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      Anti-PD-1 pembrolizumab induced autoimmune diabetes in Chinese patient : A case report

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          Programmed cell death-1 protein (PD-1) antibody is an immune-checkpoint inhibitor that triggers anti-tumor response by enhancing immune response. Although PD-1 antibody has been reported effective in some malignant tumor, it can also induce significant immune-related adverse events (irAEs) such as autoimmune diabetes.

          Patient concerns:

          A 67-year-old male patient with non-small cell lung cancer (NSCLS) presented with polydipsia, polyuria, weakness, and weight loss after use of anti-programmed cell death-1 antibody therapy. Hyperglycemia, high serum ketone, low bicarbonate and high anion gap were compatible with the criteria of diabetic ketoacidosis (DKA).


          Autoimmune diabetes and diabetic ketoacidosis (DKA). The presence of low serum titers of c-peptide, high blood glucose together with diabetic ketoacidosis (DKA) that occurs shortly after the use of pembrolizumab strongly supported the diagnosis of anti-PD-1 induced autoimmune diabetes.


          The patient stopped using pembrolizumab while continuous subcutaneous insulin infusion (CSII) was started at the same time. The insulin infusion was switched to multiple daily injection (MDI) after he was discharged from hospital.


          The patient is now a well-controlled insulin-dependent patient with palliative care of NSCLS.


          Autoimmune diabetes induced by anti-programmed cell death-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) therapy is a rare, but life threatening immune-related side effect. Physicians should closely monitor diabetes-related indexes of patients who have been undergoing the treatment of anti-PD-1/PD-L1 therapy.

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          Most cited references 6

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          The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

          Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.
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            Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

            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.
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              Programmed Cell Death-1 Inhibitor–Induced Type 1 Diabetes Mellitus

              Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.

                Author and article information

                Medicine (Baltimore)
                Medicine (Baltimore)
                Wolters Kluwer Health
                November 2018
                09 November 2018
                : 97
                : 45
                [a ]Department of Endocrinology, Second Affiliated Hospital of Soochow University, Suzhou
                [b ]Department of Endocrinology, Quanzhou First Hospital, Fujian Medical University, Quanzhou, China.
                Author notes
                []Correspondence: Chen Fang, Department of Endocrinology, Second Affiliated Hospital of Soochow University, Suzhou 215004, China (e-mail: afa9911@ ).
                MD-D-18-03028 12907
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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