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Machine learning-based imaging diagnostics has recently reached or even surpassed the level of clinical experts in several clinical domains.,However, classification decisions of a trained machine learning system are typically non-transparent, a major hindrance for clinical integration, error tracking or knowledge discovery.,In this study, we present a transparent deep learning framework relying on 3D convolutional neural networks (CNNs) and layer-wise relevance propagation (LRP) for diagnosing multiple sclerosis (MS), the most widespread autoimmune neuroinflammatory disease.,MS is commonly diagnosed utilizing a combination of clinical presentation and conventional magnetic resonance imaging (MRI), specifically the occurrence and presentation of white matter lesions in T2-weighted images.,We hypothesized that using LRP in a naive predictive model would enable us to uncover relevant image features that a trained CNN uses for decision-making.,Since imaging markers in MS are well-established this would enable us to validate the respective CNN model.,First, we pre-trained a CNN on MRI data from the Alzheimer's Disease Neuroimaging Initiative (n = 921), afterwards specializing the CNN to discriminate between MS patients (n = 76) and healthy controls (n = 71).,Using LRP, we then produced a heatmap for each subject in the holdout set depicting the voxel-wise relevance for a particular classification decision.,The resulting CNN model resulted in a balanced accuracy of 87.04% and an area under the curve of 96.08% in a receiver operating characteristic curve.,The subsequent LRP visualization revealed that the CNN model focuses indeed on individual lesions, but also incorporates additional information such as lesion location, non-lesional white matter or gray matter areas such as the thalamus, which are established conventional and advanced MRI markers in MS.,We conclude that LRP and the proposed framework have the capability to make diagnostic decisions of CNN models transparent, which could serve to justify classification decisions for clinical review, verify diagnosis-relevant features and potentially gather new disease knowledge.,•LRP helps in explaining individual CNN decisions for diagnosing multiple sclerosis (MS) based on conventional MRI data•CNNs learn to identify hyperintense lesions as an important biomarker of MS•CNNs learn to identify relevant areas beyond lesions•Transfer learning improves learning across diseases and MRI sequences•Transparent CNNs show potential in validating models, verifying diagnosis-relevant features and gathering disease knowledge,LRP helps in explaining individual CNN decisions for diagnosing multiple sclerosis (MS) based on conventional MRI data,CNNs learn to identify hyperintense lesions as an important biomarker of MS,CNNs learn to identify relevant areas beyond lesions,Transfer learning improves learning across diseases and MRI sequences,Transparent CNNs show potential in validating models, verifying diagnosis-relevant features and gathering disease knowledge

Multiple Sclerosis patients' clinical symptoms do not correlate strongly with structural assessment done with traditional magnetic resonance images.,However, its diagnosis and evaluation of the disease's progression are based on a combination of this imaging analysis complemented with clinical examination.,Therefore, other biomarkers are necessary to better understand the disease.,In this paper, we capitalize on machine learning techniques to classify relapsing-remitting multiple sclerosis patients and healthy volunteers based on machine learning techniques, and to identify relevant brain areas and connectivity measures for characterizing patients.,To this end, we acquired magnetic resonance imaging data from relapsing-remitting multiple sclerosis patients and healthy subjects.,Fractional anisotropy maps, structural and functional connectivity were extracted from the scans.,Each of them were used as separate input features to construct support vector machine classifiers.,A fourth input feature was created by combining structural and functional connectivity.,Patients were divided in two groups according to their degree of disability and, together with the control group, three group pairs were formed for comparison.,Twelve separate classifiers were built from the combination of these four input features and three group pairs.,The classifiers were able to distinguish between patients and healthy subjects, reaching accuracy levels as high as 89% ± 2%.,In contrast, the performance was noticeably lower when comparing the two groups of patients with different levels of disability, reaching levels below 63% ± 5%.,The brain regions that contributed the most to the classification were the right occipital, left frontal orbital, medial frontal cortices and lingual gyrus.,The developed classifiers based on MRI data were able to distinguish multiple sclerosis patients and healthy subjects reliably.,Moreover, the resulting classification models identified brain regions, and functional and structural connections relevant for better understanding of the disease.,Unlabelled Image,•Classifiers based on functional and diffusion imaging data identified multiple sclerosis patients.,•These classifiers allowed to identify brain regions relevant for the disease.,•Functional imaging data was more relevant than diffusion data for the classification.,Classifiers based on functional and diffusion imaging data identified multiple sclerosis patients.,These classifiers allowed to identify brain regions relevant for the disease.,Functional imaging data was more relevant than diffusion data for the classification.

Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis.,Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3).,The nuclear vitamin D receptor (VDR) for 1,25-(OH)2D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells.,In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH)2D3, so that immune microenvironments are able to both activate and respond to vitamin D.,As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA).,The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA.,As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA.,The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.,The online version of this article (10.1007/s00223-019-00577-2) contains supplementary material, which is available to authorized users.

Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE).,Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN.,As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNα amplification loop in SLE.,Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNα-regulated genes in vitro.,In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients.,Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml.,The degree of vitamin D deficiency correlated inversely with disease activity; R = −.234, p = .002.,In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype.,Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D.,Additionally, vitamin D conditioning reduced expression of IFNα-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma.,We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity.,Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation.,We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNα activity in vivo and, most importantly, improves clinical outcome.

To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren’s syndrome (SS) patients.,Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union.,Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells.,SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production.,Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA.,Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4.,In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L.,In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression.,Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α).,Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

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.

Molecular biomarkers for multiple sclerosis have so far mainly been limited to measures in cerebrospinal fluid (CSF).,Here, we identified additional biomarkers for multiple sclerosis, 2 in plasma as well as 10 in CSF.,Furthermore, we identified 2 biomarkers: eotaxin-1 (CCL11), associated with disease duration and progression in both CSF and plasma, and plasma CCL20 which showed association with disease severity.,However, these findings will require further validation.,The capability of measuring biomarkers for multiple sclerosis may assist in the monitoring of patients during routine clinical care such as assessing treatment response but may also allow researchers to more accurately characterize pathological processes of inflammation and neurodegeneration in both the CNS and periphery of patients with multiple sclerosis.,Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking.,We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay.,Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases.,We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95).,Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls.,Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively.,In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease (PCSF < 4 × 10−5, Pplasma < 4 × 10−5), and plasma CCL20 was associated with disease severity (P = 4 × 10−5), although both require further validation.,Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy.,We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity.,Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with brain neurodegeneration.,MS patients present heterogeneous clinical manifestations in which both genetic and environmental factors are involved.,The diagnosis is very complex due to the high heterogeneity of the pathophysiology of the disease.,The diagnostic criteria have been modified several times over the years.,Basically, they include clinical symptoms, presence of typical lesions detected by magnetic resonance imaging (MRI), and laboratory findings.,The analysis of cerebrospinal fluid (CSF) allows an evaluation of inflammatory processes circumscribed to the CNS and reflects changes in the immunological pattern due to the progression of the pathology, being fundamental in the diagnosis and monitoring of MS.,The detection of the oligoclonal bands (OCBs) in both CSF and serum is recognized as the “gold standard” for laboratory diagnosis of MS, though presents analytical limitations.,Indeed, current protocols for OCBs assay are time-consuming and require an operator-dependent interpretation.,In recent years, the quantification of free light chain (FLC) in CSF has emerged to assist clinicians in the diagnosis of MS.,This article reviews the current knowledge on CSF biomarkers used in the diagnosis of MS, in particular on the validated assays and on the alternative biomarkers of intrathecal synthesis.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19.,However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients.,We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination.,Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution.,By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination.,Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming.,Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses.,These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans.,Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.,SARS-CoV-2-specific antibodies and memory B cells are significantly reduced, but CD4+ and CD8+ T cells are robustly activated, in patients with multiple sclerosis on anti-CD20 monotherapy versus healthy controls after BNT162b2 or mRNA-1273 mRNA vaccination.

High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts.,The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels.,Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis.,Regional analyses and comparisons with 2013 data were conducted.,A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population).,MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist.,The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years.,Females are twice as likely to live with MS as males.,The global prevalence of MS has risen since 2013, but good surveillance data is not universal.,Action is needed by multiple stakeholders to close knowledge gaps.

The autoantibody profile of seropositive rheumatoid arthritis (RA) is very diverse and consists of various isotypes and antibodies to multiple post-translational modifications.,It is yet unknown whether this varying breadth of the autoantibody profile is associated with treatment outcomes.,Therefore, we investigated whether the composition of the autoantibody profile in RA, as a marker of the underlying immunopathology, influences initial and long-term treatment outcomes.,In serum from 399 seropositive patients with RA in the IMPROVED study, drawn at baseline and at the moment of drug tapering, we measured IgG, IgM, and IgA isotypes for anti-cyclic citrullinated peptide-2 and anti‐carbamylated protein antibodies, IgM and IgA rheumatoid factor, and reactivity against four citrullinated and two acetylated peptides (anti-modified protein antibodies (AMPAs)).,We investigated the effect of the breadth of the autoantibody profile on (1) change in disease activity score (DAS)44 between 0 and 4 months, (2) initial drug-free remission (DFR, drug-free DAS44 < 1.6) achieved between 1 and 2 years of follow up, and (3) long-term sustained DFR until last follow up.,Patients with a broad autoantibody profile at baseline had a significantly better early treatment response: ΔDAS 0-4 months of 1-2, 3-4, and 5-6 vs 7-8 isotypes, -1.5 (p < 0.001), -1.7 (p = 0.03), and -1.8 (p = 0.04) vs -2.2.,Similar results were observed for AMPA number.,However, patients with a broad baseline autoantibody profile achieved less initial DFR.,For long-term sustained DFR there was no longer an association with the breadth of the autoantibody response.,When assessing autoantibodies at the moment of tapering, similar trends were observed.,A broad baseline autoantibody profile is associated with a better early treatment response.,The breadth of the baseline autoantibody profile, reflecting a break in tolerance against several different autoantigens and extensive isotype switching, may indicate a more active humoral autoimmunity, which could make the underlying disease processes initially more suppressible by medication.,The lack of association with long-term sustained DFR suggests that the relevance of the baseline autoantibody profile diminishes over time.,ISRCTN11916566.,Registered on 7 November 2006.,EudraCT, 2006- 06186-16.,Registered on 16 July 2007.,The online version of this article (10.1186/s13075-018-1520-4) contains supplementary material, which is available to authorized users.

Antibodies against citrullinated proteins (ACPAs) are highly specific for RA.,Since the discovery of these antibodies, several of studies that focused on the presence and identity of citrullinated proteins in the joints of RA patients have been carried out.,The best-known antigens that bind ACPAs are citrullinated filaggrin, Type II collagen (CII), α-enolase, fibrinogen and vimentin.,This review compares citrullinated filaggrin, CII, α-enolase and fibrinogen with vimentin in their contribution to ACPA triggering, and gives an overview of the literature in which the role of citrullinated and non-citrullinated vimentin in the onset of ACPA production and the pathogenesis of RA is discussed.

In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS).,In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS).,Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS.,We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other.,The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques.,The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles.,This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter.,The first type of inflammation dominates in acute and relapsing MS.,The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age.,It is suggested that CD8+ T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen.,B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors.,Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown.,Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8+ T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis.,The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan.,These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.,Ann Neurol 2011

What is the prevalence of periodontal disease and citrullinating periodontopathic bacteria in anti-cyclic citrullinated protein-positive at-risk individuals (CCP+ at-risk) compared with a healthy control group and patients with early rheumatoid arthritis (RA)?,This cross-sectional study identified an increased prevalence of periodontal disease sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals and those with early RA compared with a control group.,Results showed that CCP+ at-risk individuals had increased abundance of Porphyromonas gingivalis at healthy periodontal sites compared with the control group and patients with early RA.,In individuals at risk of RA, periodontitis and P gingivalis were increased before joint disease and may be a target for prevention.,This cross-sectional study estimates the prevalence of periodontal disease and citrullinating periodontopathic bacteria in individuals who test positive for anti-cyclic citrullinated protein (anti-CCP) antibody without rheumatoid arthritis compared with groups of healthy control participants and patients with early rheumatoid arthritis.,The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and periodontopathic bacteria can citrullinate proteins.,Periodontitis may, therefore, be an initiator of RA and a target for prevention.,Periodontal disease and periodontal bacteria have not been investigated in at-risk individuals with RA autoimmunity but no arthritis.,To examine periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein (anti-CCP) antibody-positive at-risk individuals without arthritis.,This cross-sectional study took place at a teaching hospital from April 27, 2015, to May 8, 2017.,Forty-eight anti-CCP-positive individuals without arthritis (CCP+ at-risk) were recruited nationally.,Twenty-six patients with early RA (ERA) and 32 healthy control individuals were recruited locally.,Data were analyzed between June 1, 2017, and December 1, 2017.,Periodontal assessment and examination of joints using ultrasonography.,Prevalence of diseased periodontal sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals compared with patients with ERA and healthy individuals matched for age and smoking.,Paired-end sequencing of DNA from subgingival plaque from diseased and healthy periodontal sites was performed and DNA was profiled and analyzed.,A total of 48 CCP+ at-risk individuals (mean [SD] age, 51.9 [11.4] years; 31 [65%] female), 26 patients with ERA (mean [SD] age, 54.4 [16.7] years; 14 [54%] female), and 32 healthy individuals (mean [SD] age, 49.4 [15.3] years; 19 [59%] female) were recruited.,Of 48 CCP+ at-risk individuals, 46 had no joint inflammation on ultrasonography.,Thirty-five CCP+ at-risk individuals (73%), 12 healthy individuals (38%), and 14 patients with ERA (54%) had clinical periodontitis.,The median (interquartile range) percentage of periodontal sites with disease was greater in CCP+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with ERA (1.1% [0%-13.1%]).,Median (interquartile range) periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2]).,Patients with CCP+ at-risk had increased relative abundance of Porphyromonas gingivalis (but not Aggregatibacter actinomycetemcomitans) at healthy periodontal sites compared with healthy individuals (effect size, 3.00; 95% CI, 1.71-4.29) and patients with ERA (effect size, 2.14; 95% CI, 0.77-3.52).,This study found increased prevalence of periodontitis and P gingivalis in CCP+ at-risk individuals.,This suggests periodontitis and P gingivalis are associated with disease initiation and could be targets for preventive interventions in RA.

Improved understanding of the immune events discriminating between seropositive arthralgia and clinical synovitis is of key importance in rheumatology research.,Ample evidence suggests a role for Th17 cells in rheumatoid arthritis.,We hypothesized that CD4+CD161+ cells representing Th17 lineage cells may be modulated prior to or after development of clinical synovitis.,Therefore, in a cross-sectional study, we investigated the occurrence of CD4+CD161+ T-cells in seropositive arthralgia patients who are at risk for developing rheumatoid arthritis and in newly diagnosed rheumatoid arthritis patients.,In a prospective study, we evaluated the effect of methotrexate treatment on circulating CD4+CD161+ T-cells.,Next, we assessed if these cells can be detected at the level of the RA joints.,Precursor Th17 lineage cells bearing CD161 were found to be increased in seropositive arthralgia patients.,In contrast, circulating CD4+CD161+T-cells were decreased in newly diagnosed rheumatoid arthritis patients.,The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein and with the 66 swollen joint count.,Methotrexate treatment led to normalization of CD4+CD161+ T-cells and reduced disease activity.,CD4+CD161+ T cells were readily detected in synovial tissues from both early and late-stage rheumatoid arthritis.,In addition, synovial fluid from late-stage disease was found to be enriched for CD4+CD161+ T-cells.,Notably, synovial fluid accumulated CD4+CD161+T-cells showed skewing towards the Th1 phenotype as evidenced by increased interferon-γ expression.,The changes in peripheral numbers of CD4+CD161+ T-cells in seropositive arthralgia and early rheumatoid arthritis and the enrichment of these cells at the level of the joint predict a role for CD4+CD161+ T-cells in the early immune events leading to clinical synovitis.,Our findings may add to the development of RA prediction models and provide opportunities for early intervention.

Signals controlling the generation of regulatory B (Breg) cells remain ill-defined.,Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells.,In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement.,CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release.,In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells.,This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α.,Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation.,Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab.,We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.,•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction,pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner,Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism,pDCs are hyperactivated in SLE and fail to induce Breg cells,Patients responding to rituximab display a normalized pDC-Breg cell interaction,The signals required for Breg cell differentiation in humans are currently unknown.,Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.

To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE).,Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m2) with the coadministration of dexamethasone (20 mg) for active SLE.,Disease activity was assessed using the SLEDAI-2K score.,Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored.,Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity.,Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies.,Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients.,Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%).,Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles.,Siglec-1 expression on monocytes significantly declined.,These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.

Here we report the transcriptional profile of human microglia, isolated from normal-appearing grey matter (GM) and white matter (WM) of multiple sclerosis (MS) and non-neurological control donors, to find possible early changes related to MS pathology.,Microglia show a clear region-specific profile, indicated by higher expression of type-I interferon genes in GM and higher expression of NF-κB pathway genes in WM.,Transcriptional changes in MS microglia also differ between GM and WM.,MS WM microglia show increased lipid metabolism gene expression, which relates to MS pathology since active MS lesion-derived microglial nuclei show similar altered gene expression.,Microglia from MS GM show increased expression of genes associated with glycolysis and iron homeostasis, possibly reflecting microglia reacting to iron depositions.,Except for ADGRG1/GPR56, expression of homeostatic genes, such as P2RY12 and TMEM119, is unaltered in normal-appearing MS tissue, demonstrating overall preservation of microglia homeostatic functions in the initiation phase of MS.,It is unclear if early pathological changes in normal-appearing multiple sclerosis (MS) tissue are reflected by molecular changes in microglia, which might contribute to lesion initiation.,Here, authors demonstrate significant intrinsic differences in the human microglial transcriptome between grey and white matter regions, isolated from MS and non-neurological control donors, and show early microglial changes related to MS pathology.

In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process.,Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown.,Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis.,In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE).,We find that silencing Chi3l3 increases severity of EAE.,We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature.,Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.,Chitinase 3-like-3 (Chi3l3) is expressed in microglia, but its function is not clear.,Here the authors show that Chi3l3 is expressed in the subventricular zone in mouse experimental immune encephalitis, which induces oligodendrogenesis.

Quantification of kappa free light chains (KFLC) in cerebrospinal fluid shows high diagnostic sensitivity in multiple sclerosis and clinically isolated syndrome patients.,However, a clearly defined threshold value is still missing and a possible prognostic value of the KFLC levels in these patients remains undefined.,Results of KFLC quantification in 420 controls were used to set an upper limit of normal KFLC concentration in CSF under different blood-CSF-barrier conditions.,Additionally, KFLC values of MS and CIS patients were assessed and results were evaluated with reference to the patients corresponding disease courses.,The calculated upper limit of normal KFLC-concentration covers 98% of these control patients.,Using this cut-off, plasma cell activity in CSF can be detected in 97% of MS patients and in 97% of CIS patients.,However, there is no evidence that the extent of KFLC elevation provides prognostic value in MS and CIS patients in this study.,KFLC determination should become a first line screen in the diagnostic algorithms of MS and CIS.,The extent of elevation of intrathecal KFLC has no prognostic value on the disease course in MS and CIS patients.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis.,The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan.,These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.,Ann Neurol 2011

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG).,Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur.,The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus.,The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG).,The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.,More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable.,The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans.,Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved.,To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients.,We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain.,In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis.,We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon.,Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4.,The online version of this article (doi:10.1007/s00401-011-0824-0) contains supplementary material, which is available to authorized users.

An important goal for personalized treatment is predicting response to a particular therapeutic.,A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome.,Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α.,By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response.,The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA− patients.,Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/β-expressing memory B cells in ADA+ vs.,ADA− RA patients.,We also assessed the predictive value of SIRPα/β expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment.,We show that a frequency of < 9.4% of SIRPα/β-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92.,Thus, measuring the frequency of SIRPα/β-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment.

Methotrexate is considered to be first-line therapy for rheumatoid arthritis (RA).,However, a substantial proportion of treated patients do not achieve the desired goals of therapy.,This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA.,The Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for <1 and <3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients.,This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months.,Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval.,In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year.,Baseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP.,Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy.,In patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months.,The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes.,These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA.,NCT00420927, NCT00195663; Post-results.

Endogenous retrovirus (ERV) sequences make up a large fraction of our genome, yet little is understood about their function and biological relevance.,Deep-sequencing data contain valuable information on a genome-wide scale.,Yet, due to their highly repetitive nature, analysis of ERVs has been computationally challenging.,We describe a bioinformatics tool called ERVmap to analyze transcription of unique sets of human ERVs in a range of cell types in health and disease settings.,Our open-source code and accompanied web tool should facilitate researchers in all fields to study the expression patterns of ERVs in sequencing data and should lead to significant advancement in understanding the biological relevance of ERVs in health and disease.,Endogenous retroviruses (ERVs) are integrated retroviral elements that make up 8% of the human genome.,However, the impact of ERVs on human health and disease is not well understood.,While select ERVs have been implicated in diseases, including autoimmune disease and cancer, the lack of tools to analyze genome-wide, locus-specific expression of proviral autonomous ERVs has hampered the progress in the field.,Here we describe a method called ERVmap, consisting of an annotated database of 3,220 human proviral ERVs and a pipeline that allows for locus-specific genome-wide identification of proviral ERVs that are transcribed based on RNA-sequencing data, and provide examples of the utility of this tool.,Using ERVmap, we revealed cell-type-specific ERV expression patterns in commonly used cell lines as well as in primary cells.,We identified 124 unique ERV loci that are significantly elevated in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus that represent an IFN-independent signature.,Finally, we identified additional tumor-associated ERVs that correlate with cytolytic activity represented by granzyme and perforin expression in breast cancer tissue samples.,The open-source code of ERVmap and the accompanied web tool are made publicly available to quantify proviral ERVs in RNA-sequencing data with ease.,Use of ERVmap across a range of diseases and experimental conditions has the potential to uncover novel disease-associated antigens and effectors involved in human health that is currently missed by focusing on protein-coding sequences.

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) which is prevalent in South China, and its association with systemic lupus erythematosus (SLE) or other autoimmune diseases has not been studied in the mainland of China.,The EBV serological tests have been performed on patients with various diseases or manifestations for years at our institution and their values need to be evaluated.,For routine medical purposes, anti-EB viral capsid antigen (VCA) IgG, IgA and IgM antibodies, anti-EBV diffuse early antigen (EA-D) IgA antibodies, and anti-EBV nuclear antigen-1(EBNA-1) IgG antibodies were tested with commercial enzyme-linked immunosorbent assay (ELISA) in patients visiting Peking Union Medical College Hospital between 2013 and 2017.,The test results were analyzed in this retrospective study.,There were a total of 11122 serum samples available to be tested in the study.,As indicators of past EBV infection, the prevalence of VCA-IgG/EBNA1-IgG were 66.6%/58.5%, 84.3%/78.8%, 92.9%/87.0% and 98.5%/95.4% in patients aged under 5 years, 6-10 years, 11-20 years and 21-30 years old, respectively, and these values maintained at this highest rate as age increased further.,The prevalence of VCA-IgM, as a parameter of acute EBV infection, was 14.6%, 10.2%, 10.4%, 6.3% and 3.1% in patients aged under 5 years, 6-10 years,11-20 years, 21-30 years, 31-40 years old, respectively, and decreased to 2%~3% in older patients.,Patients with elevated serum liver enzymes were more likely to have a higher prevalence of EA/D IgA antibody (P < 0.01) and young patients (≤30 years) with lymphadenopathy were more likely to have higher prevalence of VCA-IgM antibody (P < 0.01).,The prevalence of VCA-IgA and EAD-IgA were 87.0% and 59.2% in NPC patients, respectively, and both were significantly higher (P < 0.001) than that in non-NPC patients.,The prevalence of VCA-IgA was 45.4% and 25.6% in SLE patients and patients with other autoimmune diseases, respectively, which were significantly (P < 0.001) and mildly (P = 0.039) higher than their controls.,In pediatric SLE patients between 6 and10 years old, the prevalence of VCA-IgG, VCA-IgA and EBNA1-IgG was 100%, 59.5% and 100%, respectively, all being significantly higher than the age (6-10y) related controls (P< 0.01).,In the 705 cerebral spinal fluid (CSF) specimens, VCA-IgG, VCA-IgM, VCA-IgA and EAD-IgA were found to be positive in 12.1%, 0.15%, 0.25% and 0.25%, respectively.,There were 157 paired specimens (CSF and serum were collected simultaneously) and VCA-IgG was identified as positive in 12.7% of the CSF and 100% of the serum specimens.,Around 98% of Chinese patients were infected with EBV before 30 years of age and the highest rate of acute EBV infection were observed in patients under 5 years old.,EBV infection was found to be associated with elevated serum liver enzymes, NPC and SLE.,Acute anti-EBV antibody was valued for young patients with lymphadenopathy but limited value for CNS neuropathy.

Primary Sjögren’s syndrome (pSS) is a progressive systemic autoimmune disease characterized by lymphocytic infiltrates in exocrine glands, leading to the injury of salivary and lachrymal glands.,Mesenchymal stem cells (MSCs) have been demonstrated to exert great potential in the treatment of various autoimmune diseases.,Although MSCs have provide an effective therapeutic approach for SS treatment, the underlying mechanisms are still elusive.,Our previous study has shown the reduced suppressive capacity of myeloid-derived suppressor cells (MDSCs) advanced the progression of experimental Sjögren’s syndrome (ESS).,In this study, we found that BM-MSCs significantly enhanced the suppressive function of MDSCs with high levels of Arginase and NO, decreased the levels of CD40, CD80, CD86, and MHC-II expression on MDSCs, thus attenuating the disease progression in ESS mice.,Furthermore, the enhanced suppressive function of MDSCs was mediated by BM-MSC-secreted TGF-β, and the therapeutic effect of BM-MSCs in inhibiting ESS was almost abolished after silencing TGF-β in BM-MSCs.,Taken together, our results demonstrated that BM-MSCs alleviated the ESS progression by up-regulating the immunosuppressive effect of MDSCs through TGF-β/Smad pathway, offering a novel mechanism for MSCs in the treatment of pSS.

In our present single-center pilot study, umbilical cord (UC)-derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE).,The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.,Forty patients with active SLE were recruited from four clinical centers in China.,Allogeneic UC MSCs were infused intravenously on days 0 and 7.,The primary endpoints were safety profiles.,The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse.,Clinical indices, including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) score and renal functional indices, were also taken into account.,The overall survival rate was 92.5% (37 of 40 patients).,UC-MSCT was well tolerated, and no transplantation-related adverse events were observed.,Thirteen and eleven patients achieved MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%), respectively, during 12 months of follow up.,Three and four patients experienced disease relapse at 9 months (12.5%) and 12 months (16.7%) of follow-up, respectively, after a prior clinical response.,SLEDAI scores significantly decreased at 3, 6, 9 and 12 months follow-up.,Total BILAG scores markedly decreased at 3 months and continued to decrease at subsequent follow-up visits.,BILAG scores for renal, hematopoietic and cutaneous systems significantly improved.,Among those patients with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistically differences at 9 and 12 months.,Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in seven relapse cases.,In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations.,Serum antinuclear antibody and anti-double-stranded DNA antibody decreased after MSCT, with statistically significant differences at 3-month follow-up examinations.,UC-MSCT results in satisfactory clinical response in SLE patients.,However, in our present study, several patients experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.,ClinicalTrials.gov identifier: NCT01741857.,Registered 26 September 2012.

Acid‐sensing ion channels (ASICs) are proton‐gated channels involved in multiple biological functions such as: pain modulation, mechanosensation, neurotransmission, and neurodegeneration.,Earlier, we described the genetic association, within the Nuoro population, between Multiple Sclerosis (MS) and rs28936, located in ASIC2 3′UTR.,Here we investigated the potential involvement of ASIC2 in MS inflammatory process.,We induced experimental autoimmune encephalomyelitis (EAE) in wild‐type (WT), knockout Asic1−/− and Asic2−/− mice and observed a significant reduction of clinical score in Asic1−/− mice and a significant reduction in the clinical score in Asic2−/− mice in a limited time window (i.e., at days 20-23 after immunization).,Immunohistochemistry confirmed the reduction in adaptive immune cell infiltrates in the spinal cord of EAE Asic1−/− mice.,Analysis of mechanical allodynia, showed a significant higher pain threshold in Asic2−/− mice under physiological conditions, before immunization, as compared to WT mice and Asic1−/−.,A significant reduction in pain threshold was observed in all three strains of mice after immunization.,More importantly, analysis of human autoptic brain tissue in MS and control samples showed an increase of ASIC2 mRNA in MS samples.,Subsequently, in vitro luciferase reporter gene assays, showed that ASIC2 expression is under possible miRNA regulation, in a rs28936 allele‐specific manner.,Taken together, these findings suggest a potential role of ASIC2 in the pathophysiology of MS.

Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin.,While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described.,Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis.,Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue.,Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis.,We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus.,At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α.,We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia.,Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.,The online version of this article (doi:10.1186/s40478-016-0343-2) contains supplementary material, which is available to authorized users.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.

There are a number of instruments that describe severity and progression of multiple sclerosis and they are increasingly used as endpoints to assess the effectiveness of therapeutic interventions.,We examined to what extent the psychometric properties of two accepted instruments - EDSS and MSFC - meet methodological standards and the value they have in clinical trials.,We conducted a systematic literature search in relevant databases [MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO & PSYNDEX, CINAHL] yielding 3,860 results.,Relevant full-text publications were identified using abstract and then full-text reviews, and the literature was reviewed.,For evaluation of psychometric properties (validity, reliability, sensitivity of change) of EDSS and MSFC, 120 relevant full-text publications were identified, 54 of them assessed the EDSS, 26 the MSFC and 40 included both instruments.,The EDSS has some documented weaknesses in reliability and sensitivity to change.,The main limitations of the MSFC are learning effects and the z-scores method used to calculate the total score.,However, the methodological criterion of validity applies sufficiently for both instruments.,For use in clinical studies, we found the EDSS to be preferred as a primary and secondary outcome measure in recent studies (50 EDSS, 9 MSFC).,Recognizing their strengths and weaknesses, both EDSS and MSFC are suitable to detect the effectiveness of clinical interventions and to monitor disease progression.,Almost all publications identify the EDSS as the most widely used tool to measure disease outcomes in clinical trials.,Despite some limitations, both instruments are accepted as endpoints and neither are discussed as surrogate parameters in identified publications.,A great advantage of the EDSS is its international acceptance (e.g. by EMA) as a primary endpoint in clinical trials and its broad use in trials, enabling cross-study comparisons.

Mesenchymal stem cell (MSC) therapies have been used as cell-based treatments for decades, owing to their anti-inflammatory, immunomodulatory, and regenerative properties.,With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat arthritic diseases.,Studies on osteoarthritis (OA) have shown positive clinical outcomes, with improved joint function, pain level, and quality of life.,In addition, few clinical MSC trials conducted on rheumatoid arthritis (RA) patients have also displayed some optimistic outlook.,The largely positive outcomes in clinical trials without severe side effects establish MSCs as promising tools for arthritis treatment.,However, further research is required to investigate its applicability in clinical settings.,This review discusses the most recent advances in clinical studies on MSC therapies for OA and RA.

Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells.,It was first used in the treatment of non-Hodgkin’s lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF) biologics.,Sustained efficacy in RA can be achieved by repeated courses of rituximab.,However, the optimal dose and retreatment schedule of rituximab in RA remains to be established.,Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab.,Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure.,Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion.,Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time.,Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections.,Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed.,Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection) is important, especially in Asian countries where hepatitis B infection is prevalent.,The rare but fatal progressive multifocal leukoencephalopathy linked to the use of rituximab has to be noted.,Postmarketing surveillance and registry data, particularly in Asia, are necessary to establish the long-term efficacy and safety of rituximab in the treatment of RA.

Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D).,We propose that defining the key gene regulatory networks that drive β-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic β-cells.,Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream.,If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the β-cell responses to the immune assault-in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)-instead of targeting only the immune system, as it is usually proposed.,Here we discuss the importance of a focus on β-cells in T1D, lessons learned from other autoimmune diseases, the “alternative splicing connection,” data mining, and drug repurposing to protect β-cells in T1D and then some of the initial candidates under testing for β-cell protection.

Alternative splicing (AS) is a complex coordinated transcriptional regulatory mechanism.,It affects nearly 95% of all protein-coding genes and occurs in nearly all human organs.,Aberrant alternative splicing can lead to various neurological diseases and cancers and is responsible for aging, infection, inflammation, immune and metabolic disorders, and so on.,Though aberrant alternative splicing events and their regulatory mechanisms are widely recognized, the association between autoimmune disease and alternative splicing has not been extensively examined.,Autoimmune diseases are characterized by the loss of tolerance of the immune system towards self-antigens and organ-specific or systemic inflammation and subsequent tissue damage.,In the present review, we summarized the most recent reports on splicing events that occur in the immunopathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and attempted to clarify the role that splicing events play in regulating autoimmune disease progression.,We also identified the changes that occur in splicing factor expression.,The foregoing information might improve our understanding of autoimmune diseases and help develop new diagnostic and therapeutic tools for them.

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed.,Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases.,SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads.,Several inhibitors and activators have been shown to affect the development of Ads.,SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents.,In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS).,The etiology of this multifactorial disease has not been clearly defined.,Conventional medical treatment of MS has progressed, but is still based on symptomatic treatment.,One of the key factors in the pathogenesis of MS is oxidative stress, enhancing inflammation and neurodegeneration.,In MS, both reactive oxygen and nitrogen species are formed in the CNS mainly by activated macrophages and microglia structures, which can lead to demyelination and axon disruption.,The course of MS is associated with the secretion of many inflammatory and oxidative stress mediators, including cytokines (IL-1b, IL-6, IL-17, TNF-α, INF-γ) and chemokines (MIP-1a, MCP-1, IP10).,The early stage of MS (RRMS) lasts about 10 years, and is dominated by inflammatory processes, whereas the chronic stage is associated with neurodegenerative axon and neuron loss.,Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated processes, antioxidant therapy could contribute to the reduction or even prevention of the progression of MS.,Further research is needed in order to establish new aims for novel treatment and provide possible benefits to MS patients.,The present review examines the roles of oxidative stress and non-pharmacological anti-oxidative therapies in MS.

Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms.,The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss.,Here, we report evidence for an ‘ADCC bystander mechanism’ in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes.,In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells.,Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures.,Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents.,In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion.,Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide.,These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss.,The online version of this article (10.1186/s40478-019-0766-7) contains supplementary material, which is available to authorized users.

It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD).,To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage.,Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses.,We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS.,Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms.,The online version of this article (10.1007/s00401-018-1950-8) contains supplementary material, which is available to authorized users.

To evaluate to which extent serum neurofilament light chain (NfL) increase is related to diffusion tensor imaging-MRI measurable diffuse normal-appearing white matter (NAWM) damage in MS.,Seventy-nine patients with MS and 10 healthy controls underwent MRI including diffusion tensor sequences and serum NfL determination by single molecule array (Simoa).,Fractional anisotropy and mean, axial, and radial diffusivities were calculated within the whole and segmented (frontal, parietal, temporal, occipital, cingulate, and deep) NAWM.,Spearman correlations and multiple regression models were used to assess the associations between diffusion tensor imaging, volumetric MRI data, and NfL.,Elevated NfL correlated with decreased fractional anisotropy and increased mean, axial, and radial diffusivities in the entire and segmented NAWM (for entire NAWM ρ = −0.49, p = 0.005; ρ = 0.49, p = 0.005; ρ = 0.43, p = 0.018; and ρ = 0.48, p = 0.006, respectively).,A multiple regression model examining the effect of diffusion tensor indices on NfL showed significant associations when adjusted for sex, age, disease type, the expanded disability status scale, treatment, and presence of relapses.,In the same model, T2 lesion volume was similarly associated with NfL.,Our findings suggest that elevated serum NfL in MS results from neuroaxonal damage both within the NAWM and focal T2 lesions.,This pathologic heterogeneity ought to be taken into account when interpreting NfL findings at the individual patient level.

Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease.,Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly.,As Purkinje cell axons are the sole output of the cerebellar cortex, understanding pathologic processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia.,We studied pathologic changes occurring within Purkinje cells of the cerebellum.,Using immunohistochemic techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament.,We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex.,These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.

This study aimed to explore the correlation of circulating microRNA (miRNA) expression profile with clinical response to tumor necrosis factor (TNF) inhibitor in treating rheumatoid arthritis (RA) patients.,Baseline PBMC samples from eight responders and eight non‐responders after 24‐week TNF inhibitor (etanercept) treatment were subjected to miRNA microarray.,Then, top 10 dysregulated miRNAs were selected and further validated by quantitative polymerase chain reaction (qPCR) in baseline PBMC samples from 92 RA patients treated with 24‐week TNF inhibitor (etanercept).,Responders and non‐responders were divided referring to the decline in disease activity score in 28 joints.,In microarray assay, total 59 upregulated and 78 downregulated miRNAs were identified in responders compared to non‐responders, which were mainly enriched in regulating immune‐ and inflammation‐related biological processes and pathways.,The top 10 dysregulated miRNAs were as follows: miR‐192‐5p, miR‐146a‐5p, miR‐19b‐3p, miR‐320c, miR‐335‐5p, miR‐149‐3p, miR‐766‐3p, let‐7a‐5p, miR‐24‐3p, and miR‐1226‐5p.,In qPCR validation, miR‐146a‐5p was increased, while let‐7a‐5p was decreased in responders compared with non‐responders.,Multivariate logistic analysis illuminated that miR‐146a‐5p and CRP independently correlated with higher clinical response, while let‐7a‐5p and biologics history independently associated with lower clinical response.,Subsequently, receiver operating characteristic curve showed that combination of these four independent factors presented with a great predictive value for clinical response with area under curve: 0.863, 95% CI 0.781‐0.945.,miRNA expression profile is closely implicated in the treatment efficacy of TNF inhibitor, and combined measurement of miR‐146a‐5p, let‐7a‐5p, CRP, and biologics history disclosed a great predictive value for clinical response to TNF inhibitor in RA patients.

The aim of this study was to determine whether the inflammatory milieu and/or hypoxia induces the dedifferentiation of synovial cells into mesenchymal stem-like cells, which may contribute to the tumor-like growth of synovial cells.,Expression of mesenchymal stem cell markers (CD24, CD44, CD90, CD106, CD146 and Stro-1) was compared among cultured fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), bone marrow mesenchymal stem cells (BM MSCs) and normal dermal fibroblasts.,After the cells were stimulated with pro-inflammatory cytokines for 3 days under hypoxia or normoxia, the stem cell markers were analyzed by FACS.,CD44 and CD90 were expressed constitutively in all four cell types.,Only the BM MSCs strongly expressed CD146.,The expression of stem cell markers was similar between FLSs from RA and those from OA patients.,In addition, the expression levels in FLSs were similar to those in normal dermal fibroblasts.,The stimulation of FLSs and dermal fibroblasts with IL-1β or a mixture of cytokines under hypoxia did not induce a marked change in the expression of stem cell markers.,These results indirectly suggest that the pro-inflammatory milieu may be not sufficient to induce the dedifferentiation of FLSs in arthritic joints.

Young adulthood is a challenging period for people with diabetes mellitus type 1 (T1DM) as they are facing multiple life transitions while managing a demanding disease.,This poses a risk for impaired health-related quality of life (HRQOL).,We assessed HRQOL in a cohort of young adults with T1DM in the Netherlands, and compared outcomes with those of Dutch norm groups of healthy young adults and young adults with a chronic disease.,We analyzed data collected in a larger evaluation study on transitional care for young adults with T1DM in a nationwide sample in the Netherlands, including twelve participating hospitals.,These data had been obtained from online questionnaires completed by young adults with T1DM after they had transferred to adult care.,HRQOL was self-reported with the Pediatric Quality of Life Inventory for young adults (PedsQL-YA).,One hundred and sixty-five young adults with T1DM participated (44.2% response); and they scored significantly worse than did healthy peers on all domains of HRQOL, except social functioning.,Particularly, functioning at school or work was worse than that of the norm group.,The study group’s HRQOL-scores were comparable to norm scores of young adults with chronic diseases, although the physical and social functioning of young people with T1DM was better.,One quarter (26.1%) of all young adults with T1DM reported fatigue.,During transition to adulthood, young adults with T1DM struggle to maintain a balance between the demands of managing a disease and their life.,Many of them encounter problems at work or school, and suffer from fatigue.,These findings underscore the need to regularly assess HRQOL, and to discuss work- and education-related issues in clinical practice.

Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes.,In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes.,Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans.,Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment.,We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months.,Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months.,An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin.,β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment.,Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin.,In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin.,Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.

Adult-onset Still’s disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA).,The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset.,To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1β inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1β targeting therapy, relative to healthy subjects.,All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects.,A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects.,Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes.,Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients.,These results further support the concept of a Still’s disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form.

C-X-C motif chemokine 10 (CXCL10) is produced in response to interferon-γ, and tumor necrosis factor-α (TNF-α) triggers the accumulation of activated lymphocytes.,CXCL13 is constitutively expressed in secondary lymphoid tissues, and the expression is upregulated by TNF-α, via T cell stimulation.,It appears that CXCL10 and CXCL13 could play a potential role in the pathogenesis of adult-onset Still’s disease (AOSD), therefore, we investigated the associations between CXCL10 and CXCL13 levels and clinical manifestations in patients with active AOSD.,Blood samples were collected from 39 active AOSD patients, 32 rheumatoid arthritis (RA) patients and 40 healthy controls (HC).,Of the AOSD patients, follow-up samples were collected from 15 9.6 ± 9.2 months later.,Serum levels of CXCL10 and CXCL13 were determined using enzyme-linked immunosorbent assay.,CXCL10, CXCL13, and C-X-C chemokine receptor type 3 (CXCR3) expression levels in biopsy specimens obtained from 26 AOSD patients with skin rashes were investigated via immunohistochemistry.,The CXCL10 levels in AOSD patients (1,031.3 ± 2,019.6 pg/mL) were higher than in RA (146.3 ± 91.4 pg/mL, p = 0.008) and HC (104.4 ± 47.9 pg/mL, p = 0.006).,Also, the CXCL13 levels of AOSD patients (158.8 ± 151.2 pg/mL) were higher than those of RA (54.4 ± 61.1 pg/mL, p < 0.001) and HC (23.5 ± 18.1 pg/mL, p < 0.001).,Serum CXCL10 levels correlated with ferritin and systemic scores.,Serum CXCL13 levels correlated with those of hemoglobin, C-reactive protein, ferritin, and albumin, and systemic scores.,In follow-up AOSD patients, the levels of CXCL10 and CXCL13 fell significantly (153.7 ± 130.1 pg/mL, p = 0.002, and 89.1 ± 117.4 pg/mL, p = 0.001, respectively).,On immunohistochemistry, the percentages of inflammatory cells expressing CXCL10 ranged from 1 to 85 %, CXCL13 from 1 to 72 %, and CXCR3 from 2 to 65 %.,The percentage of CXCL10-positive inflammatory cells was higher in skin biopsy samples exhibiting mucin deposition than in those that did not (p = 0.01).,CXCL13 levels were correlated with those of CD4 and CD68.,Serum CXCL10 and CXCL13 levels may serve as clinical markers for assessment of disease activity in AOSD.,CXCL10/CXCR3 and CXCL13 may contribute to the inflammatory response, especially skin manifestations thereof, in AOSD.,The online version of this article (doi:10.1186/s13075-015-0773-4) contains supplementary material, which is available to authorized users.

Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults.,Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented.,Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions.,Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach.,However, this generally accepted concept has been challenged recently.,To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia.,Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage.,These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions.,Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.,The online version of this article (10.1007/s00401-020-02189-9) contains supplementary material, which is available to authorized users.

Numerous nanomaterials have been reported in the treatment of multiple sclerosis or experimental autoimmune encephalomyelitis (EAE).,But most of these nanoscale therapeutics deliver myelin antigens together with toxins or cytokines and underlay the cellular uptake and induction of tolerogenic antigen-presenting cells by which they indirectly induce T cell tolerance.,This study focuses on the on-target and direct modulation of myelin-autoreactive T cells and combined use of multiple regulatory molecules by generating a tolerogenic nanoparticle.,Poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) were fabricated by co-coupling MOG40-54/H-2Db-Ig dimer, MOG35-55/I-Ab multimer, anti-Fas, PD-L1-Fc and CD47-Fc and encapsulating transforming growth factor-β1.,The resulting 217 nm tolerogenic nanoparticles (tNPs) were administered intravenously into MOG35-55 peptide-induced EAE mice, which was followed by the investigation of therapeutic outcomes and the in vivo mechanism.,Four infusions of the tNPs durably ameliorated EAE with a marked reduction of clinical score, neuroinflammation and demyelination.,They were distributed in secondary lymphoid tissues, various organs and brain after intravenous injection, with retention over 36 h, and made contacts with CD4+ and CD8+ T cells.,Two injections of the tNPs markedly decreased the MOG35-55-reactive Th1 and Th17 cells and MOG40-55-reactive Tc1 and Tc17 cells, increased regulatory T cells, inhibited T cell proliferation and elevated T cell apoptosis in spleen.,Transforming growth factor-β1 and interleukin-10 were upregulated in the homogenates of central nervous system and supernatant of spleen cells.,Our data suggest a novel therapeutic nanoparticle to directly modulate autoreactive T cells by surface presentation of multiple ligands and paracrine release of cytokine in the antigen-specific combination immunotherapy for T cell-mediated autoimmune diseases.

Severe hypoglycaemia (SH), when blood glucose falls too low to support brain function, is the most feared acute complication of insulin therapy for type 1 diabetes mellitus (T1DM). 10% of people with T1DM contribute nearly 70% of all episodes, with impaired awareness of hypoglycaemia (IAH) a major risk factor.,People with IAH may be refractory to conventional approaches to reduce SH, with evidence for cognitive barriers to hypoglycaemia avoidance.,This paper describes the protocol for the Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc) study, a trial to assess the impact on hypoglycaemia experience of a novel intervention that addresses cognitive barriers to hypoglycaemia avoidance, compared with an existing control intervention, recommended by the National Institute of Health and Care Excellence.,A randomised parallel two-arm trial of two group therapies: HARPdoc versus Blood Glucose Awareness Training, among 96 adults with T1DM and problematic hypoglycaemia, despite attendance at education with or without technology use, in four centres providing specialist T1DM services.,The primary outcome will be the SH rate at 12 and/or 24 months after randomisation to either course.,Secondary outcomes include rates of SH requiring parenteral therapy, involving unconsciousness or needing emergency services; hypoglycaemia awareness status, overall diabetes control and quality of life measures.,An implementation study to evaluate how the interventions are delivered and how implementation impacts on clinical effectiveness is planned as a parallel study, with its own protocol.,The protocol was approved by the London Dulwich Research Ethics Committee, the Health Research Authority, National Health Service R&D and the Institutional Review Board of the Joslin Diabetes Center in the USA.,Study findings will be disseminated to study participants and through peer-reviewed publications and conference presentations, including user groups.,NCY02940873; Pre-results.

To perform the first comprehensive psychometric evaluation of the Hypoglycemia Fear Survey-II (HFS-II), a measure of the behavioral and affective dimensions of fear of hypoglycemia, using modern test-theory methods, including item-response theory (IRT).,Surveys completed in four previous studies by 777 adults with type 1 diabetes were aggregated for analysis, with 289 subjects completing both subscales of the HFS-II and 488 subjects completing only the Worry subscale.,The aggregated sample (53.3% female, 44.4% using insulin pumps) had a mean age of 41.9 years, diabetes duration of 23.8 years, HbA1c value of 7.7%, and 1.4 severe hypoglycemic episodes in the past year.,Data analysis included exploratory factor analysis using polychoric correlations and IRT.,Factors were analyzed for fit, trait-level locations, point-measure correlations, and separation values.,Internal and test-retest reliability was good, as well as convergent validity, as demonstrated by significant correlations with other measures of psychological distress.,Scores were significantly higher in subjects who had experienced severe hypoglycemia in the past year.,Factor analyses validated the two subscales of the HFS-II.,Item analyses showed that 12 of 15 items on the Behavior subscale, and all of the items on the Worry subscale had good-fit statistics.,The HFS-II is a reliable and valid measure of the fear of hypoglycemia in adults with type 1 diabetes, and factor analyses and IRT support the two separate subscales of the survey.

To understand organ function, it is important to have an inventory of its cell types and of their corresponding marker genes.,This is a particularly challenging task for human tissues like the pancreas, because reliable markers are limited.,Hence, transcriptome-wide studies are typically done on pooled islets of Langerhans, obscuring contributions from rare cell types and of potential subpopulations.,To overcome this challenge, we developed an automated platform that uses FACS, robotics, and the CEL-Seq2 protocol to obtain the transcriptomes of thousands of single pancreatic cells from deceased organ donors, allowing in silico purification of all main pancreatic cell types.,We identify cell type-specific transcription factors and a subpopulation of REG3A-positive acinar cells.,We also show that CD24 and TM4SF4 expression can be used to sort live alpha and beta cells with high purity.,This resource will be useful for developing a deeper understanding of pancreatic biology and pathophysiology of diabetes mellitus.,•Single-cell sequencing of human pancreas allows in silico purification of cell types•We provide cell-type-specific genes, transcription factors, and cell-surface markers•StemID finds outlier populations of acinar and beta cells•CD24 and TM4SF4 function as two markers to enrich for alpha and beta cells,Single-cell sequencing of human pancreas allows in silico purification of cell types,We provide cell-type-specific genes, transcription factors, and cell-surface markers,StemID finds outlier populations of acinar and beta cells,CD24 and TM4SF4 function as two markers to enrich for alpha and beta cells,Single-cell mRNA sequencing was used to describe the transcriptome of adult human pancreatic cell types.,This resource was mined to find subpopulations of existing cell types and markers that can be used to purify live alpha and beta cells.

HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date.,Cases were from Children’s Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]).,Controls were from the T1DGC and from newborn bloodspot cards.,The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans.,Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes.,Notably, the African-specific “DR3” haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01-DQB1*02:01.,Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g.,The heterozygous DR4/DR9 genotype, containing the African-derived “DR9” haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations.,Disease risk assessment for African Americans differs greatly from risk assessment in European populations.,This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened.

Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH).,The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain.,Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH.,In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).,We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS.,The clinical features and laboratory data were compared between the AOSD and adult HLH groups.,In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups.,A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18.,We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.,Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data.,Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH.,In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83-1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.,IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity.,The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases.,IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood.,Here, IL-1β and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort.,Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively.,184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC.,SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0-2].,Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs.,Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels.,The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage.,High baseline serum IL-18 levels were associated with organ damage at the subsequent visit.,Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses.,Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.

The EULAR/ACR 2019 classification criteria for SLE constitute a current and optimized clinical approach to SLE classification.,Classification is still not based on molecular approaches and the results from large studies using polyomics may be interpreted as demonstrating the relevance of the genetic and environmental background rather than splitting SLE into several entities.,In fact, an association study within the EULAR/ACR classification criteria project found associations between manifestations only within organ domains.,This independency of various organ manifestations argues for SLE as one disease entity.,The current review article will therefore concentrate on the clinical and immunological manifestations of SLE and on what we have already learned in this century.,Moreover, the structure and essential rules of the EULAR/ACR 2019 classification criteria will be discussed.,While classification and diagnosis are distinct concepts, which have to remain clearly separated, information derived from the process towards the classification criteria is also useful for diagnostic purposes.,Therefore this article also tries to delineate what classification can teach us for diagnosis, covering a wide variety of SLE manifestations.

Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition.,Approximately 15-20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE).,Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE.,This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study.,Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years) and adolescent (14-18 years).,The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up.,A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence.,At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4-20] vs. 7(3-13] vs. 7(3-14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001).,Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001).,Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups.,No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up.,Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients.,Patients diagnosed during adolescence exhibit greater disease activity and “classic” autoantibody, immune cell and complement patterns when compared with younger patients.,This supports the hypothesis that pathomechanisms may vary between patient age groups.

To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers.,Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6<DAS<2.4 for at least 6 months) and patients with PsA in remission (n=18) (DAS<1.6 and Psoriasis Area Severity Index (PASI)=0 for at least 6 months) achieved by MTX+anti-TNF (adalimumab 40 mg or etanercept 50 mg) with power Doppler (PDUS)-negative synovial hypertrophy underwent synovial tissue biopsy.,Patients with RA with high/moderate disease naïve to treatment (n=50) were included as a comparison group.,Immunostaining for cluster designation (CD)68, CD21, CD20, CD3, CD31 and collagen was performed.,PDUS-negative patients with RA in remission showed lower histological scores for synovial CD68+, CD20+, CD3+ cells and CD31+ vessels and collagen deposition (p<0.05 for both lining and sublining) compared with PDUS-positive patients with RA with high/moderate disease.,In addition, there was no significant difference in terms of lining and sublining CD68+, CD20+, CD3+, CD31+ cells and collagen comparing PDUS-negative patients with RA in remission and in LDA, respectively.,On the contrary, PDUS-negative patients with PsA in remission showed higher histological scores for sublining CD68+ (p=0.02) and CD3+ cells (p=0.04) as well as CD31+ vessels (p<0.001) than PDUS-negative patients with RA in remission.,PDUS-negative patients with RA in remission have comparable synovial histological features than PDUS-negative patients with RA in LDA.,However, patients with PsA in remission are characterised by a higher degree of residual synovial inflammation than patients with RA in remission, despite PDUS negativity under TNF inhibition.

Early diagnosis of and subsequent monitoring of therapy for rheumatoid arthritis (RA) could benefit from detection of (sub)clinical synovitis.,Imaging of (sub)clinical arthritis by targeting the translocator protein (TSPO) on activated macrophages is feasible using (R)-[11C] PK11195-based positron emission tomography (PET), but clinical applications are limited by background uptake in peri-articular bone/bone marrow.,The purpose of the present study was to evaluate two other TSPO ligands with potentially lower background uptake in neurological studies, [11C]DPA-713 and [18F]DPA-714, in a rat model of arthritis.,TSPO binding of DPA-713, DPA-714 and PK11195 were assessed by in vitro competition studies with [3H]DPA-713 using human macrophage THP-1 cells and CD14+ monocytes from healthy volunteers.,In vivo studies were performed in rats with methylated bovine serum albumin-induced knee arthritis.,Immunohistochemistry with anti-TSPO antibody was performed on paraffin-embedded sections.,Rats were imaged with [11C]DPA-713 or [18F]DPA-714 PET, followed by ex vivo tissue distribution studies.,Results were compared with those obtained with the tracer (R)-[11C]PK11195, the established ligand for TSPO.,In THP-1 cells, relative TSPO binding of DPA-713 and DPA-714 were 7-fold and 25-fold higher, respectively, than in PK11195.,Comparable results were observed in CD14+ monocytes from healthy volunteers.,In the arthritis rat model, immunohistochemistry confirmed the presence of TSPO-positive inflammatory cells in the arthritic knee.,PET images showed that uptake of [11C]DPA-713 and [18F]DPA-714 in arthritic knees was significantly increased compared with contralateral knees and knees of normal rats.,Uptake in arthritic knees could be largely blocked by an excess of PK11195.,[11C]DPA-713 and [18F]DPA-714 provided improved contrast compared with (R)-[11C]PK11195, as was shown by significantly higher arthritic knee-to-bone ratios of [11C]DPA-713 (1.60 ± 0.31) and [18F]DPA-714 (1.55 ± 0.10) compared with (R)-[11C]PK11195 (1.14 ± 0.19).,[11C]DPA-713 and [18F]DPA-714 clearly visualized arthritis and exhibited lower (peri-articular) bone/bone marrow uptake than (R)-[11C]PK11195.,These features merit further investigation of these tracers for early diagnosis and therapy monitoring of RA in a clinical setting.

Three different subsets of circulating human monocytes, CD14brightCD16- (classical), CD14brightCD16+ (intermediate), and CD14dimCD16+ (non-classical) have been recently identified.,It has been reported that CD14brightCD16+ monocytes are increased in rheumatoid arthritis (RA).,However, the role of each monocyte subset in the pathogenesis of RA is still unclear.,The purpose of this study was to investigate the association of CD14brightCD16+ monocytes with RA.,The study enrolled 35 patients with RA and 14 healthy volunteers.,The three subsets of peripheral blood monocytes were analyzed by flow cytometry.,Serum cytokines were measured at baseline in patients with RA and in healthy volunteers.,CD14brightCD16- monocytes were isolated and cultured in vitro with different cytokines for 14 hours, and CD16 induction was assessed.,The proportion of CD14brightCD16+ monocytes, and serum interleukin (IL)-6, IL-8, and IL-10 were increased in patients with RA compared to healthy controls.,The proportion of CD14brightCD16+ monocytes correlated with the disease activity of RA positively, whereas the proportion of CD14brightCD16- monocytes correlated negatively.,When isolated CD14brightCD16- monocytes were stimulated with IL-6, IL-8, and IL-10, the only cytokine that significantly induced CD16 expression on the cells was IL-10.,The proportion of CD16brightCD14+ monocytes was positively correlated with RA disease activity.,The expression of CD16 in monocytes was induced by IL-10 but not IL-6, and IL-8 was enhanced in the sera of patients with RA.,Our results suggest that CD16brightCD14+ monocytes are involved in the pathogenesis of RA and that IL-10 is a key cytokine that regulates CD16 expression in monocytes.,The online version of this article (doi:10.1186/s13075-016-1216-6) contains supplementary material, which is available to authorized users.

Innate immune responses, including monocyte functions, seem to play an important role in the pathogenesis of axial spondyloarthritis (axSpA).,Therefore, we characterized the phenotype and functional state of monocytes of patients with axSpA.,Fifty-seven patients with axSpA, 11 patients with rheumatoid arthritis (RA), and 29 healthy controls were included in the study.,We determined the percentage of classic, intermediate, and non-classic monocytes according to CD14 and CD16 expression and the expression of Toll-like receptor (TLR) 1, 2, and 4 in whole blood by flow cytometry.,The percentage of monocytes producing interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNFα), IL-12/23p40, and IL-1 receptor antagonist (IL-1ra) was detected by flow cytometry after stimulation of whole blood without and with different TLR and nucleotide-binding oligomerization domain ligands-i.e., lipopolysaccharide (LPS), fibroblast-stimulating lipopeptid-1, PAM3CSK4, and muramyl dipeptide (MDP)-for 5 h.,IL-10 production was measured after 18 h of stimulation in supernatants by enzyme-linked immunosorbent assay.,In patients with axSpA but not patients with RA, we found higher frequencies of classic monocytes than in controls (median of 90.4 % versus 80.4 %, P < 0.05), higher frequencies of monocytes spontaneously producing IL-1beta and IL-1ra (P < 0.05), and a higher percentage of monocytes producing IL-1beta after MDP stimulation (P < 0.05).,Elevated cytokine production was confined to axSpA patients under conventional therapy (non-steroidal anti-inflammatory drugs) and not found in patients under TNFα inhibitor treatment.,The LPS-induced production of IL-6 and IL-10 was lower in axSpA patients compared with controls (P < 0.05).,Monocytic TLR expression was unaffected in patients with axSpA.,Enhanced spontaneous and MDP-induced cytokine secretion by monocytes suggests in vivo pre-activation of monocytes in axSpA patients under conventional therapy which is reverted under TNF inhibitor treatment.

To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.,Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg).,Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed.,Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.,The Kaplan-Meier estimates of the primary outcome measure ‘no evidence of disease activity’ was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001.,The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03.,At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation.,The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.,In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining ‘no evidence of disease activity’.,Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.

Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect.,In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients.,Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.,Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×106 bone-marrow-derived-MSCs/Kg or placebo.,After 6 months, the treatment was reversed and patients were followed-up for another 6 months.,Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures.,Immunological tests were explored to assess the immunomodulatory effects.,At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4).,One patient on placebo withdrew after having 3 relapses in the first 5 months.,We did not identify any serious adverse events.,At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (−2.8±5.9 vs 3±5.4, p = 0.075).,No significant treatment differences were detected in the secondary endpoints.,We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients.,Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties.,ClinicalTrials.gov NCT01228266

to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.,We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02.,In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score.,Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients.,The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.,HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4.,None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92).,The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB− (7.412) patients.,After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10−7) outside the HLA region (65 Mb).,genetic factors predispose to the development of OCB.

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS).,We applied data from Norwegian, Swedish and Danish (i.e.,Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status.,GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients.,HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls.,Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status.,In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10−15) and rs3817963 (p = 5.7×10−10) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively.,We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10−7).,In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS.,Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups.,The groups were different with regard to age at onset (AAO), MS outcome measures and gender.,This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups.,This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms.,Diagnostic criteria include the presence of chronic mucositis and polymorphic cutaneous lesions with occult or confirmed neoplasia; histopathological analysis exhibiting intraepidermal acantholysis, necrotic keratinocytes, and vacuolar interface dermatitis; direct immunofluorescence with intercellular deposits (IgG and C3) and at the basement membrane zone (IgG); indirect immunofluorescence with intercellular deposition of IgG (substrates: monkey esophagus and simple, columnar, and transitional epithelium); and, autoreactivity to desmogleins 1 and 3, desmocollins 1, 2, and 3, desmoplakins I and II, envoplakin, periplakin, epiplakin, plectin, BP230, and α-2-macroglobulin-like protein 1.,Neoplasias frequently related to paraneoplastic pemphigus include chronic lymphocytic leukemia, non-Hodgkin lymphoma, carcinomas, Castleman disease, thymoma, and others.,Currently, there is no standardized treatment for paraneoplastic pemphigus.,Systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin have been used, with variable outcomes.,Reported survival rates in 1, 2, and 5 years are 49%, 41%, and 38%, respectively.

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA).,A 43-year-old man who presented with multiple swollen lymph nodes was diagnosed with iMCD.,He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study.,The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies.,Tocilizumab was therefore switched to rituximab, and his anemia was improved.,Complication with AIHA should be carefully considered when iMCD patients present with severe anemia.

The EULAR/ACR 2019 classification criteria for SLE constitute a current and optimized clinical approach to SLE classification.,Classification is still not based on molecular approaches and the results from large studies using polyomics may be interpreted as demonstrating the relevance of the genetic and environmental background rather than splitting SLE into several entities.,In fact, an association study within the EULAR/ACR classification criteria project found associations between manifestations only within organ domains.,This independency of various organ manifestations argues for SLE as one disease entity.,The current review article will therefore concentrate on the clinical and immunological manifestations of SLE and on what we have already learned in this century.,Moreover, the structure and essential rules of the EULAR/ACR 2019 classification criteria will be discussed.,While classification and diagnosis are distinct concepts, which have to remain clearly separated, information derived from the process towards the classification criteria is also useful for diagnostic purposes.,Therefore this article also tries to delineate what classification can teach us for diagnosis, covering a wide variety of SLE manifestations.

For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS).,Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses.,Other viruses that have been studied in this context include, measles, mumps, and rubella.,Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection.,Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce.,Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells.,Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena.,Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted.,Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

miR-431-5p is dysregulated in various cancers and plays an important function in the development of cancer.,However, its role in fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) remains to be understood.,Quantitative real-time polymerase chain reaction was used to detect the relative expression of miR-431-5p in synovial tissues and FLSs.,Cell proliferation assays helped examine RA FLS proliferation.,Flow cytometry was performed to determine apoptosis and cell cycle progression in RA FLSs.,We used dual-luciferase assays to determine the correlation between miR-431-5p and its putative target, X-linked inhibitor of apoptosis (XIAP).,Quantitative real-time PCR and western blotting were used to measure XIAP levels in synovial tissues and transfected RA FLSs.,miR-431-5p was downregulated in synovial tissues and FLSs of patients with RA.,Upregulation of miR-431-5p prohibited cell proliferation and the G0/G1-to-S phase transition but promoted apoptosis in RA FLSs, while miR-431-5p inhibition showed the opposite results. miR-431-5p directly targeted XIAP in RA FLSs and reversely correlated with XIAP levels in synovial tissues.,Notably, XIAP silencing partially restored the effects of miR-431-5p inhibition in RA FLSs.,miR-431-5p regulates cell proliferation, apoptosis, and cell cycle of RA FLSs by targeting XIAP, suggesting its potential in the treatment of RA.

Objective: Circular RNAs (circRNAs) are a significant class of molecules involved in a wide range of diverse biological functions that are abnormally expressed in many types of diseases.,The present study aimed to determine the circRNAs specifically expressed in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients to identify their possible molecular mechanisms.,Methods: To identify the circRNAs specifically expressed in RA, we started by sequencing the of PBMCs circRNA and microRNAs (miRNAs) from a RA group (n = 3) and a control group (n = 3).,We constructed a network of differentially expressed circRNAs and miRNAs.,Then, we selected differentially expressed circRNAs in PBMCs from 10 RA patients relative to 10 age- and sex-matched controls using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR).,Spearman’s correlation test was used to evaluate the correlation of circRNAs with biochemical measurements.,Results: A total of 165 circRNAs and 63 miRNAs were differently expressed between RA patients and healthy people according to RNA-seq, including 109 circRNAs that were significantly up-regulated and 56 circRNAs that were down-regulated among the RA patients.,RT-qPCR validation demonstrated that the expression levels of hsa_circ_0001200, hsa_circ_0001566, hsa_circ_0003972, and hsa_circ_0008360 were consistent with the results from the sequencing analysis.,Then, we found that there were significant correlations between the circRNAs and disease severity.,Conclusion: Generally, these results suggest that expression of hsa_circ_0001200, hsa_circ_0001566, hsa_circ_0003972, and hsa_circ_0008360 in PBMCs from RA patients may serve as potential biomarkers for the diagnosis of RA, and these circRNAs may influence the occurrence and development of RA.

Comorbidity is an area of increasing interest in multiple sclerosis (MS).,The objective of this review is to estimate the incidence and prevalence of comorbidity in people with MS and assess the quality of included studies.,We searched the PubMed, SCOPUS, EMBASE and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles.,Two reviewers independently screened abstracts.,One reviewer abstracted data using a standardized form and the abstraction was verified by a second reviewer.,We assessed study quality using a standardized approach.,We quantitatively assessed population-based studies using the I2 statistic, and conducted random-effects meta-analyses.,We included 249 articles.,Study designs were variable with respect to source populations, case definitions, methods of ascertainment and approaches to reporting findings.,Prevalence was reported more frequently than incidence; estimates for prevalence and incidence varied substantially for all conditions.,Heterogeneity was high.,This review highlights substantial gaps in the epidemiological knowledge of comorbidity in MS worldwide.,Little is known about comorbidity in Central or South America, Asia or Africa.,Findings in North America and Europe are inconsistent.,Future studies should report age-, sex- and ethnicity-specific estimates of incidence and prevalence, and standardize findings to a common population.

Multiple sclerosis (MS) and epilepsy are both fairly common and it follows that they may sometimes occur together in the same people by chance.,We sought to determine whether hospitalisation for MS and hospitalisation for epilepsy occur together more often than expected by chance alone.,We analysed two datasets of linked statistical hospital admission records covering the Oxford Record Linkage Study area (ORLS, 1963-1998) and all England (1999-2011).,In each, we calculated the rate of occurrence of hospital admission for epilepsy in people after admission for MS, compared with equivalent rates in a control cohort, and expressed the results as a relative risk (RR).,The RR for hospital admission for epilepsy following an admission for MS was significantly high at 4.1 (95% confidence interval 3.1-5.3) in the ORLS and 3.3 (95% CI 3.1-3.4) in the all-England cohort.,The RR for a first recorded admission for epilepsy 10 years and more after first recorded admission for MS was 4.7 (2.8-7.3) in ORLS and 3.9 (3.1-4.9) in the national cohort.,The RR for the converse-MS following hospitalisation for epilepsy-was 2.5 (95% CI 1.7-3.5) in the ORLS and 1.9 (95% CI 1.8-2.1) in the English dataset.,MS and epilepsy occur together more commonly than by chance.,One possible explanation is that an MS lesion acts as a focus of an epileptic seizure; but other possibilities are discussed.,Clinicians should be aware of the risk of epilepsy in people with MS.,The findings may also suggest clues for researchers in developing hypotheses about underlying mechanisms for the two conditions.

Recent metabolomics studies of Rheumatoid Arthritis (RA) reported few metabolites that were associated with the disease, either due to small cohort sizes or limited coverage of metabolic pathways.,Our objective is to identify metabolites associated with RA and its cofounders using a new untargeted metabolomics platform.,Moreover, to investigate the pathomechanism of RA by identifying correlations between RA-associated metabolites.,132 RA patients and 104 controls were analyzed for 927 metabolites.,Metabolites were tested for association with RA using linear regression.,OPLS-DA was used to discriminate RA patients from controls.,Gaussian Graphical Models (GGMs) were used to identify correlated metabolites. 32 metabolites are identified as significantly (Bonferroni) associated with RA, including the previously reported metabolites as DHEAS, cortisol and androstenedione and extending that to a larger set of metabolites in the steroid pathway.,RA classification using metabolic profiles shows a sensitivity of 91% and specificity of 88%.,Steroid levels show variation among the RA patients according to the corticosteroid treatment; lowest in those taking the treatment at the time of the study, higher in those who never took the treatment, and highest in those who took it in the past.,Finally, the GGM reflects metabolite relations from the steroidogenesis pathway.

Anti-Tumor Necrosis Factor (TNF) therapies are able to control rheumatoid arthritis (RA) disease activity and limit structural damage.,Yet no predictive factor of response to anti-TNF has been identified.,Metabolomic profile is known to vary in response to different inflammatory rheumatisms so determining it could substantially improve diagnosis and, consequently, prognosis.,The aim of this study was to use mass spectrometry to determine whether there is variation in the metabolome in patients treated with anti-TNF and whether any particular metabolomic profile can serve as a predictor of therapeutic response.,Blood samples were analyzed in 140 patients with active RA before initiation of anti-TNF treatment and after 6 months of Anti-TNF treatment (100 good responders and 40 non-responders).,Plasma was deproteinized, extracted and analyzed by reverse-phase chromatography-QToF mass spectrometry.,Extracted and normalized ions were tested by univariate and ANOVA analysis followed by partial least-squares regression-discriminant analysis (PLS-DA).,Orthogonal Signal Correction (OSC) was also used to filter data from unwanted non-related effects.,Disease activity scores (DAS 28) obtained at 6 months were correlated with metabolome variation findings to identify a metabolite that is predictive of therapeutic response to anti-TNF.,After 6 months of anti-TNF therapy, 100 patients rated as good responders and 40 patients as non-responders according to EULAR criteria.,Metabolomic investigations suggested two different metabolic fingerprints splitting the good-responders group and the non-responders group, without differences in anti-TNF therapies.,Univariate analysis revealed 24 significant ions in positive mode (p < 0.05) and 31 significant ions in negative mode (p < 0.05).,Once intersected with PLS results, only 35 ions remained.,Carbohydrate derivates emerged as strong candidate determinants of therapeutic response.,This is the first study describing metabolic profiling in response to anti-TNF treatments using plasma samples.,The study highlighted two different metabolic profiles splitting good responders from non-responders.

To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial.,In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128).,X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year.,Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders.,79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression.,The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26).,Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45).,These results remained after further adjustment for treatment strategy.,Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12-63% risk gradient from patients carrying none compared with all predictors.,Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off.,In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses.,The other parameters also remained significant using this lower cut-off.,In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA.,NCT00764725.

Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve.,This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab.,This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks.,Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared.,Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline.,In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14-0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12-0.56] at 24 weeks.,In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept.,Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab.,Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab.,Clinical efficacy of abatacept was affected by baseline disease activity.,There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research.

Renal biopsy is the cornerstone of diagnostic approaches in nephrology, as they provide invaluable diagnostic information.,In this study, we analyzed and reported renal biopsy results from northeast China from the past 10 years to describe the epidemiological trend.,We analyzed clinical features, indications, and histological diagnoses of renal biopsies collected between January 1, 2007, and December 31, 2016.,There were 2725 identified cases (with a mean age of 41.24 ± 15.18 years, 55% male) during the study period.,The main clinical indication was nephrotic syndrome (59.9%).,Membranous nephropathy (29.1%) was the most common pathological finding in the entire study population, followed by IgA nephropathy (23.4%), minimal change disease (12.7%), and mesangio-proliferative glomerulonephritis (7.4%).,We divided the study period into 2 subperiods: 2007 to 2011 (period 1) and 2012 to 2016 (period 2).,Membranous nephropathy and minimal change disease were more frequent in period 2 than in period 1.,Conversely, IgAN and non-IgA mesangio-proliferative glomerulonephritis were less frequent in period 2 than in period 1.,Cases of Henöch-Schönlein purpura nephritis and lupus nephritis were observed less over time, while cases of nephroangiosclerosis increased significantly over time.,Finally, there was a significant increase in the number of tubulointerstitial diseases observed over time, while there was a significant decrease in glomerulosclerosis and unclassified findings over time.,Membranous nephropathy was the most common pathological finding from renal biopsy and the prevalence has increased significantly in recent years in northeast China.

Background: Several registries and centers have reported the results of renal biopsies from different parts of the world.,As there are few data regarding the epidemiology of glomerulonephritis (GN) in South Korea, we conducted this study on renal biopsy findings during the last 20 years from a single center.,Methods: Data for 818 patients who underwent renal biopsy at our center between 1992 and 2011 were collected retrospectively.,All kidney specimens were examined with light microscopy (LM) and immunofluorescent microscopy (IF).,Results: There were 818 cases of native kidney biopsies.,In cases of primary GN, the most frequent type of renal pathology in adults (18-59 years) was mesangial proliferative GN (MsPGN, 34.5%) followed by IgA nephropathy (IgAN, 33.3%) and membranous GN (MGN, 8.8%).,Indications in adults (18-59 years) were asymptomatic urinary abnormalities (75.3%) followed by nephrotic syndrome (19.8%) and acute kidney injury (AKI, 3.4%).,Conclusions: Among 818 renal biopsy specimens, MsPGN and IgAN were the most frequent biopsy-proven renal diseases.,MGN was the third most common cause of primary GN and lupus nephritis (LN) was the most common secondary glomerular disease.,Our data contribute to the epidemiology of renal disease in South Korea.

Aim.,Rheumatoid arthritis is one of the most severe chronic diseases.,In many cases it leads to disability and results in a decreased quality of life and increased levels of anxiety and depression.,The problem that needs to be addressed is the following: which mental processes lead to increased levels of depression in patients with rheumatoid arthritis?,Methods. 210 patients with rheumatoid arthritis hospitalized in rheumatology wards took part in the research.,They filled in illness perception questionnaires (IPQ-R) and questionnaires for testing strategies of handling stress (Mini-COPE) and the level of depression (CES-D).,Results.,The observed correlation coefficients indicate that several elements of the perception of one's disease moderately contribute to a high level of depression.,Moreover, frequent use of dysfunctional coping strategies contributed to high levels of depression.,Dysfunctional coping was moderately linked to depression.,Conclusion.,The conducted analyses confirmed the links between the beliefs about the disease and levels of depression and showed that the use of dysfunctional coping strategies mediates the relationship between the following elements of the representation of the disease: illness coherence, emotional representation, psychological attribution, risk factors, and the level of depression.

Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.,To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.,Study design: international, cross-sectional.,Patients: consecutive RA patients.,Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).,Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%.,The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%.,High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities.,The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.,Among RA patients, there is a high prevalence of comorbidities and their risk factors.,In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities.,Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury.,Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA).,B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation.,We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells.,To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction.,Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage.,We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay.,Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice.,The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase.,Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a.,In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells.,Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner.,Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane.

The objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients.,Patients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study.,Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W).,Regardless of prior treatment, all patients in this study received subcutaneous 60-mg tabalumab Q4W for the first 3 months, then a one-time increase to 120-mg tabalumab Q4W (60-mg/120-mg group) and a one-time decrease to 60-mg tabalumab Q4W per patient was allowed (60-mg/120-mg/60-mg group).,There were 182 patients enrolled: 60 mg (n = 60), 60/120 mg (n = 121) and 60/120/60 mg (n = 1).,Pretabalumab baseline disease activity was generally higher in the 60-mg/120-mg group.,There was a higher frequency of serious adverse events and treatment-emergent adverse events, as well as infections and injection-site reactions, in the 60-mg/120-mg group.,One death unrelated to the study drug occurred (60-mg/120-mg group).,In both groups, total B-cell counts decreased by approximately 40% from the baseline level in the RCT originating study.,Both groups demonstrated efficacy through 52 weeks of treatment relative to baseline pretabalumab disease activity based on American College of Rheumatology criteria improvement ≥20%, ≥50% and ≥70%; European League against Rheumatism Responder Index in 28 joints; Disease Activity Score in 28 joints-C-reactive protein; and Health Assessment Questionnaire-Disability Index.,With long-term, open-label tabalumab treatment, no unexpected safety signals were observed, and B-cell reductions were consistent with previous findings.,Despite differences in RCT originating studies, both groups demonstrated an efficacy response through the 52-week extension.,ClinicalTrials.gov Identifier: NCT00837811 (registered 3 February 2009).,The online version of this article (doi:10.1186/s13075-014-0415-2) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA), a chronic autoimmune disease, affects around 1% population worldwide, with the life quality of patients severely reduced.,In this study, it is intended to explore the role of long non‐coding RNA X‐inactive specific transcript (lncRNA XIST) in RA and the underlying mechanisms associated with let‐7c‐5p and signal transducer and activator of transcription 3 (STAT3).,LncRNA XIST, let‐7c‐5p, and STAT3 expressions were determined in RA and normal cartilage tissues, and their relationship was analyzed in osteoblasts.,The regulatory effects of lncRNA XIST in RA were investigated when XIST expression was upregulated or downregulated in osteoblasts.,TNF‐α, IL‐2, IL‐6, alkaline phosphatase (ALP), osteocalcin, TGF‐β1, and IGF1 were measured in vivo in RA rats.,LncRNA XIST and STAT3 were expressed at high levels and let‐7c‐5p expressed at a low level in RA cartilage tissues.,LncRNA XIST silencing or let‐7c‐5p enhancement led to decreased levels of TNF‐α, IL‐2, and IL‐6, suggestive of suppressed inflammatory response, and increased levels of ALP, osteocalcin, TGF‐β1, and IGF‐1 as well as reduced damage in cartilage tissues.,LncRNA XIST downregulation could promote proliferation and differentiation of osteoblasts in RA, serving as a future therapeutic target for RA.,LncRNA XIST downregulation could promote proliferation and differentiation of osteoblasts in RA via the inhibition of STAT3 by increasing the expression of let‐7c‐5p.

Backgrounds: Rheumatoid arthritis (RA) is a frequent autoimmune disease.,Emerging evidence indicated that ZNFX1 antisense RNA1 (ZFAS1) participates in the physiological and pathological processes in RA.,However, knowledge of ZFAS1 in RA is limited, the potential work pathway of ZFAS1 needs to be further investigated.,Methods: Levels of ZFAS1, microRNA (miR)-2682-5p, and ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) were estimated using quantitative real-time polymerase chain reaction (qRT-PCR) assay.,3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to explore the ability of cell proliferation in fibroblast-like synoviocytes (FLS-RA).,Cell apoptosis was measured via flow cytometry.,Also, levels of ADAMTS9, apoptosis-related proteins, cleaved-caspase-3 (active large subunit), and autophagy-related proteins were identified adopting Western blot.,Enzyme-linked immunosorbent assay (ELISA) was performed to determine the productions of inflammatory cytokines.,Beside, the interrelation between miR-2682-5p and ZFAS1 or ADAMTS9 was verified utilizing dual-luciferase reporter assay.,Results: High levels of ZFAS1 and ADAMTS9, and a low level of miR-2682-5p were observed in RA synovial tissues and FLS-RA.,Knockdown of ZFAS1 led to the curbs of cell proliferation, inflammation, autophagy, and boost apoptosis in FLS-RA, while these effects were abolished via regaining miR-2682-5p inhibition.,Additionally, the influence of miR-2682-5p on cell phenotypes and inflammatory response were eliminated by ADAMTS9 up-regulation in FLS-RA.,Mechanically, ZFAS1 exerted its role through miR-2682-5p/ADAMTS9 axis in RA.,Conclusion: ZFAS1/miR-2682-5p/ADAMTS9 axis could modulate the cell behaviors, inflammatory response in FLS-RA, might provide a potential therapeutic target for RA treatment.

Oligodendrocytes wrap nerve fibers in the central nervous system with layers of specialized cell membrane to form myelin sheaths1.,Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered.,In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not appear to contribute to this process2-4.,Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5-9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis.,We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10.,The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients.,Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients.,The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis.,We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.

Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS).,It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.,The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.,The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase.,Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo.,The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON).,The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye.,Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.,Ninety-three patients received MD1003 (n = 65) or placebo (n = 28).,The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (− 0.061 logMAR, + 3.1 letters) than with placebo (− 0.036 logMAR, + 1.8 letters).,Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (− 0.058 logMAR) with MD1003 and worsened by − 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON.,MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients.,There was no superiority of MD1003 vs placebo in patients with AON.,The safety profile of MD1003 was similar to that of placebo.,MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss.,An interesting trend favoring MD1003 was observed in the subgroup of patients with PON.,Treatment was overall well tolerated.,EudraCT identifier 2013-002112-27.,ClinicalTrials.gov Identifier: NCT02220244,MedDay Pharmaceuticals.,The online version of this article (10.1007/s40263-018-0528-2) contains supplementary material, which is available to authorized users.

Although Janus kinase inhibitors (JAKi) could reduce patient-reported pain in rheumatoid arthritis (RA), their mechanism remains unclear.,Therefore, we examined lipid metabolites change in JAKi-treated patients and evaluate their association with pain reduction.,We used 1H-NMR-based lipid/metabolomics to determine serum levels of lipid metabolites at baseline and week 24 of treatment.,Serum levels of significant lipid metabolites were replicated by ELISA in 24 JAKi-treated and 12 tocilizumab-treated patients.,Pain was evaluated with patients’ assessment on a 0-100 mm VAS, and disease activity assessed using DAS28.,JAKi or tocilizumab therapy significantly reduced disease activity.,Acceptable pain (VAS pain ≤20) at week 24 was observed in 66.7% of JAKi-treated patients, and pain decrement was greater than tocilizumab-treated patients (ΔVAS pain 70.0 vs.,52.5, p = 0.0595).,Levels of omega-3 fatty acids and docosahexaenoic acid (DHA) were increased in JAKi-treated patients (median 0.55 mmol/L versus 0.71 mmol/L, p = 0.0005; 0.29 mmol/L versus 0.35 mmol/L, p = 0.0004; respectively), which were not observed in tocilizumab-treated patients.,ELISA results showed increased DHA levels in JAKi-treated patients with acceptable pain (44.30 µg/mL versus 45.61 µg/mL, p = 0.028).,A significant association of pain decrement with DHA change, not with DAS28 change, was seen in JAKi-treated patients.,The pain reduction effect of JAKi probably links to increased levels of omega-3 fatty acids and DHA.

Methotrexate (MTX) is a common first-line treatment for new-onset rheumatoid arthritis (RA).,However, MTX is ineffective for 30-40% of patients and there is no way to know which patients might benefit.,Here, we built statistical models based on serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on-drug) to investigate if MTX response (by 6 months) could be predicted.,Patients about to commence MTX treatment for the first time were selected from the Rheumatoid Arthritis Medication Study (RAMS).,Patients were categorised as good or non-responders following 6 months on-drug using EULAR response criteria.,Serum lipids were measured using ultra‐performance liquid chromatography-mass spectrometry and supervised machine learning methods (including regularized regression, support vector machine and random forest) were used to predict EULAR response.,Models including lipid levels were compared to models including clinical covariates alone.,The best performing classifier including lipid levels (assessed at 4 weeks) was constructed using regularized regression (ROC AUC 0.61 ± 0.02).,However, the clinical covariate based model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.68 ± 0.02).,Pre- or early-treatment serum lipid profiles are unlikely to inform classification of MTX response by 6 months with performance adequate for use in RA clinical management.

A considerable proportion of patients with rheumatoid arthritis (RA) do not have a satisfactory response to biological therapies.,We investigated the use of metabolomics approach to identify biomarkers able to anticipate the response to biologics in RA patients.,Due to gender differences in metabolomic profiling, the analysis was restricted to female patients starting etanercept as the first biological treatment and having a minimum of six months’ follow-up.,Each patient was evaluated by the same rheumatologist before and after six months of treatment.,At this time, the clinical response (good, moderate, none) was determined according to the EUropean League Against Rheumatism (EULAR) criteria, based on both erythrocyte sedimentation rate (EULAR-ESR) and C-reactive protein (EULAR-CRP).,Sera collected prior and after six months of etanercept were analyzed by 1H-nuclear magnetic resonance (NMR) spectroscopy in combination with multivariate data analysis.,Twenty-seven patients were enrolled: 18 had a good/moderate response and 9 were non responders according to both EULAR-ESR and EULAR-CRP after six months of etanercept.,Metabolomic analysis at baseline was able to discriminate good, moderate, and non-responders with a very good predictivity (Q2 = 0.68) and an excellent sensitivity, specificity, and accuracy (100%).,In good responders, we found an increase in isoleucine, leucine, valine, alanine, glutamine, tyrosine, and glucose levels and a decrease in 3-hydroxybutyrate levels after six months of treatment with etanercept with respect to baseline.,Our study confirms the potential of metabolomic analysis to predict the response to biological agents.,Changes in metabolic profiles during treatment may help elucidate their mechanism of action.

Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division.,We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA).,Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis.,Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood.,Here, we present experimental evidence connecting survivin and Flt3L signaling.,Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells.,Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow.,Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen.,Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L.,We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in diabetic patients1.,Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but are limited by the adverse effects of lifetime immunosuppression and the limited supply of donor tissue3.,The latter concern may be addressed by recently described glucose responsive mature β-cells derived from human embryonic stem cells; called SC-β, these cells may represent an unlimited human cell source for pancreas replacement therapy4.,Strategies to address the immunosuppression concern include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier5,6.,However, clinical implementation has been challenging due to host immune responses to implant materials7.,Here, we report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells.,SC-β cells were encapsulated with alginate-derivatives capable of mitigating foreign body responses in vivo, and implanted into the intraperitoneal (IP) space of streptozotocin-treated (STZ) C57BL/6J mice.,These implants induced glycemic correction until removal at 174 days without any immunosuppression.,Human C-peptide concentrations and in vivo glucose responsiveness demonstrate therapeutically relevant glycemic control.,Implants retrieved after 174 days contained viable insulin-producing cells.

Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases.,For type 1 diabetes, >40 susceptibility loci have been discovered.,However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated with disease, and they do not typically inform the broader context in which the disease genes operate.,Here, we integrated type 1 diabetes GWAS data with protein-protein interactions to construct biological networks of relevance for disease.,A total of 17 networks were identified.,To prioritize and substantiate these networks, we performed expressional profiling in human pancreatic islets exposed to proinflammatory cytokines.,Three networks were significantly enriched for cytokine-regulated genes and, thus, likely to play an important role for type 1 diabetes in pancreatic islets.,Eight of the regulated genes (CD83, IFNGR1, IL17RD, TRAF3IP2, IL27RA, PLCG2, MYO1B, and CXCR7) in these networks also harbored single nucleotide polymorphisms nominally associated with type 1 diabetes.,Finally, the expression and cytokine regulation of these new candidate genes were confirmed in insulin-secreting INS-1 β-cells.,Our results provide novel insight to the mechanisms behind type 1 diabetes pathogenesis and, thus, may provide the basis for the design of novel treatment strategies.

Human intestinal microbes can mediate development of arthritis - Studies indicate that certain bacterial nucleic acids may exist in synovial fluid (SF) and could be involved in arthritis, although the underlying mechanism remains unclear.,To characterize potential SF bacterial nucleic acids, we used 16S rRNA gene amplicon sequencing to assess bacterial nucleic acid communities in 15 synovial tissue (ST) and 110 SF samples from 125 patients with rheumatoid arthritis (RA) and 16 ST and 42 SF samples from 58 patients with osteoarthritis (OA).,Our results showed an abundant diversity of bacterial nucleic acids in these clinical samples, including presence of Porphyromonas and Bacteroides in all 183 samples.,Agrobacterium, Comamonas, Kocuria, Meiothermus, and Rhodoplanes were more abundant in synovial tissues of rheumatoid arthritis (STRA).,Atopobium, Phascolarctobacterium, Rhodotorula mucilaginosa, Bacteroides uniformis, Rothia, Megasphaera, Turicibacter, Leptotrichia, Haemophilus parainfluenzae, Bacteroides fragilis, Porphyromonas, and Streptococcus were more abundant in synovial tissues of osteoarthritis (STOA).,Veillonella dispar, Haemophilus parainfluenzae, Prevotella copri and Treponema amylovorum were more abundant in synovial fluid of rheumatoid arthritis (SFRA), while Bacteroides caccae was more abundant in the synovial fluid of osteoarthritis (SFOA).,Overall, this study confirms existence of bacterial nucleic acids in SF and ST samples of RA and OA lesions and reveals potential correlations with degree of disease.

Periodontitis (PD) is a known risk factor for rheumatoid arthritis (RA) and there is increasing evidence that the link between the two diseases is due to citrullination by the unique bacterial peptidylarginine deiminase (PAD) enzyme expressed by periodontal pathogen Pophyromonas gingivalis (PPAD).,However, the precise mechanism by which PPAD could generate potentially immunogenic peptides has remained controversial due to lack of information about the structural and catalytic mechanisms of the enzyme.,By solving the 3D structure of PPAD we aim to characterise activity and elucidate potential mechanisms involved in breach of tolerance to citrullinated proteins in RA.,PPAD and a catalytically inactive mutant PPADC351A were crystallised and their 3D structures solved.,Key residues identified from 3D structures were examined by mutations.,Fibrinogen and α-enolase were incubated with PPAD and P. gingivalis arginine gingipain (RgpB) and citrullinated peptides formed were sequenced and quantified by mass spectrometry.,Here, we solve the crystal structure of a truncated, highly active form of PPAD.,We confirm catalysis is mediated by the following residues: Asp130, His236, Asp238, Asn297 and Cys351 and show Arg152 and Arg154 may determine the substrate specificity of PPAD for C-terminal arginines.,We demonstrate the formation of 37 C-terminally citrullinated peptides from fibrinogen and 11 from α-enolase following incubation with tPPAD and RgpB.,PPAD displays an unequivocal specificity for C-terminal arginine residues and readily citrullinates peptides from key RA autoantigens.,The formation of these novel citrullinated peptides may be involved in breach of tolerance to citrullinated proteins in RA.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by synovial inflammation and joint disability.,Curcumin is known to be effective in ameliorating joint inflammation in RA.,To obtain new insights into the effect of curcumin on primary fibroblast-like synoviocytes (FLS, N = 3), which are key effector cells in RA, we employed gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS)-based metabolomics.,Metabolomic profiling of tumor necrosis factor (TNF)-α-stimulated and curcumin-treated FLS was performed using GC/TOF-MS in conjunction with univariate and multivariate statistical analyses.,A total of 119 metabolites were identified.,Metabolomic analysis revealed that metabolite profiles were clearly distinct between TNF-α-stimulated vs. the control group (not stimulated by TNF-α or curcumin).,Treatment of FLS with curcumin showed that the metabolic perturbation by TNF-α could be reversed to that of the control group to a considerable extent.,Curcumin-treated FLS had higher restoration of amino acid and fatty acid metabolism, as indicated by the prominent metabolic restoration of intermediates of amino acid and fatty acid metabolism, compared with that observed in TNF-α-stimulated FLS.,In particular, the abundance of glycine, citrulline, arachidonic acid, and saturated fatty acids in TNF-α-stimulated FLS was restored to the control level after treatment with curcumin, suggesting that the effect of curcumin on preventing joint inflammation may be elucidated with the levels of these metabolites.,Our results suggest that GC/TOF-MS-based metabolomic investigation using FLS has the potential for discovering the mechanism of action of curcumin and new targets for therapeutic drugs in RA.

Objective.,Inflammatory arthritis is associated with systemic manifestations including alterations in metabolism.,We used nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to assess metabolic fingerprints in serum from patients with established rheumatoid arthritis (RA) and those with early arthritis.,Methods.,Serum samples were collected from newly presenting patients with established RA who were naive for disease-modifying antirheumatic drugs, matched healthy controls, and 2 groups of patients with synovitis of ≤3 months' duration whose outcomes were determined at clinical followup.,Serum metabolomic profiles were assessed using 1-dimensional 1H-NMR spectroscopy.,Discriminating metabolites were identified, and the relationships between metabolomic profiles and clinical variables including outcomes were examined.,Results.,The serum metabolic fingerprint in established RA was clearly distinct from that of healthy controls.,In early arthritis, we were able to stratify the patients according to the level of current inflammation, with C-reactive protein correlating with metabolic differences in 2 separate groups (P < 0.001).,Lactate and lipids were important discriminators of inflammatory burden in both early arthritis patient groups.,The sensitivities and specificities of models to predict the development of either RA or persistent arthritis in patients with early arthritis were low.,Conclusion.,The metabolic fingerprint reflects inflammatory disease activity in patients with synovitis, demonstrating that underlying inflammatory processes drive significant changes in metabolism that can be measured in the peripheral blood.,The identification of metabolic alterations may provide insights into disease mechanisms operating in patients with inflammatory arthritis.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans.,It is not known if these differences represent variation in genes, environment, or ascertainment.,In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus).,These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease.,We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations.,Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10−32-3×10−10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60).,Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval.,We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10−4).,A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10−128).,This model paralleled the known East-West gradient in disease risk.,Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes.,Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations.,These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

Transglutaminase 2 is required for the development of IgA nephropathy.,IgA nephropathy (IgAN) is a common cause of renal failure worldwide.,Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium.,IgA receptor abnormalities are implicated, including circulating IgA-soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1).,Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1-sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium.,IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89-TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression.,In the absence of TGase2, IgA1-sCD89 deposits were dramatically impaired.,These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development.,They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1-sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.

Quinoline-3-carboxamides (Q compounds) are immunomodulatory compounds that have shown efficacy both in autoimmune disease and cancer.,We have in here investigated the impact of one such compound, paquinimod, on the development of diabetes in the NOD mouse model for type I diabetes (T1D).,In cohorts of NOD mice treated with paquinimod between weeks 10 to 20 of age and followed up until 40 weeks of age, we observed dose-dependent reduction in incidence of disease as well as delayed onset of disease.,Further, in contrast to untreated controls, the majority of NOD mice treated from 15 weeks of age did not develop diabetes at 30 weeks of age.,Importantly, these mice displayed significantly less insulitis, which correlated with selectively reduced number of splenic macrophages and splenic Ly6Chi inflammatory monocytes at end point as compared to untreated controls.,Collectively, these results demonstrate that paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse.,We propose that the effect of paquinimod on disease progression may be related to the reduced number of these myeloid cell populations.,Our finding also indicates that this compound could be a candidate for clinical development towards diabetes therapy in humans.

Descriptions of insulitis in human islets throughout the natural history of type 1 diabetes are limited.,We determined insulitis frequency (the percent of islets displaying insulitis to total islets), infiltrating leukocyte subtypes, and β-cell and α-cell mass in pancreata recovered from organ donors with type 1 diabetes (n = 80), as well as from donors without diabetes, both with islet autoantibodies (AAb+, n = 18) and without islet autoantibodies (AAb−, n = 61).,Insulitis was observed in four of four donors (100%) with type 1 diabetes duration of ≤1 year and two AAb+ donors (2 of 18 donors, 11%).,Insulitis frequency showed a significant but limited inverse correlation with diabetes duration (r = −0.58, P = 0.01) but not with age at disease onset.,Residual β-cells were observed in all type 1 diabetes donors with insulitis, while β-cell area and mass were significantly higher in type 1 diabetes donors with insulitis compared with those without insulitis.,Insulitis affected 33% of insulin+ islets compared with 2% of insulin− islets in donors with type 1 diabetes.,A significant correlation was observed between insulitis frequency and CD45+, CD3+, CD4+, CD8+, and CD20+ cell numbers within the insulitis (r = 0.53-0.73, P = 0.004-0.04), but not CD68+ or CD11c+ cells.,The presence of β-cells as well as insulitis several years after diagnosis in children and young adults suggests that the chronicity of islet autoimmunity extends well into the postdiagnosis period.,This information should aid considerations of therapeutic strategies seeking type 1 diabetes prevention and reversal.

Sphingosine-1-phosphate receptor (S1P) modulators and anti-CD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines.,Relatively few studies have assessed the impact of an array of disease modifying therapies (DMTs) for multiple sclerosis (MS) on T cell immune responses to SARS-CoV-2 vaccination.,In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum.,We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech, Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1µg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each).,Plates were read on an AID iSpot Spectrum to determine the number of spot forming cells (SFC)/106 PBMCs.,We tested for differences in immune responses across DMTs using linear models.,Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs.,In a subset (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies.,Anti-CD20 therapies were associated with an increase in IFN-γ SFC counts relative to those on no DMT or other DMTs (for anti-CD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for anti-CD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001).,We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination.,Follow up studies are needed to determine if this translates to protection against COVID-19 infection.,This study was funded partially by 1K01MH121582-01 from NIH/NIMH and TA-1805-31136 from the National MS Society (NMSS) to KCF and TA-1503-03465 and JF-2007-37655 from the NMSS to PB.,This study was also supported through the generosity of the collective community of donors to the Johns Hopkins University School of Medicine for COVID research.

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge.,Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant.,Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders.,It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease.,One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual’s life span.,Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%.,It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events.,In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.

Genetic background, epigenetic modifications, and environmental factors trigger autoimmune response in rheumatoid arthritis (RA).,Several pathogenic infections have been related to the onset of RA and may cause an inadequate immunological tolerance towards critical self-antigens leading to chronic joint inflammation and an imbalance between different T helper (Th) subsets.,Vasoactive intestinal peptide (VIP) is a mediator that modulates all the stages comprised between the arrival of pathogens and Th cell differentiation in RA through its known anti-inflammatory and immunomodulatory actions.,This “neuroimmunopeptide” modulates the pathogenic activity of diverse cell subpopulations involved in RA as lymphocytes, fibroblast-like synoviocytes (FLS), or macrophages.,In addition, VIP decreases the expression of pattern recognition receptor (PRR) such as toll-like receptors (TLRs) in FLS from RA patients.,These receptors act as sensors of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) connecting the innate and adaptive immune system.,Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells.,Finally, VIP regulates the plasticity between theses subsets.,In this review, we provide an overview of VIP effects on the aforementioned features of RA pathology.

Our aim is to study the behavior of memory Th cells (Th17, Th17/1, and Th1 profiles) from early rheumatoid arthritis (eRA) patients after their in vitro activation/expansion to provide information about its contribution to RA chronicity.,Moreover, we analyzed the potential involvement of vasoactive intestinal peptide (VIP) as an endogenous healing mediator.,CD4+CD45RO+ T cells from PBMCs of HD and eRA were activated/expanded in vitro in the presence/absence of VIP.,FACS, ELISA, RT-PCR, and immunocytochemistry analyses were performed.,An increase in CCR6+/RORC+ cells and in RORC-proliferating cells and a decrease in T-bet-proliferating cells and T-bet+/RORC+ cells were shown in eRA. mRNA expression of IL-17, IL-2, RORC, RORA, STAT3, and Tbx21 and protein secretion of IL-17, IFNγ, and GM-CSF were higher in eRA.,VIP decreased the mRNA expression of IL-22, IL-2, STAT3, Tbx21, IL-12Rβ2, IL-23R, and IL-21R in HD and it decreased IL-21, IL-2, and STAT3 in eRA.,VIP decreased IL-22 and GM-CSF secretion and increased IL-9 secretion in HD and it decreased IL-21 secretion in eRA.,VPAC2/VPAC1 ratio expression was increased in eRA.,All in all, memory Th cells from eRA patients show a greater proportion of Th17 cells with a pathogenic Th17 and Th17/1 profile compared to HD.,VIP is able to modulate the pathogenic profile, mostly in HD.,Our results are promising for therapy in the early stages of RA because they suggest that targeting molecules involved in the pathogenic Th17, Th17/1, and Th1 phenotypes and targeting VIP receptors could have a therapeutic effect modulating these subsets.,Th17 cells are more important than Th1 in the contribution to pathogenesis in eRA patients.Pathogenic Th17 and Th17/1 profile are abundant in activated/expanded memory Th cells from eRA patients.VIP decreases the pathogenic Th17, Th1, and Th17/1 profiles, mainly in healthy donors.The expression of VIP receptors is reduced in eRA patients respect to healthy donors, whereas the ratio of VPAC2/VPAC1 expression is higher.,Th17 cells are more important than Th1 in the contribution to pathogenesis in eRA patients.,Pathogenic Th17 and Th17/1 profile are abundant in activated/expanded memory Th cells from eRA patients.,VIP decreases the pathogenic Th17, Th1, and Th17/1 profiles, mainly in healthy donors.,The expression of VIP receptors is reduced in eRA patients respect to healthy donors, whereas the ratio of VPAC2/VPAC1 expression is higher.

Immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, can evoke chronic inflammatory or autoimmune disorders via their activation of innate immune receptors.,Since an association of RNA-sensing Toll-like receptor 7 (TLR7) signaling with autoimmunity is well-documented, identification of a DAMP(s) that triggers TLR7 is critical to understanding the disease pathogenesis.,By generating the synthetic compound KN69 that inhibits autoimmunity in mouse models, we identified U11 small nuclear RNA (U11snRNA) as a target of KN69 and strong activator of TLR7.,We found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and mouse models.,Finally, we generated TLR7 agonists and TLR7 antagonists.,Our study provides therapeutic insight into autoimmunity and other diseases.,The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections.,On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders.,One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure.,However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified.,Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models.,A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity.,We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo.,We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models.,Finally, by revealing the structural basis for U11snRNA’s ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases.,Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.

Toll-like receptors (TLRs), as innate immunity sensors, play critical roles in immune responses.,Six SNPs of TLR3, TLR7, and TLR8 were genotyped to determine their associations with systemic lupus erythematosus (SLE) and clinical manifestations of SLE.,TLR7 SNP rs3853839 was independently associated with SLE susceptibility in females (G vs.,C: p = 0.0051).,TLR7 rs3853839-G (G vs.,C: p = 0.0100) and TLR8 rs3764880-G (recessive model: p = 0.0173; additive model: p = 0.0161) were associated with pericardial effusion in females relative to healthy females.,Anti-SSA positive cases were more likely to have the dominant TLR7 rs179010-T allele than normal controls (p = 0.0435).,TLR3 rs3775296-T was associated with photosensitivity (p = 0.0020) and anemia (p = 0.0082).,The “G-G” haplotype of TLR7 rs3853839 and TLR8 rs3764880 increased risk of SLE in females (age adjusted p = 0.0032).,These findings suggest that TLR variations that modify gene expression affect risk for SLE susceptibility, clinical phenotype development, and production of autoantibodies.

T cell search behavior is dictated by their need to encounter their specific antigen to eliminate target cells.,However, mechanisms controlling effector T cell motility are highly tissue-dependent.,Specifically, how diabetogenic T cells encounter their target beta cells in dispersed islets throughout the pancreas (PA) during autoimmune diabetes remains unclear.,Using intra-vital 2-photon microscopy in a mouse model of diabetes, we found that CXCR3 chemokine downregulated CD8+ T cell motility specifically within islets, promoting effector cell confinement to their target sites.,By contrast, T cell velocity and directionality in the exocrine tissue were enhanced along blood vessels and extracellular matrix fibers.,This guided migration implicated integrin-dependent interactions, since integrin blockade impaired exocrine T cell motility.,In addition, integrin β1 blockade decreased CD4+ T cell effector phenotype specifically in the PA.,Thus, we unveil an important role for integrins in the PA during autoimmune diabetes that may have important implications for the design of new therapies.

Cytotoxic T lymphocytes (CTLs) constitute a major effector population in pancreatic islets from patients suffering from type 1 diabetes (T1D) and thus represent attractive targets for intervention.,Some studies have suggested that blocking the interaction between the chemokine CXCL10 and its receptor CXCR3 on activated CTLs potently inhibits their recruitment and prevents β-cell death.,Since recent studies on human pancreata from T1D patients have indicated that both ligand and receptor are abundantly present, we reevaluated whether their interaction constitutes a pivotal node within the chemokine network associated with T1D.,Our present data in a viral mouse model challenge the notion that specific blockade of the CXCL10/CXCR3 chemokine axis halts T1D onset and progression.

To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment.,We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach.,Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008).,The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review.,Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group.,Five trials dealt with early RA patients.,All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches.,Disability was reported in two studies with no difference between groups.,Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach.,Only few studies employed randomised controlled settings to test the value of treatment to a specific target.,However, they provided unanimous evidence for benefits of targeted approaches.,Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.

A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.,The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases.,Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.,We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients).,A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling.,Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients.,Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes.,For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1-50.0) for haplotype 1 and 14.2 mg/l (9.5-23.2) for haplotype 4.,Our findings raise questions about the interpretation of acute-phase serum CRP.,In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants.,CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms.,For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone.,The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.,Please see later in the article for the Editors' Summary,C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system).,Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process.,After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection.,Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable.,Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options.,Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.,Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis.,Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.,The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia.,A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level.,The relationship between genotype and serum CRP was explored by linear modeling.,The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants.,For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.,The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation.,The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making.,Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP-associated genetic variants.,CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms.,The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000341,Lab Test Online provides information on CRP,The Wellcome Trust provides a glossary of genetic terms,Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project

This integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA).,Treatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised.,Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks).,3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure.,Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib.,Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate.,Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg.,Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups.,In the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab.,Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab.,SELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.

Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate.,Upadacitinib is currently under regulatory review by other agencies around the world.,Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases.,In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.

We developed a model to predict remissions in patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) and to identify important clinical features associated with remission using explainable artificial intelligence (XAI).,We gathered the follow-up data of 1204 patients treated with bDMARDs (etanercept, adalimumab, golimumab, infliximab, abatacept, and tocilizumab) from the Korean College of Rheumatology Biologics and Targeted Therapy Registry.,Remission was predicted at 1-year follow-up using baseline clinical data obtained at the time of enrollment.,Machine learning methods (e.g., lasso, ridge, support vector machine, random forest, and XGBoost) were used for the predictions.,The Shapley additive explanation (SHAP) value was used for interpretability of the predictions.,The ranges for accuracy and area under the receiver operating characteristic of the newly developed machine learning model for predicting remission were 52.8-72.9% and 0.511-0.694, respectively.,The Shapley plot in XAI showed that the impacts of the variables on predicting remission differed for each bDMARD.,The most important features were age for adalimumab, rheumatoid factor for etanercept, erythrocyte sedimentation rate for infliximab and golimumab, disease duration for abatacept, and C-reactive protein for tocilizumab, with mean SHAP values of − 0.250, − 0.234, − 0.514, − 0.227, − 0.804, and 0.135, respectively.,Our proposed machine learning model successfully identified clinical features that were predictive of remission in each of the bDMARDs.,This approach may be useful for improving treatment outcomes by identifying clinical information related to remissions in patients with rheumatoid arthritis.,The online version contains supplementary material available at 10.1186/s13075-021-02567-y.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis.,An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer.,Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.

The 24‐week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate‐to‐severe rheumatoid arthritis (RA) have been reported previously.,We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks.,In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week).,At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group).,Efficacy, safety, and immunogenicity were evaluated up to 52 weeks.,The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group).,The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study.,ACR20 response rates ranged from 73.4% to 78.8% at week 52.,Radiographic progression was minimal and comparable across treatment groups.,The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition.,SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA.,Switching from ADA to SB5 had no treatment‐emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy.

There is a need for comparative studies to provide evidence-based treatment guidance for biologic agents in rheumatoid arthritis (RA).,Therefore, this study was undertaken as the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA.,Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2-year study.,The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year.,Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment.,At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval −5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab.,All efficacy measures showed similar results and kinetics of response between treatments.,The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept-treated patients and 88.6% for SC adalimumab-treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively.,In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively.,In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively.,Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P = 0.006).,The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment.,The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.

We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France.,The association of baseline characteristics and DMTs with Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included.,In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid‐19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047).,This pooled‐analysis confirms an increased risk of severe Covid‐19 in patients on anti‐CD20 therapies and supports the protective role of interferon.

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy.,These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid.,In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations.,The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid.,This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles.,Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance.,In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow-Robin spaces and the periventricular ependymal barrier.,An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood-cerebrospinal fluid barrier and inflammation in the choroid plexus.,Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.

The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA).,This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS).,We conducted MWAS of the RA gut microbiome in the Japanese population (n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample).,Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).,Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome.,The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy.,Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls.,A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison.,A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results.,No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.,Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.,In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained.,Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.,Compared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI).,Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties.,Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested.,Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4.,These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans.,Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR.,Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.,These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.

Human genetic diversity is the result of population genetic forces.,This genetic variation influences disease risk and contributes to health disparities.,Autoimmune diseases (ADs) are a family of complex heterogeneous disorders with similar underlying mechanisms characterized by immune responses against self.,Collectively, ADs are common, exhibit gender and ethnic disparities, and increasing incidence.,As natural selection is an important influence on human genetic variation, and immune function genes are enriched for signals of positive selection, it is thought that the prevalence of AD risk alleles seen in different population is partially the result of differing selective pressures (for example, due to pathogens).,With the advent of high-throughput technologies, new analytical methodologies and large-scale projects, evidence for the role of natural selection in contributing to the heritable component of ADs keeps growing.,This review summarizes the genetic regions associated with susceptibility to different ADs and concomitant evidence for selection, including known agents of selection exerting selective pressure in these regions.,Examples of specific adaptive variants with phenotypic effects are included as an evidence of natural selection increasing AD susceptibility.,Many of the complexities of gene effects in different ADs can be explained by population genetics phenomena.,Integrating AD susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help to identify functional variants and elucidate biological mechanisms.,As such, the study of population genetics in human population holds untapped potential for elucidating the genetic causes of human disease and more rapidly focusing to personalized medicine.

To assess the association between PTPN22 1858C>T gene polymorphism and susceptibility to, and clinical presentation of, systemic lupus erythematosus (SLE).,Our study included 135 SLE patients (120 women and 15 men; mean age 45.1 years; mean course of disease from 0.5 to 31 years) and 201 healthy subjects.,The PTPN22 1858C>T gene polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism.,A significantly higher incidence of genotype CT in patients with SLE (36.3 %) was found, compared with the control group (24.9 %).,The frequencies of C1858 and T1858 alleles were 78.1 and 21.9 % in SLE patients and 86.1 and 13.9 % in controls, respectively.,Significantly higher SLE susceptibility was observed in patients carrying at least one T allele (p = 0.009; OR 1.86; 95 % CI 0.14-3.05).,Significant association of the PTPN22 T1858 allele (CT + TT vs.CC) and secondary antiphospholipid syndrome was observed (p = 0.049).,In SLE patients carrying the T1858 allele, higher levels of antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant) were found (p = 0.030; OR 2.17; 95 % CI 1.07-4.44).

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS).,The use of magnetic resonance imaging (MRI) has revolutionized the study of MS.,However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease.,Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women.,BDNF levels were measured by ELISA.,T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist.,BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42).,We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS.,BDNF may be a promising biomarker of MS.

Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS).,Mitochondria are now established to play a part in the pathogenesis of MS.,Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system.,We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.,Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.,Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls.,The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions.,Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS.,The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level.,Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.,Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation.,We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation due to unknown causes.,Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and tofacitinib, a targeted sDMARD, can be used to treat RA.,In clinical trials, molecular-targeted therapies showed a significant reduction in RA symptoms and provided pain relief for patients with active RA.,Even if patients did not show clinical improvement with combination therapy with a bDMARD and methotrexate (MTX), some patients showed a significant inhibition in structural damage.,The clinical efficacies of tofacitinib were shown to be equivalent to adalimumab, a bDMARD, in patients with RA treated with MTX.,MTX is the first-line agent for the treatment of RA.,Higher doses of MTX might be needed to maintain the effects of bDMARDs.,Patients receiving some bDMARDs have been shown to have a higher risk for serious infections; thus, pre-screening for infections is important before beginning treatment with bDMARDs.,The rates of patients maintaining targeted levels of disease activity after stopping bDMARDs are relatively low.,It is uncertain whether remission or low disease activity can be maintained after stopping molecular-targeted therapies.,The development of bDMARDs and targeted-molecular sDMARDs has provided a wide range of treatment options for RA.,Patients with active RA should be treated with a treat-to-target strategy after assessment of risks and benefits.

To compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis.,In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B.,Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression.,281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97).,The AUC DAS and HAQ were respectively −2.39 (95% CI −4.77 to −0.00) and −1.67 (95% CI −3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM.,After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications.,The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time.,No differences were seen between the two GC bridging therapies.,Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year.,Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM.,Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM.,However, no difference in radiographic progression is seen.,Both GC bridging therapies are equally effective and, therefore, both can be used.,ISRCTN26791028.

We explored whether, how and why moving onto and using a hybrid day‐and‐night closed‐loop system affected people's food choices and dietary practices to better understand the impact of this technology on everyday life and inform recommendations for training and support given to future users.,Twenty‐four adults, adolescents and parents were interviewed before commencing use of the closed‐loop system and following its 3‐month use.,Data were analysed thematically and longitudinally.,While participants described preparing and/or eating similar meals to those consumed prior to using a closed‐loop, many described feeling more normal and less burdened by diabetes in dietary situations.,Individuals also noted how the use of this technology could lead to deskilling (less precise carbohydrate counting) and less healthy eating (increased snacking and portion sizes and consumption of fatty, energy‐dense foods) because of the perceived ability of the system to deal with errors in carbohydrate counting and address small rises in blood glucose without a corrective dose needing to be administered.,While there may be quality‐of‐life benefits to using a closed‐loop, individuals might benefit from additional nutritional and behavioural education to help promote healthy eating.,Refresher training in carbohydrate counting may also be necessary to help ensure that users are able to undertake diabetes management in situations where the technology might fail or that they take a break from using it.,This is the first study to explore how moving onto and using a closed‐loop system may affect people's food choices and eating practices.Using a closed‐loop can help people to feel more normal, and less anxious and burdened by diabetes in dietary situations.While we did not find the level of unrestrained eating behaviour hypothesized by others, we did observe some potential slippage into increased snacking and unhealthier eating as a result of using a closed‐loop.We support recommendations for people to be given tailored training and nutritional support to help promote healthy eating while using a closed‐loop.,This is the first study to explore how moving onto and using a closed‐loop system may affect people's food choices and eating practices.,Using a closed‐loop can help people to feel more normal, and less anxious and burdened by diabetes in dietary situations.,While we did not find the level of unrestrained eating behaviour hypothesized by others, we did observe some potential slippage into increased snacking and unhealthier eating as a result of using a closed‐loop.,We support recommendations for people to be given tailored training and nutritional support to help promote healthy eating while using a closed‐loop.

Background: Relatively little is known about parents' or children's attitudes toward recruitment for, and participation in, studies of new diabetes technologies immediately after diagnosis.,This study investigated factors affecting recruitment of participants for studies in newly diagnosed youth with type 1 diabetes.,Methods: Qualitative focus group study incorporating four recorded focus groups, conducted in four outpatient pediatric diabetes clinics in large regional hospitals in England.,Participants comprised four groups of parents (n = 22) and youth (n = 17) with type 1 diabetes, purposively sampled on the basis of past involvement (either participation or nonparticipation) in an ongoing two-arm randomized trial comparing multiple daily injection with conventional continuous subcutaneous insulin infusion regimens from the onset of type 1 diabetes.,Results: Stress associated with diagnosis presents significant challenges in terms of study recruitment, with parents demonstrating varied levels of willingness to be approached soon after diagnosis.,Additional challenges arise regarding the following: randomization when study arms are perceived as sharply differentiated in terms of therapy effectiveness; burdens arising from study participation; and the need to surrender new technologies following the end of the study.,However, these challenges were mostly insufficient to rule out study participation.,Participants emphasized the benefits and reassurance arising from support provided by staff and fellow study participants.,Conclusions: Recruitment to studies of new diabetes technologies immediately after diagnosis in youth presents significant challenges, but these are not insurmountable.,The stress and uncertainty arising from potential participation may be alleviated by personalized discussion with staff and peer support from fellow study participants.

In multiple sclerosis (MS), human endogenous retrovirus W family (HERV-W) envelope protein, pHERV-W ENV, limits remyelination and induces microglia-mediated neurodegeneration.,To better understand its role, we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies.,Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1. pHERV-W ENV monomers and trimers remained associated with membranes, while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain.,Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties.,HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described high-molecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis.,Adapted methods are now needed to identify encoding HERV provirus(es) in affected cells DNA.,The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis.,The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.,The online version contains supplementary material available at 10.1007/s12250-021-00372-0.

Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue.,Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation.,The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders.,A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses.,HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease.,The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions.,Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells.,Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients.,Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases.,Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies.,►HERVs express proteins in the brain.,►HERVs represent 8% of the human genome.,►The HERV-W envelope protein protein, Syncytin-1, is found in MS lesions.,►Syncytin-1 induces endoplasmic reticulum (ER) stress in astrocytes.

This cross-sectional study examines outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with multiple sclerosis.,How do patients with multiple sclerosis (MS) who have COVID-19 fare and are there patient and disease characteristics associated with worse outcome?,In this registry-based cross-sectional study of 1626 North American patients with MS and COVID-19 infection, ambulatory disability, both nonambulatory and requiring assistance to walk, was independently associated with increased odds of poor clinical severity levels after adjusting for other risk factors.,Other factors including older age, male sex, Black race, cardiovascular comorbidities, and corticosteroid use in the past 2 months were associated with increased odds of increasing clinical severity compared with those not requiring hospitalization or worse.,Identification of risk factors can improve the treatment of patients with MS and COVID-19 by alerting clinicians of patients requiring more intense treatment or monitoring.,Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections.,To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS.,This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry.,Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death.,Data collection began April 1, 2020, and is ongoing.,Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19.,Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death.,Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]).,A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx.,The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity.,The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%).,Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]).,In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19.,Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids.,Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Approximately 200,000 multiple sclerosis (MS) patients worldwide receive B-cell-depleting immunotherapy with rituximab (anti-CD20), which eliminates the ability to generate an antibody response to new infections.,As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies might help viral clearance, these patients could be at risk of severe complications if infected.,Here, we report on an MS patient who had received rituximab for ~3 years.,The patient was examined 5 days before the onset of coronavirus disease 2019 (COVID-19) symptoms and was admitted to the hospital 2 days after.,She recovered 14 days after symptom onset despite having a 0% B lymphocyte count and not developing SARS-CoV-2 immunoglobulin G (IgG) antibodies.

Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined.,Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1−dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC).,To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody-negative (AA−) high HLA−risk siblings (HRS) (DR3 and/or DR4) and AA− low HLA−risk siblings (LRS) (non-DR3/non-DR4).,Signatures, scored with a novel ontology-based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus.,Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1α, IL-12p40, CCL2, CCL3, and CCL4 levels.,Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias.,Conversely, HRS possessing decreasing AA titers revealed emergence of an IL-10/transforming growth factor-β−mediated regulatory state that paralleled temporal increases in peripheral activated CD4+/CD45RA−/FoxP3high regulatory T-cell frequencies.,In AA− HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.

A subset of children develops persistent insulin autoantibodies (IAA; almost always as the only islet autoantibody) without evidence of progression to diabetes.,The aim of the current study was the development and characterization of the performance of a nonradioactive fluid phase IAA assay in relation to standard IAA radioassay.,We developed a nonradioactive IAA assay where bivalent IAA cross-link two insulin moieties in a fluid phase.,The serum samples positive for anti-islet autoantibodies from 150 newly diagnosed patients with diabetes (Barbara Davis Center plus Diabetes Autoantibody Standardization Program [DASP] workshop) and 70 prediabetic subjects who were followed to diabetes were studied.,In addition, sequential samples from 64 nondiabetic subjects who were persistently IAA+ were analyzed.,With 99th percentile of specificity, the new assay with the technology from Meso Scale Discovery Company (MSD-IAA) detects as positive 61% (61 of 100) of new-onset patients and 80% (56 of 70) of prediabetic patients compared with our current fluid phase micro-IAA radioassay (mIAA; 44 and 74%, respectively).,In addition, MSD-IAA demonstrated better sensitivity than our mIAA from blinded DASP workshop (68 vs. 56% with the same 99% specificity).,Of 64 IAA+ nondiabetic subjects, 25% (8 of 32) who had only IAA and thus the low risk for progression to diabetes were positive with MSD-IAA assay.,In contrast, 100% (32 of 32) high-risk children (IAA plus other islet autoantibodies) were positive with MSD-IAA.,The IAA detectable by radioassay, but not MSD-IAA, were usually of lower affinity compared with the IAA of the high-risk children.,These data suggest that a subset of IAA with current radioassay (not MSD-IAA) represents biologic false positives in terms of autoimmunity leading to diabetes.,We hypothesize that factors related to the mechanism of loss of tolerance leading to diabetes determine high affinity and MSD-IAA reactivity.

This 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte-macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF-IR).,Patients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF-IR (1-2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate.,The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures.,This study was not powered to formally compare the 2 treatments.,At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF-IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively.,Differences in the percentage of patients achieving a DAS28‐CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti‐TNF-IR group.,The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups.,Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients.,No deaths were reported, and no specific safety signals were identified.,The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA.,Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.

We compared the effectiveness of abatacept (ABA) versus a subsequent anti-tumour necrosis factor inhibitor (anti-TNF) in rheumatoid arthritis (RA) patients with prior anti-TNF use.,We identified RA patients from a large observational US cohort (2/1/2000-8/7/2011) who had discontinued at least one anti-TNF and initiated either ABA or a subsequent anti-TNF.,Using propensity score (PS) matching (n:1 match), effectiveness was measured at 6 and 12 months after initiation based on mean change in Clinical Disease Activity Index (CDAI), modified American College of Rheumatology (mACR) 20, 50 and 70 responses, modified Health Assessment Questionnaire (mHAQ) and CDAI remission in adjusted regression models.,The PS-matched groups included 431 ABA and 746 anti-TNF users at 6 months and 311 ABA and 493 anti-TNF users at 12 months.,In adjusted analyses comparing response following treatment with ABA and anti-TNF, the difference in weighted mean change in CDAI (range 6-8) at 6 months (0.46, 95% CI −0.82 to 1.73) and 12 months was similar (−1.64, 95% CI −3.47 to 0.19).,The mACR20 responses were similar at 6 (28-32%, p=0.73) and 12 months (35-37%, p=0.48) as were the mACR50 and mACR70 (12 months: 20-22%, p=0.25 and 10-12%, p=0.49, respectively).,Meaningful change in mHAQ was similar at 6 and 12 months (30-33%, p=0.41 and 29-30%, p=0.39, respectively) as was CDAI remission rates (9-10%, p=0.42 and 12-13%, p=0.91, respectively).,RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA.

Based on the role of oxidative stress in the pathogenesis of Graves’ hyperthyroidism (GH) and Graves’ Orbitopathy (GO), a therapy with the antioxidant agent selenium has been proposed and a number of studies have been performed, both in vitro and in vivo.,In GH, reactive oxygen species (ROS) contribute to the thyroid and peripheral tissues damage.,In GO, tissue hypoxia, as well as ROS, are involved in the typical changes that occur in fibroadipose orbital tissue and the perimysium of extraocular muscles.,Antioxidants have been proposed to improve the effects of antithyroid drugs in GH patients, as well as the remodeling of orbital tissues in patients with GO.,Here, we reviewed the literature on the possible beneficial effects and clinical use of selenium in the management of patients with GH and GO.,A randomized clinical trial on the use of selenium in patients with mild GO provided evidence for a beneficial effect; no data are available on more severe forms of GO.,Although the real effectiveness of selenium in patients with GH remains questionable, its use in the management of mild GO is generally believed to be beneficial, and selenium administration has been included in the clinical practice for the patients with mild eye disease.

To evaluate changes in corneal astigmatism in patients undergoing orbital decompression surgery.,This retrospective, non randomized comparative study involved 42 eyes from 21 patients with thyroid ophthalmopathy who underwent orbital decompression surgery between September 2011 and September 2014.,The 42 eyes were divided into three groups: control (9 eyes), two-wall decompression (25 eyes), and three-wall decompression (8 eyes).,The control group was defined as the contralateral eyes of nine patients who underwent orbital decompression surgery in only one eye.,Corneal topography (Orbscan II), Hertel exophthalmometry, and intraocular pressure were measured at 1 month before and 3 months after surgery.,Corneal topographic parameters analyzed were total astigmatism (TA), steepest axis (SA), central corneal thickness (CCT), and anterior chamber depth (ACD).,Exophthalmometry values and intraocular pressure decreased significantly after the decompression surgery.,The change (absolute value (|x|) of the difference) in astigmatism at the 3 mm zone was significantly different between the decompression group and the controls (p = 0.025).,There was also a significant change in the steepest axis at the 3 mm zone between the decompression group and the controls (p = 0.033).,An analysis of relevant changes in astigmatism showed that there was a dominant tendency for incyclotorsion of the steepest axis in eyes that underwent decompression surgery.,Using Astig PLOT, the mean surgically induced astigmatism (SIA) was 0.21±0.88 D with an axis of 46±22°, suggesting that decompression surgery did change the corneal shape and induced incyclotorsion of the steepest axis.,There was a significant change in corneal astigmatism after orbital decompression surgery and this change was sufficient to affect the optical function of the cornea.,Surgeons and patients should be aware of these changes.

In common with several other autoimmune diseases, autoimmune Addison’s disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events.,To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4.,The contribution of other genetic variants has been inconsistent.,We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls.,We have also performed a meta-analysis including 1002 patients from European countries.,The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients.,The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002).,A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013).,This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region.,The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements.,We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis.,Two loci passed a stringent genome-wide significance level (p<10−10): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA.,Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA.,Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).

It is well established that thyroiditis and other thyroid disorders can be induced by COVID-19 infection, but there is limited information about the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.,We report two cases of thyrotoxicosis following SARS-CoV-2 vaccine.,Two young health care peoples (wife and husband) received a first dose of SARS-CoV-2 vaccine, and few weeks later developed clinical manifestations of thyroid hyperactivity, with increased thyroid hormone levels on thyroid function tests, suppressed thyroid-stimulating hormone and negative antithyroid antibodies, despite being healthy before vaccination.,They were diagnosed at the 4th week after first dose of SARS-Cov-2 vaccine as silent thyroiditis and followed without treatment, since their symptoms were not severe.,At the 6th week, the patients became wholly asymptomatic and their thyroid function returned to normal.,Thyrotoxicosis can occur after SARS-CoV-2 vaccination probably related to silent thyroiditis.

Graves’ disease (GD) is a common autoimmune disorder with a genetic predisposition.,Owing to the biological effect of tumor necrosis factor-α (TNF-α) on the thyroid gland and its gene location, TNF-α should be able to influence an individual’s susceptibility to GD.,In the present study, we conduct a meta-analysis of rs1800629 and rs361525 in TNF-α gene from all eligible case-control studies to assess the associations amongst reported TNF-α gene with GD.,A total of ten case-control studies involving 2790 GD patients and 3472 healthy controls were included.,The results showed that a significant association was characterized between the rs1800629 polymorphism and GD in the homozygous model (AA compared with GG: odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.27-3.06, P=0.002) and recessive model (AA compared with GA + GG: OR = 1.62, 95% CI = 1.04-2.50, P=0.03).,GD susceptibility was significantly detected in European population in all genetic models after ethnicity stratification.,In sharp contrast, no significant association could be detected in Asian population.,Next, we conducted a meta-analysis for another promoter SNP rs361525.,However, SNP rs361525 did not show a significant association with GD in any genetic model before and after ethnicity stratification.,Together, our data support that only the promoter single-nucleotide polymorphism (SNP) rs1800629 within the TNF-α gene is associated with increased risk for developing GD, especially in European population.,Future large-scale studies are required to validate the associations between TNF-α gene and GD.

Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology.,It has been shown that genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors.,Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality.,Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data.,The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design.,In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis.,We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions.,The application of MR design in the field of rheumatology remains limited.,Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found.,Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results.,Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers).,As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered.,Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates.,To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.

Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA).,However, the underlying mechanism is not fully understood.,This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.,We investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA).,The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA).,Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.,We identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723.,This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723.,We showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.,The online version of this article (doi:10.1186/s13075-017-1276-2) contains supplementary material, which is available to authorized users.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).,There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes.,There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS.,The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances.,Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage.,This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future.

The ability of the Blood Brain Barrier (BBB) to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS) activity and regulating leukocytes’ access, can be affected in CNS diseases.,Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function.,Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P.,Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS): fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes.,Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two.,Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines.,When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF) that reduced the effects of cytokines on endothelium.,In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.

Given the potential shared aetiology between type 1 and type 2 diabetes, we aimed to identify any genetic regions associated with both diseases.,For associations where there is a shared signal and the allele that increases risk to one disease also increases risk to the other, inference about shared aetiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously.,Alternatively, if a genetic signal co-localises with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently.,Using publicly available type 2 diabetes summary statistics from a genome-wide association study (GWAS) meta-analysis of European ancestry individuals (74,124 cases and 824,006 controls) and type 1 diabetes GWAS summary statistics from a meta-analysis of studies on individuals from the UK and Sardinia (7467 cases and 10,218 controls), we identified all regions of 0.5 Mb that contained variants associated with both diseases (false discovery rate <0.01).,In each region, we performed forward stepwise logistic regression to identify independent association signals, then examined co-localisation of each type 1 diabetes signal with each type 2 diabetes signal using coloc.,Any association with a co-localisation posterior probability of ≥0.9 was considered a genuine shared association with both diseases.,Of the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals co-localised between both diseases (posterior probability ≥0.9): (1) chromosome 16q23.1, near CTRB1/BCAR1, which has been previously identified; (2) chromosome 11p15.5, near the INS gene; (3) chromosome 4p16.3, near TMEM129 and (4) chromosome 1p31.3, near PGM1.,In each of these regions, the effect of genetic variants on type 1 diabetes was in the opposite direction to the effect on type 2 diabetes.,Use of additional datasets also supported the previously identified co-localisation on chromosome 9p24.2, near the GLIS3 gene, in this case with a concordant direction of effect.,Four of five association signals that co-localise between type 1 diabetes and type 2 diabetes are in opposite directions, suggesting a complex genetic relationship between the two diseases.,The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05428-0.

Background: Several genetic association studies already investigated potential roles of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms in diabetes mellitus (DM), with inconsistent results.,Therefore, we performed this meta-analysis to better assess the relationship between CTLA-4 gene polymorphisms and DM in a larger pooled population.,Methods: PubMed, Embase, Web of Science, and CNKI were systematically searched for eligible studies.,Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations between CTLA-4 gene polymorphisms and DM in all possible genetic models.,Results: A total of 76 studies were finally included in our analyses.,Significant associations with susceptibility to type 1 diabetes mellitus (T1DM) were detected for rs231775 (dominant model: P=0.008, OR = 0.83, 95%CI 0.73-0.95; recessive model: P=0.003, OR = 1.27, 95%CI 1.09-1.50; allele model: P=0.004, OR = 0.85, 95%CI 0.77-0.95) and rs5742909 (recessive model: P=0.02, OR = 1.50, 95%CI 1.05-2.13) polymorphisms in overall population.,Further subgroup analyses revealed that rs231775 polymorphism was significantly associated with susceptibility to T1DM in Caucasians and South Asians, and rs5742909 polymorphism was significantly associated with susceptibility to T1DM in South Asians.,Moreover, rs231775 polymorphism was also found to be significantly associated with susceptibility to type 2 diabetes mellitus (T2DM) in East Asians and South Asians.,Conclusions: Our findings indicated that rs231775 and rs5742909 polymorphisms may serve as genetic biomarkers of T1DM, and rs231775 polymorphism may also serve as a genetic biomarker of T2DM.

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment.,Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified.,However, it is not clear whether these loci have significant impact on joint destruction or not.,This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.,Sharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients.,Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2).,These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.,The number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).,In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients.,The results of this study give important knowledge of the risks on progressive joint damage in RA patients.

To find out whether a high number of auto-antibodies can increase the probability of a “good-EULAR response” and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT).,One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT.,The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy.,The IL6 and BAFF levels were also determined.,At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response.,Having up to 5-AABs positivity increased the chances for treatment response.,After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count <1875/uL (OR = 10.74), a RF-IgG level >52.1 IU/ml (OR = 8.37) and BAFF levels <1011 pg/ml (OR = 7.38).,When all the AABs, except for RF-IgM and ACPA-IgG, were left in the analysis, the two final predictors were no-steroid therapy and low lymphocyte count.,The number of AABs increased the chances of being a “good-EULAR” responder.,The only predictors, however, at the baseline of a good response in this seropositive cohort of RA patients were 2 simple variables - no steroids and lymphocyte count - and two laboratory assays - IgG-RF and BAFF.

Rheumatoid arthritis (RA)-associated IgG antibodies such as anti-citrullinated protein antibodies (ACPAs) have diverse glycosylation variants; however, key sugar chains modulating the arthritogenic activity of IgG remain to be clarified.,Here, we show that reduced sialylation is a common feature of RA-associated IgG in humans and in mouse models of arthritis.,Genetically blocking sialylation in activated B cells results in exacerbation of joint inflammation in a collagen-induced arthritis (CIA) model.,On the other hand, artificial sialylation of anti-type II collagen antibodies, including ACPAs, not only attenuates arthritogenic activity, but also suppresses the development of CIA in the antibody-infused mice, whereas sialylation of other IgG does not prevent CIA.,Thus, our data demonstrate that sialylation levels control the arthritogenicity of RA-associated IgG, presenting a potential target for antigen-specific immunotherapy.,Post-translational modifications, such as glycosylation and sialylation, are thought to confer disease modifying effects on autoimmune-associated antibodies, including anti-citrullinated protein antibodies in rheumatoid arthritis.,Here the authors show that sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis in mice.

The presence of self-reactive IgG autoantibodies in human sera is largely thought to represent a breakdown in central tolerance and is typically regarded as a harbinger of autoimmune pathology.,In the present study, immune-response profiling of human serum from 166 individuals via human protein microarrays demonstrates that IgG autoantibodies are abundant in all human serum, usually numbering in the thousands.,These IgG autoantibodies bind to human antigens from organs and tissues all over the body and their serum diversity is strongly influenced by age, gender, and the presence of specific diseases.,We also found that serum IgG autoantibody profiles are unique to an individual and remarkably stable over time.,Similar profiles exist in rat and swine, suggesting conservation of this immunological feature among mammals.,The number, diversity, and apparent evolutionary conservation of autoantibody profiles suggest that IgG autoantibodies have some important, as yet unrecognized, physiological function.,We propose that IgG autoantibodies have evolved as an adaptive mechanism for debris-clearance, a function consistent with their apparent utility as diagnostic indicators of disease as already established for Alzheimer’s and Parkinson’s diseases.

Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors.,However, the impact of microglia depletion and repopulation in the long-term state of the CNS environment has not been characterized.,Here, we report that acute and synchronous microglia depletion and subsequent repopulation induces gray matter microgliosis, neuronal death in the somatosensory cortex and ataxia-like behavior.,We find a type 1 interferon inflammatory signature in degenerating somatosensory cortex from microglia-depleted mice.,Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state.,Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type 1 interferon-driven inflammation, restore microglia homeostasis and reduce ataxic behavior.,Neither microglia depletion nor repopulation impact neuropathology or T-cell responses during experimental autoimmune encephalomyelitis.,Together, we found that acute microglia ablation induces a type 1 interferon activation state of gray matter microglia associated with acute neurodegeneration.,Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death.,Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.

Iron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age.,Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.,We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.,We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration.,In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age.,This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases.,In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages.,Iron-containing microglia showed signs of cell degeneration.,At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.,Iron decreases in the NAWM of MS patients with increasing disease duration.,Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation.,In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain.,Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed.,Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed.,Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks.,Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE.,Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE.,Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells.

Macrophages play a dual role in multiple sclerosis (MS) pathology.,They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators.,The effector function of macrophages is determined by the way they are activated.,Stimulation of monocyte-derived macrophages in vitro with interferon-γ and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages.,For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry.,This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively.,Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples.,Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions.,M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages.,Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status.,Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.

There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes.,This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR.,The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates.,RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function.,Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01).,The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects.

Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D).,Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D.,We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects.,Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell-associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells.,Treatment also suppresses interferon γ production by pancreas-infiltrating T cells.,Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely.,We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS).,Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment.,This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS.,We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS.,Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established.,Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

Multiple Sclerosis (MS) is a chronic and disabling disease with a considerable social impact and economic consequences.,In Europe, it is the most common cause of non-traumatic disability in young adults.,Existing therapies that target immune modulation are largely ineffective in halting the progression of the disease and are fraught with severe side effects.,Therefore, managing the comorbidities of MS is of utmost importance for long-term patient care and quality of life.

The epidemiological studies confirm an increased risk of cardiovascular disease in multiple sclerosis, especially prothrombotic events directly associated with abnormal platelet activity.,The aim of our study was to investigate the level of blood platelet activation in the circulation of patients with chronic phase of multiple sclerosis (SP MS) and their reactivity in response to typical platelets’ physiological agonists.,We examined 85 SP MS patients diagnosed according to the revised McDonald’s criteria and 50 healthy volunteers as a control group.,The platelet activation and reactivity were assessed using flow cytometry analysis of the following: P-selectin expression (CD62P), activation of GP IIb/IIIa complex (PAC-1 binding), and formation of platelet microparticles (PMPs) and platelet aggregates (PA) in agonist-stimulated (ADP, collagen) and unstimulated whole blood samples.,Furthermore, we measured the level of soluble P-selectin (sP-selectin) in plasma using ELISA method, to evaluate the in vivo level of platelet activation, both in healthy and SP MS subjects.,We found a statistically significant increase in P-selectin expression, GP IIb/IIIa activation, and formation of PMPs and PA, as well as in unstimulated and agonist-stimulated (ADP, collagen) platelets in whole blood samples from patients with SP MS in comparison to the control group.,We also determined the higher sP-selectin level in plasma of SP MS subjects than in the control group.,Based on the obtained results, we might conclude that during the course of SP MS platelets are chronically activated and display hyperreactivity to physiological agonists, such as ADP or collagen.

Immunoglobulins, antigens and complement can assemble to form immune complexes (IC).,ICs can be detrimental as they propagate inflammation in autoimmune diseases.,Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis.,We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy.,We find that the MPs in RA synovial fluid are highly heterogeneous in size.,The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs.,These mpICs frequently express the integrin CD41, consistent with platelet origin.,Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor.,Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs.,Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils.,Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.

Prior studies suggest that fish may be protective for rheumatoid arthritis (RA) risk perhaps through the anti-inflammatory effect of omega-3 fatty acid, but this relationship has not been clearly established.,Therefore, we investigated fish intake and RA risk by serologic status, age of onset, and smoking using a prospective cohort study with large sample size, repeated measures of dietary intake, and lengthy follow-up.,We studied fish intake and RA risk among 166,013 women in two prospective cohorts, the Nurses’ Health Study (NHS, 1984-2014) and NHSII (1991-2015).,Fish intake was assessed using food frequency questionnaires at baseline and every 4 years.,Incident RA during follow-up and serologic status were determined by medical record review.,Pooled Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for RA (overall and by serologic status and age at diagnosis) for fish intake frequency.,We tested for a smoking-fish interaction for RA risk.,During 3,863,909 person-years of follow-up, we identified 1080 incident RA cases.,Increasing fish intake was not associated with all RA (≥4 servings/week: multivariable HR 0.93 [95%CI 0.67-1.28] vs. < 1 serving/month; p for trend = 0.42), seropositive RA (p for trend = 0.66), or seronegative RA (p for trend = 0.45), but had increased risk for RA diagnosed > 55 years old (p for trend = 0.037).,Among women ≤55 years old, frequent fish intake (vs. infrequent) had HRs (95%CIs) of: 0.73 (0.52-1.02) for all RA, 0.85 (0.55-1.32) for seropositive RA, and 0.55 (0.32-0.94) for seronegative RA.,Ever smokers with infrequent fish intake had highly elevated risk for RA onset ≤55 years (HR 2.59, 95%CI 1.65-4.06), while ever smokers with frequent fish intake had modestly elevated RA risk (HR 1.29, 95%CI 1.07-1.57; vs. never smokers/frequent fish intake; p for smoking-fish interaction = 0.039).,In this large prospective cohort study, we found no clear protective effect of fish or marine omega-3 fatty acid intake on RA risk, overall or by serologic status.,We found that fish intake attenuated the strong association of smoking for RA diagnosed ≤55 years of age, but this requires further study.

Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD).,Our aim was to evaluate the impact of factors related to CVD, such as smoking, lipid levels, hypertension, body mass index (BMI) and diabetes, in individuals prior to the onset of symptoms of RA.,A nested case-control study was performed including data from 547 pre-symptomatic individuals (i.e. individuals who had participated in population surveys in northern Sweden prior to onset of symptoms of RA, median time to symptom onset 5.0 (interquartile range 2.0-9.0) years) and 1641 matched controls.,Within the survey, health examinations prior to symptom onset were performed, blood samples were analysed for plasma glucose and lipids, and data on lifestyle factors had been collected with a questionnaire.,CVD risk factors were extracted and further analysed with conditional logistic regression models for association with subsequent RA development, including hypertension, apolipoprotein (Apo)B/ApoA1 ratio, BMI, diabetes and smoking habits.,Smoking and BMI ≥ 25 (odds ratio (OR) (95% confidence interval (CI)) =1.86 (1.48-2.35) and OR = 1.28 (1.01-1.62), respectively) were associated with increased risk for future RA development.,In women, elevated ApoB/ApoA1 ratio (OR = 1.36 (1.03-1.80)) and smoking (OR = 1.82 (1.37-2.41)) were significantly associated with being pre-symptomatic for RA, whilst in men smoking (OR = 1.92 (1.26-2.92)) and diabetes (OR = 3.62 (95% CI 1.13-11.64)) were significant.,In older (>50.19 years) individuals, only smoking (OR = 1.74 (1.24-2.45)) was significantly associated with increased risk of future RA, whereas in younger individuals the significant factors were elevated ApoB/ApoA1 ratio (OR = 1.39 (1.00-1.93)), BMI ≥ 25.0 (OR = 1.45 (1.04-2.02)) and smoking (OR = 2.11 (1.51-2.95)).,Pre-symptomatic individuals had a higher frequency of risk factors: 41.5% had ≥3 compared with 30.4% among matched controls (OR = 2.81 (1.78-4.44)).,Several risk factors for CVD were present in pre-symptomatic individuals and significantly associated with increased risk for future RA.,These factors differed in women and men.,The CVD risk factors had a greater impact in younger individuals.,These results urge an early analysis of cardiovascular risk factors for proposed prevention in patients with early RA.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (PR3) are pathogenic in ANCA-associated vasculitis (AAV).,The respective role of IgG Fc and Fab glycosylation in mediating ANCA pathogenicity is incompletely understood.,Herein we investigate in detail the changes in Fc and Fab glycosylation in MPO-ANCA and Pr3-ANCA and examine the association of glycosylation aberrancies with disease activity.,Total IgG was isolated from serum or plasma of a cohort of 30 patients with AAV (14 MPO-ANCA; 16 PR3-ANCA), and 19 healthy control subjects.,Anti-MPO specific IgG was affinity-purified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis.,We used lectin binding assays, liquid chromatography, and mass spectrometry-based methods to analyze Fc and Fab glycosylation, the degree of sialylation of Fc and Fab fragments and to determine the exact localization of N-glycans on Fc and Fab fragments.,IgG1 Fc glycosylation of total IgG was significantly reduced in patients with active AAV compared to controls.,Clinical remission was associated with complete glycan normalization for PR3-ANCA patients but not for MPO-ANCA patients.,Fc-glycosylation of anti-MPO specific IgG was similar to total IgG purified from plasma.,A major fraction of anti-MPO specific IgG harbor extensive glycosylation within the variable domain on the Fab portion.,Significant differences exist between MPO and PR3-ANCA regarding the changes in amounts and types of glycans on Fc fragment and the association with disease activity.,These differences may contribute to significant clinical difference in the disease course observed between the two diseases.

Rheumatoid arthritis (RA)-associated IgG antibodies such as anti-citrullinated protein antibodies (ACPAs) have diverse glycosylation variants; however, key sugar chains modulating the arthritogenic activity of IgG remain to be clarified.,Here, we show that reduced sialylation is a common feature of RA-associated IgG in humans and in mouse models of arthritis.,Genetically blocking sialylation in activated B cells results in exacerbation of joint inflammation in a collagen-induced arthritis (CIA) model.,On the other hand, artificial sialylation of anti-type II collagen antibodies, including ACPAs, not only attenuates arthritogenic activity, but also suppresses the development of CIA in the antibody-infused mice, whereas sialylation of other IgG does not prevent CIA.,Thus, our data demonstrate that sialylation levels control the arthritogenicity of RA-associated IgG, presenting a potential target for antigen-specific immunotherapy.,Post-translational modifications, such as glycosylation and sialylation, are thought to confer disease modifying effects on autoimmune-associated antibodies, including anti-citrullinated protein antibodies in rheumatoid arthritis.,Here the authors show that sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis in mice.

Metabolic reprogramming is shaped to support specific cell functions since cellular metabolism controls the final outcome of immune response.,Multiple sclerosis (MS) is an autoimmune disease resulting from loss of immune tolerance against central nervous system (CNS) myelin.,Metabolic alterations of T cells occurring during MS are not yet well understood and their studies could have relevance in the comprehension of the pathogenetic events leading to loss of immune tolerance to self and to develop novel therapeutic strategies aimed at limiting MS progression.,In this report, we observed that extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), indicators of glycolysis and oxidative phosphorylation, respectively, were impaired during T cell activation in naïve-to-treatment relapsing remitting (RR)MS patients when compared with healthy controls.,These results were also corroborated at biochemical level by a reduced expression of the glycolitic enzymes aldolase, enolase 1, hexokinase I, and by reduction of Krebs cycle enzymes dihydrolipoamide-S-acetyl transferase (DLAT) and dihydrolipoamide-S-succinyl transferase (DLST).,Treatment of RRMS patients with interferon beta-1a (IFN beta-1a) was able to restore T cell glycolysis and mitochondrial respiration as well as the amount of the metabolic enzymes to a level comparable to that of healthy controls.,These changes associated with an up-regulation of the glucose transporter-1 (GLUT-1), a key element in intracellular transport of glucose.,Our data suggest that T cells from RRMS patients display a reduced engagement of glycolysis and mitochondrial respiration, reversible upon IFN beta-1a treatment, thus suggesting an involvement of an altered metabolism in the pathogenesis of MS.

The headquarter of our immune system resides in the gut and modulates autoimmune disease activation in multiple sclerosis.,T helper 17 (TH17) cells are key players in multiple sclerosis (MS), and studies in animal models demonstrated that effector TH17 cells that trigger brain autoimmunity originate in the intestine.,We validate in humans the crucial role of the intestinal environment in promoting TH17 cell expansion in MS patients.,We found that increased frequency of TH17 cells correlates with high disease activity and with specific alterations of the gut mucosa-associated microbiota in MS patients.,By using 16S ribosomal RNA sequencing, we analyzed the microbiota isolated from small intestinal tissues and found that MS patients with high disease activity and increased intestinal TH17 cell frequency showed a higher Firmicutes/Bacteroidetes ratio, increased relative abundance of Streptococcus, and decreased Prevotella strains compared to healthy controls and MS patients with no disease activity.,We demonstrated that the intestinal TH17 cell frequency is inversely related to the relative abundance of Prevotella strains in the human small intestine.,Our data demonstrate that brain autoimmunity is associated with specific microbiota modifications and excessive TH17 cell expansion in the human intestine.

To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).,A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019.,234 abstracts were selected for detailed assessment, with 136 finally included.,They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs.,Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed.,The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab.,The efficacy of many bDMARDs and tsDMARDs was shown.,Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious.,Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering.,Biosimilars are non-inferior to their reference products.,This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR’s RA management recommendation.

To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi.,SWITCH-RA was a prospective, global, observational, real-life study.,Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi.,Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months.,604 patients received rituximab, and 507 an alternative TNFi as second biological therapy.,Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21).,A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323).,Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001.,Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: −1.5 (0.2) vs −1.1 (0.2); p=0.007.,The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (−1.7 vs −1.3; p=0.017) but not intolerance (−0.7 vs −0.7; p=0.894).,Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (−1.6 (0.3) vs −1.2 (0.3); p=0.011), particularly those switching because of inefficacy (−1.9 (0.3) vs −1.5 (0.4); p=0.021).,The overall incidence of adverse events was similar between the rituximab and TNFi groups.,These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi.,This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Patients with Systemic Lupus Erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved.,Using single-cell RNA-seq, we profiled ~276,000 PBMCs from 33 children with SLE (cSLE) with different degrees of disease activity (DA) and 11 matched controls.,Increased expression of interferon-stimulated genes (ISGs) distinguished cSLE from healthy control cells.,The high-ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), B cells and especially plasma cells.,Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest DA.,Profiling of ~82,000 single peripheral blood mononuclear cells (PBMCs) from adult SLE patients confirmed the expansion of similar subpopulations in patients with the highest DA.,This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood.,We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease.,Type I interferon (IFN) response signatures in tubular cells and in keratinocytes distinguished patients with LN from healthy control subjects.,Moreover, a high IFN response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment.,Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences.,In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Over the past two decades it has been increasingly recognized that vitamin D, aside from its crucial involvement in calcium and phosphate homeostasis and the dynamics of the musculoskeletal system, exerts its influential impact on the immune system.,The mechanistic roles that vitamin D plays regarding immune activation for combating infection, as well as pathologically and mediating autoimmune conditions, have been progressively unraveled.,In vitro and in vivo models have demonstrated that the action of vitamin D on various immunocytes is not unidirectional.,Rather, how vitamin D affects immunocyte functions depends on the context of the immune response, in the way that its suppressive or stimulatory action offers physiologically appropriate and immunologically advantageous outcomes.,In this review, the relationship between various aspects of vitamin D, starting from its adequacy in circulation to its immunological functions, as well as its autoimmune conditions, in particular systemic lupus erythematosus (SLE), a prototype autoimmune condition characterized by immune-complex mediated inflammation, will be discussed.,Concurring with other groups of investigators, our group found that vitamin D deficiency is highly prevalent in patients with SLE.,Furthermore, the circulating vitamin D levels appear to be correlated with a higher disease activity of SLE as well as extra-musculoskeletal complications of SLE such as fatigue, cardiovascular risk, and cognitive impairment.

Vitamin D has several reported immunomodulatory properties including the reduced generation of pro-inflammatory CD4+ T helper 1 (Th1) cells and the increase in levels of the anti-inflammatory Th2 subset.,Less clear has been the impact of vitamin D on the pro-inflammatory Th17 subset, and whether and how vitamin D may preferentially drive the polarization of one of the T helper subsets.,Using human peripheral blood-derived mononuclear cells and mouse splenocytes and lymph node cells in culture, we examined whether and how vitamin D preferentially skews T cells towards the Th1, Th2 or Th17 subsets.,Mice afflicted with the multiple sclerosis-like condition, experimental autoimmune encephalomyelitis (EAE), were examined in vivo for the relevance of the tissue culture-derived results.,We report that the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 {1,25(OH)2D3}, consistently generates human and murine Th2 cells in culture, frequently leaving unchanged the levels of Th1/Th17 cytokines.,As a result, the ratio of Th2 to Th1 and Th17 is increased by 1,25(OH)2D3.,The upregulation of Th2 to Th1 or Th17 subsets by 1,25(OH)2D3 is enabled by an increase of the GATA-3 transcription factor, which itself is promoted upstream by an elevation of the STAT6 transcription factor.,In mice, the alleviation of EAE severity by 1,25(OH)2D3 is accompanied by elevation of levels of GATA-3 and STAT6.,Significantly, the efficacy of 1,25(OH)2D3 in ameliorating EAE is completely lost in mice genetically deficient for STAT6, which was accompanied by the inability of 1,25(OH)2D3 to raise GATA-3 in STAT6 null lymphocytes.,These results of vitamin D promoting a Th2 shift through upstream GATA-3 and STAT6 transcription factors shed mechanistic understanding on the utility of vitamin D in MS.

In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS.,Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included.,From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113).,The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48.,At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80).,Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: −0.074; p = 0.035).,SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS.,NCT01285401.,This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.

Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS).,To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels.,This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo (n = 23) over 48 weeks.,Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured.,EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored.,The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023).,EBV load and cytotoxic T-cell responses were unaffected.,Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures.,High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients.,Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.

Late-onset type 1 diabetes can be difficult to identify.,Measurement of endogenous insulin secretion using C-peptide provides a gold standard classification of diabetes type in longstanding diabetes that closely relates to treatment requirements.,We aimed to determine the prevalence and characteristics of type 1 diabetes defined by severe endogenous insulin deficiency after age 30 and assess whether these individuals are identified and managed as having type 1 diabetes in clinical practice.,We assessed the characteristics of type 1 diabetes defined by rapid insulin requirement (within 3 years of diagnosis) and severe endogenous insulin deficiency (non-fasting C-peptide <200 pmol/l) in 583 participants with insulin-treated diabetes, diagnosed after age 30, from the Diabetes Alliance for Research in England (DARE) population cohort.,We compared characteristics with participants with retained endogenous insulin secretion (>600 pmol/l) and 220 participants with severe insulin deficiency who were diagnosed under age 30.,Twenty-one per cent of participants with insulin-treated diabetes who were diagnosed after age 30 met the study criteria for type 1 diabetes.,Of these participants, 38% did not receive insulin at diagnosis, of whom 47% self-reported type 2 diabetes.,Rapid insulin requirement was highly predictive of severe endogenous insulin deficiency: 85% required insulin within 1 year of diagnosis, and 47% of all those initially treated without insulin who progressed to insulin treatment within 3 years of diagnosis had severe endogenous insulin deficiency.,Participants with late-onset type 1 diabetes defined by development of severe insulin deficiency had similar clinical characteristics to those with young-onset type 1 diabetes.,However, those with later onset type 1 diabetes had a modestly lower type 1 diabetes genetic risk score (0.268 vs 0.279; p < 0.001 [expected type 2 diabetes population median, 0.231]), a higher islet autoantibody prevalence (GAD-, islet antigen 2 [IA2]- or zinc transporter protein 8 [ZnT8]-positive) of 78% at 13 years vs 62% at 26 years of diabetes duration; (p = 0.02), and were less likely to identify as having type 1 diabetes (79% vs 100%; p < 0.001) vs those with young-onset disease.,Type 1 diabetes diagnosed over 30 years of age, defined by severe insulin deficiency, has similar clinical and biological characteristics to that occurring at younger ages, but is frequently not identified.,Clinicians should be aware that patients progressing to insulin within 3 years of diagnosis have a high likelihood of type 1 diabetes, regardless of initial diagnosis.,The online version of this article (10.1007/s00125-019-4863-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

We aimed at estimating the incidence of diabetic retinopathy (DR) and maculopathy (DMP) among newly diagnosed type 1 (t1DM) and type 2 diabetic patients (t2DM) in the United Kingdom primary care system.,The incidence of DMP among patients with DR was also estimated.,We conducted a cohort study using The Health Improvement Network database.,The cohort included 64,983 incident diabetic patients (97.3% were t2DM) aged 1-84 years diagnosed between 2000 and 2007.,This cohort was followed from the date of diabetes diagnosis until recording of DR or DMP in two separate follow-ups.,Follow-up was censored at 85 years of age, death, or end of 2008.,An additional follow-up was conducted from DR to DMP diagnosis using similar censoring reasons.,DR and DMP cumulative incidences were calculated as well as incidence rates (IR; cases per 1,000 person-years) per calendar period (2000-2001 and 2006-2007).,Follow-up for DR: 9 years after diabetes diagnosis, 28% of t2DM and 24% of t1DM patients had developed DR (7,899 incident DR cases).,During the first 2 years with diabetes, the IR was almost 2 times higher in patients diagnosed with diabetes in 2006-2007 (47.7) than among those diagnosed in 2000-2001 (24.5).,Follow-up for DMP: 9 years after diabetes diagnosis, 3.6% of t2DM and 4.4% of t2DM patients had developed DMP (912 incident DMP cases).,During the first 2 years with diabetes, the IR was three times higher in patients diagnosed with diabetes in 2006-2007 (5.8) than among those diagnosed in 2000-2001 (1.8).,Macular oedema occurred in 0.8% of patients.,In a cohort of incident diabetes, 28% of patients developed retinopathy and 4% maculopathy within the first 9 years.,The 2-year IRs of DR and DMP were higher in patients diagnosed with diabetes during the period 2006-2007 than in those diagnosed during the 2000-2001 period.

Free light chains (FLC) are a promising biomarker to detect intrathecal inflammation in patients with inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS).,The diagnostic use of this biomarker, in particular the kappa isoform of FLC (“KFLC”), has been investigated for more than 40 years.,Based on an extensive literature review, we found that an agreement on the correct method for evaluating KFLC concentrations has not yet been reached.,KFLC indices with varying cut-off values and blood-CSF-barrier (QAlbumin) related non-linear formulas for KFLC interpretation have been investigated in several studies.,All approaches revealed high diagnostic sensitivity and specificity compared with the oligoclonal bands, which are considered the gold standard for the detection of intrathecally synthesized immunoglobulins.,Measurement of KFLC is fully automated, rater-independent, and has been shown to be stable against most pre-analytic influencing factors.,In conclusion, the determination of KFLC represents a promising diagnostic approach to show intrathecal inflammation in neuroinflammatory diseases.,Multicenter studies are needed to show the diagnostic sensitivity and specificity of KFLC in MS by using the latest McDonald criteria and appropriate, as well as standardized, cut-off values for KFLC concentrations, preferably considering non-linear formulas such as Reiber’s diagram.

To investigate whether κ-free light chain (κ-FLC) index predicts multiple sclerosis (MS) disease activity independent of demographics, clinical characteristics, and MRI findings.,Patients with early MS who had CSF and serum sampling at disease onset were followed for 4 years.,At baseline, age, sex, type of symptoms, corticosteroid treatment, and number of T2 hyperintense (T2L) and contrast-enhancing T1 lesions (CELs) on MRI were determined.,During follow-up, the occurrence of a second clinical attack and start of disease-modifying therapy (DMT) were registered. κ-FLCs were measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient.,A total of 88 patients at a mean age of 33 ± 10 years and female predominance of 68% were included; 38 (43%) patients experienced a second clinical attack during follow-up.,In multivariate Cox regression analysis adjusting for age, sex, T2L, CEL, disease and follow-up duration, administration of corticosteroids at baseline and DMT during follow-up revealed that κ-FLC index predicts time to second clinical attack.,Patients with κ-FLC index >100 (median value 147) at baseline had a twice as high probability for a second clinical attack within 12 months than patients with low κ-FLC index (median 28); within 24 months, the chance in patients with high κ-FLC index was 4 times as high as in patients with low κ-FLC index.,The median time to second attack was 11 months in patients with high κ-FLC index whereas 36 months in those with low κ-FLC index.,High κ-FLC index predicts early MS disease activity.,This study provides Class II evidence that in patients with early MS, high κ-FLC index is an independent risk factor for early second clinical attack.

The aim of this study was to investigate the possible association in the interleukin-6 (IL-6) gene with Rheumatoid arthritis (RA) in Chinese Han population from Shandong Province.,Target regions of IL-6 gene were amplified by polymerase chain reaction (PCR) and genotyped.,A logistic regression analysis was performed to detect potential associations in our case-control sample, the odd ratio(OR) and 95% confidence intervals(CIs) were calculated.,Furthermore, we systematically tracked all the published studies in the field and performed a meta-analysis for the single nucleotide polymorphisms (SNPs) under study.,256 RA patients and 331 healthy controls were recruited into the case-control study.,We found allele frequencies of rs1800795, rs1800797 and rs1474347 in RA patients differ from control subjects (P = 0.016, 0.024, 0.020, respectively).,Significant difference was observed in haplotype frequencies of GCCGCT between RA patients and controls (P = 0.0001, OR = 4.066, 95%CI = 1.891 ~ 8.746), while GGCGCT frequencies was found lower in RA than controls (P = 0.006, OR = 0.669, 95%CI = 0.501 ~ 0.894).,The results of the meta-analysis showed association polymorphism within the IL-6 promoter with RA.,These findings suggest that rare IL-6 gene polymorphisms may associate with RA susceptibility in Han Chinese populations; however further studies are needed to assess the validity of the association of IL-6 with RA.

The association between rheumatoid arthritis (RA) and periodontitis is suggested to be linked to the periodontal pathogen Porphyromonas gingivalis.,Colonization of P. gingivalis in the oral cavity of RA patients has been scarcely considered.,To further explore whether the association between periodontitis and RA is dependent on P. gingivalis, we compared host immune responses in RA patients with and without periodontitis in relation to presence of cultivable P. gingivalis in subgingival plaque.,In 95 RA patients, the periodontal condition was examined using the Dutch Periodontal Screening Index for treatment needs.,Subgingival plaque samples were tested for presence of P. gingivalis by anaerobic culture technique.,IgA, IgG and IgM antibody titers to P. gingivalis were measured by ELISA.,Serum and subgingival plaque measures were compared to a matched control group of non-RA subjects.,A higher prevalence of severe periodontitis was observed in RA patients in comparison to matched non-RA controls (27% versus 12%, p < 0.001).,RA patients with severe periodontitis had higher DAS28 scores than RA patients with no or moderate periodontitis (p < 0.001), while no differences were seen in IgM-RF or ACPA reactivity.,Furthermore, RA patients with severe periodontitis had higher IgG- and IgM-anti P. gingivalis titers than non-RA controls with severe periodontitis (p < 0.01 resp. p < 0.05), although subgingival occurrence of P. gingivalis was not different.,Severity of periodontitis is related to severity of RA.,RA patients with severe periodontitis have a more robust antibody response against P. gingivalis than non-RA controls, but not all RA patients have cultivable P. gingivalis.

We report the clinical and immunological features in a case of SARS-CoV-2-induced Guillain-Barré syndrome (Si-GBS), suggesting that (1) Si-GBS can develop even after paucisymptomatic COVID-19 infection; (2) a distinctive cytokine repertoire is associated with this autoimmune complication, with increased CSF concentration of IL-8, and moderately increased serum levels of IL-6, IL-8, and TNF-α; (3) a particular genetic predisposition can be relevant, since the patient carried several HLA alleles known to be associated with GBS, including distinctive class I (HLA-A33) and class II alleles (DRB1*03:01 and DQB1*05:01).,To the best of our knowledge, this is the first case of GBS in which SARS-CoV-2 antibodies were detected in the CSF, further strengthening the role of the virus as a trigger.,In conclusion, our study suggests that SARS-CoV-2 antibodies need to be searched in the serum and CSF in patients with GBS living in endemic areas, even in the absence of a clinically severe COVID-19 infection, and that IL-8 pathway can be relevant in Si-GBS pathogenesis.,Further studies are needed to conclude on the relevance of the genetic findings, but it is likely that HLA plays a role in this setting as in other autoimmune neurological syndromes, including those triggered by infections.

•A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,•SARS-CoV-2 has also been shown to affect the peripheral nervous system.,•Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,•Some GBS have led to hypothesize a possible parainfectious pathogenesis.,A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,SARS-CoV-2 has also been shown to affect the peripheral nervous system.,Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,Some GBS have led to hypothesize a possible parainfectious pathogenesis.,In recent months, the new beta-coronavirus has caused a pandemic with symptoms affecting mainly the respiratory system.,It is established that the virus may play a neurotropic role and in recent months several cases of Guillain-Barré-Strohl syndrome (GBS) have been reported in patients infected with COVID-19.,We report the case of a 54-year-old patient with acute demyelinating polyneuropathy during infection by SARS-CoV-2 who progressed clinically to require assisted ventilation.,After several weeks of specific symptomatic treatment, the patient had a favorable outcome.,In conclusion, despite being a rare complication, we think it is important to consider the possibility of diffuse involvement of the peripheral nervous system in patients with COVID-19 to adjust clinical monitoring and treatment in these cases.

To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data.,Regions of association were defined based on the significance of linkage disequilibrium blocks.,Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins.,Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery.,The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively).,Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages.,A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells.,This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

Interferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway.,IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis.,The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions.,Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays.,The experimental results were interpreted by means of a theoretical model of the pathway.,Phosphorylation of the STAT1 protein (pSTAT1) and mRNA levels of the pSTAT1 inhibitor SOCS1 displayed an attenuated oscillatory behavior after IFN-beta activation.,In turn, mRNA levels of the interferon regulatory factor IRF1 grew rapidly in the first 50-90 minutes after stimulation until a maximum value, and started to decrease slowly around 200-250 min.,The analysis of our kinetic model identified a significant role of the negative feedback from SOCS1 in driving the observed damped oscillatory dynamics, and of the positive feedback from IRF1 in increasing STAT1 basal levels.,Our study shows that the system works as a biological damped relaxation oscillator based on a phosphorylation-dephosphorylation network centered on STAT1.,Moreover, a bifurcation analysis identified translocation of pSTAT1 dimers to the nucleus as a critical step for regulating the dynamics of type I IFN pathway in the first steps, which may be important in defining the response to IFN-beta therapy.,The immunomodulatory effect of IFN-beta signaling in macrophages takes the form of transient oscillatory dynamics of the JAK-STAT pathway, whose specific relaxation properties determine the lifetime of the cellular response to the cytokine.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1.,Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs).,We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012-4.,We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7-9 - as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes - to identify 98 biological candidate genes at these 101 risk loci.,We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA.,Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

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.

Other than age, diabetes is the largest contributor to overall healthcare costs and reduced life expectancy in Europe.,This paper aims to more exactly quantify the net impact of diabetes on different aspects of healthcare provision in hospitals in England, building on previous work that looked at the determinants of outcome in type 1 diabetes (T1DM) and type 2 diabetes (T2DM).,NHS Digital Hospital Episode Statistics (HES) in England was combined with the National Diabetes Audit (NDA) to provide the total number in practice of people with T1DM/T2DM.,We compared differences between T1DM/T2DM and non-diabetes individuals in relation to hospital activity and associated cost.,The study captured 90% of hospital activity and £36 billion/year of hospital spend.,The NDA Register showed that out of a total reported population of 58 million, 2.9 million (6.5%) had T2DM and 240 000 (0.6%) had T1DM.,Bed-day analysis showed 17% of beds are occupied by T2DM and 3% by T1DM.,The overall cost of hospital care for people with diabetes is £5.5 billion/year.,Once the normally expected costs including the older age of T2DM hospital attenders are allowed for this fell to £3.0 billion/year or 8% of the total captured secondary care costs.,This equates to £560/non-diabetes person compared with £3280/person with T1DM and £1686/person with T2DM.,For people with diabetes, the net excess impact on non-elective/emergency work is £1.2 billion with additional estimated diabetes-related accident & emergency attendances at 440 000 costing the NHS £70 million/year.,T1DM individuals required five times more secondary care support than non-diabetes individuals.,T2DM individuals, even allowing for the age, require twice as much support as non-diabetes individuals.,This analysis shows that additional cost of provision of hospital services due to their diabetes comorbidities is £3 billion above that for non-diabetes, and that within this, T1DM has three times as much cost impact as T2DM.,We suggest that supporting patients in diabetes management may significantly reduce hospital activity.

Type 1 diabetes is typically considered a disease of children and young adults.,Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes.,It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years.,We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.,In this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes.,We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life.,We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group.,All remaining cases were defined as type 2 diabetes.,We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes.,13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility.,These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31-60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years.,The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31-60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger.,For individuals diagnosed with diabetes when aged 31-60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 [95% CI 26·7-28·0] vs 32·4 kg/m2 [32·2-32·5]; p<0·0001), were more likely to use insulin in the first year after diagnosis (89% [476/537] vs 6% [648/11 696]; p<0·0001), and were more likely to have diabetic ketoacidosis (11% [61/537] vs 0·3% [30/11 696]; p<0·0001).,Genetic susceptibility to type 1 diabetes results in non-obesity-related, insulin-dependent diabetes, which presents throughout the first six decades of life.,Our results highlight the difficulty of identifying type 1 diabetes after age 30 years because of the increasing background prevalence of type 2 diabetes.,Failure to diagnose late-onset type 1 diabetes can have serious consequences because these patients rapidly develop insulin dependency.,Wellcome Trust and Diabetes UK.

The vaccine for the coronavirus disease 2019 (COVID‐19) has been reported to potentially cause or worsen diabetes.,A 73‐year‐old Japanese woman received two doses of Moderna COVID‐19 vaccine.,Four weeks after the second vaccination, her glycemic control began to deteriorate, and 8 weeks after the second vaccination, the patient was diagnosed with new‐onset type 1 diabetes that was strongly positive for autoantibodies and showed a disease‐susceptible human leukocyte antigen haplotype, DRB1*04:05:01‐DQB1*04:01:01.,The glucagon stimulation test suggested an insulin‐dependent state, and induction of intensive insulin therapy brought about fair glycemic control.,The time period from the COVID‐19 vaccination to the development of type 1 diabetes was relatively longer than to the onset or exacerbation of type 2 diabetes, as previously reported, suggesting the complicated immunological mechanisms for the destruction of β‐cells associated with the vaccination.,In recipients with the disease‐susceptible haplotypes, one should be cautious about autoimmune responses for several months after the vaccination.,We experienced a case of newly diagnosed type 1 diabetes with strongly positivity for autoantibodies that developed after the coronavirus disease 2019 vaccination and showed a disease‐susceptible human leukocyte antigen haplotype.,The time period from the coronavirus disease 2019 vaccination to the development of type 1 diabetes is relatively longer than to the onset or exacerbation of type 2 diabetes, as previously reported, suggesting the complicated immunological mechanisms for the destruction of β‐cells associated with the vaccination.,In recipients with the disease‐susceptible haplotypes, one should be cautious about autoimmune responses for several months after the vaccination.

Background: Mounting evidence has revealed the interrelationship between thyroid and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to explain the thyroid dysfunction and autoimmune thyroid disorders observed after coronavirus disease 2019 (COVID-19).,There are limited reports of thyroid dysfunction after SARS-CoV-2 vaccination.,Methods: We report a case of a 40-year-old Chinese woman who developed Graves' disease after BNT162b2 mRNA vaccine.,A search of PubMed and Embase databases from 1 September 2019 to 31 August 2021 was performed using the following keywords: “COVID,” “vaccine,” “thyroid,” “thyroiditis,” and “Graves.”,Results: A 40-year-old Chinese woman who had 8-year history of hypothyroidism requiring thyroxine replacement.,Her anti-thyroid peroxidase and anti-thyroglobulin antibodies were negative at diagnosis.,She received her first and second doses of BNT162b2 mRNA vaccine on 6 April and 1 May 2021, respectively.,She developed thyrotoxicosis and was diagnosed to have Graves' disease 5 weeks after the second dose of vaccine, with positive thyroid stimulating immunoglobulin level, diffuse goiter with hypervascularity on thyroid ultrasonography and diffusely increased thyroid uptake on technetium thyroid scan.,Both anti-thyroid peroxidase and anti-thyroglobulin antibodies became positive.,She was treated with carbimazole.,Literature search revealed four cases of Graves' disease after SARS-CoV-2 vaccination, all after mRNA vaccines; and nine cases of subacute thyroiditis, after different types of SARS-CoV-2 vaccines.,Conclusion: Our case represents the fifth in the literature of Graves' disease after SARS-CoV-2 vaccination, with an unusual presentation on a longstanding history of hypothyroidism.,Clinicians should remain vigilant about potential thyroid dysfunction after SARS-CoV-2 vaccination in the current pandemic.

MicroRNA-21 (miR-21) is overexpressed in patients with rheumatoid arthritis (RA).,This study was designed to investigate the effect and mechanism of miR-21 on cell proliferation in fibroblast-like synoviocytes (FLS) of RA.,FLS were primary-cultured from a rat RA model.,RA-FLS and normal FLS were infected with lentivirus (anti-miR-21 or pro-miR-21) for overexpression or downregulation of miR-21, respectively.,The effects of miR-21 overexpression or inhibition on nucleoprotein NF-κB levels and FLS cell proliferation were evaluated by western blotting and MTT assays.,The effects of an inhibitor of NF-κB nuclear translocation (BAY 11-7082) were also evaluated.,The results showed that the levels of miR-21 and nucleoprotein NF-κB were increased in FLS of RA model rats compared to the control group.,Downregulation of miR-21 in RA FLS led to a significant decrease in nucleoprotein NF-κB levels and cell proliferation rates compared to the antinegative control (NC) group.,However, miR-21 overexpression in normal FLS resulted in a significant increase of nucleoprotein NF-κB levels and cell proliferation rates compared to the pro-NC group.,The effects of miR-21 overexpression were reversed by BAY 11-7082.,We concluded that upregulated miR-21 in FLS in RA model rats may promote cell proliferation by facilitating NF-κB nuclear translocation, thus affecting the NF-κB pathway.

Although biologic therapies have changed the course of rheumatoid arthritis (RA), today's major challenge remains to identify biomarkers to target treatments to selected patient groups.,Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA.,Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab.,Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors.,The increase was however also found in patients with other forms of chronic inflammatory arthritis.,Importantly, high serum levels of miR-125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P = 0.002).,This predictive value was not limited to RA as it was also found in patients with B lymphomas.,Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment.

The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies.,Primary Sjögren’s syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function.,Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS.,Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands.,In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes.,Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib.,These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.

Interleukin (IL)-17 is one of the critical inflammatory cytokines that plays a direct role in development of Sjögren’s syndrome (SjS), a systemic autoimmune disease characterized by a progressive chronic attack against the exocrine glands.,The expression levels of IL-17 are correlated with a number of essential clinical parameters such as focus score and disease duration in human patients.,Significantly immunological differences of Th17 cells were detected at the onset of clinical disease in female SjS mice compared to males.,To further define the role of IL-17 in SjS and elucidate its involvement in the sexual dimorphism, we examined the systemic effect of IL-17 by genetically ablating Il-17 in the C57BL/6.,NOD-Aec1Aec2, spontaneous SjS murine model.,The results indicate that IL-17 is a potent inflammatory molecule in the induction of chemoattractants, cytokines, and glandular apoptosis in males and females.,Elimination of IL-17 reduced sialadenitis more drastically in females than males.,IL-17 is highly involved in modulating Th2 cytokines and altering autoantibody profiles which has a greater impact on changing plasma cells and germinal center B cell populations in females than males.,The result supports a much more important role for IL-17 and demonstrates the sexual dimorphic function of IL-17 in SjS.