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To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24.,ACT-RAY was a double-blind, 3-year trial.,Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy).,Tocilizumab 8 mg/kg was administered every 4 weeks.,Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2.,556 patients were randomised; 85% completed 52 weeks.,The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms.,Overall, week 24 results were maintained or further improved at week 52 in both arms.,Some endpoints favoured the add-on strategy.,Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression.,At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%).,Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients.,In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients.,Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.

In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.,Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO).,The primary endpoint was the DAS28-erythrocyte sedimentation rate (ESR) remission rate at week 24.,Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.,Of 556 randomly assigned patients, 512 (92%) completed 24 weeks.,DAS28-ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant).,A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%).,Radiographic progression was small and not different between groups (Genant-Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)).,Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO.,Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.,No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed.,The combination was more commonly associated with transaminase increases.,Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.

Background: The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background.,We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype.,Methods: We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls).,Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs).,The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction.,Results: An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02-0.5 in the incident study, and AP 0.4, 95% CI 0.1-0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02.,Compared with non-smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3-6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5-10.8).,Conclusions: The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking.,The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease.

We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).,We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls).,Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression.,Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction.,In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status.,Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status.,In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5-35.2) compared to nonobese subjects without the genetic risk factors.,The corresponding OR in the prevalent study was 13.8 (95% CI 4.1-46.8).,We observed striking interactions between BMI status and HLA genotype with regard to MS risk.,Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule-restricted arm of the immune system, causing MS.,Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.

Monogenic causes of autoimmunity give key insights to the complex regulation of the immune system.,We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in 5 individuals with a spectrum of early-onset autoimmune disease including type 1 diabetes.,These findings emphasise the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in Hyper IgE syndrome.

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases.,Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known.,Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]).,To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource.,We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10−22) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10−22).,Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10−7).,Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

The aim of this study was to discuss the possible roles and clinical value of 2 circRNAs (hsa_circ_0049224 and has_circ_0049220) in SLE patients.,Reverse-transcription real-time polymerase chain reaction (RT-PCR) was conducted to detect the expressions of hsa_circ_0049224, has_circ_0049220, and DNMT1 in peripheral blood mononuclear cells (PBMCs) from 18 diagnosed SLE patients and 10 healthy controls.,We found that the expressions of hsa_circ_0049224 and has_circ_0049220 in healthy control groups were both much higher than those in inactive and active SLE patients.,The expression level of DNMT1 is positively correlated with the expressions of hsa_circ_0049224 and has_circ_0049220.,Moreover, there was a negative correlation between the SLE Disease Activity Index (SLEDAI) and the expressions of hsa_circ_0049224 and has_circ_0049220.,We also found that these 2 circRNAs are associated with some clinical characteristics of SLE.,Hsa_circ_0049224 and has_circ_0049220 are probable factors involved in the pathogenesis of SLE, and they have potential clinical value in SLE.

The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted.,Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease.,On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified.,The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.,Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks.,Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up.,Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline.,Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration.,Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA.,However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level.

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells.,We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the β-cell regulatory landscape.,We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and 3D chromatin structure.,Our data indicate that the β cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors.,We find that T1D-associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells.,Our study illustrates how β cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.

The Type 1 Diabetes Genetics Consortium (T1DGC) sponsored an Autoantibody Workshop, providing data from a large number of type 1 diabetes-affected sibling pair families with multiple autoantibodies assayed (both islet and nonislet targets) and extensive genetic and clinical information.,Multiple groups analyzed the autoantibody data and various forms of genetic data.,The groups presented their results at the T1DGC Autoantibody Workshop and compared results across genes and autoantibodies.,The reports of the analyses of the autoantibody data with genetic information are contained as individual articles in this supplement.,There were several consistent findings that emerged from the T1DGC Autoantibody Workshop.,The human MHC (HLA genes) is the major contributor to variation in the presence of islet and nonislet autoantibodies in subjects with established type 1 diabetes.,The contribution of non-MHC genes/variants to autoantibody prevalence is dependent on the set of single nucleotide polymorphisms tested, the autoantibody evaluated, and the inclusion criteria for sample selection.,On the basis of these results, the HLA alleles DRB1*0101 and DRB1*0404 and the PTPN22 R620W variant are consistently associated with autoimmunity in the T1DGC Autoantibody Workshop data.

Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players.,Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity.,Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure.,Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA.,We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity.,Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ.,Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.

To provide a table indicating the risk for developing anti citrullinated protein antibody (ACPA) positive rheumatoid arthritis (RA) according to one’s HLA-DRB1 genotype.,We HLA-DRB1 genotyped 857 patients with ACPA positive RA and 2178 controls from South Eastern and Eastern France and calculated Odds Ratios (OR) for developing RA for 106 of 132 possible genotypes accounting for 97% of subjects.,HLA-DRB1 genotypic ORs for developing ACPA positive RA range from 28 to 0.19.,HLA-DRB1 genotypes with HLA-DRB1*04SE (HLA-DRB1*0404, HLA-DRB1*0405, HLA-DRB1*0408), HLA-DRB1*04∶01, HLA-DRB1*01 are usually associated with high risk for developing RA.,The second HLA-DRB1 allele in genotype somewhat modulates shared epitope associated risk.,We did not identify any absolutely protective allele.,Neither the Reviron, nor the du Montcel models accurately explains our data which are compatible with the shared epitope hypothesis and suggest a dosage effect among shared epitope positive HLA-DRB1 alleles, double dose genotypes carrying higher ORs than single dose genotypes.,HLA-DRB1 genotypic risk for developing ACPA positive RA is influenced by both HLA-DRB1 alleles in genotype.,We provide an HLA-DRB1 genotypic risk table for ACPA positive RA.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are liver-specific autoimmune conditions that are characterized by chronic hepatic damage and often lead to cirrhosis and hepatic failure.,Specifically, the protein tyrosine phosphatase N22 (PTPN22) gene encodes the lymphoid protein tyrosine phosphatase, which acts as a negative regulator of T-cell receptor signaling.,A missense single nucleotide polymorphism (SNP) (rs2476601) in PTPN22 has been linked to numerous autoimmune diseases in Caucasians.,In the present series, nine SNPs in the PTPN22 gene were analyzed in 166 patients with AIH, 262 patients with PBC, and 322 healthy controls in the Japanese population using TaqMan assays.,Although the functional rs3996649 and rs2476601 were non-polymorphic in all subject groups, the frequencies of the minor alleles at rs1217412, rs1217388, rs1217407, and rs2488458 were significantly decreased in AIH patients as compared with controls (all Pc < 0.05).,There were no significant relationships with PTPN22 SNPs in PBC patients.,Interestingly, the AAGTCCC haplotype was significantly associated with resistance to both AIH (odds ratio [OR] = 0.58, P = 0.0067) and PBC (OR = 0.58, P = 0.0048).,SNPs in the PTPN22 gene may therefore play key roles in the genetic resistance to autoimmune liver disease in the Japanese.

Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in the TNFAIP3 region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations.,In this study, we investigated whether SNPs in the TNFAIP3 region are associated with SLE also in a Japanese population.,A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls.,Association of rs2230926 G allele with SLE was replicated in Japanese (allelic association P = .033, odds ratio [OR] 1.47, recessive model P = .023, OR 8.52).,The association was preferentially observed in the SLE patients with nephritis.,When the TNFAIP3 mRNA levels of the HapMap samples were examined using GENEVAR database, the presence of TNFAIP3 rs2230926 G allele was associated with lower mRNA expression of TNFAIP3 (P = .013).,These results indicated that TNFAIP3 is a susceptibility gene to SLE both in the Caucasian and Asian populations.

Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA).,To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).,Total RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12).,Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.,Whole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs.,Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups.,Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart.,We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs.,Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks.,Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.,We highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA.,Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.,The online version of this article (doi:10.1186/s13075-017-1459-x) contains supplementary material, which is available to authorized users.

Dominant-negative somatic mutations of p53 has been identified in the synovium of patients with rheumatoid arthritis (RA), in which interleukin (IL)-6 has been established as a pivotal inflammatory cytokine.,The aim of this study was to clarify the significance of p53 in the longstanding inflammation in RA by modulating IL-6.,We established adjuvant-induced arthritis (AIA) in Lewis rats and treated them with p53 activator, and then analyzed the histopathology of the synovium and IL-6 expression.,Human fibroblast-like synoviocytes (FLS) were cultured and transfected with p53-siRNA or transduced with adenovirus (Ad)-p53, and then assessed with MTT, TUNEL staining, and luciferase assay.,IL-1β, tumor necrosis factor (TNF)-α and IL-17 were used to stimulate FLS, and subsequent IL-6 expression as well as relevant signal pathways were explored.,p53 significantly reduced synovitis as well as the IL-6 level in the AIA rats.,It controlled cell cycle arrest and proliferation, but not apoptosis.,Proinflammatory cytokines inhibited p53 expression in FLS, while p53 significantly suppressed the production of IL-6.,Furthermore, IL-6 expression in p53-deficient FLS was profoundly reduced by NF-kappaB, p38, JNK, and ERK inhibitors.,Our findings reveal a novel function of p53 in controlling inflammatory responses and suggest that p53 abnormalities in RA could sustain and accelerate synovial inflammation mainly through IL-6. p53 may be a key modulator of IL-6 in the synovium and plays a pivotal role in suppressing inflammation by interaction with the signal pathways in RA-FLS.,Interfering with the p53 pathway could therefore be an effective strategy to treat RA.

Interleukin 17 (IL-17)-producing TH17 cells are often present at the sites of tissue inflammation in autoimmune diseases, which has lead to the conclusion that TH17 are main drivers of autoimmune tissue injury.,However, not all TH17 cells are pathogenic, in fact TH17 generated with TGF-β1 and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23.,Here we show that TGF-β3, produced by developing TH17 cells, is dependent on IL-23, which together with IL-6 induces highly pathogenic TH17 cells.,Moreover, TGF-β3-induced TH17 cells are functionally and molecularly distinct from TGF-β1-induced TH17 cells and possess a molecular signature that defines pathogenic effector TH17 cells in autoimmune disease.

CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4.,Crucial for T helper17 (Th17) cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation.,Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification7-10.,Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling.,Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β.,Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet.,T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model.,These data suggest an alternative mode for Th17 differentiation.,Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features.,RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction.,PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues.,Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors.,Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD.,Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA.,However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD.,This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases.,In addition, the current available treatments targeting both RA and PD were revised.

Risk of cardiovascular (CV) disease is increased among RA patients.,High inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk.,Inflammation is linked with accelerated atherosclerosis and associated with a paradoxical inversion of the relationship between CV risk and lipid levels in patients with untreated RA, recently coined the lipid paradox.,Furthermore, the inflammatory burden is also associated with qualitative as well as quantitative changes in lipoproteins, with the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol significantly altered.,RA therapies can increase lipid levels, which may reflect the normalization of lipids due to their inflammatory-dampening effects.,However, these confounding influences of inflammation and RA therapies on lipid profiles pose challenges for assessing CV risk in RA patients and interpretation of traditional CV risk scores.,In this review we examine the relationship between the increased inflammatory burden in RA and CV risk, exploring how inflammation influences lipid profiles, the impact of RA therapies and strategies for identifying and monitoring CV risk in RA patients aimed at improving CV outcomes.

Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology.,The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role.,Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment.,Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity.,Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases.,In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts.,Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases.,These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments.,And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that causes deformity of the joints and physical disability.,Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proven to have various pharmacological activities.,A recent study showed that icariin suppressed cartilage and bone degradation in mice of collagen-induced arthritis.,However, the mechanism needs to be further investigated.,In our current study, we found that icariin reduced the arthritis score and the incidence of arthritis compared with that in mice treated with water.,Icariin inhibits the expression of various osteoclastogenic markers, such as β3 integrin, cathepsin K, and MMP9 in vitro.,Icariin treatment in mice with CIA also resulted in less number of Th17 cells and decreased ratio of CD4+IL-17+ cells.,The alleviated arthritis score and incidence of arthritis and reduced serum levels of IgG2a induced by icariin were abolished with additional IL-17 administration.,Furthermore, icariin inhibited STAT3 activation in T cells and STAT3 inhibitor resulted in decreased IL-17 production and alleviated RA.,In conclusion, icariin decreases Th17 cells and suppresses the production of IL-17, which contributes to the alleviated rheumatoid arthritis, through the inhibition of STAT3 activation.

To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE).,Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks.,Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay.,The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24).,Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52.,The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN-high subpopulation.,The study result was considered positive if the primary end point was met in either of the 2 study populations.,The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis.,The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively.,At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points.,Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups.,Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively).,Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE).,Here, we report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population.,Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls.,We identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively.,Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation.,Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1.,In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression.,Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE.,Our epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis.,Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells.

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females.,Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease.,We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells.,In this study, tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice.,Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein (MOG) one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages.,We demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice.,Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells.,An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

The potential of autologous cell‐based therapies including those using multipotent mesenchymal stromal cells (MSCs) is being investigated for multiple sclerosis (MS) and other neurological conditions.,However, the phenotype of MSC in neurological diseases has not been fully characterized.,We have previously shown that MSC isolated from patients with progressive MS (MS‐MSC) have reduced expansion potential, premature senescence, and reduced neuroprotective potential in vitro.,In view of the role of antioxidants in ageing and neuroprotection, we examined the antioxidant capacity of MS‐MSC demonstrating that MS‐MSC secretion of antioxidants superoxide dismutase 1 (SOD1) and glutathione S‐transferase P (GSTP) is reduced and correlates negatively with the duration of progressive phase of MS.,We confirmed reduced expression of SOD1 and GSTP by MS‐MSC along with reduced activity of SOD and GST and, to examine the antioxidant capacity of MS‐MSC under conditions of nitrosative stress, we established an in vitro cell survival assay using nitric oxide‐induced cell death.,MS‐MSC displayed differential susceptibility to nitrosative stress with accelerated senescence and greater decline in expression of SOD1 and GSTP in keeping with reduced expression of master regulators of antioxidant responses nuclear factor erythroid 2‐related factor 2 and peroxisome proliferator‐activated receptor gamma coactivator 1‐α.,Our results are compatible with dysregulation of antioxidant responses in MS‐MSC and have significant implications for development of autologous MSC‐based therapies for MS, optimization of which may require that these functional deficits are reversed.,Furthermore, improved understanding of the underlying mechanisms may yield novel insights into MS pathophysiology and biomarker identification.,Stem Cells Translational Medicine 2018;7:748-758

This article presents the first detailed analysis of the prevalence and disability burden of Guillain-Barré syndrome (GBS) from 1990 to 2019 by cause, age, sex, and Socio-demographic Index (SDI) in 204 countries and territories.,Data from the Global Burden of Diseases Study (GBD) 2019 were used.,GBD 2019 modelled the prevalence of GBS using hospital and claims data.,Years lived with disability (YLDs) were estimated as the product of the GBS prevalence and the disability weight.,This article also reported proportions in the age-standardised prevalence rate that were due to six underlying causes of GBS.,In 2019, there were 150,095 [95% uncertainty intervals (UI) 119,924 to 188,309] total cases of GBS worldwide, which resulted in 44,407 (95% UI 28,016 to 64,777) YLDs.,Globally, there was a 6.4% (95% UI 3.6 to 9.5) increase in the age-standardised prevalence of GBS per 100,000 population between 1990 and 2019.,High-income Asia Pacific [1.9 (95% UI: 1.5 to 2.4)] and East Asia [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000), respectively, in 2019.,Nationally, Japan [6.4 (95% UI: 5.3 to 7.7)] and China [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000).,The age-standardised burden of GBS increased with increasing age and was higher in males in all age groups.,Furthermore, the age-standardised prevalence of GBS (per 100,000) had a positive association with the level of development, as measured by SDI, although this association was not strong.,Upper respiratory infections and unknown causes accounted for the highest proportions of underlying causes.,Globally, the prevalence of GBS continues to increase.,Geographical differences and strategies aimed at preventing infectious diseases should be considered in future health policy planning and decision-making processes.,This study had several limitations, such as using the same disability weight for all causes and a reliance on hospital- and self-reported data, which should be addressed in future research.,The online version contains supplementary material available at 10.1186/s12974-021-02319-4.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP).,To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open‐label, single‐arm study of IVIG in immunoglobulin (Ig)‐naïve or IVIG pre‐treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double‐blind, randomized study including an open‐label, single‐arm IVIG phase in IVIG pre‐treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235).,Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score.,Adverse drug reactions (ADRs) and ADRs/infusion were recorded.,Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre‐treated subjects) and 72.9% in PATH.,In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks.,No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21).,In the pooled cohort, median change from baseline to last observation was −1.0 (interquartile range −2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score.,In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion.,This analysis confirms the efficacy and safety of IgPro10, a recently FDA‐approved IVIG for CIDP, in a population of mainly pre‐treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].

Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation.,As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown.,Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis.,The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions.,C3d+ microglial clusters were found in chronic but not acute MS.,They were not associated with antibody deposits or terminal complement activation.,They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production.,C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI.,We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons.,As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease.,GLIA 2017;65:264-277

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.

Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood.,The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross‐reactivity.,IgG‐secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full‐length mAb (n = 93) and also as germline‐reverted versions.,The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated.,Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA.,The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation.,This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients.,The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets.,They also conveyed different effector functions as revealed in an osteoclast activation assay.,These findings suggest that the high level of cross‐reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points.,This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Ro52/TRIM21 plays a key role in antibody-dependent pathogen neutralization and is a major autoantigen in systemic lupus erythematosus, Sjögren’s syndrome (SS), and other autoimmune diseases.,Here we evaluated immunoreactivity against Ro52-related molecules in SS and healthy volunteers.,Although most proteins examined were not antigenic, several TRIM paralogs, including TRIM22, and TRIM38, showed sporadic immunoreactivity in SS.,In contrast, the murine Ro52 ortholog with limited linear homology demonstrated high levels of autoantibodies implicating the importance of shared conformational epitopes.,To further explore the autoantigencity of Ro52, deletion and point mutant analyses were employed revealing previously hidden, robust autoantibodies directed against its C-terminal immunoglobulin-binding domain.,Another autoantibody, rheumatoid factor, targeting the Fc region of IgG, strongly overlapped with Ro52 seropositivity (odds ratio 14; P < 0.0001).,These convergent mechanistic findings support a model whereby intracellular Ro52-bound antibody-coated pathogen complexes, released or misprocessed from infected cells, drive autoantigenicity against Ro52 and the Fc region of IgG.

T cells from RA patients are hypoglycolytic due to insufficient induction of the glycolytic activator PFKFB3, resulting in impaired autophagy and reduced ROS production.,In the HLA class II-associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity.,We have explored the metabolic activity of RA T cells and its impact on cellular function and fate.,Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible.,The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect.,Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis.,Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS).,PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules.,PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation.,In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.

Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells.,The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO2) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators.,Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO2 under direct visualisation.,Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology.,In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay.,Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA.,The tPO2 was 22.5 (range 3.2-54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p<0.01) and sublining CD68 cells (r=−0.615, p<0.001).,No relationship with cell proliferation or apoptosis was found.,Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO2 in vivo) induced cell migration.,This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO2 <20 mm Hg (all p values <0.05).,This is the first study to show a direct in vivo correlation between synovial tPO2, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

The cause of multiple sclerosis (MS) is currently unknown, but it is thought that oxidative damage and iron metabolism mechanisms are involved.,The aim of this study was to examine ceruloplasmin concentration in MS patients based on various immunomodifying therapies and to test the effect of antioxidative melatonin on ceruloplasmin levels.,This prospective study included 102 MS patients and 15 healthy controls.,Patients were divided into groups according to different immunomodifying therapies: interferons beta 1a, interferons beta 1b, glatiramer acetate, mitoxantrone, and immunomodifying pre-treatment (A, B, G, Mx, and P groups, respectively), and the relapse R group.,MS patients were supplemented with melatonin for 3 months.,Serum ceruloplasmin concentrations, EDSS, brain MRI, serum C-reactive protein level, and white blood cell count were examined.,The results indicated significantly increased levels of ceruloplasmin in MS patients.,No differences in ceruloplasmin concentrations between the relapse group and controls were observed.,In A and G groups, ceruloplasmin levels before and after melatonin were similar to levels in controls.,In group B, ceruloplasmin concentration was significantly higher vs. control and relapse groups.,After melatonin administration in group B, ceruloplasmin levels decreased.,Ceruloplasmin concentrations in the Mx group were significantly higher compared to controls.,We found for the first time that ceruloplasmin concentration in MS patients varies depending on different immunomodulatory treatment and decrease after 3 months of melatonin administration.,Ceruloplasmin could be a valuable serum marker for the chronic demyelinating process participating in oxidative stress mechanisms, as well as a neurodegenerative marker, but not a marker of acute-phase MS.

There is still no curative treatment for multiple sclerosis (MS), but during the last 20 years eight different disease-modifying compounds have been approved for relapsing−remitting MS (RRMS).,A literature search was conducted on published randomized controlled phase III trials indexed in PubMed on the approved medications until 21 May 2015.,In this review the mode of action, documented treatment effects and side effects of the approved MS therapies are briefly discussed.,Based on current knowledge of risk−benefit of the approved MS medications, including factors influencing adherence, it is suggested that oral treatment with dimethyl fumarate or teriflunomide should be preferred as a starting therapy amongst the first-line preparations for de novo RRMS.,In the case of breakthrough disease on first-line therapy, or rapidly evolving severe RRMS, second-line therapy with natalizumab, fingolimod or alemtuzumab should be chosen based on careful risk−benefit stratification.

The measurement of gait characteristics during a self-administered 2-minute walk test (2MWT), in persons with multiple sclerosis (PwMS), using a single body-worn device, has the potential to provide high-density longitudinal information on disease progression, beyond what is currently measured in the clinician-administered 2MWT.,The purpose of this study is to determine the test-retest reliability, standard error of measurement (SEM) and minimum detectable change (MDC) of features calculated on gait characteristics, harvested during a self-administered 2MWT in a home environment, in 51 PwMS and 11 healthy control (HC) subjects over 24 weeks, using a single waist-worn inertial sensor-based smartphone.,Excellent, or good to excellent test-retest reliability were observed in 58 of the 92 temporal, spatial and spatiotemporal gait features in PwMS.,However, these were less reliable for HCs.,Low SEM% and MDC% values were observed for most of the distribution measures for all gait characteristics for PwMS and HCs.,This study demonstrates the inter-session test-retest reliability and provides an indication of clinically important change estimates, for interpreting the outcomes of gait characteristics measured using a body-worn smartphone, during a self-administered 2MWT.,This system thus provides a reliable measure of gait characteristics in PwMS, supporting its application for the longitudinal assessment of gait deficits in this population.

We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.,Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions.,The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models.,The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.,Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all).,The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all).,During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01).,Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL.,Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.

•Cladribine is a highly effective, recently available treatment in multiple sclerosis.,•This case report describes a patient with a mild COVID-19 infection during second year treatment with cladribine.,•Normal immune response with detectable antibodies to SARS-CoV2 three months after the infection.,Cladribine is a highly effective, recently available treatment in multiple sclerosis.,This case report describes a patient with a mild COVID-19 infection during second year treatment with cladribine.,Normal immune response with detectable antibodies to SARS-CoV2 three months after the infection.,Cladribine is a highly effective, recently available treatment in multiple sclerosis.,This case report describes a patient with COVID-19 infection during second year treatment with cladribine.,The infection was mild and she was able to mount an adequate immune response with detectable antibodies three months later.

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells.,This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis.,Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments.,However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination.,As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity.,This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered.,However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here.,This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.,Graphical AbstractBased on the known and emerging biology of autoimmune diseases and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit or blunt the protective immunity following infection and vaccination.,This is supported clinically, as the majority of SARS-CoV-2 infected, CD20-depleted people with autoimmunity, have recovered.,However, in CD-20 treated people until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.,Based on the known and emerging biology of autoimmune diseases and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit or blunt the protective immunity following infection and vaccination.,This is supported clinically, as the majority of SARS-CoV-2 infected, CD20-depleted people with autoimmunity, have recovered.,However, in CD-20 treated people until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

Our studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice.,In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor.,Macrophage depletion, either at the start of the autoimmune process or when diabetogenesis is active, leads to a significant reduction in diabetes incidence.,Depletion of the islet macrophages reduces the entrance of T cells into islets and results in the absence of antigen presentation.,Concordantly, a regulatory pathway develops that controls diabetes progression.,We conclude that treatments that target the islet macrophages may have important clinical relevance for the control of autoimmune type 1 diabetes.,Treatment of C57BL/6 or NOD mice with a monoclonal antibody to the CSF-1 receptor resulted in depletion of the resident macrophages of pancreatic islets of Langerhans that lasted for several weeks.,Depletion of macrophages in C57BL/6 mice did not affect multiple parameters of islet function, including glucose response, insulin content, and transcriptional profile.,In NOD mice depleted of islet-resident macrophages starting at 3 wk of age, several changes occurred: (i) the early entrance of CD4 T cells and dendritic cells into pancreatic islets was reduced, (ii) presentation of insulin epitopes by dispersed islet cells to T cells was impaired, and (iii) the development of autoimmune diabetes was significantly reduced.,Treatment of NOD mice starting at 10 wk of age, when the autoimmune process has progressed, also significantly reduced the incidence of diabetes.,Despite the absence of diabetes, NOD mice treated with anti-CSF-1 receptor starting at 3 or 10 wk of age still contained variably elevated leukocytic infiltrates in their islets when examined at 20-40 wk of age.,Diabetes occurred in the anti-CSF-1 receptor protected mice after treatment with a blocking antibody directed against PD-1.,We conclude that treatment of NOD mice with an antibody against CSF-1 receptor reduced diabetes incidence and led to the development of a regulatory pathway that controlled autoimmune progression.

Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of the pancreatic β-cells, causing inability to produce insulin.,Proinflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-γ, IL-12, IL-17, and NO can be released by CD4 and CD8+ lymphocytes as well as by classically activated macrophages (CAMϕs), which are important in the development of T1D.,Helminth infections have been shown to prevent T1D, mainly through Th2-biased responses and increased recruitment of regulatory cell populations.,Previously, we have shown that Taenia crassiceps infection in mice significantly reduces hyperglycemia, insulitis, and the incidence of T1D.,In this study, we determined whether T. crassiceps-derived products such as soluble (TcS) or excreted/secreted (TcES) antigens might have a beneficial influence on the development of experimental T1D.,Treatment with different doses before or after induction of T1D was analyzed.,Mice that were pretreated with TcS were unable to develop T1D, whereas those receiving TcES early after T1D induction displayed significantly reduced insulitis and hyperglycemia along with increased recruitment of alternatively activated macrophages (AAMϕs) and myeloid-derived suppressor cells (MDSCs).,Finally, we examined the modulatory role of AAMϕs on T1D by depleting macrophages with clodronate-loaded liposomes, demonstrating that AAMϕs are key cells in T1D regulation.

Neuromyelitis optica spectrum disorder (NMOSD) is a rapidly disabling disease.,Epidemiologic studies have suggested varying NMOSD mortality across ethnic groups.,However, NMOSD mortality data in China are scarce.,This study’s objectives were to explore mortality and causes of death among Chinese NMOSD patients and to identify independent predictors of death.,We performed a retrospective study with a 10‐year follow‐up of Chinese NMOSD patients.,A Cox proportional hazards model was used to identify independent predictors of death.,Five hundred and sixty‐nine patients were included; 24 patients died during follow‐up, for overall mortality of 4.2%.,In these patients, the median disease duration at the time of death was 3.4 years.,The most common cause of death was secondary infection (62.5%), especially respiratory infection (45.8%).,The second most common cause of death was extensive cervical myelitis with respiratory failure (16.7%).,Other causes included suicide (8.3%), cancer (4.2%), cerebral embolism (4.2%), and unknown causes (4.2%).,The multivariate Cox analyses indicated that a short first interattack interval (HR = 0.93, 95% CI 0.89-0.98, p = 0.003), lack of regular immunotherapy (HR = 10.34, 95% CI 4.05-26.37, p < 0.001), and older age at onset were independent predictors of death.,Every increasing decade of onset age increased the risk of death 2.59 times (95% CI 1.74-3.86, p < 0.001).,Infections were more common in patients not treated with any immunotherapy, indicating that early and consequent immunotherapy might prevent death by infections, which is of great importance for further treatment of NMOSD patients to avoid undertreatment due to fear of treatment‐associated infections.

Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed.,Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients.,We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients.,Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose.,There were three cases of COVID-19 infection encountered after the first dose.,Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache.,No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively.,The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period.,Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs.,COVID-19 BNT162b2 vaccine proved safe for MS patients.,No increased risk of relapse activity was noted.

Genetic deficiency in C1q is a strong susceptibility factor for systemic lupus erythematosus (SLE).,There are two major hypotheses that potentially explain the role of C1q in SLE.,The first postulates that C1q deficiency abrogates apoptotic cell clearance, leading to persistently high loads of potentially immunogenic self-antigens that trigger autoimmune responses.,While C1q undoubtedly plays an important role in apoptotic clearance, an essential biological process such as removal of self- waste is so critical for host survival that multiple ligand-receptor combinations do fortunately exist to ensure that proper disposal of apoptotic debris is accomplished even in the absence of C1q.,The second hypothesis is based on the observation that locally synthesized C1q plays a critical role in regulating the earliest stages of monocyte to dendritic cell (DC) differentiation and function.,Indeed, circulating C1q has been shown to keep monocytes in a pre-dendritic state by silencing key molecular players and ensuring that unwarranted DC-driven immune responses do not occur.,Monocytes are also able to display macromolecular C1 on their surface, representing a novel mechanism for the recognition of circulating “danger.”,Translation of this danger signal in turn, provides the requisite “license” to trigger a differentiation pathway that leads to adaptive immune response.,Based on this evidence, the second hypothesis proposes that deficiency in C1q dysregulates monocyte-to-DC differentiation and causes inefficient or defective maintenance of self-tolerance.,The fact that C1q receptors (cC1qR and gC1qR) are also expressed on the surface of both monocytes and DCs, suggests that C1q/C1qR may regulate DC differentiation and function through specific cell-signaling pathways.,While their primary ligand is C1q, C1qRs can also independently recognize a vast array of plasma proteins as well as pathogen-associated molecular ligands, indicating that these molecules may collaborate in antigen recognition and processing, and thus regulate DC-differentiation.,This review will therefore focus on the role of C1q and C1qRs in SLE and explore the gC1qR/C1q axis as a potential target for therapy.

Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous.,However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain.,The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level.,We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis.,Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha.,We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies.,Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect.,Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome.,In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature.,Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells.,Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.,The online version of this article (doi:10.1186/s13075-015-0588-3) contains supplementary material, which is available to authorized users.

Cortical, thalamic and hippocampal gray matter atrophy in relapsing-remitting MS (RRMS) is associated cognitive deficits.,However, the role of interconnecting white matter pathways including the fornix, cingulum, and uncinate fasciculus (UF) is less well studied.,To assess MS damage to a hippocampal-thalamic-prefrontal network and the relative contributions of its components to specific cognitive domains.,We calculated diffusion tensor fractional anisotropy (FA) in the fornix, cingulum and UF as well as thalamic and hippocampal volumes in 27 RRMS patients and 20 healthy controls.,A neuropsychological battery was administered and 4 core tests known to be sensitive to MS changes were used to assess cognitive impairment.,To determine the relationships between structure and cognition, all tests were grouped into 4 domains: attention/executive function, processing speed, verbal memory, and spatial memory.,Univariate correlations with structural measures and depressive symptoms identified potential contributors to cognitive performance and subsequent linear regression determined their relative effects on performance in each domain.,For significant predictors, we also explored the effects of laterality and axial versus radial diffusivity.,RRMS patients had worse performance on the Symbol Digit Modalities Test, but no significant impairment in the 4 cognitive domains.,RRMS had reduced mean FA of all 3 pathways and reduced thalamic and hippocampal volumes compared to controls.,In RRMS we found that thalamic volume and BDI predicted attention/executive function, UF FA predicted processing speed, thalamic volume predicted verbal memory, and UF FA and BDI predicted spatial memory.,Hippocampal-thalamic-prefrontal disruption affects cognitive performance in early RRMS with mild to minimal cognitive impairment, confirming both white and gray matter involvement in MS and demonstrating utility in assessing functional networks to monitor cognition.,•We detect limbic white matter and gray matter insult in early RRMS patients with mild to minimal cognitive impairment.,•Thalamic atrophy and uncinate fasciculus microstructural changes are associated with cognitive performance in early RRMS.,•Depressive symptomatology also independently predicts cognitive performance,We detect limbic white matter and gray matter insult in early RRMS patients with mild to minimal cognitive impairment.,Thalamic atrophy and uncinate fasciculus microstructural changes are associated with cognitive performance in early RRMS.,Depressive symptomatology also independently predicts cognitive performance

Grey matter (GM) damage is a clinically relevant feature of multiple sclerosis (MS) that has been previously assessed with diffusion tensor imaging (DTI).,Fractional anisotropy (FA) of the basal ganglia and thalamus might be increased in MS patients, and correlates with disability scores.,Despite the established role of the striatum and thalamus in motor control, mood and cognition, the impact of DTI changes within these structures on motor and neuropsychological performance has not yet been specifically addressed in MS.,We investigated DTI metrics of deep GM nuclei and their potential association with mobility and neuropsychological function.,DTI metrics from 3T MRI were assessed in the caudate, putamen, and thalamus of 30 MS patients and 10 controls.,Sixteen of the patients underwent neuropsychological testing.,FA of the caudate and putamen was higher in MS patients compared to controls.,Caudate FA correlated with Expanded Disability Status Scale score, Ambulation Index, and severity of depressive symptomatology.,Putamen and thalamus FA correlated with deficits in memory tests.,In contrast, cerebral white matter (WM) lesion burden showed no significant correlation with any of the disability, mobility and psychometric parameters.,Our findings support evidence of FA changes in the basal ganglia in MS patients, as well as deep GM involvement in disabling features of MS, including mobility and cognitive impairment.,Deep GM FA appears to be a more sensitive correlate of disability than WM lesion burden.

In 9-20% of cases, Sjögren's syndrome is associated with various respiratory symptoms.,The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease.,The most common manifestation of ILD is nonspecific interstitial pneumonia in its fibrosing variant.,Other types of ILD, such as organising pneumonia, usual interstitial pneumonia and lymphocytic interstitial pneumonitis, are rare.,Their radiological presentation is less distinctive, and definitive diagnosis may require the use of transbronchial or surgical lung biopsy.,Corticosteroid therapy is the mainstay of ILD treatment in Sjögren's syndrome, but the use of other immunosuppressive drugs needs to be determined.,ILD is a significant cause of death in Sjögren's syndrome.,Tracheobronchial disease is common in Sjögren's syndrome, characterised by diffuse lymphocytic infiltration of the airway.,It is sometimes responsible for a crippling chronic cough.,It can also present in the form of bronchial hyperresponsiveness, bronchiectasis, bronchiolitis or recurrent respiratory infections.,The management of these manifestations may require treatment for dryness and/or inflammation of the airways.,Airway disease has little effect on respiratory function and is rarely the cause of death in Sjögren's syndrome patients.,Rare respiratory complications such as amyloidosis, lymphoma or pulmonary hypertension should not be disregarded in Sjögren's syndrome patients.,We present the features, diagnostic tests and treatments of thoracic manifestations of Sjögren's syndromehttp://ow.ly/10m8vd

A number of reports have indicated an association between thyroid diseases and primary Sjögren's syndrome (pSS).,However, fewer studies have investigated whether the presence of thyroid diseases is associated with increased risk of developing pSS.,Thus, the aim of our study was to use a nationwide health claims database to explore the prevalence and risk of pSS in female patients with thyroid diseases.,From the Registry of Catastrophic Illness database in the National Health Insurance Research Database in Taiwan, we identified 389 female patients with a diagnosis of pSS from 2005 to 2010.,We also obtained 1945 control subjects frequency-matched on sex, 10-year age interval, and year of index date from the Longitudinal Health Insurance Database (LHID2000).,Both groups were retrospectively traced back to a period of eight years to obtain diagnosis of thyroid diseases prior to index date.,A significantly higher risk of pSS was associated with the presence of thyroid diseases (adjusted odds ratio (AOR) = 2.1, 95% confidence interval (CI) = 1.6-2.9).,Among the sub-categories of thyroid diseases, patients with thyroiditis (AOR = 3.6, 95% CI = 1.7-7.5), thyrotoxicosis (AOR = 2.5, 95% CI = 1.6-3.8), and unspecified hypothyroidism (AOR = 2.4, 95% CI = 1.2-4.6), and simple and unspecified goiter (AOR = 2.0, 95% CI = 1.3-3.3) were significantly associated with increased risk of pSS.,The associations were generally stronger in the mid-forties to mid-sixties age group, except in patients with unspecified hypothyroidism.,The risk of pSS was significantly increased in female patients with thyroid diseases, particularly those in their mid-forties to mid-sixties.,An increased awareness of the possibility of pSS in perimenopausal females with thyroid diseases is important to preserve their quality of life and to avoid comorbidity.

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease.,In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter.,In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions.,In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage.,Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique.,Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions.,Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.

Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors.,We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod.,Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry.,In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naïve T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy.,The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly.,Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively).,The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834).,The CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.

Among autoimmune diseases, systemic lupus erythematosus (SLE) patients have a unique predisposition to develop infections, which represents one of their main causes of morbidity and mortality.,Many infections occur at disease diagnosis in the absence of immunosuppressive therapy, suggesting that the immunological abnormalities in SLE patients might be fundamental for the development of this complication.,The aim of this study was to address the main clinical and immunological features associated with the development of infection and to create and validate a compound clinical-immunological infection predictive index in a cohort of SLE patients.,We included 55 SLE patients with < 5 years since diagnosis.,The clinical and immunological features were evaluated periodically and patients were followed-up during 1 year, searching for the development of infection.,Immunophenotyping was performed by multiparametric flow cytometry and neutrophil extracellular traps (NETs) were assessed by confocal microscopy.,Eighteen patients (32.7%) presented 19 infectious events, 5 (26.3%) were severe.,For the construction of the index, we performed a logistic regression analysis and the cutoff points were determined with ROC curves.,Increased numbers of peripheral Th17 cells, B cell lymphopenia, and lower TLR2 expression in monocytes, as well as the use of cyclophosphamide were the major risk factors for the development of infection and thus were included in the index.,Besides, patients that developed infection were characterized by increased numbers of low-density granulocytes (LDGs) and higher expression of LL-37 in NETs upon infection.,Finally, we validated the index retrospectively in a nested case-control study.,A score >1.5 points was able to predict infection in the following year (AUC = 0.97; LR- = 0.001, specificity 100%, P = 0.0003).,Our index encompasses novel immunological features able to prospectively predict the risk of infection in SLE patients.

The available clinical as well as experimental studies implicate participation of T regulatory (Treg) subsets in the pathogenesis and course of systemic lupus erythematosus (SLE).,Introduction of the CD4+CD25+CD127− and CD4+CD25+Foxp3+ regulatory subpopulations analysis into immunological processes assessment and disease activation prognosis in patients with lupus nephritis (LN) may improve monitoring of disease activity and enable an early, and thus more effective, therapeutic treatment.,The main goal of the study was to investigate whether the quantitative changes of Treg subpopulations are related to the clinical status of patients with LN.,Fifty-four adult SLE patients divided into two groups according to their SLEDAI and renal SLEDAI scores were enrolled into the study.,Subpopulations of CD4+CD25+CD127− and CD4+CD25+Foxp3+ phenotypes were determined by flow cytometry.,The control group had higher absolute number of CD4+CD25+Foxp3+ cells compared with the study group (p < 0.001).,Also, significant inverse correlation in the absolute number of CD4+CD25+Foxp3+ cells and SLEDAI score was observed.,There were significant differences in the percentage and absolute number of CD4+CD25+Foxp3+ lymphocytes between active and non-active LN groups.,The study group had statistically lower values of CD4+CD25+CD127− cells, both in the percentage (p < 0.001) as well as their absolute number (p = 0.014) compared to the control group.,There were also statistically significant positive correlations between the absolute number of CD4+CD25+CD127− and CD4+CD25+Foxp3+ Tregs.,In conclusion: (1) reduction in the number of regulatory CD4+CD25+Foxp3+ cells is a promising indicator of the activity of SLE, particularly of renal involvement; (2) determination of the number of regulatory cells using the CD4+CD25+CD127− phenotype is unreliable in patients with SLE.

Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed.,Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients.,We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients.,Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose.,There were three cases of COVID-19 infection encountered after the first dose.,Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache.,No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively.,The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period.,Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs.,COVID-19 BNT162b2 vaccine proved safe for MS patients.,No increased risk of relapse activity was noted.

It is unknown whether MS disease modifying therapies impact ability to mount an antibody response to SARS-CoV-2.,Case series and literature review.,We report a series of two MS patients who developed COVID-19 while on Ocrelizumab therapy and subsequently exhibited negative SARS-CoV-2 serology.,A 42-year-old man and 39-year-old woman with MS developed COVID-19 while on Ocrelizumab therapy.,Neither patient required hospitalization.,The man exhibited negative serology at 7- and 9-weeks post-infection.,The woman exhibited negative serology at 6- and 12-weeks post-infection.,Large studies are essential to determine whether certain DMTs may blunt SARS-CoV-2 antibody production.

Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder.,The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor.,It occurs more often in females than in males.,Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines.,In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination.,To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria.,This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

MicroRNAs (miRNAs) are single-stranded 19-25 nucleotide-long RNAs and have an important role in post-transcriptional gene silencing.,It has been demonstrated that miRNAs are dysregulated in patients with multiple sclerosis (MS).,For instance, miR-21, miR-142-3p, miR-146a, miR-146b, miR-155 and miR-326 were up-regulated in both peripheral blood mononuclear cells (PBMCs) and brain white matter lesions from MS patients and mouse model as well.,These up-regulated miRNAs may be used as a signature for MS and play critical roles in MS pathogenesis.,Moreover, miR-15a, miR-19a, miR-22, miR-210 and miR-223 were up-regulated in both regulatory T cells (Tregs) and other samples such as plasma, blood cells, PBMCs and brain white matter tissues from MS patients, suggesting that these up-regulated miRNAs and Tregs may also play a role in MS pathogenesis.,Contrarily, other miRNAs such as miR-15a, miR-15b, miR-181c and miR-328 were down-regulated in MS.,Drugs such as interferon-β and glatiramer acetate for MS treatment may regulate miRNA expression and thus have benefits for MS patients.,The dysregulated miRNAs such as miR-155 and miR-326 may be used as diagnostic markers and therapeutic targets for MS.

Resting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared.,Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer.,CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells.,Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells.,Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg.,Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors.,Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors.,Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD.,Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III.,In MS, CCR6+Treg were lower in Population III.,This study found MS is associated with significant shifts in CD4+T cells subpopulations.,MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment.,Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS).,However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood.,In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS.,We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE).,AAV-IL-27 administration reduced the frequencies of Th17, Treg, and GM-CSF-producing CD4+ T cells and induced T cell expression of IFN-γ, IL-10, and PD-L1.,However, experiments involving IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and PD-L1 expression were not required for the prevention of EAE development.,Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development and Th17 responses when given at disease onset.,We found that mice with established EAE had significant expansion of CD11b+Gr-1+ cells, and AAV-IL-27 treatment further expanded these cells and induced their expression of Th17-promoting cytokines such as IL-6.,Adoptive transfer of AAV-IL-27-expanded CD11b+Gr-1+ cells enhanced EAE development.,Thus, expansion of CD11b+Gr-1+ cells provides an explanation for the resistance to IL-27 therapy in mice with established disease.

Optical coherence tomography (OCT)‐derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long‐term disability is unknown.,We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later.,Between 2006 and 2008, 172 people with MS underwent Stratus time domain‐OCT imaging [160 with measurement of total macular volume (TMV)] and high and low‐contrast letter acuity (LCLA) testing (n = 150; 87%).,All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10‐year follow‐up.,We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10‐year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status.,In multivariable models, lower baseline TMV was associated with higher 10‐year EDSS scores (mean increase in EDSS of 0.75 per 1 mm3 loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39; P = 0.02).,In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5‐fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; P trend = 0.008). pRNFL and LCLA predicted the 10‐year EDSS scores only in univariate models.,Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood.,Various diseases causing neuronal damage have resulted in elevated CSF concentrations.,We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).,sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0-4.0).,We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.,sNfL levels were higher in both MS cohorts than in HC (p < 0.001).,We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001).,Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003).,Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034).,These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.,Ann Neurol 2017;81:857-870

Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist.,One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators.,Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics.,However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging.,Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2.,This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.,Unmet medical needs in the treatment of autoimmune and inflammatory diseases still exist.,This Review discusses the activity of kinases that regulate production of inflammatory mediators and the recent advances in developing inhibitors to target such kinases.

Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension.,Such targets have not been defined for rheumatoid arthritis (RA).,To develop recommendations for achieving optimal therapeutic outcomes in RA.,A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure.,Levels of evidence, strength of recommendations and levels of agreement were derived.,The treat-to-target activity resulted in 10 recommendations.,The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease.,Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended.,Follow-up examinations ought to employ composite measures of disease activity which include joint counts.,Additional items provide further details for particular aspects of the disease.,Levels of agreement were very high for many of these recommendations (≥9/10).,The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.

The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set.,The objective of this study is to describe the Novartis-Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes.,We report key characteristics of NO.MS.,We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients’ baseline age, using phase III study data (≈8000 patients).,NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up.,(1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%-75%) in older, disabled or progressive MS patients.,Young patients benefit most from treatment.,NO.MS will illuminate questions related to MS characterisation, progression and prognosis.,Age modulates relapse frequency and, thus, the phenotypic presentation of MS.,Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.

The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS).,Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases.,Here, we show that the differentiation potential of adult rodent OPCs decreases with age.,Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation.,This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage.,Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination.,Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies.,These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.,•Aged OPCs fail to respond to differentiation signals•Aged OPCs acquire many of the hallmarks of cell aging•Fasting and the fasting mimetic metformin rejuvenate poor remyelination in aged rodents•Metformin reverses age-related changes, making OPCs respond to differentiation factors,Aged OPCs fail to respond to differentiation signals,Aged OPCs acquire many of the hallmarks of cell aging,Fasting and the fasting mimetic metformin rejuvenate poor remyelination in aged rodents,Metformin reverses age-related changes, making OPCs respond to differentiation factors,Neumann et al. demonstrate that aging renders adult oligodendrocyte progenitor cells unresponsive to pro-differentiation factors, which can be reversed both in vitro and in vivo by calorie restriction (CR) and the CR mimetic metformin.

Janus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA).,We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA.,Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover.,Janus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA).,We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers.,The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA.,Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months.,We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3.,Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively.,Twenty-six patients (13 on each arm) completed the study.,Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ.,This was accompanied by the attenuation of further bone loss.,Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05).,Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2-4 and femoral neck BMD by DXA.,CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT.,Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes.,One-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers.,Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.,The online version contains supplementary material available at 10.1007/s00198-021-05871-0.

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints.,Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response.,The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA.,Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information.,First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium.,Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy.,The clinical response was determined at week 14 using the EULAR criteria.,Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level.,For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain.,The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients.,Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses.,Results: A total of 149 GCMs were identified in the RA synovium.,From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05).,At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort.,Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019).,The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041).,Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.

Background: Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation.,Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown.,The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity.,Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release.,Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID.,Results: Patients with SJIA and active systemic features demonstrated a higher proportion of CD16+CD62Llo neutrophil population compared to controls.,This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features.,Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils.,Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts.,Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils.,Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes (DEG) compared to neutrophils from healthy controls.,The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4.,Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation.,Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8.,Conclusion: We identify features of neutrophil activation in SJIA patients with both active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation.,Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

Anticardiolipin antibodies (aCL) have been reported to be present in 15-20% of sera from subjects with periodontitis at concentrations exceeding those found in 95% of the healthy adult population.,These antibodies, albeit at concentrations exceeding those generally found in periodontitis subjects, are typically present in patients with the antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. aCL from APS patients are proinflammatory and can activate trophoblasts, macrophages, and platelets via cell-surface interactions with their target antigen beta-2-glycoprotein-I (β2GPI). β2GPI is an anionic phospholipid-binding serum protein that can associate with toll-like receptors (TLR’s) on the cell-surface, leading to cell activation following interaction with autoimmune aCL.,We examined an expanded series of 629 sera from clinically characterized subjects for aCL content, and observed that 14-19% of these sera contained elevated (>95th %-tile) levels of aCL.,We purified IgG from 16 subjects with elevated or normal levels of aCL and examined their ability to activate TLR2- or TLR4-transfected human embryonic kidney (HEK) cells, and observed that IgG from periodontitis patients with elevated aCL activated HEK-TLR4 cells, but not HEK-TLR2 cells.,Prior removal of aCL by immunoabsorption significantly reduced the ability of IgG preparations from these sera to activate TLR4.,Further experiments using a human first trimester trophoblastic cell line (HTR8 sv/neo) revealed that aCL from periodontitis patients stimulated IL-8 production, which was profoundly decreased if aCL was removed by immunoabsorption or if HTR8 sv/neo were pretreated with blocking anti-TLR4 antibodies.,Thus, it appears that aCL from periodontitis patients can be proinflammatory, activating cells via TLR4.,Since these antibodies are likely produced via molecular mimicry due to similarities between oral bacterial antigens and β2GPI, the data indicate that circulating serum aCL may induce or influence inflammatory responses at sites distant from the oral cavity.

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight.,The type 1 diabetes patient cohort is highly heterogeneous, with individuals presenting with disease at different stages and severities, arising from distinct etiologies, and overlaying varied genetic backgrounds.,At present, the “one-size-fits-all” treatment for type 1 diabetes is exogenic insulin substitution therapy, but this approach fails to achieve optimal blood glucose control in many individuals.,With advances in our understanding of early-stage diabetes development, diabetes stratification, and the role of genetics, type 1 diabetes is a promising candidate for a personalized medicine approach, which aims to apply “the right therapy at the right time, to the right patient”.,In the case of type 1 diabetes, great efforts are now being focused on risk stratification for diabetes development to enable pre-clinical detection, and the application of treatments such as gene therapy, to prevent pancreatic destruction in a sub-set of patients.,Alongside this, breakthroughs in stem cell therapies hold great promise for the regeneration of pancreatic tissues in some individuals.,Here we review the recent initiatives in the field of personalized medicine for type 1 diabetes, including the latest discoveries in stem cell and gene therapy for the disease, and current obstacles that must be overcome before the dream of personalized medicine for all type 1 diabetes patients can be realized.

The lysosomal protease cathepsin L uses pancreatic secretory granule protein precursors and a reverse proteolysis mechanism, transpeptidation, to generate chimeric super-epitopes specific for diabetogenic CD4 T cells.,The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades.,In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes.,We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy).,Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L).,This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.

We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy.,Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance.,In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio.,The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4+T subsets were compared before and after the treatment.,Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study.,By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints (p < 0.001).,Notably, they had a higher level of Tregs as compared with those with conventional therapy alone (p < 0.05), indicating that sirolimus could partly restore the reduced Tregs.,Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups (p > 0.05).,Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect.,Further study is required using a large sample of RA patients treated with sirolimus for a longer period.,This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?,proj=17245).

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection.,Recent studies have identified a unique stem-like T cell subset in exhausted CD8+ T cells in chronic infection1-3, but it remains unclear whether CD4+ T cell subsets with similar features exist in chronic inflammatory conditions.,Among helper T cells, TH17 cells play prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although the regulation of plasticity is poorly understood.,Here we demonstrate that TH17 cells in autoimmune disease are functionally and metabolically heterogeneous and contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports the transdifferentiation into TH1 cells.,These two TH17 cell subsets are defined by selective expression of transcription factors TCF-1 and T-bet, and discrete CD27 expression levels.,Moreover, we identify mTORC1 signaling as a central regulator to orchestrate TH17 cell fates by coordinating metabolic and transcriptional programs.,TH17 cells with disrupted mTORC1 or anabolic metabolism fail to induce autoimmune neuroinflammation or develop into TH1-like cells, but instead upregulate TCF-1 expression and activity and acquire stemness-associated features.,Single cell RNA-sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon mTORC1 deletion or metabolic perturbation.,Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of helper T cell plasticity.

To determine (i) correlates for etanercept (ETA) discontinuation after achieving an inactive disease and for the subsequent risk of flare and (ii) to analyze the effectiveness of ETA in the re-treatment after a disease flare.,Data from two ongoing prospective registries, BiKeR and JuMBO, were used for the analysis.,Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in juvenile idiopathic arthritis (JIA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) and conventional synthetic DMARDs (csDMARDs).,A total of 1724 patients were treated first with ETA treatment course (338 with second, 54 with third ETA course).,Similar rates of discontinuation due to ineffectiveness and adverse events could be observed for the first (19.4%/6.2%), second (18.6%/5.9%), and third (14.8%/5.6%) ETA course.,A total of 332 patients (+/−methotrexate, 19.3%) discontinued ETA after achieving remission with the first ETA course.,Younger age (hazard ratio (HR) 1.08, p < 0.001), persistent oligoarthritis (HR 1.89, p = 0.004), and shorter duration between JIA onset and ETA start (HR 1.10, p < 0.001), as well as good response to therapy within the first 6 months of treatment (HR 1.11, p < 0.001) significantly correlated to discontinuation with inactive disease.,Reoccurrence of active disease was reported for 77% of patients with mean time to flare of 12.1 months.,We could not identify any factor correlating to flare risk.,The majority of patients were re-treated with ETA (n = 117 of 161; 72.7%) after the flare.,One in five patients (n = 23, 19.7%) discontinued ETA again after achieving an inactive disease and about 70% of the patients achieved an inactive disease 12 months after restarting ETA.,The study confirms the effectiveness of ETA even for re-treatment of patients with JIA.,Our data highlight the association of an early bDMARD treatment with a higher rate of inactive disease indicating a window of opportunity.

Biologicals are very effective for inhibiting disease progression in active juvenile idiopathic arthritis (JIA).,To date, there have been no recommendations on how and when to stop therapy with TNF inhibitors.,Our objective was to analyze characteristics and the disease course of JIA patients who discontinued etanercept due to achievement of inactive disease.,Data of 39 patients with JIA from two clinical pediatric rheumatology centers in Bydgoszcz and Lublin (Poland) were analyzed retrospectively.,All patients discontinued etanercept due to a remission on treatment.,Etanercept was started after a mean 33.7 ± 36 (range 3-137) months of disease.,The mean duration of therapy with etanercept was 34.7 ± 16.7 (range 6-72) months, with a mean duration of remission on medication 21.3 ± 9.6 (range 4-42) months before withdrawal of etanercept.,The mean duration of remission after etanercept discontinuation was 14.2 ± 12.1 (range of 1-60) months.,Only 12/39 (30.8 %) patients did not develop a disease exacerbation until the end of the study.,Early flares, that is less than 6 months after termination of etanercept, were observed in 15/39 (38.5 %) patients.,Twelve (30.8 %) patients restarted etanercept after exacerbation-all patients responded satisfactorily.,Our data show that etanercept discontinuation in a substantial proportion of JIA patients results in early disease exacerbation.,In many cases, reintroduction of etanercept is needed.,Patients, in whom etanercept was restarted, responded satisfactorily.

Follicular helper T (Tfh) cells exert an important role in autoimmune diseases.,Whether it might be involved in type 1 diabetes (T1D) is unknown.,Our aim was to investigate the role of Tfh cells in patients with T1D and the effect of anti-CD20 monoclonal antibody (rituximab) on Tfh cells from T1D patients.,Fifty-four patients with T1D and 37 healthy controls were enrolled in the current study. 20 of those patients were treated with rituximab.,The frequencies of circulating CD4+CXCR5+ICOS+T cells were analyzed by flow cytometry.,The serum autoantibodies were detected by radioligand assay.,The levels of IL-21, IL-6 and BCL-6 were assessed using ELISA and/or real-time PCR.,Increased frequencies of circulating Tfh cells together with enhanced expression of IL-21 were detected in patients.,The correlation between the frequencies of circulating Tfh cells and the serum autoantibodies or C-peptide level was comfirmed.,After rituximab therapy, follow-up analysis demonstrated that the frequencies of circulating Tfh cell and serum IA2A were decreased.,The levels of IL-21, IL-6 and Bcl-6 mRNA were decreased after treatment.,Furthermore, beta cell function in 10 of 20 patients was improved.,These data indicate Tfh cells may participate in the T1D-relatede immune responses and B cells might play a role in the development of Tfh responses in the disease progression.

Type 1 diabetes presents clinically with overt hyperglycemia resulting from progressive immune-mediated destruction of pancreatic β-cells and associated metabolic dysfunction.,Combined genetic and immunological studies now highlight deficiencies in both the interleukin-2 (IL-2) receptor and its downstream signaling pathway as a central defect in the pathogenesis of type 1 diabetes.,Prior intervention studies in animal models indicate that augmenting IL-2 signaling can prevent and reverse disease, with protection conferred primarily by restoration of regulatory T-cell (Treg) function.,In this article, we will focus on studies of type 1 diabetes noting deficient IL-2 signaling and build what we believe forms the molecular framework for their contribution to the disease.,This activity results in the identification of a series of potentially novel therapeutic targets that could restore proper immune regulation in type 1 diabetes by augmenting the IL-2 pathway.

Available evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes.,Genetic susceptibility linked to HLA Class II lends strong support.,Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells.,While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells.,Functional arguments from ex vivo and in vitro human studies and in vivo ‘humanised’ mouse models are instead neutral or against a T cell role.,Clinical support is provided by the appearance of islet autoantibodies before disease onset.,The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes.,Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk.,Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the ‘benign’ islet autoimmunity of healthy individuals.,Graphical abstract,Graphical abstract,The online version of this article (10.1007/s00125-020-05298-y) contains a slideset of the figures for download, which is available to authorised users.

Functional interpretation of noncoding genetic variants identified by genome-wide association studies is a major challenge in human genetics and gene regulation.,We generated epigenomics data using primary cells from type 1 diabetes patients.,Using these data, we identified and validated multiple novel risk variants for this disease.,In addition, our ranked list of candidate risk SNPs represents the most comprehensive annotation based on T1D-specific T-cell data.,Because many autoimmune diseases share some genetic underpinnings, our dataset may be used to understand causal noncoding mutations in related autoimmune diseases.,Genome-wide association studies (GWASs) have revealed 59 genomic loci associated with type 1 diabetes (T1D).,Functional interpretation of the SNPs located in the noncoding region of these loci remains challenging.,We perform epigenomic profiling of two enhancer marks, H3K4me1 and H3K27ac, using primary TH1 and TREG cells isolated from healthy and T1D subjects.,We uncover a large number of deregulated enhancers and altered transcriptional circuitries in both cell types of T1D patients.,We identify four SNPs (rs10772119, rs10772120, rs3176792, rs883868) in linkage disequilibrium (LD) with T1D-associated GWAS lead SNPs that alter enhancer activity and expression of immune genes.,Among them, rs10772119 and rs883868 disrupt the binding of retinoic acid receptor α (RARA) and Yin and Yang 1 (YY1), respectively.,Loss of binding by YY1 also results in the loss of long-range enhancer-promoter interaction.,These findings provide insights into how noncoding variants affect the transcriptomes of two T-cell subtypes that play critical roles in T1D pathogenesis.

We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations.,Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes.,We used a risk set sampled nested case-control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY).,The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres.,Control participants were matched for family history of type 1 diabetes, clinical centre and sex.,Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years.,SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray.,Comparisons were adjusted for HLA genotypes and for background population stratification.,Childhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]).,The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]).,Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes.,Further studies are warranted to confirm these findings.,The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.,The online version of this article (10.1007/s00125-019-05028-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of β-cell autoimmunity, and HLA genotype in the index case.,Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register.,Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire.,Antibodies to β-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed.,A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative.,Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and β-hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001).,There were no differences in signs of β-cell autoimmunity.,The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs.,67.0%, P = 0.02).,When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%.,A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected.,Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms.

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability.,The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials.,In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically.,The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS.,Here, we report the initial conclusions of the panel and its recommendations for further research.,Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established.,Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment.,Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging.,More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes.,The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.

Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses.,To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP).,TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks.,Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score.,This analysis included 5562 patients.,Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively).,In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

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

Endothelial injury, which may present clinically as hypertension, proteinuria and increased von Willebrand Factor (vWF) level, is a common manifestation in IgA nephropathy (IgAN).,However, causal factors for endothelial injury in IgAN are not completely understood.,An imbalance of vascular endothelial growth factor/Soluble fms-like tyrosine kinase-1 (VEGF/sFlt-1) has been observed in many diseases with endothelial dysfunction, including pre-eclampsia and diabetic retinopathy, but whether it contributes to endothelial injury in IgAN requires further exploration.,Initially, 96 IgAN patients and 22 healthy volunteers were enrolled as a discovery cohort.,VEGF/sFlt-1, sFlt-1 and VEGF levels were compared between patients with IgAN and healthy volunteers to explore the underlying factors that contribute to endothelial injury in IgAN.,The identified contributor (sFlt-1) was further confirmed in a replication cohort, which included 109 IgAN patients and 30 healthy volunteers.,Correlations of sFlt-1 with hypertension, proteinuria, Oxford-E score and plasma vWF were further evaluated in the combined 205 patients with IgAN.,VEGF/sFlt-1 levels were significantly lower in IgAN patients than healthy volunteers (0.33±0.27 vs.,0.43±0.22, p = 0.02) in the discovery cohort.,Within the ratio, plasma sFlt-1 levels were significantly elevated (101.18±25.19 vs.,79.73±18.85 pg/ml, p<0.001), but plasma VEGF levels showed no significant differences.,Elevated sFlt-1 levels in the replication cohort were confirmed in IgAN patients (93.40±39.78 vs.,71.92±15.78 pg/ml, p<0.001).,Plasma sFlt-1 levels in IgAN patients correlated with proteinuria (severe (>3.5 g/d) vs. moderate (1-3.5 g/d) vs. mild (<1 g/d) proteinuria: 115.95±39.09 vs.,99.89±28.55 vs.,83.24±33.92 pg/ml; severe vs. mild: p<0.001, moderate vs. mild p = 0.001, severe vs. moderate: p = 0.014), hypertension (with vs. without hypertension: 107.87±31.94 vs.,87.32±32.76 pg/ml, p = 0.015) and vWF levels (r = 0.161, p = 0.021).,The present study found elevated sFlt-1 in IgAN patients and further identified its correlation with proteinuria, hypertension and vWF levels.,These results suggested that elevated sFlt-1 contributes to endothelial injury in IgAN.

The efficacy of cyclosporine A (CsA) in the treatment of idiopathic membranous nephropathy (IMN) is unclear.,This meta-analysis was conducted to assess the efficacy and the safety of CsA in the treatment of IMN in Asians.,We searched the Pubmed, China Biomedical Database, CNKI, Wanfang Data, VIP, and EMBASE (November 30, 2018) systematically to identify the appropriate randomized controlled trials (RCTs) reporting the efficacy and the safety of CsA and glucocorticoid (GC) treatment vs other immunosuppressants and GC on patients with IMN in Asian populations.,The CsA treated group entered complete remission (CR) faster (3 months) than a cyclophosphamide (CTX) group.,While the CsA group lower inefficacy rates and higher total remission (TR, CR, or partial remission) than the CTX group in the total treatment (3 months, 6 months, and 12 months), it had a higher relapse rate.,As for the CsA group vs the tacrolimus (TAC) group, the TAC had a significant effect in increasing the CR and the TR, with decreased no remission.,With the therapeutic regimens of CsA+GC vs CTX+GC, the CsA exhibited better efficacy in lowering the proteinuria levels only at 12 months, not at 3 months or 6 months.,Severe events like leucopenia, hemorrhagic cystitis, and alopecia were observed in the CTX group.,Gingival hyperplasia, hirsutism, and elevated blood pressure were reported only in the CsA group.,Gastrointestinal syndrome, liver function lesion, happened more frequently in the CTX group, and elevated uric acid was more common in the CsA group.,In brief, the CsA has better efficacy than the CTX group in the Asian population, with mild adverse effects but higher relapse rates in short-term treatment.

New therapeutic agents are warranted in idiopathic membranous nephropathy.,Synthetic ACTH may be advantageous with reported remission rates up to 85% and few side effects.,We conducted a prospective open label cohort study from 2008 till 2010 (NCT00694863).,We prospectively selected patients with idiopathic membranous nephropathy and high risk for progression (defined as βeta-2-microglobulin (β2m) excretion of >500 ng/min).,For comparison, we selected matched historical controls treated with cyclophosphamide.,The prospectively selected patients received intramuscular injections of synthetic ACTH during 9 months (maximal dose 1 mg twice a week).,The primary endpoints concerned the feasibility and incidence of remissions as a primary event.,Secondary endpoints included side effects of treatment and the incidence of remissions and relapses at long-term follow-up.,Twenty patients (15 men) were included (age 54±14 years, serum creatinine 104 μmol/l [IQR 90-113], urine protein:creatinine ratio 8.7 g/10 mmol creatinine [IQR 4.3-11.1]).,Seventeen patients (85%) completed treatment. 97% of injections were administered correctly.,Cumulative remission rate was 55% (complete remission in 4 patients, partial remission 7 patients).,In a group of historical controls treated with cyclophosphamide and steroids, 19 of 20 patients (95%) developed a remission (complete remission in 13 patients, partial remission in 6 patients) (p<0.01).,The main limitation of our study is its small size and the use of a historical control group.,We show that treatment with intramuscular injections of synthetic ACTH is feasible.,Our data suggest that synthetic ACTH is less effective than cyclophosphamide in inducing a remission in high risk patients with idiopathic membranous nephropathy.,The use of synthetic ACTH was also associated with many adverse events.,Therefore, we advise against synthetic ACTH as standard treatment in membranous nephropathy.,ClinicalTrials.gov NCT00694863

Thyroid-associated ophthalmoapthy (TAO) is the most common orbital disease.,As an autoimmune disorder, it is caused by self-reactive lymphocytes that escape immune tolerance, but the mechanism is not fully understood.,The basic process of TAO is the infiltration of immune cells in orbital tissues, the activation of orbital fibroblasts (OFs), and the proliferation and differentiation of OFs and lymphocytes.,Activated OFs secrete inflammatory regulators, growth factors, and chemokines, thereby maintaining and amplifying the immune responses.,The interactions between OFs and lymphocytes lead to the expansion and the remodeling of the orbital tissues, presenting the clinical manifestations of TAO.,This review will focus on the role of T cell subsets (Type 1, Type 2, Type 17 helper T cells, and regulatory T cells) in the pathogenesis of TAO.,However, we still need further studies to unravel the pathogenesis, to confirm current hypotheses, and to provide novel ideas for appropriate clinical treatment of TAO.

Graves’ Disease (GD) is an autoimmune condition in which thyroid-stimulating antibodies (TRAB) mimic thyroid-stimulating hormone function causing hyperthyroidism. 5% of GD patients develop inflammatory Graves’ orbitopathy (GO) characterized by proptosis and attendant sight problems.,A major challenge is to identify which GD patients are most likely to develop GO and has relied on TRAB measurement.,We screened sera/plasma from 14 GD, 19 GO and 13 healthy controls using high-throughput proteomics and miRNA sequencing (Illumina’s HiSeq2000 and Agilent-6550 Funnel quadrupole-time-of-flight mass spectrometry) to identify potential biomarkers for diagnosis or prognosis evaluation.,Euclidean distances and differential expression (DE) based on miRNA and protein quantification were analysed by multidimensional scaling (MDS) and multinomial regression respectively.,We detected 3025 miRNAs and 1886 proteins and MDS revealed good separation of the 3 groups.,Biomarkers were identified by combined DE and Lasso-penalized predictive models; accuracy of predictions was 0.86 (±0:18), and 5 miRNA and 20 proteins were found including Zonulin, Alpha-2 macroglobulin, Beta-2 glycoprotein 1 and Fibronectin.,Functional analysis identified relevant metabolic pathways, including hippo signaling, bacterial invasion of epithelial cells and mRNA surveillance.,Proteomic and miRNA analyses, combined with robust bioinformatics, identified circulating biomarkers applicable to diagnose GD, predict GO disease status and optimize patient management.

Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases.,However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron.,By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration.,120 MS patients and 40 age‐ and sex‐matched healthy controls were included.,Clinical testing and MRI were performed both at baseline and after 2 years.,Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus.,MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing-remitting patients.,Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls.,In the thalamus, decreasing iron content over 2 years was associated with disability progression.,Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease‐related atrophy.,Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.,Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases.,The study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease‐related atrophy.,Declining deep gray matter iron content suggests that, contrary to the current understanding, iron is being removed from the deep gray matter in patients with MS.

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role.,Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions.,Recent studies have described an altered macrophage phenotype after myelin internalization.,However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression.,Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation.,Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux.,In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol.,In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β.,Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.

The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod.,Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs.,Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT.,The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score.,Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I).,All outcomes were evaluated after 6 months of treatment.,Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001).,Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111).,FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024).,Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001).,After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment.,ClinicalTrials.gov NCT01216072.

The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was developed to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient’s perspective.,To determine the responder definition (RD) of the MSIS-29 physical impact subscale (PHYS) in a group of patients with relapsing-remitting MS (RRMS) participating in a clinical trial.,Data from the SELECT trial comparing daclizumab high-yield process with placebo in patients with RRMS were used.,Physical function was evaluated in SELECT using three patient-reported outcomes measures and the Expanded Disability Status Scale (EDSS).,Anchor- and distribution-based methods were used to identify an RD for the MSIS-29.,Results across the anchor-based approach suggested MSIS-29 PHYS RD values of 6.91 (mean), 7.14 (median) and 7.50 (mode).,Distribution-based RD estimates ranged from 6.24 to 10.40.,An RD of 7.50 was selected as the most appropriate threshold for physical worsening based on corresponding changes in the EDSS (primary anchor of interest).,These findings indicate that a ≥7.50 point worsening on the MSIS-29 PHYS is a reasonable and practical threshold for identifying patients with RRMS who have experienced a clinically significant change in the physical impact of MS.

The role of the intestinal microbiota as a regulator of autoimmune diabetes in animal models is well-established, but data on human type 1 diabetes are tentative and based on studies including only a few study subjects.,To exclude secondary effects of diabetes and HLA risk genotype on gut microbiota, we compared the intestinal microbiota composition in children with at least two diabetes-associated autoantibodies (n = 18) with autoantibody-negative children matched for age, sex, early feeding history, and HLA risk genotype using pyrosequencing.,Principal component analysis indicated that a low abundance of lactate-producing and butyrate-producing species was associated with β-cell autoimmunity.,In addition, a dearth of the two most dominant Bifidobacterium species, Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and an increased abundance of the Bacteroides genus were observed in the children with β-cell autoimmunity.,We did not find increased fecal calprotectin or IgA as marker of inflammation in children with β-cell autoimmunity.,Functional studies related to the observed alterations in the gut microbiome are warranted because the low abundance of bifidobacteria and butyrate-producing species could adversely affect the intestinal epithelial barrier function and inflammation, whereas the apparent importance of the Bacteroides genus in development of type 1 diabetes is insufficiently understood.

The incidence of type 1 diabetes is increasing.,Delivery by cesarean section is also more prevalent, and it is suggested that cesarean section is associated with type 1 diabetes risk.,We examine associations between cesarean delivery, islet autoimmunity and type 1 diabetes, and genes involved in type 1 diabetes susceptibility.,Cesarean section was examined as a risk factor in 1,650 children born to a parent with type 1 diabetes and followed from birth for the development of islet autoantibodies and type 1 diabetes.,Children delivered by cesarean section (n = 495) had more than twofold higher risk for type 1 diabetes than children born by vaginal delivery (hazard ratio [HR] 2.5; 95% CI 1.4-4.3; P = 0.001).,Cesarean section did not increase the risk for islet autoantibodies (P = 0.6) but was associated with a faster progression to diabetes after the appearance of autoimmunity (P = 0.015).,Cesarean section-associated risk was independent of potential confounder variables (adjusted HR 2.7;1.5-5.0; P = 0.001) and observed in children with and without high-risk HLA genotypes.,Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes-susceptible IFIH1 genotypes (12-year risk, 9.1 vs. <3% for all other combinations; P < 0.0001).,These findings suggest that type 1 diabetes risk modification by cesarean section may be linked to viral responses in the preclinical autoantibody-positive disease phase.

In the majority of patients with rheumatoid arthritis (RA), antibodies specifically recognize citrullinated autoantigens that are generated by peptidylarginine deiminases (PADs).,Neutrophils express high levels of PAD and accumulate in the synovial fluid (SF) of RA patients during disease flares.,This study was undertaken to test the hypothesis that neutrophil cell death, induced by either NETosis (extrusion of genomic DNA-protein complexes known as neutrophil extracellular traps [NETs]) or necrosis, can contribute to production of autoantigens in the inflamed joint.,Extracellular DNA was quantified in the SF of patients with RA, patients with osteoarthritis (OA), and patients with psoriatic arthritis (PsA).,Release of PAD from neutrophils was investigated by Western blotting, mass spectrometry, immunofluorescence staining, and PAD activity assays.,PAD2 and PAD4 protein expression, as well as PAD enzymatic activity, were assessed in the SF of patients with RA and those with OA.,Extracellular DNA was detected at significantly higher levels in RA SF than in OA SF (P < 0.001) or PsA SF (P < 0.05), and its expression levels correlated with neutrophil concentrations and PAD activity in RA SF.,Necrotic neutrophils released less soluble extracellular DNA compared to NETotic cells in vitro (P < 0.05).,Higher PAD activity was detected in RA SF than in OA SF (P < 0.05).,The citrullinated proteins PAD2 and PAD4 were found attached to NETs and also freely diffused in the supernatant.,PAD enzymatic activity was detected in supernatants of neutrophils undergoing either NETosis or necrosis.,Release of active PAD isoforms into the SF by neutrophil cell death is a plausible explanation for the generation of extracellular autoantigens in RA.

The persistence of activated T cells in rheumatoid arthritis (RA) synovium may be attributable to increased homing, increased retention or a possible imbalance between cell proliferation and programmed cell death.,Induction of apoptosis may represent a potential therapeutic approach.,Galactoxylomannan (GalXM) from the opportunistic fungus Cryptococcus neoformans can interact with T cells and induce T-cell apoptosis through the inhibition of CD45 phosphatase activity.,The aim of this study was to determine the effect of GalXM on circulating T cells from patients with RA and the underlying mechanisms.,GalXM immunomodulating effect on apoptosis and signal transduction pathway involved in IL-17A production was evaluated on T cells.,RA T-cell apoptosis, higher than that of control T cells, was further increased by GalXM through induction of caspase-3 activation.,Activated T cells expressing the CD45RO molecule and producing IL-17A were the main target of GalXM-induced apoptosis.,GalXM induced consistent impairment of IL-17A production and inhibition of STAT3, which was hyperactivated in RA.,In conclusion, GalXM triggered apoptosis of activated memory T cells and interfered with IL-17A production in RA.,These data suggest therapeutic targeting of deleterious Th17 cells in RA and other autoimmune diseases.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor.,In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.,DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome.,Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.,We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome.,The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE.,We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE.,The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3.,In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.,Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

In a Genome Wide Association Study (GWAS) of individuals of European ancestry afflicted with Systemic Lupus Erythematosus (SLE) the extensive utilization of imputation, stepwise multiple regression, lasso regularization, and increasing study power by utilizing False Discovery Rate (FDR) instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of 4 genes previously reported to be associated.,Novel genes associated with SLE susceptibility included two transcription factors (EHF, and MED1), two components of the NFκB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6), and two genes involved in antigen presentation (BIN1 and SEC61G).,In addition, the strongly significant association of multiple single nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals.,The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.

Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5′ and 3′ end back-splicing.,The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs.,Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce.,In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM).,We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450.,Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.

This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D).,We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRNAs expression levels to beta-cell function and glycaemic control.,Global miRNA sequencing analyses were performed on sera pools from two T1D cohorts (n = 275 and 129, resp.) and one control group (n = 151).,We identified twelve upregulated human miRNAs in T1D patients (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, miR-200a); several of these miRNAs were linked to apoptosis and beta-cell networks.,Furthermore, we identified miR-25 as negatively associated with residual beta-cell function (est.: −0.12, P = 0.0037), and positively associated with glycaemic control (HbA1c) (est.: 0.11, P = 0.0035) 3 months after onset.,In conclusion this study demonstrates that miR-25 might be a “tissue-specific” miRNA for glycaemic control 3 months after diagnosis in new onset T1D children and therefore supports the role of circulating miRNAs as predictive biomarkers for tissue physiopathology and potential intervention targets.

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors.,How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear.,Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype.,Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner.,Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation.,T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.,Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells.,These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.,•Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis•The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation•Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells•Autoproliferating T cells recognize antigens expressed in B cells and brain lesions,Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis,The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation,Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells,Autoproliferating T cells recognize antigens expressed in B cells and brain lesions,Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord.,The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy.,Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination.,A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS.,The aim of this consensus statement is to provide practical advice for the use of MRI in this setting.,The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees.,It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.