Abstract Introduction Immune checkpoint inhibitors (ICIs) such as pembrolizumab (anti-PD-1) have transformed oncologic treatment but are associated with immune-related adverse events (irAEs) that can affect various organ systems, especially the endocrine system. ICI-induced diabetes mellitus (ICI-DM) is a rare but potentially serious irAE, characterized by acute β-cell failure and a permanent insulin-dependent state, with reported incidence of 1%. The immunopathogenic mechanisms and genetic predispositions that cause this complication have not been well established. We present a case of new-onset, non-DKA hyperglycemia in an elderly male following pembrolizumab therapy, highlighting mechanistic and genetic considerations. Case Presentation An 84-year-old male with non-small cell lung cancer (NSCLC) on pembrolizumab presented 20 days after initial infusion with polyuria, polydipsia and confusion. Initial laboratory testing revealed serum glucose of 863 mg/dL and HbA1c of 9.1%. There was no anion gap, and the patient was in hyperosmolar hyperglycemic state instead of diabetic ketoacidosis. He had no prior history of diabetes. He was also found to have acute kidney injury (Cr 1.32 mg/dL), which resolved with IV hydration. Subsequent autoimmune workup revealed glutamic acid decarboxylase 65 (GAD65) antibody 250 IU/mL, consistent with autoimmune β-cell destruction, and ZNT8 antibodies of 11. C-peptide, IA-2, and HLA typing were not obtained. Pembrolizumab was held and the patient was initiated on a basal-bolus insulin regimen for glycemic control. His symptoms improved and he was discharged on insulin therapy with endocrinology follow-up. Discussion There is growing recognition of ICI-DM as an emerging immune-related adverse event associated with PD-1/PD-L1 immunotherapy, especially in thoracic malignancy treatment. The hypothesized pathogenesis is the destruction of pancreatic β-cells by T cells after the loss of immune self-tolerance, which leads to irreversible insulin-dependent states. Pembrolizumab enhances the effect of cytotoxic T cells while inhibiting regulatory T-cell function, thereby allowing autoreactive lymphocytes to attack pancreatic islets. The elevated GAD65 antibody in this patient supports an autoimmune mechanism. Genetic susceptibility also appears relevant: HLA-DR4 and HLA-DQ8 haplotypes, common in classic type 1 diabetes, are also overrepresented in ICI-DM. Other variants of PTPN22, CTLA4, and INS genes might also contribute to β-cell autoimmunity. The absence of HLA testing in our patient underscores a potential gap in pre-immunotherapy screening. Emerging of irAEs such as ICI-DM, thyroiditis, pneumonitis can be expected with the expanding use of immunotherapy. Future studies are needed to determine whether baseline autoimmune and HLA screening can be used to identify identify at-risk individuals and guide surveillance or therapeutic strategies. This abstract is funded by: None
Liu et al. (Fri,) studied this question.