Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency.

BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.

Metreleptin Supplementation for Improving Lipid and Glycemic Profiles in Acquired Diabetes Lipodystrophy: A Case Report.

Most childhood cancer survivors who undergo hematopoietic stem cell transplantation subsequently develop impaired glucose tolerance and hypertriglyceridemia. These conditions are presumably associated with total-body irradiation-related acquired lipodystrophy and may lead to cardiovascular disease. Metreleptin (recombinant leptin) may help improve the lipoprotein profile, insulin sensitivity, and quality of life of patients with total-body irradiation-related lipodystrophy. This report describes the safe and effective use of metreleptin supplementation for insulin resistance and dyslipidemia in acquired incomplete lipodystrophy. A 24-year-old Japanese woman with diabetes mellitus and hypertriglyceridemia was admitted to our hospital. She was diagnosed with acute lymphocytic leukemia at 3 years of age and had undergone systemic chemotherapy and total-body irradiation before allogeneic stem cell transplantation. She was also diagnosed with hypertriglyceridemia and diabetes mellitus at 11 years of age. She had a low adiponectin level, low-normal leptin level, and diabetes mellitus with marked insulin resistance. Thus, acquired incomplete lipodystrophy was diagnosed. Her serum triglyceride and lipoprotein profiles improved within 1 month of treatment initiation. Glycemic metabolism and insulin sensitivity in the skeletal muscles improved after 6 months. As previously reported, metreleptin therapy is effective in improving lipid and glycemic profiles in generalized lipodystrophy. In the present case, we considered that metreleptin supplementation could reduce the remnant VLDL cholesterol fraction and improve diabetes mellitus. We conclude that it may be an effective alternative therapy for improving the expected prognosis of patients with acquired incomplete lipodystrophy, including childhood cancer survivors.

Effects of a sodium glucose co-transporter 2 selective inhibitor, ipragliflozin, on the diurnal profile of plasma glucose in patients with type 2 diabetes: A study using continuous glucose monitoring.

AIMS/INTRODUCTION: To assess the effects of sodium glucose co-transporter 2 inhibitor therapy on the pathophysiology of type 2 diabetes. MATERIALS AND METHODS: We administered ipragliflozin to 21 inpatients with type 2 diabetes for 7 days, and analyzed the diurnal profiles of plasma glucose and 3-hydroxybutyrate. A total of 21 age-, sex- and body mass index-matched diabetic patients served as controls. RESULTS: Continuous glucose monitoring showed that the 24-h glucose curve was shifted downward without hypoglycemia by the administration of ipragliflozin. The average glucose level was reduced from 182 ± 54 mg/dL to 141 ± 33 mg/dL (P < 0.0001). The magnitude of the reduction was highly correlated with the baseline average glucose level. Homeostasis model assessment of insulin resistance was decreased, and homeostasis model assessment of ß-cell function was increased during the treatment. Urinary glucose excretion was correlated with the average glucose level both on day 0 and on day 7, although the regression line was steeper and shifted leftward on day 7. The ipragliflozin-treated patients lost more weight than the control patients (1.4 ± 0.5 vs 0.5 ± 0.6 kg, P < 0.0001). Plasma levels of 3-hydroxybutyrate were significantly increased with peaks before breakfast and before dinner. Patient age and bodyweight loss were negatively and positively correlated with the peak levels of 3-hydroxybutyrate on day 7, respectively. CONCLUSIONS: The ipragliflozin treatment improved the 24-h glucose curve without causing hypoglycemia. The close correlation between the magnitude of glucose reduction and the baseline plasma glucose concentration suggests that the risk of hypoglycemia is likely low. It might be prudent to monitor ketone body levels in younger patients and in patients with rapid weight loss.