Skip to main content

Advertisement

SpringerLink
Log in

Autoimmune diabetes induced by PD-1 inhibitor—retrospective analysis and pathogenesis: a case report and literature review

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

BMS:

Bristol–Myers Squibb

BRAF:

Murine sarcoma viral oncogene homolog B1

GADA:

Glutamic acid decarboxylase antibody

HbA1c:

Glycated haemoglobin Insulinoma antigen-2 antibody

IA2A:

Insulinoma antigen-2 antibody

MEK:

Mitogen activated protein kinase kinase

NOD:

Non-obese diabetic

ZnT8A:

Zinc transporter 8 antibody

References

  1. Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. doi:10.1056/NEJMoa1412082

    Article  CAS  PubMed  Google Scholar 

  2. Wang J, Yoshida T, Nakaki F et al (2005) Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 102:11823–11828. doi:10.1073/pnas.0505497102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rajasalu T, Brosi H, Schuster C et al (2010) Deficiency in B7–H1 (PD-L1)/PD-1 coinhibition triggers pancreatic β-cell destruction by insulin-specific, murine CD8 T-cells. Diabetes 59:1966–1973. doi:10.2337/db09-1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Guleria I, Gubbels Bupp M, Dada S et al (2007) Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clin Immunol 125:16–25. doi:10.1016/j.clim.2007.05.013

    Article  CAS  PubMed  Google Scholar 

  5. Hansen E, Sahasrabudhe D, Sievert L (2016) A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome. Cancer Immunol Immunother 65:765–767. doi:10.1007/s00262-016-1835-4

    Article  PubMed  Google Scholar 

  6. Martin-Liberal J, Furness AJS, Joshi K et al (2015) Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother 64:765–767. doi:10.1007/s00262-015-1689-1

    Article  PubMed  Google Scholar 

  7. Mellati M, Eaton KD, Brooks-Worrell BM et al (2015) Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 38:e137–e138. doi:10.2337/dc15-0889

    Article  CAS  PubMed  Google Scholar 

  8. Hughes J, Vudattu N, Sznol M et al (2015) Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 38:e55–e57. doi:10.2337/dc14-2349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gaudy C, Clévy C, Monestier S et al (2015) Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 38:e182–e183. doi:10.2337/dc15-1331

    Article  PubMed  Google Scholar 

  10. Munakata W, Ohashi K, Yamauchi N, Tobinai K (2017) Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. Int J Hematol 105:383–386. doi:10.1007/s12185-016-2101-4

    Article  PubMed  Google Scholar 

  11. Teramoto Y, Nakamura Y, Asami Y et al (2017) Case of type 1 diabetes associated with less-dose nivolumab therapy in a melanoma patient. J Dermatol 44:605–606. doi:10.1111/1346-8138.13486

    Article  PubMed  Google Scholar 

  12. Miyoshi Y, Ogawa O, Oyama Y (2016) Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med 239:155–158. doi:10.1620/tjem.239.155

    Article  CAS  PubMed  Google Scholar 

  13. Okamoto M, Okamoto M, Gotoh K et al (2016) Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig 7:915–918. doi:10.1111/jdi.12531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hofmann L, Forschner A, Loquai C et al (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–199. doi:10.1016/j.ejca.2016.02.025

    Article  CAS  PubMed  Google Scholar 

  15. Aleksova J, Lau PKH, Soldatos G, McArthur G (2016) Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma. BMJ Case Rep 2016:2016217454. doi:10.1136/bcr-2016-217454

    Article  Google Scholar 

  16. Lowe JR, Perry DJ, Salama AKS et al (2016) Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer 4:89. doi:10.1186/s40425-016-0196-z

    Article  PubMed  PubMed Central  Google Scholar 

  17. Usui Y, Udagawa H, Matsumoto S et al (2017) 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 12:e41–e43. doi:10.1016/j.jtho.2016.12.015

    Article  PubMed  Google Scholar 

  18. Chae YK, Chiec L, Mohindra N et al (2017) A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother 66:25–32. doi:10.1007/s00262-016-1913-7

    Article  CAS  PubMed  Google Scholar 

  19. Ishikawa K, Shono-Saito T, Yamate T et al (2017) A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. Eur J Dermatol 27:184–185. doi:10.1684/ejd.2016.2923

    PubMed  Google Scholar 

  20. Imagawa A, Hanafusa T, Miyagawa JI et al (2000) A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med 342:301–307. doi:10.1056/NEJM200002033420501

    Article  CAS  PubMed  Google Scholar 

  21. Moreau C, Drui D, Arnault-Ouary G et al (2008) Fulminant type 1 diabetes in Caucasians: a report of three cases. Diabetes Metab 34:529–532. doi:10.1016/j.diabet.2008.05.003

    Article  CAS  PubMed  Google Scholar 

  22. Imagawa A, Hanafusa T, Awata T et al (2012) 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 (2012). J Diabetes Investig 3:536–539. doi:10.1111/jdi.12024

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lampasona V, Liberati D (2016) Islet autoantibodies. Curr Diab Rep 16:53. doi:10.1007/s11892-016-0738-2

    Article  PubMed  Google Scholar 

  24. Kochupurakkal NM, Kruger AJ, Tripathi S et al (2014) Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes. PLoS ONE 9:e89561. doi:10.1371/journal.pone.0089561

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fujisawa R, Haseda F, Tsutsumi C et al (2015) Low programmed cell death-1 (PD-1) expression in peripheral CD4(+) T cells in Japanese patients with autoimmune type 1 diabetes. Clin Exp Immunol 180:452–457. doi:10.1111/cei.12603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author Contributions

Marie-Léa Gauci, Philippe Boudou, Céleste Lebbé and Jean-François Gautier had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors made substantial contributions to study conception, and subsequent acquisition, analysis and interpretation of data. All authors made substantial scientific and intellectual contributions to the drafting and rewriting of the initial and revised manuscript.

Funding sources

This research did not receive any specific grant from any funding agencies in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France

    Marie-Léa Gauci, Pauline Laly, Barouyr Baroudjian, Jérémy Gottlieb, Nika Madjlessi-Ezra, Laetitia Da Meda, Martine Bagot, Nicole Basset-Seguin, Cécile Pages & Céleste Lebbé

  2. INSERM U976, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France

    Marie-Léa Gauci, Pauline Laly, Barouyr Baroudjian, Jérémy Gottlieb, Nika Madjlessi-Ezra, Laetitia Da Meda, Isabelle Madelaine-Chambrin, Martine Bagot, Nicole Basset-Seguin, Cécile Pages, Samia Mourah & Céleste Lebbé

  3. AP-HP Hormonology Department, Saint-Louis Hospital, Paris, France

    Philippe Boudou

  4. Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France

    Philippe Boudou

  5. AP-HP Diabetology Department, Lariboisière Hospital, Paris, France

    Tiphaine Vidal-Trecan & Jean-François Gautier

  6. INSERM U1138, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France

    Tiphaine Vidal-Trecan & Jean-François Gautier

  7. AP-HP Pharmacology Department, Saint-Louis Hospital, Paris, France

    Isabelle Madelaine-Chambrin

  8. AP-HP Pharmacogenomic Laboratory, Saint-Louis Hospital, Paris, France

    Samia Mourah

Authors
  1. Marie-Léa Gauci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pauline Laly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tiphaine Vidal-Trecan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barouyr Baroudjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jérémy Gottlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nika Madjlessi-Ezra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laetitia Da Meda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isabelle Madelaine-Chambrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Martine Bagot
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicole Basset-Seguin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cécile Pages
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Samia Mourah
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Philippe Boudou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Céleste Lebbé
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jean-François Gautier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie-Léa Gauci.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from the participant in the study.

Additional information

Philippe Boudou, Céleste Lebbé and Jean-François Gautier are co-last authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gauci, ML., Laly, P., Vidal-Trecan, T. et al. Autoimmune diabetes induced by PD-1 inhibitor—retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother 66, 1399–1410 (2017). https://doi.org/10.1007/s00262-017-2033-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2033-8

Keywords

Search

Navigation