LAUSR

Nivolumab, an Immune Checkpoint Inhibitor (ICI) against programmed death-1 receptors expressed on T-lymphocytes, has been approved by the Food and Drug Administration (FDA) for the treatment of multiple cancers such as Nonsquamous Cell Lung Cancer [1]. There are some concerns on this class of ICIs about immune-related adverse events, including thyroid dysfunction, hypophysitis, adrenal insufficiency and autoimmune diabetes mellitus (DM) [1]. Fulminant DM is a clinical entity firstly described in Japan, mainly characterized by markedly rapid onset of hyperglycemia with ketoacidosis, near normal glycated hemoglobin (HbA1c) levels despite remarkable hyperglycemia. Peculiar genetic factors, including human leukocyte antigen genes, are associated with the development of this subtype of diabetes and this could be the reason of the more frequent presentation of these cases in Asian populations. The Japanese Diabetes association has provided criteria for the diagnosis of this form of DM [2]. Nivolumab-induced DM resembles fulminant DM as the severe acute onset with extremely acute hyperglycemia and DKA could lead, if not recognized and properly treated, to patient exitus. Several nivolumab-induced diabetic cases are reported in literature but mainly in Asia or other continents, also recently reviewed [3]. Here, we present, to our knowledge, the first Italian nivolumab-induced fulminant type 1 DM case report. The patient is a 42-year-old man affected by a pulmonary adenocarcinoma at stage IV. Despite his positive family history for T1DM (his father died at 55 years for cardiac diabetic complications), the patient had neither a history of diabetes mellitus himself nor evidence of pancreatic metastases. He had been started on nivolumab (3 mg/kg) once every 2 weeks on the 21st of July 2016 for four cycles (last cycle the 2nd of September). Fasting plasma glucose (FPG) was 87 mg/dL before starting nivolumab, still 84 mg/dL in August and 103 mg/dL on the 12th of September 2016. On 20th of September FPG rose to 147 mg/dL. Preoperative checks required by thoracic surgeon few days later revealed an FBG of 335 mg/dl and HbA1c 6% (42 mmol/mol). He was admitted in our Division on the 5th of October 2016 with mild diabetic ketoacidosis (arterial pH 7.29, highly positive urine ketones), random PG of 632 mg/ dL with fructosamine 183.7 umol/l (vn < 285), 33 days after the last administration of nivolumab. Basal serum C-peptide was 0.2 ng/dL with no response to the glucagon stimulation test (0.2 ng/mL in all the four determinations of the test). Serum amylase and lipase were normal on admission. No history of flu-like symptoms in the last 3 months before admission was reported. The patient was diagnosed as having nivolumab-induced fulminant T1DM with severe insulin deficiency. Antibodies against glutamic acid decarboxylase were positive (22.9 U/ml), whereas anti-IA2 (insulinoma-associated antigen-2) antibodies and Islet Cell Autoantibodies (ICA) were negative. Human leukocyte antigen class II haplotypes were DRB1*03:15-DQB1*02:06. He was treated with intravenous hydration, insulin drip, and electrolyte replacement. Thereafter, he continued to require insulin therapy and was subsequently discharged on subcutaneous multiple daily insulin (MDI) treatment. Serum C-peptide was still low at 0.1 ng/mL 3 months after the discharge, with a poor metabolic control persistent until nowadays (about 2 years from Managed by Massimo Porta.