Immune Checkpoint Inhibitor Associated Type 1 Diabetes

Abstract

Background: Immune-checkpoint inhibitors are increasingly being used in cancer therapy. Nivolumab is a monoclonal antibody that has been used in a variety of conditions such as metastatic melanoma. Treatment with immune checkpoint inhibitors enhances immune response but is also known to diminish immune tolerance and increase autoimmune toxicity. Nivolumab works by binding and inhibiting the programmed death cell 1 receptor (PDC1). This is a negative regulator of the activity of the T lymphocytes. Normally the biding of PDC1 with PDL1 and PDL2 ligand will leads to inhibition of protein kinase signaling pathways that would lead to inhibition of T cells proliferation and production of cytokines. So Nivolumab will increase the response of T cells by blocking PDC1 increasing selectivity with tumoral cells. On the other hand, the use of nivolumab inhibiting the PD1 pathway could result in the loss of self-tolerance that can be related to an increase of autoimmune events. Such as autoimmune DM1. Case description: A 67-year-old woman was referred to the Endocrinology service for hypothyroidism in 2016. She had been diagnosed 5 years earlier with malignant melanoma on left forearm that was surgically removed, along with her lymph nodes. No chemo or radiation was required. There was no personal or family history of DM. Blood glucose levels were normal. About one month later, she found out her melanoma came back on her face, (edge of her mouth) and got treated with Nivolumab. A couple of months later she reported to the consult with fatigue, dry mouth, polydipsia, and polyuria. Symptoms were progressive and was hospitalized at initial dx of DM w/glucose >800. She got diagnosed with New onset diabetes. The Diagnosis confirmed with + GAD antibodies and low C-Peptide. Her hemoglobin A1C today (4 years later) is 6% with a fingerstick blood sugar of 147 mg/dl. Average glucose is 131 mg/dl with a standard deviation of 38.87. 87.1% of her blood sugars are staying in target range, low blood sugars less than 70 are 4.3%, high blood sugars are 8.6%. Conclusion: The diagnosis of insulin dependent DM is confirmed because of the clinical presentation, persistent hyperglycemia, and low C-peptide. The normal pre-nivolumab fasting blood glucose levels suggest the absence of diabetes prior to nivolumab. 4 years later, the patient has not shown any signs of remission, so, if develops, DM1 should be considered as a permanent complication of using Nivolumab.