Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab

Abstract

Background Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case A 61-year-old male with advanced melanoma presented with a three-day history of nausea, vomiting, and malaise. He was started on nivolumab and ipilimumab. After the third dose, he developed a generalized rash and was prescribed high-dose prednisone. Labs revealed potassium 9.5 mmol/L, sodium 127 mmol/L, bicarbonate <10 mmol/L, blood glucose 1211 mg/dL, anion gap >31 mmol, arterial blood pH 7.14, and beta-hydroxybutyrate 13.7 mmol/L. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 6.9%. C-peptide was undetectable (<0.1 ng/ml). Glutamic acid decarboxylase autoantibodies, zinc transporter 8 autoantibodies, insulin autoantibodies, islet antigen 2 autoantibodies, and islet cell antibodies were all negative. Conclusion Anti-PD-1 immunotherapy is effective in cancers refractory to standard chemotherapy. These agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects. We recommend conducting routine blood glucose checks in patients on these agents.

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

“…Supplementary Table 1 (see section on supplementary data given at the end of this article) provides an overview of our search terms. Additionally, the authors reviewed the reference lists of the included articles (4, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) and identified five additional cases (69, 70, 71, 72). The following data were extracted from each manuscript: author, year of publication, age, gender and ethnicity of the patient, cancer type, checkpoint inhibitor therapy, number of cycles of therapy, prior immunotherapy, relevant past medical history (PMH), presence of diabetic ketoacidosis, glycemia, glycated hemoglobin, C-peptide, islet autoantibodies, lipase, other irAE and HLA genotype.…”

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

“…Programmed cell death receptor (PD-1) and programmed cell death ligand (PD-L1) represent an immune checkpoint involved in regulating T-cells at the level of the peripheral tissues. Tumors can express PD-L1 and use these ligands to evade the host's immune system, making this checkpoint a potential target for cancer therapy [ 40 , 41 ]. This pathway inspired the development of monoclonal antibodies that block the interaction between PD-1 receptors and PD-L1 ligands to help restore anticancer immune responses [ 42 ].…”

“…Some of the adverse effects are mild and easily controlled with systemic steroids, but others can be serious and fatal. In their attempt to augment the immune response, PD-1 inhibitors can breach immunologic tolerance by upregulating autoreactive T-cells causing immune mediated reactions such as rash, pneumonitis, colitis, thyroiditis, hepatitis, nephritis, uveitis, adrenalitis, facial nerve paresis, hypophysitis, aseptic meningitis, and fulminant diabetes [ 41 ]. The role of autoimmunity has been recognized as a pathogenic mechanism in low risk MDS but is still under discussion and not clearly delineated.…”

Rapid onset type-1 diabetes and diabetic ketoacidosis secondary to nivolumab immunotherapy: a review of existing literature

“…Only cases that involved nivolumab and had developed DKA were included in this study. A total of 20 patients were included in this study, and their patient data is presented in table 1 1 16–31…”