Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy
We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy.
We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search.
Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile–third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4–9.4) μg/day, and 0.46 (0.20–0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive.
Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.
KeywordsNivolumab Pembrolizumab Anti-PD-1 antibody Fulminant type 1 diabetes Type 1 diabetes Immune-checkpoint inhibitors
The other member of the Japan Diabetes Society Committee on Type 1 Diabetes Mellitus Research is Seiho Nagafuchi (Faculty of Medicine, Saga University). The authors express their sincere gratitude to the authors of the referenced cases, attending doctors, and diabetes specialists affiliated with the JDS for answering the questionnaire: Drs. Masahide Okamoto (Oita University), Osamu Ogawa (Kameda Medical Center), Emi Itateyama (Oita Red Cross Hospital), Hiroyuki Ohtake (Saitama Medical Center), Yushi Hirota (Kobe University), Masako Tomoyasu (Tokyu Hospital), Yasushi Nakajima (Nippon Medical School Hospital), Seiichi Yano (Kyushu University), Kenji Ashida (Kyushu University), Ryo Kumagai (Mito Kyodo General Hospital), Hiroaki Yagyu (Mito Kyodo General Hospital), Nobuyuki Koriyama (Kagoshima Medical Center), Michiaki Fukui (Kyoto Prefectural University of Medicine), Harumi Daikoku (Showa General Hospital), Shiko Asai (Kawasaki Municipal Tama Hospital), Akihiro Mochida (Juntendo University Urayasu Hospital), Fumitaka Okajima (Nippon Medical School Chiba Hokusoh Hospital), Satoshi Takagi (Tokyo Women’s Medical University), Kaoru Nagasawa (Toranomon Hospital), and Yasunori Taketomo (Kindai University). The authors also sincerely thank the doctors at Osaka University for their assistance with this study: Drs. Chisaki Ishibashi, Kenji Fukui, Hiromi Iwahashi, and Iichiro Shimomura.
Compliance with ethical standards
Conflict of interest
Akihisa Imagawa received scholarship donations from Ono Pharmaceutical Co., Ltd. and MSD and honoraria for lectures from Ono Pharmaceutical Co., Ltd. Norio Abiru received research grants from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Hiroshi Ikegami received a scholarship grant from Ono Pharmaceutical Co., Ltd. Yumiko Kawabata received a scholarship grant from Ono Pharmaceutical Co., Ltd. Other authors declare that they have no conflicts of interest.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (The Ethics Committees of the JDS, date of approval: 26 August 2016, approval number: 28-003-(2), Osaka University Hospital, date of approval: 27 April 2016, approval number: 15589, and Osaka Medical College, date of approval: 10 January 2017, approval number: 2098) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
- 4.Baden MY, Imagawa A, Iwahashi H, Shimomura I, Awata T, Ikegami H, Uchigata Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Shimada A, Takahashi K, Tanaka S, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T. Risk factors for sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus. Diabetol Int. 2016;7:281–8.CrossRefGoogle Scholar
- 6.Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand JP, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria JC, Marabelle A, Lambotte O. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.CrossRefPubMedGoogle Scholar
- 9.Ono Pharmaceutical Co., Ltd. Safety appropriate use information. https://www.opdivo.jp/basic-info/report/ (article in Japanese). Accessed 9 Feb 2018
- 10.MSD. Side effect. https://www.msdconnect.jp/products/keytruda/safety.xhtml (article in Japanese). Accessed 9 Feb 2018
- 11.Murao S, Makino H, Kaino Y, Konoue E, Ohashi J, Kida K, Fujii Y, Shimizu I, Kawasaki E, Fujiyama M, Kondo S, Tanaka K, Tarumi Y, Seto I, Kato K, Ohno K, Kusunoki Y, Ebisui O, Takada Y, Tanabe K, Takemoto K, Onuma H, Nishimiya T, Osawa H. Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients. Diabetes. 2004;53:2684–90.CrossRefPubMedGoogle Scholar
- 12.Imagawa A, Hanafusa T, Iwahashi H, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Maruyama T, Makino H. Uniformity in clinical and HLA-DR status regardless of age and gender within fulminant type 1 diabetes. Diabetes Res Clin Pract. 2008;82:233–7.CrossRefPubMedGoogle Scholar
- 14.Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, Shimizu I, Takahashi K, Nagata M, Makino H, Maruyama T. Report of the Committee of the Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus. Diabetol Int. 2012;3:179–83.CrossRefGoogle Scholar
- 15.Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, Shimizu I, Takahashi K, Nagata M, Makino H, Maruyama T. Report of the Committee of the Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus. J Diabetes Investig. 2012;3:536–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, Tominaga M, Oikawa S, Noda M, Kawamura T, Sanke T, Namba M, Hashiramoto M, Sasahara T, Nishio Y, Kuwa K, Ueki K, Takei I, Umemoto M, Murakami M, Yamakado M, Yatomi Y, Ohashi H. International clinical harmonization of glycated hemoglobin in Japan: from Japan Diabetes Society to National Glycohemoglobin Standardization Program values. J Diabetes Investig. 2012;3:39–40.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Daikoku H, Shigeta M, Minakata M, Hidaka N. A case of acute-onset type 1 diabetes mellitus developed after the administration of anti-PD-1 antibody. J Jpn Diabetes Soc. 2016;59:811–8 (article in Japanese).Google Scholar
- 22.Usui Y, Udagawa H, Matsumoto S, Imai K, Ohashi K, Ishibashi M, Kirita K, Umemura S, Yoh K, Niho S, Osame K, Goto K. Association of serum anti-GAD antibody and HLA haplotypes with type 1 diabetes mellitus triggered by nivolumab in patients with non-small cell lung cancer. J Thorac Oncol. 2017;12:e41–3.CrossRefPubMedGoogle Scholar
- 24.Kumagai R, Muramatsu A, Nakajima R, Fujii M, Kaino K, Katakura Y, Okumura N, Ohara G, Kagohashi K, Satoh H, Yagyu H. Acute-onset type 1 diabetes mellitus caused by nivolumab in a patient with advanced pulmonary adenocarcinoma. J Diabetes Investig. 2017;8:798–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Asai S, Katabami T, Kawanabe S, Igarashi K, Fukuda H, Tanaka Y. A case of fulminant type 1 diabates mellitus developed after the administration of nibormab, an immune checkpoint inhibitor. J Jpn Diabetes Soc. 2017;60:237–43 (article in Japanese).Google Scholar
- 26.Matsumura K, Nagasawa K, Oshima Y, Kikuno S, Hayashi K, Nishimura A, Okubo M, Uruga H, Kishi K, Kobayashi T, Mori Y. Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab. J Diabetes Investig. 2018;9:438–41 (epub ahead of print) CrossRefPubMedGoogle Scholar
- 27.Hanafusa T, Imagawa A, Iwahashi H, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Maruyama T, Makino H. Report of the Japan Diabetes Society’s Committee on research on fulminant type 1 diabetes mellitus: analysis of antiviral antibodies at disease onset. J Jpn Diabetes Soc. 2008;51:531–6 (article in Japanese).Google Scholar
- 28.Gauci ML, Laly P, Vidal-Trecan T, Baroudjian B, Gottlieb J, Madjlessi-Ezra N, Da Meda L, Madelaine-Chambrin I, Bagot M, Basset-Seguin N, Pages C, Mourah S, Boudou P, Lebbe C, Gautier JF. Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother. 2017;66:1399–410.CrossRefPubMedGoogle Scholar
- 29.Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Göppner D, Hassel JC, Meier F, Tietze JK, Thomas I, Weishaupt C, Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209.CrossRefPubMedGoogle Scholar
- 34.Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68. https://doi.org/10.1200/jco.2017.77.6385 (Epub ahead of print).CrossRefPubMedGoogle Scholar