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Interleukin-1 inhibition has revealed to be a successful treatment approach for patients with adult-onset Still's disease (AOSD).,However, real-life experience is focused on the use of anakinra, while data about canakinumab (CAN) are mainly based on case reports and small case series.,Patients and Methods.,Patients classified with AOSD according to Yamaguchi criteria and treated with CAN were consecutively enrolled.,Their clinical and therapeutic data were retrospectively collected and statistically analysed to assess the role of CAN as a therapeutic opportunity in AOSD patients in terms of clinical and laboratory disease control along with corticosteroid-sparing effect.,Nine AOSD patients (8 females and 1 male) treated with CAN for 15.00 ± 12.3 months were enrolled.,Resolution of clinical manifestations was reported in 8/9 cases at the 3-month assessment; a significant decrease in the number of tender joints (p = 0.009), swollen joints (p = 0.027), and disease activity score on 28 joints-C-reactive protein (DAS28-CRP) (p = 0.044) was observed during the study period.,The systemic score of disease activity significantly decreased at the 3-month and 6-month assessments and at the last visit compared to the start of treatment (p = 0.028, p = 0.028, and p = 0.018, respectively).,The daily corticosteroid dosage was significantly reduced at the 3-month and at the last follow-up visits (p = 0.017 and p = 0.018, respectively).,None of the patients experienced adverse events or severe adverse events during the follow-up.,CAN has shown prompt and remarkable effectiveness in controlling AOSD activity in a real-life contest, with a significant glucocorticoid-sparing effect and an excellent safety profile.

GM-CSF is a potential therapeutic target in inflammation and autoimmunity.,This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.,Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells.,Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology.,Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions.,Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis.,This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.

In order to better understand the perspectives of patients and physicians regarding the treatment and management of rheumatoid arthritis (RA), we present and compare results from a patient-based and a physician-based survey developed by the RA NarRAtive advisory panel.,The RA NarRAtive initiative is directed by a global advisory panel of 39 healthcare providers and patient organization leaders from 17 countries.,A survey of patients self-reporting a diagnosis of RA and a physician-based survey, designed by the advisory panel, were fielded online by Harris Poll from September 2014 to April 2016, and from August 2015 to October 2015, respectively.,We present findings from 1805 patients whose RA was primarily managed by a rheumatologist, and 1736 physicians managing patients with RA.,Results confirmed that RA carries a substantial disease burden; half of the patients surveyed reported stopping participation in certain activities as a result of their disease.,While 90% of physicians were satisfied with their communications with their patients regarding RA treatment, 61% of patients felt uncomfortable raising concerns or fears with their physician.,Of the patients providing responses, 52% felt that improved dialogue/discussion would optimize their RA management, and 68% of physicians wished that they and their patients talked more about their RA goals and treatment.,Overall, 88% of physicians agreed that patients involved in making treatment decisions tend to be more satisfied with their treatment experience.,The results of these surveys highlight the impact of RA on patients, and a discrepancy between patient and physician views on communication.,Further research, focused on improving patient-physician dialogue, shared goal-setting, and treatment planning, is needed.,The online version of this article (10.1186/s12955-018-1035-3) contains supplementary material, which is available to authorized users.

To assess the clinical evidence for bee venom acupuncture (BVA) for rheumatoid arthritis (RA).,Systematic review of randomised controlled trials (RCTs).,We searched 14 databases up to March 2014 without a language restriction.,Patients with RA.,BVA involved injecting purified, diluted BV into acupoints.,We included trials on BVA used alone or in combination with a conventional therapy versus the conventional therapy alone.,Morning stiffness, pain and joint swelling,Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), rheumatoid factor, the number of joints affected by RA and adverse effects likely related to RA.,A total of 304 potentially relevant studies were identified; only one RCT met our inclusion criteria.,Compared with placebo, BVA may more effectively improve joint pain, swollen joint counts, tender joint counts, ESR and CRP but was not shown to improve morning stiffness.,There is low-quality evidence, based on one trial, that BVA can significantly reduce pain, morning stiffness, tender joint counts, swollen joint counts and improve the quality of life of patients with RA compared with placebo (normal saline injection) control.,However, the number of trials, their quality and the total sample size were too low to draw firm conclusions.,PROSPERO 2013: CRD42013005853.

Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens.,Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression.,Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear.,Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells.,In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood.,Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation.,To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli.,CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects.,In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified.,Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β.,An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells.,Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia.,In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8).,Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others.,These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.

To investigate autoantigens in β-cells, we have used a panel of pathogenic T-cell clones that were derived from the NOD mouse.,Our particular focus in this study was on the identification of the target antigen for the highly diabetogenic T-cell clone BDC-5.2.9.,To purify β-cell antigens, we applied sequential size exclusion chromatography and reverse-phase high-performance liquid chromatography to membrane preparations of β-cell tumors.,The presence of antigen was monitored by measuring the interferon-γ production of BDC-5.2.9 in response to chromatographic fractions in the presence of NOD antigen-presenting cells.,Peak antigenic fractions were analyzed by ion-trap mass spectrometry, and candidate proteins were further investigated through peptide analysis and, where possible, testing of islet tissue from gene knockout mice.,Mass-spectrometric analysis revealed the presence of islet amyloid polypeptide (IAPP) in antigen-containing fractions.,Confirmation of IAPP as the antigen target was demonstrated by the inability of islets from IAPP-deficient mice to stimulate BDC-5.2.9 in vitro and in vivo and by the existence of an IAPP-derived peptide that strongly stimulates BCD-5.2.9.,IAPP is the target antigen for the diabetogenic CD4 T-cell clone BDC-5.2.9.

Although type 1 diabetes autoimmunity frequently begins in childhood, little is known about the relationship between age and autoimmunity development.,Our aim was to determine the timing of seroconversion to diabetes-associated autoantibody (DAA) positivity and risk in first- and second-degree relatives of patients with type 1 diabetes.,Study subjects were identified through the Diabetes Prevention Trial-Type 1 (DPT-1).,Children 3-18 years of age (n = 42,447) were screened for DAAs; 1,454 were ICA positive (≥10 JDF units), 1,758 were GAD65 positive, and 899 were ICA512 positive at the time of initial screening.,Subjects who were initially antibody negative (n = 39,212) were recalled for rescreening, and 11,813 returned for rescreening.,DAA seroconversion occurred in 469 (4%) children; 258 seroconverted to ICA, 234 to GAD65, and 99 to ICA512.,The median time to seroconversion was 2 years.,The 2-year risk for DAAs was highest in early childhood.,For each 1-year increase in age in this cohort, the risk of any autoantibody seroconversion (HR 0.95, 95% CI 0.92-0.97) decreased by 5%, and for any two autoantibodies risk decreased by 13% (0.87, 0.82-0.93).,Risk of autoantibody seroconversion among children followed in DPT-1 is age dependent.,Younger children have the highest risk for DAAs, with the majority of children seroconverting by 13 years of age (75%).,This suggests that annual screenings should be started in early childhood and continued through early adolescence to identify the majority of subjects at risk for type 1 diabetes and eligible for prevention trials.

The purpose of the present studies was to investigate the impact of chronic inflammation of the lacrimal gland, as occurs in Sjögren’s syndrome, on the morphology and function of myoepithelial cells (MECs).,In spite of the importance of MECs for lacrimal gland function, the effect of inflammation on MECs has not been well defined.,We studied changes in MEC structure and function in two animal models of aqueous deficient dry eye, NOD and MRL/lpr mice.,We found a statistically significant reduction in the size of MECs in diseased compared to control lacrimal glands.,We also found that oxytocin receptor was highly expressed in MECs of mouse and human lacrimal glands and that its expression was strongly reduced in diseased glands.,Furthermore, we found a significant decrease in the amount of two MEC contractile proteins, α-smooth muscle actin (SMA) and calponin.,Finally, oxytocin-mediated contraction was impaired in lacrimal gland acini from diseased glands.,We conclude that chronic inflammation of the lacrimal gland leads to a substantial thinning of MECs, down-regulation of contractile proteins and oxytocin receptor expression, and therefore impaired acini contraction.,This is the first study highlighting the role of oxytocin mediated MEC contraction on lacrimal gland function.

Primary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women.,For patients with PSS there is currently no effective therapy that can alter the progression of the disease.,The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.,TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS.,Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks.,The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness.,Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.,The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.,UKCRN Portfolio ID: 9809 ISRCTN65360827.

The etiology of rheumatoid arthritis (RA) remains poorly understood.,Early and accurate diagnosis still difficult to achieve.,Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases.,We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers.,A 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls).,Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions.,Potentially altered pathways were analyzed by Reactome pathway database search.,STRING database was used to predict protein-protein interaction networks.,Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163.,Signature biomarker candidates were statistical analyzed.,We detected 11 differentially expressed exomiRNAs in early RA pilot study.,Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA.,Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity.,The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways.,A novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA.,A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is associated with inflammation and dysfunction of salivary and lacrimal glands.,The molecular mechanism(s) underlying this exocrinopathy is not known, although the syndrome has been associated with viruses, such as the Epstein Barr Virus (EBV).,We report herein that an EBV-specific microRNA (ebv-miR-BART13-3p) is significantly elevated in salivary glands (SGs) of pSS patients and we show that it targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca2 + entry (SOCE) pathway that is essential for SG function, leading to loss of SOCE and Ca2 +-dependent activation of NFAT.,Although EBV typically infects B cells and not salivary epithelial cells, ebv-miR-BART13-3p is present in both cell types in pSS SGs.,Importantly, we further demonstrate that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes and it recapitulates its functional effects on calcium signaling in a model system.,•Sjögren's syndrome is an autoimmune disease characterized by dysfunction and inflammation of the salivary and lacrimal glands•The pathogenesis of Sjögren's syndrome has not been elucidated, but the role of viruses has been suggested.,•Ebv-miR-BART13-3p downregulates STIM1 affecting the calcium influx mechanisms that regulate salivary gland function.,Sjögren's syndrome is an autoimmune disease characterized by dysfunction and inflammation of the salivary and lacrimal glands,The pathogenesis of Sjögren's syndrome has not been elucidated, but the role of viruses has been suggested.,Ebv-miR-BART13-3p downregulates STIM1 affecting the calcium influx mechanisms that regulate salivary gland function.,In this study we report that the EBV-specific microRNA ebv-miR-BART13-3p, that is significantly elevated in salivary glands of primary Sjögren's syndrome patients, targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca2 + entry pathway that is essential for salivary gland function.,This interaction affects the intracellular Ca2 + entry and subsequently the Ca2 +-dependent activation of NFAT.,Ebv-miR-BART13-3p is present in both B cells and salivary epithelial cells, even though EBV infects B cells and not salivary epithelial cells.,We demonstrate here that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes, recapitulating the functional effects on calcium signaling.

Objective.,Non-adherence to DMARDs is common, but little is known about adherence to biologic therapies and its relationship to treatment response.,The purpose of this study was to investigate the association between self-reported non-adherence to s.c. anti-TNF therapy and response in individuals with RA.,Methods.,Participants about to start s.c. anti-TNF therapy were recruited to a large UK multicentre prospective observational cohort study.,Demographic information and disease characteristics were assessed at baseline.,Self-reported non-adherence, defined as whether the previous due dose of biologic therapy was reported as not taken on the day agreed with the health care professional, was recorded at 3 and 6 months following the start of therapy.,The 28-joint DAS (DAS28) was recorded at baseline and following 3 and 6 months of therapy.,Multivariate linear regression was used to examine these relationships.,Results.,Three hundred and ninety-two patients with a median disease duration of 7 years [interquartile range (IQR) 3-15] were recruited.,Adherence data were available in 286 patients.,Of these, 27% reported non-adherence to biologic therapy according to the defined criteria at least once within the first 6-month period.,In multivariate linear regression analysis, older age, lower baseline DAS28 and ever non-adherence at either 3 or 6 months from baseline were significantly associated with a poorer DAS28 response at 6 months to anti-TNF therapy.,Conclusion.,Patients with RA who reported not taking their biologic on the day agreed with their health care professional showed poorer clinical outcomes than their counterparts, emphasizing the need to investigate causes of non-adherence to biologics.

Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients.,However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown.,The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome.,In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece.,The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete.,The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach.,Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP.,None of the 7 genetic markers correlated with treatment response.,We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.

The rise in the prevalence of autoimmune diseases in developed societies has been associated with a change in lifestyle patterns.,Among other factors, increased consumption of certain dietary components, such as table salt and fatty acids and excessive caloric intake has been associated with defective immunological tolerance.,Dietary nutrients have shown to modulate the immune response by a direct effect on the function of immune cells or, indirectly, by acting on the microbiome of the gastrointestinal tract.,FOXP3+ regulatory T cells (Tregs) suppress immune responses and are critical for maintaining peripheral tolerance and immune homeostasis, modulating chronic tissue inflammation and autoimmune disease.,It is now well-recognized that Tregs show certain degree of plasticity and can gain effector functions to adapt their regulatory function to different physiological situations during an immune response.,However, plasticity of Tregs might also result in conversion into effector T cells that may contribute to autoimmune pathogenesis.,Yet, which environmental cues regulate Treg plasticity and function is currently poorly understood, but it is of significant importance for therapeutic purposes.,Here we review the current understanding on the effect of certain dietary nutrients that characterize Western diets in Treg metabolism, stability, and function.,Moreover, we will discuss the role of Tregs linking diet and autoimmunity and the potential of dietary-based interventions to modulate Treg function in disease.

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells1.,TH17 cells can drive antigen specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE)2, the mouse model for multiple sclerosis.,The factors that are needed for the generation of TH17 cells have been well-characterized3-6.,However, where and how the immune system controls TH17 cells in vivo remains unclear.,Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine.,TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis.,Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen and simultaneously pro-inflammatory TH17 cells acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17).,These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury.,Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration.,Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis.,We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions.,We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination.,Zinc in MS lesions was generally decreased, paralleling myelin loss.,Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques.,Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.,The online version of this article (doi:10.1007/s00401-017-1696-8) contains supplementary material, which is available to authorized users.

Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes.,Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration.,Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE).,Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions.,As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting.,We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state.

The incidence of type 1 diabetes mellitus (T1DM) increased worldwide.,The objective of the paper was to compare the incidence trend of T1DM in children and adolescents aged 0-19 and in adults under 30 years of age in Serbia from 2006 to 2017.,Additional aim was to compare incidence rates of T1DM and type 2 diabetes mellitus (T2DM) among adults aged 20-24 and 25-29 years of age.,Trends and annual percentage change (APC) of the incidence rate with corresponding 95% confidence intervals (CI) were calculated by Joinpoint Regression Analyses.,We found a significant increase of incidence in children aged 5-9 with the APC of 5.7% (95%CI: 2.3-9.1), and in children aged 10-14 with the APC of 2.1% (95%CI: 0.6-3.6).,A significant decrease of incidence was determined in adolescents aged 15-19 with the APC -4.9% (95%CI: − 8.9 to - 0.7) and in adults aged 25-29 with the APC -7.3% (95%CI: − 12.5 to − 1.8).,The increase of incidence in children aged 0-14 and its decrease after 15 years of age showed that T1DM is predominantly a metabolic disease of children in Serbia.,A significant increase in incidence was recorded in two age groups, namely 5-9 and 10-14 years of age.,The highest increase was in children aged 5-9 and the highest incidence rate was in children aged 10-14.,An insignificant increasing of T2DM incidence was observed in young adults aged 25-29.,The increase in incidence rates in children, but not in young adults, suggests that the precipitating factors of children-onset disease may differ from those of adult-onset T1DM.

To develop and validate multivariable clinical diagnostic models to assist distinguishing between type 1 and type 2 diabetes in adults aged 18-50.,Multivariable logistic regression analysis was used to develop classification models integrating five pre-specified predictor variables, including clinical features (age of diagnosis, body mass index) and clinical biomarkers (GADA and Islet Antigen 2 islet autoantibodies, Type 1 Diabetes Genetic Risk Score), to identify type 1 diabetes with rapid insulin requirement using data from existing cohorts.,UK cohorts recruited from primary and secondary care.,1352 (model development) and 582 (external validation) participants diagnosed with diabetes between the age of 18 and 50 years of white European origin.,Type 1 diabetes was defined by rapid insulin requirement (within 3 years of diagnosis) and severe endogenous insulin deficiency (C-peptide <200 pmol/L).,Type 2 diabetes was defined by either a lack of rapid insulin requirement or, where insulin treated within 3 years, retained endogenous insulin secretion (C-peptide >600 pmol/L at ≥5 years diabetes duration).,Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC), and internal and external validation.,Type 1 diabetes was present in 13% of participants in the development cohort.,All five predictor variables were discriminative and independent predictors of type 1 diabetes (p<0.001 for all) with individual ROC AUC ranging from 0.82 to 0.85.,Model performance was high: ROC AUC range 0.90 (95% CI 0.88 to 0.93) (clinical features only) to 0.97 (95% CI 0.96 to 0.98) (all predictors) with low prediction error.,Results were consistent in external validation (clinical features and GADA ROC AUC 0.93 (0.90 to 0.96)).,Clinical diagnostic models integrating clinical features with biomarkers have high accuracy for identifying type 1 diabetes with rapid insulin requirement, and could assist clinicians and researchers in accurately identifying patients with type 1 diabetes.

To investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment and after being switched from ADL-EU to ADL-PF.,In this multinational, double-blind study, patients with active RA were initially randomised to ADL-PF or ADL-EU for 26 weeks (treatment period (TP) 1).,At the start of TP2 (weeks 26-52), patients in the ADL-EU arm were blindly re-randomised 1:1 to remain on ADL-EU (ADL-EU/ADL-EU; n=135) or switched to ADL-PF (ADL-EU/ADL-PF; n=134); patients receiving ADL-PF continued blinded treatment (ADL-PF/ADL-PF; n=283).,The American College of Rheumatology 20% improvement (ACR20) response rates were comparable between treatment groups at all visits during TP2.,At week 52, ACR20 response rates were 82.7% (ADL-PF/ADL-PF), 79.3% (ADL-EU/ADL-EU) and 84.3% (ADL-EU/ADL-PF).,Other measures of deep response (ACR50/70, ACR/EULAR-defined remission, EULAR good response, and Disease Activity Score in 28 Joints Based on High-Sensitivity C-Reactive Protein <2.6) and Health Assessment Questionnaire−Disability Index were maintained over TP2 and comparable between groups.,Treatment-emergent adverse events were reported in 43.5% (ADL-PF/ADL-PF), 44.4% (ADL-EU/ADL-EU) and 38.3% (ADL-EU/ADL-PF) of patients; there were no clinically meaningful differences in the safety profiles between groups.,The percentage of patients who were antidrug antibody positive was comparable overall among ADL-PF/ADL-PF (47.3%), ADL-EU/ADL-EU (54.1%) and ADL-EU/ADL-PF (45.9%).,The similar efficacy, safety, immunogenicity and pharmacokinetics of ADL-PF and ADL-EU, maintained up to week 52, were unaffected by blinded treatment switch from ADL-EU to ADL-PF at week 26.,ClinicalTrials.gov identifier: NCT02480153; EudraCT number: 2014-000352-29.

To investigate the efficacy, safety and immunogenicity of PF-06438179/GP1111 (PF-SZ-IFX) compared with European reference infliximab (Remicade®; ref-IFX) in patients with moderate-to-severe, active rheumatoid arthritis after continued long-term use of PF-SZ-IFX, and in patients who were switched from ref-IFX to PF-SZ-IFX.,REFLECTIONS B537-02 was a double-blind, active-controlled, multinational study in which patients (N=650) were initially randomised to PF-SZ-IFX or ref-IFX for 30 weeks (treatment period [TP] 1).,During weeks 30-54 (TP2), the PF-SZ-IFX group (n=280) continued treatment with PF-SZ-IFX (PF-SZ-IFX/PF-SZ-IFX) and patients in the ref-IFX group (n=286) were rerandomised (1:1) to continue ref-IFX (ref-IFX/ref-IFX) (n=143) or switch to PF-SZ-IFX (ref-IFX/PF-SZ-IFX) (n=143) for a further 24 weeks.,Efficacy, safety, immunogenicity and pharmacokinetics were evaluated.,During TP2, patients in all three treatment groups continued to maintain comparable treatment response.,At week 54, the American College of Rheumatology (ACR20) response rates were 71.1% (PF-SZ-IFX/PF-SZ-IFX), 64.3% (ref-IFX/ref-IFX) and 70.6% (ref-IFX/PF-SZ-IFX).,Observations for other endpoints, including ACR50/70, Disease Activity Score in 28 Joints Based on High-Sensitivity C Reactive Protein(DAS28-CRP) remission, and mean change in DAS28-CRP and Health Assessment Questionnaire-Disability Index, were also comparable.,Treatment-emergent adverse events were reported in 36.8% (PF-SZ-IFX/PF-SZ-IFX), 33.6% (ref-IFX/ref-IFX) and 37.8% (ref-IFX/PF-SZ-IFX) of patients; there were no clinically meaningful differences in the safety profiles between groups.,The percentage of patients who were antidrug antibody-positive was generally stable through the treatment period and comparable overall between the PF-SZ-IFX/PF-SZ-IFX (52.1%; neutralising: 80.8%), ref-IFX/ref-IFX (60.1%; neutralising: 84.9%) and ref-IFX/PF-SZ-IFX (58.0%; neutralising 78.3%) groups.,The similar efficacy, safety and immunogenicity of PF-SZ-IFX compared with ref-IFX were maintained for up to 54 weeks and were not affected by blinded treatment switch from ref-IFX to PF-SZ-IFX at week 30.,NCT02222493.

Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases.,Our study evaluated the use of S100 proteins in a pediatric clinical setting for estimating disease activity and supporting diagnosis.,Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes.,Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS).,Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p < 0.0001).,Compared to CRP [area under the receiver operating characteristics curve (AUC) = 0.7], S100 proteins were superior in differentiating sJIA from AID and SURFS [AUC = 0.9].,S100A8/9 and S100A12 levels were not associated with disease activity in nsJIA, AID or SURFS.,S100A8/9 and S100A12 levels were significantly higher in active sJIA compared to inactive (p = 0.0002 and p = 0.0002 respectively).,Compared to other autoinflammatory and fever syndromes, sJIA patients have markedly higher levels of S100A8/9 and S100A12 proteins which may assist with diagnosis.,S100 levels slightly outperformed CRP in distinguishing sJIA from other diagnoses and in sJIA disease activity.,S100 proteins may aid in monitoring disease activity in sJIA patients.

The involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent.,To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers.,Serum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA.,The children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls.,A positive correlation between serum HMGB1 and ESR, CRP, α2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA.,Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA.,The inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE.,HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients.,Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity.

Epidermolysis bullosa acquisita (EBA) is an antibody-mediated blistering skin disease associated with tissue-bound and circulating autoantibodies to type VII collagen (COL7).,Transfer of antibodies against COL7 into mice results in a subepidermal blistering phenotype, strictly depending on the complement component C5.,Further, activation predominantly by the alternative pathway is required to induce experimental EBA, as blistering was delayed and significantly ameliorated only in factor B−/− mice.,However, C5 deficiency not only blocked the activation of terminal complement components and assembly of the membrane attack complex (MAC) but also eliminated the formation of C5a.,Therefore, in the present study, we first aimed to elucidate which molecules downstream of C5 are relevant for blister formation in this EBA model and could be subsequently pharmaceutically targeted.,For this purpose, we injected mice deficient in C5a receptor 1 (C5aR1) or C6 with antibodies to murine COL7.,Importantly, C5ar1−/− mice were significantly protected from experimental EBA, demonstrating that C5a-C5aR1 interactions are critical intermediates linking pathogenic antibodies to tissue damage in this experimental model of EBA.,By contrast, C6−/− mice developed widespread blistering disease, suggesting that MAC is dispensable for blister formation in this model.,In further experiments, we tested the therapeutic potential of inhibitors of complement components which were identified to play a key role in this experimental model.,Complement components C5, factor B (fB), and C5aR1 were specifically targeted using complement inhibitors both prophylactically and in mice that had already developed disease.,All complement inhibitors led to a significant improvement of the blistering phenotype when injected shortly before anti-COL7 antibodies.,To simulate a therapeutic intervention, anti-fB treatment was first administered in full-blown EBA (day 5) and induced significant amelioration only in the final phase of disease evolution, suggesting that early intervention in disease development may be necessary to achieve higher efficacy.,Anti-C5 treatment in incipient EBA (day 2) significantly ameliorated disease during the whole experiment.,This finding is therapeutically relevant, since the humanized anti-C5 antibody eculizumab is already successfully used in patients.,In conclusion, in this study, we have identified promising candidate molecules for complement-directed therapeutic intervention in EBA and similar autoantibody-mediated diseases.

Pemphigus vulgaris (PV) is a potentially fatal blistering disease caused by autoantibodies against desmoglein 3 (Dsg3).,Here, we clone anti-Dsg3 antibodies from four PV patients and identify pathogenic VH1-46 autoantibodies from all four patients.,Unexpectedly, VH1-46 autoantibodies had relatively few replacement mutations.,We reverted antibody somatic mutations to their germline sequences to determine the requirement of mutations for autoreactivity.,Three of five VH1-46 germline-reverted antibodies maintain Dsg3 binding, compared to zero of five non-VH1-46 germline-reverted antibodies.,Site-directed mutagenesis of VH1-46 antibodies demonstrate that acidic amino acid residues introduced by somatic mutation or heavy chain VDJ recombination are necessary and sufficient for Dsg3 binding.,Our data suggest that VH1-46 autoantibody gene usage is commonly found in PV because VH1-46 antibodies require few to no mutations to acquire Dsg3 autoreactivity, which may favor their early selection.,Common VH gene usage indicates common humoral immune responses, even among unrelated patients.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions1,2 (www.T1DBase.org) revealing major pathways contributing to risk3, with some loci shared across immune disorders4-6.,In order to make genetic comparisons across autoimmune disorders as informative as possible a dense genotyping array, the ImmunoChip, was developed, from which four novel T1D regions were identified (P < 5 × 10−8).,A comparative analysis with 15 immune diseases (www.ImmunoBase.org) revealed that T1D is more similar genetically to other autoantibody-positive diseases, most significantly to juvenile idiopathic arthritis and least to ulcerative colitis, and provided support for three additional novel T1D loci.,Using a Bayesian approach, we defined credible sets for the T1D SNPs.,These T1D SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34+ stem cells.,Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

Studies in NOD mice have provided important insight into the genetics and pathogenesis of type 1 diabetes (T1D).,Our goal was to further explore novel methods of genetic manipulation in this mouse model.,We tested the feasibility of using zinc-finger nucleases (ZFNs) to knock out a gene directly in a pure NOD background, bypassing the need of embryonic stem cells.,We report here the successful application of ZFN pairs to specifically and efficiently knock out Tnfrsf9 (encoding CD137/4-1BB) directly in the NOD mouse by embryo microinjection.,Histology and T1D incidence studies indicated that CD137 was dispensable for the development of insulitis but played a role to promote progression to overt diabetes in NOD mice.,We also demonstrated that CD137-deficient T-cells were less diabetogenic than their wild-type counterpart when adoptively transferred into NOD.Rag1−/− recipients, even when CD25+ cells were predepleted.,In vitro assays suggested that CD137 deficiency had a limited effect on the suppressive function of CD4+CD25+ regulatory T-cells (Tregs).,Therefore, CD137 deficiency predominately affected effector T-cells rather than Tregs.,Our study demonstrates the ability to generate gene-targeted knockouts in a pure NOD background by using ZFNs without potential confounding factors introduced by contaminating genetic materials obtained from other strains.

Rheumatoid arthritis is a common systemic and autoimmune disease characterized by symmetrical and inflammatory destruction of distal joints.,Its primary pathological characters are synovitis and vasculitis.,Accumulating studies have implicated the critical role of non-coding RNAs (ncRNAs) in inflammation and autoimmune regulation, primarily including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA).,NcRNAs are significant regulators in distinct physiological and pathophysiological processes.,Many validated non-coding RNAs have been identified as promising biomarkers for the diagnosis and treatment of RA.,This review will shed some light on RA pathogenesis and be helpful for identifying potential ncRNA biomarkers for RA.

Synovial tissue is a membranous non-immune organ lining joint cavities where it supports local immune responses, and functions directly and indirectly in joint destruction due to chronic inflammatory diseases such as rheumatoid arthritis (RA).,Fibroblast-like synoviocytes (FLS), the dominant non-immune cells of synovial tissues, mainly contribute to joint destruction via multiple mechanisms.,In RA, FLS respond to endogenous ligands of pattern recognition receptors (PRRs) and inflammatory cytokines as non-immune cells.,In addition, FLS aid in the activation of immune responses by interacting with immune cells and by supporting ectopic lymphoid-like structure (ELS) formation in synovial tissues.,Moreover, FLS directly cause the pathogenicity of RA i.e., joint deformities.,Here, we describe new findings and review the mechanisms underlying the regulation of immune reactions by non-immune FLS and their roles in inflammatory diseases such as RA.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are both debilitating diseases that cause significant morbidity in the US population.,Extracellular vesicles (EVs), including exosomes and microvesicles, are now recognized to play important roles in cell-to-cell communication by transporting various proteins, microRNAs (miRNAs), and mRNAs.,EV-derived proteins and miRNAs impact cell viability and cell differentiation, and are likely to play a prominent role in the pathophysiology of both OA and RA.,Some of the processes by which these membrane-bound vesicles can alter joint tissue include extracellular matrix degradation, cell-to-cell communication, modulation of inflammation, angiogenesis, and antigen presentation.,For example, EVs from IL-1β-stimulated fibroblast-like synoviocytes have been shown to induce osteoarthritic changes in chondrocytes.,RA models have shown that EVs stimulated with inflammatory cytokines are capable of inducing apoptosis resistance in T cells, presenting antigen to T cells, and causing extracellular damage with matrix-degrading enzymes.,EVs derived from rheumatoid models have also been shown to induce secretion of COX-2 and stimulate angiogenesis.,Additionally, there is evidence that synovium-derived EVs may be promising biomarkers of disease in both OA and RA.,The characterization of EVs in the joint space has also opened up the possibility for delivery of small molecules.,This article reviews current knowledge on the role of EVs in both RA and OA, and their potential role as therapeutic targets for modulation of these debilitating diseases.

In rheumatoid arthritis, prediction of response to TNF-alpha inhibitor (TNFi) treatment would be of clinical value.,This study aims to discover miRNAs that predict response and aims to replicate results of two previous studies addressing this topic.,From the observational BiOCURA cohort, 40 adalimumab- (ADA) and 40 etanercept- (ETN) treated patients were selected to enter the discovery cohort and baseline serum profiling on 758 miRNAs was performed.,The added value of univariately selected miRNAs (p < 0.05) over clinical parameters in prediction of response was determined by means of the area under the receiver operating characteristic curve (AUC-ROC).,Validation was performed by TaqMan single qPCR assays in 40 new patients.,Expression of miR-99a and miR-143 predicted response to ADA, and miR-23a and miR-197 predicted response to ETN.,The addition of miRNAs increased the AUC-ROC of a model containing only clinical parameters for ADA (0.75 to 0.97) and ETN (0.68 to 0.78).,In validation, none of the selected miRNAs significantly predicted response. miR-23a was the only overlapping miRNA compared to the two previous studies, however inversely related with response in one of these studies.,The reasons for the inability to replicate previously proposed miRNAs predicting response to TNFi and replicate those from the discovery cohort were investigated and discussed.,To date, no miRNA consistently predicting response to TNFi therapy in RA has been identified.,Future studies on this topic should meet a minimum of standards in design that are addressed in this study, in order to increase the reproducibility.,The online version of this article (doi:10.1186/s13075-016-1085-z) contains supplementary material, which is available to authorized users.

Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups.,In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.,Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region.,Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored.,Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases.,We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles.,We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls).,After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8).,We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5).,From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP.,These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

Epstein-Barr virus (EBV) infection may be necessary for the development of Multiple sclerosis (MS).,Earlier we had identified six MS risk loci that are co-located with binding sites for the EBV transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) in EBV-infected B cells (lymphoblastoid cell lines - LCLs).,We used an allele-specific chromatin immunoprecipitation PCR assay to assess EBNA2 allelic preference.,We treated LCLs with a peptide inhibitor of EBNA2 (EBNA2-TAT), reasoning that inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2.,We found that EBNA2 binding was dependent on the risk allele for five of these six MS risk loci (p < 0·05).,Treatment with EBNA2-TAT significantly altered the expression of TRAF3 (p < 0·05), CD40 (p < 0·001), CLECL1 (p <0·0001), TNFAIP8 (p < 0·001) and TNFRSF1A (p < 0·001).,These data suggest that EBNA2 can enhance or reduce expression of the gene depending on the risk allele, likely promoting EBV infection.,This is consistent with the concept that these MS risk loci affect MS risk through altering the response to EBNA2.,Together with the extensive data indicating a pathogenic role for EBV in MS, this study supports targeting EBV and EBNA2 to reduce their effect on MS pathogenesis.,Funding was provided by grants from MS Research Australia, National Health and Medical Research Council of Australia, Australian Government Research Training Program, Multiple Sclerosis International Federation, Trish Multiple Sclerosis Research Foundation.

A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS).,Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation.,Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals.,A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen.,Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena.,Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain.

Pain remains the most important problem for people with rheumatoid arthritis (RA).,Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity.,We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA.,In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status.,Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status.,More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health.,A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health.,Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA.,The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA.,The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.

Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children.,Synovial inflammation results in pain, swelling and stiffness.,Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity.,The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission.,Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children.,60 children aged 7-17 years with JIA participated.,QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence.,Joint site included finger, wrist, knee and ankle.,Clinical status was measured using objective and subjective markers of disease severity.,Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue.,QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92).,Statistical analyses were performed using Kruskal-Wallis with Dunn’s post-hoc comparison, Mann-Whitney or Fisher’s exact test, where appropriate.,Overall, children with JIA reported low pain scores and low degrees of functional disability.,Sensory detection thresholds and pain thresholds were similar in “active” compared to “inactive” joints.,Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs.,EU p < 0.001), light touch (vs.,EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001).,JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity.,Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes.,The online version of this article (doi:10.1186/1546-0096-12-39) contains supplementary material, which is available to authorized users.

To report the understanding and decision-making of neuroimmunologists and their treatment of patients with multiple sclerosis (MS) during the early stages of the SARS-CoV-2 (COVID-19) outbreak.,A survey instrument was designed and distributed online to neurologists in April 2020.,There were 250 respondents (response rate 21.8%). 243 saw > = 10 MS patients in the prior 6 months (average 197 patients) and were analyzed further (92% USA, 8% Canada; average practice duration 16 years; 5% rural, 17% small city, 38% large city, 40% highly urbanized).,Patient volume dropped an average of 79% (53-11 per month). 23% were aware of patients self-discontinuing a DMT due to fear of COVID-19 with 43% estimated to be doing so against medical advice. 65% of respondents reported deferring > = 1 doses of a DMT (49%), changing the dosing interval (34%), changing to home infusions (20%), switching a DMT (9%), and discontinuing DMTs altogether (8%) as a result of COVID-19.,Changes in DMTs were most common with the high-efficacy therapies alemtuzumab, cladribine, ocrelizumab, rituximab, and natalizumab. 35% made no changes to DMT prescribing. 98% expressed worry about their patients contracting COVID-19 and 78% expressed the same degree of worry about themselves. > 50% believed high-efficacy DMTs prolong viral shedding of SARS-CoV-2 and that B-cell therapies might prevent protective vaccine effects.,Accelerated pace of telemedicine and practice model changes were identified as major shifts in practice.,Reported prescribing changes and practice disruptions due to COVID-19 may be temporary but could have a lasting influence on MS care.,The online version of this article (10.1007/s00415-020-10045-9) contains supplementary material, which is available to authorized users.

•90% of MS patients knew that COVID-19 is in a pandemic stage.•73% followed quarantine guidelines completely.,•All participants believed high person-to-person transmission rate of COVID-19.,90% of MS patients knew that COVID-19 is in a pandemic stage.,73% followed quarantine guidelines completely.,All participants believed high person-to-person transmission rate of COVID-19.

: Development of long-term immunologic memory relies upon humoral and cellular immune responses.,Vaccinations aim to stimulate these responses against pathogens.,Several studies have evaluated the impact of multiple sclerosis disease-modifying therapies on immune response to vaccines.,Findings from these studies have important implications for people with multiple sclerosis who require vaccination and are using disease-modifying therapies.,: Searches using PubMed and other engines were conducted in May 2020 to collect studies evaluating the impact of various disease-modifying therapies on immune responses to vaccination.,: Several studies demonstrated preserved immune responses in people treated with beta-interferons to multiple vaccine types.,Limited data suggest vaccine responses to be preserved with dimethyl fumarate treatment, as well.,Vaccine responses were reduced to varying degrees in those treated with glatiramer acetate, teriflunomide, sphingosine-1-phosphate receptor modulators, and natalizumab.,The timing of vaccination played an important role in those treated with alemtuzumab.,Humoral vaccine responses were significantly impaired by B cell depleting anti-CD20 monoclonal antibody therapies, particularly to a neoantigen.,Data are lacking on vaccine responses in patients with multiple sclerosis taking cladribine and high-dose corticosteroids.,Notably, the majority of these studies have focused on humoral responses, with few examining cellular immune responses to vaccination.,: Prior investigations into the effects of individual disease-modifying therapies on immune responses to existing vaccines can serve as a guide to expected responses to a SARS-CoV-2 vaccine.,Responses to any vaccination depend on the vaccine type, the type of response (recall versus response to a novel antigen), and the impact of the individual disease-modifying therapy on humoral and cellular immunity in response to that vaccine type.,When considering a given therapy, clinicians should weigh its efficacy against MS for the individual patient versus potential impact on responses to vaccinations that may be needed in the future.

To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT).,High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy.,The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI.,Participants were evaluated through 5 years posttransplant.,Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE).,Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT.,Median follow-up was 62 months (range 12-72).,EFS was 69.2% (90% confidence interval [CI] 50.2-82.1).,Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively.,AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted.,Improvements were noted in neurologic disability with a median change in EDSS of −0.5 (interquartile range −1.5 to 0.0; p = 0.001) among participants who survived and completed the study.,HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years.,NCT00288626.,This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.

Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA).,However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial.,Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls.,The aim of this study is to investigate the expression and activity of class I HDACs (1-3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients.,The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs.,The nuclear HAT activities were dramatically increased.,Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group.,The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (p < 0.01).,In RA PBMCs, the activity and expression of class I HDACs are decreased, which is accompanied with enhanced HAT activity.,An altered balance between HDAC and HAT activity was found in RA PBMCs.

Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability.,Inflammatory response mediated the RA.,It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear.,Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used.,Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot.,The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA).,The expression of CD69 and CD25 was detected using flow cytometry.,The RA mouse model was constructed for verification of the role of MiR-128-3p.,Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients.,Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells.,MiR-128-3p targets TNFAIP3 to regulate its expression.,MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown.,The in vivo experiments verified the potential role of MiR-128-3p on RA.,Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.

To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira.,Patients with active rheumatoid arthritis on stable methotrexate were randomised to BI 695501 or Humira in a double-blind, parallel-group, equivalence study.,At week 24, patients were rerandomised to continue BI 695501 or Humira, or switch from Humira to BI 695501.,The coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at weeks 12 and 24.,Further efficacy and safety endpoints and immunogenicity were assessed up to week 58.,645 patients were randomised.,At week 12, 67.0% and 61.1% (90% CI -0.9 to 12.7) of patients receiving BI 695501 (n=324) and Humira (n=321), respectively, achieved ACR20; at week 24 the corresponding values were 69.0% and 64.5% (95% CI -3.4 to 12.5).,These differences were within prespecified margins (week 12: 90% CI (-12% to 15%); week 24: 95% CI (−15% to 15%)), demonstrating therapeutic bioequivalence. 593 patients were rerandomised at week 24.,Up to week 48, mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n=147), continuous BI 695501 (n=298) and continuous Humira (n=148) groups.,Similar immunogenicity (antidrug antibodies (ADAs), ADA titres and neutralising antibodies) was seen between BI 695501 and Humira (to week 24) and across rerandomised groups (to week 48).,Safety and tolerability profiles were similar between groups.,BI 695501 demonstrated similar efficacy, safety and immunogenicity to Humira; switch from Humira to BI 695501 had no impact on efficacy, safety and immunogenicity.,NCT02137226, Results.

SB5 is a biosimilar agent for adalimumab (ADA).,The aim of this study was to evaluate the efficacy, pharmacokinetics (PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis (RA).,In this phase III, randomized, double‐blind, parallel‐group study, patients with moderately to severely active RA despite treatment with methotrexate were randomized 1:1 to receive SB5 or reference ADA at a dosage of 40 mg subcutaneously every other week.,The primary efficacy end point was the response rate based on the American College of Rheumatology 20% improvement criteria (ACR20) at week 24 in the per‐protocol set (completer analysis).,Additional end points included efficacy, PK, safety, and immunogenicity assessments.,Of the 544 patients randomized to receive a study drug, the full analysis set comprised 542 patients (269 in the SB5 group, 273 in the reference ADA group) and the per‐protocol set comprised 476 patients (239 receiving SB5, 237 receiving reference ADA).,The ACR20 response rate at week 24 in the per‐protocol set was equivalent between those receiving SB5 and those receiving reference ADA (72.4% and 72.2%, respectively); the difference in the ACR20 response rate (0.1%, [95% confidence interval −7.83%, 8.13%]) was within the predefined equivalence margin (±15%).,Similar results were seen in the full analysis set (missing data being considered a nonresponse).,The SB5 and reference ADA treatment groups were comparable across other end points, including the ACR 50% and ACR 70% improvement response rates, Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate, PK data, incidence of treatment‐emergent adverse events, and the antidrug antibody response.,Subgroup analyses showed that the efficacy and safety of SB5 and reference ADA were comparable regardless of antidrug antibody status.,The ACR20 response rate at week 24 was equivalent between patients treated with the biosimilar agent SB5 and those treated with reference ADA.,SB5 and reference ADA were both well tolerated, with comparable safety profiles, in patients with RA.

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE).,This study tested miR-146a and its target gene TRAF6 expression in LN patients and discussed their relationship with LN.,One hundred twenty-eight LN patients and 30 healthy controls were enrolled in this study.,MiR-146a and TRAF6 expression in peripheral blood mononuclear cells (PBMCs) were detected.,Serum cytokines content was determined by ELISA.,The diagnostic role of miR-146a and TRAF6 in LN activity was evaluated by ROC curve.,The impact of miR-146a and TRAF6 on end-stage renal disease (ESRD) was compared by survival curve.,The effect of miR-146a and TRAF6 on LN recurrence was analyzed.,Compared with healthy controls, miR-146a expression was significantly reduced and TRAF6 was upregulated in LN patients.,The expression was related to LN activity.,MiR-146a expression was negatively correlated, whereas TRAF6 was positively correlated with serum IL-1β, IL-6, IL-8, and TNF-α activity.,The area under the ROC curve (AUC) of miR-146a and TRAF6 on the diagnosis of LN was 0.821 and 0.897, respectively.,The AUC of miR-146a and TRAF6 on LN activity differentiation was 0.921 and 0.872, respectively.,Downregulation of miR-146a and upregulation of TRAF6 increased the incidence of ESRD progression.,Downregulation of miR-146a and upregulation of TRAF6 elevated the possibility of recurrence within one year.,MiR-146a declined, while TRAF6 increased in LN patients compared with healthy controls.,Their expression can be used to effectively differentiate LN and evaluate activity.,MiR-146a reduction and TRAF6 upregulation increased the possibility of ESRD progress and recurrence within one year.

MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE).,However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and organ involvement, as well as heterogeneous cell populations.,Here, we aimed at identifying a miRNA signature of purified B cells from renal and non-renal severe SLE patients of Latin American background, a population known to express severe disease.,Genome-wide miRNA expression analyses were performed on naive and memory B cells and revealed two categories of miRNA signatures.,The first signature represents B cell subset-specific miRNAs deregulated in SLE: 11 and six miRNAs discriminating naive and memory B cells of SLE patients from healthy controls (HC), respectively.,Whether the miRNA was up or down-regulated in memory B cells as compared with naive B cells in HC, this difference was abolished in SLE patients, and vice versa.,The second signature identifies six miRNAs associated with specific pathologic features affecting renal outcome, providing a further understanding for SLE pathogenesis.,Overall, the present work provided promising biomarkers in molecular diagnostics for disease severity as well as potential new targets for therapeutic intervention in SLE.

To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA).,In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes.,We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database.,Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses.,False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status.,Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response.,Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response.,TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response.,NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response.,The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4-16.3),p = 0.0002,q = 0.024).,No other association withstood correction for multiple testing.,Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association.,We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA.,Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5.,Furthermore, we identified other candidate genes that require replication in independent cohorts.

Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond.,The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.,Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data.,Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion.,American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes.,Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status.,False discovery rate (FDR) controlling was used to adjust for multiple testing.,Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76).,Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).,In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported.,The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers.,Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response.,All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.

A long-term neurologic sequela arising from COVID-19 infection in multiple sclerosis (MS) patients could be related both to the increase of cytokines and the activation of NLRP3 inflammasome by the Sars-CoV2.,These two mechanisms may cause a worsening of MS several months after the resolution of the infection.

Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19.,Here, we examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS).,Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe.,Participants included 131 individuals with PMS.,Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread.,During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and MS symptomatology that were previously administered pre-pandemic.,4% of respondents reported COVID-19 infection.,No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown.,While total HADS-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression.,No significant relationships were noted between disease duration, processing speed ability or EDSS, and changes in symptoms of depression or anxiety.,Most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being.,The perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of MS symptomatology on daily life, as well as changes in depression.,Overall, little change was noted in symptoms of depression or anxiety or overall quality of life.

The emergency represented by the COVID-19 pandemic represents a new challenge for clinicians who deal with autoimmune diseases because of patients undergoing immunosuppressive therapy.,Few cases of Multiple Sclerosis (MS) patients receiving ocrelizumab who contracted COVID-19 with a benign course have recently been published.,We present the case of a MS patient with mild COVID-19 who developed SARS-CoV-2 specific IgA without IgG ten weeks after infection.,Patients on B-cell depleting drugs have a reduced antibody immune response to viral neoantigens.,A relative sparing of mucosal-associated lymphoid tissues (MALT) could be responsible for IgA response in our patient.

A multiple sclerosis patient infected by SARS-CoV-2 during fingolimod therapy was hospitalized with moderate clinical features, and recovered in 15 days.,High levels of CCL5 and CCL10 chemokines and of antibody-secreting B cells were detected, while the levels other B- and T-cell subsets were comparable to that of appropriate controls.,However, CD4+ and CD8+ cells were oligoclonally expanded and prone to apoptosis when stimulated in vitro.,This study suggests that fingolimod-immunosuppressed patients, despite the low circulating lymphocytes, may rapidly expand antibody-secreting cells and mount an effective immune response that favors COVID-19 recovery after drug discontinuation.,Unlabelled Image

Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3+CD31+CXCR4+ T cells (Tang), a subpopulation of T cells which promotes repair of damaged endothelium.,This happens due to the concomitant expansion of a Tang subset with immunosenescent features, such as the loss of CD28.,Therefore, the aim of this study was to elucidate the interplay between Tang subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events.,Twenty SLE female patients and 10 healthy controls (HCs) were recruited.,Flow cytometric analysis of endothelial progenitor cells (EPCs) and Tang subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-γ were measured.,Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects’ serum stimulation were also evaluated.,Results showed that the percentage of Tang and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28null cells among Tang subset.,SLE disease activity index-2000 (SLEDAI-2K) was inversed related to Tang cells percentage.,Furthermore, IL-8 serum levels were directly correlated with the percentage of Tang and inversely related to the CD28null Tang subsets.,We indirectly evaluated the role of the Tang subset on the endothelium upon stimulation with serum from subjects with a low percentage of Tang CD3+ cells in HUVECs.,HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1.,Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage.,In highly selected young SLE patients without previous CV events, we found that the deterioration of Tang compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms.,The overcome of the CD28null subset exerts detrimental role over the Tang phenotype, where Tang could exert an anti-inflammatory effect on endothelial cells and might orchestrate via IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.

Umbilical cord (UC)‐derived mesenchymal stem cells (MSCs) show immunoregulatory properties on various immune cells and display therapeutic effects on various autoimmune diseases such as systemic lupus erythematosus (SLE).,The aim of this study was to investigate the effect of the SLE environment on UC MSCs and to identify a potential serum biomarker to predict the therapeutic effect.,UC MSCs were cocultured with peripheral blood mononuclear cells (PBMCs) from active lupus patients, and the proliferation, apoptosis and surface markers of UC MSCs were observed.,UC MSC functional molecules were assessed by real‐time polymerase chain reaction, and the signaling pathways were analyzed by Western blot.,The clinical effect of MSC transplantation (MSCT) for lupus patients was followed‐up, whereas baseline serum cytokines were analyzed by enzyme‐linked immunosorbent assay.,The coculture of PBMC from lupus patients promoted MSC proliferation.,Lupus PBMCs were more potent in stimulating UC MSCs to secrete vascular endothelial growth factor (VEGF) and CXCL‐12.,Furthermore, lupus PBMCs activated Akt, IκB, and Stat5 signaling pathways in UC MSCs but did not affect Erk1/2 and Smad1/5/8 pathways.,Moreover, our clinical study showed that higher baseline levels of IFN‐γ might predict a good response to MSCT in active lupus patients.,Baseline IFN‐γ levels may predict clinical response to MSC therapy for active lupus patients, which will help to choose suitable patients for clinical transplantation. stem cells translational medicine 2017;6:1777-1785

Using a novel model of rheumatoid arthritis, we identified a critical role for reduced tissue-resident macrophages.,Little is known about the mechanisms regulating the transition of circulating monocytes into pro- or anti-inflammatory macrophages in chronic inflammation.,Here, we took advantage of our novel mouse model of rheumatoid arthritis, in which Flip is deleted under the control of a CD11c promoter (HUPO mice).,During synovial tissue homeostasis, both monocyte-derived F4/80int and self-renewing F4/80hi tissue-resident, macrophage populations were identified.,However, in HUPO mice, decreased synovial tissue-resident macrophages preceded chronic arthritis, opened a niche permitting the influx of activated monocytes, with impaired ability to differentiate into F4/80hi tissue-resident macrophages.,In contrast, Flip-replete monocytes entered the vacated niche and differentiated into tissue-resident macrophages, which suppressed arthritis.,Genes important in macrophage tissue residency were reduced in HUPO F4/80hi macrophages and in leukocyte-rich rheumatoid arthritis synovial tissue monocytes.,Our observations demonstrate that the macrophage tissue-resident niche is necessary for suppression of chronic inflammation and may contribute to the pathogenesis of rheumatoid arthritis.

Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis.,In this study, we evaluated how these TLR4 ligands may drive pathogenic processes and whether the fine profiling of anti-citrullinated protein antibodies (ACPA) based on their target specificity might provide a simple means to predict therapeutic benefit when neutralizing TLR4 in this disease.,The capacity of RA synovial fluids (RASF) to stimulate cytokine production in monocytes from patients with RA was analyzed by ELISA.,The presence of TLR4 activators in RASF was determined by measuring the levels of ACPA, ACPA subtypes with reactivity to specific citrullinated peptides and other TLR4 ligands.,Neutralization of TLR4 signaling was investigated using NI-0101, a therapeutic antibody that targets TLR4.,RASF exhibited a heterogeneous capacity to induce production of proinflammatory cytokines by monocytes isolated from patients with RA.,Such cytokine responses were significantly modified by TLR4 blockade achieved using NI-0101.,The analysis of the content of RASF and matched sera demonstrated that ACPA fine specificities in patient samples predict cellular response to anti-TLR4 exposure in vitro.,TLR4 represents a possible therapeutic target in RA.,Our study demonstrates that TLR4 inhibition in an ex vivo model of RA pathogenesis can significantly modulate cytokine release and does so in specific subgroups of RA patient-derived samples.,It also suggests that ACPA fine profiling has the potential to identify RA patients with a predominantly TLR4-driven pathotype that could be used to predict preferential response to TLR4 antagonism.,The online version of this article (doi:10.1186/s13075-016-1128-5) contains supplementary material, which is available to authorized users.

The current focus in multiple sclerosis (MS) is on early diagnosis and drug intervention, with a view to modifying disease progression.,Consequently, healthcare costs have shifted from inpatient care and rehabilitation to outpatient care.,This European burden of illness study provides data that can be combined with other evidence to assess whether management approaches provide value to society.,A cross-sectional study was conducted in 16 countries.,Patients reported on their disease, health-related quality of life (HRQoL) and resource consumption.,Descriptive analyses were performed by disease severity.,Costs are reported from a societal perspective in 2015€ PPP (adjusted for purchasing power parity).,The 16,808 participants had a mean age of 51.5 years, and 52% had relapsing-remitting multiple sclerosis (RRMS).,Work capacity declined from 82% to 8%, and utility declined from normal population values to less than zero with advancing disease.,Mean costs were 22,800€ PPP in mild, 37,100€ PPP in moderate and 57,500€ PPP in severe disease; healthcare accounted for 68%, 47% and 26%, respectively.,Fatigue and cognitive difficulties were reported by 95% and 71% of participants, respectively; both had a significant independent effect on utility.,Costs and utility were highly correlated with disease severity, but resource consumption was heavily influenced by healthcare systems organisation and availability of services.

Quetiapine (Que), a commonly used atypical antipsychotic drug (APD), can prevent myelin from breakdown without immune attack.,Multiple sclerosisis (MS), an autoimmune reactive inflammation demyelinating disease, is triggered by activated myelin-specific T lymphocytes (T cells).,In this study, we investigated the potential efficacy of Que as an immune-modulating therapeutic agent for experimental autoimmune encephalomyelitis (EAE), a mouse model for MS.,Que treatment was initiated on the onset of MOG35-55 peptide induced EAE mice and the efficacy of Que on modulating the immune response was determined by Flow Cytometry through analyzing CD4+/CD8+ populations and the proliferation of effector T cells (CD4+CD25−) in peripheral immune organs.,Our results show that Que dramatically attenuates the severity of EAE symptoms.,Que treatment decreases the extent of CD4+/CD8+ T cell infiltration into the spinal cord and suppresses local glial activation, thereby diminishing the loss of mature oligodendrocytes and myelin breakdown in the spinal cord of EAE mice.,Our results further demonstrate that Que treatment decreases the CD4+/CD8+ T cell populations in lymph nodes and spleens of EAE mice and inhibits either MOG35-55 or anti-CD3 induced proliferation as well as IL-2 production of effector T cells (CD4+CD25−) isolated from EAE mice spleen.,Together, these findings suggest that Que displays an immune-modulating role during the course of EAE, and thus may be a promising candidate for treatment of MS.

‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity.,Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.,To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’),We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%).,At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001).,Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001).,NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001).,NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

To assess whether it is feasible to establish specific cut-off values able to discriminate ‘physiological’ or ‘pathological’ brain volume rates in patients with multiple sclerosis (MS).,The study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing-remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35).,Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1-12) for patients with MS and 6.3 years (range 1-12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y).,A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics.,The weighted PBVC/y was −0.51±0.27% in patients with MS and −0.27±0.15% in HC (p<0.0001).,There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age (p=0.02), but not in patients with MS (p=0.8).,The cut-off of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was −0.37%, with 67% sensitivity and 80% specificity.,According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above −0.52% with 95% specificity, above −0.46% with 90% specificity and above −0.40% with 80% specificity.,Our evidence-based criteria provide values able to discriminate the presence or absence of ‘pathological’ brain volume loss in MS with high specificity.,Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS.

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals.,Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals.,In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice.,During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D.,In NOD mice, an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity.,In the absence of this systemic response, the dietary intervention led to exacerbated insulitis.,Consistent with the compartmentalization of AhR activation, dietary I3C did not alter T helper cell differentiation in the spleen or pancreatic draining lymph nodes.,Instead, dietary I3C increased the percentage of CD4+RORγt+Foxp3- (Th17 cells) in the lamina propria, intraepithelial layer, and Peyer’s patches of the small intestine.,The immune modulation in the gut was accompanied by alterations to the intestinal microbiome, with changes in bacterial communities observed within one week of I3C supplementation.,A transkingdom network was generated to predict host-microbe interactions that were influenced by dietary I3C.,Within the phylum Firmicutes, several genera (Intestinimonas, Ruminiclostridium 9, and unclassified Lachnospiraceae) were negatively regulated by I3C.,Using AhR knockout mice, we validated that Intestinimonas is negatively regulated by AhR.,I3C-mediated microbial dysbiosis was linked to increases in CD25high Th17 cells.,Collectively, these data demonstrate that site of AhR activation and subsequent interactions with the host microbiome are important considerations in developing AhR-targeted interventions for T1D.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease in humans and is characterized by the presence of hyperactive immune cells and aberrant antibody responses to nuclear and cytoplasmic antigens, including characteristic anti-double-stranded DNA antibodies.,We performed a cross-sectional study in order to determine if an SLE-associated gut dysbiosis exists in patients without active disease.,A group of 20 SLE patients in remission, for which there was strict inclusion and exclusion criteria, was recruited, and we used an optimized Ion Torrent 16S rRNA gene-based analysis protocol to decipher the fecal microbial profiles of these patients and compare them with those of 20 age- and sex-matched healthy control subjects.,We found diversity to be comparable based on Shannon’s index.,However, we saw a significantly lower Firmicutes/Bacteroidetes ratio in SLE individuals (median ratio, 1.97) than in healthy subjects (median ratio, 4.86; P < 0.002).,A lower Firmicutes/Bacteroidetes ratio in SLE individuals was corroborated by quantitative PCR analysis.,Notably, a decrease of some Firmicutes families was also detected.,This dysbiosis is reflected, based on in silico functional inference, in an overrepresentation of oxidative phosphorylation and glycan utilization pathways in SLE patient microbiota.,Growing evidence suggests that the gut microbiota might impact symptoms and progression of some autoimmune diseases.,However, how and why this microbial community influences SLE remains to be elucidated.,This is the first report describing an SLE-associated intestinal dysbiosis, and it contributes to the understanding of the interplay between the intestinal microbiota and the host in autoimmune disorders.

Vitamin D (VitD) insufficiency is common in multiple sclerosis (MS).,VitD has possible anti-inflammatory effects on the immune system.,The ratio between VitD metabolites in MS patients and the severity of the disease are suggested to be related.,However, the exact effect of the bone-derived hormone fibroblast-growth-factor-23 (FGF23) and VitD binding protein (VDBP) on this ratio is not fully elucidated yet.,Therefore, the aim is to study differences in total, free, and bioavailable VD metabolites and FGF23 between MS patients and healthy controls (HCs).,FGF23, vitD (25(OH)D), active vitD (1,25(OH)2D), inactive 24,25(OH)D, and VDBP were measured in 91 MS patients and 92 HCs.,Bioavailable and free concentrations were calculated.,No difference in FGF23 (p = 0.65) and 25(OH)D/24.25(OH)2D ratio (p = 0.21) between MS patients and HCs was observed.,Bioavailable 25(OH)D and bioavailable 1.25(OH)2D were lower (p < 0.01), while VDBP concentrations were higher in MS patients (p = 0.02) compared with HCs, specifically in male MS patients (p = 0.01).,In conclusion, FGF23 and 25(OH)D/24.25(OH)2D did not differ between MS patients and HCs, yet bioavailable VitD concentrations are of potential clinical relevance in MS patients.,The possible immunomodulating role of VDBP and gender-related differences in the VD-FGF23 axis in MS need further study.

Vitamin D (vitD) low status is currently considered a main environmental factor in multiple sclerosis (MS) etiology and pathogenesis.,VitD and its metabolites are highly hydrophobic and circulate mostly bound to the vitamin D binding protein (DBP) and with lower affinity to albumin, while less than 1% are in a free form.,The aim of this study was to investigate whether the circulating levels of either of the two vitD plasma carriers and/or their relationship are altered in MS.,We measured DBP and albumin plasma levels in 28 MS patients and 24 healthy controls.,MS patients were found to have higher DBP levels than healthy subjects.,Concomitant interferon beta therapy did not influence DBP concentration, and the difference with the control group was significant in both females and males.,No significant correlation between DBP and albumin levels was observed either in healthy controls or in patients.,These observations suggest the involvement of DBP in the patho-physiology of MS.

To develop and validate multivariable clinical diagnostic models to assist distinguishing between type 1 and type 2 diabetes in adults aged 18-50.,Multivariable logistic regression analysis was used to develop classification models integrating five pre-specified predictor variables, including clinical features (age of diagnosis, body mass index) and clinical biomarkers (GADA and Islet Antigen 2 islet autoantibodies, Type 1 Diabetes Genetic Risk Score), to identify type 1 diabetes with rapid insulin requirement using data from existing cohorts.,UK cohorts recruited from primary and secondary care.,1352 (model development) and 582 (external validation) participants diagnosed with diabetes between the age of 18 and 50 years of white European origin.,Type 1 diabetes was defined by rapid insulin requirement (within 3 years of diagnosis) and severe endogenous insulin deficiency (C-peptide <200 pmol/L).,Type 2 diabetes was defined by either a lack of rapid insulin requirement or, where insulin treated within 3 years, retained endogenous insulin secretion (C-peptide >600 pmol/L at ≥5 years diabetes duration).,Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC), and internal and external validation.,Type 1 diabetes was present in 13% of participants in the development cohort.,All five predictor variables were discriminative and independent predictors of type 1 diabetes (p<0.001 for all) with individual ROC AUC ranging from 0.82 to 0.85.,Model performance was high: ROC AUC range 0.90 (95% CI 0.88 to 0.93) (clinical features only) to 0.97 (95% CI 0.96 to 0.98) (all predictors) with low prediction error.,Results were consistent in external validation (clinical features and GADA ROC AUC 0.93 (0.90 to 0.96)).,Clinical diagnostic models integrating clinical features with biomarkers have high accuracy for identifying type 1 diabetes with rapid insulin requirement, and could assist clinicians and researchers in accurately identifying patients with type 1 diabetes.

Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non-insulin requiring, e.g., with latent autoimmune diabetes (LADA).,We aimed to characterize adult-onset autoimmune diabetes.,We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30-70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).,Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone.,More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs.,13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes.,Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs.,39.7%) (P < 0.02 for each).,Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).,Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes.,Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum.,At diagnosis, patients with adult-onset autoimmune diabetes are usually non-insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner.,Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic.,Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly).,Median interval until re-dosing or last B-cell count was 34 [30-38] weeks.,No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression.,Monthly serum neurofilament light levels remained stable during extended intervals.,Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity.,Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS.,Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19 +, CD27 + memory B cells.,This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity.,Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS.,This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.,•Memory B cells activity is consistent with the etiology, pathology and therapy of MS, thought to be T cell-mediated.,•Deletion of memory B cells occurs with all effective MS treatments and is more marked with high-efficacy treatments.,•Drugs that worsen MS, can also increase memory B cell production.,Memory B cells activity is consistent with the etiology, pathology and therapy of MS, thought to be T cell-mediated.,Deletion of memory B cells occurs with all effective MS treatments and is more marked with high-efficacy treatments.,Drugs that worsen MS, can also increase memory B cell production.

ST266 is the biological secretome of cultured Amnion-derived Multipotent Progenitor cells containing multiple growth factors and cytokines.,While intranasally-administered ST266 improves the phenotype in experimental optic neuritis, specific ST266 components mediating these effects are not known.,We compared the effects of ST266 with and without removal of large molecular weight proteins both in vitro and in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice.,Mice were treated daily with intranasal vehicle, ST266 or lower molecular weight fraction of ST266.,Retinal ganglion cells were counted in isolated retinas, and optic nerves were assessed for inflammation and demyelination.,ST266 treatment significantly improved retinal ganglion cell survival and reduced optic nerve demyelination in EAE mice.,The lower molecular weight ST266 fraction significantly improved optic nerve demyelination, but only showed a trend towards improved retinal ganglion cell survival.,ST266 fractions below 50kDa increased Schwann cell proliferation in vitro, but were less effective than non-fractionated ST266.,Demyelination attenuation was partially associated with the lower molecular weight ST266 fraction, but removal of higher molecular weight biomolecules from ST266 diminishes its neuroprotective effects, suggesting at least some high molecular weight proteins play a role in ST266-mediated neuroprotection.

The ability of a novel intranasally delivered amnion cell derived biologic to suppress inflammation, prevent neuronal damage and preserve neurologic function in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis was assessed.,Currently, there are no existing optic nerve treatment methods for disease or trauma that result in permanent vision loss.,Demyelinating optic nerve inflammation, termed optic neuritis, induces permanent visual dysfunction due to retinal ganglion cell damage in multiple sclerosis and experimental autoimmune encephalomyelitis.,ST266, the biological secretome of Amnion-derived Multipotent Progenitor cells, contains multiple anti-inflammatory cytokines and growth factors.,Intranasally administered ST266 accumulated in rodent eyes and optic nerves, attenuated visual dysfunction, and prevented retinal ganglion cell loss in experimental optic neuritis, with reduced inflammation and demyelination.,Additionally, ST266 reduced retinal ganglion cell death in vitro.,Neuroprotective effects involved oxidative stress reduction, SIRT1-mediated mitochondrial function promotion, and pAKT signaling.,Intranasal delivery of neuroprotective ST266 is a potential novel, noninvasive therapeutic modality for the eyes, optic nerves and brain.,The unique combination of biologic molecules in ST266 provides an innovative approach with broad implications for suppressing inflammation in autoimmune diseases, and for preventing neuronal damage in acute neuronal injury and chronic neurodegenerative diseases such as multiple sclerosis.

A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 μM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A).,The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner.,Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 μM treated for 4 days compared to the control.,The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times.,Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions.,Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells.,The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.

Since the initial description of apoptosis, a number of different forms of cell death have been described.,In this review we will focus on classic caspase-dependent apoptosis and its variations that contribute to diseases.,Over fifty years of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these pathways lead to human diseases.,Indeed both reduced and increased apoptosis can result in pathology.,More recently these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).,In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms.,However, which of these two treatment strategies has superior effectiveness and safety is unknown.,In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed.,Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed.,Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed.,Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy.,Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12.,Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity.,In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm.,Primary outcome is a change in CDAI from baseline to 12 months.,Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility.,Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs.,This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy.,It will yield important information for clinical rheumatology practice.,This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070).,The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.

To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival.,Data of the German biologics register RABBIT were used.,Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking.,During 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)).,Patients with persistent, highly active disease (mean DAS28 > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2).,Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity.,Significantly lower mortality was observed in patients treated with tumour necrosis factor α (TNFα) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate.,To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNFα inhibitors or rituximab was calculated.,This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97).,Patients with long-standing high disease activity are at substantially increased risk of mortality.,Effective control of disease activity decreases mortality.,TNFα inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.

To find an association between human leukocyte antigen (HLA) class II DRB1, DRB3, DRB4, and DRB5 alleles frequencies in a sample of Iraqi patients with Guillain-Barré syndrome (GBS) and compare with a healthy control group.,We performed a cross-sectional study consisting of 30 Iraqi Arab patients with GBS attending the Neurological Department in the Neuroscience Hospital, Baghdad, Iraq between September 2012 and June 2013.,The control group comprised 42 apparently healthy volunteers.,Human leukocyte antigen genotyping for HLA DRB1, DRB3, DRB4, and DRB5 was performed using the polymerase chain reaction-sequence-specific primers method.,The allele frequencies were compared across both groups.,Major histocompatibility complex (MHC)-class II HLA-DR genotyping and serotyping were performed by software analysis.,We found increased frequencies of HLA genotype DRB1*03:01 (p=0.0009), DRB1*07:01 (p=0.0015), and DRB4*01:01 (p<0.0001) in patients with GBS compared with healthy controls.,The HLA DR6 was increased in the control group (p<0.0001).,Our results suggest an association between HLA-DRB1*03:01, DRB1*07:01, DRB4*01:01, and HLA DR3, DR7 and a susceptibility to GBS.

Aims.,Interleukin-37 (IL-37) is an anti-inflammatory cytokine.,This study aims to investigate the concentrations of plasma and cerebrospinal fluid (CSF) IL-37 in patients with Guillain-Barré Syndrome (GBS).,Methods.,The levels of plasma and CSF IL-37, IL-17A, IFN-γ, and TNF-α in 25 GBS patients and 20 healthy controls (HC) were determined by enzyme-linked immunoabsorbent assay and flow cytometric bead array assay, respectively.,The values of clinical parameters in the patients were also measured.,Results.,The concentrations of plasma IL-37, IL-17A, IFN-γ, and TNF-α and CSF IL-37 and IL-17A in patients at the acute phase of GBS were significantly higher than those in the HC.,The levels of plasma IL-37, IL-17A, IFN-γ, and TNF-α were positively correlated in those patients, and the levels of CSF IL-37 and IL-17A as well as the levels of plasma TNF-α were correlated positively with the GBS disability scale scores (GDSs) in those patients.,Treatment with intravenous immunoglobulin significantly reduced the levels of plasma IL-37, IL-17A, IFN-γ, and TNF-α in the drug-responding patients.,Conclusions.,Our findings indicate higher levels of plasma and CSF IL-37 and IL-17A and other proinflammatory cytokines in patients with GBS.

Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction.,We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process.,Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA.,Monoclonal ACPAs were isolated from single SF B-cells of patients with RA.,OCs were developed from blood cell precursors with or without ACPAs.,We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array.,The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures.,Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin.,Protein citrullination by PADs is essential for OC differentiation.,Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation.,Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures.,Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin.,We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation.,Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability.,Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear.,To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA.,To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset.,We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines.,We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing).,We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes.,At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA.,Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ.,Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread.,Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Genome wide association studies have identified many disease-associated non-coding single nucleotide polymorphisms, but cannot distinguish functional SNPs (fSNPs) from others that reside incidentally within risk loci.,To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins.,We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by 3 disease-associated fSNPs via 4 regulatory proteins, RBPJ, RSRC2, and FUBP-1/TRAP150.,Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2.,Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA).,Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry).,Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009).,We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry.,We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6).,Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT).,Together, these data suggest that PLB1 is a candidate risk gene for RA.,Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.

Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions.,We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilamentandlongtermoutcome inMS (NaloMS) cohort.,The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204).,Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated.,During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs.,7.2 pg/ml (4.5-12.5), p<0.017).,In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine.,In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs.,0.96 (0.75-1.23), p=0.011).,This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning.,sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later.,While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion.,This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung.

Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs).,In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS).,Moreover, several studies have documented an unbalance in alternatively-spliced isoforms in MS patients possibly contributing to the disease etiology.,In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to asthma and AIDs.,The in-depth characterization of GSDMB AS and backsplicing profiles led us to the identification of an exonic circular RNA (ecircRNA) as well as of novel GSDMB in-frame and out-of-frame isoforms.,The non-productive splicing variants were shown to be downregulated by the nonsense-mediated mRNA decay (NMD) in human cell lines, suggesting that GSDMB levels are significantly modulated by NMD.,Importantly, both AS isoforms and the identified ecircRNA were significantly dysregulated in peripheral blood mononuclear cells of relapsing-remitting MS patients compared to controls, further supporting the notion that aberrant RNA metabolism is a characteristic feature of the disease.

Preliminary studies suggest that a modified Paleolithic diet may benefit symptoms of fatigue in progressive multiple sclerosis (MS).,However, this diet restricts the consumption of eggs, dairy, and gluten-containing grains, which may increase the risk of micronutrient deficiencies.,Therefore, we evaluated the nutritional safety of this diet among people with progressive MS.,Three nonconsecutive 24-h dietary recalls were collected from (n = 19) progressive MS participants in the final months of a diet intervention study and analyzed using Nutrition Data System for Research (NDSR) software.,Food group intake was calculated, and intake of micronutrients was evaluated and compared to individual recommendations using Nutrient Adequacy Ratios (NARs).,Blood was drawn at baseline and the end of the study to evaluate biomarker changes.,Mean intake of fruits and vegetables exceeded nine servings/day and most participants excluded food groups.,The intake of all micronutrients from food were above 100% NAR except for vitamin D (29.6 ± 34.6%), choline (73.2 ± 27.2%), and calcium (60.3 ± 22.8%), and one participant (1/19) exceeded the Tolerable Upper Limit (UL) for zinc, one (1/19) for vitamin A, and 37% (7/19) exceeded the chronic disease risk reduction (CDRR) for sodium.,When intake from supplements was included in the analysis, several individuals exceeded ULs for magnesium (5/19), zinc (2/19), sodium (7/19), and vitamins A (2/19), D (9/19), C (1/19), B6 (3/19), and niacin (10/19).,Serum values of vitamins D, B12, K1, K2, and folate significantly increased compared to respective baseline values, while homocysteine and magnesium values were significantly lower at 12 months.,Calcium and vitamin A serum levels did not change.,This modified Paleolithic diet is associated with minimal nutritional risks.,However, excessive intake from supplements may be of concern.

The precise etiology of multiple sclerosis (MS) is unknown but epidemiologic evidence suggests this immune-mediated, neurodegenerative condition is the result of a complex interaction between genes and lifetime environmental exposures.,Diet choices are modifiable environmental factors that may influence MS disease activity.,Two diets promoted for MS, low saturated fat Swank and modified Paleolithic Wahls Elimination (WahlsElim), are currently being investigated for their effect on MS-related fatigue and quality of life (NCT02914964).,Dr.,Swank theorized restriction of saturated fat would reduce vascular dysfunction in the central nervous system (CNS).,Dr.,Wahls initially theorized that detailed guidance to increase intake of specific foodstuffs would facilitate increased intake of nutrients key to neuronal health (Wahls™ diet).,Dr.,Wahls further theorized restriction of lectins would reduce intestinal permeability and CNS inflammation (WahlsElim version).,The purpose of this paper is to review the published research of the low saturated fat (Swank) and the modified Paleolithic (Wahls™) diets and the rationale for the structure of the Swank diet and low lectin version of the Wahls™ diet (WahlsElim) being investigated in the clinical trial.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution.,Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy.,Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome.,NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression.,We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS.,A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics.,Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.

Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking.,Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response.,From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as ‘Active’ or ‘Stable’ based on clinical and/or radiological activity on-treatment.,Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples.,Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment.,Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment.,An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment.,Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort.,Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

To estimate the incidence of type 1 diabetes in all age groups in China during 2010-13.,Population based, registry study using data from multiple independent sources.,National registration system in all 505 hospitals providing diabetes care, and communities of patients with diabetes in 13 areas across China, covering more than 133 million person years at risk, approximately 10% of the whole population.,5018 people of all ages with newly diagnosed type 1 diabetes and resident in the study areas from 1 January 2010 to 31 December 2013.,Incidence of type 1 diabetes per 100 000 person years by age, sex, and study area.,Type 1 diabetes was doctor diagnosed and further validated by onsite follow-up.,Completeness of case ascertainment was assessed using the capture mark recapture method.,5018 cases of newly diagnosed type 1 diabetes were ascertained: 1239 participants were aged <15 years, 1799 were aged 15-29 years, and 1980 were aged ≥30 years.,The proportion of new onset cases in participants aged ≥20 years was 65.3%.,The estimated incidence of type 1 diabetes per 100 000 persons years for all ages in China was 1.01 (95% confidence interval 0.18 to 1.84).,Incidence per 100 000 persons years by age group was 1.93 (0.83 to 3.03) for 0-14 years, 1.28 (0.45 to 2.11) for 15-29 years, and 0.69 (0.00 to 1.51) for ≥30 years, with a peak in age group 10-14 years.,The incidence in under 15s was positively correlated with latitude (r=0.88, P<0.001), although this association was not observed in age groups 15-29 years or ≥30 years.,Most cases of new onset type 1 diabetes in China occurred among adults.,The incidence of type 1 diabetes in Chinese children was among the lowest reported in the study.

Recent studies have indicated that an imbalance of gut microbiota is associated with the development of type 1 diabetes mellitus (T1DM) and there is no literature regarding it in Chinese children yet.,The aim of this study was to evaluate the alteration of gut microbiota between children with newly diagnosed T1DM and healthy controls and to determine if gut microbiota could partly explain the etiology of this disease.,A case-control study was carried out with 15 children with T1DM and 15 healthy children.,The fecal bacteria composition was investigated by high-throughput sequencing of the V3-V4 region of the 16S rDNA gene and analyzed by the estimators of community richness (Chao) indexes.,There was a notable lower richness of fecal bacteria in T1DM group than controls (156.53 ± 36.96 vs.,130.0 ± 32.85, P = 0.047).,At the genus level, the composition of Blautia was increased in T1DM group than control group whereas the composition of Haemophilus, Lachnospira, Dialister, and Acidaminococcus was decreased.,In addition, we found that the percentage of Blautia was correlated positively with HbA1c (ρ = 0.40, P = 0.031), the numbers of T1DM autoantibodies (ρ = 0.42, P = 0.023), and the titers of tyrosine phosphatase autoantibodies (IA-2) (ρ = 0.82, P = 0.000) in the study.,This study showed that gut microbiota was associated with the development of T1DM by affecting the autoimmunity, and the results suggested a potential therapy for T1DM via modulating the gut microbiota.

Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing β-cells in pancreatic islets that is mediated by autoimmune mechanisms.,The classic view is that autoreactive T cells mistakenly destroy healthy (‘innocent’) β-cells.,We propose an alternative view in which the β-cell is the key contributor to the disease.,By their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defence. β-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone.,This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize β-cells, in combination with immune intervention strategies, to reverse the disease.,We present the case that dysfunction occurs in both the immune system and β-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus.,Next, we build the case for the β-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity.,Finally, we synthesize a model (‘connecting the dots’) in which both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.,This Review examines the evidence that β-cells are active participants in the dialogue with the immune system during the development of type 1 diabetes mellitus.,The authors suggest that therapies targeting β-cell health, vitality and function might prove essential, in combination with immunotherapy, to change the course of events leading to β-cell destruction.,Autoreactive T cells are part of the normal T cell repertoire.β-Cells are poorly equipped to survive an inflammatory milieu and participate in their own destruction.Metabolic activity drives β-cell dysfunction and destruction.Inflammation triggers profound metabolic, epigenetic and autoantigenic changes, which expose β-cells to the immune system.The immune response to distressed β-cells might be one with ‘good intentions’, as infected tissues or tumours provoke the immune system in similar ways.Immunotherapy might be insufficient to cure type 1 diabetes mellitus; β-cell therapy might contribute to reducing β-cell immunogenicity and islet autoimmunity.,Autoreactive T cells are part of the normal T cell repertoire.,β-Cells are poorly equipped to survive an inflammatory milieu and participate in their own destruction.,Metabolic activity drives β-cell dysfunction and destruction.,Inflammation triggers profound metabolic, epigenetic and autoantigenic changes, which expose β-cells to the immune system.,The immune response to distressed β-cells might be one with ‘good intentions’, as infected tissues or tumours provoke the immune system in similar ways.,Immunotherapy might be insufficient to cure type 1 diabetes mellitus; β-cell therapy might contribute to reducing β-cell immunogenicity and islet autoimmunity.

Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies.,Consequent hyperglycemia is requiring lifelong insulin replacement therapy.,T1DM is caused by the interaction of multiple environmental and genetic factors.,The integrations of environments and genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression.,T1DM has increased several-fold over the past half century.,Such a short time indicates involvement of environment factors and excludes genetic changes.,This review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.

Changes in long noncoding RNA expression in autoimmune hepatitis (AIH) have not been studied previously.,We investigated differentially expressed long noncoding RNAs and differentially expressed mRNAs in a Con A‐induced AIH mouse model with microarray for the first time and reveal expression changes involved in the pathogenesis of AIH.,These candidates might have potential to serve as potential diagnostic and therapeutic biomarkers for AIH.,Long noncoding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that do not typically code for a protein. lncRNAs have regulatory roles in many physiological processes, and their dysregulation can contribute to cancer, cardiovascular and neurodegenerative diseases, as well as the onset of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis.,However, lncRNA expression changes in autoimmune hepatitis (AIH), a form of inflammation induced by immunological tolerance disorders, are poorly understood.,Here, for the first time to our knowledge, we used microarrays to profile 1161 differentially expressed lncRNAs (DELs; 608 up‐ and 553 down‐regulated) and 11 512 differentially expressed mRNAs (DEMs; 5189 up‐ and 6323 down‐ regulated) in a concanavalin A‐induced AIH mouse model.,We used quantitative real‐time PCR to confirm the expression of eight DELs and DEMs, and analyzed the coexpression relationship between them.,Potential biological functions of screened DELs and DEMs were predicted with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.,DEL‐DEM interaction networks were also constructed.,Our study revealed the roles of DELs and DEMs in the pathogenesis of AIH.,We also provided potential candidate biomarkers that may have potential for future development into possible diagnostics or as a treatment for this disorder.

Persistent and excessive cytokine production is a hallmark of autoimmune diseases and may play a role in disease pathogenesis and amplification.,Therefore, cytokine neutralization is a useful therapeutic strategy to treat immune-mediated conditions.,MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological processes.,Altered miRNA levels are observed in most autoimmune diseases and are recognized to influence autoimmunity through different mechanisms.,Here, we review the impact of altered miRNA levels on the expression of cytokines that play a relevant pathogenic role in autoimmunity, namely primary pro-inflammatory cytokines, the IL-17/IL-23 axis, type I interferons and IL-10.,Regulation can be either “direct” on the target cytokine, or “indirect,” meaning that one given miRNA post-transcriptionally regulates the expression of a protein that in turn influences the level of the cytokine.,In addition, miRNAs associated with extracellular vesicles can regulate cytokine production in neighboring cells, either post-transcriptionally or via the stimulation of innate immune RNA-sensors, such as Toll-like receptors.,Because of their tremendous potential as physiological and pathological regulators, miRNAs are in the limelight as promising future biopharmaceuticals.,Thus, these studies may lead in the near future to the design and testing of therapeutic miRNAs as next generation drugs to target pathogenic cytokines in autoimmunity.

To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function.,Ten type 1 diabetic patients with residual β-cell function (C-peptide positive) and 19 without (C-peptide negative) were studied.,All C-peptide-positive patients were treated with liraglutide plus insulin, whereas C-peptide-negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy.,Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment.,Differences in insulin dose; HbA1c; time spent with blood glucose <3.9, >10, and 3.9-9.9 mmol/L; and body weight were evaluated.,Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P < 0.001) in C-peptide-positive patients and from 0.72 ± 0.08 to 0.59 ± 0.06 units/kg per day (P < 0.01) in C-peptide-negative patients treated with liraglutide but did not change with insulin monotherapy.,HbA1c decreased in both liraglutide-treated groups.,The percent reduction in daily insulin dose was positively correlated with β-cell function at baseline, and two patients discontinued insulin treatment.,In C-peptide-positive patients, time spent with blood glucose <3.9 mmol/L decreased from 3.0 to 1.0 h (P = 0.03).,A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] −2.3 ± 0.3 kg [−0.5 to −5.1]; P < 0.001).,Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide.,Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control.

Little is known concerning the primary cause(s) of mortality in type 1 diabetes responsible for the excess mortality seen in this population.,The Allegheny County (Pennsylvania) childhood-onset (age <18 years) type 1 diabetes registry (n = 1,075) with diagnosis from 1965 to 1979 was used to explore patterns in cause-specific mortality.,Cause of death was determined by a mortality classification committee of at least three physician epidemiologists, based on the death certificate and additional records surrounding the death.,Vital status for 1,043 (97%) participants was ascertained as of 1 January 2008, revealing 279 (26.0%) deaths overall (141 females and 138 males).,Within the first 10 years after diagnosis, the leading cause of death was acute diabetes complications (73.6%), while during the next 10 years, deaths were nearly evenly attributed to acute (15%), cardiovascular (22%), renal (20%), or infectious (18%) causes.,After 20 years' duration, chronic diabetes complications (cardiovascular, renal, or infectious) accounted for >70% of all deaths, with cardiovascular disease as the leading cause of death (40%).,Women (P < 0.05) and African Americans (P < 0.001) have significantly higher diabetes-related mortality rates than men and Caucasians, respectively.,Standardized mortality ratios (SMRs) for non-diabetes-related causes do not significantly differ from the general population (violent deaths: SMR 1.2, 95% CI 0.6-1.8; cancer: SMR 1.2, 0.5-2.0).,The excess mortality seen in type 1 diabetes is almost entirely related to diabetes and its comorbidities but varies by duration of diabetes and particularly affects women and African Americans.

We aimed to find out the asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence among pediatric patients with rheumatic diseases and healthy children and to compare them with each other.,Patients with familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), and juvenile systemic lupus erythematosus (jSLE) and healthy children as healthy control (HC) group who remained asymptomatic during the pandemic are examined by ELISA immunoglobulin (Ig) A and IgG tests in this cross-sectional study.,Overall, 149 subjects (90 females) were included in the study.,While IgA was positive in 15 subjects (10%) (HC: 8, jSLE: 3, FMF: 2, JIA: 2; p = 0.196), IgG was positive in 14 subjects (9.4%) (HC: 7, JIA: 5, FMF: 1, jSLE: 1; p = 0.156).,Nineteen subjects (12.75%) were IgA or IgG positive (HC: 8, JIA: 5, jSLE: 3, FMF: 3; p = 0.644).,Although not significant, seropositivity was more often in HC group.,Both IgA and IgG positivity were not found to be related to age, sex, underlying rheumatic diseases, and received treatments of the patients.,We revealed that patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication such as biologic or conventional disease-modifying anti-rheumatic drugs, might have an asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.,Key points• Although it has been already known that children are most likely to have asymptomatic SARS-CoV-2 infection, there is a lack of data on the disease course of children with rheumatic disease.,• There was no significant difference regarding the asymptomatic SARS-CoV-2 seropositivity rates between healthy children and the patients with childhood-onset rheumatic diseases.,• Patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication, might have asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.,Key points,• Although it has been already known that children are most likely to have asymptomatic SARS-CoV-2 infection, there is a lack of data on the disease course of children with rheumatic disease.,• There was no significant difference regarding the asymptomatic SARS-CoV-2 seropositivity rates between healthy children and the patients with childhood-onset rheumatic diseases.,• Patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication, might have asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.

Juvenile idiopathic arthritis and adult rheumatoid arthritis are two major groups with chronic joint pain and inflammation, extra-articular manifestations, and high risk of comorbidities, which can cause physical and ocular disability, as well as create great socio-economic pressure worldwide.,The pathogenesis of arthritis manifested in childhood and adulthood is multifactorial, unclear, and overly complex, in which immunity plays an important role.,Although there are more and more biological agents with different mechanisms of action for the treatment of arthritis, the results are not as expected, because there are partial responses or non-responsive patients to these compounds, high therapeutic costs, side effects, and so on; therefore, we must turn our attention to other therapeutic modalities.,Updating knowledge on molecular and cellular mechanisms in the comparative pathogenesis of chronic arthritis in both children and adults is necessary in the early and correct approach to treatment.,Photobiomodulation (PBM) represents a good option, offering cost-effective advantages over drug therapy, with a quicker, more positive response to treatment and no side effects.,The successful management of PBM in arthritis is based on the clinician’s ability to evaluate correctly the inflammatory status of the patient, to seek the optimal solution, to choose the best technology with the best physical parameters, and to select the mode of action to target very precisely the immune system and the molecular signaling pathways at the molecular level with the exact amount of quantum light energy in order to obtain the desired immune modulation and the remission of the disease.,Light is a very powerful tool in medicine because it can simultaneously target many cascades of immune system activation in comparison with drugs, so PBM can perform very delicate tasks inside our cells to modulate cellular dysfunctions, helping to initiate self-organization phenomena and finally, healing the disease.,Interdisciplinary teams should work diligently to meet these needs by also using single-cell imaging devices for multispectral laser photobiomodulation on immune cells.

Angiogenesis is a critical process in the formation of new capillaries and a key participant in rheumatoid arthritis (RA) pathogenesis.,The chemokine (C-X-C motif) ligand 13 (CXCL13) plays important roles in several cellular functions such as infiltration, migration, and motility.,We report significantly higher levels of CXCL13 expression in collagen-induced arthritis (CIA) mice compared with controls and also in synovial fluid from RA patients compared with human osteoarthritis (OA) samples.,RA synovial fluid increased endothelial progenitor cell (EPC) homing and angiogenesis, which was blocked by the CXCL13 antibody.,By interacting with the CXCR5 receptor, CXCL13 facilitated vascular endothelial growth factor (VEGF) expression and angiogenesis in EPC through the PLC, MEK, and AP-1 signaling pathways.,Importantly, infection with CXCL13 short hairpin RNA (shRNA) mitigated EPC homing and angiogenesis, articular swelling, and cartilage erosion in ankle joints of mice with CIA.,CXCL13 is therefore a novel therapeutic target for RA.

Increased extracellular Ca2+ concentrations ([Ca2+]ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR).,To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs).,Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca2+]ex.,Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1β release.,Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1β release in response to CaSR signaling.,CaSR expression in these monocytes and local [Ca2+] in afflicted joints are increased, probably contributing to this enhanced response.,We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions.,Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA.,How extracellular calcium can trigger Nlrp3 inflammasome activation has been somewhat controversial and unclear.,Here the authors show calciprotein particles are taken up by myeloid cells via calcium-sensing receptor-dependent macropinocytosis in response to high levels of extracellular Ca2+ and this pathway might be critical to inflammatory conditions.

To examine the metabolic, gluco-regulatory-hormonal and inflammatory cytokine responses to large reductions in rapid-acting insulin dose administered prandially before and after intensive running exercise in male type 1 diabetes patients.,This was a single centre, randomised, controlled open label study.,Following preliminary testing, 8 male patients (24±2 years, HbA1c 7.7±0.4%/61±4 mmol.l−1) treated with insulin's glargine and aspart, or lispro attended the laboratory on two mornings at ∼08:00 h and consumed a standardised breakfast carbohydrate bolus (1 g carbohydrate.kg−1BM; 380±10 kcal) and self-administered a 75% reduced rapid-acting insulin dose 60 minutes before 45 minutes of intensive treadmill running at 73.1±0.9% VO2peak.,At 60 minutes post-exercise, patients ingested a meal (1 g carbohydrate.kg−1BM; 660±21 kcal) and administered either a Full or 50% reduced rapid-acting insulin dose.,Blood glucose and lactate, serum insulin, cortisol, non-esterified-fatty-acids, β-Hydroxybutyrate, and plasma glucagon, adrenaline, noradrenaline, IL-6, and TNF-α concentrations were measured for 180 minutes post-meal.,All participants were analysed.,All glycaemic, metabolic, hormonal, and cytokine responses were similar between conditions up to 60 minutes following exercise.,Following the post-exercise meal, serum insulin concentrations were lower under 50% (p<0.05) resulting in 75% of patients experiencing hyperglycaemia (blood glucose ≥8.0 mmol.l−1; 50% n = 6, Full n = 3). β-Hydroxybutyrate concentrations decreased similarly, such that at 180 minutes post-meal concentrations were lower than rest under Full and 50%.,IL-6 and TNF-α concentrations remained similar to fasting levels under 50% but declined under Full.,Under 50% IL-6 concentrations were inversely related with serum insulin concentrations (r = −0.484, p = 0.017).,Heavily reducing rapid-acting insulin dose with a carbohydrate bolus before, and a meal after intensive running exercise may cause hyperglycaemia, but does not augment ketonaemia, raise inflammatory cytokines TNF-α and IL-6 above fasting levels, or cause other adverse metabolic or hormonal disturbances.,ClinicalTrials.gov NCT01531855

To determine the effects of exercise order on acute glycemic responses in individuals with type 1 diabetes performing both aerobic and resistance exercise in the same session.,Twelve physically active individuals with type 1 diabetes (HbA1c 7.1 ± 1.0%) performed aerobic exercise (45 min of running at 60% V̇o2peak) before 45 min of resistance training (three sets of eight, seven different exercises) (AR) or performed the resistance exercise before aerobic exercise (RA).,Plasma glucose was measured during exercise and for 60 min after exercise.,Interstitial glucose was measured by continuous glucose monitoring 24 h before, during, and 24 h after exercise.,Significant declines in blood glucose levels were seen in AR but not in RA throughout the first exercise modality, resulting in higher glucose levels in RA (AR = 5.5 ± 0.7, RA = 9.2 ± 1.2 mmol/L, P = 0.006 after 45 min of exercise).,Glucose subsequently decreased in RA and increased in AR over the course of the second 45-min exercise bout, resulting in levels that were not significantly different by the end of exercise (AR = 7.5 ± 0.8, RA = 6.9 ± 1.0 mmol/L, P = 0.436).,Although there were no differences in frequency of postexercise hypoglycemia, the duration (105 vs. 48 min) and severity (area under the curve 112 vs. 59 units ⋅ min) of hypoglycemia were nonsignificantly greater after AR compared with RA.,Performing resistance exercise before aerobic exercise improves glycemic stability throughout exercise and reduces the duration and severity of postexercise hypoglycemia for individuals with type 1 diabetes.

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy in multiple sclerosis affects certain areas preferentially.,Eshaghi et al. use a data-driven computational model to predict the order in which regions atrophy, and use this sequence to stage patients.,Atrophy begins in deep grey matter nuclei and posterior cortical regions, before spreading to other cortical areas.,See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood.,We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation.,In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres.,Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97).,Disability was scored using the Expanded Disability Status Scale.,We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty.,We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions.,Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation.,The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus.,A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex.,The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis.,Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry.,All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls.,T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed.,The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001).,The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time.,The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes.,The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.

‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity.,Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.,To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’),We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%).,At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001).,Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001).,NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001).,NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

Notch signaling coordinates numerous cellular processes and has been implicated in many pathological conditions, including rheumatoid arthritis (RA).,Although the role of Notch signaling in development, maturation, differentiation, and activation of lymphocytes has been comprehensively reported, less is known about its role in myeloid cells.,Certainly, limited data are available about the role of Notch signaling in macrophages during inflammation and infection.,In this review, we discuss the recent advances pertaining to the role of Notch signaling in differentiation, activation, and metabolism of macrophages during inflammation and infection.,We also highlight the reciprocal interplay between Notch signaling and other signaling pathways in macrophages under different inflammatory and infectious conditions including pathogenesis of RA.,Finally, we discuss approaches that could consider Notch signaling as a potential therapeutic target against infection- and inflammation-driven diseases.

Rheumatoid arthritis is an autoimmune disease that causes serious functional loss in patients.,Early and accurate diagnosis of rheumatoid arthritis may attenuate its severity.,Despite a diagnosis guideline in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis, the practical difficulties in its diagnosis highlight the need of developing new methods for diagnosing rheumatoid arthritis.,The current study aimed to identify rheumatoid arthritis diagnostic biomarkers by using a proteomics approach.,Serum protein profiling was conducted using mass spectrometry, and five distinguishable biomarkers were identified therefrom.,In the validation study, the five biomarkers were quantitatively verified by multiple reaction monitoring (MRM) analysis.,Two proteins, namely serum amyloid A4 and vitamin D binding protein, showed high performance in distinguishing patients with rheumatoid arthritis from healthy controls.,Logistic analysis was conducted to evaluate how accurately the two biomarkers distinguish patients with rheumatoid arthritis from healthy controls.,The classification accuracy was 86.0% and 81.4% in patients with rheumatoid arthritis and in healthy controls, respectively.,Serum amyloid A4 and vitamin D binding protein could be potential biomarkers related to the inflammatory response and joint destruction that accompany rheumatoid arthritis.

Regulatory T cells (Treg) play a critical role in the prevention of autoimmunity, and the suppressive activity of these cells is impaired in rheumatoid arthritis (RA).,The aim of the present study was to investigate function and properties of Treg of RA patients in response to purified polysaccharide glucuronoxylomannogalactan (GXMGal).,Flow cytometry and western blot analysis were used to investigate the frequency, function and properties of Treg cells.,GXMGal was able to: i) induce strong increase of FOXP3 on CD4+ T cells without affecting the number of CD4+CD25+FOXP3+ Treg cells with parallel increase in the percentage of non-conventional CD4+CD25−FOXP3+ Treg cells; ii) increase intracellular levels of TGF-β1 in CD4+CD25−FOXP3+ Treg cells and of IL-10 in both CD4+CD25+FOXP3+ and CD4+CD25−FOXP3+ Treg cells; iii) enhance the suppressive activity of CD4+CD25+FOXP3+ and CD4+CD25−FOXP3+ Treg cells in terms of inhibition of effector T cell activity and increased secretion of IL-10; iv) decrease Th1 response as demonstrated by inhibition of T-bet activation and down-regulation of IFN-γ and IL-12p70 production; v) decrease Th17 differentiation by down-regulating pSTAT3 activation and IL-17A, IL-23, IL-21, IL-22 and IL-6 production.,These data show that GXMGal improves Treg functions and increases the number and function of CD4+CD25−FOXP3+ Treg cells of RA patients.,It is suggested that GXMGal may be potentially useful for restoring impaired Treg functions in autoimmune disorders and for developing Treg cell-based strategies for the treatment of these diseases.

Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease.,Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator.,Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well.,We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients.,Synovial samples of anticitrullinated protein antibody-positive (ACPA+) and ACPA-negative (ACPA-) RA and osteoarthritis (OA) patients were stained for IL-17 in combination with CD117 (mast cells), CD3 (T cells) and CD68 (macrophages).,Concentrations of IL-17 in synovial fluid were determined by ELISA.,The number of IL-17+ cells in synovium was comparable in all groups.,Although the vast majority of IL-17+ cells are mast cells, no difference in the percentage of IL-17+ mast cells was observed.,Nonetheless, levels of IL-17 in synovial fluid were increased in ACPA+ RA patients compared to ACPA- RA and OA patients.,The synovial mast cell is the main IL-17+ cell in all three arthritis groups analyzed.,These data are relevant for studies aimed at blocking IL-17 in the treatment of arthritis.

To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature.,In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened.,The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics.,In February 2019, the international panel was reconvened with the addition of one member to represent South America.,All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature.,Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input.,A simple majority vote (80% of panel members voting “yes”) was used to approve minor changes in grammar and syntax to improve clarity.,The previous recommendations for thymectomy were updated.,New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment.,This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.

The aim was to collate all myasthenia gravis (MG) epidemiological studies including AChR MG and MuSK MG specific studies.,To synthesize data on incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the condition and investigate the influence of environmental and technical factors on any trends or variation observed.,Studies were identified using multiple sources and meta-analysis performed to calculate pooled estimates for IR, PR and MR.,55 studies performed between 1950 and 2007 were included, representing 1.7 billion population-years.,For All MG estimated pooled IR (eIR): 5.3 per million person-years (C.I.:4.4, 6.1), range: 1.7 to 21.3; estimated pooled PR: 77.7 per million persons (C.I.:64.0, 94.3), range 15 to 179; MR range 0.1 to 0.9 per millions person-years.,AChR MG eIR: 7.3 (C.I.:5.5, 7.8), range: 4.3 to 18.0; MuSK MG IR range: 0.1 to 0.32.,However marked variation persisted between populations studied with similar methodology and in similar areas.,We report marked variation in observed frequencies of MG.,We show evidence of increasing frequency of MG with year of study and improved study quality.,This probably reflects improved case ascertainment.,But other factors must also influence disease onset resulting in the observed variation in IR across geographically and genetically similar populations.

Extensive gray matter (GM) involvement has been demonstrated in multiple sclerosis (MS) patients.,This study was aimed to identify GM alterations in relapsing-remitting MS (RRMS) patients using synthetic quantitative MRI (qMRI).,We assessed myelin volume fraction (MVF) in each voxel on the basis of R1 and R2 relaxation rates and proton density in 14 early and 28 late (disease duration ≤5 and >5 years, respectively) RRMS patients, and 15 healthy controls (HCs).,The MVF and myelin volumes of GM (GM-MyVol) were compared between groups using GM-based spatial statistics (GBSS) and the Kruskal-Wallis test, respectively.,Correlations between MVF or GM-MyVol and disease duration or expanded disability status scale were also evaluated.,RRMS patients showed a lower MVF than HCs, predominantly in the limbic and para-limbic areas, with more extensive areas noted in late RRMS patients.,Late-RRMS patients had the smallest GM-MyVol (20.44 mL; early RRMS, 22.77 mL; HCs, 23.36 mL).,Furthermore, the GM-MyVol in the RRMS group was inversely correlated with disease duration (r = −0.43, p = 0.005).,In conclusion, the MVF and MyVol obtained by synthetic qMRI can be used to evaluate GM differences in RRMS patients.

In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM).,We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS).,A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans.,SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR.,MS subgroups were compared with controls, adjusting for age and gender.,A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping.,MTR reduction was more extensive than atrophy.,RRMS and SPMS patients showed proportionately more atrophy in the deep GM.,SPMS and PPMS patients showed proportionately greater cortical MTR reduction.,RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM.,In SPMS and PPMS patients, there was less extensive correlation.,These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently.

The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS).,Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects.,To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels.,Blood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug.,Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF.,We observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab.,Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice.,Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith.,Our results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab-in particular when additional treatment courses are required-and to consider preventive action in critical cases.,This study provides Class IV evidence that for patients with RRMS alemtuzumab reduces immunoglobulin levels.

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS.,Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19 +, CD27 + memory B cells.,This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity.,Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS.,This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.,•Memory B cells activity is consistent with the etiology, pathology and therapy of MS, thought to be T cell-mediated.,•Deletion of memory B cells occurs with all effective MS treatments and is more marked with high-efficacy treatments.,•Drugs that worsen MS, can also increase memory B cell production.,Memory B cells activity is consistent with the etiology, pathology and therapy of MS, thought to be T cell-mediated.,Deletion of memory B cells occurs with all effective MS treatments and is more marked with high-efficacy treatments.,Drugs that worsen MS, can also increase memory B cell production.

Long noncoding RNAs (lncRNAs) have recently emerged as important biological regulators, and the aberrant expression of lncRNAs has been reported in numerous diseases.,However, the expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) has not been well documented.,We applied a microarray analysis to profile the lncRNA and mRNA expression in 3 pairs of samples.,Each sample was mixed with equivalent PBMCs from 9 female RA patients and 9 corresponding healthy controls, and the data were validated via qPCR using another cohort that comprised 36 RA patients and 24 healthy controls.,A bioinformatic analysis was performed to investigate the potential functions of differentially expressed genes.,Overall, 2,099 lncRNAs and 2,307 mRNAs were differentially expressed between the RA patients and healthy controls.,The bioinformatic analysis indicated that the differentially expressed lncRNAs regulated the abnormally expressed mRNAs, which were involved in the pathogenesis of RA through several different pathways.,The qPCR results showed that the expression levels of ENST00000456270 and NR_002838 were significantly increased in the RA patients, whereas the expression levels of NR_026812 and uc001zwf.1 were significantly decreased.,Furthermore, the expression level of ENST00000456270 was strongly associated with the serum levels of IL-6 and TNF-a and the Simplified Disease Activity Index (SDAI) of the RA patients.,Our data provided comprehensive evidence regarding the differential expression of lncRNAs in PBMCs of RA patients, which shed light on the understanding of the molecular mechanisms of lncRNAs in the pathogenesis of RA.

Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time.,Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6).,Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis.,The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively.,Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.

Follicular helper T cells (Tfh) are implicated in type 1 diabetes (T1D) and their development has been linked to CD28 costimulation.,We tested whether Tfh were decreased by costimulation blockade using the CTLA-4-Ig fusion protein (Abatacept) in a mouse model of diabetes and in individuals with new onset T1D.,Unbiased bioinformatic analysis identified that ICOS+ Tfh, and other ICOS+ populations including T-peripheral helper cells, were highly sensitive to costimulation blockade.,We were able to use pre-treatment Tfh profiles to derive a model that could predict clinical response to Abatacept in individuals with T1D.,Using two independent approaches we demonstrated that higher frequencies of ICOS+ Tfh at baseline were associated with a poor clinical response following Abatacept administration.,Tfh analysis may therefore represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.

Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence.,By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation.,Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors.,Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut.,Further, it remains unclear how they interact to cause the destructive autoimmune process.,This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways.,Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response.,Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements.,Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.

IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide.,However, IgAN rarely affects African Blacks and is uncommon in African Americans.,Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences.,Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers.,We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract.,Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls.,Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells.,Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth.,At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells.,Consequently, EBV infects cells secreting immunoglobulins other than IgA.,Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors.,Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome.,Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain.,The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN.,Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs.,M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival.,Their value was also assessed in patients not represented in the Oxford cohort.,In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival.,In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more.,The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%).,The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease.,The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony‐stimulating factor receptor α.,We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).,In study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate.,In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate.,Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate.,Long‐term safety and efficacy of mavrilimumab were assessed.,A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies).,The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years).,The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years).,At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted).,Most pulmonary changes were transient and only infrequently associated with AEs.,Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.,Long‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs.,Safety data were comparable with those from both phase IIb qualifying studies.

MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA).,Through NF-κB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17.,It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development.,These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR-146a-5p expression in patients’ sera in relation to clinical outcome of the treatment as well as predisposition to RA.,Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-α inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level.,Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023).,In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 ± 0.171) as compared to those detected after three months of treatment (1.809 ± 0.658, p = 0.033) and observed for healthy controls (5.302 ± 2.112, p = 0.048).,Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032).,These results support the hypothesis that miR-146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF-α treatment.