[Autoimmune polyendocrine syndrome in adults. Focus on rheumatological aspects of the problem: A review].

Autoimmune polyglandular syndromes (APS) are a heterogeneous group of clinical conditions characterized by functional impairment of multiple endocrine glands due to loss of central or peripheral immune tolerance. These syndromes are also often accompanied by autoimmune damage to non-endocrine organs. Taking into account the wide range of components and variants of the disease, APS is usually divided into a rare juvenile type (APS 1) and a more common adult type (APS 2-4). APS type 1 is caused by a monogenic mutation, while APS types 2-4 have a polygenic mode of inheritance. One subtype of adult APS (APS 3D) is characterized by a combination of autoimmune thyroid disease and autoimmune rheumatic disease. This review considers the available literature data on combinations that meet the above criteria. Many studies have noted a significantly higher prevalence of rheumatic diseases in patients with autoimmune thyroid disease compared with the control group. Also, as in a number of rheumatic diseases, a more frequent occurrence of autoimmune thyroiditis, primary hypothyroidism and Graves' disease was noted.

Autoimmune polyglandular syndrome type 4: experience from a single reference center.

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure.

Alopecia areata and occurrence of vitiligo and hypothyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited disorder of immunity which leads to increased risk for mucocutaneous candidiasis and multiorgan autoimmune disease. While alopecia areata (AA) has been described in some patients with APECED, the extent and timing of AA is not well established and extent and timing of concomitant vitiligo and hypothyroidism has not been described. We evaluated an APECED cohort followed at the National Institutes of Health for the timing of development of associated diseases. We found AA occurred earlier in those with APECED than in the general population, was rarely the first sign of APECED, and the timing of AA onset did correlate with the timing of onset of vitiligo or hypothyroidism which also occurred at high rates and early age.

Type 3 autoimmune polyglandular syndrome (APS-3) or type 3 multiple autoimmune syndrome (MAS-3): an expanding galaxy.

BACKGROUND: The number of recognised distinct autoimmune diseases (AIDs) has progressively increased over the years with more than 100 being reported today. The natural history of AIDs is characterized by progression from latent and subclinical to clinical stages and is associated with the presence of the specific circulating autoantibodies. Once presented, AIDs are generally chronic conditions. AIDs have the tendency to cluster and co-occur in a single patient. Autoimmune thyroid diseases (AITD) are the most prevalent of AIDs in the world population, and about one-third of the AITD patients also present with a non-thyroid AID during their life-span. Furthermore, patient with non-thyroid AIDs often presents with a form of AITD as a concurrent condition. Many of the clusters of AIDs are well characterized as distinctive syndromes, while some are infrequent and only described in case reports. PURPOSE: In this review, we describe the wide spectrum of the combinations and the intricate relationships between AITD and the other AIDs, excluding Addison's disease. These combinations are collectively termed type 3 Autoimmune Polyglandular Syndrome (APS-3), also called type 3 Multiple Autoimmune Syndrome (MAS-3), and represent the most frequent APS in the world populations. CONCLUSIONS: Numerous associations of AITD with various AIDs could be viewed as if the other AIDs were gravitating like satellites around AITD located in the center of a progressively expanding galaxy of autoimmunity.

Clinical Characteristics in the Longitudinal Follow-Up of APECED Syndrome in Southern Croatia-Case Series.

BACKGROUND: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare monogenetic autosomal recessive disorder caused by a mutation in the autoimmune regulator (AIRE) gene characterized by complex phenotypic characteristics discovered over years of follow-up. METHODS: 7 patients were recruited in this case series in a period of the last 37 years from Southern Croatia. All patients were screened for AIRE R257X mutations. RESULTS: This study group had a mean current age of 25.3 years (age range from 5.4 to 40.2 years), while the mean age at the onset of the disease was 6.5 years (age range from 0.7 to 9.2 years) and with a mean follow-up period of 17.8 years. The overall prevalence of APECED syndrome is estimated to be 1 in 75,000. The most common initial manifestation of the disease was onychodystrophy, while the first major component of APECED syndrome was chronic mucocutaneous candidiasis. CONCLUSIONS: APECED is a ''multi-faced'' disease based on the very unpredictable and inconsistent onset of major components. Furthermore, based on our results, we suggest that onychodystrophy could be included as a warning sign of APECED syndrome.

Clinical characteristics of polyglandular autoimmune syndromes in pediatric age: an observational study.

OBJECTIVES: Polyglandular autoimmune syndromes (PAS) are characterized by the association of two or more autoimmune diseases (AID) and are classified into four types. PAS type 1 is more frequently manifested in childhood, but the prevalence of other PAS in children, less described in the literature, seems to be underestimated. METHODS: This study aimed to evaluate the prevalence of PAS in a selected pediatric population of 879 children with Diabetes mellitus type 1 (DM1), autoimmune thyroid disease (AITD), and Addison's disease (AD) followed in our hospital for 10 years and describe and classify the manifestations of different PAS. RESULTS: We diagnosed 35 children with PAS, most fulfilled criteria for PAS type 3 (65.7%), and AITD was the AID more frequently detected (74.3%). PAS type 1 was not diagnosed in our sample. Patients with PAS manifested DM1 and AITD at a younger age than children with monoglandular pathology (7.7 vs. 9.3 years, p=0.04 and 7.7 vs. 13.1 years, p<0.01). CONCLUSIONS: This is the first study that analyzes the prevalence of different types of PAS in a pediatric population followed by endocrine pathologies, namely DM1, AD, and AITD. As PAS manifestations are often preceded by a long latency period characterized by the presence of autoantibodies, we reinforce the need to value these markers for timely diagnosis and to screen PAS in patients with AD throughout their lives.

The Prevalence of Selective and Partial Immunoglobulin A Deficiency in Patients with Autoimmune Polyendocrinopathy.

BACKGROUND: Autoimmune disorders are reported as presenting signs in patients with immunoglobulin A (IgA) deficiency. Herein, we aim to evaluate serum IgA among patients with autoimmune polyendocrinopathy. METHODS: Patients with two or more autoimmune endocrinopathies were selected and the serum IgA levels were measured. Patients with an isolated low serum IgA (<7 mg/dL) after exclusion of other causes of hypogammaglobulinemia were considered as selective IgA deficiency (SIgAD), while partial IgA deficiency (PIgAD) was defined as IgA levels below lower limits of IgA normal range for age but higher than 7 mg/dL. RESULTS: Fifty-three patients (19 [35.8%] male and 34 [64.2%] female) with autoimmune polyendocrinopathy enrolled in the study. Parental consanguinity and positive family history of autoimmunity were reported in 38.0% and 52.9% of patients, respectively. Overall, IgA deficiency was observed in 5 (9.4%) patients including PIgAD in 3 (5.7%) and SIgAD in 2 (3.8%) patients. Among IgA deficient patients, the first autoimmune disorder was developed at earlier ages (p = .002), and the prevalence of infection (p = .002), lymphoproliferation (p = .021), and overlap between insulin-dependent diabetes mellitus and autoimmune thyroiditis (p = .032) were significantly higher than patients with normal IgA. Also, the number of autoimmune comorbidities was closely correlated with the occurrence of IgA deficiency (p = .008). CONCLUSION: The prevalence of IgA deficiency in patients with autoimmune polyendocrinopathy is higher than that in the general population. In these patients, immunologic workup may lead to early diagnosis of inborn error of immunity, which can positively impact the evolution of complications and even management of the autoimmune disorders.

Endocrine Disorders and Genital Infections Impair Gynecological Health in APECED (APS-1).

Objective: In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) defects in the autoimmune regulator gene lead to impaired immunotolerance. We explored the effects of immunodeficiency and endocrinopathies on gynecologic health in patients with APECED. Design: Cross-sectional cohort study combined with longitudinal follow-up data. Methods: We carried out a gynecologic evaluation, pelvic ultrasound, and laboratory and microbiologic assessment in 19 women with APECED. Retrospective data were collected from previous study visits and hospital records. Results: The study subjects' median age was 42.6 years (range, 16.7-65.5). Sixteen patients (84%) had premature ovarian insufficiency, diagnosed at the median age of 16.5 years; 75% of them used currently either combined contraception or hormonal replacement therapy. In 76% of women, the morphology and size of the uterus were determined normal for age, menopausal status, and current hormonal therapy. Fifteen patients (79%) had primary adrenal insufficiency; three of them used dehydroepiandrosterone substitution. All androgen concentrations were under the detection limit in 11 patients (58%). Genital infections were detected in nine patients (47%); most of them were asymptomatic. Gynecologic C. albicans infection was detected in four patients (21%); one of the strains was resistant to azoles. Five patients (26%) had human papillomavirus infection, three of which were high-risk subtypes. Cervical cell atypia was detected in one patient. No correlation between genital infections and anti-cytokine autoantibodies was found. Conclusions: Ovarian and adrenal insufficiencies manifested with very low androgen levels in over half of the patients. Asymptomatic genital infections, but not cervical cell atypia, were common in female patients with APECED.

Infections in the monogenic autoimmune syndrome APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the 'signature' APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.

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.

Rituximab as Maintenance Therapy in Type 1 Autoimmune Pancreatitis: An Italian Experience.

OBJECTIVE: Rituximab (RTX) has been proposed for the induction of remission and maintenance therapy in relapsing type 1 autoimmune pancreatitis (AIP). The aim of the study was to describe the use of RTX as maintenance therapy for patients with type 1 AIP. METHODS: Patients with type 1 AIP based on the International Consensus Diagnostic Criteria and treated with RTX were selected from our database. Two doses of RTX (1000 mg each) were administered 15 days apart and repeated after 6 months. RESULTS: Eighteen patients were treated with RTX as maintenance therapy. Of these, the involvement of other organs was observed in 16 patients (89%). Eight of the 18 patients (44%) relapsed during follow-up. Median time to relapse after the last infusion was 30 months (range, 12-35 months). No disease relapse was observed in the first year after the last infusion. Probability of disease relapse was 80% between 1 and 3 years from initial treatment. No adverse effects were observed. CONCLUSIONS: Rituximab seems be safe and effective for maintenance therapy of type 1 AIP during the first year after completing RTX infusion. However, the probability of disease relapse is high within 1 and 3 years from the last infusion.

Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). CONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

[The prevalence of newly diagnosed autoimmune diseases among patients with Graves' disease and autoimmune polyglandular syndrome of adults].

Gravess disease is a common part of Autoimmune polyglandular syndrome (APS) and among thyroid autoimmune disorders is usually preceded the onset of the syndrome. AIM: The aim of this study was to determine the frequency of occurrence of APS type 2, 3 among patients with Graves disease. MATERIALS AND METHODS: Sera of 94 patients with Gravess disease, 116 patients with APS 24 types and 80 healthy subjects were screened for 21-OH Ab, insulin-Ab (IAA), Islet Cell-Ab (ICA), glutamic acid decarboxylase-Ab (GADA), protein tyrosine phosphatase-Ab (IA2), Zinc Transporter 8-Ab (ZnT8), Anti-gliadin-Ab (IgA+IgG) (AGA), Anti-transglutaminase-Ab (IgA+IgG) (Anti-tTG), Anti-parietal cell-Ab (APCA), Intrinsic Factor-Ab (IF), Rheumatoid factor (RF), Anti Ovarian Antibodies (AOA). Serum cortisol, fasting plasma glucose levels were measured. RESULTS: The presence of Addisons disease and the onset of Type 1 DM was not determined among Graves disease patients. None of the patients with Graves disease and in the healthy control group had 21-OH-antibodies detected. The frequency of 21-OH-Ab was 4.2% in APS type 3 (p=0.07) and 91.6% in APS type 2, 4 (p0.001). The prevalence of diabetes-associated autoantibodies was 20.2% among Gravess disease patients against 8.75% in healthy subjects control group (p0.05); OR 2.64; 95% CI 1.056.66 and 30.2% in APS of adults (DM 1 negative group) (p=0.18). The prevalence of APCA-markers of autoimmune gastritis was 31.9% in Gravess disease, 48.3% in APS 24 types (p=0.01); OR 1.99; 95% CI 1.183.51, and 12.5% in control group (p0.01); OR 3.28; 95% CI 1.497.24. There were no significant differences in the frequency of occurrence of IF-Ab and RF-Ab in the groups. The frequency of AGA and ATA was 28.7% in Graves disease, 36.2% in APS types 24 (p=0.3), 10% in the control group ((р0.01); OR 3.63; 95% CI 1.548.54. Graves disease patients with risk of developing APS type 3 (positive diabetes-associated and other autoantibodies) had relatives with autoimmune diseases in 57.5% of cases (p=0.05); OR 2.18; 95% CI 1.034.63. CONCLUSION: Graves disease patients are at high risk for future development of APS 3 type, especially those with inheritance for autoimmune diseases. Screening for the immunological markers, pathognomonic for coexisting autoimmune diseases in such patients with Graves disease, as well as in patients with APS type 3, should be done regularly.

Prevalence of other autoimmune diseases in polyglandular autoimmune syndromes type II and III.

PURPOSE: Polyglandular autoimmune syndromes (PAS) are complex, heterogeneous disorders in which various autoimmune diseases can occur, affecting both endocrine and non-endocrine organs. In this meta-analysis, the prevalence of associated autoimmune disorders was investigated in PAS II and III. METHODS: A comprehensive search in MEDLINE and Embase databases identified 479 studies with the keywords of PAS II and PAS III. 18 records containing a total of 1312 patients fulfilled our inclusion criteria (original studies reporting at least 10 cases and containing the combination of other autoimmune disorders) and were selected for further analysis. A meta-analysis of prevalence was performed using the random-effects model with the calculation of 95% confidence intervals (CI). Results of each meta-analysis were displayed graphically using forest plots. RESULTS: Distinction between PAS II and PAS III was made in 842 cases, of which 177 and 665 were PAS II and III (21.1 vs 78.9%), respectively. The prevalence of Hashimoto's thyroiditis was significantly higher than that of Graves's disease (39% [95% CI 17-65%] vs. 4% [95% CI 0-10%], respectively; p = 0.001). In PAS II, Addison's disease (AD) coexisted with AITDs, T1DM or the combination of these conditions in 65, 18 and 10% of cases, respectively. In addition, one other endocrine and five non-endocrine organ-specific autoimmune disorders were reported. In PAS III, two other autoimmune endocrinopathies, six non-endocrine organ-specific, and four systemic autoimmune disorders were found in combination with AITDs. CONCLUSIONS: AITDs, T1DM and AD are the most common combinations in PAS, thus screening for these conditions seems to be reasonable.

Severe Phenotype of APECED (APS1) Increases Risk for Structural Bone Alterations.

Objective: Immunological abnormalities, the resulting endocrinopathies and their treatments may impact bone health in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1). The aim of the present study was to describe skeletal characteristics in patients with APECED and the prevalence and risk factors of compromised bone health. Patients and methods: We performed a cross-sectional study on 44 patients (27 females) with APECED and 82 age-, gender- and ethnicity-matched control subjects (54 females). We determined the prevalence of osteoporosis by dual-energy X-ray absorptiometry and skeletal characteristics by peripheral quantitative computed tomography at radius and tibia. Results: Patients were examined at the median age of 37.8 years (range, 7.0-70.1). Dual-energy X-ray absorptiometry indicated osteoporosis in four adult patients (9%); radiographs showed vertebral fractures in three patients. The prevalence of multiple non-spinal fractures was higher in patients than in controls. On peripheral quantitative computed tomography, bone characteristics at distal and proximal radius did not differ between the groups. At distal tibia, patients had lower total (p = 0.009) and trabecular (p = 0.033) volumetric bone mineral density. At the proximal tibia, patients had lower cortical thickness (p < 0.001) than controls. Severity of APECED phenotype influenced both radial and tibial characteristics: cortical thickness and total and trabecular volumetric bone mineral density were lower in patients with ≥7 disease manifestations as compared with more mildly affected patients, whose values were similar to controls. Conclusions: APECED associated with bone structural alterations, especially in patients with a high number of disease manifestations. This may increase the risk of fractures with aging, but symptomatic osteoporosis was rare.

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.

Autoimmune Polyendocrinopathy.

CONTEXT: This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments. DESIGN AND RESULTS: Systematic search for studies related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended. CONCLUSION: Timely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.

Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy.

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.

Celiac Disease and Glandular Autoimmunity.

Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. Prevalence of celiac disease is increased in patients with mono- and/or polyglandular autoimmunity and their relatives. We have reviewed the current and pertinent literature that addresses the close association between celiac disease and endocrine autoimmunity. The close relationship between celiac disease and glandular autoimmunity can be largely explained by sharing of a common genetic background. Further, between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5⁻7% of patients with autoimmune thyroid disease, type 1 diabetes, and/or polyglandular autoimmunity are IgA anti-tissue transglutaminase antibody positive. While a gluten free diet does not reverse glandular autoimmunity, its early institution may delay or even prevent its first manifestation. In conclusion, this brief review highlighting the close association between celiac disease and both monoglandular and polyglandular autoimmunity, aims to underline the need for prospective studies to establish whether an early diagnosis of celiac disease and a prompt gluten-free diet may positively impact the evolution and manifestation of glandular autoimmunity.

PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity.

Context: Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce. Objective: Evaluate potential associations of eight SNPs with APSs. Setting: Academic referral endocrine clinic. Patients: A total of 543 patients with APS and monoglandular autoimmunity and controls. Intervention: The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte‒associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor α rs1800630 (-863); and interleukin-2 receptor alpha rs10795791 were tested by single-base extension in all subjects. Results: The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P = 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001). T-allele carriers' risk for APS was increased (OR: 3.76; 95% CI: 1.97 to 7.14; P < 0.001). T-allele frequency was higher among APS than controls (OR: 3.25; 95% CI: 1.82 to 5.82; P < 0.001), T1D (OR: 2.54; 95% CI: 1.48 to 4.36; P = 0.001), or GD (OR: 1.89; 95% CI: 1.15 to 3.11; P = 0.012). The SNP CTLA-4 CT60 G-allele carriers were more frequent in APS (85%) than controls (78%) (OR: 1.55; 95% CI: 0.81 to 2.99). Combined analysis of CTLA-4 AG49 and CT60 revealed OR 4.89; 95% CI: 1.86 to13.59; P = 0.00018 of the genotype combination AG/GG for APS vs controls. VDR polymorphisms Bsm I, Apa I, and Taq I did not, but the haplotypes differed between APS and controls (P = 0.0011). Conclusions: PTPN22 and CTLA-4 polymorphisms are associated with APS and differentiate between polyglandular and monoglandular autoimmunity.