Endocrinology and Metabolism

Hiroshi Arima

3 Articles

Diabetes, Obesity and Metabolism
Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors: Hidefumi Inaba, Yosuke Kaido, Saya Ito, Tomonao Hirobata, Gen Inoue, Takakazu Sugita, Yuki Yamamoto, Masatoshi Jinnin, Hiroaki Kimura, Tomoko Kobayashi, Shintaro Iwama, Hiroshi Arima, Takaaki Matsuoka; Endocrinol Metab. 2022;37(1):84-95. Published online February 28, 2022; DOI: https://doi.org/10.3803/EnM.2021.1282

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Background
Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear.
Methods
In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021.
Results
Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset.
Conclusion
Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

Citations

Citations to this article as recorded by

Immune checkpoint inhibitor‐related type 1 diabetes incidence, risk, and survival association
Fumika Kamitani, Yuichi Nishioka, Miyuki Koizumi, Hiroki Nakajima, Yukako Kurematsu, Sadanori Okada, Shinichiro Kubo, Tomoya Myojin, Tatsuya Noda, Tomoaki Imamura, Yutaka Takahashi
Journal of Diabetes Investigation.2025; 16(2): 334. CrossRef
Immune checkpoint inhibitor-related diabetes mellitus associated with high signal intensity in diffusion-weighted magnetic resonance imaging of the pancreas at an early clinical stage
Masaki Suzuki, Yushi Hirota, Shin Urai, Masaaki Yamamoto, Keitaro Sofue, Wataru Ogawa
Hormones.2025;[Epub] CrossRef
Durvalumab-induced Type 1 Diabetes in a Patient With Pre-existing GADA-positive Diabetes and Preserved Insulin Secretion
Nobuhiro Nakatake, Megumi Matsuda, Hiroki Kontani
JCEM Case Reports.2025;[Epub] CrossRef
Machine-Learning Parsimonious Prediction Model for Diagnostic Screening of Severe Hematological Adverse Events in Cancer Patients Treated with PD-1/PD-L1 Inhibitors: Retrospective Observational Study by Using the Common Data Model
Seok Jun Park, Seungwon Yang, Suhyun Lee, Sung Hwan Joo, Taemin Park, Dong Hyun Kim, Hyeonji Kim, Soyun Park, Jung-Tae Kim, Won Gun Kwack, Sung Wook Kang, Yun-Kyoung Song, Jae Myung Cha, Sang Youl Rhee, Eun Kyoung Chung
Diagnostics.2025; 15(2): 226. CrossRef
Type 1 diabetes mellitus affected by potential toxicity from long-term use of nivolumab
Yuma Motomura, Shin Urai, Yushi Hirota, Naoki Takegawa, Hironori Bando, Masaaki Yamamoto, Hidenori Fukuoka, Masahiro Tsuda, Wataru Ogawa
Diabetology International.2024; 15(1): 130. CrossRef
Review – The impact of pharmacogenetics on the outcome of immune checkpoint inhibitors
Karlijn de Joode, Niels Heersche, Edwin A. Basak, Sander Bins, Astrid A.M. van der Veldt, Ron H.N. van Schaik, Ron H.J. Mathijssen
Cancer Treatment Reviews.2024; 122: 102662. CrossRef
Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes
Shunya Yabuki, Hiroyuki Hirai, Chihiro Moriya, Yoshiro Kusano, Takeo Hasegawa
Frontiers in Endocrinology.2024;[Epub] CrossRef
Reaching the Diagnosis of Checkpoint Inhibitor-Induced Diabetes Mellitus in Different Clinical Scenarios: A Real-World Application of Updated Diagnostic Criteria
Anna Angelousi, Dimitrios C. Ziogas, Vasiliki Siampanopoulou, Chrysoula Mytareli, Amalia Anastasopoulou, George Lyrarakis, Helen Gogas
Diseases.2024; 12(2): 40. CrossRef
Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors
Ben Ponvilawan, Abdul Wali Khan, Janakiraman Subramanian, Dhruv Bansal
Cancers.2024; 16(6): 1225. CrossRef
A case of rapidly progressive insulin-dependent diabetes mellitus without islet autoantibodies developed over two years after the first dose of nivolumab
Kota Nishihama, Yuko Okano, Chisa Inoue, Kanako Maki, Kazuhito Eguchi, Soichiro Tanaka, Atsuro Takeshita, Mei Uemura, Taro Yasuma, Toshinari Suzuki, Esteban C. Gabazza, Yutaka Yano
Diabetology International.2024; 15(3): 583. CrossRef
HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis
Mayo Ono, Mototsugu Nagao, Haruki Takeuchi, Etsuya Fukunaga, Tomoko Nagamine, Kyoko Inagaki, Izumi Fukuda, Masato Iwabu
European Journal of Endocrinology.2024; 191(1): 9. CrossRef
Pathophysiology, diagnosis, and management of immune checkpoint inhibitor-induced diabetes mellitus
Eleni-Rafaela Kani, Eleftheria Karaviti, Dimitra Karaviti, Eleni Gerontiti, Ioanna A. Paschou, Katerina Saltiki, Katerina Stefanaki, Theodora Psaltopoulou, Stavroula A. Paschou
Endocrine.2024; 87(3): 875. CrossRef
A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome
John Marsiglio, Jordan P. McPherson, Magdalena Kovacsovics-Bankowski, Joanne Jeter, Christos Vaklavas, Umang Swami, Douglas Grossmann, Alyssa Erickson-Wayman, Heloisa P. Soares, Katie Kerrigan, Berit Gibson, Jennifer Anne Doherty, John Hyngstrom, Sheetal
Frontiers in Immunology.2023;[Epub] CrossRef
Predictive Biomarkers for Immune-Related Endocrinopathies following Immune Checkpoint Inhibitors Treatment
Almog Shalit, Panagiotis Sarantis, Evangelos Koustas, Eleni-Myrto Trifylli, Dimitris Matthaios, Michalis V. Karamouzis
Cancers.2023; 15(2): 375. CrossRef
Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events
Iñigo Les, Mireia Martínez, Inés Pérez-Francisco, María Cabero, Lucía Teijeira, Virginia Arrazubi, Nuria Torrego, Ana Campillo-Calatayud, Iñaki Elejalde, Grazyna Kochan, David Escors
Cancers.2023; 15(5): 1629. CrossRef
Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors
Hidefumi Inaba, Shuhei Morita, Daisuke Kosugi, Yuki Asai, Yosuke Kaido, Saya Ito, Tomonao Hirobata, Gen Inoue, Yuki Yamamoto, Masatoshi Jinnin, Hiroaki Kimura, Masao Ota, Yuko Okudaira, Hiroyasu Nakatani, Tomoko Kobayashi, Shintaro Iwama, Hiroshi Arima, T
Frontiers in Immunology.2023;[Epub] CrossRef
Clinical characteristics and human leukocyte antigens in patients with immune checkpoint inhibitor-induced type 1 diabetes and pituitary dysfunction: a single center prospective study
Natsuko Hara, Hirotsugu Suwanai, Fumiyoshi Yakou, Keitaro Ishii, Hajime Iwasaki, Hironori Abe, Jumpei Shikuma, Hiroyuki Sakai, Takashi Miwa, Ryo Suzuki
Endocrine.2023; 81(3): 477. CrossRef
Autoimmunity in immune checkpoint inhibitor‐induced immune‐related adverse events: A focus on autoimmune skin toxicity and pneumonitis
Fiamma Berner, Lukas Flatz
Immunological Reviews.2023; 318(1): 37. CrossRef
Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland
Ichiro Yamauchi, Takuro Hakata, Taku Sugawa, Daisuke Kosugi, Haruka Fujita, Kentaro Okamoto, Yohei Ueda, Toshihito Fujii, Daisuke Taura, Norio Harada, Nobuya Inagaki
Endocrine Journal.2023; 70(10): 987. CrossRef
Key Determinants of Immune-Mediated Adverse Reactions to Oncology Drugs
Yihan Zhou, Shan Ding
Cancers.2023; 15(23): 5622. CrossRef
Risk factors and predictors of immune-related adverse events: implications for patients with non-small cell lung cancer
Majd Issa, Joy Tang, Yizhen Guo, Chris Coss, Thomas A. Mace, Jason Bischof, Mitch Phelps, Carolyn J Presley, Dwight H Owen
Expert Review of Anticancer Therapy.2022; 22(8): 861. CrossRef
Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors
Adithya Chennamadhavuni, Laith Abushahin, Ning Jin, Carolyn J. Presley, Ashish Manne
Frontiers in Immunology.2022;[Epub] CrossRef
Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice
Pablo Rodríguez de Vera-Gómez, Ana Piñar-Gutiérrez, Raquel Guerrero-Vázquez, Virginia Bellido, Cristóbal Morales-Portillo, María Pilar Sancho-Márquez, Pablo Espejo-García, Noelia Gros-Herguido, Gema López-Gallardo, María Asunción Martínez-Brocca, Alfonso
Journal of Diabetes Research.2022; 2022: 1. CrossRef

Miscellaneous
Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors: Shintaro Iwama, Tomoko Kobayashi, Hiroshi Arima; Endocrinol Metab. 2021;36(2):312-321. Published online April 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1007

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Immune-related adverse events (irAEs) affecting the endocrine glands are among the most frequent irAEs induced by immune checkpoint inhibitors (ICIs) and include hypopituitarism, primary adrenal insufficiency, thyrotoxicosis, hypothyroidism, hypoparathyroidism, and type 1 diabetes mellitus. Since the incidence and clinical features of endocrine irAEs vary according to the ICI used, it is important to understand the characteristics of these irAEs and to manage each one appropriately. Since some endocrine irAEs, including adrenal crisis and diabetic ketoacidosis, are potentially life-threatening, predicting the risk of endocrine irAEs before their onset is critical. Several autoantibodies have been detected in patients who develop endocrine irAEs, among which anti-thyroid antibodies may be predictive biomarkers of thyroid dysfunction. In this review, we describe the clinical features of each endocrine irAE induced by ICIs and discuss their potential biomarkers, including autoantibodies.

Citations

Citations to this article as recorded by

Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors
Shintaro Iwama, Tomoko Kobayashi, Hiroshi Arima
Nature Reviews Endocrinology.2025;[Epub] CrossRef
Thyroid Dysfunction After Intensity-Modulated Radiotherapy and PD⁃1 Inhibitor Treatment for Locally Advanced Nasopharyngeal Carcinoma
Kai Shang, Qianyong He, Xinyu Xu, Xunyan Luo, Chaofen Zhao, Lina Liu, Zhuoling Li, Yuanyuan Li, Feng Jin
Therapeutics and Clinical Risk Management.2025; Volume 21: 15. CrossRef
Subacute thyroiditis during anti-programmed cell death protein 1 antibody therapy: A case report
Makiko Ikemoto, Yasufumi Seki, Daisuke Watanabe, Toshio Takagi, Atsuhiro Ichihara
Thyroid Science.2025; 2(2): 100024. CrossRef
Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events
Tomoko Kobayashi, Shintaro Iwama, Hiroshi Arima
Endocrine Journal.2024; 71(1): 23. CrossRef
A case of rapidly progressive insulin-dependent diabetes mellitus without islet autoantibodies developed over two years after the first dose of nivolumab
Kota Nishihama, Yuko Okano, Chisa Inoue, Kanako Maki, Kazuhito Eguchi, Soichiro Tanaka, Atsuro Takeshita, Mei Uemura, Taro Yasuma, Toshinari Suzuki, Esteban C. Gabazza, Yutaka Yano
Diabetology International.2024; 15(3): 583. CrossRef
Endocrinopathies Associated With Immune Checkpoint Inhibitor Use
Anupam Kotwal, Randol Kennedy, Nupur Kikani, Sonali Thosani, Whitney Goldner, Afreen Shariff
Endocrine Practice.2024; 30(6): 584. CrossRef
Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study
Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Tetsushi Izuchi, Koji Suzuki, Koki Otake, Yoshinori Yasuda, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Naoki Nishio, Shoi
Cancer Immunology, Immunotherapy.2024;[Epub] CrossRef
Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review
Kaoruko Fukushima, Saori Kitayama, Manami Sazuka, Remi Kodera, Kazuhito Oba, Kenji Toyoshima, Yuko Chiba, Hiroshi Yamamoto, Atsushi Araki, Yoshiaki Tamura
Cureus.2024;[Epub] CrossRef
Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade
Ayana Yamagami, Shintaro Iwama, Tomoko Kobayashi, Xin Zhou, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Tetsushi Izuchi, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima
Endocrine Journal.2024; 71(5): 515. CrossRef
Single-cell RNA sequencing analysis of peripheral blood mononuclear cells in PD-1-induced renal toxicity in patients with lung cancer
Shusu Liu, Peiyu Lu, Bixia Yang, Yan Yang, Hua Zhou, Min Yang
BMC Nephrology.2024;[Epub] CrossRef
Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction
Koji Suzuki, Tomoko Kobayashi, Tetsushi Izuchi, Koki Otake, Masahiko Ando, Tomoko Handa, Takashi Miyata, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Megumi Inoue, Makoto Ishii, Hiroshi Arima, Shintaro Iw
Frontiers in Endocrinology.2024;[Epub] CrossRef
Recovery from insulin dependence in immune checkpoint inhibitor‐associated diabetes mellitus: A case report
Marie Okubo, Yuji Hataya, Kanta Fujimoto, Toshio Iwakura, Naoki Matsuoka
Journal of Diabetes Investigation.2023; 14(1): 147. CrossRef
Case Report: A Rising Cause of New-Onset Endocrinopathies After Immunotherapy
Charity Tan, Sarah Hendricks, Kristina Hernandez, Martha Benavides, Rupinderjit Samra
The Journal for Nurse Practitioners.2023; 19(5): 104582. CrossRef
Risk of Thyroid Dysfunction in PD-1 Blockade Is Stratified by the Pattern of TgAb and TPOAb Positivity at Baseline
Xin Zhou, Shintaro Iwama, Tomoko Kobayashi, Masahiko Ando, Hiroshi Arima
The Journal of Clinical Endocrinology & Metabolism.2023; 108(10): e1056. CrossRef
Severe thyrotoxicosis induced by tislelizumab: a case report and literature review
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Frontiers in Oncology.2023;[Epub] CrossRef
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Cancers.2023; 15(24): 5786. CrossRef
Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline
Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Masahiko Ando, Xin Zhou, Ayana Yamagami, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tets
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Immune Checkpoint Inhibitors as a Threat to the Hypothalamus–Pituitary Axis: A Completed Puzzle
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Cancers.2022; 14(4): 1057. CrossRef
Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade
Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Xin Zhou, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Taka
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Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors
Fabiana Pani, Yoshinori Yasuda, Sylvie T Rousseau, Kevin C Bermea, Solmaz Roshanmehr, Rulin Wang, Srinivasan Yegnasubramanian, Patrizio Caturegli, Luigi Adamo
Journal for ImmunoTherapy of Cancer.2022; 10(12): e005538. CrossRef
Survival benefit of endocrine dysfunction following immune checkpoint inhibitors for nonthyroidal cancers
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Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study: Shintaro Iwama, Tomoko Kobayashi, Tetsushi Izuchi, Koji Suzuki, Takanori Murase, Masahiko Ando, Tomoko Handa, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Shoichiro Mori, Tomoyasu Sano, Shusuke Akamatsu, Masashi Akiyama, Makoto Ishii, Hiroshi Arima; Received September 24, 2024 Accepted November 18, 2024 Published online February 11, 2025; DOI: https://doi.org/10.3803/EnM.2024.2180 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) monotherapy induces two types of pituitary immunerelated adverse events (irAEs): multiple pituitary hormone deficiency (Multi-D; impairment of ≥2 anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD). Combination therapy with CTLA-4-Ab and anti-programmed cell death-1 antibody (PD-1/CTLA-4-Abs), which is increasingly replacing CTLA-4-Ab monotherapy, frequently causes pituitary irAEs; however, whether it increases Multi-D/IAD incidence is unknown.
Methods
In total, 74 and 748 patients with malignancies treated with PD-1/CTLA-4-Abs and PD-1-Ab, respectively, were prospectively evaluated for ACTH and cortisol levels at baseline and every 6 weeks after treatment initiation, and then observed until the last clinical visit. The characteristics of pituitary irAEs were evaluated by pituitary stimulation tests and compared with those induced by PD-1-Ab monotherapy.
Results
PD-1/CTLA-4-Abs therapy showed higher incidence rates of pituitary irAEs (16/74 [21.6%] vs. 25/748 [3.3%], P<0.001), Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001), and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) than PD-1-Ab monotherapy. ACTH deficiency was observed in all cases, whereas the prevalence rates of luteinizing hormone deficiency (8/16 [50.0%] vs. 1/25 [4.0%]), follicle-stimulating hormone deficiency (6/16 [37.5%] vs. 1/25 [4.0%]), and thyrotropin deficiency (4/16 [25.0%] vs. 0/25 [0%]) were significantly higher after PD-1/CTLA-4-Abs than after PD-1-Ab treatment. Pituitary enlargement, which was observed only in the Multi-D cases, was significantly more frequent after PD-1/CTLA-4-Abs than after PD-1-Ab treatment (6/16 [37.5%] vs. 0/25 [0%], P=0.002).
Conclusion
This prospective study revealed high risks of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, emphasizing the need for careful evaluation of pituitary function.

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