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1.
Graves' disease in clinical perspective.
Ehlers, M, Schott, M, Allelein, S
Frontiers in bioscience (Landmark edition). 2019;(1):35-47
Abstract
Graves' disease (GD) is the most common cause for hyperthyroidism in iodine-replete areas. The disease is caused by the appearance of stimulating TSH receptor autoantibodies (TRAb) leading to hyperthyroidism. Blocking and neutral TRAb have, however, also been described. TRAb can be measured either by competition assays, assays using a bridge technology or bioassays (for discriminating stimulating vs. blocking antibodies). Therapy of GD with antithyroid drugs belonging to the group of thionamides is the first-line treatment to be continued for 12 up to 18 months. In case of relapse, thyroid ablative therapy including radioiodine therapy or thyroidectomy, respectively, should be performed. Risk factors for relapse are a large thyroid volume, persistence of high TRAb serum titer, smoking, and others. Within this review, we will give insights into the pathogenesis of GD including the pathogenesis of Graves' ophthalmopathy. We also describe recent developments of TRAb measurement, which is used for the diagnosis of GD as well as for outcome prediction. Finally, we discuss therapy aspects as well as the important issue of GD and pregnancy.
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2.
Survey of the initial management of celiac disease antibody tests by ordering physicians.
Potter, K, de Koning, L, Butzner, JD, Gidrewicz, D
BMC pediatrics. 2019;(1):243
Abstract
BACKGROUND Appropriate interpretation of a positive celiac antibody test by an ordering physician is important in order to institute proper management. We evaluated why children with an initial positive celiac serology were not referred for diagnostic biopsy or followed with serial testing by the ordering physician. METHODS Consecutive celiac serologies in all patients less than 18 years of age were evaluated over 3.5 years and 775 children with a positive tissue transglutaminase antibody (TTG) were identified. If no management of a positive TTG could be identified, a survey was sent to the ordering physician. Responses were categorized as appropriate or inappropriate management. RESULTS Of the 775 patients with a positive TTG, 193 (24.9%, 95% CI 21.9-28.1%) received no follow-up management. We contacted 173 ordering physicians and 120 (69%) responded. Of the 120 responses, 55 patients (45.8%, 95% CI 36.8-55.1%) were managed appropriately and 46 (38.3%, 95% CI 29.7-47.7%) were considered to be inappropriately managed when no repeat TTG was obtained within 18 months. Reasons for inappropriate management included: screen considered to be false positive (44.7%), patient was not experiencing symptoms of celiac disease (31.6%), symptoms had resolved (15.8%), results were not indicative of celiac disease (26.3%) and patients started a gluten-free diet with no evaluation of response (15.8%). In 19 patients the TTG was not acted upon for technical reasons. CONCLUSIONS Positive TTGs require appropriate interventions. These include: subspecialist referral for further evaluation and/or repeat testing to evaluate: 1) treatment response or 2) patients with minimal or no symptoms.
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3.
Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol.
Ziegler, AG, Achenbach, P, Berner, R, Casteels, K, Danne, T, Gündert, M, Hasford, J, Hoffmann, VS, Kordonouri, O, Lange, K, et al
BMJ open. 2019;(6):e028578
Abstract
INTRODUCTION The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes. METHODS AND ANALYSIS Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes. ETHICS AND DISSEMINATION The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. TRIAL REGISTRATION NUMBER NCT03364868.
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4.
The structure, specificity and function of anti-citrullinated protein antibodies.
Ge, C, Holmdahl, R
Nature reviews. Rheumatology. 2019;(8):503-508
Abstract
In this Perspectives article, we outline a proposed model for understanding the specificity and function of anti-citrullinated protein antibodies (ACPAs). We suggest that ACPAs vary in specificity between two extremes: some are 'promiscuous' in that they are highly specific for the citrulline side chain, but cross-react with a range of citrullinated peptides, whereas others are 'private' in that their recognition of citrulline as well as proximal amino acid side chains enables protein-specific interactions. Promiscuous ACPAs tend to dominate in the sera both before and after the onset of rheumatoid arthritis, but their functional role has not been clarified. No firm evidence exists that these ACPAs are pathogenic. By contrast, private ACPAs encompass antibodies that specifically recognize citrullinated epitopes on joint proteins or that cross-react with joint proteins, thereby opening up the possibility that these private ACPAs are arthritogenic. These joint-reactive antibodies are more likely to target joints by binding to joint tissues and to promote the formation of local immune complexes leading to bone erosions, pain and arthritis.
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5.
Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk.
Andrén Aronsson, C, Lee, HS, Hård Af Segerstad, EM, Uusitalo, U, Yang, J, Koletzko, S, Liu, E, Kurppa, K, Bingley, PJ, Toppari, J, et al
JAMA. 2019;(6):514-523
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Abstract
IMPORTANCE High gluten intake during childhood may confer risk of celiac disease. OBJECTIVES To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. DESIGN, SETTING, AND PARTICIPANTS The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. EXPOSURES Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. MAIN OUTCOMES AND MEASURES The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. RESULTS Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). CONCLUSIONS AND RELEVANCE Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.
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SYNDROMES OF KETOSIS-PRONE DIABETES.
Balasubramanyam, A
Transactions of the American Clinical and Climatological Association. 2019;:145-155
Abstract
Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.
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7.
Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes.
Sørgjerd, EP
Current diabetes reviews. 2019;(3):199-204
Abstract
Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.
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8.
Inflammatory myopathy associated with PD-1 inhibitors.
Seki, M, Uruha, A, Ohnuki, Y, Kamada, S, Noda, T, Onda, A, Ohira, M, Isami, A, Hiramatsu, S, Hibino, M, et al
Journal of autoimmunity. 2019;:105-113
Abstract
OBJECTIVE To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). METHODS We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. RESULTS In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. CONCLUSIONS Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.
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9.
[Three cases report of juvenile dermatomyositis with positive anti-melanoma differentiation associated gene 5 (MDA5) antibody and severe interstitial lung disease and literature review].
Hou, J, Zhou, ZX, Li, JG, Xu, YJ, Ding, YC
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2019;(12):928-933
Abstract
Objective: To report the clinical features of anti-MDA5 antibody positive juvenile dermatomyositis (JDM) complicated with severe interstitial lung disease (ILD). Methods: The clinical data of three patients, who was admitted to the Department of Rheumatology and Immunology, Children's Hospital of the Capital Institute of Pediatrics from September 2016 to July 2017, with anti-melanoma differentiation associated gene 5 (MDA5) antibody positive JDM complicated with ILD were retrospectively extracted and analyzed. Meanwhile, PubMed database, CNKI, Wanfang database and China Biology Medicine disc (from their establishment to February 2019) with the key words "juvenile dermatomyositis" "interstitial lung disease" , and "anti-MAD5 antibody" both in English and Chinese were searched. Results: There were 2 females and 1 male (P1-P3), aged from 10 years 3 months to13 years 4 months, the time from onset to diagnosis were 2 months, 4 months and 10 months. All presented with rash. One of them had decreased muscle strength, and two had decreased activity tolerance. Creatine kinase was 588, 915 and 74 U/L, and serum ferritin were 1 792, >2 000 and 195.4 μg/L. All three patients had positive anti-MDA5 antibodies. At the time of diagnosis, all of them had ILD, pneumothorax and mediastinal emphysema, but had no respiratory symptoms. All three patients received oral methylprednisolone and cyclophosphamide pulse therapy, while human immunoglobulin was given only to P1 and P2. P1 developed rapid progressive pulmonary interstitial disease (RPILD) and died of respiratory failure after 2 months. While P2 and P3 were followed up for 1 to 2 years, who had complete remission, as anti-MDA5 antibody turned to negative and ILD improved significantly. Ten related reports in literature were retrieved, without reported Chinese cases, and most cases initiated with rash and very likely complicated with arthritis. Some of them were more likely to have ILD rather than muscle weakness. It also showed that Japanese JDM children had higher rate of positive anti-MDA5 antibody than patients from the U.S. and U.K., and are more susceptible to ILD and RPILD. The mortality rate of patients with RPILD is extremely high. Conclusions: The cases of JDM with positive anti-MDA5 antibody mainly presented with rash and mild muscle weakness, and could be complicated with ILD, pneumothorax and mediastinal emphysema without respiratory symptoms at early stage. Anti-MDA5 antibody titer is related to disease activity and can turn to negative after treatment.
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10.
Multi-dimensional immunoproteomics coupled with in vitro recapitulation of oncogenic NRASQ61R identifies diagnostically relevant autoantibody biomarkers in thyroid neoplasia.
Belousov, PV, Afanasyeva, MA, Gubernatorova, EO, Bogolyubova, AV, Uvarova, AN, Putlyaeva, LV, Ramanauskaite, EM, Kopylov, AT, Demin, DE, Tatosyan, KA, et al
Cancer letters. 2019;:96-106
Abstract
Tumor-associated antigen (TAA)-specific autoantibodies have been widely implicated in cancer diagnosis. However, cancer cell lines that are typically exploited as candidate TAA sources in immunoproteomic studies may fail to accurately represent the autoantigen-ome of lower-grade neoplasms. Here, we established an integrated strategy for the identification of disease-relevant TAAs in thyroid neoplasia, which combined NRASQ61R oncogene expression in non-tumorous thyroid Nthy-ori 3-1 cells with a multi-dimensional proteomic technique DISER that consisted of profiling NRASQ61R-induced proteins using 2-dimensional difference gel electrophoresis (2D-DIGE) coupled with serological proteome analysis (SERPA) of the TAA repertoire of patients with thyroid encapsulated follicular-patterned/RAS-like phenotype (EFP/RLP) tumors. We identified several candidate cell-based (nicotinamide phosphoribosyltransferase NAMPT, glutamate dehydrogenase GLUD1, and glutathione S-transferase omega-1 GSTO1) and autoantibody (fumarate hydratase FH, calponin-3 CNN3, and pyruvate kinase PKM autoantibodies) biomarkers, including NRASQ61R-induced TAA phosphoglycerate kinase 1 PGK1. Meta-profiling of the reactivity of the identified autoantibodies across an independent SERPA series implicated the PKM autoantibody as a histological phenotype-independent biomarker of thyroid malignancy (11/38 (29%) patients with overtly malignant and uncertain malignant potential (UMP) tumors vs 0/22 (p = 0.0046) and 0/20 (p = 0.011) patients with non-invasive EFP/RLP tumors and healthy controls, respectively). PGK1 and CNN3 autoantibodies were identified as EFP/RLP-specific biomarkers, potentially suitable for further discriminating tumors with different malignant potential (PGK1: 7/22 (32%) patients with non-invasive EFP/RLP tumors vs 0/38 (p = 0.00044) and 0/20 (p = 0.0092) patients with other tumors and healthy controls, respectively; СNN3: 9/29 (31%) patients with malignant and borderline EFP/RLP tumors vs 0/31 (p = 0.00068) and 0/20 (p = 0.0067) patients with other tumors and healthy controls, respectively). The combined use of PKM, CNN3, and PGK1 autoantibodies allowed the reclassification of malignant/UMP tumor risk in 19/41 (46%) of EFP/RLP tumor patients. Taken together, we established an experimental pipeline DISER for the concurrent identification of cell-based and TAA biomarkers. The combination of DISER with in vitro oncogene expression allows further targeted identification of oncogene-induced TAAs. Using this integrated approach, we identified candidate autoantibody biomarkers that might be of value for differential diagnostic purposes in thyroid neoplasia.