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1.
Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift.
Deane, KD, Holers, VM
Arthritis & rheumatology (Hoboken, N.J.). 2021;(2):181-193
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Abstract
Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today.
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Persistence of islet autoantibodies after diagnosis in type 1 diabetes.
Long, AE, George, G, Williams, CL
Diabetic medicine : a journal of the British Diabetic Association. 2021;(12):e14712
Abstract
The presence of islet autoantibodies remains a reliable biomarker to identify individuals at high risk of developing type 1 diabetes. As such, these autoantibodies play a pivotal role in understanding the prodrome of diabetes and selecting individuals for both prevention and intervention clinical trials. Over the last few decades, studies have sought to investigate autoantibody prevalence after diabetes onset to better understand ongoing islet autoimmunity; however, many findings are contradictory, and little is known about factors that may influence autoantibody persistence. Generally, glutamate decarboxylase autoantibodies (GADAs) are the most prevalent autoantibodies after diagnosis, particularly in adults, whilst zinc transporter 8 autoantibodies (ZnT8A) prevalence declines more rapidly. However, when studies with islet autoantibody data at diagnosis are considered, it becomes clear that overall islet antigen-2 autoantibodies (IA-2A) tend to persist for longer than GADA or ZnT8A. In this review, we assess the major studies that have contributed to our understanding of autoantibody persistence after diabetes onset and what factors affect this. Islet autoantibodies may provide biomarkers for long-term β-cell function and insights into how to prevent ongoing islet autoimmunity but larger studies collecting samples at and decades after diabetes onset are required to leverage the information they could provide.
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The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children.
Bauer, W, Gyenesei, A, Krętowski, A
International journal of molecular sciences. 2021;(14)
Abstract
Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3-5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.
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4.
Membranous Nephropathy: Core Curriculum 2021.
Alsharhan, L, Beck, LH
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(3):440-453
Abstract
The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.
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Four decades of the Bart's Oxford study: Improved tests to predict type 1 diabetes.
Gillespie, KM, Fareed, R, Mortimer, GL
Diabetic medicine : a journal of the British Diabetic Association. 2021;(12):e14717
Abstract
Recent success in clinical trials to delay the onset of type 1 diabetes has heralded a new era of type 1 diabetes research focused on the most accurate methods to predict risk and progression rate in the general population. Risk prediction for type 1 diabetes has been ongoing since the 1970s and 1980s when human leucocyte antigen (HLA) variants and islet autoantibodies associated with type 1 diabetes were first described. Development of prediction methodologies has relied on well-characterised cohorts and samples. The Bart's Oxford (BOX) study of type 1 diabetes has been recruiting children with type 1 diabetes and their first (and second)-degree relatives since 1985. In this review, we use the timeline of the study to review the accompanying basic science developments which have facilitated improved prediction by genetic (HLA analysis through to genetic risk scores) and biochemical strategies (islet cell autoantibodies through to improved individual tests for antibodies to insulin, glutamate decarboxylase, the tyrosine phosphatase IA-2, zinc transporter 8 and tetraspanin 7). The type 1 diabetes community are poised to move forward using the best predictive markers to predict and delay the onset of type 1 diabetes.
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6.
Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.
Michael, S, Waters, P, Irani, SR
Practical neurology. 2020;(5):377-384
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Abstract
Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.
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7.
Autoimmune Vestibulocerebellar Syndromes.
Narayan, RN, McKeon, A, Fife, TD
Seminars in neurology. 2020;(1):97-115
Abstract
Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.
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8.
Neuronal Surface Antibody Syndrome: A Review of the Characteristics of the Disease and Its Association with Autoantibodies.
Liu, R, Zhang, M, Liu, L, Chen, G, Hou, Y, Wang, M, Li, J
Neuroimmunomodulation. 2020;(1):1-8
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Abstract
Several studies have certified that autoantibodies play an important role in the manifestation of neuromuscular diseases. Scientists have discovered specific neuronal tumor antibodies in patients with typical paraneoplastic neurological disorders. But in some clinical cases, it is not useful to cure this disease with common treatments unless the autoantibodies are addressed. In addition, recent studies have shown a close relationship between certain antibodies and neuronal surface proteins in some special cases. These antibodies, which act on the surface of neurons, mainly include voltage-gated calcium channel (VGKC) antibodies. VGKC antibodies are further divided into several types including anti-leucine-rich glioma inactivated 1 (LGI1), anti-contactin-associated protein-like 2 (Caspr2), anti-N-methyl-D-aspartate receptor (NMDAR), anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), anti-γ-aminobutyric acid receptor (GABAR), and glycine receptor. For the purpose of this review, cases of clinical studies of autoantibody-associated encephalitis were collected, the key points regarding the pathogenesis were summarized, the clinical manifestation was discussed, and all this information was organized as this review in order to introduce the relationship between autoantibodies and autoimmune encephalitis. Furthermore, it is hoped that it can effectively direct the development of diagnostic and therapeutic approach in the future.
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9.
The Clinical Value and Variation of Antithyroid Antibodies during Pregnancy.
Li, C, Zhou, J, Huang, Z, Pan, X, Leung, W, Chen, L, Zhang, Y, Wang, L, Sima, Y, Gober, HJ, et al
Disease markers. 2020;:8871951
Abstract
Antithyroid antibodies, which include thyroid-stimulating hormone receptor antibodies (TRAbs), thyroid peroxidase antibodies (TPOAbs), and thyroid globulin antibodies (TgAbs), are widely known for their tight association with thyroid autoimmune diseases. The variation in all three kinds of antibodies also showed different trends during and after pregnancy (Weetman, 2010). This article reviewed the the physiological changes, while focusing on the variation of thyroid antibodies concentration in women during and after pregnancy, and adverse consequences related to their elevation. Since abnormal elevations of these antithyroid antibodies may lead to adverse outcomes in both mothers and fetuses, special attention must be paid to the titer of the antibodies during pregnancy. The molecular mechanisms of the variations in those antibodies have yet to be explained. The frequency and timing of thyroid antibody measurement, as well as different reference levels, also remain to be elucidated.
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10.
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.