|
1
|
Mori JI, Miyakoshi T, Yuzuriha H, Kondo T, Nishimori E, Naka M, Sato A, Komatsu M, Yamashita K, Aizawa T. Snap diagnosis of fulminant type 1 diabetes by the normalized glucose/HbA1c ratio. Endocr J 2024; 71:1093-1096. [PMID: 39135233 PMCID: PMC11778347 DOI: 10.1507/endocrj.ej24-0226] [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: 04/16/2024] [Accepted: 07/09/2024] [Indexed: 11/06/2024] Open
Abstract
Elevated Fulminant Index (FI), [plasma glucose (PG)/glycosylated hemoglobin A1c (HbA1c)], was reportedly a sensitive index to differentiate fulminant type 1 diabetes (FT1D) from non-fulminant T1D (nFT1D). Aim of this study was to describe a better, but simpler index of FT1D. 49 and 52 patients with FT1D and nFT1D, respectively, were registered, and the discriminating ability of the rounded, normalized ratio, [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0], and the original ratio, [PG (mmol/L)]/[HbA1c (%)], was compared. Normalizing the ratio significantly raised its accuracy: area under the curve for receiver operating curve, AUROC (95%CI), 0.927 (0.858-0.964) and 0.851 (0.763-0.910), respectively, with and without the normalization (p < 0.01). Rounding of the figure into [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0] did not significantly sacrifice the discriminating ability of the index. Namely, the optimal cut point of rounded and normalized GAR, 10.0, showed 89.8% sensitivity. In conclusion, rounded, normalized (rn) GAR ≥10 (the rounded optimal cut-off) could be used for the snap diagnosis of FT1D.
Collapse
Affiliation(s)
- Jun-Ichiro Mori
- Department of Medical Education, Shinshu University, Matsumoto 390-8621, Japan
| | | | - Hanae Yuzuriha
- Resident of Internal Medicine, Aizawa Hospital, Matsumoto 390-8510, Japan
| | - Teruki Kondo
- Diabetes, Endocrinology and Metabolism, Nagano Chuo Hospital, Nagano 380-0814, Japan
| | - Eita Nishimori
- Department of Diabetes Medicine, Asama Central Hospital, Nagano 385-8558, Japan
| | - Motoji Naka
- Department of Diabetes Medicine, Asama Central Hospital, Nagano 385-8558, Japan
| | - Ai Sato
- Diabetes Center, Okaya City Hospital, Okaya 394-0028, Japan
| | - Mitsuhisa Komatsu
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Koh Yamashita
- Diabetes Center, Aizawa Hospital, Matsumoto 390-8510, Japan
| | - Toru Aizawa
- Diabetes Center, Aizawa Hospital, Matsumoto 390-8510, Japan
| |
Collapse
|
|
2
|
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: 3] [Impact Index Per Article: 3.0] [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.
Collapse
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
| |
Collapse
|
|
3
|
Al-Taie A, Sheta N. Clinically Approved Monoclonal Antibodies-based Immunotherapy: Association With Glycemic Control and Impact Role of Clinical Pharmacist for Cancer Patient Care. Clin Ther 2024; 46:e29-e44. [PMID: 37932154 DOI: 10.1016/j.clinthera.2023.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/17/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Compared with more conventional, nonspecific therapy options, such as radiotherapy and chemotherapy, monoclonal antibodies (mAbs) constitute a crucial approach of cancer treatment. Multiple autoimmune diseases have been observed during treatment with mAb medications, including autoimmune diabetes mellitus (DM). This study provides a narrative review of clinically approved mAbs in cancer treatment and focuses on the development of hyperglycemia and DM arising from using these therapies. Furthermore, it highlights the critical role of oncology clinical pharmacists in the management of autoimmune DM and patient care while using these medications in an oncology setting. METHODS An extensive literature search was conducted using various sources of electronic databases, such as Scopus, Embase, Web of Science, and PubMed, and search engines, such as Google Scholar, for studies on mAb classification, types, mechanisms of action, pharmacokinetic properties, current clinical applications, and the associated common adverse effects with significant recommendations for patient care in an oncology setting, along with focusing on the proposed mechanisms and clinical studies that reported the association of DM after the use of these therapies. FINDINGS There are 4 types (murine, chimeric, humanized, and human) and 3 classes (unconjugated, conjugated, and bispecific) of mAbs with several mechanisms of action that can destroy cancer cells, including preventing tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, evading programmed cell death, and bypassing immune checkpoints. However, multiple endocrinopathies, autoimmune diseases, and complications were reported from the use of these medications, including the development of autoimmune DM and diabetic ketoacidosis. These autoimmune disorders were reported most with the use of immune checkpoint inhibitors, including inhibitors of the programmed cell death protein 1 (nivolumab and pembrolizumab), its ligand (atezolizumab, avelumab, and durvalumab), and cytotoxic T-lymphocyte-associated protein 4 (ipilimumab). IMPLICATIONS mAbs are considered important approaches for the treatment of many cancer types. However, a high incidence of hyperglycemia, type 1 DM, and diabetic ketoacidosis is observed with the use of these medications, particularly immune checkpoint inhibitors. It is important for oncologic clinical pharmacists to be involved in addressing these autoimmune disorders from the use of these immunotherapies via the provision of patient education, medication adherence support, close monitoring, and follow-up, which will lead to better health-related outcomes and improved patient quality of life.
Collapse
Affiliation(s)
- Anmar Al-Taie
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye.
| | - Najat Sheta
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Imagawa A, Hanafusa T. Fulminant Type 1 Diabetes-East and West. J Clin Endocrinol Metab 2023; 108:e1473-e1478. [PMID: 37309685 DOI: 10.1210/clinem/dgad329] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/29/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
Fulminant type 1 diabetes is a subtype of type 1 diabetes in which beta cells are destroyed within days or a few weeks. The first criterion indicates a rise in blood glucose levels shown in the patient's history. The second suggests that the increase occurs suddenly within a very short period, as shown by the laboratory findings of the discrepancy between the glycated hemoglobin concentration and plasma glucose level. The third indicates a marked reduction in endogenous insulin secretion, which indicates almost complete destruction of beta cells. Fulminant type 1 diabetes is a common subtype in East Asian countries, including Japan, but rare in Western countries. Class II human leukocyte antigen and other genetic factors may have contributed to the skewed distribution. Environmental factors may also be involved including entero and herpes viruses and immune regulation during drug-induced hypersensitivity syndrome; pregnancy may also affect it. In contrast, treatment with an immune checkpoint inhibitor of the anti-programmed cell death 1 antibody induces similar characteristics and incidence of diabetes as fulminant type 1 diabetes. Further studies are needed to clarify the etiology and clinical characteristics of fulminant type 1 diabetes. Although the incidence of this disease differs between the East and West, it is life-threatening; thus, it is important to diagnose fulminant type 1 diabetes without delay and treat it appropriately.
Collapse
Affiliation(s)
- Akihisa Imagawa
- Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | | |
Collapse
|
|
6
|
Aviv-Shimoni S, Uri I, Milloh-Raz H, Percik R. Isolated autoimmune adrenocorticotropic hormone deficiency: A positive predictor of survival among cancer patients treated with checkpoint inhibitors. Autoimmun Rev 2023; 22:103387. [PMID: 37352903 DOI: 10.1016/j.autrev.2023.103387] [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: 05/31/2023] [Accepted: 06/18/2023] [Indexed: 06/25/2023]
Abstract
OBJECTIVE We aimed to characterize cancer patients who developed isolated adrenocorticotrophic hormone (ACTH) deficiency (IAD) after treatment with checkpoint-inhibitors (CPIs), including clinical manifestations, laboratory findings and risk factors, and to evaluate the prognostic significance of this complication. DESIGN A retrospective case-control study. METHODS We conducted a retrospective analysis of 2225 cancer patients treated with CPIs between 2015 and 2021 in our institute. We identified a subgroup of patients with sub-normal cortisol levels due to ACTH deficiency, and comprehensively extracted all relevant data. We compared the patients survival rates using a log-rank test and a multi-variable Cox regression. RESULTS Among 2225 patients, hypocortisolemia was documented in 99 (4.45%) patients, and 19 of them were diagnosed with IAD (0.85%). Asthenia and diarrhea were the most reported complaints (36.8%), and melanoma was the most common malignancy (68.42%) within the IAD group. In multivariable analysis, IAD was associated with better survival rates (p = .018), female gender (63.2% vs 40%, p = .041), treatment with Ipilimumab (57.9% vs. 19.4%, p < .001), and younger age (median 56 IQR 51-69, vs. median 69 IQR 60-76, p = .004). CONCLUSIONS IAD is the dominant autoimmune etiology for cortisol deficiency among patients receiving immunotherapy and is reported for the first time as a positive predictor of survival among cancer patients treated with CPIs. In our patients, IAD development was associated with female gender, treatment with ipilimumab, and younger age.
Collapse
Affiliation(s)
- Shir Aviv-Shimoni
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; School of Public Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Inbal Uri
- Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
| | - Hadar Milloh-Raz
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Ruth Percik
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
7
|
Stephen B, Hajjar J, Sarda S, Duose DY, Conroy JM, Morrison C, Alshawa A, Xu M, Zarifa A, Patel SP, Yuan Y, Kwiatkowski E, Wang L, Rodon Ahnert J, Fu S, Meric-Bernstam F, Lowman GM, Looney T, Naing A. T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy. J Immunother Cancer 2023; 11:e007236. [PMID: 37604642 PMCID: PMC10445351 DOI: 10.1136/jitc-2023-007236] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.
Collapse
Affiliation(s)
- Bettzy Stephen
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Joud Hajjar
- Adult Allergy and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | | | - Dzifa Yawa Duose
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Carl Morrison
- Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Anas Alshawa
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mingxuan Xu
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Abdulrazzak Zarifa
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sapna P Patel
- Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ying Yuan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Evan Kwiatkowski
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Linghua Wang
- Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jordi Rodon Ahnert
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Siqing Fu
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Funda Meric-Bernstam
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Timothy Looney
- Thermo Fisher Scientific, Clinical Next-Generation Sequencing, Austin, Texas, USA
| | - Aung Naing
- Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| |
Collapse
|
|
8
|
Shen M, Chen D, Zhao R, Zheng X, Gu Y, Yang T, Shi Y. Real-world adherence to toxicity management guidelines for immune checkpoint inhibitor-induced diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1213225. [PMID: 37554766 PMCID: PMC10405819 DOI: 10.3389/fendo.2023.1213225] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/04/2023] [Indexed: 08/10/2023] Open
Abstract
Objective Immune checkpoint inhibitors(ICIs) have improved survival and are increasingly used for cancer. However, ICIs use may be limited by immune-related adverse events (irAEs), such as ICI-induced diabetes mellitus(ICI-DM). The objective of the present study was to characterize ICI-DM patients and real-world adherence to guidelines. Research design and methods The present study was a retrospective review of electronic records of ICI-DM patients at the First Affiliated Hospital of Nanjing Medical University between July 2018 and October 2022. Results 34.8% (8/23)patients monitored blood glucose in every treatment cycle. The proportion of patients with severe diabetic ketoacidosis(DKA) was lower in the tight glycemic monitoring group than the non-tight glycemic monitoring group (16.7% vs. 55.6%, p = 0.049). 78.3%(18/23) patients with hyperglycemia visited a non-endocrinologist first, but 95.7% of patients were then referred to an endocrinologist. Twenty patients were tested for distinguishing the etiology of hyperglycemia and 20% patients with positive glutamic acid decarboxylase antibody(GADA), 55% with C-peptide <3.33pmol/L. High screening rates for other ICI-induced endocrinopathies were observed and half of the patients with ICI-DM developed other endocrine gland irAEs, with the most common being thyroiditis. Moreover, five patients developed non-endocrine serious adverse events(SAEs). Twelve (52.2%) patients were withdrawn from ICI due to ICI-DM. The time to progression of tumor in ICI-DM patients in the continue and interruption group was longer than in the withdrawal group (333.5 ± 82.5 days vs. 183.1 ± 62.4 days, p = 0.161). Only 17.4% of ICI-DM patients were completely managed according to guidelines. Thus, the present study proposed a screening, diagnosis, and management algorithm for ICI-DM in real-world practice. Conclusion The present study reported the largest number of ICI-DM cases described in a single institute, providing insight into real-world ICI-DM management guideline adherence and highlighting the clinical challenges in ICI-DM management.
Collapse
Affiliation(s)
| | | | | | | | | | - Tao Yang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yun Shi
- *Correspondence: Yun Shi, ; Tao Yang,
| |
Collapse
|
|
9
|
Liu YC, Liu H, Zhao SL, Chen K, Jin P. Clinical and HLA genotype analysis of immune checkpoint inhibitor-associated diabetes mellitus: a single-center case series from China. Front Immunol 2023; 14:1164120. [PMID: 37359544 PMCID: PMC10288983 DOI: 10.3389/fimmu.2023.1164120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
Objective To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China. Methods We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing. Results The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m2, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 vs 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (P<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB1*0901-DQA1*03-DQB1*0303 (DR9) and DRB1*0405-DQA1*03-DQB1*0401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA1*0501-DQB1*0201 (DR3) and DR9 haplotypes were less frequent (17.7% vs 2.3%; P=0.011 and 34.4% vs 15.9%; P=0.025), whereas the protective haplotypes (DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301) were more frequent in ICI-DM patients (2.1% vs 13.6%; P=0.006 and 4.2% vs 15.9%; P=0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (P<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB1*0405-DQB1*0401 or DRB1*0901-DQB1*0303). Conclusion ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.
Collapse
|
|
10
|
Erdem N, Chen KT, Qi M, Zhao Y, Wu X, Garcia I, Ku HT, Montero E, Al-Abdullah IH, Kandeel F, Roep BO, Isenberg JS. Thrombospondin-1, CD47, and SIRPα display cell-specific molecular signatures in human islets and pancreata. Am J Physiol Endocrinol Metab 2023; 324:E347-E357. [PMID: 36791324 PMCID: PMC11967708 DOI: 10.1152/ajpendo.00221.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/10/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
Thrombospondin-1 (TSP1) is a secreted protein minimally expressed in health but increased in disease and age. TSP1 binds to the cell membrane receptor CD47, which itself engages signal regulatory protein α (SIRPα), and the latter creates a checkpoint for immune activation. Individuals with cancer administered checkpoint-blocking molecules developed insulin-dependent diabetes. Relevant to this, CD47 blocking antibodies and SIRPα fusion proteins are in clinical trials. We characterized the molecular signature of TSP1, CD47, and SIRPα in human islets and pancreata. Fresh islets and pancreatic tissue from nondiabetic individuals were obtained. The expression of THBS1, CD47, and SIRPA was determined using single-cell mRNA sequencing, immunofluorescence microscopy, Western blot, and flow cytometry. Islets were exposed to diabetes-affiliated inflammatory cytokines and changes in protein expression were determined. CD47 mRNA was expressed in all islet cell types. THBS1 mRNA was restricted primarily to endothelial and mesenchymal cells, whereas SIRPA mRNA was found mostly in macrophages. Immunofluorescence staining showed CD47 protein expressed by β cells and present in the exocrine pancreas. TSP1 and SIRPα proteins were not seen in islets or the exocrine pancreas. Western blot and flow cytometry confirmed immunofluorescent expression patterns. Importantly, human islets produced substantial quantities of secreted TSP1. Human pancreatic exocrine and endocrine tissue expressed CD47, whereas fresh islets displayed cell surface CD47 and secreted TSP1 at baseline and in inflammation. These findings suggest unexpected effects on islets from agents that intersect TSP1-CD47-SIRPα.NEW & NOTEWORTHY CD47 is a cell surface receptor with two primary ligands, soluble thrombospondin-1 (TSP1) and cell surface signal regulatory protein alpha (SIRPα). Both interactions provide checkpoints for immune cell activity. We determined that fresh human islets display CD47 and secrete TSP1. However, human islet endocrine cells lack SIRPα. These gene signatures are likely important given the increasing use of CD47 and SIRPα blocking molecules in individuals with cancer.
Collapse
Affiliation(s)
- Neslihan Erdem
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States
- Department of Molecular & Cellular Endocrinology, City of Hope National Medical Center, Duarte, California, United States
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Kuan-Tsen Chen
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Meirigeng Qi
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Yuqi Zhao
- Integrative Genomics Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Isaac Garcia
- Department of Molecular & Cellular Endocrinology, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Hsun Teresa Ku
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Enrique Montero
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Ismail H Al-Abdullah
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Bart O Roep
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| | - Jeffrey S Isenberg
- Department of Diabetes Complications & Metabolism, City of Hope National Medical Center, Duarte, California, United States
- Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States
| |
Collapse
|
|
11
|
Nishino K, Nakagawa K, Yase E, Terashima M, Murata T. Diabetic ketoacidosis after the second dose of SARS-CoV-2 mRNA vaccination in a patient with pembrolizumab-induced fulminant type 1 diabetes. Diabetol Int 2022; 14:206-210. [PMID: 36575722 PMCID: PMC9780095 DOI: 10.1007/s13340-022-00614-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 11/24/2022] [Indexed: 12/24/2022]
Abstract
We report a case of 77-year-old woman with fulminant type 1 diabetes (T1D) who developed diabetic ketoacidosis (DKA) after the second dose of SARS-CoV-2 vaccine tozinameran. The patient had been diagnosed as having T1D associated with an immune-related adverse event caused by pembrolizumab at the age of 75. After the second dose of tozinameran, she developed DKA and needed intravenous insulin infusion and mechanical ventilation. Although the direct causal relationship between the vaccination and the DKA episode could not be proven in this case, published literatures had suggested the possibility of developing DKA after SARS-CoV-2 vaccination in patients with T1D. As the magnitude of the risk of the combination of the known adverse drug reactions of SARS-CoV-2 mRNA vaccine and T1D patients' vulnerability to sick-day conditions is not yet thoroughly assessed, future studies such as a non-interventional study with adequate sample size would be required to address this issue.
Collapse
Affiliation(s)
- Kohei Nishino
- Diabetes Center, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555 Japan
| | - Kimiko Nakagawa
- Department of Emergency and Critical Care Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555 Japan
| | - Eriko Yase
- Department of Pharmacy, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555 Japan
| | - Mariko Terashima
- Department of Emergency and Critical Care Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555 Japan
| | - Takashi Murata
- Diabetes Center, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555 Japan
- Department of Clinical Nutrition, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusamukaihata-Cho, Fushimi-Ku, Kyoto, 612-8555 Japan
| |
Collapse
|
|
12
|
Qiu J, Luo S, Yin W, Guo K, Xiang Y, Li X, Liu Z, Zhou Z. Characterization of immune checkpoint inhibitor-associated fulminant type 1 diabetes associated with autoantibody status and ethnic origin. Front Immunol 2022; 13:968798. [PMID: 36451831 PMCID: PMC9702060 DOI: 10.3389/fimmu.2022.968798] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/07/2022] [Indexed: 12/05/2023] Open
Abstract
OBJECTIVE Fulminant type 1 diabetes may uniquely occur as a fatal adverse event during immune checkpoint inhibitor (ICI) therapy. We investigated the clinical and immunological characteristics of ICI-associated fulminant type 1 diabetes (IFD). RESEARCH DESIGN AND METHODS We enrolled 80 patients with IFD (77 cases from the literature), 56 patients with ICI-associated type 1 diabetes (IT1D) (55 cases from the literature), 45 patients with traditional fulminant type 1 diabetes (TFD), and 43 patients with acute-onset type 1 diabetes for comprehensive analysis including islet autoantibodies and subgroup analysis based on ethnic origin. RESULTS Patients with IFD accounted for 58.8% (80/136) of patients with ICI-related diabetes. IFD had a more rapid onset than IT1D after ICI therapy (90.5 days vs. 120 days, p <0.05). The onset time and number of infusions after ICI therapy initiation were lower in the antibody-positive IFD group than that in the antibody-negative IFD group (both p <0.001). IFD had a more rapid onset and more serious among Caucasians than that among Asians (p <0.01, p <0.05, respectively), and the prevalence of islet autoantibody positivity in the Caucasian IFD were prominently higher than those in the Asian IFD (p <0.05). Onset age and plasma glucose levels were significantly higher in the IFD group than those in the TFD and acute-onset type 1 diabetes groups. HbA1c levels were slightly higher in patients with IFD than those with TFD. CONCLUSIONS IFD is relatively common in Caucasian population where TFD is very rare or almost absent. IFD occurrence is significantly related to islet autoantibody status and ethnic origin.
Collapse
Affiliation(s)
- Junlin Qiu
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wenfeng Yin
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Keyu Guo
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yufei Xiang
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, United States
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
|
13
|
Guha A, Gong Y, DeRemer D, Owusu-Guha J, Dent SF, Cheng RK, Weintraub NL, Agarwal N, Fradley MG. Cardiometabolic Consequences of Targeted Anticancer Therapies. J Cardiovasc Pharmacol 2022; 80:515-521. [PMID: 34654781 PMCID: PMC8977391 DOI: 10.1097/fjc.0000000000001149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/25/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Cardiometabolic disease (CMD) is the most common preventable cause of death in the world. A number of components are included in the spectrum of CMD, such as metabolic syndrome/obesity, hyperglycemia/diabetes, dyslipidemia, and hypertension, which are independently associated with cardiovascular disease risk. These conditions often occur together, and patients with cancer frequently undergo treatments that can generate or worsen CMD. This review highlights and presents mechanistic and epidemiological evidence regarding CMD in 4 categories of anticancer medications, namely, mTOR/PI3K-Akt inhibitors, multitargeted tyrosine kinase inhibitor, immune checkpoint inhibitor therapy, and endocrine therapy. Patients taking these medications need careful monitoring during therapy. There is a role for cardio-oncology and onco-primary care specialists in optimally managing patients at risk to mitigate CMD during treatment with these and other investigational anticancer medications.
Collapse
Affiliation(s)
- Avirup Guha
- Harrington Heart and Vascular Institute, Case Western Reserve University, Cleveland, OH, USA
- Division of Cardiology, Department of Medicine, Augusta University, Augusta, GA
| | - Yan Gong
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - David DeRemer
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | | | - Susan F Dent
- Duke Cancer Institute, Duke University, Durham, NC, USA
| | - Richard K Cheng
- Cardiology Division, University of Washington, Seattle, WA, USA
| | - Neal L Weintraub
- Division of Cardiology, Department of Medicine, Augusta University, Augusta, GA
- Vascular Biology Center, Augusta University, Augusta, GA, USA
| | - Neeraj Agarwal
- Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, UT, USA
| | - Michael G Fradley
- Division of Cardiology, Department of Medicine, University of Pennsylvania, PA, USA
| |
Collapse
|
|
14
|
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang ML, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC. Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes. JCI Insight 2022; 7:e156330. [PMID: 35925682 PMCID: PMC9536276 DOI: 10.1172/jci.insight.156330] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFN-γ and anti-TNF-α prevented CPI-DM in anti-PD-L1-treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Gary Israel
- Department of Radiology and Biomedical Imaging, and
| | - Marie E. Robert
- Department of Pathology, Yale University, New Haven, Connecticut, USA
| | - Stuart P. Weisberg
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | | | - Angeliki M. Stamatouli
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | | | - Zoe Quandt
- Department of Medicine and
- Diabetes Center, University of California, San Francisco, San Francisco, California, USA
| | - Arabella Young
- Diabetes Center, University of California, San Francisco, San Francisco, California, USA
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | | | | | | | - Mark S. Anderson
- Department of Medicine and
- Diabetes Center, University of California, San Francisco, San Francisco, California, USA
| | | | | |
Collapse
|
|
15
|
Chen J, Wen Y, Chu X, Liu Y, Su C. Pulmonary adverse events associated with hypertension in non-small cell lung cancer patients receiving PD-1/PD-L1 inhibitors. Front Pharmacol 2022; 13:944342. [PMID: 36110543 PMCID: PMC9468816 DOI: 10.3389/fphar.2022.944342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/04/2022] [Indexed: 12/19/2022] Open
Abstract
Introduction: Non-small cell lung cancer patients have gained therapeutic benefits from immune checkpoint inhibitors, although immune-related adverse events (irAEs) could be inevitable. Whether irAEs are associated with chronic diseases is still unclear, our study aims to clarify the distinct adverse events in NSCLC patients with concomitant hypertension. Methods: Adverse event cases were searched and collected in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 2015 to December 2021. We performed disproportionality analysis to detect safety signals by calculating reporting odds ratios (ROR) and corresponding 95% confidence intervals (95% CIs), information component (IC), and the lower bound of the information component 95% credibility interval (IC025). Results: Among 17,163 NSCLC patients under treatment with single-agent anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitor (nivolumab, pembrolizumab, cemiplimab, durvalumab, atezolizumab, and avelumab), 497 patients had hypertension while 16,666 patients had no hypertension. 4,283 pulmonary AEs were reported, including 166 patients with hypertension and 4,117 patients without hypertension. Compared with patients without hypertension, patients with hypertension were positively associated with increased reporting of interstitial lung disease (ROR = 3.62, 95%CI 2.68-4.89, IC = 1.54, IC025 = 0.57) among patients receiving anti-PD-1 treatment. The median duration of onset from the time of initiation of anti-PD-1 administration was 28 days (IQR, 12.00-84.25). Conclusion: Our pharmacovigilance analysis showed the profile of pulmonary toxicities in NSCLC patients with hypertension caused by anti-PD-1/PD-L1 inhibitors. Interstitial lung disease was the statistically significant reporting adverse event in patients with hypertension receiving anti-PD-1 treatment.
Collapse
Affiliation(s)
- Jianing Chen
- School of Medicine, Tongji University, Shanghai, China
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University, School of Medicine, Shanghai, China
| | - Yaokai Wen
- School of Medicine, Tongji University, Shanghai, China
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University, School of Medicine, Shanghai, China
| | - Xiangling Chu
- School of Medicine, Tongji University, Shanghai, China
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University, School of Medicine, Shanghai, China
| | - Yuzhi Liu
- School of Medicine, Tongji University, Shanghai, China
- Department of Oncology, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Chunxia Su
- School of Medicine, Tongji University, Shanghai, China
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University, School of Medicine, Shanghai, China
| |
Collapse
|
|
16
|
Lin C, Li X, Qiu Y, Chen Z, Liu J. PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review. Front Public Health 2022; 10:885001. [PMID: 35991054 PMCID: PMC9389003 DOI: 10.3389/fpubh.2022.885001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/22/2022] [Indexed: 12/01/2022] Open
Abstract
Objective This study aimed to summarize the clinical characteristics of programmed death receptor 1 (PD-1) inhibitor-associated type 1 diabetes so as to improve the ability of clinicians to correctly diagnose and treat it. Methods We reported a case of a 70-year-old woman with gastric cancer who developed hyperosmolar hyperglycemic coma during camrelizumab (a PD-1 inhibitor) treatment and was diagnosed with PD-1 inhibitor-associated type 1 diabetes. We conducted a systematic review of 74 case reports of type 1 diabetes associated with PD-1 inhibitor therapy published before June 2022. Results The patient developed type 1 diabetes with hyperosmolar hyperglycemic coma after receiving camrelizumab chemotherapy for 6 months (9 cycles). We searched 69 English articles comprising 75 patients, all of whom had been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and progressed to diabetes after an average of 6.11 (1–28) cycles. Nivolumab combined with ipilimumab (a cytotoxic T lymphocyte-associated protein 4 inhibitor) had the shortest onset (4.47 cycles on average). A total of 76% (57/75) of patients developed diabetic ketoacidosis (DKA) at onset, and 50.67% (38/75) of patients had C-peptide <0.1 ng/mL. Most of the patients were tested for insulin autoantibodies, with a positive rate of 33.33% (23/69); of these, 86.96% (20/23) were tested for glutamate decarboxylase antibody and 46.67% (35/75) were tested for human leukocyte antigen (HLA). HLA-DR4 was the most common type. Conclusions The progression of type 1 diabetes induced by PD-1 inhibitors is relatively rapid. Islet failure often occurs when detected, seriously endangering patients' lives. Patients treated with PD-1 inhibitors should closely monitor their plasma glucose level during treatment to detect, diagnose, and treat diabetes on time.
Collapse
|
|
17
|
Liu J, Shi Y, Liu X, Zhang D, Zhang H, Chen M, Xu Y, Zhao J, Zhong W, Wang M. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus. Transl Oncol 2022; 24:101473. [PMID: 35905639 PMCID: PMC9334308 DOI: 10.1016/j.tranon.2022.101473] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/06/2022] [Accepted: 06/26/2022] [Indexed: 11/07/2022] Open
Abstract
This article summarized a total of 172 published cases of immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM). Found that glutamic acid decarboxylase antibodies positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of diabetic ketoacidosis development. Presented a case of ICI-induced DM following obvious lipase and amylase elevation and discussed possible relationship between ICI-associated injuries to pancreatic exocrine function and endocrine function. Objective To better understand immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM) in cancer patients. Design and method We present a case of ICI-induced diabetic ketoacidosis (DKA) and conduct a systematic review of the PubMed and Web of Science databases up to September 2021 to identify all published cases of ICI-induced diabetes. Results In addition to our case, a total of 171 published cases were identified during the literature search. Summary and statistical analyzes were conducted for all 172 cases. The median onset time from ICI initiation to DM diagnosis was 12 weeks (range: 0–122). DKA was present in 67.4% (116/172) of the cases, and low C-peptide levels were detected in 91.8% (123/134), indicating an acute onset of diabetes. Patients with positive glutamic acid decarboxylase antibodies (GADA) had an earlier onset of ICI-induced diabetes (median time 7 weeks vs. 16 weeks for GADA-negative patients, p < 0.001) and a higher frequency of DKA development (82.8 vs. 62.1%, p = 0.006). All but two patients developed insulin-dependent diabetes permanently. Immunotherapy rechallenge was reported in 53 cases after glycemia was well controlled. Conclusion ICI-induced DM is a serious adverse event that often presents with life-threatening ketoacidosis. GADA positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of DKA development. Close monitoring of glucose levels is needed in patients receiving ICI treatment. ICI-induced DM is usually insulin-dependent since damage to β cells is irreversible. On the premise of well-controlled glycemia, immunotherapy rechallenge is feasible.
Collapse
Affiliation(s)
- Jia Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuequan Shi
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongming Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haoran Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Zhong
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
18
|
Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG, Varricchi G. Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events. Front Immunol 2022; 13:804597. [PMID: 35432346 PMCID: PMC9005797 DOI: 10.3389/fimmu.2022.804597] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.
Collapse
Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Teresa Troiani
- Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Gjada Criscuolo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | | | - Fortunato Ciardiello
- Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, Naples, Italy
| |
Collapse
|
|
19
|
Lee S, Tse G. A Patient with Atezolizumab-Induced Autoimmune Diabetes Mellitus Presenting with Diabetic Ketoacidosis. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2021. [DOI: 10.15212/cvia.2021.0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background: Atezolizumab, an immune checkpoint inhibitor, is a humanized monoclonal, anti-programmed death ligand 1 (PD-L1) antibody used for the treatment of metastatic urothelial carcinoma that has progressed after chemotherapy.Case Presentation: We describe a patient
with a known history of urothelial carcinoma who presented with diabetic ketoacidosis 6 weeks following his second cycle of atezolizumab. His serum lactate level was slightly elevated (2 mM) and his β-hydroxybutyrate level was elevated (3.9 mM). High anion gap metabolic acidosis secondary
to diabetic ketoacidosis was diagnosed. Subsequent testing demonstrated hemoglobin A1c level of 9.9%, positivity for anti-glutamic acid decarboxylase antibody (0.03 nM, reference range <0.02 nM), and suppressed C-peptide level (0.1 μg/L, reference range 0.9‐7.1 μg/L)
in the absence of detectable anti-islet antigen 2 (IA-2) or anti-insulin antibodies. His initial management included cessation of atezolizumab treatment, intravenous sodium chloride administration, and insulin pump infusion, after which metabolic acidosis gradually resolved. The insulin pump
was subsequently switched to Protaphane at 18 units before breakfast and 8 units before dinner, together with metformin at 1000 mg twice daily. Four weeks later his medication was changed to human isophane insulin plus neutral insulin (70%/30%; Mixtard 30 HM; 26 units/4 units). Linagliptin
at 5 mg was added 1 month later. His hemoglobin A1c level declined to 8.1% 1 year later.Conclusions: PD-L1 inhibitors can induce type 1 diabetes, and patients can present with diabetic ketoacidosis. Blood glucose levels should be regularly monitored in patients who are
prescribed these medications.
Collapse
Affiliation(s)
- Sharen Lee
- Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, HKG, China
| | - Gary Tse
- Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, HKG, China
| |
Collapse
|
|
20
|
Di Bona C, Stühler V, Rausch S, Stenzl A, Bedke J. Pembrolizumab for the treatment of renal cell carcinoma. Expert Opin Biol Ther 2021; 21:1157-1164. [PMID: 34042015 DOI: 10.1080/14712598.2021.1935856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The acquisition of resistance to VEGF-inhibiting therapies has prompted research toward immunotherapy for the treatment of metastatic renal cell carcinoma (mRCC). Among several, checkpoint inhibitors including PD-1 and PD-L1 inhibitors are the most promising approach. AREAS COVERED This review addresses the clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab in first- and second-line treatment for mRCC regarding the most recent and significant published and ongoing studies. Attention is also given to its pharmacological characteristics as well as adverse events and its impact on patients' quality of life. EXPERT OPINION Immunotherapy has become the backbone for the treatment of advanced RCC. With the approval of several therapeutic options, research needs now to focus on defining the appropriate therapy for each patient. Axitinib plus pembrolizumab belongs to the combinations of tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors for the first-line treatment of metastatic RCC. New combinations of pembrolizumab plus TKI for the evaluation in first- and second-line treatment of mRCC available. However, studies directly comparing the various treatment regimens using predictive biomarkers and long-term endpoints, including treatment-free survival, are lacking.
Collapse
Affiliation(s)
- Carlo Di Bona
- Department of Urology, University of Tübingen, Tuebingen, Germany
| | - Viktoria Stühler
- Department of Urology, University of Tübingen, Tuebingen, Germany
| | - Steffen Rausch
- Department of Urology, University of Tübingen, Tuebingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University of Tübingen, Tuebingen, Germany
| | - Jens Bedke
- Department of Urology, University of Tübingen, Tuebingen, Germany
| |
Collapse
|
|
21
|
Lo Preiato V, Salvagni S, Ricci C, Ardizzoni A, Pagotto U, Pelusi C. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature. Rev Endocr Metab Disord 2021; 22:337-349. [PMID: 33409866 DOI: 10.1007/s11154-020-09618-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Immune Check-Point Inhibitors (CPIs) have improved long-term patients' outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs' side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.
Collapse
Affiliation(s)
- V Lo Preiato
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - S Salvagni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - C Ricci
- Surgical Department, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola Hospital, Bologna, Italy
| | - A Ardizzoni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - U Pagotto
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy.
| | - C Pelusi
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| |
Collapse
|
|
22
|
Kyriacou A, Melson E, Chen W, Kempegowda P. Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus? Clin Med (Lond) 2021; 20:417-423. [PMID: 32675150 DOI: 10.7861/clinmed.2020-0054] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication.
Collapse
Affiliation(s)
- Angelos Kyriacou
- Centre of Endocrinology, Diabetes and Metabolism, Limassol, Cyprus
| | - Eka Melson
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Punith Kempegowda
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| |
Collapse
|
|
23
|
Huang X, Yang M, Wang L, Li L, Zhong X. Sintilimab induced diabetic ketoacidosis in a patient with small cell lung cancer: A case report and literature review. Medicine (Baltimore) 2021; 100:e25795. [PMID: 34106616 PMCID: PMC8133135 DOI: 10.1097/md.0000000000025795] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/11/2021] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Sintilimab is a novel programmed cell death receptor-1 (PD-1) inhibitor approved in the treatment of classical Hodgkin's lymphoma and undergoing clinical trials for various malignancies. As a PD-1 inhibitor, sintilimab is known to cause autoimmune adverse events similar to other PD-1 inhibitors. Diabetic ketoacidosis (DKA) is a rare but severe adverse event of this therapy. PATIENT CONCERNS We report a case of a 59-year-old man who developed DKA after 5 doses of sintilimab for small cell lung cancer. His fasting glycemia level was 14.07 mmol/L, urine ketone bodies were 4+, arterial blood pH was 7.271, bicarbonate was 12.3 mmol/L, and glycated hemoglobin (HbA1c) was 7.4%. Extended investigations revealed that fasting C-peptide was undetectable (<0.003 nmol/L). DIAGNOSIS These laboratory investigations supported the diagnosis of fulminant type 1 diabetes mellitus, but no β-cell related antibodies were positive. INTERVENTIONS After remission of DKA, he was treated with insulin therapy to acquire a normalization of glycemia and the disappearance of symptoms. OUTCOMES Sintilimab was withheld after 6 cycles and was converted to durvalumab to sustain the therapeutic effect. LESSONS This case and associated literature review illustrate the importance of educating and monitoring patients who start PD-1 inhibitor therapy regarding this potentially life-threatening complication.
Collapse
Affiliation(s)
| | - Mei Yang
- Department of Endocrinology and Metabolism
| | - Liu Wang
- Department of Endocrinology and Metabolism
| | - Libo Li
- Department of Hematology, The Third People's Hospital of Chengdu, The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | | |
Collapse
|
|
24
|
Calderon B, Stancu A, Vanel FR, Vazquez L. Pembrolizumab Treatment-Induced Liver Toxicity. Case Rep Gastroenterol 2021; 15:742-750. [PMID: 34594175 PMCID: PMC8436642 DOI: 10.1159/000518128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/11/2021] [Indexed: 11/19/2022] Open
Abstract
T cells play a critical role in immune responses against neoplasm. This finding contributed to the immunotherapy development, an effective treatment for many cancers nowadays. Programmed cell death protein 1 (PD1) is an inhibitory receptor on T cells which downregulate T-cell function per ligation with its ligands (PDL1 and PDL2). PD1 blockade is used to enhance antitumor immunity. Pembrolizumab is a humanized monoclonal anti-PD1 antibody currently used in the management of melanoma, non-small-cell lung cancer, and Hodgkin lymphoma. Most of the treatment toxicities are immune-related adverse events, but grade 3-4 toxicities occur in up to 5% of patients, mainly dermatologic. We present a case of grade 4 pembrolizumab-induced liver toxicity associated with an excellent treatment response in a Caucasian woman.
Collapse
|
|
25
|
Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report. J Med Case Rep 2021; 15:214. [PMID: 33892782 PMCID: PMC8067320 DOI: 10.1186/s13256-020-02656-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 12/28/2020] [Indexed: 11/24/2022] Open
Abstract
Background Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). Case presentation A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. Conclusions Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.
Collapse
|
|
26
|
Goyal I, Pandey MR, Sharma R, Chaudhuri A, Dandona P. The side effects of immune checkpoint inhibitor therapy on the endocrine system. Indian J Med Res 2021; 154:559-570. [PMID: 35435341 PMCID: PMC9205006 DOI: 10.4103/ijmr.ijmr_313_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte–associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary–adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary–adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.
Collapse
Affiliation(s)
- Itivrita Goyal
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Manu Raj Pandey
- Department of Hematology & Oncology, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rajeev Sharma
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Ajay Chaudhuri
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Paresh Dandona
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| |
Collapse
|
|
27
|
Anderson B, Morganstein DL. Endocrine toxicity of cancer immunotherapy: clinical challenges. Endocr Connect 2021; 10:R116-R124. [PMID: 33544091 PMCID: PMC8052567 DOI: 10.1530/ec-20-0489] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune-related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune-related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.
Collapse
Affiliation(s)
- Bliss Anderson
- Department of Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Daniel L Morganstein
- Department of Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
- Correspondence should be addressed to D L Morganstein:
| |
Collapse
|
|
28
|
Liu Y, Zhang H, Zhou L, Li W, Yang L, Li W, Li K, Liu X. Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management. Front Oncol 2021; 11:627612. [PMID: 33732647 PMCID: PMC7959713 DOI: 10.3389/fonc.2021.627612] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 (PD-1) and its ligand PD-L1 and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are involved in T cell-mediated immune response augmentation and promote anti-tumor immunity. Cancer patients treated with combination of immunotherapy, chemotherapy, radiotherapy, and targeted therapy exhibit superior clinical outcomes and tolerance compared with patients treated with monotherapies. However, immutherapy is associated with several concomitant immune-related adverse events (irAEs). For instance, IrAEs interferes with function of gastrointestinal tract, endocrine, dermatological, nervous system and musculoskeletal systems. ICIs-associated pancreatic injury might causes decrease in endocrine and exocrine pancreatic function, resulting in metabolic and nutritional disorders. Clinicians who administer immune checkpoint inhibitors to cancer patients are diagnosed with hyperglycemia, abdominal pain and steatorrhea. Currently, the precise mechanism of ICIs-associated pancreatic injury has not been fully explored. This paper summarizes incidence, diagnosis, clinical characteristics, potential mechanisms, and treatment management patterns of ICIs-associated pancreatic AEs based on previous studies. In addition, possible management approaches of these adverse effects are presented in this paper. in the findings summarized in this paper lay a basis for management of ICIs-associated pancreatic AEs and expanding future immunotherapy applications.
Collapse
Affiliation(s)
- Ya Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Zhou
- Core Facilities, West China Hospital, Sichuan University, Chengdu, China
| | - Weichun Li
- CAAC Academy, Civil Aviation Flight University of China, Guanghan, China
| | - Le Yang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wen Li
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kezhou Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xubao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
29
|
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.
Collapse
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.
| |
Collapse
|
|
30
|
Zhang AL, Wang F, Chang LS, McDonnell ME, Min L. Coexistence of Immune Checkpoint Inhibitor-Induced Autoimmune Diabetes and Pancreatitis. Front Endocrinol (Lausanne) 2021; 12:620522. [PMID: 33927691 PMCID: PMC8076788 DOI: 10.3389/fendo.2021.620522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/16/2021] [Indexed: 02/05/2023] Open
Abstract
Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.
Collapse
|
|
31
|
Zhai Y, Ye X, Hu F, Xu J, Guo X, Zhou X, Zheng Y, Zhao X, Xu X, Cao Y, He J. Metabolic and Nutritional Disorders Following the Administration of Immune Checkpoint Inhibitors: A Pharmacovigilance Study. Front Endocrinol (Lausanne) 2021; 12:809063. [PMID: 35145482 PMCID: PMC8821653 DOI: 10.3389/fendo.2021.809063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/28/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Although several metabolic and nutritional disorders (MNDs) have been reported in the recipients of immune checkpoint inhibitors (ICIs), these events have not been fully captured and comprehensively characterized in real-world population. OBJECTIVES To provide complete metabolic and nutritional toxicity profiles after ICIs (single and combined) initiation through an integrated big database. METHODS Reporting odds ratios (ROR) and information component (IC) based on statistical shrinkage transformation were utilized to perform disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System. Both ROR and IC were used to calculate disproportionality when compared with the whole database, but only ROR was used when comparison was made for different ICI strategies. Only when both the lower limits of 95% confidence intervals (CIs) for ROR (ROR025) and IC (IC025) exceeded specified threshold values (1 and 0, respectively) was regarded as a signal. RESULTS A total of 29,294,335 records were involved and 8,662 records were for MNDs in patients exposed to ICIs. Statistically significant association was detected between ICIs use and total MNDs (IC025/ROR025 = 1.06/2.19). For monotherapy, three ICI monotherapies (anti-PD-1, anti-PDL-1, and anti-CTLA-4) were all disproportionately associated with MNDs. Statistically significant differences in reporting frequencies also emerged when comparing anti-PD-1 with anti-PD-L1/anti-CTLA-4 monotherapy, with RORs of 1.11 (95%CI 1.01-1.21), and 1.35 (95%CI 1.23-1.48), respectively. Notably, combination therapy was associated with a higher reporting frequency of theses toxicities compared to monotherapy with a ROR of 1.56 (95%CI 1.48-1.64). Additionally, disproportionality analysis at High-level Group Term level highlighted eight broad entities of MNDs. Further disproportionality analysis at Preferred Term level indicated a wide range and varied strength of signals. For ICI monotherapy, nivolumab and pembrolizumab showed the broadest spectrum of MNDs. For combination therapy, a variety of signals were detected for nivolumab + ipilimumab therapy even comparable to two PD-1 monotherapies. CONCLUSION Metabolic and nutritional complications could be provoked by ICI monotherapy (especially anti-PD-1) and further reinforced by combination therapy. Clinicians and patients should be informed about these potential risks that might be encountered in real-world practice. Aforehand education and regular monitoring of related biochemical parameters (calcium, sodium, potassium, protein) are recommended to ensure better cancer survivorship.
Collapse
Affiliation(s)
- Yinghong Zhai
- Tongji University School of Medicine, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Fangyuan Hu
- Department of Health Statistics, Second Military Medical University, Shanghai, China
- Department of Medical Service, Naval Hospital of Eastern Theater Zhoushan, Zhejiang, China
| | - Jinfang Xu
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xiaojing Guo
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xiang Zhou
- Tongji University School of Medicine, Shanghai, China
| | - Yi Zheng
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xinxin Zhao
- Tongji University School of Medicine, Shanghai, China
| | - Xiao Xu
- Tongji University School of Medicine, Shanghai, China
| | - Yang Cao
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jia He
- Tongji University School of Medicine, Shanghai, China
- Department of Health Statistics, Second Military Medical University, Shanghai, China
- *Correspondence: Jia He,
| |
Collapse
|
|
32
|
Yeung SJ, Qdaisat A, Chaftari P, Lipe D, Merlin J, Rajha E, Wechsler A, Sandoval M, Viets J, Al‐Breiki A, Shah M, Pandey R, Kamal M, Khattab O, Toale K, Wattana M, Elsayem A, Gaeta S, Brock P, Reyes‐Gibby C, Alagappan K. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. J Am Coll Emerg Physicians Open 2020; 1:1637-1659. [PMID: 33392573 PMCID: PMC7771833 DOI: 10.1002/emp2.12209] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 07/02/2020] [Accepted: 07/13/2020] [Indexed: 12/14/2022] Open
Abstract
Rapid advances in cancer immunotherapy using immune checkpoint inhibitors have led to significantly improved survival. Rapid identification of the toxicity syndromes associated with these therapeutic agents is very important for emergency physicians because the population of patients diagnosed with cancer is increasing and cancer therapies including immune checkpoint inhibitors have become the first-line treatment for more and more types of cancer. The emergency medicine literature lags behind rapid advances in oncology, and oncology guidelines for rapid recognition and management of these emerging toxicity syndromes are not familiar to emergency physicians. In this review article, we discuss the clinical presentation and management of immune-related adverse effects during the critical first hours of emergency care. We also suggest a workflow for the recognition and treatment of emergencies arising from serious immune-related adverse effects, including but not limited to colitis, adrenal crisis, myocarditis, pneumonitis, myasthenic crisis, diabetic ketoacidosis, bullous pemphigus, and hemophagocytic lymphohistiocytosis. Rapid advances in cancer therapy are bringing new diagnostic and therapeutic challenges to emergency providers, and therefore it is crucial to raise awareness and provide guidelines for the management of new treatment-related toxicities.
Collapse
Affiliation(s)
- Sai‐Ching Jim Yeung
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Aiham Qdaisat
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Patrick Chaftari
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Demis Lipe
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Jeffrey Merlin
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Eva Rajha
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Adriana Wechsler
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Marcelo Sandoval
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Jayne Viets
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Aisha Al‐Breiki
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Mohsin Shah
- Center for Clinical Epidemiology and BiostatisticsPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Ramesh Pandey
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Mona Kamal
- Department of Symptom ResearchThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Department of Clinical Oncology and Nuclear MedicineFaculty of MedicineAin Shams UniversityCairoEgypt
| | - Osama Khattab
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Katy Toale
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Monica Wattana
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Ahmed Elsayem
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Susan Gaeta
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Patricia Brock
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Cielito Reyes‐Gibby
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Kumar Alagappan
- Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Byun DJ, Braunstein R, Flynn J, Zheng J, Lefkowitz RA, Kanbour S, Girotra M. Immune Checkpoint Inhibitor-Associated Diabetes: A Single-Institution Experience. Diabetes Care 2020; 43:3106-3109. [PMID: 33051330 PMCID: PMC7770268 DOI: 10.2337/dc20-0609] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 09/14/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To characterize immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in a single-institution case series. RESEARCH DESIGN AND METHODS Retrospective chart review of 18 patients with new-onset ICI-DM following anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death protein ligand 1 (PD-L1) therapy for advanced carcinomas. RESULTS Of 18 patients, 9 had diabetic ketoacidosis (median glucose 27.92 mmol/L; median glucose before presentation 6.35 mmol/L). Median C-peptide at ICI-DM diagnosis was low, and it declined during follow-up. Median anti-PD-1/anti-PD-L1 duration before ICI-DM was 3.65 months (range 0.56-12.23 months). Time to ICI-DM onset was a median 1.4 months/3 ICI cycles and 6 months/10 cycles in those patients who were positive and negative for GAD65 autoantibodies, respectively. Time to ICI-DM onset was a median 2.5 months/3 ICI cycles and 4.8 months/8 cycles after anti-PD-L1 or anti-PD-1 therapy, respectively. Significant pancreatic atrophy was seen radiographically. CONCLUSIONS ICI-DM presents abruptly, appears irreversible, is characterized by pancreatic atrophy, and may occur both earlier following PD-L1 blockade compared with PD-1 inhibition and in those who have positive GAD65 autoantibodies.
Collapse
Affiliation(s)
- David J Byun
- Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.,Weill Cornell Medical College, New York, NY
| | - Rebecca Braunstein
- Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jessica Flynn
- Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Junting Zheng
- Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Robert A Lefkowitz
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sarah Kanbour
- Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Monica Girotra
- Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY .,Weill Cornell Medical College, New York, NY
| |
Collapse
|
|
35
|
Shimada A, Ikegami H. Twenty years since the discovery of fulminant type 1 diabetes. Diabetol Int 2020; 11:309. [PMID: 33088635 DOI: 10.1007/s13340-020-00464-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Akira Shimada
- Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan
| | - Hiroshi Ikegami
- Department of Endocrinology, Metabolism and Diabetes, Faculty of Medicine, Kindai University, Osaka, Japan
| |
Collapse
|
|
36
|
Imagawa A, Tachibana M. Fulminant type 1 diabetes: recent research progress and future prospects. Diabetol Int 2020; 11:336-341. [PMID: 33088640 PMCID: PMC7538502 DOI: 10.1007/s13340-020-00466-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022]
Abstract
To clarify the clinical and etiological characteristics of fulminant type 1 diabetes, we reviewed data from patients who had developed type 1 diabetes following anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) therapy, and research on pancreatic beta cells derived from induced pluripotent stem (iPS) cells from patients with fulminant type 1 diabetes. As determined from the disease classifications and clinical and genetic characteristics, anti-PD-1/PD-L1 therapy-related type 1 diabetes includes both fulminant type 1 diabetes and acute-onset type 1 diabetes. Using insulin-positive cells derived from iPS cells, beta-cell fragility to inflammatory cytokines, but not its regeneration failure, was observed in fulminant type 1 diabetes. Moreover, severe hyperglycemia was reported as a risk factor of sudden death or cardiac arrest at disease onset, diffusion-weighted magnetic resonance imaging was suggested as an additional tool for making a diagnosis, and the CSAD/lnc-ITGB7-1 locus was genetically associated with fulminant type 1 diabetes. To fully understand fulminant type 1 diabetes, it is important to clarify the molecular mechanisms step by step through multifaceted approaches such as through analyses of the genetic factors, clinical features, histological findings, and cell biology. The careful and detailed study of patients is a great means for clarifying the etiology and pathophysiology of the disease.
Collapse
Affiliation(s)
- Akihisa Imagawa
- Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, 569-8686 Japan
| | - Megumi Tachibana
- Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, 569-8686 Japan
| |
Collapse
|
|
37
|
Silvestris N, Argentiero A, Beretta GD, Di Bartolo P, Montagnani M, Danesi R, Ferrari P, D'Oronzo S, Gori S, Russo A, Acquati S, Gallo M. Management of metabolic adverse events of targeted therapies and immune checkpoint inhibitors in cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper. Crit Rev Oncol Hematol 2020; 154:103066. [PMID: 32853883 DOI: 10.1016/j.critrevonc.2020.103066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/16/2022] Open
Abstract
The growing insights in the next-generation immunotherapy and the state-of-the-art advancement in targeted-agents significantly improved clinical outcome of cancer patients by pointing towards a unexplored Achilles' heel. Novel toxicity profiles have been uncovered, representing unmet medical needs. Thus, a panel of expert provide comprehensive pharmacological and clinical evidence, to provide a patient-tailored approach to metabolic adverse events associated with novel anti-cancer treatments. Prompted by the need of a multidisciplinary cooperation, a working group of Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD) and Società Italiana Farmacologia (SIF) examined the available literature data. The identification of patient risk profile and the characterization of metabolic effects of novel anti-tumour drugs is clearly a clinical challenge that can be addressed by a multidisciplinary clinical approach. Therefore, this review pinpoints the relevance of the challenging profiling of the patient suffering from dysmetabolic conditions induced by the novel therapeutics in medical oncology.
Collapse
Affiliation(s)
- Nicola Silvestris
- IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy.
| | | | | | - Paolo Di Bartolo
- Diabetology Unit, Rete Clinica di Diabetologia Aziendale - Dipartimento, Internistico di Ravenna - AUSL Romagna, Ravenna, Italy
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Pietro Ferrari
- Palliative Care Unit, Istituti Clinici Scientifici Maugeri SPA SB, IRCCS (PV), Italy
| | - Stella D'Oronzo
- IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Stefania Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Italy
| | - Silvia Acquati
- Endocrinology Unit, Ospedale Pierantoni-Morgagni, Forlì, Italy
| | - Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy
| |
Collapse
|
|
38
|
Hanafusa T. Fulminant type 1 diabetes: 20 years of discovery and development. Diabetol Int 2020; 11:310-314. [PMID: 33088636 PMCID: PMC7538472 DOI: 10.1007/s13340-020-00458-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 10/23/2022]
Abstract
Twenty years have passed since the first article on fulminant type 1 diabetes (FT1D) was published. FT1D is characterized by an extremely rapid onset of ketoacidosis, high plasma glucose and, conversely, a near-normal glycosylated hemoglobin level. Digestive or flu-like symptoms frequently precede the onset of ketoacidosis. Patients are usually negative for islet-related autoantibodies, with near-complete destruction of pancreatic β-cells, even at the onset of disease. Massive infiltration of immunocytes (insulitis) can be seen in the islets of patients with new-onset FT1D, but this subsides within a few weeks. Early discovery and development of research on FT1D were carried out in Japan, with some reports from Korea and China. Recently, the recognition of FT1D as an immune-related adverse effect of immune-checkpoint inhibitor therapy for various malignant tumors in some patients has drawn the attention of Western countries. The discovery and successful establishment of FT1D as a disease entity was the product of three essential factors: (1) accumulated research data spanning more than 10 years; (2) fortuitous clinical observation; and (3) organization of a dedicated Japanese research committee. We anticipate that continued investigations of FT1D by a new generation of researchers will further elucidate the pathogenesis and yield new therapies.
Collapse
Affiliation(s)
- Toshiaki Hanafusa
- Sakai City Medical Center, 1-1-1 Ebaraji-cho, Nishi-ku, Sakai-City, Osaka 593-8304 Japan
| |
Collapse
|
|
39
|
Chujo D, Kawabe A, Matsushita M, Takahashi N, Tsutsumi C, Haseda F, Imagawa A, Hanafusa T, Ueki K, Kajio H, Yagi K, Tobe K, Shimoda M. Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells Among the 3 Subtypes of Type 1 Diabetes. J Clin Endocrinol Metab 2020; 105:dgaa447. [PMID: 32652026 DOI: 10.1210/clinem/dgaa447] [Citation(s) in RCA: 5] [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: 02/20/2020] [Accepted: 07/08/2020] [Indexed: 01/06/2023]
Abstract
CONTEXT Type 1 diabetes (T1D) is classified into 3 subtypes: acute-onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined. OBJECTIVE To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D. PARTICIPANTS Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND). METHODS We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex vivo assay involving a 48-hour stimulation of peripheral blood mononuclear cells with antigen peptides and an expansion assay involving intracytoplasmic cytokine analysis. RESULTS The results of the ex vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses and preproinsulin (PPI)-specific IP-10 responses were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte colony-stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed toward a type 1 helper T (Th1)- cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with human leukocyte antigen-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all 4 antigens than ND. CONCLUSIONS The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction.
Collapse
Affiliation(s)
- Daisuke Chujo
- Center for Clinical Research, Toyama University Hospital, Toyama, Japan
- Islet Cell Transplantation Project, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Internal Medicine (I), Toyama University Hospital, Toyama, Japan
| | - Akitsu Kawabe
- Islet Cell Transplantation Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Maya Matsushita
- Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nobuyuki Takahashi
- Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
| | - Chiharu Tsutsumi
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan
| | - Fumitaka Haseda
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan
| | - Akihisa Imagawa
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan
| | - Toshiaki Hanafusa
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan
- Sakai City Medical Center, Sakai, Japan
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
- Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroshi Kajio
- Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kunimasa Yagi
- Department of Internal Medicine (I), Toyama University Hospital, Toyama, Japan
| | - Kazuyuki Tobe
- Center for Clinical Research, Toyama University Hospital, Toyama, Japan
- Department of Internal Medicine (I), Toyama University Hospital, Toyama, Japan
| | - Masayuki Shimoda
- Islet Cell Transplantation Project, National Center for Global Health and Medicine, Tokyo, Japan
| |
Collapse
|
|
40
|
Luo S, Ma X, Li X, Xie Z, Zhou Z. Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition. Diabetes Metab Res Rev 2020; 36:e3317. [PMID: 32223049 DOI: 10.1002/dmrr.3317] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 03/17/2020] [Accepted: 03/19/2020] [Indexed: 12/18/2022]
Abstract
Fulminant type 1 diabetes (FT1D) is a subset of type 1 diabetes characterized by extremely rapid pancreatic β-cell destruction with aggressive progression of hyperglycaemia and ketoacidosis. It was initially classified as idiopathic type 1 diabetes due to the absence of autoimmune markers. However, subsequent studies provide evidences supporting the involvement of autoimmunity in rapid β-cell loss in FT1D pathogenesis, which are crucial for FT1D being an autoimmune disease. This article highlights the role of immunological aspects in FT1D according to the autoimmune-associated genetic background, viral infection, innate immunity, adaptive immunity, and pancreas histology.
Collapse
Affiliation(s)
- Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Xiaoxi Ma
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| |
Collapse
|
|
41
|
Akturk HK, Michels AW. Adverse events associated with immune checkpoint inhibitors: a new era in autoimmune diabetes. Curr Opin Endocrinol Diabetes Obes 2020; 27:187-193. [PMID: 32618630 PMCID: PMC7357891 DOI: 10.1097/med.0000000000000546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. RECENT FINDINGS A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. SUMMARY Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.
Collapse
Affiliation(s)
- Halis Kaan Akturk
- Barbara Davis Center for Diabetes, University of Colorado, School of Medicine, Aurora, CO, USA
- Corresponding author: Halis Kaan Akturk MD, Assistant Professor of Medicine and Pediatrics, Barbara Davis Center for Diabetes, University of Colorado, 1775 Aurora Ct. Room 1318 Aurora, CO, 80045, P: 303-724-0467,
| | - Aaron W. Michels
- Barbara Davis Center for Diabetes, University of Colorado, School of Medicine, Aurora, CO, USA
| |
Collapse
|
|
42
|
Zagouras A, Patil PD, Yogi-Morren D, Pennell NA. Cases from the Immune-Related Adverse Event Tumor Board: Diagnosis and Management of Immune Checkpoint Blockade-Induced Diabetes. Oncologist 2020; 25:921-924. [PMID: 32564463 DOI: 10.1634/theoncologist.2019-0806] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 05/14/2020] [Indexed: 01/15/2023] Open
Abstract
The addition of immune checkpoint inhibitors to the armamentarium of cancer therapies has resulted in unprecedented improvement in clinical outcomes for a vast range of malignancies. Because they interfere with the physiologic function of immune checkpoints, such as programmed cell death protein 1 or cytotoxic T-lymphocyte-associated protein 4, to promote self-tolerance, these agents are associated with a unique spectrum of immune-related adverse events (irAEs). Immune-mediated endocrinopathies are among the most commonly noted irAEs. Immune-mediated diabetes is an uncommon irAE but can be associated with significant morbidity if it is not recognized and treated in a time-sensitive manner. In this manuscript, we present a case based discussion and review of the literature pertaining to immune-mediated diabetes associated with immune checkpoint blockade. KEY POINTS: Immune checkpoint inhibitor associated diabetes mellitus often resembles type 1 diabetes mellitus (DM) in its pathophysiology and clinical manifestations. However, some patients may present with type 2 DM or worsening hyperglycemia in the setting of pre-existent DM. Early recognition and management is key to preventing life-threatening events such as diabetic ketoacidosis. Endocrinology referral and interdisciplinary management should be considered for every patient to optimize glycemic control and to ensure optimal monitoring for long-term microvascular complications.
Collapse
Affiliation(s)
- Alexia Zagouras
- Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA
| | - Pradnya D Patil
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, Ohio, USA
| | - Divya Yogi-Morren
- Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nathan A Pennell
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, Ohio, USA
| |
Collapse
|
|
43
|
Kusuki K, Suzuki S, Mizuno Y. Pembrolizumab-induced fulminant type 1 diabetes with C-peptide persistence at first referral. Endocrinol Diabetes Metab Case Rep 2020; 2020:EDM190152. [PMID: 32478673 PMCID: PMC7219158 DOI: 10.1530/edm-19-0152] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/07/2020] [Indexed: 11/25/2022] Open
Abstract
SUMMARY A 72-year-old man with no history of diabetes was referred to our department due to hyperglycemia during pembrolizumab treatment for non-small-cell lung carcinoma. His blood glucose level was 209 mg/dL, but he was not in a state of ketosis or ketoacidosis. Serum C-peptide levels persisted at first, but gradually decreased, and 18 days later, he was admitted to our hospital with diabetic ketoacidosis (DKA). The patient was diagnosed with fulminant type 1 diabetes (FT1D) induced by pembrolizumab. According to the literature, the insulin secretion capacity of a patient with type 1 diabetes (T1D) induced by anti-programmed cell death-1 (anti-PD-1) antibody is depleted in approximately 2 to 3 weeks, which is longer than that of typical FT1D. Patients with hyperglycemia and C-peptide persistence should be considered for hospitalization or frequent outpatient visits with insulin treatment because these could indicate the onset of life-threatening FT1D induced by anti-PD-1 antibodies. Based on the clinical course of this patient and the literature, we suggest monitoring anti-PD-1 antibody-related T1D. LEARNING POINTS Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are increasingly used as anticancer drugs. Anti-PD-1 antibodies can cause immune-related adverse events, including T1D. FT1D, a novel subtype of T1D, is characterized by the abrupt onset of hyperglycemia with ketoacidosis, a relatively low glycated hemoglobin level and depletion of C-peptide level at onset. In patients being treated with anti-PD-1 antibody, hyperglycemia with C-peptide level persistence should be monitored through regular blood tests. Because of C-peptide persistence and mild hyperglycemia, it is possible to miss a diagnosis of life-threatening FT1D induced by anti-PD-1 antibody. In particular, in patients who have no history of diabetes, hyperglycemia without DKA is likely to be the very beginning of anti-PD-1 antibody-induced T1D. Therefore, such patients must be considered for either hospitalization or frequent outpatient visits with insulin injections and self-monitoring of blood glucose.
Collapse
Affiliation(s)
- Kazuhisa Kusuki
- Department of Diabetes and Endocrinology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Setagaya-ku, Tokyo, Japan
| | - Saya Suzuki
- Department of Diabetes and Endocrinology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Setagaya-ku, Tokyo, Japan
| | - Yuzo Mizuno
- Department of Diabetes and Endocrinology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Setagaya-ku, Tokyo, Japan
| |
Collapse
|
|
44
|
Fulminant type 1 diabetes: Report of a new French Caucasian case and recent findings. DIABETES & METABOLISM 2020; 46:174-176. [DOI: 10.1016/j.diabet.2018.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 04/10/2018] [Accepted: 04/18/2018] [Indexed: 01/03/2023]
|
|
45
|
Shah M, Rajha E, DiNardo C, Muckey E, Wierda WG, Yeung SCJ. Adverse Events of Novel Therapies for Hematologic Malignancies: What Emergency Physicians Should Know. Ann Emerg Med 2020; 75:264-286. [PMID: 31561995 DOI: 10.1016/j.annemergmed.2019.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/02/2019] [Accepted: 07/05/2019] [Indexed: 02/07/2023]
Abstract
In the past decade, rapid advances in therapeutic target discovery in hematologic malignancies have led to many clinical studies demonstrating efficacy of novel agents. Between 2014 and 2018, Food and Drug Administration approvals of new drugs and agents have increased, with greater than 2 dozen novel agents. Rapidly identifying the risk profiles of these cancer therapeutics that may present with acute toxicities and understanding the timing, sequence, duration, and treatment of disease processes are the most important challenges faced by practitioners in emergency medicine, even in nononcologic centers. The emergency medicine literature lags behind rapid advances in oncology, and guidelines for rapid recognition and management of these emerging entities are not familiar. In this Review Article, we discuss the most recent and clinically relevant developments in the arena of hematologic malignancies, further expanding on drug toxicities and their clinical presentations and offering suggestions for management. Specifically, we discuss immune-related adverse events after immune checkpoint inhibitor therapy (including myocarditis and hemophagocytic lymphohistiocytosis), chimeric antigen receptor-T cell therapy, cytokine release syndrome, chimeric antigen receptor-T cell-related encephalopathy syndrome, differentiation syndrome, sinusoid occlusion syndrome, QT-interval prolongation, and tumor lysis syndrome. Rapid advances in hematology and oncology will bring many new challenges for emergency health care providers in the near future; thus, the urgency to raise awareness among this community.
Collapse
Affiliation(s)
- Mohsin Shah
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Eva Rajha
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Courtney DiNardo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Erin Muckey
- Department of Emergency Medicine, NYU Langone Health, Bellevue Hospital Center, New York, NY
| | - William G Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sai-Ching J Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
| |
Collapse
|
|
46
|
Zafar MI. Suitability of APINCH high-risk medications use in diabetes mellitus. Eur J Pharmacol 2020; 867:172845. [DOI: 10.1016/j.ejphar.2019.172845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 11/15/2019] [Accepted: 12/03/2019] [Indexed: 12/17/2022]
|
|
47
|
Percik R, Shoenfeld Y. Check point inhibitors and autoimmunity: Why endocrinopathies and who is prone to? Best Pract Res Clin Endocrinol Metab 2020; 34:101411. [PMID: 32278687 DOI: 10.1016/j.beem.2020.101411] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Immunotherapy has transformed the treatment of cancer by restoring the power of the immune system against tumor cells. Disruption of the innate immune inhibition has introduced a large and growing spectrum of immune-related adverse effects (irAEs), with the endocrine system being a prominent target to autoimmune damage. What makes the endocrine system a prominent target when facing an unleashed immune system? Why are the endocrine irAEs mostly irreversible and unresponsive to glucocorticoid therapy? Is it possible to identify those prone to develop irAEs? The presents review describes the unique characteristics of the endocrine system and its crosstalk with the immune system. In a broader perspective, the iatrogenic side effects of immunotherapy provide a unique opportunity to explore the genetic, humoral and cytotoxic immune confounders.
Collapse
Affiliation(s)
- Ruth Percik
- Division of Endocrinology, Sheba Medical Center, Israel; Endo-Oncology Clinic, Oncology Institute, Sheba Medical Center, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yehuda Shoenfeld
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Russia.
| |
Collapse
|
|
48
|
Zezza M, Kosinski C, Mekoguem C, Marino L, Chtioui H, Pitteloud N, Lamine F. Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports. BMC Endocr Disord 2019; 19:144. [PMID: 31870373 PMCID: PMC6929418 DOI: 10.1186/s12902-019-0467-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/02/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.
Collapse
Affiliation(s)
- Marco Zezza
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Christophe Kosinski
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Carine Mekoguem
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Laura Marino
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Haithem Chtioui
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland
| | - Nelly Pitteloud
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Faiza Lamine
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland.
| |
Collapse
|
|
49
|
Percik R, Shlomai G, Tirosh A, Tirosh A, Leibowitz-Amit R, Eshet Y, Greenberg G, Merlinsky A, Barhod E, Steinberg-Silman Y, Sella T. Isolated autoimmune adrenocorticotropic hormone deficiency: From a rare disease to the dominant cause of adrenal insufficiency related to check point inhibitors. Autoimmun Rev 2019; 19:102454. [PMID: 31838158 DOI: 10.1016/j.autrev.2019.102454] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 08/03/2019] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. DESIGN A retrospective cohort study of a tertiary cancer center. METHODS Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis. RESULTS Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively. CONCLUSIONS IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.
Collapse
Affiliation(s)
- Ruth Percik
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Gadi Shlomai
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel; Pinchas Burstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Amir Tirosh
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amit Tirosh
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Raya Leibowitz-Amit
- Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yael Eshet
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Nuclear Medicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Gahl Greenberg
- Department of Diagnostic Imaging, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Alex Merlinsky
- Institute of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Ehud Barhod
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Yael Steinberg-Silman
- The Ella Lemelbaum Institute for Immuno-Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Tal Sella
- Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Pinchas Burstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Dana-Farber Cancer Institute, Boston, MA, USA
| |
Collapse
|
|
50
|
Immune Checkpoint Inhibitor Induced Diabetes Mellitus Treated with Insulin and Metformin: Evolution of Diabetes Management in the Era of Immunotherapy. Case Rep Oncol Med 2019; 2019:8781347. [PMID: 31781446 PMCID: PMC6875347 DOI: 10.1155/2019/8781347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/26/2019] [Indexed: 11/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICPIs) are a breakthrough therapy in oncology and have been approved by the Food and Drug Administration for the treatment of several malignancies. ICPIs have been reported to cause immune-mediated damage of islet cells leading to ICPI-induced type 1 diabetes mellitus (T1DM). These reports described patients presenting with severe diabetic ketoacidosis (DKA). We present a case of a 69-year-old Caucasian male with type 2 diabetes suffering from non-small cell lung cancer and undergoing treatment with pembrolizumab, an anti-programmed cell death protein-1 antibody, who presented to our emergency department with complaints of nausea, vomiting, polyuria, and polydipsia. He was found to have high anion gap metabolic acidosis with ketosis and elevated blood glucose levels consistent with DKA. Lab workup was consistent with T1DM. Despite being on a tailored insulin regimen, his blood glucose remained elevated, necessitating the addition of metformin to his regimen which effectively controlled his blood glucose.
Collapse
|