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Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype

  • Lucien Marchand
  • Arnaud Thivolet
  • Stéphane Dalle
  • Karim Chikh
  • Sophie Reffet
  • Julien Vouillarmet
  • Nicole Fabien
  • Christine Cugnet-Anceau
  • Charles Thivolet
Original Article

Abstract

Aims

Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors.

Methods

We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes.

Results

There were five men and one woman. Median age was 67 years (range 55–83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2–13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up.

Conclusions

In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Keywords

Diabetes mellitus Fulminant diabetes Autoimmune diabetes Immune checkpoint inhibitors side-effects Immunotherapy Programmed cell death-1 Anti-PD-1 Programmed death ligand 1 Anti-PD-L1 Pancreas volume Beta-cell pancreatic function Alpha-cell pancreatic function Exocrine pancreatic function Mixed meal test 

Notes

Acknowledgements

We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for help in manuscript preparation.

Author contributions

LM and CT collected clinical data and wrote the manuscript. LM, SR, JV, CCA and CT were clinicians in charge of managing patients’ endocrinopathies. AT analyzed the evolution of pancreas volume. NF tested autoantibodies. KC tested glucagon and C-peptide levels. SD analyzed the data, reviewed/edited the manuscript and contributed to the discussion. All authors gave final approval of the version to be published. CT is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no duality of interest associated with this manuscript.

Research involving human participants and/or animals

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent

Informed consent was obtained from all patients for being included in the study.

Supplementary material

592_2018_1234_MOESM1_ESM.docx (28 kb)
Supplemental Table 1: Glucose response during mixed meal test (DOCX 28 KB)
592_2018_1234_MOESM2_ESM.docx (28 kb)
Supplemental Table 2: Evolution of pancreas volume during immunotherapy in control patients who did not present diabetes (DOCX 28 KB)
592_2018_1234_MOESM3_ESM.jpg (3.2 mb)
Supplemental Figure 1 Change over time of pancreatic segmentation and volume. Subjects #1, #3, #5, and #6 presented fulminant diabetes. Timing of the 4 CT scans for each subject (in months after initiation of immunotherapy) was, respectively, 0/2/5/8 for subject #1; 0/12/13/16 for subject #3; 0/6/8.5/12 for subject #5; 0/2/3/5 for subject #6; 0/0/2/14 for subject #2 and 0/0/2.5/6 for subject #4. PV: Pancreatic volume (JPG 3285 KB)

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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Lucien Marchand
    • 1
  • Arnaud Thivolet
    • 2
  • Stéphane Dalle
    • 3
    • 4
  • Karim Chikh
    • 5
  • Sophie Reffet
    • 1
  • Julien Vouillarmet
    • 1
  • Nicole Fabien
    • 6
  • Christine Cugnet-Anceau
    • 1
    • 4
  • Charles Thivolet
    • 1
    • 7
  1. 1.Department of Endocrinology and DiabetesHospices Civils de Lyon, Lyon-Sud HospitalPierre-BéniteFrance
  2. 2.Department of RadiologyHospices Civils de LyonLyonFrance
  3. 3.Department of DermatologyHospices Civils de Lyon, Lyon-Sud HospitalPierre-BéniteFrance
  4. 4.ImmuCare (Immunology Cancer Research)Hospices Civils de LyonLyonFrance
  5. 5.Department of BiochemistryHospices Civils de Lyon, Lyon-Sud HospitalPierre-BéniteFrance
  6. 6.Department of ImmunologyHospices Civils de Lyon, Lyon-Sud HospitalPierre-BéniteFrance
  7. 7.CarMeN Laboratory (INSERM U1060, INRA U1235, Université Claude Bernard Lyon1, INSA-Lyon)Lyon 1 UniversityOullinsFrance

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