Abstract
Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
Highlights
Aprimary insufficiency of adrenal hormones is most often caused by autoimmune destruction of the adrenal cortex, autoimmune Addison disease (AAD) [1]
Without early detection and continuous treatment, it can quickly develop into a lethal adrenal crisis [2]
AAD is generally a disease with complex inheritance and has been associated with multiple human leukocyte antigen haplotypes, such as the coinherited diseases type 1 diabetes and autoimmune thyroid disease [6, 7]. It can be caused by monogenic autoimmunity syndromes [8]
Summary
Patients In this study, 677 patients consecutively enrolled into the SAR (years 2009 to 2013) were included for investigation of serological, clinical, and genetic aspects of primary adrenal insufficiency and APS1. All patients fulfilled the diagnostic criteria for primary adrenal insufficiency, with low morning serum cortisol and elevated adrenocorticotropic hormone levels or failure to adequately respond to corticotropin stimulation. Time points for diagnosis, probable etiology, concomitant diseases, medication, and family history of AAD were recorded by the responsible physician. Missing data were complemented with information from medical records. Aliquots of sera and whole blood were stored at 270°C in a biobank until use. The study was approved by the regional ethics committee, permit 2008/296-31/2, and all patients gave their written informed consent. Autoantibody detection All patients were screened for autoantibodies against 21-
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