Clinical and Immunological Characteristics of Autoimmune Addison Disease: A Nationwide Swedish Multicenter Study.

Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008-2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

BACKGROUND: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. AIM: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. METHODS: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. RESULTS: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. CONCLUSIONS: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.