Comparative analysis of human leucocyte antigen between idiopathic and anti-PD-1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study

Background: Adult-onset idiopathic isolated adrenocorticotropic hormone deficiency (id-IAD) is a rare disease with unknown aetiology. Recently, numerous cases of anti-PD-1 antibody-induced IAD (PD1-IAD) have been reported, but the clinical course, predictive factors and relationship to id-IAD have not been clarified. Moreover, associations of id-IAD and PD1-IAD with human leucocyte antigen (HLA) require elucidation.

Methods: Clinical characteristics of 13 Japanese patients with id-IAD and eight Japanese patients with PD1-IAD were analysed, and HLA-typing test was performed for each patient. Allele and haplotype frequencies of the patients were compared to those of healthy Japanese controls.

Results: In the HLA allele and haplotype analyses of id-IAD, the frequencies of HLA-C*14:02, HLA-DPB1*05:01, HLA-DRB1*04:05-DQB1*04:01-DPB1*05:01 and HLA-DRB1*09:01-DQB1*03:03-DPB1*05:01 were significantly increased. On the other hand, HLA alleles account for PD1-IAD susceptibility as follows: HLA-DQB1*06:01, HLA-DPB1*09:01 and HLA-DRB5*01:02. Moreover, protective effect for HLA-C*03:03 was suggested in combined id-IAD and PD1-IAD patients. Comparison of the effects of HLA on id-IAD and PD1-IAD revealed some differences. Alleles or haplotypes frequencies increased in id-IAD group were as follows: HLA-DPB1*05:01, HLA-DRB1*09:01, HLA-DRB4*01:03:02, HLA-DQB1*03:03 and HLA-DRB1*09:01-DQB1*03:03. In clinical settings, hyponatremia, disturbance of consciousness and hypoglycaemia were less frequently seen in patients with PD1-IAD than in patients with id-IAD.

Conclusions: Distinct clinical characteristics and predisposing HLA allele contributions were proposed between id-IAD and PD1-IAD. Further investigations with greater number of cases are warranted to clarify the detailed mechanisms of id-IAD and PD1-IAD.