21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison's Disease Are Restricted by HLA-A2 and HLA-C7 Molecules.

Objectives: CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison's disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. Methods: Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH. Results: We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. Conclusion: We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.

Overexpression of miR-7977 in CD4+ T cells is associated with multiplex autoimmunity in patients with Addison's disease.

OBJECTIVE: Autoimmune Addison's disease (AD) results from a combination of the genetic predisposition, unclear environmental triggers and ensuing immune dysfunction. MicroRNA molecules (miRNAs) are involved in post-transcriptional regulation of numerous target genes, hence may affect the immune function and promote autoimmunity. A deregulated miRNAs profile was reported in several autoimmune conditions. Our study was aimed at a global analysis of miRNA expression in CD4+ T cells from patients with AD. METHODS: CD4+ T cells were separated from peripheral blood, total RNA enriched in miRNAs extracted, and miRNA expression determined by small RNA sequencing. Global miRNA was investigated in 11 AD subjects and 9 age-matched healthy controls, with subsequent validation of the differentially expressed miRNAs by RT-qPCR in 29 patients and 28 controls. RESULTS: The analysis revealed upregulation of 9 miRNAs and downregulation of miR-509-3p in CD4+ T cells from patients with AD (cut-off fold change (FC) >2, Benjamini-Hochberg P < 0.05). RT-qPCR validation confirmed overexpression of miR-7977 (P < 0.0001, FC = 2.7), miR-374a-5p and miR-1260b (P < 0.05, FC = 1.3 and 1.2, respectively). miR-7977 was upregulated in patients with coexisting autoimmune conditions vs those with isolated AD (P = 0.005, mean FC = 2.2). Moreover, miR-7977 abundance appeared correlated with the number of autoimmune comorbidities (P <0.0001, r = 0.736) and serum autoantibodies against thyroid peroxidase (P < 0.001, r = 0.588). CONCLUSIONS: Our study demonstrates upregulated expression of miR-7977 in CD4+ T cells from patients with AD, especially with its polyendocrine form. Further analyses are warranted to replicate our results, establish the marker utility of miR-7977, and elucidate its functional role in autoimmunity.

Primary Ovarian Insufficiency in Women With Addison's Disease.

CONTEXT: Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison's disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. OBJECTIVE: To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics. METHODS: An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation. RESULTS: The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). CONCLUSION: One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC.

Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence.

The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)-chronic mucocutaneous candidiasis-autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.

Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event.

The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 µg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.

New era of therapy for endocrine autoimmune disorders.

The new era of immune and reconstitution therapy of autoimmune disorders is ongoing. However, endocrine autoimmune diseases comprise a group of elaborating pathologies where the development of new treatment strategies remains slow. Substitution of the missing hormones is still standard practice, taking care of the devastating symptoms but not the cause of disease. As our knowledge of the genetic contribution to the aetiology of endocrine disorders increases and early diagnostic tools are available, it is now possible to identify persons at risk before they acquire full-blown disease. This review summarizes current knowledge and treatment of endocrine autoimmune disorders, focusing on type 1 diabetes, Addison's disease, autoimmune thyroid diseases and primary ovarian insufficiency. We explore which new therapies might be used in the different stages of the disease, focus on legalized therapy and elaborate on the ongoing clinical studies for these diseases and the research front, before hypothesizing on the way ahead.

Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison's disease.

OBJECTIVE: Autoimmune conditions tend to cluster in subjects with Addison's disease (AD) and probably also among their relatives. The aim of the study was to estimate the frequency of the endocrine gland-specific autoantibodies in first-degree relatives of patients with AD. METHODS: Autoantibodies were investigated in 113 family members using RIA and ELISA assays. The control group comprised 143 age-matched volunteers. RESULTS: Autoimmune diseases were diagnosed in 38.1% relatives. Hashimoto's thyroiditis was found in 20.3%, Graves' disease in 8.0%, vitiligo and type 1 diabetes in 3.5%, whereas AD, rheumatoid arthritis and atrophic gastritis with pernicious anaemia in 2.7% each. All studied antibodies except for islet antigen-2 (P = 0.085) were significantly more frequent in AD relatives than in controls (P < 0.05). Antibodies to 21-hydroxylase were detected in 6.2% relatives, thyroid peroxidase in 28.3%, thyroglobulin in 19.5%, glutamic acid decarboxylase in 8.0%, and zinc transporter-8 in 7.1%. Two and more autoantibodies were detected in 18.6% subjects. Significant gender difference was revealed only for aTPO, more common in female relatives (P = 0.014; OR: 3.16; 95% CI: 1.23-8.12). Circulating autoantibodies were found more frequently in the relatives of affected males (P = 0.008; OR: 3.31; 95% CI: 1.33-8.23), and in family members of patients with polyendocrine autoimmunity (P = 0.009; OR: 3.55; 95% CI: 1.31-9.57). CONCLUSIONS: This study provides evidence of increased susceptibility for the endocrine autoimmunity, especially thyroid disease, in close relatives of patients with AD. Relatives of the male AD patients and of those with autoimmune polyendocrine syndrome are at particular risk and should undergo periodic screening for autoimmune endocrine disorders.

Type 1 diabetes, thyroid, gastric and adrenal humoral autoantibodies are present altogether in almost one third of adult celiac patients at diagnosis, with a higher frequency than children and adolescent celiac patients.

Background: No data are available on the frequency of organ-specific humoral autoimmunity at diagnosis of adult celiac disease (CD).Aim: To evaluate the humoral immunoreactivities specific of type 1 diabetes (T1D), thyroid (THD), atrophic-gastritis (AG) and Addison's (AD) diseases in 92 adult CD patients at diagnosis and 237 adult healthy subjects (CTRL).Methods: T1D, THD and AD specific autoantibodies were analyzed by radioimmunoprecipitation assays. AG autoantibodies were detected by enzyme-linked immunosorbent assay.Results: Of 92 CD patients, 31.5% were positive for at least one of the organ-specific autoantibodies investigated (p < .0001 vs CTRL). Thyroid, diabetes, gastric and adrenal-autoantibodies, that increase with age at diagnosis, were detected in 12.0%, 10.9%, 10.9%, 2.2% of CD patients, respectively. Gastric- and diabetes- rather than thyroid- and adrenal-autoimmunity seem to be specifically related to presence of CD.Conclusions: One third of adult CD patients at diagnosis is target of at least one organ-specific autoantibody. A systematic organ-specific autoantibody screening in these patients might be of value to promptly identify, prevent or treat the relative diseases.

Primary antiphospholipid syndrome, Addison disease, and adrenal incidentaloma.

Primary adrenal failure comprises an insufficient production of mineralocorticoids and glucocorticoids in the adrenal cortex. A rare manifestation of antiphospholipid syndrome (APS) is adrenal failure. The majority of patients with adrenal involvement in APS develop an irreversible cortisol deficiency and atrophy of the adrenal glands. Adrenal incidentalomas are adrenal masses larger than 1 cm that are discovered in the course of diagnostic evaluation or treatment for another medical condition. Its prevalence is calculated in 1.5-9% of individuals. We describe an exceptional case of a 23-year-old male patient with APS with persistent high levels of antiphospholipid antibodies (aPL) from the time of diagnosis, who developed Addison's disease as a manifestation of APS with atrophy of the adrenal glands, in whom an adrenal incidentaloma was developed later and was corroborated as an aldosterone-producing adenoma. Currently, the patient is asymptomatic and without manifestations of tumor recurrence. The protumoral effect of elevated and persistent aPL is discussed.

Autoimmune Addison's disease.

Primary adrenal insufficiency (PAI) occurs in 1/5000-1/7000 individuals in the general population. Autoimmune Addison's disease (AAD) is the major cause of PAI and is a major component of autoimmune polyendocrine syndrome type 1 (APS1) and type 2 (APS2). Presence of 21-hydroxylase autoantibodies (21OHAb) identifies subjects with ongoing clinical or pre-clinical adrenal autoimmunity. AAD requires life-long substitutive therapy with two-three daily doses of hydrocortisone (HC) (15-25 mg/day) or one daily dose of dual-release HC and with fludrocortisone (0.5-2.0 mg/day). The lowest possible HC dose must be identified according to clinical and biochemical parameters to minimize long-term complications that include osteoporosis and cardiovascular and metabolic alterations. Women with AAD have lower fertility and parity as compared to age-matched healthy controls. Patients must be educated to double-triple HC dose in the case of fever or infections and to switch to parenteral HC in the case of vomiting, diarrhoea or acute hypotension.

Concomitant presentation of IgG4-negative idiopathic retroperitoneal fibrosis and Addison's disease.

We describe a patient who was admitted to our medical centre with acute renal failure, hyponatraemia and hyperkalaemia. CT of the abdomen and pelvis showed a retroperitoneal mass with bilateral ureteral obstruction. Biopsy revealed fibrosis with inflammatory infiltrate, but rare IgG4-positive plasma cells. After placement of bilateral pigtail nephrostomy catheters, renal failure improved but metabolic derangements remained. Morning serum cortisol level was equivocal, but with blunted response on cosyntropin stimulation testing indicating adrenal insufficiency. Serology for 21-hydroxylase antibodies was strongly positive, supporting the diagnosis of Addison's disease. In addition to nephrostomy catheters for obstructive uropathy, idiopathic retroperitoneal fibrosis was treated with mycophenolate mofetil. Physiological doses of hydrocortisone and fludrocortisone for Addison's disease were also initiated. The patient continues to be monitored for regression of the mass. Based on review of the literature, this is the first reported case of IgG4-negative idiopathic retroperitoneal fibrosis presenting with autoimmune primary adrenal insufficiency.

Insights into the autoimmune aspect of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to a continuum of decreasing ovarian function in women before the age of 40. To date, the cause of POI in the majority of cases remain unresolved. Many cases has been linked to genetic, toxic, infections, enzymatic and iatrogenic causes. A key function of the immune system is to identify and differentiate "self" and "non self" i.e. tolerance. Loss of self-tolerance results in an immune response against self-tissues and thus autoimmunity. Various investigations have highlighted the role of autoimmunity and its pertinence to POI. Several potential immune antigenic targets in the ovary have been reported to be involved in autoantibody induced autoimmune attack. The presence of lymphocytic oöphorits in ovarian samples of patients with POI provides histopathological evidence of autoimmune ovarian involvement. Finally, POI is strongly associated with other autoimmune conditions including for instance Addison disease, autoimmune polyglandular syndrome (APS) -1, APS-4, hypothyroidism, and diabetes mellitus among other autoimmune diseases. Taken together, these lines of evidence provide strong basis that support the role of autoimmunity as a potential cause of disease etiopathogenesis. Continuing research is increasingly providing more insight into the complex disease process. The aim of this review is to summarize the current literature related to the autoimmune nature of POI.

Annexin-A1: Therapeutic Potential in Microvascular Disease.

Annexin-A1 (ANXA1) was first discovered in the early 1980's as a protein, which mediates (some of the) anti-inflammatory effects of glucocorticoids. Subsequently, the role of ANXA1 in inflammation has been extensively studied. The biology of ANXA1 is complex and it has many different roles in both health and disease. Its effects as a potent endogenous anti-inflammatory mediator are well-described in both acute and chronic inflammation and its role in activating the pro-resolution phase receptor, FPR2, has been described and is now being exploited for therapeutic benefit. In the present mini review, we will endeavor to give an overview of ANXA1 biology in relation to inflammation and functions that mediate pro-resolution that are independent of glucocorticoid induction. We will focus on the role of ANXA1 in diseases with a large inflammatory component focusing on diabetes and microvascular disease. Finally, we will explore the possibility of exploiting ANXA1 as a novel therapeutic target in diabetes and the treatment of microvascular disease.

A longitudinal study of autoantibodies against cytochrome P450 side-chain cleavage enzyme in dogs (Canis lupus familiaris) affected with hypoadrenocorticism (Addison's disease).

Autoantibodies directed against the P450 side chain cleavage enzyme (P450scc) have been recently described in dogs affected with hypoadrenocorticism, consistent with an immune-mediated pathogenesis of this endocrinopathy. In human autoimmune Addison's disease, autoantibodies may have a predictive value, being detectable before clinical signs developing, and have been shown to persist for a period of time after diagnosis. Furthermore, an autoantibody positive status post-diagnosis has been associated with successful remission of Addison's disease following B-cell depletion, suggesting active immunopathology in these cases. The current study was designed to investigate changes in serum P450scc autoantibody status over time in dogs diagnosed with spontaneous hypoadrenocorticism. P450scc autoantibodies were measured using a species-specific radioimmunoprecipitation assay in an initial cohort of 213 dogs, indicating a prevalence of 24%. Thirty two of these dogs had repeat samples (n = 80 in total) available for analysis. Five dogs were consistently P450scc autoantibody positive in all samples, for up to 425 days following first sampling. Three dogs were initially autoantibody positive, then became seronegative at later time points. One dog, a 1 year old female entire standard poodle, was initially negative for P450scc autoantibodies, but seroconverted 18 months after diagnosis. The remaining 23 dogs with multiple samples available were consistently P450scc autoantibody negative. Persistence was not associated with sex (p = .673). This study demonstrates persistence of P450scc autoantibodies in a subset of dogs affected with hypoadrenocorticism and seroconversion over one year post-diagnosis. P450scc autoantibody reactivity in human autoimmune Addison's disease has been associated with sex, with females having a higher prevalence, possibly due to P450scc expression in the ovary acting as an additional source of antigenic stimulation. However, there was no sex difference in autoantibody persistence in the dogs affected with hypoadrenocorticism. Autontibody persistence in dogs with hypoadrenocorticism might represent persistent pathology, due to residual antigenic stimulation and autoimmune inflammation in the adrenal gland.

Evidence of increased humoral endocrine organ-specific autoimmunity in severe and classic X-chromosome aneuploidies in comparison with 46,XY control subjects.

OBJECTIVE: In literature, the importance of X-linked gene dosage as a contributing factor for autoimmune diseases is generally assumed. However, little information is available on the frequency of humoral endocrine organ-specific autoimmunity in X-chromosome aneuploidies. In our preliminary study, we investigated the endocrine organ-specific humoral autoimmunity relative to four different organ-specific autoimmune diseases in a group of adult 47,XXY KS patients and in adults 46,XY control males (type 1 diabetes, T1DM; Addison's disease, AD; Hashimoto thyroiditis, HT; autoimmune chronic atrophic gastritis, AG). The aim of the present study is to evaluate the frequency of autoantibodies (Abs) specific for T1DM, AD, HT, and AG in rarer higher grade X-chromosome aneuploidies (HGA) and in 47,XXY children. DESIGN AND METHODS: Samples from 192 Caucasian patients with an X-chromosome aneuploidy (176 patients (55 children, 121 adults) with 47,XXY karyotype (KS patients) and 16 HGA patients (eight children, eight adults)) recruited from Sapienza, University of Rome (2007-2017) were tested for Abs specific for T1DM (insulin-Abs, GAD-Abs, IA-2-Abs, Znt8-Abs), HT (TPO-Abs), AD (21-OH-Abs), and AG (APC-Abs). The results were compared to those found in 213 46,XY control subjects (96 children, 117 adults). RESULTS: Altogether humoral organ-specific immunoreactivity was found in 13% of KS and HGA patients, with a significantly higher frequency than in the controls (p=.008). Almost 19% of HGA patients were positive for at least one of the organ-specific Abs investigated compared to 12.5% of KS patients. The frequency of the overall immunoreactivity was higher in KS children than in KS adults. The frequency of diabetes-specific Abs was significantly higher in the patient cohort than in controls (p=.005). Thyroid- and gastric-specific autoimmunity was also found in KS and HGA patients, while adrenal-specific immunoreactivity was rare. CONCLUSIONS: These results suggest for the first time that the risk of endocrine organ-specific humoral autoimmunity progressively increases with the severity of X-chromosome polisomy. The screening for diabetes-, thyroid-, and gastric-specific autoimmunity should be considered in clinical practice for identifying rare and classic X-chromosome aneuploid patients at risk of developing organ-specific autoimmune diseases.

Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study.

Context: Adrenal insufficiency (AI) requires lifelong glucocorticoid (GC) replacement. Conventional therapies do not mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the machinery controlling circadian functions and are influenced by GCs. However, clock gene expression has never been investigated in patients with AI. Objective: To evaluate the effect of the timing of GC administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients from the Dual Release Hydrocortisone vs Conventional Glucocorticoid Replacement in Hypocortisolism (DREAM) trial. Design: Outcome assessor-blinded, randomized, active comparator clinical trial. Participants and Intervention: Eighty-nine patients with AI were randomly assigned to continue their multiple daily GC doses or switch to an equivalent dose of once-daily modified-release hydrocortisone and were compared with 25 healthy controls; 65 patients with AI and 18 controls consented to gene expression analysis. Results: Compared with healthy controls, 19 of the 68 genes were found modulated in patients with AI at baseline, 18 of which were restored to control levels 12 weeks after therapy was switched: ARNTL [BMAL] (P = 0.024), CLOCK (P = 0.016), AANAT (P = 0.021), CREB1 (P = 0.010), CREB3 (P = 0.037), MAT2A (P = 0.013); PRKAR1A, PRKAR2A, and PRKCB (all P < 0.010) and PER3, TIMELESS, CAMK2D, MAPK1, SP1, WEE1, CSNK1A1, ONP3, and PRF1 (all P < 0.001). Changes in WEE1, PRF1, and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes, and CD16+ natural killer cells. Conclusions: Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).

Autoimmune Addison's disease - An update on pathogenesis.

Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries, with prevalence estimates ranging from 93-220 per million in Europe. The immune-mediated attack on adrenocortical cells cripples their ability to synthesize vital steroid hormones and necessitates life-long hormone replacement therapy. The autoimmune disease etiology is multifactorial involving variants in immune genes and environmental factors. Recently, we have come to appreciate that the adrenocortical cell itself is an active player in the autoimmune process. Here we summarize the complex interplay between the immune system and the adrenal cortex and highlight unanswered questions and gaps in our current understanding of the disease.

The natural history of autoimmune Addison's disease with a non-classical presentation: a case report and review of literature.

Autoimmune Addison's disease (AAD) is the most frequent cause of adrenocortical insufficiency. The natural history of AAD usually comprises five consecutive stages with the first stage characterized by the increase of plasma renin consistent with the impairment of pars glomerulosa, which is usually the first affected layer of the adrenal cortex. We describe a 19-year-old female with Hashimoto's thyroiditis (HT) who underwent an autoantibody screening due to having the personal and family history of other autoimmune diseases in the absence of relevant clinical manifestations. She was positive for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OH Ab) at high titers. She had increased basal levels of ACTH with normal basal cortisol not responding to ACTH stimulation, reduced levels of dehydroepiandrosterone-sulfate but normal levels of orthostatic renin and aldosterone. This scenario was consistent with a subclinical AAD presenting with first impairments in pars fasciculata and reticularis and conserved pars glomerulosa function. Only subsequently, progressive deficiency in pars glomerulosa function has become evident. Review of the literature showed that there was only one case, reported to date, with a similar atypical natural history of AAD. The strategies for screening for ACA/21-OH Ab in patients with HT are discussed.

Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.

Context: 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. Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. Design: 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. Results: 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. Conclusion: 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.