The purpose of our work was to provide a data-driven perspective to autoimmune polyglandular syndrome (APS), a complex autoimmune disorder, supplementing traditional clinical observations.

Medical records of 7559 patients were analyzed, and autoimmune origin was proved in 3180 cases of which 380 (12%) had APS. Associations of component disorders were investigated by computational methods to reveal typical patterns of disease development.

Twenty-eight distinct autoimmune disorders were diagnosed forming 113 combinations. The 10 most frequent combinations were responsible for 51.3% of cases. Hashimoto's thyroiditis (HT) and Graves' disease (GD) were differentiated as the main cornerstones of APS, sharing several comorbidities. HT was the most common manifestation (67.4%), followed by GD (26.8%) and type 1 diabetes mellitus (T1D) (20.8%). APS started significantly earlier in men than in women. Thyroid autoimmunity was frequently linked to gastrointestinal and systemic manifestations, and these patterns of associations substantially differed from that of T1D, Addison's disease, or coeliac disease when present as first manifestations, suggesting the possibility of a common biological cause.

APS is more frequent than reported. Classifying APS requires a shift of perspective toward disease associations rather than disorder prevalence.

Autoimmune polyendocrine syndrome type 2 (APS-2) is a rare disorder characterized by autoimmune damage to multiple endocrine glands and typically involves primary adrenal insufficiency (PAI), autoimmune thyroid disease (AITD), and type 1 diabetes mellitus (T1DM). Clinical presentations that feature the full triad alongside adrenal crisis (AC) are rare, with only four such cases reported globally. While AC is the most life-threatening acute complication of APS-2, its pathogenesis is complex and incompletely understood. While there are multiple potential triggers, the role of exogenous substances such as traditional Chinese medicine [TCM] has not been systematically examined.

A 69-year-old female was hospitalized with a 9-year history of increasing fatigue, which had recently worsened due to high fever, anorexia, and vomiting lasting 2 days. She has previously been diagnosed with T1DM (nine years prior) and AITD (five years prior). Four years earlier, she underwent thymoma resection. Three years before admission, she self-administered an unknown TCM remedy that coincided with increased fatigue and mucocutaneous hyperpigmentation. On admission, she was in hypovolemic shock and severe hyponatremia (118.0 mmol/L). Laboratory tests revealed low basal cortisol (2.38 μg/dL) and markedly elevated adrenocorticotropic hormone (>1250 pg/mL). An adrenocorticotropic hormone stimulation test confirmed non-responsive adrenal function, indicating PAI. Together with her medical history and positive antibody profile, APS-2 with AC was diagnosed. She responded well to high-dose intravenous glucocorticoid therapy, sodium supplementation, and symptomatic management. Although persistent hyponatremia recurred following discharge, it resolved following fludrocortisone acetate supplementation, and her condition remained stable at the last follow-up.

We report the fifth case of full-triad APS-2 with AC and document a 9-year diagnostic delay due to non-specific symptoms with asynchronous multi-glandular involvement. Thyroxine replacement therapy and potential TCM-induced changes may have aggravated cortisol metabolism and immune imbalances, hastening adrenal failure. Clinicians should implement stepwise organ-function monitoring in patients with any single-gland autoimmune disease, maintain vigilance for exogenous medication use, and implement multidisciplinary management strategies to mitigate the risk of AC. This case provides critical insights into both the pathogenesis and clinical management of APS-2.

Autoimmune polyendocrine syndrome (APS) is a clinical disorder characterized by the loss of immune tolerance, leading to dysfunction in multiple endocrine glands. According to the latest disease classification, APS is categorized into three main subtypes: APS-1, APS-2, and IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. APS-2 is defined by the presence of at least two autoimmune endocrine disorders, such as type 1 diabetes mellitus, autoimmune thyroiditis, or Addison's disease. APS-2 typically manifests later than APS-1, with onset most commonly occurring in early adulthood. However, pediatric cases involving a combination of autoimmune thyroid disease, type 1 diabetes mellitus, and myasthenia gravis, are extremely rare.

This article reported the case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 (APS-2). The patient initially presented with hyperthyroidism and exophthalmos and was subsequently diagnosed with type 1 diabetes mellitus and myasthenia gravis. To our knowledge, this case represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands.

Through a retrospective analysis, we comprehensively reviewed the phenotypic characteristics of APS-2 and explored its potential immune mechanisms. This article aims to provide clinicians with a valuable reference case to enhance early recognition and facilitate the implementation of targeted prevention and treatment strategies.

Patients with ulcerative colitis (UC) often exhibit susceptibilities to multiple autoimmune diseases such as Sjogren's syndrome, primary sclerosing cholangitis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus. This propensity likely stems from common pathogenic mechanisms underlying immune-mediated conditions. This report highlights the occurrence of autoimmune thyroid disease during UC exacerbations. Notably, the patient displayed petrified auricles.Case Summary.A 57-year-old male complained of sustained abdominal pain, diarrhea, hematochezia, and mucus for a duration of 20 days. The diagnosis of UC was confirmed via colonoscopy, histopathological examination, and small bowel MRE. Clinical evaluations revealed bilateral ectopic ossification in his ears, which appeared to develop over an unspecified timeframe. Imaging and histological evaluations substantiated the ectopic ossification diagnosis while eliminating the possibility of adrenal insufficiency. The presented case offers a unique instance of bilateral auricular ossification, which is hypothesized to result from hyperthyroidism.

Our case report underscores the necessity of enhancing awareness of the rare complications associated with UC. Medical practitioners should recognize the potential overlap of autoimmune thyroid disorders in UC patients. It is imperative to test for thyroid-related antibodies in such individuals, irrespective of overt thyroid dysfunction.

The increasing prevalence of autoimmune diseases globally has prompted extensive research and the development of immunosuppressants. Currently, immunosuppressive drugs such as cyclosporine, rapamycin, and tacrolimus have been utilized in clinical practice. However, long-term use of these drugs may lead to a series of adverse effects. Therefore, there is an urgent need to explore novel drug candidates for treating autoimmune diseases. This review aims to find potential candidate molecules for natural immunosuppressive compounds derived from plants, animals, and fungi over the past decade. These compounds include terpenoids, alkaloids, phenolic compounds, flavonoids, and others. Among them, compounds 49, 151, 173, 200, 204, and 247 have excellent activity; their IC50 were less than 1 μM. A total of 109 compounds have good immunosuppressive activity, with IC50 ranging from 1 to 10 μM. These active compounds have high medicinal potential. The names, sources, structures, immunosuppressive activity, and the structure-activity relationship were summarized and analyzed.

To characterize patients with APS and to propose a new approach for their follow-up. Query ID="Q1" Text="Please check the given names and familynames."

Monocentric observational retrospective study enrolling patients referred to the Outpatients clinic of the Units of Endocrinology, Diabetology, Gastroenterology, Rheumatology and Clinical Immunology of our Hospital for Autoimmune diseases.

Among 9852 patients, 1174 (11.9%) [869 (73.9%) female] were diagnosed with APS. In 254 subjects, the diagnosis was made at first clinical evaluation (Group 1), all the other patients were diagnosed with a mean latency of 11.3 ± 10.6 years (Group 2). Group 1 and 2 were comparable for age at diagnosis (35.7 ± 16.3 vs. 40.4 ± 16.6 yrs, p = .698), but different in male/female ratio (81/173 vs 226/696, p = .019). In Group 2, 50% of patients developed the syndrome within 8 years of follow-up. A significant difference was found after subdividing the first clinical manifestation into the different outpatient clinic to which they referred (8.7 ± 8.0 vs. 13.4 ± 11.6 vs. 19.8 ± 8.7 vs. 7.4 ± 8.1 for endocrine, diabetic, rheumatologic, and gastroenterological diseases, respectively, p < .001).

We described a large series of patients affected by APS according to splitters and lumpers. We propose a flowchart tailored for each specialist outpatient clinic taking care of the patients. Finally, we recommend regular reproductive system assessment due to the non-negligible risk of developing premature ovarian failure.

Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) are autoimmune diseases. Previous case reports and case series suggest an association may exist between these diseases, as well as an increased risk of SLE after thymectomy for MG. We undertook this study to determine whether SLE and MG were associated in large cohorts.

We searched the IBM Watson Health Explorys platform and the Department of Veterans Affairs Million Veteran Program (MVP) database for diagnoses of SLE and MG. In addition, we examined subjects enrolled in the Lupus Family Registry and Repository (LFRR) as well as controls for a diagnosis of MG.

Among 59,780,210 individuals captured in Explorys, there were 25,750 with MG and 65,370 with SLE. 370 subjects had both. Those with MG were >10 times more likely to have SLE than those without MG. Those with both diseases were more likely to be women, African American, and at a younger age than MG subjects without SLE. In addition, the MG patients who underwent thymectomy had an increased risk of SLE compared to MG patients who had not undergone thymectomy (OR 3.11, 95% CI: 2.12 to 4.55). Autoimmune diseases such as pernicious anemia and miscellaneous comorbidities such as chronic kidney disease were significantly more common in MG patients who developed SLE. In the MVP, SLE and MG were also significantly associated. Association of SLE and MG in a large SLE cohort with rigorous SLE classification confirmed the association of SLE with MG at a similar level.

While the number of patients with both MG and SLE is small, SLE and MG are strongly associated together in very large databases and a large SLE cohort.

to describe a clinical case of ocular sarcoidosis in a patient with Autoimmune Polyglandular Syndrome Type 2 (APS-2).

an 86-year-old female diagnosed with APS-2 was referred to our uveitis department with rapid visual loss in her left eye during a 3-month period. Her best-corrected visual acuity (BCVA) was counting fingers in her left eye (OS) and 20/40 in her right eye (OD). Slit-lamp biomicroscopy was unremarkable OD but revealed granulomatous keratic precipitates OS. Fundoscopy revealed bilateral optic disc oedema and +2 and 4+ vitritis (SUN classification) in her OD and OS, respectively.

the patient underwent chest X-Ray which revealed bilateral hilar lymphadenopathy and fibrosis. On high-resolution computed tomography of the lungs, ground-glass opacities were visible, and a diagnosis of ocular sarcoidosis was presumed. After exclusion of infectious diseases, the patient was treated with methotrexate and oral corticosteroids and there was substantial improvement of the optic nerve oedema and vitritis. At the most recent visit, 2 years later, OS BCVA was 20/50.

There may be an association between ocular sarcoidosis and APS or other autoimmune disorders.

Autoimmune polyglandular syndrome II (APS-II), also known as Schmidt syndrome, is a rare endocrine disorder characterized by endocrine and non-endocrine illnesses. Addison's disease and at least one additional autoimmune condition, such as autoimmune thyroid disease or type 1 diabetes mellitus (T1DM), are features of APS-II. It can result from genetic and non-genetic factors. We present a case of a 60-year-old female patient with a history of T1DM and a recent diagnosis of Hashimoto's thyroiditis who was admitted to the nephrology department for hyponatremia. Investigations showed the presence of adrenal insufficiency (AI), so she was diagnosed with APS-II and had the full triad of this syndrome. Thus, it is important to think about the diagnosis of AI or other autoimmune conditions in a patient who already has one or more autoimmune diseases.

A variety of inflammatory conditions may directly involve the endocrine glands, leading to endocrine dysfunction that can cause severe consequences on patients' health, if left untreated. Inflammation of the endocrine system may be caused by either infectious agents or other mechanisms, including autoimmune and other immune-mediated processes. Not infrequently, inflammatory and infectious diseases may appear as tumor-like lesions of endocrine organs and simulate neoplastic processes. These diseases may be clinically under-recognized and not infrequently the diagnosis is suggested on pathological samples. Thus, the pathologist should be aware of the basic principles of their pathogenesis, as well as of their morphological features, clinicopathological correlates, and differential diagnosis. Interestingly, several systemic inflammatory conditions show a peculiar tropism to the endocrine system as a whole. In turn, organ-specific inflammatory disorders are observed in endocrine glands. This review will focus on the morphological aspects and clinicopathological features of infectious diseases, autoimmune disorders, drug-induced inflammatory reactions, IgG4-related disease, and other inflammatory disorders involving the endocrine system. A mixed entity-based and organ-based approach will be used, with the aim to provide the practicing pathologist with a comprehensive and practical guide to the diagnosis of infectious and inflammatory disorders of the endocrine system.

To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes.

Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed.

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.

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.

Autoimmune polyglandular syndrome type 2 (APS2) is characterized by autoimmune adrenal insufficiency (AI) in conjunction with autoimmune thyroid disease (AITD) and/or type 1 diabetes mellitus (T1DM). The aim is to report an 11-year-old girl with concurrence of Addison disease, celiac disease and thyroid autoimmunity.

She initially presented at the age of 5 with vomiting, dehydration, hyponatremia, hyperkalemia and low glucose. She recovered with intravenous hydration but the diagnosis was not established. She presented again at the age of 11 with hyperpigmentation, weakness and signs of impending adrenal crisis. Diagnosis of autoimmune AI was established together with celiac disease and thyroid autoimmunity. Thus, she met criteria for APS, being the third pediatric case report of APS2 with this combination.

This case is notable for the atypical age of onset, given that APS2 is rare in the pediatric population. Furthermore, it depicts the insidious course of Addison disease with symptoms fluctuating for years before diagnosis.

The recurrence risk ratio (λ) expresses the risk ratio of index patients' first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature.

Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings).

As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11-21 and 16, 12-19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17-30.69)/17.57 (11.80-24.36) and 13.48 (8.42-20.52)/10.68 (6.76-16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated.

These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD.

Autoimmune disease, including autoimmune thyroid disease, with uncharacteristic symptoms can be due to additional severe disease. We report a life-threatening debut of autoimmune polyglandular syndrome type II (APS II) defined as Addison's disease combined with autoimmune diabetes and/or thyroid disease.

A 33-year-old male with newly diagnosed hypothyroidism was referred to a tertiary center due to fatigue and 20-kg rapid weight loss. Malignancy was excluded. After a gastroscopy, he developed Addison's crisis; he was admitted to our hospital and stabilized. Final diagnoses included Hashimoto's thyroiditis, Addison's disease, vitiligo, and pernicious anemia. Whole genome sequencing found no genetic variants associated with component diseases. Human leukocyte antigen typing revealed DR3/DR4 and DQ8/DQ2 heterozygosity associated with APS II. A patient with Hashimoto's thyroiditis and weight loss presented with Addison's crisis and was diagnosed with APS II.

Awareness of potential polyautoimmunity in clinical evaluation of patients with thyroid disease improves diagnosis and can be lifesaving.

Autoimmune polyglandular syndrome 2(APS 2) is immune-mediated destruction that affects two or more endocrine glands and causes a constellation of multiple glands insufficiencies.

we reported a rare case 9 years old male diagnosed with APS 2; he had adrenal insufficiency three years ago due to leak adherence to hydrocortisone. He was admitted to the hospital for adrenal crises after hemodynamic stability; laboratory evaluation showed that he had Hashimoto's thyroiditis, celiac disease, and the glutamic acid decarboxylase antibody (GAD) Anti-islet cell antibodies were positive, so he was also predisposed to DM 1 later.

APS 2, also known as Schmidt's syndrome, is usually defined by the occurrence of the same fludrocortisone or more of the followings: primary adrenal insufficiency (Addison's disease), Grave's disease, primary hypothyroidism, type 1 diabetes mellitus, celiac disease, and pernicious anemia.

This case report underlines the importance of early recognition and treatment of acute endocrine diseases and the necessity to investigate pediatric patients with autoimmune diseases for coexisting conditions.

The C1858T variant of the protein tyrosine phosphatase N22 (PTPN22) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.

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 cells (Tconv, CD45RChigh), their precursors and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs, CD45RClow/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation but its potential has not been examined in autoimmune diseases. APECED is a rare genetic syndrome caused by loss-of-function mutations of the key central tolerance mediator, autoimmune regulator (AIRE) leading to abnormal auto-reactive T cell responses and autoantibodies production. Herein, we showed that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective both as prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChigh T cells, inhibited CD45RChigh B cells, and restored the Treg/Tconv ratio and the altered Tregs transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells and lesioned organs from APECED patients were infiltrated by CD45RChigh cells. Our observations highlight the potential role for CD45RChigh cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.

Autoimmune endocrine disorders, such as type 1 diabetes (T1D) and thyroiditis, at present are treated with only hormone replacement therapy. This emphasizes the need to identify personalized effective immunotherapeutic strategies targeting T and B lymphocytes. Among the genetic variants associated with several autoimmune disorders, the C1858T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, encoding for Lyp variant R620W, affects the innate and adaptive immunity. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes) that selectively inhibit variant allele expression. In this manuscript, we improved lipoplexes carrying siRNA for variant C1858T by functionalizing them with Fab of Rituximab antibody (RituxFab-Lipoplex) to specifically target B lymphocytes in autoimmune conditions, such as T1D. RituxFab-Lipoplexes specifically bind to B lymphocytes of the human Raji cell line and of human PBMC of healthy donors. RituxFab-Lipoplexes have impact on the function of B lymphocytes of T1D patients upon CpG stimulation showing a higher inhibitory effect on total cell proliferation and IgM+ plasma cell differentiation than the not functionalized ones. These results might open new pathways of applicability of RituxFab-Lipoplexes, such as personalized immunotherapy, to other autoimmune disorders, where B lymphocytes are the prevalent pathogenic immunocytes.

Celiac disease (CD) is an autoimmune intestinal disease caused by the intake of gluten-containing cereals and their products by individuals with genetic susceptibility genes. Vitiligo is a commonly acquired depigmentation of the skin; its clinical manifestation are skin patches caused by localized or generalized melanin deficiency. Both diseases have similar global incidence rates (approximately 1%) and are associated to similar diseases, including autoimmune bullous disease, inflammatory bowel disease, autoimmune thyroiditis, autoimmune gastritis, and type 1 diabetes. The relationship between CD and vitiligo has been reported in several studies, but their conclusions are inconsistent. Further, it has also been reported that a gluten-free diet (GFD) can improve the symptoms of immune-related skin diseases such as vitiligo. In this mini-review, we summarize and review the literature on the relationship between CD and vitiligo, assess the therapeutic significance of GFD for patients with vitiligo, and explore their possible physiopathology. We are hopeful that the information summarized here will assist physicians who treat patients with CD or vitiligo, thereby improving the prognosis.

Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitis are caused by the body's immune response to autoantigens. The pathogenesis of autoimmune diseases is complex. RNA methylation is known to play a key role in disease progression as it regulates almost all aspects of RNA processing, including RNA nuclear export, translation, splicing, and noncoding RNA processing. This review summarizes the mechanisms, molecular structures of RNA methylations and their roles in biological functions. Similar to the roles of RNA methylation in cancers, RNA methylation in RA and SLE involves "writers" that deposit methyl groups to form N6-methyladenosine (m6A) and 5-methylcytosine (m5C), "erasers" that remove these modifications, and "readers" that further affect mRNA splicing, export, translation, and degradation. Recent advances in detection methods have identified N1-methyladenosine (m1A), N6,2-O-dimethyladenosine (m6Am), and 7-methylguanosine (m7G) RNA modifications, and their roles in RA and SLE need to be further studied. The relationship between RNA methylation and other autoimmune diseases has not been reported, and the roles and mechanisms of RNA modifications in these diseases need to be explored in the future.

Autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic vasculitis, dermatomyositis, systemic sclerosis (SSc), mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroiditis (AITD) and ulcerative colitis. Exosomes exist in body fluids, including blood, saliva, urine, cerebrospinal fluid and milk. They are mainly derived from the invagination of intracellular lysosomal particles, which are released into the extracellular matrix after fusion of the outer membrane of the exosomes with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying proteins, nucleic acids and lipids. Evidences show that exosomes are involved in the pathogenesis of various autoimmune diseases. In view of the important roles of exosomes in autoimmune diseases, this work systematically reviewed the effects of exosomes on the pathogenesis of autoimmune diseases, especially the regulatory roles of exosome derived microRNAs (miRNAs) in the pathogenesis of RA, SLE, dermatomyositis, SSc, AITD and ulcerative colitis. The review of the roles of exosomes in autoimmune diseases will help to clarify the pathogenesis of these diseases and explore new diagnostic markers and therapeutic targets.

Pluriglandular autoimmune syndrome (APS) can affect multiple endocrine glands and is associated with other autoimmune diseases. APS type 1 presents with hypoparathyroidism, mucocutaneous candidiasis and Addison's disease. It is caused by AutoImmune Regulator (AIRE) gene mutation. The diagnosis includes clinical manifestations in addition to AIRE gene sequencing. SPA type 2 presents with Addison's disease, type 1 diabetes, or autoimmune thyroid disease. Multiple genes have been implicated, including those of the class II major histocompatibility complex. SPA type 3 is characterized by autoimmune thyroid disease and other autoimmune disease, excluding Addison's disease and hypoparathyroidism, 4 genes have been implicated and confer susceptibility. The diagnosis of APS type 2 and type 3 includes clinical manifestations, nevertheless, the determination of autoantibodies can be useful to predict the risk of disease manifestation and to confirm the autoimmune disease in some cases.

Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).

Guidelines, pertinent original articles, systemic reviews, and meta-analyses.

Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.

A clear trend towards serological diagnosis and medical treatment of GD has emerged.

Common autoimmune diseases (AID) tend to occur together in the same individual and families. Type 1 diabetes (T1D) is caused by an autoimmune-induced inflammatory destruction of the pancreatic tissue and clusters with several other AID.

To compare the demographic, clinical, and serological features of patients with single T1D vs those with T1D and associated AID.

From October 1999 to February 2020, a total of 665 patients with T1D and their first-degree relatives were evaluated.

Compared to patients with isolated T1D, those with T1D + AID were older and had a higher female: male ratio. Average patient age and age at disease onset were higher in T1D + AID vs T1D only. The average time interval between T1D onset and the onset of a second glandular AID was markedly shorter than the time interval between T1D and the occurrence of a non-endocrine AID. T1D-specific autoantibodies were more frequent in patients with T1D + AID and relatives vs those with T1D only. However, the prevalence of AID and autoantibodies against various tissues were found to be higher in relatives of patients with T1D only compared to relatives of patients with T1D + AID.

Annual serological and subsequent functional screening for AID in patients with T1D and their first-degree relatives is recommended.

Addison's disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs.

We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks.

The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain-Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren's syndrome.

The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.

Although dermatitis herpetiformis is closely associated with celiac disease (CD), data on the relationship between CD and other dermatologic disorders have been mixed. We aimed to quantify the risk of skin disorders in patients after CD diagnosis in a population-based setting.

Using data from all 28 pathology departments in Sweden 1969-2016, we identified patients with CD. Each patient was matched by age, sex, calendar year, and geographic region to up to 5 population controls. We calculated the risk of any skin disease and specific skin diseases using Cox proportional hazards.

We identified 43,300 patients with CD and 198,532 matched controls. After a median follow-up time of 11.4 years, the incidences of skin disease in CD patients and controls were 22.6 and 14.8 per 1000 person-years respectively (HR=1.55; 95%CI 1.51-1.58). Increased risks were present for eczema (HR=1.67; 95%CI 1.56-1.79), psoriasis (HR=1.55; 95%CI 1.43-1.68), urticaria (HR=1.52; 95% CI 1.42-1.64), vitiligo (HR=1.90; 95%CI 1.52-2.39), acne (HR=1.39; 95%CI 1.29-1.50), and alopecia areata (HR=1.78; 95%CI 1.43-2.20).

Compared to the general population, patients with CD are at increased risk of multiple common skin disorders, a risk that persists in the long-term.