Fulminant diabetes mellitus and concomitant enterovirus infection: a clinical case

Fulminant type 1 diabetes mellitus is a subtype of diabetes mellitus. It is characterized by the extremely rapid development of hyperglycemia and ketoacidosis because of the near-total destruction of pancreatic -cells. A clinical case of lethal, type 1, fulminant diabetes mellitus is presented. The patient management strategy and possible causes of the adverse course and outcome of the disease are analyzed.

Nivolumab-induced type 1 diabetes mellitus as an immune-related adverse event

Background Immune checkpoint inhibitors are medications that activate anti-tumor responses by disrupting the inhibitory signaling to T cells. Nivolumab is an immune checkpoint inhibitor that selectively blocks the programmed cell death-1 (PD-1). 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. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case A 49-year-old male with a body mass index of 26.4 kg/m2, a history of Dandy–Walker syndrome and epilepsy, and no personal or family history of diabetes underwent left radical nephrectomy and retroperitoneal lymph node dissection for stage IV metastatic renal cell carcinoma (metastases to lungs). He received first-line sunitinib treatment for three months. He developed new hepatic metastasis, and a second-line treatment with nivolumab 3 mg/kg every two weeks was introduced. At 10 months of nivolumab, before the 22nd infusion, the patient suddenly complained of severe asthenia, somnolence, weight loss, polydipsia, and polyuria. Laboratory tests revealed potassium 4.2 mmol/L, sodium 138 mmol/L, bicarbonate 17.8 mmol/L, blood glucose 801 mg/dL, and arterial blood pH 7.27. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 10.9%. C-peptide was so low as 0.24. Glutamic acid decarboxylase autoantibodies, insulin autoantibodies and islet cell antibodies were all negative. Conclusion Anti-PD-1 immunotherapy is effective in the treatment of cancers. 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.

French Endocrine Society Guidance on endocrine side effects of immunotherapy

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using ‘common terminology criteria for adverse events’ (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab

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.

Glycemic disorders in melanoma patients treated with anti-PD1.

9525 Background: Anti-PD1 are now the backbone of immunotherapy (IT) of metastatic melanoma (MM). Although they are overall well- tolerated, a number of severe immune-related adverse events (IRAE) have been described, among which type 1 diabetes. We observed 3 cases of fulminant diabetes (FD) in our center, and also had the impression that diabetics patients became more difficult to manage when receiving anti-PD1. Methods: Retrospective analysis of blood glucose samples collected before, during and after anti-PD1 treatment (trt ) in all mm patients (pts) receiving anti-PD1 in our department over a 36-month period. Study of FD cases observed. Results: A total of 163 pts were treated with 1920 cures of anti-PD1 including 27 treated within clinical trials. Anti-PD1 was the 1st line of IT in 70% of cases. As a whole, 1470 glycaemia were available. There was no significant difference between the median pre and post-trt glycaemia (5.37 +/-1.6 vs 5.6 +/-1.3 mmol/L (p = 0.033)). In the 28 pts with a type I (n = 0) or II (n = 28) diabetes prior to trt, there was very slight drift toward an increase of glycaemia along with the successive trt infusions (+0.05mmol/L/Cure, p = 0.004 with linear regression tendency test) .Three pts (1.84%) developed a FD revealed by a severe episode of ketosis with acute polyuria polydipsia, hyperglycaemia until 50mmol/L and weight loss. Two additional cases of FD were observed in pts treated within clinical trial comparing anti-PD1 with anti-CTLA4 in adjuvant and metastatic situation (imputability of anti-PD1 likely but uncertain until unblinding). None of these pts had any glucose increase in weeks prior to FD diagnosis. Four out of 5 FD cases had an HLA group at risk for type 1 diabetes development (HLA DRB3/4), a rare group in general population (1%). Conclusions: We could not document any systematic tendency to glycemic disorder in mm pts treated by anti-PD1. In diabetic pts prior to trt, a slight drift toward increase of glycaemia may be explained by other interfering factors (diet, metastatic disease itself, corticosteroids, anxiety etc). FD is not exceptional (2% of patients in our series) and does not seem to be announced by any minor preliminary glycemic disorder. Despite apparently stochastic onset, FD may be associated with HLA DRB3/4 subgroup.