A Case in Which HLA-DR4 is Involved in the Development of Complex Immune-Related Endocrinological Adverse Events following Combination Therapy with Nivolumab and Ipilimumab

Abstract

Immune checkpoint inhibitors (ICIs) have become a focal point in cancer immunotherapy, though their utilization is also linked to the occurrence of diverse immune-related adverse events (irAEs). Herein, we present details of a 42-year-old woman diagnosed with a malignant vaginal melanoma who underwent ICI therapy with the combination of nivolumab and ipilimumab. Approximately two months after initiating therapy, the patient manifested destructive thyroiditis and fulminant type 1 diabetes mellitus, thus necessitating intensive insulin therapy. Following the onset of adrenocorticotropic hormone deficiency, frequent hypoglycemic episodes prompted the initiation of replacement therapy with hydrocortisone. Human leukocyte antigen (HLA)-DNA typing revealed the presence of HLA-DRB1^∗04 : 05 and DQB1^∗04 : 01. HLA-DR4 has been suggested to be associated with the development of multiple endocrine irAEs. This is the first reported case of three endocrine irAEs occurring within a short period, in which the presence of HLA-DR4 may have contributed to the pathogenesis.

Figure 1

Time course for clinical parameters, diagnosis, and treatment. Nivolumab and ipilimumab were administered at 0, 4, 7, 10, 12, 16, and 18 weeks. CPR: C-peptide reactivity; ACTH: adrenocorticotropic hormone; FT4: free thyroxine; TSH: thyroid-stimulating hormone.

Figure 2

(a) Diurnal variations for blood ACTH and cortisol, and urinary cortisol indicated low levels. (b) Corticotropin-releasing hormone (CRH) stimulation testing showed no change in adrenocorticotropic hormone (ACTH) or cortisol level. The CRH stimulation test was conducted in the morning under a fasting condition.

Figure 3

Pituitary contrast-enhanced MRI revealed heterogeneous enhancement of the pituitary gland.