A Systematic Review of Autoimmune Oophoritis Therapies.

Autoimmune primary ovarian insufficiency (POI) is a devastating disease with limited clinical guidance. The objective of this systematic review was to identify treatments for autoimmune POI and analyze their efficacy. A comprehensive search of CINAHL, Cochrane, Embase, PubMed, Scopus, and Web of Science was performed from inception to April 2022. English language publications that evaluated women with autoimmune POI after a documented intervention were included. Animal models of autoimmune POI were also included. Risk of bias was assessed with the SYRCLE's risk of bias tool for animal studies or the NIH Quality Assessment Tool for Case Series as appropriate. Twenty-eight studies were included in this review, with 11 RCTs, 15 case reports, and 2 case series. Seventeen studies were in humans, and 11 were in animal models. No completed RCTs, cohort studies, or case-control studies were identified in humans. In observational human studies, corticosteroids were effective in select patients. In many case reports, adequate treatment of comorbid autoimmune conditions resulted in return of menses, hormonal normalization, or spontaneous pregnancy. In terms of assisted reproductive technologies, there was case report evidence for both in vitro fertilization (IVF) and in vitro maturation (IVM) in women wishing to conceive with their own oocytes. Ovulation induction, IVF, and IVM resulted in a total of 15 pregnancies and 14 live births. In animal models, there was additional evidence for stem cell therapies and treatments used in traditional Chinese medicine, although this research may not be generalizable to humans. Furthermore, litter size was not evaluated in any of the animal studies. Additional research is needed to establish the efficacy of current treatments for autoimmune POI with a controlled experimental design and larger sample size. Additionally, there is a critical need to develop novel therapies for this condition, as understanding of its pathophysiology and  available tools to modulate the immune response have progressed.

IPEX syndrome from diagnosis to cure, learning along the way.

In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome.

Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations.

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

[Polyendocrine syndromes in dogs]. / Polyendokrine Syndrome beim Hund.

The autoimmune polyendocrine syndrome (APS) refers to a combination of autoimmune endocrine disorders. It is rarely described in dogs. The most common combinations are hypoadrenocorticism and hypothyroidism, followed by diabetes mellitus, and less often hypoparathyroidism and orchitis. The diagnosis of the APS is based on the diagnosis of each endocrinopathy, as is the therapy, which involves the substitution of deficient hormones. If a patient was previously stable under treatment and is showing further signs (e.g. polyuria, polydipsia, or weight loss), the development of additional endocrinopathies like hypoadrenocorticism or diabetes mellitus should be considered. The diagnosis of the initially diagnosed endocrinopathy should also be critically questioned. This article summarizes some cases of our own animal hospital and selected cases published in the available literature.

Autoimmune adrenal insufficiency in children: a hint for polyglandular syndrome type 2?

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

APECED and the place of AIRE in the puzzle of the immune network associated with autoimmunity.

In the last 20 years, discoveries about the autoimmune regulator (AIRE) protein and its critical role in immune tolerance have provided fundamental insights into understanding the molecular basis of autoimmunity. This review provides a comprehensive overview of the effect of AIRE on immunological tolerance and the characteristics of autoimmune diseases in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is caused by biallelic AIRE mutations. A better understanding of the immunological mechanisms of AIRE deficiency may enlighten immune tolerance mechanisms and new diagnostic and treatment strategies for autoimmune diseases. Considering that not all clinical features of APECED are present in a given follow-up period, the diagnosis is not easy in a patient at the first visit. Longer follow-up and a multidisciplinary approach are essential for diagnosis. It is challenging to prevent endocrine and other organ damage compared with other diseases associated with multiple autoimmunities, such as FOXP3, LRBA, and CTLA4 deficiencies. Unfortunately, no curative therapy like haematopoietic stem cell transplantation or specific immunomodulation is present that is successful in the treatment.

Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach.

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive hereditary pathology that develops with endocrine and non-endocrine manifestations in childhood. The classic triad of APS-1 includes chronic candidiasis of the skin and mucous membranes, adrenal insufficiency, and hypoparathyroidism. APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis. The prevalence rate is highest in genetically isolated populations (up to 1:6500-1:9000). APS-1 occurs because of mutations in the autoimmune regulator (AIRE) gene, leading to a disrupted mechanism of normal antigen expression, the formation of abnormal clones of immune cells, and autoimmune damage to various organs. Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications. This paper analyzes scientific information characterizing clinical manifestations of autoimmune polyendocrine syndrome type 1 in association with its pathogenetic features, epidemiology, and current management.

Generation and Characterization of iPS Cells Derived from APECED Patients for Gene Correction.

APECED (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy) is a severe and incurable multiorgan autoimmune disease caused by mutations in the AIRE (autoimmune regulator) gene. Without functional AIRE, the development of central and peripheral immune tolerance is severely impaired allowing the accumulation of autoreactive immune cells in the periphery. This leads to multiple endocrine and non-endocrine autoimmune disorders and mucocutaneous candidiasis in APECED patients. Recent studies have suggested that AIRE also has novel functions in stem cells and contributes to the regulatory network of pluripotency. In preparation of therapeutic gene correction, we generated and assessed patient blood cell-derived iPSCs, potentially suitable for cell therapy in APECED. Here, we describe APECED-patient derived iPSCs's properties, expression of AIRE as well as classical stem cell markers by qPCR and immunocytochemistry. We further generated self-aggregated EBs of the iPSCs. We show that APECED patient-derived iPSCs and EBs do not have any major proliferative or apoptotic defects and that they express all the classical pluripotency markers similarly to healthy person iPSCs. The results suggest that the common AIRE R257X truncation mutation does not affect stem cell properties and that APECED iPSCs can be propagated in vitro and used for subsequent gene-correction. This first study on APECED patient-derived iPSCs validates their pluripotency and confirms their ability for differentiation and potential therapeutic use.

Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RChi), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RClo/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChi T cells, inhibited CD45RChi B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RChi cells. Our observations highlight the potential role for CD45RChi cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.

Infections and demanding endocrine care contribute to increased mortality in patients with APECED.

OBJECTIVE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) has variable clinical course. Overall mortality is increased but reasons for this remain largely unknown. Our objective was to assess the causes of death and factors contributing to increased mortality. DESIGN: A follow-up study of the Finnish APECED cohort in 1970-2019. METHODS: In 33 deceased patients with APECED, causes of death and clinical course preceding the death were analyzed using national registry data, death certificates, autopsy reports, and patient records. RESULTS: Most common causes leading to death were infections (24%), oral and esophageal malignancies (15%; median age at death 36.7 years; median survival 1.5 years), and diseases of the circulatory system (18%). Adrenal crisis was an independent cause of death in two patients. In addition, in four patients, the adrenal crisis was a complicating factor during a fatal infection. Other APECED manifestations leading to death were hypoparathyroidism, diabetes, and hepatitis. Other causes of death included accidents (12%), alcohol-related causes, and amyotrophic lateral sclerosis. Challenges in overall, and especially in the endocrine, care contributed to deaths related to carcinomas and adrenal crisis. Age at death and year of death correlated (r = 0.345, P = 0.045), suggesting improved longevity. CONCLUSIONS: Infections, malignancies, and diseases of the circulatory system are the most common primary causes of death in patients with APECED. Adrenal crisis is an independent cause of death but more often a contributing factor in fatal infections. Despite the high overall mortality and the demanding care, our results suggest improved patient survival in recent years.

Autoimmune Polyendocrine Syndrome Complicated by Pulmonary Hypertension.

A 24-years old female was admitted for acute renal failure, melanoderma, hyponatremia, and hyperkalemia. The clinical suspicion of Addison's disease was confirmed by laboratory test and the appropriate replacement therapy with corticosteroids and fludrocortisone was started. In the meantime primary hypothyroidism and diabetes mellitus type 1 were disclosed and treated, thus fulfilling a diagnosis of autoimmune polyendocrine syndrome type 2. Eighteen months later she was admitted for right-sided heart failure. The work-up allowed to diagnose pulmonary arterial hypertension. Here, we report the clinical course and discuss the putative link between these two rare diseases.

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

BACKGROUND AND AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. APPROACH AND RESULTS: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. CONCLUSIONS: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.

In vitro maturation of oocytes for preserving fertility in autoimmune premature ovarian insufficiency.

OBJECTIVE: To test whether in vitro maturation (IVM) of oocytes is an option for preserving the fertility of women diagnosed with premature ovarian insufficiency (POI). DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 36-year-old amenorrheic patient was referred for fertility preservation (FP) counseling with a diagnosis of autoimmune POI. Serum follicle-stimulating hormone (21.0 and 36.3 mIU/mL) and luteinizing hormone (35.0 and 60.0 mIU/mL) levels taken 4 weeks apart were around the menopausal range. Although serum antimüllerian hormone level was low (0.76 and 0.65 ng/mL), total counts of antral follicles remained unexpectedly normal (24 and 22). Significant levels of serum antiperoxidase, anti-21-hydroxylase, and antiovary antibodies led to the diagnosis of autoimmune polyendocrinopathy. Due to the unknown time before follicular exhaustion, we undertook a FP program. INTERVENTION(S): After unsuccessful follicular growth following a trial of ovarian stimulation using recombinant follicle-stimulating hormone (300 IU/day for 10 days), we decided to try IVM of immature oocytes aspirated from the remaining antral-stage follicles. MAIN OUTCOME MEASURE(S): Obtention of immature oocyte capable of maturing in vitro in a context of acute ovarian dysfunction. RESULT(S): Two cycles of IVM were performed, leading, after human chorionic gonadotropin priming, to six and 10 cumulus-oocyte complexes recovered and four and eight metaphase II oocytes. Finally, after intracytoplasmic sperm injection, a total of eight cleavage-stage embryos were frozen. When the patient presented in the clinic 1 year later for reutilization of the cryopreserved embryos, thyroid and adrenal functions were controlled with levothyroxine and hydrocortisone. Endometrium was primed with 17ß-estradiol (2 mg/day, vaginally) for 14 days. Progesterone (600 mg/day, vaginally) was subsequently combined with E2. Two embryos were thawed and further transferred into the uterus. The patient became pregnant and uneventfully delivered two baby boys at term. CONCLUSION(S): We report the first pregnancy and live birth achieved using IVM for FP in a woman diagnosed with autoimmune POI. The confirmation of our results would lead to modification in the management of young women diagnosed with autoimmune POI, who are usually not considered candidates for FP and often referred for egg donation when seeking pregnancy.

A case report and literature review: Identification of a novel AIRE gene mutation associated with Autoimmune Polyendocrine Syndrome Type 1 in East Asians.

RATIONALE: Autoimmune polyendocrine syndrome type 1 (APS-1), also referred as the autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED), is a rare autosomal inherited disease predominantly among Caucasians from Northern Europe. This syndrome is very rare in East Asian population. PATIENTS CONCERNS: Here, we describe a case of a 15-year-old Chinese boy admitted due to a 1-month history of intermittent fatigue, nausea, vomiting, and diarrhea. His symptom became worse accompanied with chest tightness 4 days before admission. On physical examination, his temperature was 38.5°C, blood pressure was 75/38 mm Hg, and pulse was 98/min. He was a thin boy with mild hyperpigmentation and xanthochromia. DIAGNOSIS: After abdominal computed technology and laboratory tests, his diagnosis was APS-1 accompanied with adrenal crisis. Further investigation on whole-exome sequencing revealed a novel homozygous mutation c.47C>G (p.T16R) in exon 1 in the autoimmune regulator (AIRE) gene. INTERVENTIONS: This patient underwent replacement therapy of glucocorticoids, corticosteroid, and levothyroxine, as well as calcium and calcitriol supplementation. OUTCOMES: He continues to do well 4 years after his hospitalization. During his last follow-up, he had serum thyroid-stimulating hormone level of 3.07 µIU/mL, free triiodothyronine level of 1.92 pg/mL, and free thyroxine level of 13.95 pg/mL. His serum cortisol and ACTH (8 a.m.) levels were 28.53 µg/dL and 69.48 pg/mL, respectively. LESSONS: APS-1 is very rare in East Asians and the variable clinical presentations of the disease make the initial diagnosis especially difficult. Autoimmune thyroiditis, type 1 diabetes mellitus, and hepatitis were the three most frequent minor components of APS-1 in East Asian patients with age of onset in late teens and 20s. Sequence analysis of AIRE gene is necessary to verify its diagnostic efficacy in association with clinical findings.

Type I Diabetes is the Main Cost Driver in Autoimmune Polyendocrinopathy.

CONTEXT: Autoimmune polyendocrinopathy (AP), a chronic complex orphan disease, encompasses at least two autoimmune-induced endocrine diseases. OBJECTIVE: To estimate for the first time total, indirect and direct costs for patients with AP, as well as cost drivers. DESIGN: Cross-sectional cost of illness study. SETTING: Academic tertiary referral center for AP. PATIENTS: 146 consecutive, unselected AP patients. INTERVENTION: Interviews pertaining to patients' socioeconomic situation covered a recall period of 12 months. Both the human capital (HCA) and the friction cost approaches (FCAs) were applied as estimation methods. MAIN OUTCOME MEASURES: Direct and indirect annual costs, and sick leave and medication costs. RESULTS: AP markedly impacts healthcare expenses. Mean overall costs of AP in Germany ranged from €5 971 090 to €29 848 187 per year (HCA). Mean indirect costs ranged from €3 388 284 to €16 937 298 per year (HCA) while mean direct costs ranged from €2 582 247 to €12 908 095/year. Mean direct costs per year were €1851 in AP patients with type 1 diabetes (T1D, 76%) and €671 without T1D, which amounts to additional direct costs of €1209 for T1D when adjusting for concomitant autoimmune disease (95% CI = €1026-1393, P < 0.0001). Sick leave cost estimates for AP patients with T1D exceeded those without T1D by 70% (FCA) and 43% (HCA), respectively. In multiple regression analyses, T1D predicted total and direct costs, medication costs and costs for diabetic devices (all P < 0.001). Overall, AP patients with T1D were 54% (FCA) more expensive than those without T1D. CONCLUSIONS: Public health socioeconomic relevance of AP was demonstrated, with T1D as main cost driver.

Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Thyro-entero-gastric autoimmunity: Pathophysiology and implications for patient management.

The association between autoimmune atrophic gastritis and thyroid disorders has been observed since the early 1960s and the expression "thyrogastric syndrome" was coined to indicate the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anemia, a late clinical stage of autoimmune atrophic gastritis. More recently, it was confirmed that autoimmune thyroid disorders, in particular Hashimoto's thyroiditis, may be frequently associated with other organ-specific, immune-mediated disorders, such as autoimmune atrophic gastritis or celiac disease. The association of Hashimoto's thyroiditis with autoimmune atrophic gastritis or celiac disease in adult patients is currently considered part of the polyglandular autoimmune syndromes which include several autoimmune disorders associated with an autoaggressive impairment of endocrine glands. From a clinical point of view, the thyro-entero-gastric autoimmunity may lead to potentially serious consequences like anemia, micronutrients deficiencies, and drugs malabsorption, as well as to an increased risk for malignancies. These alterations may frequently present in an underhand manner, with consequent diagnostic and treatment delays. Many aspects of the association between thyroid, gastric and intestinal autoimmune diseases still await clarification. The present review focuses on the embryological, genetic and pathophysiological aspects of thyro-entero-gastric autoimmunity. In particular, the current diagnostic criteria of autoimmune thyroid disease, autoimmune atrophic gastritis, and celiac disease are reviewed, along with the evidences for their association in poly-autoimmunity syndromes. The benefits of proactive screening of autoimmune thyroid disorders in patients with autoimmune gastritis or enteropathy and viceversa are also discussed.

Autoimmune polyglandular diseases.

Autoimmune polyglandular diseases (APD) are defined as the presence of two autoimmune -induced endocrine failures. With respect to the significant morbidity and potential mortality of APD, the diagnostic objective is to detect APD at an early stage, with the advantage of less frequent complications, effective therapy and better prognosis. This requires that patients at risk be regularly screened for subclinical endocrinopathies prior to clinical manifestation. Regarding the time interval between manifestation of first and further endocrinopathies, regular and long-term follow-up is warranted. Quality of life and psychosocial status are poor in APD patients and involved relatives. Familial clustering is high in patients with APD. Considering the high incidence of one or more endocrinopathies in first-degree relatives of patients with APD, family members should be regularly screened since they may also develop autoimmune endocrinopathies. Multidisciplinary management of these multiplex families in specialized centers is warranted.