Joe‐Elie Salem
- Pharmacovigilance Unit, Department of Pharmacology, Unité de Cardio‐Oncologie Sorbonne Université–Groupe de Recherche Clinique en Cardio‐Oncologie (UNICO‐GRECO), INSERM Centre d'Investigation Clinique (CIC)‐1901, Pitié‐Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris (AP‐HP)ParisFrance
- Cardio‐Oncology Program, Departments of Medicine and Pharmacology, Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Anne Bachelot
- Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance and Centre de Référence des Pathologies Gynécologiques Rares, Institute of Cardiometabolism and Nutrition (ICAN), Pitié‐Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris (AP‐HP)ParisFrance
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50
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Yudin DI, Laktionov KK, Sarantseva KA, Borisova OI, Breder VV, Reutova EV, Beloyartseva MF, Kruteleva SY, Dzhanyan IA. Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors. ACTA ACUST UNITED AC 2020. [DOI: 10.21518/2079-701x-2020-9-16-24] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.
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Affiliation(s)
- D. I. Yudin
- N.N. Blokhin National Medical Research Center of Oncology
| | - K. K. Laktionov
- N.N. Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University
| | | | - O. I. Borisova
- N.N. Blokhin National Medical Research Center of Oncology
| | - V. V. Breder
- N.N. Blokhin National Medical Research Center of Oncology
| | - E. V. Reutova
- N.N. Blokhin National Medical Research Center of Oncology
| | | | | | - I. A. Dzhanyan
- N.N. Blokhin National Medical Research Center of Oncology
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