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

Abstract

Context: 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. Evidence Acquisition: Systematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms diabetes or ketoacidosis and pembrolizumab, nivolumab, PD-1 inhibitor, or immunotherapy. Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers. Evidence Synthesis: We provide an overview of all published cases (n = 42) of PD-1 inhibitorinduced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and glutamic acid decarboxylase antibodypositive diabetes mellitus, in a patient with a diabetes-prone HLA genotype. She presented with diabetic ketoacidosis during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (b-cell antibodies and HLA type), treatment, and a screening protocol. Conclusions: Because the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during antiPD-1 therapy is necessary.