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Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS).,Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.,RRMS patients (18-65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks.,Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.,1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks).,Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p < 0.0001.,Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48.,Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]).,Consistent results were seen when allowing for minimal MRI activity.,During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing.,NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.,ClinicalTrials.gov: NCT00906399,The online version of this article (doi:10.1186/s12883-014-0240-x) contains supplementary material, which is available to authorized users.
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No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis.,Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies.,No evidence of disease activity (NEDA) was evaluated as the proportion of patients free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite).,For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies.,These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies.,Models predicted the indirect relative risk of achieving NEDA status for fingolimod versus dimethyl fumarate or teriflunomide in an average patient from their respective phase 3 trials.,The estimated relative risks of achieving NEDA status for fingolimod versus placebo in a pooled fingolimod trial population were numerically greater (i.e., fingolimod more efficacious) than the estimated relative risks for dimethyl fumarate or teriflunomide versus placebo in each respective trial population.,In indirect comparisons, the predicted relative risks for all composite measures were better for fingolimod than comparator when tested against the trial populations of those treated with dimethyl fumarate (relative risk, clinical: 1.21 [95% confidence interval 1.06-1.39]; overall: 1.67 [1.08-2.57]), teriflunomide 7 mg (clinical: 1.22 [1.02-1.46]; overall: 2.01 [1.38-2.93]) and teriflunomide 14 mg (clinical: 1.14 [0.96-1.36]; overall: 1.61 [1.12-2.31]).,Our modeling approach suggests that fingolimod therapy results in a higher probability of NEDA than dimethyl fumarate and teriflunomide therapy when phase 3 trial data are indirectly compared and differences between trials are adjusted for.,The online version of this article (doi:10.1007/s12325-014-0167-z) contains supplementary material, which is available to authorized users.
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Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs).,A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library.,Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation.,3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13).,Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated.,Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included.,Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn’s disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA).,Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events.,No increased malignancy rates or major adverse cardiac events were observed.,JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile.,This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.
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Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others.,JAKs are the key initiating players of the JAK/STAT pathway.,Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus.,A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members.,Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond.,In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
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A single amino acid shift in TCR recognition of self peptide-MHC determines whether potentially diabetogenic CD4 T cells will be purged in the thymus or have the opportunity to undergo activation in the islets of Langerhans of mice.,In nonobese diabetic (NOD) mice, two sets of autoreactive CD4+ T cells recognize the B:9-23 segment of the insulin B chain.,One set, type A, recognizes insulin presented by antigen-presenting cells (APCs).,These T cells are highly deleted in the thymus.,The second set, type B, does not recognize insulin protein but reacts with soluble B chain peptide.,This set is not deleted in the thymus but is activated in the islets of Langerhans.,In this study, we examine the specificity of these two types of T cells.,The protein-reactive set recognizes the stretch of residues 13-21 of the insulin B chain.,The set reactive to peptide only recognizes the stretch from residues 12-20.,A single amino acid shift of the B chain peptide bound to I-Ag7 determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging.,Biochemical experiments indicate that peptides bound in the 13-21 register interact more favorably with I-Ag7 than peptides that bind in the 12-20 register.,Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in registers distinct from those found in the thymus.
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Besides the genetic framework, there are two critical requirements for the development of tissue-specific autoimmune diseases.,First, autoreactive T cells need to escape thymic negative selection.,Second, they need to find suitable conditions for autoantigen presentation and activation in the target tissue.,We show here that these two conditions are fulfilled in diabetic NOD mice.,A set of autoreactive CD4+ T cells specific for an insulin peptide, with the noteworthy feature of not recognizing the insulin protein when processed by the antigen presenting cells (APC) escape thymic control, participate in diabetes and can cause disease.,We also find that APCs situated in close contact with the beta cells in the islets of Langerhans bear vesicles with the antigenic insulin peptides and activate the peptide-specific T cells.,These findings may be relevant for other cases of endocrine autoimmunity.
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In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks.,Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response.,Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks.,Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26.,Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed).,Treatment-emergent adverse events per 100 patient-years were summarised.,Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation).,Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab.,Safety at week 48 was comparable to week 26.,Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48.,Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.
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We undertook this phase III study to evaluate baricitinib, an orally administered JAK‐1/JAK‐2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.,A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks.,The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.,The study met its primary objective.,Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01).,Similar results were observed for combination therapy.,Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1.,Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX.,The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment‐emergent AEs, including infections, were increased with baricitinib plus MTX.,Three deaths were reported, all occurring in the MTX monotherapy group.,Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.,Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
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In addition to the long‐established link with smoking, periodontitis (PD) is a risk factor for rheumatoid arthritis (RA).,This study was undertaken to elucidate the mechanism by which PD could induce antibodies to citrullinated peptides (ACPAs), by examining the antibody response to a novel citrullinated peptide of cytokeratin 13 (CK‐13) identified in gingival crevicular fluid (GCF), and comparing the response to 4 other citrullinated peptides in patients with RA who were well‐characterized for PD and smoking.,The citrullinomes of GCF and periodontal tissue from patients with PD were mapped by mass spectrometry.,ACPAs of CK13 (cCK13), tenascin‐C (cTNC5), vimentin (cVIM), α‐enolase (CEP‐1), and fibrinogen β (cFIBβ) were examined by enzyme‐linked immunosorbent assay in patients with RA (n = 287) and patients with osteoarthritis (n = 330), and cross‐reactivity was assessed by inhibition assays.,A novel citrullinated peptide cCK13‐1 (444 TSNASGR‐Cit‐TSDV‐Cit‐RP 458) identified in GCF exhibited elevated antibody responses in RA patients (24%).,Anti-cCK13‐1 antibody levels correlated with anti-cTNC5 antibody levels, and absorption experiments confirmed this was not due to cross‐reactivity.,Only anti-cCK13‐1 and anti‐cTNC5 were associated with antibodies to the periodontal pathogen Prevotella intermedia (P = 0.05 and P = 0.001, respectively), but not with antibodies to Porphyromonas gingivalis arginine gingipains.,Levels of antibodies to CEP‐1, cFIBβ, and cVIM correlated with each other, and with smoking and shared epitope risk factors in RA.,This study identifies 2 groups of ACPA fine specificities associated with different RA risk factors.,One is predominantly linked to smoking and shared epitope, and the other links anti-cTNC5 and cCK13‐1 to infection with the periodontal pathogen P intermedia.
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Periodontitis has been regarded as a potential risk factor for rheumatoid arthritis (RA).,A systematic review is made to determine whether nonsurgical periodontal treatment in patients with RA offers benefits in terms of the clinical activity and inflammatory markers of the disease.,A search was made of the Medline-PubMed, Cochrane, Embase and Scopus databases to identify studies on the relationship between the two disease processes, and especially on the effects of nonsurgical treatment in patients of this kind.,The search was based on the following keywords: rheumatoid arthritis AND periodontitis (MeSH), rheumatoid arthritis AND periodontal treatment.,Eight articles on the nonsurgical treatment of patients with periodontitis and RA were finally included in the study.,All of them evaluated clinical (DAS28) and laboratory test activity (ESR, CRP, IL-6, TNFα) before and after treatment.,A clear decrease in DAS28 score and ESR was recorded, while other parameters such as CRP, IL-6 and TNFα showed a non significant tendency to decrease as a result of treatment.,Nonsurgical treatment improved the periodontal condition of patients with periodontitis and RA, with beneficial effects upon the clinical and laboratory test parameters (DAS28 and ESR), while other inflammatory markers showed a marked tendency to decrease.,However, all the studies included in the review involved small samples sizes and follow-up periods of no more than 6 months.,Larger and particularly longitudinal studies are therefore needed to more firmly establish possible significant relations between the two disease processes.,Key words:Periodontitis, rheumatoid arthritis, periodontal treatment.
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Management of Type 1 Diabetes (T1D) poses numerous challenges, especially for young children and their families.,Parental care positively influences the outcomes of children with T1D, while there are often criticisms in school environment.,The COVID-19 pandemic has forced children and parents to spend many hours at home and diabetes care has returned mainly in the hands of parents.,To evaluate the effectiveness of exclusive return to parental care in pre-school and school children with T1D treated with Tandem Basal IQ system during the COVID-19 pandemic.,22 children (M:F = 14:8) with T1D have been evaluated.,We compared insulin and CGM data (TIR, TBR and TAR) of two periods: PRE-COV and IN-COV, in which children have transitioned from normal school attendance to the exclusive care of their parents.,During the IN-COV period a significantly (p < 0.001) higher median value of TIR (66,41%) was observed as compared to PRE-COV period (61,45%).,Patients also showed a statistically significant difference (p < 0.002) between the IN-COV period and the PRE-COV period as concerning the TAR metric: respectively 29,86 ± 10,6% vs 34,73 ± 12,8%.,The difference between the bolus insulin doses was statistically significant (PRE-COV 5,3 IU/day, IN-COV 7,9 IU/day - p < 0.05).,Our observational real-life study confirms the positive effect of parental care in T1D very young children and demonstrates that during the COVID-19 pandemic it was possible to obtain a good glycometabolic compensation despite the significant change in lifestyle.
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Objective: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries.,The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control.,The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence.,The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey.,Methods: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood.,Epidemiological and clinical characteristics of the patients were recorded.,Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated.,Results: Mean age, diabetes duration, and hemoglobin A1c level were 12.5±4.1 years, 4.7±3.2 years, and 8.5±1.6%, respectively.,Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%.,Chronic lymphocytic thyroiditis was noted in 12%, Graves’ disease in 0.1%, and celiac disease in 4.3% of the patients.,Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively.,Diabetic nephropathy was not present in any of the patients.,Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01).,A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively).,Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese.,Conclusions: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered.,Conflict of interest:None declared.
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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.
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IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response.,IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function.,Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala.,This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala946, may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles.,We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-β stimulated peripheral blood mononuclear cells (overall p = 0.012).,In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D-associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1).,We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1.,These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D.
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Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes.,The contribution of AQP4‐specific T cells to the class switch recombination of pathogenic AQP4‐specific antibodies and the inflammation of the blood-brain barrier is incompletely understood, as immunogenic naturally processed T‐cell epitopes of AQP4 are unknown.,By immunizing Aqp4 −/− mice with full‐length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201‐220) as the major immunogenic IAb‐restricted epitope of AQP4.,We show that WT mice do not harbor AQP4(201-220)‐specific T‐cell clones in their natural repertoire due to deletional tolerance.,However, immunization with AQP4(201-220) of Rag1 −/− mice reconstituted with the mature T‐cell repertoire of Aqp4 −/− mice elicits an encephalomyelitic syndrome.,Similarly to the T‐cell repertoire, the B‐cell repertoire of WT mice is “purged” of AQP4‐specific B cells, and robust serum responses to AQP4 are only mounted in Aqp4 −/− mice.,While AQP4(201-220)‐specific T cells alone induce encephalomyelitis, NMO‐specific lesional patterns in the CNS and the retina only occur in the additional presence of anti‐AQP4 antibodies.,Thus, failure of deletional T‐cell and B‐cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.
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Neuromyelitis optica (NMO) is a severe demyelinating disorder of the central nervous system (CNS) associated with the presence of an autoimmune antibody response (AQP4-IgG) against the water channel aquaporin-4 (AQP4).,It remains unclear whether pathologic AQP4-IgG in the CNS is produced entirely by peripheral plasma cells or is generated in part by infiltrating B cells.,To determine the overlap of AQP4-IgG idiotypes between the CNS and periphery, we compared the immunoglobulin G (IgG) transcriptome of cerebrospinal fluid (CSF) plasmablasts with the CSF and serum IgG proteomes in 7 AQP4-seropositive NMO patients following exacerbation.,CSF variable region Ig heavy- (VH) and light-chain (VL) transcriptome libraries were generated for each patient from CSF plasmablasts by single cell sorting, reverse transcriptase polymerase chain reaction (RT-PCR), and DNA sequencing.,Recombinant antibodies were generated from clonally expanded, paired VH and VL sequences and tested for AQP4-reactivity by cell-binding assay.,CSF and serum IgG fractions were searched for sequences that matched their respective CSF IgG transcriptome.,Matching peptides within the same patient’s CSF and serum IgG proteomes were also identified.,In each NMO patient, we recovered CSF IgG VH and VL sequences that matched germline-mutated IgG protein sequences from the patient’s CSF and serum IgG proteomes.,Although a modest variation was observed between patients, the overlap between the transcriptome and proteome sequences was found primarily, but not exclusively, within the CSF.,More than 50% of the CSF IgG transcriptome sequences were exclusively found in the CSF IgG proteome, whereas 28% were found in both the CSF and blood IgG proteome, and 18% were found exclusively in the blood proteome.,A comparable distribution was noted when only AQP4-specific IgG clones were considered.,Similarly, on average, only 50% of the CSF IgG proteome matched corresponding peptide sequences in the serum.,During NMO exacerbations, a substantial fraction of the intrathecal Ig proteome is generated by an intrathecal B cell population composed of both novel and peripherally-derived clones.,Intrathecal CSF B cell clones may contribute to NMO disease exacerbation and lesion formation and may be an important target for preventative therapies.
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For the foreseeable future, vaccines are the cornerstone in the global campaign against the Coronavirus Disease-19 (COVID-19) pandemic.,As the number and fatalities due to COVID-19 decline and the lockdown anywise rescinded, we recognize an increase in the incidence of autoimmune disease post-COVID-19 vaccination.,However, the causality of the most vaccine-induced side effects is debatable and, at best, limited to a temporal correlation.,We herein report a case of a 51-year-old gentleman who developed Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV) 2 week post-COVID-19 vaccination.,The patient responded favorably to oral steroids and rituximab.,Additionally, we conducted a case-based review of vaccine-associated AAV describing their clinical manifestations and treatment response of this emerging entity.,The online version contains supplementary material available at 10.1007/s00296-021-05069-x.
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Autoimmune and other chronic inflammatory diseases (AID) are prevalent diseases which can severely impact the quality of life of those that suffer from the disease.,In most cases, the etiology of these conditions have remained unclear.,Immune responses that take place e.g. during natural infection or after vaccination are often linked with the development or exacerbation of AID.,It is highly debated if vaccines induce or aggravate AID and in particular adjuvants are mentioned as potential cause.,Since vaccines are given on a large scale to healthy individuals but also to elderly and immunocompromised individuals, more research is warranted.,Non-specific induction of naïve or memory autoreactive T cells via bystander activation is one of the proposed mechanisms of how vaccination might be involved in AID.,During bystander activation, T cells unrelated to the antigen presented can be activated without (strong) T cell receptor (TCR) ligation, but via signals derived from the ongoing response directed against the vaccine-antigen or adjuvant at hand.,In this study we have set up a TCR transgenic T cell transfer mouse model by which we were able to measure local bystander activation of transferred and labeled CD4+ T cells.,Intramuscular injection with the highly immunogenic Complete Freund’s Adjuvant (CFA) led to local in vivo proliferation and activation of intravenously transferred CD4+ T cells in the iliac lymph node.,This local bystander activation was also observed after CFA prime and Incomplete Freund’s Adjuvant (IFA) boost injection.,Furthermore, we showed that an antigen specific response is sufficient for the induction of a bystander activation response and the general, immune stimulating effect of CFA or IFA does not appear to increase this effect.,In other words, no evidence was obtained that adjuvation of antigen specific responses is essential for bystander activation.
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The Coxsackie and adenovirus receptor (CAR) is a transmembrane cell-adhesion protein that serves as an entry receptor for enteroviruses and may be essential for their ability to infect cells.,Since enteroviral infection of beta cells has been implicated as a factor that could contribute to the development of type 1 diabetes, it is often assumed that CAR is displayed on the surface of human beta cells.,However, CAR exists as multiple isoforms and it is not known whether all isoforms subserve similar physiological functions.,In the present study, we have determined the profile of CAR isoforms present in human beta cells and monitored the subcellular localisation of the principal isoform within the cells.,Formalin-fixed, paraffin-embedded pancreatic sections from non-diabetic individuals and those with type 1 diabetes were studied.,Immunohistochemistry, confocal immunofluorescence, electron microscopy and western blotting with isoform-specific antisera were employed to examine the expression and cellular localisation of the five known CAR isoforms.,Isoform-specific qRT-PCR and RNA sequencing (RNAseq) were performed on RNA extracted from isolated human islets.,An isoform of CAR with a terminal SIV motif and a unique PDZ-binding domain was expressed at high levels in human beta cells at the protein level.,A second isoform, CAR-TVV, was also present.,Both forms were readily detected by qRT-PCR and RNAseq analysis in isolated human islets.,Immunocytochemical studies indicated that CAR-SIV was the principal isoform in islets and was localised mainly within the cytoplasm of beta cells, rather than at the plasma membrane.,Within the cells it displayed a punctate pattern of immunolabelling, consistent with its retention within a specific membrane-bound compartment.,Co-immunofluorescence analysis revealed significant co-localisation of CAR-SIV with zinc transporter protein 8 (ZnT8), prohormone convertase 1/3 (PC1/3) and insulin, but not proinsulin.,This suggests that CAR-SIV may be resident mainly in the membranes of insulin secretory granules.,Immunogold labelling and electron microscopic analysis confirmed that CAR-SIV was localised to dense-core (insulin) secretory granules in human islets, whereas no immunolabelling of the protein was detected on the secretory granules of adjacent exocrine cells.,Importantly, CAR-SIV was also found to co-localise with protein interacting with C-kinase 1 (PICK1), a protein recently demonstrated to play a role in insulin granule maturation and trafficking.,The SIV isoform of CAR is abundant in human beta cells and is localised mainly to insulin secretory granules, implying that it may be involved in granule trafficking and maturation.,We propose that this subcellular localisation of CAR-SIV contributes to the unique sensitivity of human beta cells to enteroviral infection.,The online version of this article (10.1007/s00125-018-4704-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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Compared with influenza-specific T cells, self-reactive T cells from patients with multiple sclerosis or type 1 diabetes fail to slow down and do not form normal immunological synapses upon encounter with cognate self-peptide presented by MHC.,Recognition of self-peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases.,We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes.,All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling.,However, they showed little or no visible pMHC accumulation or transport of TCR-pMHC complexes into a central supramolecular activation cluster (cSMAC).,In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities.,The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells.,2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC.,These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus.,However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.
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Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens.,Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability.,Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study.,We have mapped 43 susceptibility loci, including 10 novel associations.,Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes.,Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells.,We found an over-representation (n=16) of transcription factors among SLE susceptibility genes.,This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
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Although previous studies found that cigarette smoking is associated with risk of rheumatoid arthritis (RA), the dose-response relationship remains unclear.,This meta-analysis quantitatively summarizes accumulated evidence regarding the association of lifelong exposure to cigarette smoking assessed as pack-years with the risk of RA.,Relevant studies were identified by a search of MEDLINE and EMBASE from 1966 to October 2013, with no restrictions.,Reference lists from retrieved articles were also reviewed.,Studies that reported relative risks (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between pack-years of cigarette smoking and rheumatoid arthritis were included in a dose-response random-effects meta-regression analysis.,We included 3 prospective cohorts and 7 case-control studies in the meta-analysis.,They included a total of 4,552 RA cases.,There was no indication of heterogeneity (Pheterogeneity = 0.32) and publication bias did not affect the results.,Compared to never smokers, the risk of developing RA increased by 26% (RR = 1.26, 95% CI 1.14 to 1.39) among those who smoked 1 to 10 pack-years and doubled among those with more than 20 pack-years (RR for 21 to 30 pack years = 1.94, 95% CI 1.65 to 2.27).,The risk of RA was not increasing further for higher exposure levels (RR for >40 pack-years = 2.07, 95% CI 1.15 to 3.73).,The risk of RA was statistically significantly higher among rheumatoid factor (RF)-positive RA cases (RR = 2.47, 95% CI 2.02 to 3.02) compared to RF-negative (RR = 1.58, 95% CI 1.15 to 2.18) when comparing the highest versus lowest category of pack-years for the individual studies.,Lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure.,The risk of RA did not further increase with an exposure higher than 20 pack-years.
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Islet transplantation has the potential to cure type 1 diabetes, but current clinical transplantation protocols are inefficient because of the extensive loss of functional islets during the immediate post‐transplantation period.,Studies in rodent models have demonstrated that co‐transplanting mesencyhmal stromal cells (MSCs) with islets improves graft functional survival and transplantation outcomes, and some of the beneficial effects of MSCs are attributable to bioactive molecules secreted by MSCs.,Clinical islet transplantation is almost exclusively via the hepatic portal vein, which does not facilitate co‐engraftment of islets and MSCs, so attention is currently focused on using cell‐free cocktails of MSC‐derived products to treat islets prior to transplantation.,This approach has the potential to overcome many of the technical and regulatory hurdles associated with using MSCs as an adjuvant therapy for human islet transplantation.,Stem Cells Translational Medicine 2018;7:559-563
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Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process.,We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo.,In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors.,This system has been optimized for the CyT49 cell line.,Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing.,Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50-100 fold expansion per week.,Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol.,Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population.,Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice.,By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia.,In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry.
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This comprehensive study identifies multiple sclerosis risk expression quantitative trait loci in purified immune cell types.,At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk.,A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression.,We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models.,We describe MS risk expression quantitative trait loci associations for 129 distinct genes.,By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04).,The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03).,Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
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Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals.,On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor.,Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes.,Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs).,Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance.,It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses.,Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG.,For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10.,Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients.,This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs.,Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L.,Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11.,In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.
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We examined data and patterns in clinical islet transplant studies registered on ClinicalTrials.gov (CTgov) for treatment of type 1 diabetes (T1D), with a goal of extracting insights to apply in the design of a pluripotent stem cell‐derived islet therapy.,Clinical islet transplantation, as a cell therapy (rather than solid organ transplant) is a unique precedent for stem cell‐based islet therapies.,Registration activity shows that the field is not growing significantly, and newer registrations suggest that the reasons for stagnation include need for a more optimal site of infusion/transplantation, and especially a need for better immune protective strategies to advance a more effective and durable therapy for T1D. stem cells translational medicine 2019;8:209&214
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Autoimmune and allergic diseases occur when an individual mounts an inappropriate immune response to a self-antigen or an innocuous environmental antigen.,This triggers a pathogenic T-cell response resulting in damage to specific tissues and organs.,In type 1 diabetes (T1D), this manifests as destruction of the insulin-secreting β cells, resulting in a life-long dependency on recombinant insulin.,Modulation of the pathogenic T-cell response with antigen-specific peptide immunotherapy offers the potential to restore the immune homeostasis and prevent further tissue destruction.,Recent clinical advances with peptide therapy approaches in both T1D and other diseases are beginning to show encouraging results.,New technologies targeting the peptides to specific cell types are also moving from pre-clinical development to the clinic.,While many challenges remain in clinical development, not least selection of the optimal dose and dosing frequency, this is clearly becoming a very active field of drug development.
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We recently reported the scalable in vitro production of functional stem cell-derived β-cells (SC-β cells).,Here we extend this approach to generate the first SC-β cells from type 1 diabetic patients (T1D). β-cells are destroyed during T1D disease progression, making it difficult to extensively study them in the past.,These T1D SC-β cells express β-cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice and respond to anti-diabetic drugs.,Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β-cell stress.,Using these assays, we find no major differences in T1D SC-β cells compared with SC-β cells derived from non-diabetic patients.,These results show that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.,Pancreatic β cells can be generated from pluripotent stem cells.,Here, the authors show that human induced pluripotent stem cells from patients with type 1 diabetes can be differentiated into β-like cells that have no detectable differences compared with cells from non-diabetic individuals.
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To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.,A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years.,Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone).,C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001).,Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects.,Fasting blood glucose stabilization also showed improvements in the most recent era.,There were also modest reductions in the occurrence of adverse events.,The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01).,Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).,The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.
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Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin.,Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability.,This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).,Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs.,IGlar OD were analysed.,Four thousand three hundred and thirty subjects (2899 IDeg OD vs.,1431 IGlar OD) were analysed.,Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs.,IGlar: estimated rate ratio (RR):0.83[0.70;0.98]95%CI, RR:0.64[0.48;0.86]95%CI and RR:0.14[0.03;0.70]95%CI.,In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs.,IGlar [RR:0.83[0.74;0.94]95%CI and RR:0.68[0.57;0.82]95%CI).,In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs.,IGlar during maintenance treatment (RR:0.75[0.60;0.94]95%CI).,Reduction in hypoglycaemia with IDeg vs.,IGlar was more pronounced during maintenance treatment in all populations.,The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia.,This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs.,IGlar across a broad spectrum of patients with diabetes.
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People with type 1 diabetes have increased risk of hospital admission compared with those without diabetes.,We hypothesized that HbA1c would be an important indicator of risk of hospital admission.,The Scottish Care Information-Diabetes Collaboration, a dynamic national register of diagnosed cases of diabetes in Scotland, was linked to national data on admissions.,We identified 24,750 people with type 1 diabetes during January 2005 to December 2007.,We assessed the relationship between deciles of mean HbA1c and hospital admissions in people with type 1 diabetes adjusting for patient characteristics.,There were 3,229 hospital admissions.,Of the admissions, 8.1% of people had mean HbA1c <7.0% (53 mmol/mol) and 16.3% had HbA1c <7.5% (58 mmol/mol).,The lowest odds of admission were associated with HbA1c 7.7-8.7% (61-72 mmol/mol).,When compared with this decile, a J-shaped relationship existed between HbA1c and admission.,The highest HbA1c decile (10.8-18.4%/95-178 mmol/mol) showed significantly higher odds ratio (95% CI) for any admission (2.80, 2.51-3.12); the lowest HbA1c decile (4.4-7.1%/25-54 mmol/mol) showed an increase in odds of admission of 1.29 (1.10-1.51).,The highest HbA1c decile experienced significantly higher odds of diabetes-related (3.31, 2.94-3.72) and diabetes ketoacidosis admissions (10.18, 7.96-13.01).,People with type 1 diabetes with highest and lowest mean HbA1c values were associated with increased odds of admission.,People with high HbA1c (>10.8%/95 mmol/mol) were at particularly high risk.,There is the need to develop effective interventions to reduce this risk.
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Neuropsychiatric symptoms affect nearly half of the patients with systemic lupus erythematosus; however, the effect on disease severity, quality of life, and prognosis is tremendous.,Symptoms of neuropsychiatric systemic lupus erythematosus may range from mild diffuse ones, to acute life threatening events.,Although the underlying mechanisms are still largely unraveled, several pathogenic pathways are identified, such as antibody-mediated neurotoxicity, vasculopathy due to anti-phospholipid antibodies and other mechanisms, and cytokine-induced neurotoxicity.,In the current review, we describe the old and the new regarding epidemiology, pathophysiology, diagnosis, and management of neuropsychiatric systemic lupus erythematosus.,The possible link between neuropsychiatric symptoms and specific mechanisms may help to facilitate our understanding of the disease in the future, thus allowing for better treatment strategies.
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To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology.,In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE.,The mouse MRL lymphoproliferation strain (a.k.a.,MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus.,We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms.,These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.
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Neurophysiological measures of brain function, such as magnetoencephalography (MEG), are widely used in clinical neurology and have strong relations with cognitive impairment and dementia but are still underdeveloped in multiple sclerosis (MS).,To demonstrate the value of clinically applicable MEG-measures in evaluating cognitive impairment in MS.,In eyes-closed resting-state, MEG data of 83 MS patients and 34 healthy controls (HCs) peak frequencies and relative power of six canonical frequency bands for 78 cortical and 10 deep gray matter (DGM) areas were calculated.,Linear regression models, correcting for age, gender, and education, assessed the relation between cognitive performance and MEG biomarkers.,Increased alpha1 and theta power was strongly associated with impaired cognition in patients, which differed between cognitively impaired (CI) patients and HCs in bilateral parietotemporal cortices.,CI patients had a lower peak frequency than HCs.,Oscillatory slowing was also widespread in the DGM, most pronounced in the thalamus.,There is a clinically relevant slowing of neuronal activity in MS patients in parietotemporal cortical areas and the thalamus, strongly related to cognitive impairment.,These measures hold promise for the application of resting-state MEG as a biomarker for cognitive disturbances in MS in a clinical setting.
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Brain functional connectivity (FC) is defined as the coherence in the activity between cerebral areas under a task or in the resting-state (RS).,By applying functional magnetic resonance imaging (fMRI), RS FC shows several patterns which define RS brain networks (RSNs) involved in specific functions, because brain function is known to depend not only on the activity within individual regions, but also on the functional interaction of different areas across the whole brain.,Region-of-interest analysis and independent component analysis are the two most commonly applied methods for RS investigation.,Multiple sclerosis (MS) is characterized by multiple lesions mainly affecting the white matter, determining both structural and functional disconnection between various areas of the central nervous system.,The study of RS FC in MS is mainly aimed at understanding alterations in the intrinsic functional architecture of the brain and their role in disease progression and clinical impairment.,In this paper, we will examine the results obtained by the application of RS fMRI in different multiple sclerosis (MS) phenotypes and the correlations of FC changes with clinical features in this pathology.,The knowledge of RS FC changes may represent a substantial step forward in the MS research field, both for clinical and therapeutic purposes.
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Here, Ding et al. sought to understand whether and how the ubiquitin-proteasomal system (UPS) contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI).,They demonstrate that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development.,Dysregulation of the ubiquitin-proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders.,However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined.,Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development.,Using proteomic analysis of the Daam2-VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination.,Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI.,Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for Nedd4 in glial biology.
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The nature of the inflammatory response in the MS brain is poorly defined.,Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.,Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain.,However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations.,In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls.,In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse.,A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen’s encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest.,Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis.,Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells.,The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions.,Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen’s encephalitis.,Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions.,Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.
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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.
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To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.,Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy.,Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry.,Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay.,4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (P < 0.008; r = -0.60).,Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05).,High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48).,Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063).,In patients whose in vivo tpO2 levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05).,In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found.,High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation.,Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment.
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Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system and compromises the health and well-being of millions of people worldwide.,B cells have been linked to MS and its progression.,This review aimed to determine the role of B cells in MS development.,Articles used in this review were obtained from PubMed, LILACS, and EBSCO.,The search terms and phrases included “multiple sclerosis,” “MS,” “B-Cells,” “pathogenesis,” and “development.”,Original research studies and articles on MS and B cells published between 2007 and 2018 were included.,Results from the selected articles showed a significant connection between B cell groups and MS.,B cells act as a significant source of plasma cells, which generate antibodies while also regulating autoimmune processes and T cell production.,In addition, B cells regulate the release of molecules that affect the proinflammatory actions of other immune cells.,B cells play key roles in immune system functioning and MS.,The findings of this review illustrate the complex nature of B cell actions, their effects on the autoimmune system, and the method by which they contribute to MS pathogenesis.,Previous research implicates biological, genetic, and environmental factors in MS pathogenesis.,This review suggests that B cells contribute to MS development and advancement by influencing and regulating autoimmune processes such as T cell production and APC activity.
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This review summarizes recent developments in platelet biology relevant to neuroinflammatory disorders.,Multiple sclerosis (MS) is taken as the "Poster Child" of these disorders but the implications are wide.,The role of platelets in inflammation is well appreciated in the cardiovascular and cancer research communities but appears to be relatively neglected in neurological research.,After a brief introduction to platelets, topics covered include the matrix metalloproteinases, platelet chemokines, cytokines and growth factors, the recent finding of platelet PPAR receptors and Toll-like receptors, complement, bioactive lipids, and other agents/functions likely to be relevant in neuroinflammatory diseases.,Each section cites literature linking the topic to areas of active research in MS or other disorders, including especially Alzheimer's disease.,The final section summarizes evidence of platelet involvement in MS.,The general conclusion is that platelets may be key players in MS and related disorders, and warrant more attention in neurological research.
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Microbial communities reside in healthy tissues but are often disrupted during disease.,Bacterial genomes and proteins are detected in brains from humans, nonhuman primates, rodents and other species in the absence of neurological disease.,We investigated the composition and abundance of microbiota in frozen and fixed autopsied brain samples from patients with multiple sclerosis (MS) and age- and sex-matched nonMS patients as controls, using neuropathological, molecular and bioinformatics tools. 16s rRNA sequencing revealed Proteobacteria to be the dominant phylum with restricted diversity in cerebral white matter (WM) from MS compared to nonMS patients.,Both clinical groups displayed 1,200-1,400 bacterial genomes/cm3 and low bacterial rRNA:rDNA ratios in WM.,RNAseq analyses showed a predominance of Proteobacteria in progressive MS patients’ WM, associated with increased inflammatory gene expression, relative to a broader range of bacterial phyla in relapsing-remitting MS patients’ WM.,Although bacterial peptidoglycan (PGN) and RNA polymerase beta subunit immunoreactivities were observed in all patients, PGN immunodetection was correlated with demyelination and neuroinflammation in MS brains.,Principal component analysis revealed that demyelination, PGN and inflammatory gene expression accounted for 86% of the observed variance.,Thus, inflammatory demyelination is linked to an organ-specific dysbiosis in MS that could contribute to underlying disease mechanisms.
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Multiple sclerosis (MS) is an immune-mediated disease, the etiology of which involves both genetic and environmental factors.,The exact nature of the environmental factors responsible for predisposition to MS remains elusive; however, it’s hypothesized that gastrointestinal microbiota might play an important role in pathogenesis of MS.,Therefore, this study was designed to investigate whether gut microbiota are altered in MS by comparing the fecal microbiota in relapsing remitting MS (RRMS) (n = 31) patients to that of age- and gender-matched healthy controls (n = 36).,Phylotype profiles of the gut microbial populations were generated using hypervariable tag sequencing of the V3-V5 region of the 16S ribosomal RNA gene.,Detailed fecal microbiome analyses revealed that MS patients had distinct microbial community profile compared to healthy controls.,We observed an increased abundance of Psuedomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera in MS patients, whereas control group showed increased abundance of Parabacteroides, Adlercreutzia and Prevotella genera.,Thus our study is consistent with the hypothesis that MS patients have gut microbial dysbiosis and further study is needed to better understand their role in the etiopathogenesis of MS.
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Many potential disease modifying therapies have been identified as suitable for clinical evaluation in Parkinson’s disease (PD).,Currently, the evaluation of compounds in phase II and phase III clinical trials in PD are set up in isolation, a process that is lengthy, costly and lacks efficiency.,This review will introduce the concept of a multi-arm, multi-stage (MAMS) trial platform which allows for the assessment of several potential therapies at once, transitioning seamlessly from a phase II safety and efficacy study to a phase III trial by means of an interim analysis.,At the interim checkpoint, ineffective arms are dropped and replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions.,MAMS trial platforms already exist for prostate, renal and oropharyngeal cancer and are currently being developed for progressive multiple sclerosis (PMS) and motor neuron disease (MND) within the UK.,As a MAMS trial will evaluate many potential treatments it is of critical importance that a widely endorsed core protocol is developed which will investigate outcomes and objectives meaningful to patients.,This review will discuss the challenges of drug selection, trial design, stratification and outcome measures and will share strategies implemented in the planned MAMS trials for MND and PMS that may be of interest to the PD field.
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Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis.,A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies.,We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.,We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK.,We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5.,Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks.,The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site.,Capsules were identical in appearance to achieve masking.,Patients, investigators, and MRI readers were unaware of treatment allocation.,The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria.,The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96).,This trial is registered with ClinicalTrials.gov, NCT01910259.,Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112).,The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99).,No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [-0·6 to 0·3; p=0·77]).,No emergent safety issues were reported.,The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group).,The most common serious adverse events were infections and infestations.,Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.,The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss.,These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials.,This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.,Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
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The SELECT‐EARLY trial was undertaken to study the effect of upadacitinib, an oral, reversible Janus kinase 1-selective inhibitor, as monotherapy in patients with predominantly early rheumatoid arthritis who were naive for or had limited exposure to methotrexate (MTX).,Patients (n = 947) were randomized 1:1:1 to receive once‐daily doses of upadacitinib 15 mg or 30 mg or weekly MTX (7.5-20 mg/week) for 24 weeks.,The primary end points were the proportion of patients who met the American College of Rheumatology 50% (ACR50) improvement criteria at week 12, and the proportion in whom a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <2.6 was achieved at week 24.,Data are presented through week 24.,At baseline, the median disease duration was 0.5 years (range 0-44 years).,A total of 840 patients (89%) completed 24 weeks of treatment.,The study met both primary end points for upadacitinib 15 mg and 30 mg versus MTX (ACR50 was achieved at week 12 in 52% and 56% of patients, respectively, versus 28% [P < 0.001], and DAS28‐CRP <2.6 was achieved at week 24 in 48% and 50% of patients, respectively, versus 19% [P < 0.001]).,Statistically significant and clinically meaningful improvements in multiple patient‐reported outcomes (PROs) were recorded for both upadacitinib doses versus MTX.,Overall, 88% of patients receiving upadacitinib 15 mg and 89% of patients receiving 30 mg, respectively, had no radiographic progression (modified total Sharp score ≤0) compared to 78% of those receiving MTX (P < 0.01).,Through week 24, the frequency of treatment‐emergent adverse events was similar between the MTX arm (65%) and upadacitinib 15 mg arm (64%), but was slightly higher in the upadacitinib 30 mg arm (71%).,Six deaths were reported (2 in the upadacitinib 15 mg arm, 3 in the upadacitinib 30 mg arm, and 1 in the MTX arm).,Our findings indicate that patients receiving either dose of upadacitinib monotherapy experienced significant improvements in clinical, radiographic, and PROs compared to patients receiving MTX.
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Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).,We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.,Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015).,Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.,6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years.,IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0).,IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4).,IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis.,IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7).,IR for gastrointestinal perforations was 0.1 (0.1 to 0.2).,Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.,This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports.,AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.,NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.
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The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells.,IL-2 and rapamycin can influence the populations of both Th17 and Treg cells.,However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms.,In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients.,Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks.,We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg.,After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased.,While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks.,After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced.,The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased.,Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE.,Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells.,As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage.,ChiCTR-IPR-16009451 Registration date: 2016/10/16
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Introduction: The role of the immune response in the pathogenesis of antiphospholipid syndrome (APS) remains elusive.,It is possible that differences in the frequencies of Th17 cells and/or defects in the immunoregulatory mechanisms are involved in the pathogenesis of APS.,Our aim was to determine the peripheral blood Th cells phenotype and the circulating cytokine profile in patients with primary APS (pAPS) and compare it with systemic lupus erythemathosus (SLE) as disease control group.,Methods: The frequencies of circulating regulatory T cells (Tregs) were determined in PBMCs from 36 patients with pAPS by flow cytometry.,As control groups we included 21 age- and gender-matched healthy controls (HC) and 11 patients with SLE.,The suppressive capacity of Tregs was evaluated in vitro by coculture assay.,On the other hand, intracellular cytokine production was assessed in Th1, Th2, and Th17 cells and circulating IL-6, IL-10, and IL-35 were measured by Cytometric Bead Array and ELISA.,The quantification of Th master gene expression levels was performed by real time quantitative PCR.,Results: pAPS patients and SLE patients did not show differences in the percentage or number of Tregs compared to HC.,The suppressive capacity of Tregs was also similar in the three study group.,Instead, we found higher FoxP3·mRNA expression levels in pAPS patients and HC than SLE patients.,Regarding the Th17 response, patients with pAPS and HC showed a significantly lower frequency of circulating Th17 cells than SLE.,However, no differences were observed in the Th1 response between patients and controls.,Thus, increased Th17/Th1 and Th17/Treg ratios were found in SLE patients but not in pAPS patients. pAPS and SLE patients had higher serum IL-6 levels than HC but there was not difference between both disease groups.,Besides, a significant increase in the immunosuppressive cytokine levels was observed only in pAPS as compared to HC.,Conclusions: Our data demonstrate an increased inflammatory profile of peripheral blood CD4+ T cells from SLE as compared with pAPS mostly due to an increased Th17 response.,In conclusion, there seems not to be a direct pathogenic role for Th cells in pAPS but in SLE.
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Guillain-Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots.,Dimethyl fumarate (DMF), a fumaric acid ester, exhibits various biological activities, including multiple immunomodulatory and neuroprotective effects.,However, the potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear.,Using EAN, an established GBS model, we investigated the effect of DMF by assessing clinical score, histological staining and electrophysiological studies.,Then, we further explored the potential mechanism by Western blot analysis, flow cytometry, fluorescence immunohistochemistry, PCR, and ELISA analysis.,The Mann-Whitney U test was used to compare differences between control group and treatment groups where appropriate.,DMF treatment reduced the neurological deficits by ameliorating inflammatory cell infiltration and demyelination of sciatic nerves.,In addition, DMF treatment decreased the level of pro-inflammatory M1 macrophages while increasing the number of anti-inflammatory M2 macrophages in the spleens and sciatic nerves of EAN rats.,In RAW 264.7, a shift in macrophage polarization from M1 to M2 phenotype was demonstrated to be depended on DMF application.,In sciatic nerves, DMF treatment elevated the level of the antioxidant transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and its target gene hemoxygenase-1 (HO-1) which could facilitate macrophage polarization toward M2 type.,Moreover, DMF improved the inflammatory milieu in spleens of EAN rats, characterized by downregulation of messenger RNA (mRNA) of IFN-γ, TNF-α, IL-6, and IL-17 and upregulation of mRNA level of IL-4 and IL-10.,Taken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation.,The online version of this article (doi:10.1186/s12974-016-0559-x) contains supplementary material, which is available to authorized users.
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Guillain-Barré syndrome (GBS) is an autoimmune disease of the peripheral nervous system, mostly triggered by an aberrant immune response to an infectious pathogen.,Although several infections have been implicated in the pathogenesis of GBS, not all such infected individuals develop this disease.,Moreover, infection with a single agent might also lead to different subtypes of GBS emphasizing the role of host factors in the development of GBS.,The host factors regulate a broad range of inflammatory processes that are involved in the pathogenesis of autoimmune diseases including GBS.,Evidences suggest that systemically and locally released cytokines and their involvement in immune-mediated demyelination and axonal damage of peripheral nerves are important in the pathogenesis of GBS.,Toll-like receptors (TLRs) link innate and adaptive immunity through transcription of several proinflammatory cytokines.,TLR genes may increase susceptibility to microbial infections; an attenuated immune response towards antigen and downregulation of cytokines occurs due to mutation in the gene.,Herein, we discuss the crucial role of host factors such as cytokines and TLRs that activate the immune response and are involved in the pathogenesis of the disease.
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Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs.,COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell.,However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients.,This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson’s disease cases following the Spanish Flu in 1918.,Moreover, the SARS-CoV-2 infection is associated with a cytokine storm.,This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2.,SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development.,The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development.
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•Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,•Most neurological diseases could be caused by coronoviruses invasion.,•Coronoviruses cause nerve damage via diverse pathways.,Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,Most neurological diseases could be caused by coronoviruses invasion.,Coronoviruses cause nerve damage via diverse pathways.,Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage.,Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases.,It is reported that CoV can be found in the brain or cerebrospinal fluid.,The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system.,Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.
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Similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), the coronavirus disease 2019 (COVID-19) has neurological symptoms.,COVID-19 patients have such clinical symptoms as headache, vomiting, nausea, dizziness, myalgia, anosmia, ageusia, and disorder of consciousness.,These symptoms confirm that the nervous system is involved in the COVID-19 infection.,Guillain-Barré syndrome (GBS) is a heterogeneous disorder which often follows a viral infection.,According to the assessment case reports from the beginning of the COVID-19 infection so far, it is possible that GBS is linked to the COVID-19 infection.,It seems that paying attention to the neurological effects of COVID-19 is necessary.
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Since coronavirus disease-2019 (COVID-19) outbreak in January 2020, several pieces of evidence suggested an association between the spectrum of Guillain-Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).,Most findings were reported in the form of case reports or case series, whereas a comprehensive overview is still lacking.,We conducted a systematic review and searched for all published cases until July 20th 2020.,We included 73 patients reported in 52 publications.,A broad age range was affected (mean 55, min 11-max 94 years) with male predominance (68.5%).,Most patients showed respiratory and/or systemic symptoms, and developed GBS manifestations after COVID-19.,However, asymptomatic cases for COVID-19 were also described.,The distributions of clinical variants and electrophysiological subtypes resemble those of classic GBS, with a higher prevalence of the classic sensorimotor form and the acute inflammatory demyelinating polyneuropathy, although rare variants like Miller Fisher syndrome were also reported.,Cerebrospinal fluid (CSF) albuminocytological dissociation was present in around 71% cases, and CSF SARS-CoV-2 RNA was absent in all tested cases.,More than 70% of patients showed a good prognosis, mostly after treatment with intravenous immunoglobulin.,Patients with less favorable outcome were associated with a significantly older age in accordance with previous findings regarding both classic GBS and COVID-19.,COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms.,Nevertheless, more extensive epidemiological studies are needed to clarify these issues.
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The study aimed to determine whether discrete subtypes of type 1 diabetes exist, based on immunoregulatory profiles at clinical onset, as this has significant implications for disease treatment and prevention as well as the design and analysis of clinical trials.,Using a plasma-based transcriptional bioassay and a gene-ontology-based scoring algorithm, we examined local participants from the Children’s Hospital of Wisconsin and conducted an ancillary analysis of TrialNet CTLA4-Ig trial (TN-09) participants.,The inflammatory/regulatory balance measured during the post-onset period was highly variable.,Notably, a significant inverse relationship was identified between baseline innate inflammatory activity and stimulated C-peptide AUC measured at 3, 6, 12, 18 and 24 months post onset among placebo-treated individuals (p ≤ 0.015).,Further, duration of persistent insulin secretion was negatively related to baseline inflammation (p ≤ 0.012) and positively associated with baseline abundance of circulating activated regulatory T cells (CD4+/CD45RA−/FOXP3high; p = 0.016).,Based on these findings, data from participants treated with CTLA4-Ig were stratified by inflammatory activity at onset; in this way, we identified pathways and transcripts consistent with inhibition of T cell activation and enhanced immunoregulation.,Variance among baseline plasma-induced signatures of TN-09 participants was further examined with weighted gene co-expression network analysis and related to clinical metrics.,Four age-independent subgroups were identified that differed in terms of baseline innate inflammatory/regulatory bias, rate of C-peptide decline and response to CTLA4-Ig treatment.,These data support the existence of multiple type 1 diabetes subtypes characterised by varying levels of baseline innate inflammation that are associated with the rate of C-peptide decline.,Gene expression data files are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE102234).,The online version of this article (10.1007/s00125-018-4708-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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CD44 is a multi-functional receptor with multiple of isoforms engaged in modulation of cell trafficking and transmission of apoptotic signals.,We have previously shown that injection of anti-CD44 antibody into NOD mice induced resistance to type 1 diabetes (T1D).,In this communication we describe our efforts to understand the mechanism underlying this effect.,We found that CD44-deficient NOD mice develop stronger resistance to T1D than wild-type littermates.,This effect is not explained by the involvement of CD44 in cell migration, because CD44-deficient inflammatory cells surprisingly had greater invasive potential than the corresponding wild type cells, probably owing to molecular redundancy.,We have previously reported and we show here again that CD44 expression and hyaluronic acid (HA, the principal ligand for CD44) accumulation are detected in pancreatic islets of diabetic NOD mice, but not of non-diabetic DBA/1 mice.,Expression of CD44 on insulin-secreting β cells renders them susceptible to the autoimmune attack, and is associated with a diminution in β-cells function (e.g., less insulin production and/or insulin secretion) and possibly also with an enhanced apoptosis rate.,The diabetes-supportive effect of CD44 expression on β cells was assessed by the TUNEL assay and further strengthened by functional assays exhibiting increased nitric oxide release, reduced insulin secretion after glucose stimulation and decreased insulin content in β cells.,All these parameters could not be detected in CD44-deficient islets.,We further suggest that HA-binding to CD44-expressing β cells is implicated in β-cell demise.,Altogether, these data agree with the concept that CD44 is a receptor capable of modulating cell fate.,This finding is important for other pathologies (e.g., cancer, neurodegenerative diseases) in which CD44 and HA appear to be implicated.
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To clarify the relationship among serum adiponectin, body composition, current disease activity and therapeutics of rheumatoid arthritis (RA).,We conducted a cross-sectional study in RA patients under treatment with agents including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors.,A total of 351 subjects from the Kyoto University RA Management Alliance cohort (KURAMA) were enrolled in the analysis.,We classified the participants into five body composition groups according to the cut-off points for obesity and visceral fat used in Japan: body mass index (BMI), 18.5 kg/m2 for underweight and 25.0 kg/m2 for obesity, and visceral fat area (VFA), 100 cm2 for visceral adiposity.,Classification of body composition revealed that serum adiponectin levels and disease activity score (DAS28-ESR) in the low BMI group were significantly higher than those in the normal and overweight groups.,Because both increased serum adiponectin and low BMI were previously reported as poor prognostic factors of RA, we performed multiple regression analysis to determine which factor was correlated with RA disease activity.,Serum adiponectin level, but not BMI, was positively associated with DAS28-ESR (estimate = 0.0127, p = 0.0258).,Subanalysis also showed that the use of bDMARD or JAK inhibitor did not have an obvious influence on circulating adiponectin.,Classification of body composition and multiple regression analysis revealed a positive and independent correlation between serum adiponectin and DAS28-ESR in Japanese RA patients.,Thus, serum adiponectin may be an important marker reflecting high disease activity of RA regardless of current medications.
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Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain.,The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others.,Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics.,The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid.,None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint.,Moreover, a number of safety concerns surround current therapies for RA and OA.,New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage.,This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA.,This evidence points to new treatment targets in these diseases.
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To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).,Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria.,Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs).,Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot.,For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.,EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS.,Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA.,In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot.,Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive.,EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.,The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS.,It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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Oligodendrocytes (OLs) are the myelinating glia of the central nervous system.,Injury to OLs causes myelin loss.,In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs.,To identify inducers of OPC to OL differentiation, a high‐throughput screening based on myelin basic protein expression using neural progenitor cells‐derived OPCs has been performed and, PD0325901-an MEK (MAPK kinase) inhibitor-is found to significantly enhance OPC to OL differentiation in a dose‐ and time‐dependent manner.,Other MEK inhibitors also display similar effect, indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs.,PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co‐culture in vitro.,And in experimental autoimmune encephalomyelitis model and cuprizone‐induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration.,Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.
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Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases.,While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology.,Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage.,Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.,Antigen-induced arthritis (AIA) was established in IL-10KO mice and wild-type controls.,Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies, we explored the regulation of inflammasome components.,These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays.,In AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores.,Here, focal bone erosions were associated with increased tartrate-resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1β.,When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components.,Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1.,In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis.,These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.,The online version of this article (doi:10.1186/s13075-014-0419-y) contains supplementary material, which is available to authorized users.
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The aim of this study was to examine whether circulating levels of the pro-inflammatory glycoprotein tenascin-C (TNC) are elevated in musculoskeletal disorders including rheumatoid arthritis (RA) and to assess in RA whether levels are related to clinical disease status and/or patient response to treatment.,TNC in serum or plasma was quantified by ELISA.,Samples from 4 cohorts of RA patients were examined and compared to normal human subjects and to patients with other inflammatory diseases.,Circulating TNC levels were significantly raised in patients with RA, as well as patients with systemic lupus erythematosus, idiopathic inflammatory myositis, psoriatic arthritis and ankylosing spondylitis, whilst patients with Sjogren's syndrome displayed levels similar to healthy controls.,The highest levels of TNC were observed in RA patients with late stage disease.,In early disease TNC levels correlated positively with ultrasound determined erosion scores.,Treatment of early RA patients with infliximab plus methotrexate (MTX) resulted in a transient decrease in circulating TNC over the first year of therapy.,In contrast, TNC levels increased over time in RA patients receiving MTX alone.,In patients treated with infliximab plus MTX, baseline TNC levels significantly correlated with tender joint counts (TJC) at 18 and 54 weeks after initiation of infliximab therapy.,Raised circulating TNC levels are detected in specific inflammatory diseases.,Levels are especially high in RA where they may act as a biomarker of bone erosion and a predictor of the effect of infliximab on RA patient joint pain.
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Glatiramer acetate (GA) is one of the first therapies approved for multiple sclerosis (MS).,We prospectively included and monitored drug-naïve and pre-treated MS patients who had been prescribed GA for 1 year, to investigate reasons for GA prescription, its effectiveness and safety in real life clinical practice.,One year, prospective, multicentre, observational study performed between 2010 and 2015 in consecutive MS and clinically isolated syndrome patients starting GA as a first (“naïve”) or second (“switcher”) line therapy.,Primary endpoint was the annualized relapse rate (ARR) over 1 year of GA treatment (from baseline, V1, to 12 months, V2) in naïve and switchers compared to previous 24 months.,Secondary endpoints were: EDSS changes between V1 and V2, frequency of adverse events, and reasons for prescribing and discontinuing GA.,Baseline demographics and clinical characteristics were retrieved from medical records, and outcome measures were documented at V1 and V2, and in case of clinical worsening.,One hundred ninety-four consecutive patients were monitored over 12 months (N = 64 naïve, N = 130 switchers).,Side effect profile (naïve = 36%, switchers = 28%) and comorbidities (naïve = 31%, switchers = 15%) were the most frequent reasons to start GA.,The ARR was reduced in both naïve and switchers during V1-2 as compared to the 24 months preceding V1 [naïve: 0.0 (0.0-0.0) vs 0.5 (0.5-1.0, p = 2.9e-10); switchers: 0.0 (0.0-0.0) vs 0.5 (0.0-0.5, p = 0.022)].,EDSS at V2 was significantly reduced only in naïve [(1.5 (1.0-2.5) vs 2.0 (1.5-2.5), p = 0.003)].,Naïve status and EDSS at V1 were negatively associated with EDSS change between V1-V2 in multivariable analysis (regression coefficient = − 0.436, p = 0.008, and regression coefficient = − 0.263, p = 6.18e-05, respectively).,No new unexpected AE was reported.,In our Swiss cohort, GA was prescribed mainly to naïve or switcher MS patients fearing interferon related side effects, with various comorbidities or considering pregnancy, and showed effectiveness and safety comparable with data of previous GA studies.,The online version of this article (10.1186/s12883-019-1383-6) contains supplementary material, which is available to authorized users.
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A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta-1a treatment was admitted to a local hospital for severe icterus and liver injury.,She was transferred to our university hospital because fulminant hepatitis (FH) was suspected.,She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy.,On hospital day 6, she died from liver failure despite intensive care.,An autopsy revealed histological findings consistent with FH.,Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases.
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In multiple sclerosis (MS), the inflammation and demyelination of the central nervous system (CNS) develop in distinct ways.,This makes diagnosing patients difficult, imperative to initiating early and proper treatment.,Several common features exist, among them a profound infiltration of monocytes into the CNS mediating demyelination and tissue destruction.,In the periphery, monocytes are divided into three subsets depending on expression of CD14 and CD16, representing different stages of activation and differentiation.,To investigate their involvement in MS, peripheral blood mononuclear cells (PBMCs) from 61 patients with incipient, untreated MS and 22 symptomatic control (SC) patients as well as 6 patients with radiologically isolated syndrome (RIS) were characterized ex vivo.,In addition, paired serum and cerebrospinal fluid (CSF) samples were analyzed with a panel of biomarkers.,In PBMC samples, we demonstrate decreased levels of nonclassical monocytes with a concomitant significant decrease of human endogenous retrovirus (HERV) H3 envelope epitopes on this monocyte subset compared with SC and RIS.,The observed HERV expression is present on nonclassical monocytes irrespective of MS and thus presumably a result of the inflammatory activation.,For the other surface markers analyzed, we found significantly decreased expression between classical and nonclassical monocytes.,In matched samples of CSF a highly significant increase in levels of soluble markers of activation and inflammation is shown, and notably this is not the case for the serum samples.,Of the soluble markers investigated, interleukin (IL)‐12/IL‐23p40 had the highest discriminatory power in differentiating patients with MS from SC and RIS, almost comparable to the immunoglobulin G index.,Characterizing monocyte subsets in newly diagnosed multiple sclerosis (MS) contributes valuable insight into disease mechanisms and potential therapeutic targets.,We present evidence of inflammation‐driven activation of monocytes in peripheral blood as well as detailed analysis of biomarker panels capable of differentiating MS from symptomatic controls.
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We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers.,In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination.,In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1.,In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination.,In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells.,In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells.,Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors.,Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35.,These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.
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In mid-2015, Salvador, Brazil, reported an outbreak of Guillain-Barré syndrome (GBS), coinciding with the introduction and spread of Zika virus (ZIKV).,We found that GBS incidence during April-July 2015 among those ≥12 years of age was 5.6 cases/100,000 population/year and increased markedly with increasing age to 14.7 among those ≥60 years of age.,We conducted interviews with 41 case-patients and 85 neighborhood controls and found no differences in demographics or exposures prior to GBS-symptom onset.,A higher proportion of case-patients (83%) compared to controls (21%) reported an antecedent illness (OR 18.1, CI 6.9-47.5), most commonly characterized by rash, headache, fever, and myalgias, within a median of 8 days prior to GBS onset.,Our investigation confirmed an outbreak of GBS, particularly in older adults, that was strongly associated with Zika-like illness and geo-temporally associated with ZIKV transmission, suggesting that ZIKV may result in severe neurologic complications.
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Guillain-Barré syndrome (GBS) has a highly variable clinical course, leading to frequent transfers within and between hospitals and high associated costs.,We defined the current admissions, transfers and costs in relation to disease severity of GBS.,Dutch neurologists were requested to report patients diagnosed with GBS between November 2009 and November 2010.,Information regarding clinical course and transfers was obtained via neurologists and general practitioners.,87 GBS patients were included with maximal GBS disability score of 1 or 2 (28%), 3 or 4 (53%), 5 (18%) and 6 (1%).,Four mildly affected GBS patients were not hospital admitted.,Of the 83 hospitalized patients 68 (82%) were initially admitted at a neurology department, 4 (5%) at an ICU, 4 (5%) at pediatrics, 4 (5%) at pediatrics neurology and 3 (4%) at internal medicine.,Median hospital stay was 17 days (IQR 11-26 days, absolute range 1-133 days).,Transfers between departments or hospitals occurred in 33 (40%) patients and 25 (30%) were transferred 2 times or more.,From a cost-effectiveness perspective 21 (25%) of the admissions was suboptimal.,Median costs for hospital admission of GBS patients were 15,060 Euro (IQR 11,226-23,683).,Maximal GBS disability score was significantly correlated with total length of stay, number of transfers, ICU admission and costs.,Hospital admissions for GBS patients are highly heterogeneous, with frequent transfers and higher costs for those with more severe disease.,Future research should aim to develop prediction models to early identify the most cost-effective allocation in individual patients.
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Human placenta-derived mesenchymal stem cells (pMSCs) are considered a good source for cell therapy.,The purpose of this study was to observe whether the transplantation of human pMSCs would affect the treatment of lupus nephritis (LN)-prone MRL/lpr mice.,Multiple injections (at the 16th, 18th, and 20th week of age) of 1 × 106 pMSCs were administered.,Urine was collected to evaluate proteinuria and urine creatinine levels.,Blood was collected for the measurement of serum antinuclear antibody (ANA) and anti-double-stranded DNA (dsDNA) antibody levels.,Renal tissues were collected for histological staining and examination by light and electron microscopy quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western Blot.,The results confirmed that pMSC treatment reduced the severity of 24-h proteinuria, decreased the production of anti-dsDNA antibodies, and ameliorated renal pathological changes in MRL/lpr mice.,Furthermore, pMSCs reduced renal inflammation by inhibiting the expression of nuclear factor kappa B (NF-κB) and then downregulating the expression of tumor necrosis factor-α (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1).,Therefore, our present study demonstrated a protective effect of pMSCs against renal injury and inflammation in MRL/lpr mice.
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Adult tissue-derived mesenchymal stromal cells (MSCs) are showing promise in clinical trials for systemic lupus erythematosus (SLE).,However, the inability to manufacture large quantities of functional cells from a single donor as well as donor-dependent variability in quality limits their clinical utility.,Human embryonic stem cell (hESC)-derived MSCs are an alternative to adult MSCs that can circumvent issues regarding scalability and consistent quality due to their derivation from a renewable starting material.,Here, we show that hESC-MSCs prevent the progression of fatal lupus nephritis (LN) in NZB/W F1 (BWF1) mice.,Treatment led to statistically significant reductions in proteinuria and serum creatinine and preserved renal architecture.,Specifically, hESC-MSC treatment prevented disease-associated interstitial inflammation, protein cast deposition, and infiltration of CD3+ lymphocytes in the kidneys.,This therapy also led to significant reductions in serum levels of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), two inflammatory cytokines associated with SLE.,Mechanistically, in vitro data support these findings, as co-culture of hESC-MSCs with lipopolysaccharide (LPS)-stimulated BWF1 lymphocytes decreased lymphocyte secretion of TNFα and IL-6, and enhanced the percentage of putative regulatory T cells.,This study represents an important step in the development of a commercially scalable and efficacious cell therapy for SLE/LN.
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Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS).,Here we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF).,Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in MS patients, characterized by the expression of GM-CSF and the C-X-C chemokine receptor type 4.,This cellular signature, which includes expression of very late antigen 4 (VLA4) in peripheral blood, was also enriched in the central nervous system of RRMS patients.,In independent validation cohorts, we confirmed that this cell population is increased in MS patients compared to other inflammatory and non-inflammatory conditions.,Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.
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This study aimed to investigate the benefits of administering perioperative high-dose prednisolone in conjunction with thymectomy in patients with myasthenia gravis.,We retrospectively reviewed data from patients with Myasthenia Gravis Foundation of America Clinical Class I to IIIB who had undergone an extended thymectomy between 1992 and 2009.,Perioperative high-dose prednisolone was administered at starting doses of 10 to 20 mg and escalated up to 100 mg on alternate days.,The treatment group comprised 70 patients receiving perioperative high-dose prednisolone, whereas the control group included 61 patients not treated with preoperative steroids.,The two groups were compared with respect to baseline clinical characteristics, incidence of postoperative complications, and follow-up disease status.,Prednisolone-treated patients presented with more advanced disease compared to controls (Class IIB or greater, 42 [60.0%] versus 7 [11.3%], respectively; P < 0.001).,Mean preoperative%FVC was lower and FEV1.0% was higher in treated patients than in controls (%FVC: 92.4 ± 2.3% versus 99.5 ± 2.4%, respectively; P = 0.037, FEV1.0%: 85.2 ± 1.3% versus 81.4 ± 0.9%, respectively; P = 0.017).,The groups were similar in other variables including presence of thymoma, and operative procedure.,In the treatment group, disease status was significantly improved only by the induction of high-dose prednisolone before the surgery (P < 0.001), and these patients discontinued anti-cholinesterase therapy more frequently than controls (P < 0.001).,Moreover, the treatment group demonstrated markedly lower rates of postoperative crisis (12.2% versus 2.9%, respectively; P = 0.045).,The incidence of infection, wound dehiscence, and diabetes mellitus were comparable between groups.,Survival analysis demonstrated higher rates of treated patients with improved disease status at three and five years (92% and 96%, respectively) compared to controls (57% and 76%, respectively; P < 0.001).,Likewise, significantly greater proportions of treated patients achieved complete stable remission or pharmacologic remission at three, five, and ten years (23%, 42%, and 72%, respectively) compared to controls (10%, 20%, and 44%, respectively; P = 0.002).,Perioperative high-dose prednisolone therapy is a safe, promising strategy for managing patients with myasthenia gravis and may reduce the incidence of postoperative crisis while improving disease status.
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Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease.,Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases.,As Foxp3 is also expressed on activated CD4+ cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge.,Comprehensive analyses were carried out by Flow cytometry.,Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains clinical samples and healthy controls.,We have systemically examined three potential markers, Helios, CD226 and TIGIT, that are possibly related to Treg identification, and found that Helios expression on CD4+Foxp3+ cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4+Foxp3+ cells in RA patients and they were not associated with disease activity of RA patients.,Taken together, our findings indicate that CD4+CD25hiCD127low/-Foxp3+Helios+ may represent the real Treg cell population in patients with RA.
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Accumulating evidence indicates a critical role for T cells and relevant cytokines in the pathogenesis of systemic lupus erythematosus (SLE).,However, the specific contribution of T cells together with the related circulating cytokines in disease pathogenesis and organ involvement is still not clear.,In the current study, we investigated relevant molecule expressions and cytokine levels in blood samples from 49 SLE patients and 22 healthy control subjects.,The expression of HLA-DR and costimulatory molecules on T cells was evaluated by flow cytometry.,Concentrations of serum C-reactive protein, erythrocyte sedimentation rate, anti-double-stranded DNA (anti-dsDNA) antibody, total lgG, complement 3, and complement 4 were measured.,Serum cytokines and chemokines were measured by a cytometric bead array assay.,Elevated frequencies of HLA-DR+ T cells and ICOS+ T cells were observed in SLE patients with positive anti-dsDNA antibodies compared with those in healthy controls (P < 0.001).,The expression of HLA-DR+ T cells was positively correlated with SLEDAI (r = 0.15, P < 0.01).,Furthermore, levels of serum IL-6, MCP-1, TNFRI, IL-10, IL-12, and CCL20 were higher in SLE patients compared with healthy controls.,In addition, patients with hematologic manifestations displayed elevated frequencies of HLA-DR+ T cells and ICOS+ T cells.,Patients with renal manifestations had a decreased frequency of TIGIT+ T cells.,These results suggested a dysregulated T cell activity and cytokine expression profiles in SLE subjects.,We also developed a chemokine and cytokine profiling strategy to predict the activity of SLE, which has clinical implication for better monitoring the flares and remission during the course of SLE and for assessing therapeutic interventions.
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New targeted therapies and improved treatment strategies have dramatically improved the outcomes of patients with rheumatoid arthritis (RA).,However, it is unknown whether different early aggressive interventions can induce stable remission or a low-active disease state that can be maintained with conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, and whether they differ in efficacy and safety.,The Nordic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) study will assess and compare (1) the proportion of patients who achieve remission in a head-to-head comparison between csDMARD plus glucocorticoid therapy and three different biological DMARD (bDMARD) therapies with different modes of action and (2) two de-escalation strategies in patients who respond to first-line therapy.,In a pragmatic, 80-160-week, multicenter, randomized, open-label, assessor-blinded, phase 4 study, 800 patients with early RA (symptom duration less than 24 months) are randomized 1:1:1:1 to one of four different treatment arms: (1) aggressive csDMARD therapy with methotrexate + sulphasalazine + hydroxychloroquine + i.a. glucocorticoids (arm 1A) or methotrexate + prednisolone p.o. (arm 1B), (2) methotrexate + certolizumab-pegol, (3) methotrexate + abatacept, or (4) methotrexate + tocilizumab.,The primary clinical endpoint is the proportion of patients reaching Clinical Disease Activity Index (CDAI) remission at week 24.,Patients in stable remission over 24 consecutive weeks enter part 2 of the study earliest after 48 weeks.,Patients not achieving sustained CDAI remission over 24 consecutive weeks, exit the study after 80 weeks.,In part 2, patients are re-randomized to two different de-escalation strategies, either immediate or delayed (after 24 weeks) tapering, followed by cessation of study medication.,All patients remain on stable doses of methotrexate.,The primary clinical endpoint in part 2 is the proportion of patients in remission (CDAI ≤2.8) 24 weeks after initiating treatment de-escalation.,Radiographic assessment will be performed regularly throughout the trial, and blood and urine samples will be stored in a biobank for later biomarker analyses.,NORD-STAR is the first investigator-initiated, randomized, early RA trial to compare (1) csDMARD and three different bDMARD therapies head to head and (2) two different de-escalation strategies.,The trial has the potential to identify which treatment strategy to apply in early RA to achieve the best possible outcomes for both patients and society.,NCT01491815 and NCT02466581.,Registered on 8 December 2011 and May 2015, respectively.,EudraCT: 2011-004720-35,The online version of this article (doi:10.1186/s13063-017-1891-x) contains supplementary material, which is available to authorized users.
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B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents.,However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response.,We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.,In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays.,Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX.,Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).,Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment.,Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively).,Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria.,Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%.,Comparable findings applied to EULAR non-response criteria.,This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.
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•The first case of multiple sclerosis (MS) shortly after COVID-19 is presented.,•Viral infections strongly relate to MS onset and its relapses.,•SARS-CoV-2 can play a role in the triggering of demyelinating diseases.,•Systemic immune response against SARS-CoV-2 could reach CNS leading to demyelination.,The first case of multiple sclerosis (MS) shortly after COVID-19 is presented.,Viral infections strongly relate to MS onset and its relapses.,SARS-CoV-2 can play a role in the triggering of demyelinating diseases.,Systemic immune response against SARS-CoV-2 could reach CNS leading to demyelination.,SARS-CoV-2 infection can produce neurological features.,The most common are headache, anosmia and dysgeusia but patients may also develop other central nervous system (CNS) injuries.,We present a patient affected by Covid-19 who initially consulted for decreased visual acuity.,The MRI showed inflammation in the right optic nerve and demyelinating lesions in the CNS.,We speculate that an immune mechanism induced by SARS-CoV-2, which can activate lymphocytes and an inflammatory response, plays a role in the clinical onset of the disease.,This pathogen may be associated with either the triggering or the exacerbation of inflammatory/demyelinating disease.
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•The role of pre-existing immunosuppression on COVID-19 risk and outcomes is unclear•Immunotherapy is being evaluated for COVID-19-related cytokine release syndrome•We report a fingolimod-treated MS patient who developed severe COVID-19•COVID-19 recovery occurred after stopping fingolimod and treating with tocilizumab,The role of pre-existing immunosuppression on COVID-19 risk and outcomes is unclear,Immunotherapy is being evaluated for COVID-19-related cytokine release syndrome,We report a fingolimod-treated MS patient who developed severe COVID-19,COVID-19 recovery occurred after stopping fingolimod and treating with tocilizumab,Treatment decisions in patients with multiple sclerosis (MS) during the coronavirus disease 2019 (COVID-19) pandemic are challenging.,It is not known whether and how various disease modifying therapies, especially immunosuppressive drugs, affect COVID-19 risk and disease course.,Case report,We report a fingolimod-treated MS patient who developed severe COVID-19 but recovered after treatment with tocilizumab.,This report suggests that a brief course of tocilizumab for the treatment of severe COVID-19 may be effective while not aggravating pre-existing MS.
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To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA).,Data were pooled from 9 RA studies.,Placebo comparison up to 24 weeks included data from 6 studies.,Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study.,The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose.,Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure).,No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib).,Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug.,In the 2 mg-4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib).,In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years.,In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF.,With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group.,During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.
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Objective.,To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care.,Methods.,Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment.,HRQoL was captured by the SF36 health survey.,Within strata of sequential bDMARD therapy, we examined patients’ HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores.,Results.,All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12.,In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24.,The improvement of HRQoL was not attributable to a particular bDMARD.,The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%.,Conclusion.,Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure.,Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population.
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Reports of severe COVID-19 being associated with thrombosis, antiphospholipid antibodies (APLA), and antiphospholipid syndrome have yielded disparate conclusions.,Studies comparing patients with COVID-19 with contemporaneous controls of similar severity are lacking.,22 COVID-19+ and 20 COVID-19- patients with respiratory failure admitted to intensive care were studied longitudinally.,Demographic and clinical data were obtained from the day of admission.,APLA testing included anticardiolipin (aCL), anti-β2glycoprotien 1 (β2GP1), antidomain 1 β2GP1 and antiphosphatidyl serine/prothrombin complex.,Antinuclear antibodies (ANAs) were detected by immunofluorescence and antibodies to cytokines by a commercially available multiplexed array.,Analysis of variance was used for continuous variables and Fisher’s exact test was used for categorical variables with α=0.05 and the false discovery rate at q=0.05.,APLAs were predominantly IgG aCL (48%), followed by IgM (21%) in all patients, with a tendency towards higher frequency among the COVID-19+. aCL was not associated with surrogate markers of thrombosis but IgG aCL was strongly associated with worse disease severity and higher ANA titres regardless of COVID-19 status.,An association between aCL and anticytokine autoantibodies tended to be higher among the COVID-19+.,Positive APLA serology was associated with more severe disease regardless of COVID-19 status.,NCT04747782
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Some patients with severe COVID-19 develop prothrombotic autoantibodies that are similar to antiphospholipid antibodies found in autoimmune diseases.,Patients with severe COVID-19 are at high risk for occlusion of blood vessels of all sizes.,This prothrombotic phenotype is reminiscent of patients with lupus and antiphospholipid syndrome, who have long-lived circulating antiphospholipid autoantibodies.,In new work, Zuo et al. measured eight types of antiphospholipid antibodies in serum from patients hospitalized with COVID-19 and found at least one antibody in half of patients.,Antibody levels were associated with neutrophil and coagulation pathway activation.,Purified antibodies from some patients activated neutrophils in vitro and potentiated thrombosis when injected into mice.,Together, these findings suggest that autoantibodies are a potential therapeutic target in severe COVID-19.,Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions.,Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease.,Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies).,Case series have recently detected aPL antibodies in patients with COVID-19.,Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19.,These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM.,We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples.,Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units).,Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate.,Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals.,Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models.,These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.
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Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking.,Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response.,From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as ‘Active’ or ‘Stable’ based on clinical and/or radiological activity on-treatment.,Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples.,Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment.,Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment.,An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment.,Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort.,Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.
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To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS).,EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls.,EBV DNA load was measured in saliva of 48 patients and 50 controls.,Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS).,The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89).,EBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls.,EBV DNA load in saliva did not differ between groups.,Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up.,Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS.,While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS.,These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.
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Interleukin (IL)-17 is one of the critical inflammatory cytokines that plays a direct role in development of Sjögren’s syndrome (SjS), a systemic autoimmune disease characterized by a progressive chronic attack against the exocrine glands.,The expression levels of IL-17 are correlated with a number of essential clinical parameters such as focus score and disease duration in human patients.,Significantly immunological differences of Th17 cells were detected at the onset of clinical disease in female SjS mice compared to males.,To further define the role of IL-17 in SjS and elucidate its involvement in the sexual dimorphism, we examined the systemic effect of IL-17 by genetically ablating Il-17 in the C57BL/6.,NOD-Aec1Aec2, spontaneous SjS murine model.,The results indicate that IL-17 is a potent inflammatory molecule in the induction of chemoattractants, cytokines, and glandular apoptosis in males and females.,Elimination of IL-17 reduced sialadenitis more drastically in females than males.,IL-17 is highly involved in modulating Th2 cytokines and altering autoantibody profiles which has a greater impact on changing plasma cells and germinal center B cell populations in females than males.,The result supports a much more important role for IL-17 and demonstrates the sexual dimorphic function of IL-17 in SjS.
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Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA).,The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells.,This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model.,In CII-treated dendritic cells (DCs) and DC/CD4+ T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6).,Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor α and γt, which were abolished by pretreatment with P2X7R antagonists.,Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A.,Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice.,Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells.,P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype.
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Based on a unique cohort of clinically suspect arthralgia (CSA) patients, we analysed which combinations of MRI features at onset were predictive for rheumatoid arthritis (RA) development.,This was done to increase our comprehension of locations of RA onset and improve the predictive accuracy of MRI in CSA.,In the discovery cohort, 225 CSA patients were followed on clinical arthritis development.,Contrast-enhanced 1.5 T MRIs were made of unilateral metacarpophalangeal (MCP) (2-5), wrist, and metatarsophalangeal (1-5) joints at baseline and scored for synovitis, tenosynovitis, and bone marrow edema.,Severity, number, and combinations of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference.,Cox regression was used for predictor selection.,Predictive values were determined at 1 year follow-up.,Results were validated in 209 CSA patients.,In both cohorts, 15% developed arthritis < 1 year.,The multivariable Cox model selected presence of MCP-extensor peritendinitis (HR 4.38 (2.07-9.25)) and the number of locations with subclinical inflammation (1-2 locations HR 2.54 (1.11-5.82); ≥ 3 locations HR 3.75 (1.49-9.48)) as predictors.,Severity and combinations of inflammatory lesions were not selected.,Based on these variables, five risk categories were defined: no subclinical inflammation, 1-2 locations, or ≥ 3 locations, with or without MCP-extensor peritendinitis.,Positive predictive values (PPVs) ranged 5% (lowest category; NPV 95%) to 67% (highest category).,Similar findings were obtained in the validation cohort; PPVs ranged 4% (lowest category; NPV 96%) to 63% (highest category).,Tenosynovitis, particularly MCP-extensor peritendinitis, is among the first tissues affected by RA.,Incorporating this feature and number of locations with subclinical inflammation improved prediction making with PPVs up to 63-67%.
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The value of joint ultrasonography (US) in the prediction of clinical arthritis in individuals at risk of developing rheumatoid arthritis (RA) is still a point of debate, due to varying scanning protocols and different populations.,We investigated whether US abnormalities assessed with a standard joint protocol can predict development of arthritis in seropositive patients with arthralgia.,Anti-citrullinated protein antibodies and/or rheumatoid factor positive patients with arthralgia, but without clinical arthritis were included.,US was performed at baseline in 16 joints: bilateral metacarpophalangeal 2-3, proximal interphalangeal 2-3, wrist and metatarsophalangeal (MTP) joints 2-3 and 5.,Images were scored semi-quantitatively for synovial thickening and for positive signs on power Doppler (PD).,Association between US abnormalities and arthritis development at the joint and at the patient level was evaluated.,Also, we investigated the added value of US over clinical parameters.,Out of 163 patients who underwent US examination, 51 (31%) developed clinical arthritis after a median follow-up time of 12 (interquartile range 5-24) months, of which 44 (86%) satisfied the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA.,US revealed synovial thickening and PD in at least one joint in 49 patients (30%) and 7 patients (4%), respectively.,Synovial thickening was associated with both development and timing of clinical arthritis in any joint (patient level) when MTP joints were excluded from the US assessment (odds ratio 6.6, confidence interval (CI) 1.9-22), and hazard ratio 3.4, CI 1.6-6.8, respectively, with a mean time to arthritis of 23 versus 45 months when synovial thickening was present versus not present).,There was no association between US and arthritis development at the joint level.,Predictive capacity was highest in the groups with an intermediate and high risk of developing arthritis based on a prediction rule with clinical parameters.,Synovial thickening on US predicted clinical arthritis development at the patient level in seropositive patients with arthralgia when MTPs were excluded from the US assessment.,Positive PD signs were infrequently seen in these at-risk individuals and was not predictive.,In patients at intermediate risk of RA, US may help to identify those at higher risk of developing arthritis.,The online version of this article (10.1186/s13075-018-1767-9) contains supplementary material, which is available to authorized users.
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, immune complex deposition, and tissue damage in the kidneys, skin, heart and lung.,Because of the pathogenic role of antinuclear antibodies and autoreactive T cells in SLE, extensive efforts have been made to demonstrate how B cells act as antibody-producing or as antigen-presenting cells that can prime autoreactive T cell activation.,With the discovery of new innate immune cells and inflammatory mediators, innate immunity is emerging as a key player in disease pathologies.,Recent work over the last decade has highlighted the importance of innate immune cells and molecules in promoting and potentiating SLE.,In this review, we discuss recent evidence of the involvement of different innate immune cells and pathways in the pathogenesis of SLE.,We also discuss new therapeutics targets directed against innate immune components as potential novel therapies in SLE.
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Clinical trials revealed a high efficacy of mycophenolate mofetil (MMF) in inducing and maintaining remission in patients with class III-V-lupus nephritis.,Also extrarenal manifestations respond to MMF treatment.,However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation.,Clinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively.,Patients were divided into treatment groups (MMF: n = 39, azathioprine (AZA) n = 30 and controls without immunosuppressive therapy n = 38).,To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed.,Although patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences.,However, profound differences in paraclinical parameters were found.,B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls.,Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment.,Differences in T cell subsets were not significant.,MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival.,The thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.
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Elastography point quantification is a convenient method for measuring liver stiffness.,It can be performed simultaneously with conventional ultrasonography.,This study aimed to evaluate its diagnostic performance for assessing hepatic fibrosis in patients with autoimmune liver disease (AILD), including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).,The diagnostic performance of elastography point quantification (ElastPQ) was evaluated and compared with that of serum fibrosis markers, including the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4), using the receiver operating characteristics analysis with histologic evaluation as the reference standard.,In 49 AIH patients, sensitivity and specificity of ElastPQ were 93.6% and 44.4%, respectively, for significant fibrosis (≥ F2, cutoff 4.47 kPa), and 63.6% and 86.8% for cirrhosis (F4, cutoff 9.28 kPa).,In 41 PBC patients, they were 81.8% and 73.3%, respectively, for significant fibrosis (≥ F2, cutoff 5.56 kPa), and 100% and 81.6%, respectively, for advanced fibrosis (≥ F3, cutoff 6.04 kPa).,The areas under the receiver operating characteristic curves of ElastPQ for significant fibrosis (0.77, 95% CI 0.67-0.86) and cirrhosis (0.81, 95% CI 0.65-0.96) were higher than those of APRI and FIB-4 in AILD patients.,According to the multivariable analysis, histological activity, steatosis, and body max index (BMI) were not significant factors that influenced the result of ElastPQ.,ElastPQ exhibited better diagnostic performance-without the influence of confounding factors-for assessing hepatic fibrosis in AILD patients than serum fibrosis markers.
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Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is a target for antinuclear autoantibodies in systemic Lupus erythematosus (SLE), rheumatoid arthritis (RA), and autoimmune hepatitis (AIH).,To monitor molecular interactions between peptides spanning the entire sequence of hnRNP A2/B1 and sera from patients and healthy controls.,Sera from 8 patients from each pathology and controls were passed across a surface plasmon resonance Imagery (SPRi) surface containing 39 overlapping peptides of 17 mers covering the human hnRNP B1.,Interactions involving the immobilised peptides were followed in real time and dissociation rate constants koff for each interaction were calculated.,Several significant interactions were observed: i) high stability (lower koff values) between P55-70 and the AIH sera compared to controls (p= 0.003); ii) lower stability (higher koff values) between P118-133 and P262-277 and SLE sera, P145-160 and RA sera compared to controls (p=0.006, p=0.002, p=0.007).,The binding curves and koff values observed after the formation of complexes with anti-IgM and anti-IgG antibodies and after nuclease treatment of the serum indicate that i) IgM isotypes are prevalent and ii) nucleic acids participate in the interaction between anti-hnRNAP B1 and P55-70 and also between controls and the peptides studied.,These results indicate that P55-70 of hnRNP B1 is a potential biomarker for AIH in immunological tests and suggest the role of circulating nucleic acids, (eg miRNA), present or absent according to the autoimmune disorders and involved in antigen-antibody stability.
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To investigate the total circular RNA (circRNA) profile in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs).,Hybridization microarray was used to define the circRNA profile in peripheral blood mononuclear cells (PBMCs) from 20 untreated patients with RRMS (10 in relapse and 10 in remission) and 10 HCs.,We analyzed close to 14,000 individual circRNAs per sample.,The discovery set data were validated using quantitative reverse transcription-PCR with an independent cohort of 47 patients with RRMS (19 in relapse and 28 in remission) and 27 HCs.,Microarray analysis revealed 914 transcripts to be differentially expressed between patients with RRMS in relapse and HCs (p < 0.05).,We validated 3 circRNAs from 5 showing highest levels of differential expression in the RRMS relapse vs HC group: hsa_circRNA_101348, hsa_circRNA_102611, and hsa_circRNA_104361.,Their expression was significantly increased during relapse in RRMS (p = 0.0002, FC = 2.9; p = 0.01, FC = 1.6; and p = 0.001, FC = 1.5, respectively) and in patients showing gadolinium enhancement on brain MRI (hsa_circRNA_101348, p = 0.0039, FC = 2.4; hsa_circRNA_104361, p = 0.029, FC = 1.7).,Bioinformatic analysis revealed 15 microRNAs interacting with these circRNAs in a complementary manner and led to the discovery and validation of 3 protein-coding RNAs upregulated in patients with RRMS during relapse.,Two of these, AK2 and IKZF3, have previously been implicated in B-cell function.,circRNAs display a distinct profile in PBMCs from patients with RRMS, and our results may implicate circRNA in the known disturbed B-cell activity in RRMS and thus represent a novel biomarker for monitoring relapse activity.
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To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS.,This observational case-control study included patients with MS.,CSF levels of NfL were determined using enzyme-linked immunosorbent assay.,Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population.,Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (-0.34 ± 1.13).,Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72).,An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = -0.944).,This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples.
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To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).,This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX.,The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12.,Additional efficacy outcomes were assessed sequentially.,Safety was assessed from adverse events and laboratory abnormalities.,The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001).,Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage.,FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority.,Adverse events and laboratory abnormalities were comparable among active treatment arms.,Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX.,FIL200 was non-inferior to adalimumab.,NCT02889796.
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JAK inhibitors have shown efficacy in rheumatoid arthritis (RA).,We undertook this study to test our hypothesis that selective inhibition of JAK‐1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.,In two 4‐week exploratory, double‐blind, placebo‐controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS‐6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib.,The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.,Treatment with filgotinib at 75-300 mg met the primary end point and showed early onset of efficacy.,ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C‐reactive protein (CRP) level decreased.,Marked and sustained improvements were observed in serum CRP level and other PD markers.,The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range.,Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK‐2 inhibition related], no effects on liver transaminases, and no increase in low‐density lipoprotein or total cholesterol).,A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK‐1 inhibition.,There were no infections.,Overall, filgotinib was well tolerated.,Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea.,Selective inhibition of JAK‐1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.
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Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms.,Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease.,Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
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Signals controlling the generation of regulatory B (Breg) cells remain ill-defined.,Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells.,In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement.,CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release.,In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells.,This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α.,Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation.,Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab.,We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.,•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction,pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner,Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism,pDCs are hyperactivated in SLE and fail to induce Breg cells,Patients responding to rituximab display a normalized pDC-Breg cell interaction,The signals required for Breg cell differentiation in humans are currently unknown.,Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.
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In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS).,In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS).,Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS.,We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other.,The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques.,The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles.,This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter.,The first type of inflammation dominates in acute and relapsing MS.,The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age.,It is suggested that CD8+ T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen.,B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors.,Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown.,Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8+ T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.
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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
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A decrease in platelet count after SARS-CoV-2 vaccination is similar in patients with ITP and healthy controls.Risk factors for exacerbation of ITP after SARS-CoV-2 vaccination include low platelet count, younger age, and current therapy.,A decrease in platelet count after SARS-CoV-2 vaccination is similar in patients with ITP and healthy controls.,Risk factors for exacerbation of ITP after SARS-CoV-2 vaccination include low platelet count, younger age, and current therapy.,Immune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk.,COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown.,We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy).,Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations.,Linear mixed-effects modeling was applied to analyze platelet counts over time.,We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L).,Platelet counts decreased by 6.3% after vaccination.,We did not observe any difference in decrease between the groups.,Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event.,Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99).,Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP.,Patients with ITP with exacerbation responded well on therapy.
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VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines.,Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation.,Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory.,Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein.,The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin.,Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS).,The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events.,Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.
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To evaluate the risk of stroke and myocardial infarction (MI) in adult patients with systemic lupus erythematosus (SLE) through a systematic review and meta-analysis.,We searched MEDLINE and EMBASE from inception to May 2020 to identify observational studies (cohort and cross-sectional) that evaluated risk of stroke and MI in adult patients with SLE compared with the general population or healthy controls.,Studies were included if they reported effect-size estimates that could be used for calculating pooled-effect estimates.,Random-effects models were used to calculate pooled risk ratios (RRs) and 95% CIs for stroke and MI.,Heterogeneity quantified by the I2 test and sensitivity analyses assessed bias.,In total, 26 studies were included in this meta-analysis: 14, 5 and 7 studies on stroke, MI and both stroke and MI, respectively.,The pooled RR for ischaemic stroke was 2.18 (95% CI 1.78 to 2.67; I2 75%), intracerebral haemorrhage 1.84 (95% CI 1.16 to 2.90; I2 67%), subarachnoid haemorrhage 1.95 (95% CI 0.69 to 5.52; I2 94%), composite stroke 2.13 (95% CI 1.73 to 2.61; I2 88%) and MI 2.99 (95% CI 2.34 to 3.82; I2 85%).,There was no evidence for publication bias, and sensitivity analyses confirmed the robustness of the results.,Overall, patients with SLE were identified to have a twofold to threefold higher risk of stroke and MI.,Future research on the interaction between known SLE-specific modifiable risk factors and risk of stroke and MI to support development of prevention and treatment strategies are needed.,CRD42018098690.
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SLE is a chronic autoimmune rheumatic disorder of high heterogeneity in clinical presentation, treatment response and prognosis.,Long-term outcomes in SLE have been dramatically improved over the past decades, however, increased morbidity and mortality, especially among young individuals, still exists.,Unmet needs include residual disease activity and frequent flares, glucocorticoid treatment dependency and toxicity, comorbidity burden, reduced health-related quality of life, health disparities and damage.,The main determinants of long-term outcomes in SLE are age, sex, race/ethnicity, genetic profile, environmental factors including smoking, disease activity, major organ involvement such as lupus nephritis and CNS involvement, comorbidities including cardiovascular disease and serious infections, coexistence with APS, treatment adherence, socio-economic factors and access to care.,In this review we discuss trends in long-term outcomes in SLE over the years and major contributors such as genetic, disease-related, treatment, comorbidity, socio-economic and other factors.
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Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).,Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID.,Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion.,Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose.,The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.,Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled.,Total tofacitinib exposure was 16,291 patient-years.,Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points).,Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies.,The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8.,For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality.,Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.,Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA.,Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.,NCT00413699, funded by Pfizer Inc (date of trial registration: December 20, 2006),The online version of this article (10.1186/s13075-019-1866-2) contains supplementary material, which is available to authorized users.
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A significant role for IFNα in the pathogenesis of systemic lupus erythematosus is well supported, and clinical trials of anti-IFNα monoclonal antibodies are in progress in this disease.,In other autoimmune diseases characterized by substantial inflammation and tissue destruction, the role of type I interferons is less clear.,Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus.,In both of those diseases, presence of the interferon signature has been associated with more significant clinical manifestations.,At the same time, evidence supports an anti-inflammatory and beneficial role of IFNβ locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNβ.,As can also be proposed for type I diabetes mellitus, type I interferon appears to contribute to the development of autoimmunity and disease progression in multiple autoimmune diseases, while maintaining some capacity to control established disease - particularly at local sites of inflammation.,Recent studies in both rheumatoid arthritis and multiple sclerosis suggest that quantification of type I interferon activity or target gene expression might be informative in predicting responses to distinct classes of therapeutic agents.
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Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS).,There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses.,Inflammation is present in all subsets of MS.,The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS.,Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS.,Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor.,In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution.,Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.
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Multiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins.,The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR).,This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms.,Unfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5 T.,Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically.,Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin.,Averaged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM.,The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R = 0.70, p = 0.0114) and - inversely - with MTR (R =−0.73, p = 0.0065).,NfH-SMI35 was not correlated to any of the MR indices.,Post-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination.,The resulting change of proton mobility influences MTR and T1.,This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS.,► Neurofilaments are phosphorylated ► Protein phosphorylation competes with the free proton binding capacity ► Magnetisation transfer depends on magnetisation exchange between macromolecular bound and free protons ► In multiple sclerosis the phosphorylation status of neurofilaments is changed in otherwise normal appearing axons ► In vivo assessment of early axonal pathology is possible using magnetisation transfer
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Foxp3+ regulatory T cells (Treg cells) are the central component of peripheral immune tolerance.,While dysregulated Treg cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive.,Here, we identify imbalance between IFN-γ and IL-10 as a shared Treg signature, present in patients with multiple sclerosis (MS) and under high salt conditions.,RNA-sequencing analysis on human Treg subpopulations reveals β-catenin as a key regulator of IFN-γ and IL-10 expression.,The activated β-catenin signature is enriched in human IFN-γ+ Treg cells, which is confirmed in vivo with Treg specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype.,Moreover, we identify prostaglandin E receptor 2 (PTGER2) as a regulator for IFN-γ and IL-10 production under high salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis.,Our findings reveal a novel PTGER2-β-catenin loop in Treg cells linking environmental high salt conditions to autoimmunity.
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Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells.,The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs).,Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children.,We have administered Tregs in 10 type 1 diabetic children (aged 8-16 years) within 2 months since diagnosis.,In total, 4 patients received 10 × 106 Tregs/kg body wt, and the remaining 6 patients received 20 × 106 Tregs/kg body wt.,The preparation consisted of sorted autologous CD3+CD4+CD25highCD127− Tregs expanded under good manufacturing practice conditions.,No toxicity of the therapy was noted.,A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion.,These patients were followed along with matched type 1 diabetic patients not treated with Tregs.,Half a year after type 1 diabetes onset (4-5 months after Tregs infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group.,In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated.,This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes.
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To classify and immunologically characterize persons with MS based on brain lesions and atrophy and their associated microRNA profiles.,Cerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were quantified and used to define MRI phenotypes as follows: type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year lngitudinal follow-up (n = 153).,Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98).,One-third of the patients had lesion-atrophy dissociation (types II or III) in both the cross-sectional and longitudinal cohorts.,At 5 years, all phenotypes had progressive atrophy (p < 0.001), disproportionally in type II (BPF −2.28%).,Only type IV worsened in physical disability.,Types I and II showed a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability.,Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%).,Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion.,Each MRI phenotype demonstrated an miRNA signature whose underlying biology implicates blood-brain barrier pathology: hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p were the most valid differentiators of MRI phenotypes.,MRI-defined MS phenotypes show high conversion rates characterized by the continuation of either predominant neurodegeneration or inflammation and support the partial independence of these 2 measures.,MicroRNA signatures of these phenotypes suggest a role for blood-brain barrier integrity.
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To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS.,CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients.,The mean follow-up time of these 301 patients was 11.7 ± 6.4 years.,High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 - 4.15); p < 0.0001).,High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 - 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 - 3.35); p = 0.04).,High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 - 20.83); p = 0.05).,CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS.,Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.
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The assessment and characterization of the gut microbiome has become a focus of research in the area of human autoimmune diseases.,Ankylosing spondylitis is an inflammatory autoimmune disease and evidence showed that ankylosing spondylitis may be a microbiome-driven disease.,To investigate the relationship between the gut microbiome and ankylosing spondylitis, a quantitative metagenomics study based on deep shotgun sequencing was performed, using gut microbial DNA from 211 Chinese individuals.,A total of 23,709 genes and 12 metagenomic species were shown to be differentially abundant between ankylosing spondylitis patients and healthy controls.,Patients were characterized by a form of gut microbial dysbiosis that is more prominent than previously reported cases with inflammatory bowel disease.,Specifically, the ankylosing spondylitis patients demonstrated increases in the abundance of Prevotella melaninogenica, Prevotella copri, and Prevotella sp.,C561 and decreases in Bacteroides spp.,It is noteworthy that the Bifidobacterium genus, which is commonly used in probiotics, accumulated in the ankylosing spondylitis patients.,Diagnostic algorithms were established using a subset of these gut microbial biomarkers.,Alterations of the gut microbiome are associated with development of ankylosing spondylitis.,Our data suggest biomarkers identified in this study might participate in the pathogenesis or development process of ankylosing spondylitis, providing new leads for the development of new diagnostic tools and potential treatments.,The online version of this article (doi:10.1186/s13059-017-1271-6) contains supplementary material, which is available to authorized users.
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Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors.,Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation.,Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples.,We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients.,Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects.,We also identified unique Prevotella genes that correlated with disease.,Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis.,This work identifies a potential role for P. copri in the pathogenesis of RA.,DOI:http://dx.doi.org/10.7554/eLife.01202.001,We share our bodies with a diverse set of microorganisms, known collectively as the human microbiome.,Indeed, estimates suggest that our bodies contain 10 times as many microbial cells as human cells.,Our stomach and intestines alone are home to many hundreds and possibly thousands of microbial species that break down indigestible compounds and help to prevent the growth of harmful bacteria.,The immune system must therefore learn to tolerate these microorganisms, while retaining the ability to launch attacks against microorganisms that cause harm.,Failure of this process may increase the risk of autoimmune diseases in which the body mistakenly attacks its own cells and tissues.,Rheumatoid arthritis is a chronic autoimmune disease marked by inflammation of the joints.,Although the causes of rheumatoid arthritis are unknown, mice with mutations that increase the risk of the disease remain healthy if they are kept under sterile conditions.,However, if these mice are exposed to certain species of bacteria sometimes found in the gut, they begin to show signs of joint inflammation.,Here, Scher et al. used genome sequencing to compare gut bacteria from patients with rheumatoid arthritis and healthy controls.,A bacterial species called Prevotella copri was more abundant in patients suffering from untreated rheumatoid arthritis than in healthy individuals.,Moreover, the presence of P. copri corresponded to a reduction in the abundance of other bacterial groups-including a number of beneficial microbes.,In a mouse model of gut inflammation, animals colonized with P. copri had more severe disease than controls, consistent with a pro-inflammatory function of this organism.,Current treatments for rheumatoid arthritis target symptoms.,However, by highlighting the role played by gut bacteria, the work of Scher et al. suggests that novel treatment options focused on curbing the spread of P. copri in the gut could delay or prevent the onset of this disease.,DOI:http://dx.doi.org/10.7554/eLife.01202.002
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Background and objectives: In healthy individuals, autonomic alterations are associated with the aggregation of cardiovascular risk factors.,However, in individuals with type 1 diabetes, who are known to present autonomic alterations, mainly characterized by a reduction in parasympathetic modulation, these associations have not yet been investigated.,We assess whether the aggregation of cardiovascular risk factors influences parasympathetic indices of heart rate variability in young people with type 1 diabetes.,Materials and methods: This cross-sectional study included 39 individuals with type 1 diabetes (22.54 ± 4.31), evaluated in relation to the risk factors: blood pressure, fat percentage, and resting heart rate.,For heart rate variability analysis, heart rate was recorded beat-to-beat using a cardio frequency meter (PolarS810i) for 30 min with the volunteers in dorsal decubitus.,The parasympathetic heart rate variability indices were calculated: rMSSD, pNN50, high frequency (HF) n.u (normalized units), SD1, 2LV, and 2ULV.,Data collection was carried out in 2014 and analyzed in 2017.,Results: Individuals with two aggregate risk factors present a reduction in the values of the indices that reflect parasympathetic autonomic modulation compared to individuals without the risk factors analyzed, regardless of sex and age.,Conclusion: In young people with type 1 diabetes, the aggregation of cardiovascular risk factors is associated with parasympathetic autonomic impairment.
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To evaluate the relationship of neuroretinal layer thickness with sensitive measures of cardiovascular autonomic neuropathy in diabetic patients with non‐proliferative diabetic retinopathy (NPDR).,Twenty‐seven eyes of 27 patients with type 1 diabetes presenting with mild‐to‐moderate NPDR were compared to 27 healthy control (HC) eyes matched for age and gender.,The total macular volume (TMV) and the volumes of individual neurosensory layers in the macula were analysed from spectral domain optical coherence tomography using automated layer segmentation.,Cardiovascular autonomic regulation was assessed by short‐term power spectrum analysis of heart rate variability (HRV) before, during and after an orthostatic challenge.,The patients had an age of 46 ± 12 years and diabetes since 28 ± 9 years.,Diastolic and mean arterial pressure was lower in the patients compared to HCs.,TMV (r = 0.58, p = 0.002), inner plexiform layer volume (IPLV; r = 0.39, p = 0.047) and inner nuclear layer volume (INLV; r = 0.60, p = 0.001) were associated with reduced recovery of low‐frequency (LF) spectral power of HRV after orthostatic load in diabetic patients but not in HCs.,The response of LF spectral power during the orthostatic manoeuvre was blunted in patients compared to HCs (p = 0.02).,Diabetes duration was negatively associated with TMV and INLV, whereas IPLV was significantly reduced in eyes with moderate NPDR compared to HCs.,The results indicate a correlation between inner retinal tissue loss and diminished autonomic regulation in type 1 diabetic patients with mild‐to‐moderate NPDR.,The observed changes can be interpreted as congruent early signs of retinal and systemic neuropathy in diabetes.
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To forecast the number of U.S. individuals aged <20 years with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) through 2050, accounting for changing demography and diabetes incidence.,We used Markov modeling framework to generate yearly forecasts of the number of individuals in each of three states (diabetes, no diabetes, and death).,We used 2001 prevalence and 2002 incidence of T1DM and T2DM from the SEARCH for Diabetes in Youth study and U.S.,Census Bureau population demographic projections.,Two scenarios were considered for T1DM and T2DM incidence: 1) constant incidence over time; 2) for T1DM yearly percentage increases of 3.5, 2.2, 1.8, and 2.1% by age-groups 0-4 years, 5-9 years, 10-14 years, and 15-19 years, respectively, and for T2DM a yearly 2.3% increase across all ages.,Under scenario 1, the projected number of youth with T1DM rises from 166,018 to 203,382 and with T2DM from 20,203 to 30,111, respectively, in 2010 and 2050.,Under scenario 2, the number of youth with T1DM nearly triples from 179,388 in 2010 to 587,488 in 2050 (prevalence 2.13/1,000 and 5.20/1,000 [+144% increase]), with the greatest increase in youth of minority racial/ethnic groups.,The number of youth with T2DM almost quadruples from 22,820 in 2010 to 84,131 in 2050; prevalence increases from 0.27/1,000 to 0.75/1,000 (+178% increase).,A linear increase in diabetes incidence could result in a substantial increase in the number of youth with T1DM and T2DM over the next 40 years, especially those of minority race/ethnicity.
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To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.,A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years.,Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone).,C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001).,Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects.,Fasting blood glucose stabilization also showed improvements in the most recent era.,There were also modest reductions in the occurrence of adverse events.,The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01).,Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).,The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.
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Hospital visitation has become challenging during the coronavirus disease 2019 pandemic because of quarantine measures and fear of infection.,Consequently, newly diagnosed patients may present with more severe diseases during the pandemic.,The present study analyzed the differences in the initial clinical presentations of newly diagnosed patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), comparing pre-pandemic and pandemic periods.,Newly diagnosed patients with T1D or T2D and aged < 18 years during 2018-2020 were included in the study.,Data were collected retrospectively from four academic centers in Gyeonggi-do, South Korea.,Initial clinical data were compared between the pre-pandemic (2018-2019) and pandemic (2020) periods.,In the pre-pandemic and pandemic periods, 99 patients (41 T1D and 58 T2D patients) and 84 patients (51 T1D and 33 T2D patients) were identified, respectively.,During the pandemic, the proportion of diabetic ketoacidosis (DKA) cases increased compared to the pre-pandemic period (21.2% during 2018-2019 vs.,38.1% in 2020; P = 0.012).,In the pre-pandemic and pandemic periods, initial pH was 7.32 ± 0.14 and 7.27 ± 0.15, respectively (P = 0.040), and HbA1c values were 11.18 ± 2.46% and 12.42 ± 2.87%, respectively (P = 0.002).,During the pandemic, there was an increased risk of DKA in patients with T1D (odds ratio, 2.42; 95% confidence interval, 1.04-5.62; P = 0.040).,During the pandemic, the proportion of DKA in newly diagnosed patients with T1D increased and clinical parameters showed a deteriorating pattern.,Increased awareness of pediatric diabetes, especially DKA, could facilitate visit to the hospital for an early diagnosis; thus, reducing the number of DKA cases during the pandemic era.
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To summarize the available evidence on the use COVID-19 vaccines in patients with diabetes mellitus.,We performed a thorough literature search with regard to COVID-19 vaccines in patients with type 1 and type 2 diabetes mellitus.,The novel coronavirus disease (COVID-19) tends to portend a poor prognosis in patients with diabetes mellitus (DM).,Primary prevention remains the mainstay for mitigating the risks associated with COVID-19 in patients with DM.,A significant step in primary prevention is timely vaccination.,Routine vaccination against pneumococcal pneumonia, influenza, and hepatitis B is recommended in patients with DM with good efficacy and reasonable safety profile.,With clinical data supporting a robust neutralizing antibody response in COVID-19 patients with DM, vaccination in individuals with DM is justified.,In fact, as the burden of the disease is borne by people with DM, COVID-19 vaccination should be prioritized in individuals with DM.,Multiple unresolved issues with regard to preferred vaccine type, vaccine efficacy and durability, frequency of administration, vaccination in children (<18 years) and pregnant/lactating women however remain, and need to be addressed through future research.,Patients with type 1 and type 2 diabetes mellitus are at a high risk of poor prognosis with COVID-19 and vaccination should be prioritized in them.,However, many unresolved issues with regard to COVID-19 vaccination need to be addressed through future research.
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Lupus nephritis (LN) is a major and severe complication of systemic lupus erythematosus (SLE).,Neutrophil gelatinase-associated lipocalin (NGAL), as a promising next-generation biomarker in clinical nephrology, has received extensive attention.,However, its diagnostic performance in LN has high variability.,Therefore, we performed an updated meta-analysis to further evaluate the diagnostic accuracy of urinary NGAL (uNGAL).,PubMed, Embase, and Cochrane Library were searched from inception to October 27, 2019.,Meta-analysis was performed with a bivariate random effects model.,Additionally, the summary receiver operating characteristic (SROC) curves were established.,The sources of heterogeneity were explored by meta-regression, subgroup analysis, and sensitivity analysis.,Publication bias was assessed using the Deeks test.,19 articles consisting of 21 eligible studies were included.,In diagnosing LN, the estimates (95% confidence interval (CI)) were as follows: sensitivity, 0.84 (0.71-0.91); specificity, 0.91 (0.70-0.98); and the SROC-AUC value, 0.92 (0.90-0.94).,In identifying active LN, the estimates were as follows: sensitivity, 0.72 (0.56-0.84); specificity, 0.71 (0.51-0.84); and the AUC value, 0.77 (0.74-0.81).,With respect to predicting renal flare, the estimates were as follows: sensitivity, 0.80 (0.57-0.92); specificity, 0.67 (0.58-0.75); and the AUC value, 0.74 (0.70-0.78).,For the studies to distinguish proliferative LN, the estimates were as follows: sensitivity, 0.87 (0.66-0.97), and specificity, 0.69 (0.39-0.91).,Deeks' funnel plot suggested that there was no significant publication bias.,Our meta-analysis indicates that uNGAL was a useful biomarker for diagnosis, estimation of activity, and prediction of renal flare of LN.,In addition, the usefulness of uNGAL to distinguish pathological types of LN needs to be further investigated.
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Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN).,Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition.,RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing.,Results were validated in a second cohort of SLE patients, using NanoString technology.,The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related.,Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN.,In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes.,As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations.,There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils.,Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively.,The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.
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Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells.,A significant proportion of patients respond poorly to therapy.,In addition, the high burden of adverse effects caused by “classical” anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated.,Bruton’s tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival.,BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity.,This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases.,The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects.,The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients.,In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.
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Treatment of multiple sclerosis (MS) is challenging: disease-modifying treatments (DMTs) must both limit unwanted immune responses associated with disease initiation and propagation (as T and B lymphocytes are critical cellular mediators in the pathophysiology of relapsing MS), and also have minimal adverse impact on normal protective immune responses.,In this review, we summarize key preclinical and clinical data relating to the proposed mechanism of action of the recently approved DMT teriflunomide in MS.,Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, leading to a reduction in proliferation of activated T and B lymphocytes without causing cell death.,Results from animal experiments modelling the immune activation implicated in MS demonstrate reductions in disease symptoms with teriflunomide treatment, accompanied by reduced central nervous system lymphocyte infiltration, reduced axonal loss, and preserved neurological functioning.,In agreement with the results obtained in these model systems, phase 3 clinical trials of teriflunomide in patients with MS have consistently shown that teriflunomide provides a therapeutic benefit, and importantly, does not cause clinical immune suppression.,Taken together, these data demonstrate how teriflunomide acts as a selective immune therapy for patients with MS.
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Fingolimod is approved for the treatment of highly active relapsing remitting multiple sclerosis (MS) patients and acts by its unique mechanism of action via sphingosine-1-phosphate receptor-modulation.,Although fingolimod-associated lymphopenia is a well-known phenomenon, the exact cause for the intra- and inter-individual differences of the fluctuation of lymphocyte count and its subtypes is still subject of debate.,In this analysis, we aim to estimate the significance of the individual variation of distinct lymphocyte subsets for differences in absolute lymphocyte decrease in fingolimod treated patients and discuss how different lymphocyte subset patterns are related to clinical presentation in a long-term real life setting.,One hundred and thirteen patients with MS were characterized by complete blood cell count and immune cell phentopying of peripheral lymphocyte subsets before, at month 1 and every 3 months up to 36 months of fingolimod treatment.,In addition, patients were monitored regarding clinical parameters (relapses, disability, MRI).,There was no significant association of baseline lymphocyte count and lymphocyte subtypes with lymphocyte decrease after fingolimod start.,The initial drop of the absolute lymphocyte count could not predict the level of lymphocyte count during steady state on fingolimod.,Variable CD8+ T cell and NK cell counts account for the remarkable intra- and inter-individual differences regarding initial drop and steady state level of lymphocyte count during fingolimod treatment, whereas CD4+ T cells and B cells mostly present a quite uniform decrease in all treated patients.,Selected patients with lymphocyte count >1.0 GPT/l differed by higher CD8+ T cells and NK cell counts compared to lymphopenic patients but presented comparable clinical effectiveness during treatment.,Monitoring of the absolute lymphocyte count at steady state seems to be a rough estimate of fingolimod induced lymphocyte redistribution.,Our results suggest, that evaluation of distinct lymphocyte subsets as CD4+ T cells allow a more detailed evaluation to weigh and interpret degree of lymphopenia and treatment response in fingolimod treated patients.
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Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.
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Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases1.,IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing Th17 cells with pathogenic effector functions2, 3.,However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated.,Here, we used transcriptional profiling of developing Th17 cells to construct a model of their signaling network and nominate major nodes that regulate Th17 development.,We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase4, as an essential node downstream of IL-23 signaling.,SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression.,SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5, 6, 7, 8.,We here show that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity.,Loss of SGK1 abrogated Na+-mediated Th17 differentiation in an IL-23-dependent manner.,These data demonstrate that SGK1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.
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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.
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In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity.,Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis.,Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions.,GC reactions are controlled by FOXP3+ T-follicular regulatory cells (TFR), but it is unknown if they participate in autoantibody production in eLFs.,Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci.,CD35+ cells, parafollicular CD138+ plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs.,However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells.,Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3+CD27+ memory and CD4+CD69+ tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation.,Intriguingly, FOXP3+ cells were almost absent in the whole brain sections and CD3+FOXP3+ TFRs were never found in the lymphoid aggregates.,This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.
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Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown.,We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset.,We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells.,IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci.,Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.
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This review takes the reader through 45 years of islet autoantibody research, from the discovery of islet‐cell antibodies in 1974 to today’s population‐based screening for presymptomatic early‐stage type 1 diabetes.,The review emphasizes the current practical value of, and factors to be considered in, the measurement of islet autoantibodies.,This review takes the reader through 45 years of islet autoantibody research, from the discovery of islet‐cell antibodies in 1974 to today’s population‐based screening for presymptomatic early‐stage type 1 diabetes.,The review emphasizes the current practical value of, and factors to be considered in, the measurement of islet autoantibodies.
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We analyzed demographic and genetic differences between children with various diabetes-associated autoantibodies reflecting the autoimmune process.,In a prospective birth cohort comprising children with HLA-conferred susceptibility to type 1 diabetes (T1D), the pattern of autoantibody appearance was analyzed in 520 children with advanced β-cell autoimmunity associated with high risk for disease.,In 315 cases, a single biochemical autoantibody could be identified in the first positive sample as insulin (insulin autoantibody [IAA]) in 180, as GAD (GAD antibody [GADA]) in 107, and as IA-2 antigen (IA-2 antibody [IA-2A]) in 28.,The age at seroconversion differed significantly between the three groups (P = 0.003).,IAA as the first autoantibody showed a peak time of appearance during the second year of life, whereas GADA as the first autoantibody peaked later, between 3 and 5 years of age.,The risk-associated insulin gene rs689 A/A genotypes were more frequent in children with IAA as the first autoantibody compared with the other children (P = 0.002).,The primary autoantigen in the development of β-cell autoimmunity and T1D seems to strongly correlate with age and genetic factors, indicating heterogeneity in the initiation of the disease process.
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This study used 2 standardized methods to evaluate anti-PLA2R antibody in sera of Chinese patients with primary membranous nephropathy (PMN) and to determine whether immunological reactivity reflected by antibody titer correlates with kidney function parameters.,Overall, 82 subjects with biopsy-proven primary membranous nephropathy (PMN), 22 cases with secondary membranous nephropathy (SMN), 40 non-MN patients with established glomerulonephritis, and 20 healthy volunteers were recruited from the Division of Nephrology, Nanfang Hospital, China.,Anti-PLA2R antibody in the serum of each patient was evaluated by both recombinant cell-based indirect immunofluorescence assay (RC-IFA) and enzyme-linked immunosorbent assay (ELISA).,Kidney function was assessed by proteinuria for 24 hours, serum albumin, blood urea nitrogen (BUN), serum creatine, and serum cystatin C.,We assessed the correlation between anti-PLA2R antibody levels and clinical parameters in the PMN patients.,Fifty-three patients with PMN (64.6%) were positive for anti-PLA2R antibody.,The level of antibody determined by RC-IFA ranged from 1: 10 to 1: 1000 and 0 to 1423 RU/ml by ELISA.,The 2 anti-PLA2R test systems correlated very well with each other and reached an agreement of 95.7% for PMN patients.,The level of antibody detected by ELISA in patients with PMN was also significantly correlated with proteinuria and nephritic-range proteinuria (>3.5 g/day).,Anti-PLA2R antibody is sensitive and extremely specific for diagnosis of Chinese patients with primary membranous nephropathy.,Concentration of autoantibody against PLA2R may be an ideal marker for monitoring the activity of immunological disease.
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The research work in the past years showed that detection of phospholipase A2 receptor (PLA2R) antigen and its dominant IgG4 autoantibody in glomerular deposits of patients with membranous nephropathy (MN) was useful for the differentiation between primary MN (PMN) and secondary MN (SMN), but so far such research data from large Chinese patient series is little.,Here, we are going to report a research work in a Chinese cohort.,This study enrolled 179 patients with PMN, 40 patients with membranous lupus nephritis (LN-MN), 26 patients with hepatitis B virus-associated MN (HBV-MN), 2 patients with malignancy-associated MN (M-MN) and one patient with IgG4-related MN (IgG4-MN).,PLA2R and IgG subclasses in glomerular deposits of these patients were examined by immunofluorescence and/or immunohistochemical staining, and the potential value of the above examinations for differential diagnosis of PMN and SMN was evaluated.,Glomerular PLA2R deposition was present in 92.2% patients with PMN and 7.7% patients with HBV-MN, but none of the patients with LN-MN.,Predominant/codominant IgG4 deposition was found in 93.3% patients with PMN and 11.5% patients with HBV-MN, but none of the patients with LN-MN.,The two M-MN patients both had glomerular PLA2R and predominant/codominant IgG4 deposition.,The one IgG4-MN patient had deeply staining IgG4 but no PLA2R in glomeruli.,The glomerular PLA2R and predominant/codominant IgG4 deposition is frequently observed in Chinese patients with PMN.,Immunofluorescence and immunohistochemical staining of renal biopsy tissue for detection of glomerular PLA2R and IgG subclasses deposition can help to distinguish PMN from LN-MN and most of HBV-MN.
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The Immune Epitope Database (IEDB, iedb.org) captures experimental data confined in figures, text and tables of the scientific literature, making it freely available and easily searchable to the public.,The scope of the IEDB extends across immune epitope data related to all species studied and includes antibody, T cell, and MHC binding contexts associated with infectious, allergic, autoimmune, and transplant related diseases.,Having been publicly accessible for >10 years, the recent focus of the IEDB has been improved query and reporting functionality to meet the needs of our users to access and summarize data that continues to grow in quantity and complexity.,Here we present an update on our current efforts and future goals.
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Multiple sclerosis (MS) is an inflammatory, demyelinating, central nervous system disease mediated by myelin-specific T cells.,Environmental triggers that cause a breakdown of myelin-specific T cell tolerance are unknown.,We found that CD8+ myelin basic protein (MBP)-specific T cell tolerance can be broken and autoimmunity induced by infection with a virus that does not express MBP cross-reactive epitopes and does not depend on bystander activation.,Instead, the virus activated dual T cell receptor (TCR)-expressing T cells capable of recognizing both MBP and viral antigens.,These results demonstrate the importance of dual TCR T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected individuals, as hypothesized in the etiology of MS.
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Neurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS).,We conducted a systematic review and meta-analysis of case-control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other.,Guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed.,Electronic databases were searched for published and ‘grey’ literature, with 151 hits.,Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis.,CSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001).,Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108).,CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001).,CSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS.,Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease ‘activity’ rather than as a marker of disability or disease stage.
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In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis.,Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population.,Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions).,In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo.,A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA.,There were consistent results for other efficacy endpoints.,The safety profile in HDA patients was consistent with the overall CLARITY population.,Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.
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Anti-carbamylated protein (anti-CarP) antibodies have recently been reported to occur in around 45% of rheumatoid arthritis (RA) patients and to have prognostic and diagnostic properties.,At present, the breadth and molecular make-up of the anti-CarP antibody response is ill defined.,To understand the anti-CarP antibody immune response and potential immune effector mechanisms it can recruit, we determined the anti-CarP antibody isotype and IgG-subclass usage in RA patients.,Anti-CarP antibody IgM, IgA, and IgG or IgG subclasses were detected by enzyme-linked immunosorbent assay (ELISA) in sera from 373 unselected RA patients and 196 healthy controls.,An additional 114 anti-citrullinated protein antibody (ACPA) and anti-CarP IgG double-positive patients were selected to study the concomitant presence of both antibody systems.,Anti-CarP IgG was present in around 45% of the patients and comprised all anti-CarP IgG subclasses.,The presence of anti-CarP IgG1 particularly associates with radiological damage.,Anti-CarP IgM was detected in 16% of RA patients, even in anti-CarP IgG-positive individuals, and is indicative of an actively ongoing immune response.,Around 45% of the patients were positive for IgA which included ACPA-positive cases but also 24% of the ACPA-negative cases.,In ACPA and anti-CarP double-positive patients, the distribution and number of isotypes and IgG subclasses was similar for both autoantibodies at the group level, but substantial variation was observed within individual patient samples.,In RA, the anti-CarP antibody response uses a broad spectrum of isotypes and seems to be an actively ongoing immune reaction.,Furthermore, the anti-CarP and ACPA autoantibody responses seems to be differentially regulated.,The online version of this article (doi:10.1186/s13075-017-1392-z) contains supplementary material, which is available to authorized users.
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To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis.,A panel of PTMPs was developed.,Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue.,Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested.,Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis).,Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis.,The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups.,Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups.,We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.
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These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development.,The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome.,Allogeneic HSCT should only be considered where potential risks are justified.,Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres.,Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).,Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity.,Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).,Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment.,ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15).,Over years 0-5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI.,Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5.,Median yearly BVL improved over years 2-4, remaining low in year 5 (years 1-5: −0.59%, −0.25%, −0.19%, −0.15%, and −0.20%).,Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study.,Thyroid disorder incidences peaked at year 3 and subsequently declined.,Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.,NCT00530348; NCT00930553.,This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.
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The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA).,The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.,Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2).,Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21-1.93; p = 0.0004), but in no other subtypes.,Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002.,Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes.,In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E−5).,For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018).,In eOJIA, rs10863962 (3′UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).,This study supports previous association of IL-20 with sJIA.,Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals.,Replication studies are required to confirm or refute these findings.,The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.
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To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).,A multicentre, randomised, double-blind, placebo-controlled trial was conducted.,The primary objective was to compare the efficacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA.,Response was defined by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline.,After month 1 (M1), patients taking placebo were switched to anakinra.,Secondary objectives included tolerance and efficacy assessment for 12 months, and analyses of treatment effect on blood gene expression profiling.,At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003).,Ten patients from the placebo group switched to anakinra; nine were responders at M2.,Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of efficacy (n=2) or a disease flare (n=2).,Blood gene expression profiling at enrolment and at 6 months' follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra.,Anakinra treatment is effective in SJIA, at least in the short term.,It is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature.,Trial Registration Number: NCT00339157.
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Th17 cells mediate inflammation and autoimmunity.,Although it was known that cytokine IL-2 inhibits Th17 cell differentiation, how it does so was elusive.,Using IL-17-specific PTEN-deficient mice, Kim et al. show that phosphatase PTEN inhibits IL-2 production and thus promotes Th17 cell differentiation.,T helper 17 (Th17) cells are a CD4+ T cell subset that produces IL-17A to mediate inflammation and autoimmunity.,IL-2 inhibits Th17 cell differentiation.,However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear.,Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production.,Th17-specific Pten deletion (Ptenfl/flIl17acre) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease.,Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation.,PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model.,Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression.
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Acute SLE courses with antibody-secreting cells (ASC) surges whose origin, diversity, and contribution to serum autoantibodies remain unknown.,Deep sequencing, autoantibody proteome and single-cell analysis demonstrated highly diversified ASC punctuated by VH4-34 clones that produce dominant serum autoantibodies.,A fraction of ASC clones contained unmutated autoantibodies, a finding consistent with differentiation outside the germinal centers.,A substantial ASC segment derived from a distinct subset of newly activated naïve cells of significant clonality that persist in the circulation for several months.,Thus, selection of SLE autoreactivities occurred during polyclonal activation with prolonged recruitment of recently activated naïve B cells.,These findings shed light into SLE pathogenesis, help explain the benefit of anti-B cell agents and facilitate the design of future therapies.
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This open‐label prospective phase I/IIa clinical study used autologous bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) followed by mesenchymal stromal cells conditioned media (MSC‐CM) for the first time to treat multiple sclerosis (MS) patients.,The primary goal was to assess the safety and feasibility and the secondary was efficacy.,The correlation between the MSC‐CM content and treatment outcome was investigated.,Ten MS patients who failed conventional therapy were enrolled.,Adverse events were recorded to assess safety.,The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9‐PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests.,The MSCs‐CM concentration of 27 inflammatory biomarkers was investigated.,The treatment protocol was well tolerated by patients.,There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly.,A decrease of 4 and 3.5 points on the EDSS was achieved in two patients.,We report a correlation between a decreased lesion number at baseline and higher IL‐6, IL‐8, and VEGF MSC‐CM content.,The used protocol was safe and feasible with possible efficacy.,The addition of MSC‐CM could be related to the magnitude of EDSS improvement observed.
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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that affects multiple organs.,Currently, therapeutic molecules present adverse side effects and are only effective in some SLE patient subgroups.,Extracellular vesicles (EV), including exosomes, microvesicles and apoptotic bodies, are released by most cell types, carry nucleic acids, proteins and lipids and play a crucial role in cell-to-cell communication.,EVs can stimulate or suppress the immune responses depending on the context.,In SLE, EVs can work as autoadjuvants, enhance immune complex formation and maintaining inflammation state.,Over the last years, EVs derived from mesenchymal stem cells and antigen presenting cells have emerged as cell-free therapeutic agents to treat autoimmune and inflammatory diseases.,In this review, we summarize the current therapeutic applications of extracellular vesicles to regulate immune responses and to ameliorate disease activity in SLE and other autoimmune disorders.
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The purpose of this study was to examine the psychometric properties of the Diabetes Eating Problem Survey-Revised (DEPS-R) in a large sample of young patients with type 1 diabetes, to establish norms, and to validate it against the Eating Attitudes Test-12 (EAT-12).,A total of 770 children and adolescents aged 11-19 years with type 1 diabetes completed the DEPS-R and the EAT-12.,In addition, age- and sex-standardized BMI and HbA1c data were obtained from the Norwegian Childhood Diabetes Registry.,In addition to tests of validity, principal axis factoring was conducted to investigate the factor structure of the 16-item DEPS-R.,The DEPS-R demonstrated satisfactory Cronbach α (0.89) and was significantly correlated with the EAT-12 (0.65; P < 0.01), indicating convergent validity.,The mean (SD) DEPS-R scores were 11.0 (10.7) for the total sample and 7.7 (7.4) and 14.2 (2.4) for males and females, respectively.,This study replicates and extends previous research demonstrating the psychometric properties of the abbreviated 16-item DEPS-R.,Findings support the utility of this important screening tool to identify disturbed eating in young patients with type 1 diabetes.
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This study examines how active coping and withdrawal, psychological (internalizing and externalizing) symptoms, and glycemic control (A1C values) influence each other across time in adolescents with type 1 diabetes.,One hundred and nine adolescents participated in a four-wave longitudinal study spanning four years (mean age at Time 1 was 13.77).,Patients were visited at home and completed questionnaires measuring coping and psychological symptoms.,The treating physicians were contacted to obtain A1C values.,Cross-lagged path analysis from a structural equation modeling approach was used for data analysis.,Clinically meaningful pathways between coping and glycemic control were found across time.,Active coping prospectively predicted lower A1C levels, which, in turn, predicted active coping.,Higher A1C levels and higher psychological symptoms consistently predicted avoidance coping across time.,Finally, psychological symptomatology constituted an important link in the observed longitudinal chain of effects.,More specifically, higher A1C values and symptomatology at Time 1 positively predicted withdrawal at Time 2, which, in turn, positively predicted symptomatology at Time 3.,Next, symptomatology at Time 3 positively predicted higher A1C values at Time 4, thus coming full circle.,Coping with everyday stress, psychological symptoms, and glycemic control were interrelated across time.,Evidence was obtained for reciprocal pathways and mutually reinforcing mechanisms, indicating the need to monitor coping strategies and psychological symptoms along with glycemic control in optimizing clinical care in adolescents with type 1 diabetes.
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To describe a case series of thyrotoxicosis likely triggered by SARS-CoV-2 vaccination and to warn physicians about this potential correlation.,To report clinical, laboratory and imaging findings and provide further information that goes in line with the underlying mechanisms.,Single-center case series based on all the information collected in the hospital medical records, as well as the temporal sequence between the onset of symptoms and COVID-19 vaccination.,We report 8 cases with thyrotoxicosis after SARS-CoV-2 vaccination. 4 cases of Graves’ disease (GD), 2 cases of subacute painful thyroiditis (SAT), 1 case of concurrent GD and SAT and 1 case of atypical subacute thyroiditis.,Five patients received BNT162b2 mRNA vaccine, 3 patients 1273 mRNA vaccine.,The onset of symptoms following vaccination ranged from 10 to 14 days in six of eight patients and from 7 to 8 weeks in two patients.,Several hypotheses have been proposed to explain the potential correlation between SARS-CoV-2 vaccination and thyrotoxicosis, including immune system hyper-stimulation, molecular mimicry and Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA).,We should pay greater attention to thyroid disorders in patients receiving vaccine against SARS-CoV-2.
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Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism.,ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2.,Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea.,A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19.,Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy.,She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin.,Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.
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Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence.,By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation.,Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors.,Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut.,Further, it remains unclear how they interact to cause the destructive autoimmune process.,This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways.,Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response.,Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements.,Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.
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This study explored the details of the immune response after autologous hematopoietic stem cell transplantation (AHSCT) treatment in type 1 diabetes mellitus.,Peripheral blood mononuclear cells (PBMCs) from 18 patients with type 1 diabetes mellitus were taken at baseline and 12 months after AHSCT or insulin-only therapy.,The lymphocyte proliferation, mRNA expression and secretion of pro-inflammatory and anti-inflammatory cytokines belonging to T-helper type 1 (Th1), T-helper type 17 (Th17) and regulatory T (Treg) cells in PBMC culture supernatants were assessed.,Compared with patients receiving insulin-only treatment, the patients receiving AHSCT treatment showed better residual C-peptide secretion, lower anti-GAD titers and less exogenous insulin dosages after 12 months of follow-up.,AHSCT treatment was associated with significantly reduced Th1 and Th17 cell proportions as well as decreased IFN-γ, IL-2, IL-12p40 and IL-17A levels in the PBMC culture supernatants (all P < 0.05).,Although there was no significant Treg cell expansion after AHSCT treatment, we observed increased IL-10, TGF-β and Foxp3 mRNA expression and increased TGF-β levels.,However, we found no significant changes in the T-cell subpopulations after insulin treatment, except for higher IL-12p40 mRNA expression and a lower proportion of Treg cells.,AHSCT treatment was associated with decreased expansion and function of Th1 and Th17 cells, which may explain the better therapeutic effect of AHSCT compared with the traditional intensive insulin therapy.,Clinicaltrials.gov NCT00807651.,Registered 18 December 2008.
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Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells.,Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors.,Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells.,Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly.,Immune response against tissue-specific antigens is a hallmark of autoimmunity.,Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.
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Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes.,In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes.,Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans.,Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment.,We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months.,Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months.,An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin.,β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment.,Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin.,In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin.,Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.
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To investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity.,A post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline.,We investigated the association of pNfL levels with disability progression, cognitive decline, and brain atrophy and their sensitivity to indicate treatment response through clinical measures.,We analyzed pNfL in 4,185 samples from 1,452 patients with SPMS and 1,172 samples from 378 patients with PPMS.,Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001).,In both studies, higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale score, more Gd+ lesions, and higher T2 lesion load (all p < 0.05).,Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]), earlier wheelchair dependence (SPMS [50%], 1.50 [0.96-2.34]; PPMS [197%], 2.97 [1.44-6.10]), cognitive decline (SPMS [41%], 1.41 [1.09-1.84]), and higher rates of brain atrophy (mean change at month 24: SPMS, −0.92; PPMS, −1.39).,Baseline pNfL levels were associated with future disability progression and the degree of brain atrophy regardless of presence or absence of acute disease activity (gadolinium-enhancing lesions or recent occurrence of relapses before baseline). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression.,pNfL was associated with future clinical and radiologic disability progression features at the group level. pNfL was reduced by treatment and may be a meaningful outcome measure in PMS studies.,EXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).
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Neuronal damage is the morphological substrate of persisting neurological disability.,Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration.,This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies.,We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF.,Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001).,Similar differences were seen in corresponding CSF samples.,CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739).,The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%.,We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfLUmea47:3); levels in ALS were more than 20-fold higher than in controls.,Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.
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Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).,An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR).,The SLR results informed consensus statements.,One overarching principle, 10 points to consider (PTC) and a research agenda were proposed.,Task force members rated their level of agreement (1-10) for each PTC.,Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals.,Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis.,Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission.,Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis.,Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA.,In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development.,Participants’ knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach.,These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.
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The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking.,We analysed lymphoid tissue responses to rituximab in RA patients.,Fourteen RA patients received 2 × 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion.,Tissues were examined by flow cytometry, immunohistochemistry and quantitative PCR.,LN biopsies from five healthy individuals (HC) served as controls.,LN biopsies of RA patients showed increased frequencies of CD21+CD23+IgDhighIgMvariable follicular B cells and CD3+CD25+CD69+ early activated, tissue resident T cells when compared with HCs.,After treatment, there was incomplete depletion of LN B cells.,There was a significant decrease in CD27−IgD+ naïve B cells, and CD27+IgD+ unswitched memory B cells including the CD27+IgD+IgM+ subset and follicular B cells.,Strikingly, CD27+IgD− switched memory B cells persisted in LN biopsies after rituximab treatment.,In the T cell compartment, a significant decrease was observed in the frequency of early activated, tissue resident T cells after rituximab treatment, but late activated T cells persisted.,B cell proliferation inducing cytokine IL-21 was higher expressed in LN biopsies of RA patients compared with HC and expression was not affected by rituximab treatment.,Rituximab does not cure RA, possibly due to persistence of switched memory B cells in lymphoid tissues suggesting that factors promoting B cell survival and differentiation need to be additionally targeted.
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In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness.,From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA.,Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA.,Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA.,Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX.,From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX.,Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes.,This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value.,This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways.,Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX.,Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response.,Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.,The online version of this article (doi:10.1186/s13075-017-1319-8) contains supplementary material, which is available to authorized users.
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Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases.,Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage.,The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA).,For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA.,The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling.,Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity.,Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities.,Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect.,Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.
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METARTHROS (Metabolic impact on joint and bone disease) is a nationwide German network to investigate the overlap between inflammatory and metabolic diseases.,The objective of this study was to compare the body mass index (BMI) distribution in patients with early and established rheumatoid arthritis (RA) with data from the general population, and to evaluate the association of BMI with patient characteristics and clinical markers.,The BMI distribution was examined with data collected at inclusion of patients in the early arthritis cohort CAPEA, the biologics register RABBIT, and the National database of the German Collaborative Arthritis Centers.,A data source with a representative sample of the German population (German Ageing Survey) was used as a comparator.,BMI categories of <18.5 kg/m2 (underweight), 18.5 to <25 kg/m2 (normal weight), 25 to <30 kg/m2 (overweight), and ≥30 kg/m2 (obese) were used.,Patients were stratified by age and sex, and compared to controls from the German Ageing Survey.,Associations between BMI and markers of disease activity were analysed with non-parametric tests and linear models.,Data from 1207 (CAPEA), 12,230 (RABBIT), and 3424 (National database) RA patients and 6202 population controls were evaluated.,The mean age was 56, 56, 62, and 62 years, respectively, the mean disease duration was 13 weeks, 9.9 years, and 13.5 years, respectively, and the mean disease activity score (DAS28) was 5.1, 5.2, and 3.1, respectively.,In all RA cohorts, obesity was more frequent (23.8 %, 23.4 %, 21.4 %, respectively) than in controls (18.2 %).,This applied to all age groups <70 years, was independent of disease duration, and was more pronounced in females.,In all cohorts, the age at RA onset was associated with BMI, being higher in overweight/obese patients compared to normal-weight patients.,Current smoking was negatively associated with BMI.,Linear analyses revealed increased erythrocyte sedimentation rate (ESR) values in underweight and obese females, and an increasing disparity between tender joint counts (TJCs) and swollen joint counts (SJCs) in higher BMI categories.,Compared to the general population, a higher prevalence of obesity was observed in all RA cohorts.,The dominance of obesity in females and the different behaviour of disease activity markers in relation to the BMI in females indicate that additional parameters need to be considered when analysing the impact of obesity on inflammation in RA.,The online version of this article (doi:10.1186/s13075-016-1043-9) contains supplementary material, which is available to authorized users.
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The evidence from published studies on the association between obesity and rheumatoid arthritis has been contradictory.,To clarify the association between obesity and rheumatoid arthritis, we conducted a systematic review and dose-response meta-analysis to assess the relationship between body mass index and rheumatoid arthritis risk.,A systematic literature search of PubMed and Embase (up to 12 July 2014) was performed to identify all eligible published reports.,The pooled relative risk results with corresponding 95% confidence intervals of rheumatoid arthritis development were estimated using a random-effects model.,Eleven eligible related citations fulfilled the inclusion criteria and were included in the study.,Compared with individuals with a body mass index under 30, obese individuals showed an association with a significantly increased risk of rheumatoid arthritis (relative risk = 1.25, 95% confidence interval: 1.07 to 1.45, Pheterogeneity <0.01, I2 = 63%).,Compared to normal weight subjects, the pooled relative risks for rheumatoid arthritis were 1.31 (1.12 to 1.53) and 1.15 (1.03 to 1.29) for the categories of obese and overweight, respectively.,In the dose-response analysis, there was evidence of a nonlinear association (Pnonlinear = 0.005) and the estimated summary relative risk for a 5-unit increment was 1.03 (95% confidence interval: 1.01 to 1.05, Pheterogeneity = 0.001, I2 = 70.0%).,An increase in body mass index can contribute to a higher risk for rheumatoid arthritis development.,However, the finding also highlights the need for research on the association between body mass index and rheumatoid arthritis risk with adjustment for more confounding factors.,The online version of this article (doi:10.1186/s13075-015-0601-x) contains supplementary material, which is available to authorized users.
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RA is a chronic, systemic, autoimmune disease characterized by inflammation and degradation of the joints, causing significant negative impact on quality of life.,In addition to joint disease, symptoms and co-morbidities associated with RA-namely pain, fatigue and mood disorders-are often as debilitating as the disease itself.,The pro-inflammatory cytokine IL-6 plays a critical role in RA-associated pathology.,However, a greater understanding of the translational effects of IL-6 outside of the immune system is needed.,This review discusses our current understanding of emerging aspects of IL-6 in RA-associated pain, fatigue and mood disorders such as depression and anxiety.,This review also describes the clinical effects of IL-6 inhibition on these symptoms and co-morbidities in patients with RA.
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To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).,In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015.,All events were validated independently by two physicians, blinded for treatment exposure.,37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs).,Only two patients had a history of diverticulitis (one in TCZ).,Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP.,The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2−0.6/1000 PYs).,The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain).,Only one patient had highly elevated C reactive protein (CRP).,One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment.,The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments.,To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.
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The inflammatory diseases rheumatoid arthritis (RA) and periodontitis show similarities in misbalances of cytokine levels, such as tumor necrosis factor-α (TNF-α).,RA has been treated for two decades with TNF inhibitors which are effective by blocking TNF’s destructive action.,Since RA and periodontitis show similarities in high levels of TNF, the periodontal status of RA patients may improve with the use of anti-TNF therapy.,To assess this, a systematic review with special emphasis on duration of therapy was performed to evaluate the effect of anti-TNF-α treatment on the periodontal status of RA patients.,Overall, studies showed an improvement in periodontal health with anti-TNF therapy.,When analyzed over time (6 weeks to 9 months), it became apparent that initial improvements concerned bleeding on probing (BOP) and gingival index (GI) after therapy duration of 6 weeks.,Periodontitis parameters that improved after prolonged treatment were: probing pocket depth (PPD) after 3 months and clinical attachment level (CAL) after 6 months.,In conclusion, this systematic review reveals that anti-TNF treatment is therefore not only beneficial for rheumatic joints but also for the gums of rheumatoid arthritis patients.,We propose that the sequential tissue recovery due to anti-TNF therapy progresses as follows: 1. block of diapedesis by lowering vessel permeability, 2 fewer leukocytes in the inflamed tissue, and 3. reduced proteolytic activity and subsequent repair of collagen fiber functionality and normalization of osteoclast activity.,Clinically, this could lead to a decrease in bleeding on probing and ultimately in an improved clinical attachment level.
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Innate lymphoid cells (ILCs) are emerging mediators of immunity, and accumulation of inflammatory ILC populations can occur in inflammatory‐mediated conditions.,Since early lymph node (LN) activation has been shown in rheumatoid arthritis (RA), we aimed to investigate the frequency and distribution of ILCs in LN biopsy specimens obtained during the earliest phases of RA.,Twelve patients with early RA, 12 individuals with IgM rheumatoid factor and/or anti-citrullinated protein antibodies without arthritis (RA risk group), and 7 healthy controls underwent ultrasound‐guided inguinal LN biopsy.,ILC subsets and the expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) by LN endothelial cells and fibroblasts were analyzed by flow cytometry.,Although no differences in the frequencies of total ILCs (Lin−CD45+/lowCD127+) were found, the distribution of the ILC subpopulations differed among groups.,RA patients showed lower numbers of lymphoid tissue-inducer (LTi) cells (c‐Kit+NKp44− ILCs) and increased ILC1 (c‐Kit−NKp44− ILCs) and ILC3 (c‐Kit+NKp44+ ILCs) numbers compared with controls (P < 0.001, P < 0.050, and P < 0.050, respectively).,Individuals at risk of RA exhibited an increased frequency of ILC1 compared with controls (P < 0.01).,LTi cells paralleled the expression of adhesion molecules on endothelial cells and fibroblasts.,Our findings indicate that during the at‐risk and earliest phases of RA, the ILC distribution in LN changes from a homeostatic profile toward a more inflammatory profile, thereby providing evidence of a role for ILCs in RA pathogenesis.
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Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis.,However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown.,Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation.,Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo.,Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia.,Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage.,Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.,Multiple sclerosis is characterized by the activation of microglia cells.,Davalos et al. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.
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Granulocytes generally exert protective roles in the central nervous system (CNS), but recent studies suggest that they can be detrimental in experimental autoimmune encephalomyelitis (EAE), the most common model of multiple sclerosis.,While the cytokines and adhesion molecules involved in granulocyte adhesion to the brain vasculature have started to be elucidated, the required chemokines remain undetermined.,CXCR2 ligand expression was examined in the CNS of mice suffering from EAE or exposed to bacterial toxins by quantitative RT-PCR and in situ hybridization.,CXCL1 expression was analyzed in IL-6-treated endothelial cell cultures by quantitative RT-PCR and ELISA.,Granulocytes were counted in the brain vasculature after treatment with a neutralizing anti-CXCL1 antibody using stereological techniques.,CXCL1 was the most highly expressed ligand of the granulocyte receptor CXCR2 in the CNS of mice subjected to EAE or infused with lipopolysaccharide (LPS) or pertussis toxin (PTX), the latter being commonly used to induce EAE.,IL-6 upregulated CXCL1 expression in brain endothelial cells by acting transcriptionally and mediated the stimulatory effect of PTX on CXCL1 expression.,The anti-CXCL1 antibody reduced granulocyte adhesion to brain capillaries in the three conditions under study.,Importantly, it attenuated EAE severity when given daily for a week during the effector phase of the disease.,This study identifies CXCL1 not only as a key regulator of granulocyte recruitment into the CNS, but also as a new potential target for the treatment of neuroinflammatory diseases such as multiple sclerosis.
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Rheumatic diseases are a group of chronic heterogeneous autoimmune disorders characterized by abnormal regulation of the innate and adaptive immune systems.,Despite extensive efforts, the full spectrum of molecular factors that contribute to the pathogenesis of rheumatic diseases remains unclear. ncRNAs can govern gene expression at the transcriptional and post-transcriptional levels in multiple diseases.,Recent studies have demonstrated an important role for ncRNAs, such as miRNAs and lncRNAs, in the development of immune cells and rheumatic diseases.,Here, we focus on the epigenetic regulatory roles of ncRNAs in the pathogenesis of rheumatic diseases and as biomarkers of disease state.
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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.
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Abnormal glycolytic metabolism contributes to joint inflammation and destruction in rheumatoid arthritis (RA).,We examine the expression and function of hexokinases in RA and evaluate the potential of their specific inhibitor for clinical treatment.,Detection of HKs was assessed in synovial tissue by immunohistology and Western blot.,SiRNA and a specific hexokinases inhibitor, lonidamine (LND), were used to evaluate the role of hexokinase-I/II (HK-I/II).,Pro-inflammatory and glycolysis factors, cell viability, and apoptosis were assessed by ELISA, RT-qPCR, MTS, and flow cytometry.,The clinical effects of LND on type II collagen-induced arthritis (CIA) in DBA-/1 mouse model was evaluated by scoring their clinical responses, synovitis, and cartilage destructions, and ELISA was employed to analyze the concentrations of antibody in the serum of CIA model.,HK-I/II expression and their activities increased in the synovium of RA compared with osteoarthritis (OA).,Silencing HK-I/II (siHK-I/II) or LND treatment decreased the production of pro-inflammatory factors, such as IL-6, IL-8, CXCL9, CXCL10, and CXCL11, and cell viability, but induced cell apoptosis of RASFs.,The expression of TNF-α and IL-1β of macrophage in response to LPS stimulation were depressed as well after treatment with siHK-I/II or LND.,Furthermore, leucocyte infiltration co-cultured with RASFs was also suppressed after inhibiting the expression or activity of HK-I/II.,These anti-inflammatory effects overlapped with their anti-glycolytic activities.,Treatment with LND in mice with CIA decreased the production of antibodies against IgG1, IgG2a, and IgG2b and consequently attenuated joint inflammation and destruction.,HK-I/II contribute to shape the inflammatory phenotype of RASFs and macrophages.,LND may be a potential drug in treating patients with RA.,The online version of this article (10.1186/s13075-019-1865-3) contains supplementary material, which is available to authorized users.
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This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation.,Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates.,Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays.,RASF metabolism was assessed by the XF24-Flux Analyzer.,Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM).,In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology.,A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging.,RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).,DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01).,This was coupled with altered mitochondrial morphology.,Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05).,In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05).,Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders.,Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation.,3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions.,Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.
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The COVID-19 pandemic has forced governments to take exceptional measures to minimize its spread, imposing lockdown policies.,The aim of this study was to evaluate the impact of lockdown on type 1 diabetes (T1D) glycemic control.,People with T1D using flash glucose monitoring were included.,Data from the 14 days before lockdown were compared with data from the last 14 days after 8 weeks of lockdown.,A total of 307 patients were included (age 45.8 ± 12.6 years, 50.2% male, diabetes duration 21.1 ± 12.3 years).,Only one patient had COVID-19 infection.,Mean glucose decreased from 166.89 ± 29.4 to 158.0 ± 29.0 mg/dL and estimated HbA1c declined from 7.4 ± 1.0 to 7.1 ± 1.0% (54 ± 10.9 vs 57 ± 10.9 mmol/mol; p < 0.001).,Time in range increased from 57.8 ± 15.8 to 62.46 ± 16.1%.,Time in hyperglycemia > 180 mg/dL and >250 mg/dL decreased from 37.3 ± 1.9% to 32.0 ± 17.1% and from 13.0 ± 11.3 to 10.3 ± 10.6%, respectively; (p < 0.001).,Time in hypoglycaemia <70 mg/dL increased from 4.9 ± 4.0% to 5.5 ± 4.4% (p < 0.001).,No differences in time <54 mg/dl, coefficient of variation (CV%) or number of scans per day were found.,Despite the limitations of lockdown, glycemic control improved in patients with T1D.,These results suggest that having more time for self-management may help improve glycemic control in the short term.
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Severe hypoglycaemia carries a significant risk of morbidity and mortality for people with type 1 diabetes.,Economic costs are also high, estimated at approximately £13 million annually in England, UK.,Continuous glucose monitoring (CGM) has been shown to reduce hypoglycaemia and associated fear, improve overall glycaemia and quality of life, and is cost-effective.,Despite effective pathways in place with high levels of resource utilization, it has been reported there are low levels of follow-up, therapy change and specialist intervention after severe hypoglycaemia.,This study is designed to assess the impact of providing real-time CGM to people with type 1 diabetes, who have had a recent episode of severe hypoglycaemia (within 72 h), compared to standard care.,Fifty-five participants with type 1 diabetes and a recent episode of severe hypoglycaemia, who are CGM naïve, will be recruited to the study.,Participants will be randomised to CGM or standard care.,The primary outcome is percentage time spent in hypoglycaemia (< 3.0 mmol/L, 55 mg/dL).,Secondary outcomes include other measures of hypoglycaemia, time in euglycaemia, overall glucose status and patient reported qualitative measures.,This study assesses the impact of providing continuous glucose monitoring at the outset in individuals at highest risk of hypoglycaemia.,Changing demand means that novel approaches need to be taken to healthcare provision.,This study has the potential to shape future national standards.,NCT03748433, November 2018 (UK).
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Rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) show resistance to methotrexate (MTX) treatment.,To better understand the mechanisms of this resistance, RA-FLS and osteoarthritis fibroblast-like synovial cells (OA-FLS) were isolated and exposed to MTX.,We analyzed the autophagy induced by MTX in vitro and its relationship to apoptosis.,Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was detected by flow cytometry and Western blot analysis.,Autophagy was determined by transmission electron microscopy as well as Western blot analysis.,The expression levels of Beclin-1, LC3, Akt, p-Akt, mammalian target of rapamycin (mTOR), p-mTOR, high mobility group box chromosomal protein 1 (HMGB1), and an 85 kDa caspase cleaved fragment of poly(ADP-ribose) polymerase were measured by Western blotting.,MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS.,However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS.,In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death.,MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway.,Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis.,The online version of this article (doi:10.1186/s13075-015-0892-y) contains supplementary material, which is available to authorized users.
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Inhibitors of apoptosis proteins (IAPs) block cell death in response to diverse stimuli.,The mitochondrial protein, second mitochondria-derived activator of caspase (Smac), negatively regulates IAP inhibition of caspase activity.,We investigated the proapoptotic activity of a synthetic Smac (Smac 066) on fibroblast-like synoviocytes (FLS) derived from patients with active rheumatoid arthritis (RA).,We found that Smac 066 induced significant apoptosis in all RA-FLS samples.,Furthermore, IAPs, which are upregulated in RA-FLS, were downregulated by Smac 066.,This suggested that IAPs upregulation was responsible for RA-FLS sensitivity to Smac 066.,Next, we analysed caspase activation and found that Smac 066 was associated with caspase 8 and caspase 3 activities.,We then investigated the mechanism underlying Smac 066 downregulation of IAPs in RA-FLS with an apoptotic pathway array.,Interestingly, Smac 066 significantly upregulated IGFBP-5, a protein involved in differentiation, apoptosis, and osteoblastic activation.,Smac 066 may represent a new therapeutic approach to RA treatment.
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It is not rare to find Immunoglobulin A (IgA) nephropathy (IgAN) combined with other glomerular diseases, which can be called compound IgAN (cIgAN).,Till now, clinical-pathological investigation of cIgAN was lacking, especially the severity of “background IgAN lesions.”,This research aimed to investigate the incidence, clinical and pathological characteristics of cIgAN, and thus improve the understanding of the clinical significance of this combination.,Patients with cIgAN diagnosed in Peking University People's Hospital from November 2012 to April 2018 were retrospectively analyzed.,Patients with IgAN without compound glomerular diseases (sIgAN) were enrolled as a control group.,Among 1407 patients diagnosed with IgAN, 80 (5.69%) were cIgAN patients.,Compared with sIgAN, cIgAN patients had a significantly lower prevalence of microscopic hematuria and more urine protein.,There were 10 pathological types of glomerular diseases combined with IgAN, led by diabetic nephropathy 37 (46.25%) and membranous nephropathy 14 (17.5%).,Histologically, although the mesangial hypercellularity was comparable in 2 groups, cIgAN patients had a lower prevalence of endocapillary proliferation, segmental glomerulosclerosis, and cellular or fibrocellular crescents formation, as well as weaker immunofluorescence intensity for IgA and C3 (all P < .05).,Eight out of 27 (29.63%) cIgAN patients with follow-up data (5-48 months) developed irreversible end-stage renal disease requiring dialysis.,The order of incidence of concomitant diseases was similar to that of the pure diseases.,The “background IgAN associated lesions” except mesangial hypercellularity were relatively mild in cIgAN group.,Those might suggest that in some cases, IgAN seems to be a chance finding, and the combined diseases may play a more important role in the clinicopathological features of the patients than the nephritis caused by IgA deposition.,While diagnosing IgAN, other combined glomerular diseases need to be carefully considered by nephrologists and pathologists.
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The clinical course of IgA nephropathy (IgAN) and its outcome are extremely variable.,Proteinuria at baseline has been considered one of the most important risk factors.,More recently, mean proteinuria of follow-up (time-average proteinuria: TAp) was described as a stronger marker of renal survival, suggesting to consider it as a marker of disease activity and response to treatment.,We evaluated predictors of renal survival in IgAN patients with different degrees of renal dysfunction and histological lesions, focusing on the role of the therapy in influencing TAp.,We performed a retrospective analysis of three prospective, randomized, clinical trials enrolling 325 IgAN patients from 1989 to 2005.,Patients were divided into 5 categories according to TAp.,The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16.6%) and renal survival was much better in groups having lower TAp.,The median follow up was 66.6 months (range 12 to 144).,The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16,6%) and renal survival was much better in groups having lower TA proteinuria.,At univariate analysis plasma creatinine and 24h proteinuria, systolic (SBP) and diastolic (DBP) blood pressure during follow-up and treatment with either steroid (CS) or steroid plus azathioprine (CS+A) were the main factors associated with lower TAp and renal survival.,At multivariate analysis, female gender, treatment with S or S+A, lower baseline proteinuria and SBP during follow-up remained as the only variables independently influencing TAp.,In conclusion, TA-proteinuria is confirmed as one of the best outcome indicators, also in patients with a severe renal insufficiency.,A 6-month course of corticosteroids seems the most effective therapy to reduce TAp.
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Impaired regulatory B cell (Breg) responses are associated with several autoimmune diseases in humans; however, the role of Bregs in type 1 diabetes (T1D) remains unclear.,We hypothesized that naturally occurring, interleukin-10 (IL-10)-producing Bregs maintain tolerance to islet autoantigens, and that hyperglycemic nonobese diabetic (NOD) mice and T1D patients lack these potent negative regulators.,IgVH transcriptome analysis revealed that islet-infiltrating B cells in long-term normoglycemic (Lnglc) NOD, which are naturally protected from diabetes, are more antigen-experienced and possess more diverse B-cell receptor repertoires compared to those of hyperglycemic (Hglc) mice.,Importantly, increased levels of Breg-promoting CD40+ B cells and IL-10-producing B cells were found within islets of Lnglc compared to Hglc NOD.,Likewise, healthy individuals showed increased frequencies of both CD40+ and IL-10+ B cells compared to T1D patients.,Rituximab-mediated B-cell depletion followed by adoptive transfer of B cells from Hglc mice induced hyperglycemia in Lnglc human CD20 transgenic NOD mouse models.,Importantly, both murine and human IL-10+ B cells significantly abrogated T-cell-mediated responses to self- or islet-specific peptides ex vivo.,Together, our data suggest that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses, and that Hglc mice and individuals with T1D lack this population of Bregs.
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For autoimmune conditions like type 1 diabetes to progress, self-reactive CD8+ T cells would need to interact with peptide-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion.,However, the mechanisms by which autoantigen is cross-presented remain to be identified.,In this study, we show cross-presentation of islet-derived autoantigens by B cells.,B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-γ+lysosomal-associated membrane protein 1+ effector cells.,B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking.,Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation.,Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cell-dependent, interleukin-21-expressing Vβ4+CD4+ T cells.,Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells.
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Vaccines are the most effective strategy to mitigate the global impact of COVID-19.,However, vaccine hesitancy is common, particularly among minorities.,Guillain-Barré syndrome (GBS) is the most common autoimmune illness of the peripheral nervous system, occurring at an incidence of 1.1/100,000 worldwide.,A causal link between mRNA vaccines and GBS has not been previously evaluated.,We analyzed a cohort of 3,890,250 Hispanic/Latinx recipients of the BNT162b2 mRNA vaccine (613,780 of whom had already received both doses) for incident GBS occurring within 30 days from vaccine administration.,Seven cases of GBS were detected among first-dose recipients, for an observed incidence of 0.18/100,000 administered doses during the prespecified timeframe of 30 days.,No cases were reported after second-dose administration.,Our data suggest that, among recipients of the BNT162b2 mRNA vaccine, GBS may occur at the expected community-based rate; however, this should be taken with caution as the current incidence of GBS among the unvaccinated population against COVID-19 is still undetermined.,We hope that this preliminary data will increase the public perception of safety toward mRNA-based vaccines and reduce vaccine hesitancy.
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Prevention strategies for COVID-19 transmission are at the forefront of healthcare paradigms worldwide, the main emphasis of which is vaccination.,We present an interesting case of a 37-year-old man who, 3 weeks following his first dose of the chimpanzee adenovirus-vectored COVID-19 vaccine, ChAdOx1, presented to hospital with a rapidly progressive ascending muscle weakness and back pain in the absence of any other triggers.,He also had a negative COVID-19 swab during admission.,A diagnosis of Guillain-Barre syndrome was confirmed by correlating the clinical features with cerebrospinal fluid analysis, nerve conduction studies and MRI of the brain and whole spine.,The patient received treatment with 5 days of intravenous immunoglobulin and did not require any respiratory support.,He was also regularly reviewed by a multidisciplinary team consisting of neurologists, speech and language therapists, and physiotherapists and is on the course to a recovery.
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Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease which is associated with autoantibodies directed against two desmosomal proteins, desmoglein (Dsg) 3 and 1.,Treatment of PV is rather challenging and relies on the long-term use of systemic corticosteroids and additional immunosuppressants.,More recently, autoantibody-depleting therapies such as rituximab, high-dose intravenous immunoglobulins, and immunoadsorption were shown to be valuable treatment options in PV.,Specific removal of pathogenic autoantibodies would further increase efficacy and usability of immunoadsorption.,Here, we tested the capacity of our recently developed prototypic Dsg1- and Dsg3-specific adsorbers to remove circulating pathogenic autoantibodies from three different PV patients.,The pathogenic potential of the Dsg3/1-depleted IgG fractions and the anti-Dsg3-specific IgG was explored in two different in vitro assays based on cultured human keratinocytes, the desmosome degradation assay and the dispase-based dissociation assay.,In addition, the neonatal mouse model of PV was used.,In both in vitro assays, no difference between the pathogenic effect of total PV IgG and anti-Dsg3-specific IgG was seen, while Dsg3/1-depleted and control IgG were not pathogenic.,For the samples of all 3 PV patients, depletion of anti-Dsg3/1 IgG resulted in a complete loss of pathogenicity when injected into neonatal mice.,In contrast, injection of anti-Dsg3-specific IgG, eluted from the column, induced gross blistering in the mice.,Our data clearly show that anti-Dsg3-specific IgG alone is pathogenic in vitro and in vivo, whereas Dsg3/1-depletion results in a complete loss of pathogenicity.,Furthermore, our data suggest that Dsg-specific adsorption may be a suitable therapeutic modality to efficiently reduce pathogenic autoantibodies in patients with severe PV.
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Evidence has accumulated that changes in intracellular signaling downstream of desmoglein 3 (Dsg3) may play a significant role in epithelial blistering in the autoimmune disease pemphigus vulgaris (PV).,Currently, most studies on PV involve passive transfer of pathogenic antibodies into neonatal mice which have not finalized epidermal morphogenesis, and do not permit analysis of mature hair follicles (HFs) and stem cell niches.,To investigate Dsg3 antibody-induced signaling in the adult epidermis at defined stages of the HF cycle, we here developed a model with passive transfer of the monospecific pathogenic Dsg3 antibody AK23 into adult 8-week-old C57Bl/6J mice.,Validated using histopathological and molecular methods, we found that this model faithfully recapitulates major features described in PV patients and PV models.,Two hours after AK23 transfer we observed widening of intercellular spaces between desmosomes and EGFR activation, followed by increased Myc expression and epidermal hyperproliferation, desmosomal Dsg3 depletion and predominant blistering in HFs and oral mucosa.,These data confirm that the adult passive transfer mouse model is ideally suited for detailed studies of Dsg3 antibody-mediated signaling in adult skin, providing the basis for investigations on novel keratinocyte-specific therapeutic strategies.
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Tolerance against self-antigens is regulated by a variety of cell types with immunoregulatory properties, such as CD1d-restricted invariant natural killer T (iNKT) cells.,In many experimental models of autoimmunity, iNKT cells promote self-tolerance and protect against autoimmunity.,These findings are supported by studies with patients suffering from autoimmune diseases.,Based on these studies, the therapeutic potential of iNKT cells in autoimmunity has been explored.,Many of these studies have been performed with the potent iNKT cell agonist KRN7000 or its structural variants.,These findings have generated promising results in several autoimmune diseases, although mechanisms by which iNKT cells modulate autoimmunity remain incompletely understood.,Here, we will review these preclinical studies and discuss the prospects for translating their findings to patients suffering from autoimmune diseases.
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Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with exocrine gland dysfunction and multi-organ involvement.,Recent progress in understanding the pathogenesis of pSS offers an opportunity to find new biomarkers for the diagnosis and assessment of disease activity.,Screening noninvasive biomarkers from the saliva and tears has significant potential.,The need for specific and sensitive biomarker candidates in pSS is significant.,This review aims to summarize recent advances in the identification of biomarkers of Sjögren syndrome, trying to identify reliable, sensitive, and specific biomarkers that can be used to guide treatment decisions.
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Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex.,In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR).,These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT.,Patients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment.,PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F).,Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures.,Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36.,Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.,Both doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52.,In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores.,In this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab.,ClinicalTrials.gov.,NCT01061736.,February 2, 2010
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RA is a complex disease that develops as a series of events often referred to as disease continuum.,RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia.,Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable.,Monitoring biomarkers would be useful in predicting relapse.,Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual.,Increasing numbers of cytokines have been involved in RA pathology.,Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology.,We will review the current knowledge's relation to cytokine used as biomarker in RA.,However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.
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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction.,Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, and the damage of cartilage as well as bone.,Resolvin D1 (RvD1) can promote inflammation resolution in acute inflammatory diseases, and recently, effects of RvD1 on chronic inflammatory diseases also attracted attention.,This study aimed to examine the effect of RvD1 on pannus formation in RA and the underlying mechanism.,Serum levels of RvD1 and CTGF were determined in RA patients and healthy persons by UPLC-MS/MS and ELISA respectively.,The levels of CTGF and inflammatory factors were assessed by qRT-PCR and ELISA.,MicroRNA expression profile was determined by miRNA microarray.,The effects of CTGF, RvD1, and miR-146a-5p on angiogenesis were evaluated with tube formation and chick chorioallantoic membrane (CAM) assays.,Collagen-induced arthritis (CIA) mice were constructed to detect the effects of RvD1 and miR146a-5p on RA.,STAT3 activation was determined by Western blotting.,RvD1 levels decreased while CTGF levels increased in RA patients’ serum, and an inverse correlation of the concentrations of RvD1 and CTGF in the serum of RA patients was synchronously observed.,In CIA mice, RvD1 suppressed angiopoiesis and decreased the expression of CTGF.,Simultaneously, RvD1 significantly decreased CTGF and pro-inflammation cytokines levels in RA FLS.,Furthermore, CTGF suppressed angiopoiesis and RvD1 inhibited the proliferation and migration of RA FLS and angiopoiesis.,MiRNA microarray and qRT-PCR results showed that RvD1 upregulated miRNA-146a-5p.,The transfection experiments demonstrated that miRNA-146a-5p could decrease inflammatory factors and CTGF levels.,Moreover, miRNA-146a-5p decreased the proliferation of FLS and angiogenesis in vivo.,MiRNA-146a-5p also suppressed angiogenesis and downregulated the expression of CTGF in CIA mice.,Finally, Western blot results revealed that miRNA-146a-5p inhibited the activation of STAT3.,RvD1 is prone to alleviate RA progression through the upregulation of miRNA-146a-5p to suppress the expression of CTGF and inflammatory mediators, thereby decreasing pannus formation and cartilage damage.,The online version of this article (10.1186/s13075-020-2133-2) contains supplementary material, which is available to authorized users.
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To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).,In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks.,PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis.,Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.,527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177).,Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs.,Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24.,At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01).,Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi.,PRO results aligned with clinical efficacy data for baricitinib.,NCT01721044; Results.
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Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases.,First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients.,The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known.,In the remaining 20% of cases, the disease may become severe and/or critical.,In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system.,A third phase corresponds to a state of hypercoagulability.,Finally, in the fourth stage organ injury and failure occur.,Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients.,Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19.,Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease.,These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy.,Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.,•Autoimmune and autoinflammatory conditions may be triggered by SARS-CoV-2.,•Bystander activation and molecular mimicry could explain the appearance of these conditions.,•In severe and critical patients, a cytokine storm syndrome (CSS) and a hypercoagulable state occur and may overlap.,•CSS may promote the appearance of autoimmune and autoinflammatory-like conditions.,•These observations should be considered in the current development of vaccines.,Autoimmune and autoinflammatory conditions may be triggered by SARS-CoV-2.,Bystander activation and molecular mimicry could explain the appearance of these conditions.,In severe and critical patients, a cytokine storm syndrome (CSS) and a hypercoagulable state occur and may overlap.,CSS may promote the appearance of autoimmune and autoinflammatory-like conditions.,These observations should be considered in the current development of vaccines.
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Emerging reports show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection precedes the appearance of various autoimmune and autoinflammatory diseases, including paediatric inflammatory multisystemic syndrome (PIMS) or multisystem inflammatory syndrome in children (MIS-C), thus adding to the growing mystery of this virus and raising questions about the nature of its link with autoimmune and autoinflammatory sequelae.
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The normal development and maintenance of CNS white matter, and its responses to disease and injury, are defined by synergies between axons, oligodendrocytes, astrocytes and microglia, and further influenced by peripheral components such as the gut microbiome and the endocrine and immune systems.,Consequently, mechanistic insights, therapeutic approaches and safety tests rely ultimately on in vivo models and clinical trials.,However, in vitro models that replicate the cellular complexity of the CNS can inform these approaches, reducing costs and minimising the use of human material or experimental animals; in line with the principles of the 3Rs.,Using electrophysiology, pharmacology, time-lapse imaging, and immunological assays, we demonstrate that murine spinal cord-derived myelinating cell cultures recapitulate spinal-like electrical activity and innate CNS immune functions, including responses to disease-relevant myelin debris and pathogen associated molecular patterns (PAMPs).,Further, we show they are (i) amenable to siRNA making them suitable for testing gene-silencing strategies; (ii) can be established on microelectrode arrays (MEAs) for electrophysiological studies; and (iii) are compatible with multi-well microplate formats for semi-high throughput screens, maximising information output whilst further reducing animal use.,We provide protocols for each of these.,Together, these advances increase the utility of this in vitro tool for studying normal and pathological development and function of white matter, and for screening therapeutic molecules or gene targets for diseases such as multiple sclerosis, motor neuron disease or spinal cord injury, whilst avoiding in vivo approaches on experimental animals.
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Molecular mechanisms underlying distinct disabilities during neurological diseases may differ based on the neurological pathway involved.,Multiple sclerosis (MS) is multifocal, characterized by distinct disabilities affecting walking, vision, cognition, and fatigue.,Neuroprotective treatments tailored for each disability may be more effective than nonspecific treatments aiming to reduce a composite of disabilities in clinical trials.,Here, we use the MS model to apply a cell-specific and region-specific gene expression approach to discover targets in distinct neuroanatomic regions.,Altered cholesterol synthesis gene expression in astrocytes in spinal cord and optic nerve was identified as a potential target for walking and visual disabilities, respectively.,This disability-specific discovery approach represents a strategy for finding neuroprotective treatments for multifocal neurodegenerative diseases.,Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease.,Multiple sclerosis (MS) is multifocal by definition.,Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE).,Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology.,Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus.,The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased.,Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression.,The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed.,Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.
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To investigate the association of anti-citrullinated protein antibodies (ACPA) with changes in systemic bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) after two years of treat-to-target.,BMD was measured at the lumbar spine (LS) and femoral neck (FN) in 100 patients with recent onset RA at baseline and after 24 months of treatment aimed at low disease activity (LDA) according to the 28-joints disease activity score (DAS28 <3.2).,Multivariable regression analyses were performed to determine independent associations between autoantibodies and other disease and treatment-related parameters with BMD loss.,After 24 months, the majority of the patients were at least in LDA (78%), with slightly more ACPA-positive subjects achieving the target.,The BMD had significantly decreased at both the LS (mean [SD] percent loss -1.8 [6.2], p=0.03) and the FN (-2.4 [7.3], p=0.03) in ACPA-positive but not in ACPA-negative patients.,Consequently, the proportion of patients with reduced BMD (Z score ≤-1) after 24 months was significantly higher among ACPA-positive patients at both the spine (39.5% vs 19.3%, p=0.05) and the hip (37.2% vs 12.2%, p=0.007).,The association between ACPA and BMD loss was independent of other variables including age, gender, disease activity, cumulative dose of glucocorticoids and duration of therapy with bisphosphonates at the LS but not the FN.,ACPA are associated with ongoing BMD loss at the spine despite suppression of inflammation and adoption of prophylactic measures.,ACPA-positive RA patients should be therefore strictly monitored for the development of osteoporosis.
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The ankyrin repeat domain-55 (ANKRD55) gene contains intronic single nucleotide polymorphisms (SNPs) associated with risk to contract multiple sclerosis, rheumatoid arthritis or other autoimmune disorders.,Risk alleles of these SNPs are associated with higher levels of ANKRD55 in CD4+ T cells.,The biological function of ANKRD55 is unknown, but given that ankyrin repeat domains constitute one of the most common protein-protein interaction platforms in nature, it is likely to function in complex with other proteins.,Thus, identification of its protein interactomes may provide clues.,We identified ANKRD55 interactomes via recombinant overexpression in HEK293 or HeLa cells and mass spectrometry.,One hundred forty-eight specifically interacting proteins were found in total protein extracts and 22 in extracts of sucrose gradient-purified nuclei.,Bioinformatic analysis suggested that the ANKRD55-protein partners from total protein extracts were related to nucleotide and ATP binding, enriched in nuclear transport terms and associated with cell cycle and RNA, lipid and amino acid metabolism.,The enrichment analysis of the ANKRD55-protein partners from nuclear extracts is related to sumoylation, RNA binding, processes associated with cell cycle, RNA transport, nucleotide and ATP binding.,The interaction between overexpressed ANKRD55 isoform 001 and endogenous RPS3, the cohesins SMC1A and SMC3, CLTC, PRKDC, VIM, β-tubulin isoforms, and 14-3-3 isoforms were validated by western blot, reverse immunoprecipitaton and/or confocal microscopy.,We also identified three phosphorylation sites in ANKRD55, with S436 exhibiting the highest score as likely 14-3-3 binding phosphosite.,Our study suggests that ANKRD55 may exert function(s) in the formation or architecture of multiple protein complexes, and is regulated by (de)phosphorylation reactions.,Based on interactome and subcellular localization analysis, ANKRD55 is likely transported into the nucleus by the classical nuclear import pathway and is involved in mitosis, probably via effects associated with mitotic spindle dynamics.
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