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

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.

Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes

“…In the subset for whom autoantibodies were present at CPI‐DM diagnosis, it is unknown if they were present preceding treatment, potentially allowing for risk prediction, or whether they have developed during the course of treatment. Pretreatment serum was available for a limited number of cases, and these have had mixed results . It is also unknown if the presence or absence of these autoantibodies represents different forms of CPI‐DM.…”

Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management

“…Gauci et al reviewed data from 24 reported cases of DM after the use of ICIs. Although the presence of serum islet β‐cell‐related autoantibodies at the onset of diabetes supports the autoimmune nature of type 1 diabetes, only 11 of 22 patients tested (50%) had positive anti‐glutamic acid decarboxylase 65.…”

New onset diabetes after nivolumab treatment

“…There is a lack of information regarding the haplotype testing in the cases published, but a few patients were found to have haplotype DRB1*04 as reported in this case 2 12 20. This haplotype has been suggested to contribute to the development of T1DM after anti-PD-1 therapy 7. Therefore, in the future, the search for specific haplotype can possibly help to identify patients at risk of DKA.…”